slide 1

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wherein
R1 is H, F, CF3, OCF3,    (C3-C10)-cycloalkyl, 3-membered to 10-
membered heterocycloalkyl comprising 1, 2 or 3 identical or different ring
5 heteroatoms chosen from nitrogen, oxygen and sulfur, (Cs-CO-aryl, (C1-C3)-alkoxy, (C3-C10)-cycloalkoxy, (C6-e14)-aryloxy, di((Ci-Ca)-alkyl)amino, di((Os-C13)- cycloalkyl)amino or dk(Ce-C14)-arY1)amino; and
R2 is H, F, CF3, OCF3,    (Cs-CiO-cycloalkyl, 3-membered to 10-
membered heterocycloalkyl comprising 1, 2 or 3 identical or different ring
10 heteroatoms chosen from nitrogen, oxygen and sulfur, (Ce-C14-aryl, 5-membered to 10-membered heteroaryl comprising 1, 2 or 3 identical or different ring heteroatoms chosen from nitrogen, oxygen and sulfur, (Ci-CO-alkoxy, (e3-C,O-cycloalkoxy, (C3- C14)-aryloxy, 5-membered to 10-membered heteroaryloxy comprising 1, 2, or 3
identical or different ring heteroatoms chosen from nitrogen, oxygen and sulfur,
15 di((Creoyalkyl)amino, di-((e3-C10)-cycloalkyl)amino or di((e6-e14)-aryl)amino; and their salts.
This invention also relates to intermediates useful in the preparation of compounds of formula I, to processes for the preparation of such intermediates, and to the use of 20 such intermediates for the preparation of such compounds.
Detailed description of the invention
In a first aspect, the present invention provides a process for the preparation of a 25 compound of the formula 1,
 
 
5
wherein
R' is H, F, CF3, OCF3, (C1-C3)-alkyl, (C3-Cio)-cycloallcyl, 3-membered to 10-membered heterocycloalkyl comprising 1, 2 or 3 identical or different ring
5 heteroatoms chosen from nitrogen, oxygen and sulfur, (Cs-C14)-aryl, (CrC8)-alkoxy, (C3-C10)-cycloalkoxy, (Orr-C14)-aryloxy, di((Ci-C3)-alkyl)amino, di((C3-C15)- cycloalkyl)amino or di((C6-Ci4)-aryl)amino; and
R2 is H, F, CF3, OCF3,    (C3-C10)-cycloalkyl, 3-membered to 10-
membered heterocycloalkyl comprising 1, 2 or 3 identical or different ring
10 heteroatoms chosen from nitrogen, oxygen and sulfur, (C6-C14)-aryl, 5-membered to 10-membered heteroaryl comprising 1, 2 or 3 identical or different ring heteroatoms chosen from nitrogen, oxygen and sulfur, (C,C8)-alkoxy, (C3-Cis)-cycloalkoxy, (C6-
Gu)-er)/loxy, 5-membered to 10-membered heteroaryloxy comprising 1, 2, or 3 identical or different ring heteroatoms chosen from nitrogen, oxygen and sulfur,
15 di((Ci-Cs)-alkyl)amino, di-((C3-Cio)-cycloalkyl)amino or di((C3-C14)-aryl)amino; or its salt,
comprising the steps of
a) treating a phenylethynylsilane compound of the formula II,
20
     G    II

wherein G is trimethylsilyl, triethylsilyl, tri-isopropylsilyl, or dimethyl-tert-butylsilyl, and R2. is R2 as defined above or is a protected derivative thereof or precursor moiety
25 thereto, in a solvent, such as an aliphatic alcohol or a mixture of an aliphatic alcohol and an ether, for example methanol or a mixture of methanol and tetrahydrofuran, with an alkali metal hydroxide, carbonate or alcoholate or an alkaline earth metal alcoholate, to form a solution of a phenylethyne of the formula III;
 
     H    6

and
b) combining the resulting solution of the phenylethyne with a compound of the 5 formula IV,
0
 

 
wherein X is bromo or iodo, Ry is R1 as defined above or is a protectea aenvauve
10 thereof or precursor moiety thereto, and Boo Is tert.butoxycarbonyl, in the presence of a homogeneous palladium catalyst, a cuprous salt, and'a hindered amine in a solvent, such as an ether or a mixture of an ether and an aliphatic alcohol, for example tetrahydrofuran or a mixture of tetrahydrofuran and methanol, to form a • protected compound of the formula V,
15
 
7
wherein R1' and R2' are R1 and R2, respectively, as defined above or are a protected derivative thereof or precursor moiety thereto, and Boc is tert-butoxycarbonyl, or its salt
5 Particular embodiments of this first aspect of the present invention are those wherein G is trimethylsilyl, and/or X is bromo, and/or the homogeneous palladium catalyst is palladium(ll)bis(triphenylphosphine) chloride, and/or the cuprous salt is
copper(1)iodide, and/or the hindered amine is triethylamine.
10 A special embodiment of this first aspect provides for further removal of the tart¬butoxycarbonyl group from the protected compound of the formula V and, if applica¬ble, removal of any other protective groups and/or conversion of precursor moieties that may be present in Ry and/or Ft2' in a compound of the formula V by standard procedures, in a solvent, for example an aliphatic alcohol or an ether, to provide a
15 compound of the formula t or its salt. Another special embodiment of this first aspect provides for removal of the tert-butoxycarbonyl group from the protected compound of the formula V, in particular from a compound in which Rf and R2' are R1 and R2, respectively, in the presence of an acid, in particular a physiologically acceptable acid, for example methanesulfonic acid, in a solvent, for example an aliphatic alcohol
20 or an ether such as isopropanol, to provide a compound of the formula I or its salt.
A second aspect of the present invention provides a process for the preparation of 4- [3-(aminomethyl)pheny1]-1-15-(2-fiuorophenylethynyI)-2-furanoyUpiperidine, i.e., the compound of the formula la,
 
8
or its salt,
comprising the steps of
a) treating a 2-fluorophenylethynylsilyl compound of the formula Ila,
5
     G    Ila

wherein G is trimethylsilyl, triethylsilyl, tri-isopropylsilyl, or dimethyl-tert-butylsilyl, in a
solvent, such as an aliphatic alcohol or a mixture of an aliphatic alcohol and an ether,
10 for example methanol or a mixture of methanol and tetrahydrofuran, with an alkali metal hydroxide, carbonate or alcoholate or an alkaline earth metal alcoholate, for example with potassium carbonate in methanol, to form a solution of 2- fluorophenylethyne; and
15 b) combining the resulting solution of 2-fluorophenylethyne with a compound of the formula IVa,
 

 
20 wherein X is bromo or iodo, and Boo is tert-butoxycarbonyl, in the presence of a homogeneous palladium catalyst, a cuprous salt, and a hindered amine in a solvent,
such as an ether or a mixture of an ether and an aliphatic alcohol, for example tetrahydrofuran or a mixture of tetrahydrofuran and methanol, to form 4-[3-(tert¬butoxycarbonylaminomethyl)pheny1]-145-(2-fluorophenylethyny1)-2-
25 furanoyllpiperidine, i.e., the compound of the formula Va,
 
9
 

 
wherein Boc is tert-butoxycarbonyl.
5 Particular embodiments of this second aspect of the present invention are those wherein G is trimethylsilyl, and/or X is bromo, and/or the homogeneous palladium catalyst is palladium(11)bis(triphenylphosphine) chloride, and/or the cuprous salt is copper(I) iodide, and/or the hindered amine is triethylamine.
10 A special embodiment of this second aspect provides for further removal of the tert-
butoxycarbonyl group from 4-[3-(tert-butoxycarbonylaminomethyl)pheny1]-145-(2- fluorophenylethynyl)-2-furanoylipiperidine of the formula Va in a solvent to provide the compound of the formula la or its salt. Another special embodiment of this second aspect provides for removal of the tert-butoxycarbonyl group from 4-[3-(tert-
15 butoxycarbonylaminomethyl)pheny13-145-(2-fluorophenylethynyl)-2-
furanoyl]piperidine of the formula Va in the presence of an acid, in particular a
physiologically acceptable acid, for example methanesulfonic acid, in a solvent, for example an aliphatic alcohol or an ether such as isopropanol, to provide the compound of the formula la or its salt, for example the methanesulfonic acid salt of 4-
20 [3-(aminomethyl)pheny1]-145-(2-fluorophenylethyny1)-2-furanoyl]piperidine.
A third aspect of the present invention provides a process for the preparation of a compound of the formula IV,
 
0
 

 
wherein
R1' is H, F, CFs, OCF3, (C1-Cs)-alkyl, (C3-C10-cycloalkyl, 3-membered to 10-
5 membered heterocycloalkyi comprising 1, 2 or 3 identical or different ring heteroatoms chosen from nitrogen, oxygen and sulfur, (Cs-C14)-aryl, (Ci-Ca)-alkoxy, (C3-C10)-cycloalkoxy, (Ca-C14-aryloxy, di((Ci-Cs)-allcyl)amino, di((Cs-Cio)- cycloalkA)amino or di((C6-C14)-aryl)amino, or a protected derivative thereof or precursor moiety thereto; and
10 X is bromo or lodo,
comprising the steps of
a) activating 5-bromo-2-furoic acid or 5-iodo-2-furoic acid, for example by converting
it into an activated acid derivative which may be prepared in situ or may be isolated,
15 such as an acid halide, in particular an acid chloride, an active ester or an anhydride or mixed anhydride, for example by treatment with a halogenating agent such as thionyl chloride or oxalyl chloride in a solvent, such as a hydrocarbon or a chlorinated
hydrocarbon, for example toluene, at a temperature of from about 0°C to about 120°C, for example at reflux temperature of the solvent, or by treatment with an alkyl
to chiorocarbonate such-as ethyl chlorocarbonate or isobutyt chlorocarbonate and a
base such as, for example, triethylamine in a solvent, for example a halogenated hydrocarbon or an ether such as tetrahydrofuran, at a temperature of from about -10°
to about 30°C, or by treating it with a condensing agent or coupling agent as is customarily used for the formation of amide bonds in peptide chemistry, for example, such as a carbodilmide like dicyclohexylcarbodiimide or diisopropylcarbodiimide or a carbonyldiazole like carbonyidlimidazole or 0-((cyano(ethoxycarbonyl)methylene)- amino)-N,N,W,N4etramethyluronium tetrafluoroborate (TOTU) or propylphosphonic
 
11
anhydride, optionally in the presence of an auxiliary agent such as 1- hydroxybenzotriazole, for example, in a solvent, for example a halogenated hydrocarbon or an ether or an amide such as tetrahydrofuran or dimethylforrnamide, at a temperature of from about 0°C to about 30°C, to provide an activated form of 5-
5 bromo-2-furoic acid or 5-iodo-2-furoic acid, for example 5-bromo-2-furoyl chloride or
5-iodo-2-furoyl chloride, respectively, which activated form may be obtained and
subsequently employed in form of a solution, for example a solution in toluene; and
b) combining the activated form of 5-bromo-2-furoic acid or 5-iodo-2-furoic acid with a 10 compound of the formula Vi,
 

 
wherein R1' is as defined for formula IV and Boc is tert-butoxycarbonyl, in a solvent,
15 for example a hydrocarbon, a chlorinated hydrocarbon or an ether such as toluene or dichloromethane, optionally in the presence of a base, for example a tertiary amine like triethytamine.
A further embodiment of this third aspect provides a process for the preparation of a ZO compound of the formula IV wherein Xis bromo, i.e. a compound of the formula IVb,
NHBoc    N \ /
5,Br
 
12
wherein
Rr is H, F, CF3, OCF3, (Cr-C8)-alkyl, (C3-Cio)-cycloalkyl, 3-membered to 10-membered heterocycloalkyl comprising 1, 2 or 3 identical or different ring heteroatoms chosen from nitrogen, oxygen and sulfur, (C.-C14)-aryl, (Ci-Co)-alkoxy,
5 (C3-Cio)-cycloalkoxy, (CB-C14)-arYloXY, di((C1-C8)-alkyl)amino, di((C3-Cua¬cycloallcyl)amino or di((C6-C14)-aryl)amino, or a protected derivative thereof or precursor moiety thereto; and
Boc is tert-butoxycarbonyl,
10 comprising the steps of
a)    activating 5-bromo-2-furoic acid to provide an activated form of 5-bromo-2-furoic acid; and
b)    combining the activated form of 5-bromo-2-furoic acid with a compound of the 15 formula VI in a solvent, optionally in the presence of base,
where all before-mentioned explanations on the third aspect of the present invention also apply to this further embodiment. For example, 5-bromo-2-furoic acid can be activated by treatment with thionyl chloride in refluxing toluene to provide a solution
20 of 5-bromo-2-furoyl chloride in toluene which is then reacted with a compound of the formula VI in the presence of base such as a tertiary amine in toluene or dichloromethane.
A fourth aspect of the present invention provides a process for the preparation of a 25 compound of the formula IV in which IR1. is hydrogen, i.e. a compound of the formula IVa,
     O
o x    IVa
 
13
wherein X is bromo or iodo; and Boo is tert-butoxycarbonyi,
5 comprising the steps of
a) activating 5-bromo-2-furoic acid or 5-iodo-2-furoic acid, for example by converting it into an activated acid derivative which may be prepared in situ or may be isolated, such as an acid halide, in particular an acid chloride, an active ester or an anhydride or mixed anhydride, for example by treatment with an halogenating agent such as
10 thionyl chloride or oxalyl chloride in a solvent, such as a hydrocarbon or a chlorinated hydrocarbon, for example toluene, at a temperature of from about 0°C to about 120°C, for example at about reflux temperature of the solvent, or by treatment with an alkyl chlorocarbonate such as ethyl chlorocarbonate or isobutyl chlorocarbonate and a base such as, for example, triethylamine in a solvent, for example a
15 halogenated hydrocarbon or an ether such as tetrahydrofuran, at a temperature of from about -10° to about 30°C, or by treating it with a condensing agent or coupling agent as is customarily used for the formation of amide bonds in peptide chemistry, for example, such as a carbodiimide like dicyclohexylcarbodiimide or
dilsopropylcarbodiimide or a carbonyldiazole like carbonyldilmidazole or
20 0-((cyano(ethoxycarbonyl)methylene)arnino)-N,N,N',Wtetramethyluronium tetrafluoroborate (TOTU) or propyiphosphonic anhydride, optionally in the presence of an auxiliary agent such as 1-hydroxybenzotriazole, for example, in an solvent, for example a halogenated hydrocarbon or an ether or an amide such as tetrahydrofuran or dimethylformamide, at a temperature of from about 0°C to about 30°C, to provide
25 an activated form of 5-bromo-2-furoic acid or 5-lodo-2-furoic acid, for example 5- bromo-2-furoyl chloride or 5-lodo-2-furoyl chloride, respectively, which activated form
may be obtained and subsequently employed in form of a solution, for example a solution in toluene; and
30 b) combining the activated form of 5-bromo-2-furoic acid or 5-iodo-2-furoic acid with a compound of the formula Via,
 
14
NI-IBoc
Vla
wherein Boc is tert-butoxycarbonyl, in a solvent, for example a hydrocarbon, a chlorinated hydrocarbon or an ether such as toluene or dichloromethane, optionally in 5 the presence of a base, for example a tertiary amine like triethylamine.
A special embodiment of this fourth aspect provides a process for the preparation of a compound of the formula IVa in which Xis bromo, i.e. the compound of the formula No,
10
O 8r
NHBoc    N
IVc
wherein BOc is tert-butoxycarbonyl,
15 comprising the steps of
a)    activating 5-bromo-2-furoic acid to provide an activated form of 5-bromo-furoic acid, and
b)    combining the activated form of 5-bromo-2-furoic acid with a compound of the 20 formula Vla
 
15
NHBoc
Via
wherein Boc is tert-butoxycarbonyl, in a solvent, optionally in the presence of base,
5 where all before-mentioned explanations on the fourth aspect of the present invention also apply to this special embodiment. For example, 5-bromo-2-furoic acid can be activated by treatment with thionyl chloride in refluxing toluene to provide 5-bromo-2- furoyl chloride, preferably in form of a solution in toluene, which is then reacted with the compound of the formula Vla in the presence of base such as a tertiary amine in
10 toluene or dichloromethane.
A fifth aspect of the present invention provides a process for the preparation of a compound of the formula VI
5         NHBoc    VI

wherein R1' is H, F, CF3, 0CF3, (CI-CEO-AA, (C3-CO-cycloalkyl, 3-membered to 10-membered heterocycloalkyl comprising 1, 2 or 3 identical or different ring heteroatoms chosen from nitrogen, oxygen and sulfur, (C.-C/4)-aryl, (Ci-C8)-alkoxy,
0 (C3-Cio)-cycloalkoxy, (Ce-C14-aryloxy, di((CI-C8)-alkyl)amino, di((C3-Cis)- cycloalkyl)amino or diffC6-C14)-arypamino, or a protected derivative thereof or precursor moiety thereto; and
Bac is tert-butoxycarbonyl,
 
16
or its salt,
comprising the steps of
a) treating a salt of a 3-halobenzylamine of the formula VII,
5
N H2
VII
with 1,2-bis(chlorodimethylelly1)ethane in a solvent, for example a halogenated hydrocarbon such as dichloromethane, in the presence of a base, for example a
10 tertiary amine like biethylamine, to provide a 1-(3-halobenzyl)-2,2,5,5-tetramethy1-1- aza-2,5-disilacyclopentane of the formula VIII;
le    I/
Si
 /TIi    VIII

15 b) treating the 1-(3-halobenzy1)-2,2,5,5-tetramethy1-1-aza-2,5-disilacyclopentane of the formula VIII in a solvent, such as an ether, for example tetrahydrofuran, with an alkyllithium compound, for example n-butyllithium, and 1-benzy1-4-pipericlone at a temperature of from about -80°C to about -40°C to provide an alcohol of the formula IX;
?0
 
c) treating the alcohol of the formula lx with an acid, for example an inorganic acid such as phosphoric acid, in a solvent, for example a halogenated hydrocarbon such 5 as dichloromethane, to provide a hydroxypiperidinylbenzylamine of the formula X
 

 
as the salt of the acid;
d) treating the hydroxypiperidinylbenzylamine of the formula X or its salt with a concentrated, non-oxidizing acid at a temperature of from about 70°C to about 150°C, followed by alkalinization to provide an olefin of the formula XI;
 
e) treating the olefin of the formula XI with di-tert-butyl dicarbonate in a solvent, for
example an aliphatic alcohol such as methanol, ethyl acetate, an ether such as
5 tetrahydrofuran, a halogenated hydrocarbon such as d1chloromethane, a mixture of two or more of such solvents or a mixture of one or more of such solvents with water, in the presence of a base, for example an alkali metal hydroxide, carbonate or alcoholate or a tertiary amine, such as sodium hydroxide or triethylamine, preferably at a temperature of from about 0°C to about 40°C, to provide a protected amine of
10 the formula X11
 

 
wherein Boc is tent-butoxycarbonyl, and where Ph in the formulae IX, X, XI and X11 is 15 phenyl, and where X' in the formulae VII and VIII is bromo or iodo, and where Rt in the formulae VII, Viii, IX, X, XI and XII is as defined above for formula VI.
A special embodiment of this fifth aspect is that wherein X is bromo.
 
19
Another special embodiment of this fifth aspect provides for further treating the protected amine of the formula XII,
 

 
5
wherein Boc is tert-butoxycarbonyl, Ph is phenyl and 1:21' is as defined above for formulae VI, with hydrogen at a pressure of from about 200 kPa to about 3000 kPa in
a solvent, for example an aliphatic alcohol or ethyl acetate, in the presence of a palladium catalyst, in the presence of an organic or inorganic acid, for example acetic
10 acid, to provide a compound of the formula VI,
 

 
wherein Fly is as defined above for formula VI and Boc is tert-butoxycarbonyl, in the 15 form of its salt or, if desired, in the form of the free compound of the formula VI.
A sixth aspect of the present invention provides a process for the preparation of a compound of the formula VI,
 
wherein R1 is H, F, CF, OCF,    (C3Cio)-cycloalkyl, 3-membered to 10-
membered heterocycloalkyl comprising 1, 2 or 3 identical or different ring
5 heteroatoms chosen from nitrogen, oxygen and sulfur, (Cs-C14)-aryl, (Ci-C8)-alkoxy, (C3-Cio)-cycloalkoxy, (C8-C14)-aryloxy, di((C,Ca)-alkyl)amino, di((C3-Cm)-
cycloalkyl)amino or dk(C6-C14)-aryl)amino, or a protected derivative thereof or precursor moiety thereto; and
Boo is tert-butoxycarbonyl,
10    or its salt,
comprising the steps of
a) treating a 3-(4-pyridyl)benzaldehyde of the formula XIII,
15
with hydroxylamine or a salt of hydroxylamine in a solvent, for example an aliphatic alcohol, optionally in the presence of base, at a temperature of from about 0°C to about 40°C to provide an oxime of the formula XIV or its salt;
20
 
b) treating the oxime of the formula XiV or its salt with hydrogen at a pressure of from about 300 kPa to about 1500 kPa in a solvent, for example a polar organic solvent
5- such as an aliphatic alcohol, for example methanol, in the presence of a palladium catalyst, at a temperature of from about 20°C to about 50°C to provide a 3-(4- pyridyl)benzylamine of the formula XV or its salt,
 

 
10
c) treating the 3-(4-pyridyl)benzylamine of the formula XV or its salt with di-tert-butyl dicarbonate in a solvent for example an aliphatic alcohol such as methanol, ethyl
acetate, an ether such as tetrahydroturan, a halogenated hydrocarbon such as dichbromethane, a mixture of two or more of such solvents or a mixture of one or
15 more of such solvents with water, in the presence of a base, for example an alkali
metal hydroxide, carbonate or alcoholate or a tertiary amine, such as sodium
hydroxide or triethylamine, preferably at a temperature of from about 0°C to about
40°C, to provide a Boo-protected 3-(4-pyridyl)benzylamine of the formula XVI,
 
wherein Boc is tert-butoxycarbonyl; and
5 d) treating the Boc-protected 3-(4-pyridyl)benzylamine of the formula XVI with hydrogen in a solvent, for example an aliphatic alcohol such as ethanol, at a pressure of from about 2000 kPa to about 6000 kPa, in the presence of a platinum catalyst, in the presence of an acid such as, for example, hydrogen chloride or sulfuric acid, to provide a compound of the formula VI or its salt;
10
where IR1. in the formulae XIII, XIV, XV and XVI is as above defined for formula VI.
A particular embodiment of this sixth aspect provides a process for the preparation of a compound of the formula VI,
15
 

 
wherein R1 is H, F, CF3, OCF3,    (C3-C15)-cycloalkyl, 3-membered to 10-
membered heterocycloalkyl comprising 1, 2 or 3 identical or different ring
20 heteroatoms chosen from nitrogen, oxygen and sulfur, (C5-C14)-aryl, (Ci-Ca)-alkoxy, (C3-C15)-cycioalkory, (C6-C14)-aryloxy, di((Ci-Cs)-alkyl)amino, di((C3.-Cio)-
 
23
 
cycloalkyl)amino or di((G.-C14)-aryl)amino, or a protected derivative thereof or precursor moiety thereto; and
Boc is tert-butoxycarbonyl,
or its salt,
comprising the steps of
a) treating a 3-(4-pyridyl)benzaldehyde of the formula XIII
 

 
with hydroxylamine hydrochloride in a solvent, for example an aliphatic alcohol such as methanol, at a temperature of from about 0°C to about 40°G to provide an oxime hydrochloride of the formula XIVa;
15         XIVa

b) treating the oxime hydrochloride of the formula XIVa with hydrogen at a pressure of from about 300 kPa to about 1500 kPa in a solvent, for example a polar organic solvent such as an aliphatic alcohol, for example methanol, in the presence of a
20 palladium catalyst, at a temperature of from about 20°C to about 50°C to provide a 3- (4-pyridyl)benzylamine hydrochloride of the formula XVa;
 
c) treating the 3-(4-pyridyl)benzylamine hydrochloride of the formula XVa with di-tert¬butyl dicarbonate in a solvent, for example an aliphatic alcohol such as methanol,
5 ethyl acetate, an ether such as tetrahydrofuran, a halogenated hydrocarbon such as dichloromethane, a mixture of two or more of such solvents or a mixture of one or more of such solvents with water, in the presence of a base, for example an alkali metal hydroxide, carbonate or alcoholate or a tertiary amine, such as sodium hydroxide or triethylamine, preferably at a temperature of from about 0°C to about
10 40°C, to provide a Boo-protected 3-(4-pyridyl)benzylamine of the formula XVI,
 

 
wherein Boc is tert-butoxycarbonyl; and
15
d) treating the Boo-protected 3-(4-pyridyl)benzylamine of the formula XVI with hydrogen in a solvent, for example an aliphatic alcohol such as ethanol, at a pressure of from about 2000 kPa to about 6000 kPa, in the presence of a platinum catalyst, in
the presence of hydrogen chloride or sulfuric acid, to provide a compound of the
20 formula VI or its salt
where Rr in the formulae XIII, XIVa, XVa and XVI is as above defined for formula VI.
 
25
A seventh aspect of the present invention provides a process for the preparation of a compound of the formula VI
R1
 

 
5
wherein Ry is H, F, CF3, OCF3,    (C3-C,0)-cycloalkyl, 3-membered to 10-
membered heterocycloalkyl comprising 1, 2 or 3 identical or different ring heteroatoms chosen from nitrogen, oxygen and sulfur, (C8-C14)-aryl, (C1-C3)-alkoxy, (Cs-C10-cycloaIkoxy, (Cs-C14-aryloxy, di((Ci-Cs)-alkyl)amino, di((C3-C10)-
10 cycloalkyl)amino or di((Cn-C14)-aryl)amino, or a protected derivative thereof or precursor moiety thereto; and
Boc is tert-butoxycarbonyl,
or its salt,
15 comprising the steps of
a) treating a 3-(4-pyridyl)benzonitrile of the formula XVII,
 

 
20 with hydrogen in the presence of a palladium catalyst at a pressure of from about
2000 kPa to about 6000 kPa in the presence of an acid, for example hydrogen chloride, or with a complex hydride such as lithium aluminium hydride, lithium
 
26
borohydride or sodium borohydride, optionally in the presence of an auxiliary agent such as an acid or chlorotrimethylsilane, in a solvent, for example an aliphatic alcohol or an ether such as tetrahydrofuran, to provide a 3-(4-pyridyl)benzylamine of the formula XV or its salt;
 

 
b) treating the 3-(4-pyridyl)benzylamine of the formula XV or its salt with di-tert-butyl dicarbonate in a solvent, for example an aliphatic alcohol such as methanol, ethyl
10 acetate, an ether such as tetrahydrofuran, a halogenated hydrocarbon such as dlchloromethane, a mixture of two or more of such solvents or a mixture of one or more of such solvents with water, in the presence of a base, for example an alkali metal hydroxide, carbonate or alcoholate or a tertiary amine, such as sodium hydroxide or triethylamine, preferably at a temperature of from about 0°C to about
15 40°C, to provide a Boo-protected 3-(4-pyridyl)benzylamine of the formula XVI,
 

 
wherein Boc is tert-butoxycarbonyl; and
c) treating the Boo-protected 3-(4-pyridyl)benzylamine of the formula XVI with hydrogen in a solvent, for example an aliphatic alcohol such as ethanol, at a pressure of from about 2000 kPa to about 6000 kPa, in the presence of a platinum catalyst, in
 
27
the presence of an acid such as hydrogen chloride or sulfuric acid, to provide a compound of the formula VI or its salt;
where Rv in the formula XV, XVI and XVII is as above defined for formula VI.
5
An eighth aspect of the present invention provides a process for the preparation of 4- [3-(tert-butoxycarbonylaminomethyl)phenyl]piperidine or its salt,
comprising the steps of
10 a) treating 3-bromobenzylamine hydrochloride or 3-iodobenzylamine hydrochloride with 1,2-bis(chlorodimethylsilyl)ethane in a halogenated aliphatic hydrocarbon in the presence of a tertiary amine to provide the corresponding 1-(3-halobenzyl)-2,2,5,5- tetramethy1-1-aza-2,5-disilacyclopentane, where halo is bromo or iodo;
15 b) treating the 1-(3-halobenzyI)-2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane in an ether with an alkyllithium compound and 1-benzyl-4-piperidone at a temperature of from about-80°C to about -40°C to provide 1-(3-(1-benzy1-4-hydroxypiperidin-4- yl)benzyl]-2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane;
20 c) treating the 143-(1-benzy1-4-hydroxypiperidin.4-yl)benzyl]-2,2,5,5-tetramethyl-1- aza-2,5-disilacyclopentane with an inorganic acid in a halogenated hydrocarbon, to provide 3-(1-benzy1-4-hydroxypiperidin-4-yl)benzylamine as the salt of the inorganic acid;
25 d) treating the 3-(1-benzy1-4-hydroxypiperidin-4-yl)benzylamine with a concentrated, non-oxidizing acid at a temperature of from about 70°C to about 150°C, followed by alkalinization to provide 3-(1-benzy1-1,2,3,6-tetrahydropyridin-4-Abenzylarnine; and
e) treating the 3-(1-benzy1-1,2,3,6-tetrahydropyridin-4-yl)benzylamine with di-tert-
30 butyl dicarbonate in an aliphatic alcohol such as methanol, ethyl acetate, an ether such as tetrahydrofuran, a halogenated hydrocarbon such as dichloromethane, a mixture of two or more of such solvents or a mixture of one or more of such solvents
 
28
with water, in the presence of an alkali metal hydroxide, carbonate or alcoholate or a tertiary amine, such as sodium hydroxide or triettylamine, preferably at a temperature of from about 0°C to about 40°C, to provide 3-(1-benzy1-1,2,3,8- tetrahydropyridin-4-Abenzylcarbamic acid tert-butyl ester.
5
A special embodiment of this eighth aspect provides a process for the preparation of 4[3-(tert-butoxycarbonylaminomethyl)phenyllpiperidine or its salt,
comprising the steps of
10 a) treating 3-bromobenzylamine hydrochloride with 1,2-bis(chlorodimethylsilyl)ethane in a halogenated aliphatic hydrocarbon, in the presence of a tertiary amine to provide 1-(3-bromobenzyl)-2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane;
b)    treating the 1-(3-bromobenzy1)-2,2,5,5-tetramethy1-1-aza-2,5-disilacyclopentane in
15 an ether, with an alkyllithium compound and 1-benzyl-4-piperidone at a temperature of from about -80°C to about -40°C to provide 143-(1-benzy1-4-hydroxypiperidin-4- yl)benzyg-2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane;
c)    treating the 143-(1-benzy1-4-hydroxypiperidin-4-yl)benzyll-2,2,5,5-tetramethyl-1-
20 aza-2,5-disilacyclopentane with an inorganic acid in a halogenated aliphatic hydrocarbon, to provide 3-(1-benzyl-4-hydroxypiperidin-4-yl)benzylamine as the salt of the Inorganic acid;
d)    treating the 3-(1-benzy1-4-hydroxypiperidin-4-yl)benzylamine with a concentrated, 25 non-oxidizing acid at a temperature of from about 70°C to about 150°C, followed by alkalinization to provide 3-(1-benzy1-1,2,3,6-tetrahydropyridin-4-yObenzylamine; and
e)    treating the 341 -benzy1-1,2,3,6-tetrahydropyridin-4.11)benzylamine with di-tert-butyl dicarbonate in an aliphatic alcohol such as methanol, ethyl acetate, an ether
30 such as tetrahydrofuran, a halogenated hydrocarbon such as dichloromethane, a mixture of two or more of such solvents or a mixture of one or more of such solvents
 
29
with water, in the presence of an alkali metal hydroxide, carbonate or alcoholate or a tertiary amine, such as sodium hydroxide or triethylamine, preferably at a temperature of from about 0°C to about 40°C, to provide 3-(1-benzy1-1,2,3,6- tetrahydropyridin-4-yl)benzylcarbamic acid tert-butyl ester.
5
Another special embodiment of this eighth aspect provides for further treating the 3-
(1-benzyl-1,2,3,6-tetrahydropyridin-411)benzylcarbamic acid tert-butyl ester with hydrogen at a pressure of from about 200 kPa to about 3000 kPa in an aliphatic alcohol or ethyl acetate, in the presence of a palladium catalyst, in the presence of an
10 organic or inorganic acid, to provide 443-(tert-butoxycarbonylaminomethyl)phenyl]- piperidine as the salt of the organic or inorganic acid.
An ninth aspect of the present invention provides a process for the preparation of 4- [3-(tert-butoxycarbonylaminomethyl)phenyl]piperldine or its salt,
comprising the steps of
a)    treating 3-(4-pyrldyl)benzaldehyde with hydroxylamine or a salt thereof in an aliphatic alcohol, optionally in the presence of base, at a temperature of from about 0°C to about 40°C to provide 3-(4-pyridyl)benzaldehyde oxime or its salt;
b)    treating the 3-(4-pyridyl)benzaldehyde oxime or its salt with hydrogen at a pressure of from about 300 kPa to about 1500 kPa in an aliphatic alcohol, in the presence of a palladium catalyst, at a temperature of from about 20°C to about 50°C to provide 3-(4-pyridyl)benzylamine or its salt;
25
c)    treating the 3-(4-pyridypbenzylamine or its salt with di-tert-butyl dicarbonate in an aliphatic alcohol such as methanol, ethyl acetate, an ether such as tetrahydrofuran, a halogenated hydrocarbon such as dichloromethane, a mixture of two or more of such solvents or a mixture of one or more of such solvents with water, in the presence of
30 an alkali metal hydroxide, carbonate or alcoholate or a tertiary amine, such as
 
30
sodium hydroxide or triethylamine, preferably at a temperature of from about 0°C to about 40°C, to provide 3-(4-pyridyl)benzylcarbamic acid tert-butyl ester, and
d)    treating the 3-(4-pyridyl)benzylcarbamic acid tert-butyl ester with hydrogen in a
5 aliphatic alcohol, at a pressure of from about 2000 kPa to about 6000 kPa, in the presence of a platinum catalyst, in the presence of an acid such as hydrogen chloride or sulfuric acid.
A special embodiment of this ninth aspect provides a process for the preparation of 10 4(3-(tert-butoxycarbonylaminornethyl)phenygpiperidine or its salt,
comprising the steps of
a)    treating 3-(4-pyridyl)benzaldehyde with hydroxylamine hydrochloride in an aliphatic alcohol, at a temperature of from about 0°C to about 40°C to provide 3-(4¬15 pyridyl)benzaldehyde °Arne hydrochloride;
b)    treating the 3-(4-pyridyl)benzaldehyde oxime hydrochloride with hydrogen at a pressure of from about 300 kPa to about 1500 kPa in an aliphatic alcohol, in the presence of a palladium catalyst, at a temperature of from about 20°C to about 50°C
20 to provide 3-(4-pyridyl)benzylamine hydrochloride;
c)    treating the 3-(4-pyridyl)benzylamine hydrochloride, with di-tert-butyl dicarbonate in an aliphatic alcohol such as methanol, ethyl acetate, an ether such as tetrahydrofuran, a halogenated hydrocarbon such as dichioromethane, a mixture of
25 two or more of such solvents or a mixture of one or more of such solvents with water, in the presence of an alkali metal hydroxide, carbonate or alcoholate or a tertiary amine, such as sodium hydroxide or triethylamine, preferably at a temperature of from about 0°C to about 40°C, to provide 3-(4-pyridyl)benzylcarbamic acid tert-butyl ester; and
30
 
31
d) treating 3-(4-pyridyl)benzylcarbamic acid tert-butyl ester with hydrogen in an
aliphatic alcohol, at a pressure of from about 2000 kPa to about 6000 kPa, in the presence of a platinum catalyst, in the presence of an acid such as hydrogen chloride or sulfuric acid.
5
A tenth aspect of the present invention provides a process for the preparation of 413- (tert-butoxycarbonylaminomethyl)phenylipiperidine or its salt,
comprising the steps of
10 a) treating 3-(4-pyridyl)benzonftrile with hydrogen in the presence of a palladium
catalyst at a pressure of from about 2000 kPa to about 6000 kPa in an aliphatic alcohol or a mixture of an aliphatic alcohol and water, or with a complex hydride such as lithium aluminium hydride, lithium borohydride or sodium borohydride, in an aliphatic alcohol or an ether such as methanol or tetrahydrofuran, at a temperature of
15 from about 0°C to about 50°C, to provide 3-(4-pyridyl)benzylamine or its salt;
b) treating the 3-(4-pyridyl)benzylamine or its salt with di-tert-butyl dicarbonate in an aliphatic alcohol such as methanol, ethyl acetate, an ether such as tetrahydrofuran, a halogenated hydrocarbon such as dichloromethane, a mixture of two or more of such
20 solvents or a mixture of one or more of such solvents with water, in the presence of an alkali metal hydroxide, carbonate or alcoholate or a tertiary amine, such as sodium hydroxide or triethylamine, preferably at a temperature of from about 0°C to about 40°C, to provide 3-(4-pyridyl)benzylcarbamic acid tert-butyl ester; and
25 c) treating the 3-(4-pyridyl)benzylcarbamic acid tert-butyl ester with hydrogen in an
aliphatic alcohol, at a pressure of from about 2000 kPa to about 6000 kPa, in the presence of a platinum catalyst, in the presence of an acid such as hydrogen chloride or sulfuric acid.
30 The present invention also provides novel intermediates useful in the processes of the present invention for the preparation of a compound of the formula I,
 
32
 
wherein
5 RI is H, F, CF3, OCF3,    (C3-Cio)-cydoalkyl, 3-membered to 10-
membered heterocycloalkyl comprising 1, 2 or 3 identical or different ring heteroatoms chosen from nitrogen, oxygen and sulfur, (Cs-C14)-aryl, (C3-C8)alkoxy, (C3-C10)-cycloalkoxy, (CB-C14-aryloxy, di((ei-Cs)-alkyffamino, di((C3-C15)- cycloalkyl)amino or digea-C141-aryDamino; and
10 R2 is H, F, CF3, OCF3,    (Cs-Cio)-cycloalicyl, 3-membered to 10-
membered heterocycloalkyl comprising 1, 2 or 3 identical or different ring heteroatoms chosen from nitrogen, oxygen and sulfur, (Cs-C14)-aryl, 5-membered to 10-membered heteroaryl comprising 1, 2 or 3 identical or different ring heteroatoms chosen from nitrogen, oxygen and sulfur, (C1-C8)-alkoxy, (Cs-C10-cycloalkm, (C6-
15 C14)-aryloxy, 5-membered to 90-membered heteroaryloxy comprising 1, 2, or 3 identical or different ring heteroatoms chosen from nitrogen, oxygen and sulfur, di((Ci-Ca)-alkyl)amino, dii(C3-C10)-cycloalkyl)amino or di((C6-G14)-aryl)amino; or its salt,
20 including:
a compound of the formula VIII,
R1    \/
,s, ,Ti    VIII
X'
 
33
 
wherein Fe is H, F, CF3, OCF3,    (C3-C10)-cycloalkyl, 3-membered to 10-
membered heterocycloalkyl comprising 1, 2 or 3 identical or different ring heteroatoms chosen from nitrogen, oxygen and sulfur, (CB-C14)-aryl, (Ci-Cs)-alkoxy,
5 (C3Cio)-cycloalkoxy, (CB-C14)-arytoxy, di((Ci-C8)-alkyl)amino, di((C3-C15)- cycloalkyl)amino or di((C6-C14)-aryl)amino, or a protected derivative thereof or precursor moiety thereto;
a compound of the formula IX,
10
 

 
wherein R1 is H, F, CF3, OCF3, (Ci-CB)-alkyl, (C3-C13)-cycloalkyl, 3-membered to 10-membered heterocycloalkyl comprising 1, 2 or 3 identical or different ring
15 heteroatoms chosen from nitrogen, oxygen and sulfur, (CB-C14)-aryl, (Ci-C8)-alkoxy, (C3-C10)-cycloalkoxy, (C6-C14)-aryloxy, di((Ci-Ca)-alkyl)amino, di((C3-C15)-
cycloalkyl)arnino or di((C6-Cia)-aryl)amino, or a protected derivative thereof or precursor moiety thereto; and Ph is phenyl;
20 a compound of the formula X,
 
wherein Rt is H, F, CF3, OCF3,    (C3-Cio)-cycloalkyi, 3-membered to 10-
membered heterocycloalkyl comprising 1, 2 or 3 identical or different ring
5 heteroatoms chosen from nitrogen, oxygen and sulfur, (C6-C14)-aryl, (Ci-Ca)-alkoxy, (C3-Cm)-cycloalkoxy, (Cs-C14)-aryloxy, di((C1-C8)-alkyl)amino, di((C3-C10-
cycloalkyl)amino or di((C6-014)-aryl)amino, or a protected derivative thereof or precursor moiety thereto; and Ph is phenyl, or its salt;
10 a compound of the formula Xi,
 

 
wherein Ftv is H, F, CF3, OCF3,    (C3-C10)-cycloalkyl, 3-membered to 10-
15 membered heterocycloalkyl comprising 1, 2 or 3 identical or different ring heteroatoms chosen from nitrogen, oxygen and sulfur; (C6-014)-aryl, (C1-C3)-alkoxy, (C3-C40)-cycloalkoxy, (Ce-C14)-aryloxy, di((C1-C3)-allcyl)amino, di((C3-Cio)-
cycloalkyl)amino or di((C6-C14)-arypamino, or a protected derivative thereof or precursor moiety thereto; and Ph is phenyl, or its salt;
2.0
 
a compound of the formula XII,
 

 
5 wherein Ry is H, F, CF3, OCF3, (CI-CO-alkyl, (C3-C1O-cycloalkyl, 3-membered to 10-membered heterocycloalkyl comprising 1, 2 or 3 identical or different ring heteroatoms chosen from nitrogen, oxygen and sulfur, (Cs-CIO-aryl, (C1-CO-alkoxy, (C3-Cio)-cycloalkoxy, Ps-C14)-aryloxy, di((Cj-Cs)-alkyl)amino, di((C3-00- cycloalkyl)amino or di((Cs-C14)-aryl)amino, or a protected derivative thereof or
0 precursor moiety thereto; Boc is tert-butoxycarbonyl; and Ph is phenyl, or its Bait;
a compound of the formula XIV,
,OH
H
 

 
wherein R1' is H, F, CF3, OCF3,    (03-C10-cycloalkyl, 3-membered to 10-
membered heterocycloalkyl comprising 1, 2 or 3 identical or different ring
heteroatoms chosen from nitrogen, oxygen and sulfur, (Cs-C14-aryl, (C1-CO-alkoxy, (C3-CiO-cycloalkm, (C5-C14)-arytoxy, di((Ci-CO-alkyl)amino, di(P3-CiO¬cycloaikyl)amino or di((C6-C10-aryparnino, or a protected derivative thereof or precursor moiety thereto, or its salt;
 
a compound of the formula XV,
 

 
5
wherein ar is H, F, CF3, OCF3,    (C3-C1o)-cycloalkyl, 3-membered to 10-
membered heterocycloalkyl comprising 1, 2 or 3 identical or different ring heteroatoms chosen from nitrogen, oxygen and sulfur, (C6-C14)-aryl, (C1-C8)-alkoxy, (C3-C15)-cycloalkoxy, (Cs-C14-arYioxY, di((Ci-C3)-alkyl)amino, di((C3-Cio)-
10 cycloalkyl)amino or di((es-C14)-aryl)amino, or a protected derivative thereof or precursor moiety thereto, or its salt;
a compound of the formula XVI,
15         NHBoc    XV1

wherein Ftv is H, F, CF3, OCF3, (C1-CB)-alkyl, (C3-C10)-cycloalkyl, 3-membered to 10-membered heterocycloalkyl comprising 1, 2 or 3 identical or different ring heteroatoms chosen from nitrogen, oxygen and sulfur, (Cs-C14)-aryl, (Ci-C8)-alkoxy,
20 (C3-C1o)-cycloalkoxy, (Cs-C14)-aryloxy, di((Ci-C8)-alkyl)amino, di((Ca-C40)- cycloallryi)amino or di((Cs-C14)-aryl)amino, or a protected derivative thereof or precursor moiety thereto; and Boc is tert-butoxycarbonyi, or its salt; and
 
a compound of the formula IVb,
0
 

 
5 wherein R1' is H, F, CF3, QCF3,    (C3-C10)-cycloalkyl, 3-membered to 10-
membered heterocycloalkyl comprising 1, 2 or 3 identical or different ring heteroatoms chosen from nitrogen, oxygen and sulfur, (Cs-C14)-aryl, (Ci-C8)-alkoxy, (C5-C10)-cycloalkoxy, (Cs-C14)-aryloxy, di((Cj-Cs)-alkyl)amino, di((C3-C10)- cycloalkyl)amino or di((Cs-C14)-aryDamino, or a protected derivative thereof or
10 precursor moiety thereto; and Boc is tert-butoxycarbonyl, or its salt;
and, in another aspect of the present invention, the use of each of these compounds as an intermediate, in particular as an intermediate for the preparation of a compound of the formula 1,
15
 
wherein Rr and R2 are defined as above, or its salt.
in a particular embodiment, the present invention also provides novel intermediates useful in the processes of the present invention for the preparation of 443- (aminomethyl)phenyli-145-(2-fluorophenylethyny1)-2-furanoyfJpiperldine or its salt,
 
38
including: 1-(3-bromobenzy1)-2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane;
143-(1-benzy1-4-hydroxypiperidin-4-yi)benzy11-2,2,5,5-tetramethyl-1-aza-2,5- disilacyclopentane;
3-(1-benzy1-4-hydroxypiPeridin-4-yl)benzylamine or its salt; 3-(1-benzy1-1,2,3,8-tetrahydropyridin-4-yl)benzylamine or its salt;
3-(1-benzyl-1,2,3,8-tetrahydropyridin-4-yl)benzylcarbamic acid tert-butyl ester or its salt;
15
3-(4-pyridyl)benzaldehyde oxime or its salt;
3-(4-pyridyl)benzylamine or its salt;
20 3-(4-pyridyl)benzylcarbamic acid tert-butyl ester or its salt; and
443-(tert-butoxycarbonylaminomethyl)pheny1]-145-bromo-2-furanoyl]piperidine;
and, in another particular embodiment of the present invention, the use of each of 25 these compounds as an intermediate for the preparation of 443- (aminomethyl)pheny1]-145-(2-fluorophenylethyny1)-2-furanoyflpiperidine or its salt.
As used herein, and unless otherwise specified, the following terms are understood to have the following meanings.
30
"Alkyl" means a residue of an aliphatic saturated hydrocarbon group which may be straight or branched having from about 1 to about 8 carbon atoms, for example 1, 2,
 
39
3, 4, 5, 6, 7 or 8 carbon atoms. Preferred alkyl residues are those which have from about 1 to about 6 carbon atoms, in particular from about 1 to about 4 carbon atoms. Exemplary alkyl residues include methyl, ethyl, n-propyl, iso-propyi, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, 3-pentyl, heptyl and octyl.
5
"Cycloalkyl" means a residue of a saturated monocyclic or bicyclic ring system containing from about 3 to about 10 ring carbon atoms, for example 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Preferred cycloalkyl residues are those which have from about 3 to about 7 carbon atoms. Exemplary cycloalkyl residues include cyclopropyl,
10 cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
"Heterocycloalkyl" means a residue of an about 3-membered to about 10-membered, for example 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-membered, saturated, monocyclic or multicyclic heterocyclic ring system which comprises 1, 2 or 3 identical or different
15 ring heteroatoms chosen from nitrogen, oxygen and sulfur, which can be bonded via any suitable ring carbon atom or ring nitrogen atom and nitrogen atoms of which, independently of one another, can carry a residue chosen from hydrogen, (C1-C.)-
alkyl, (Cs-C14)-aryl and (C5-C14)-aryl-(Cj-C4)-alkyl-. Heterocycloalkyl includes, for example, (i) a cycloalkyl group of from about 3 to about 7 ring members of which 1, 2
20 or 3 are ring heteroatoms chosen from nitrogen, oxygen and sulfur, i. e. a saturated monocyclic heterocyclic group, and (ii) a residue of a saturated multicyclic, for example bicyclic or tricyclic, heterocyclic group of from about 6 to about 10 ring members of which 1, 2 or 3 are ring heteroatoms chosen from nitrogen, oxygen and sulfur, in which a saturated monocyclic heterocyclic group is fused to one or more, for
25 example one or two, cycloalkyl groups and/or saturated monocyclic heterocyclic groups to form a multicyclic cyclic structure. Exemplary heterocycloalkyl groups include piperidinyl, pyrrolidinyl, morpholinyl, tetrahydropyranyl, or tetrahydrothienyl.
"Aryl' as a group or part of a group means a residue of a monocyclic or multicyclic
30 ring system comprising from about 6 to about 14 ring carbon atoms, for example 6, 8, 9, 10, 12, 13 or 14 ring carbon atoms. Aryl includes: (i) a residue of a monocyclic or multicyclic, for example bicyclic or tricyclic, aromatic carbocyclic group of from about
 
40
6 to about 14 ring carbon atoms, all rings of which are aromatic, such as phenyl or
naphthyl; or (ii) a residue of partially saturated multicyclic, for example bicyclic or tricyclic, aromatic carbocyclic group in which an aryl group and a cycloalkyl group are
fused together to form a cyclic structure, such as a tetrahydronaphthyl or indanyl
5 residue.
"Heteroaryr means a residue of an about 5-membered to about 10-membered, for example 5-, 6-, 8-, 9- or 10-membered, heteroaromatic ring system which comprises 1, 2 or 3 identical or different ring heteroatoms chosen from nitrogen, oxygen and
10 sulfur, which can be bonded via any suitable ring carbon atom or ring nitrogen atom and nitrogen atoms of which, independently of one another, can cany a residue chosen from hydrogen, (Ci-Cr)-alkyl, (C6-C14)-aryl and (Ce-C10-arylC1-C4)-alkyl-. Heteroaryl includes: (i) a residue of a monocyclic or bicyclic aromatic heterocyclic group all rings of which are aromatic, including, for example, residues like
15 benzimidazolyl, benzothiazolyl, benzoxazolyl, benzothienyl, furyl, imidazolyl, indolyl, indolizinyl, isoxazolyl, isoquinofinyl, isothiazolyl, oxadiazolyl, pyrazinyl, pyridazinyl,
pyrazolyl, pyridyl, pyrimidinyl, pyrrolyi, quinazolinyl, quinolinyl, 1,3,4-thiarliazolyl, thiazolyl, thienyl or triazolyl, or (i) a residue of a partially saturated bicyclic heteroaromatic group in which a heteroaryt group and a cycloalkyl group or an aryl
20 group and a heterocycloalkyl group or a heteroaryl and a heterocycloalkyl group are fused together to form a cyclic structure, for example a pyrindanyl residue.
"Alkoxy" means an alkyl-O- residue in which the alkyl group is as described herein. Exemplary alkoxy groups include methoxy, ethoxy,-n-propoxy, isopropoq, n-butoxy, 25 isobutoxy, tert-butoxy and heptoxy.
"Cycloalkoxy" means a cycloalkyl-O- residue, in which the cycloalkyl group is as described herein.
30 "Aryloxy" means an aryl-O- residue, in which the aryl group is as described herein.
 
41
"Heteroarylon" means a heteroaryl-O- residue, in which the heteroaryl group is as described herein.
"Dialkylamino" means an -N(alkyl)(alkyl) residue in which the alkyl groups may be the 5 same or different and are as described herein.
"Dicycloalkyiamino" means an -N(cycloalkyl)(cycloalkyl) residue in which the
cycloalkyl groups may be the same or different and are as described herein.
10 "Diarylamino" means an -N(aryl)(aryl) residue in which the aryl groups may be the same or different and are as described herein.
In the processes and compounds according to the invention the groups R1, R1', R2 and R°', which are attached to the benzene rings depicted in the formulae herein,
15 may independently of one another be present one or more times, for example one, two or three times. Preferably they are independently of one another present one or two times. More preferably, one group R1 or RI is present and one group R2 or R7 is present. When more than one of any of the groups R1, RI, R2 and R2' is present, they can all independently of one another have the meanings indicated herein and can be
20 the same or different. Positions on the benzene rings depicted in the formulae herein which do not carry a group R1, R1', R2 or R2 or another group drawn in the formulae, carry hydrogen atoms. I.e., in a compound of the formula I in which one group R1 and one group R2 is present, the benzene ring carrying R1 carries three hydrogen atoms in addition to the group R1 and the group -CH2NH2, and the benzene ring carrying R2
25 carries four hydrogen atoms in addition to the group R2. In a compound of the formula I in which two groups R2 are present, the benzene ring carrying R2 carries three hydrogen atoms in addition to the group R2. The groups R1, R1', R2 and R2' can be present in any desired positions. For example, in a compound of the formula t in which one group R2 is present that is different from hydrogen, R2 can be present in
30 position 2, 3 and 4 will respect to the ethyne moiety which, by definition, is present in position 1. If two groups R2 are present that are different from hydrogen, they can be present in 2,3-, 2,4-, 2,5-, 2,6-, 3,4. and 3,5-position. Similarly, if one group R1 is
 
42
present that is different from hydrogen, it can be present in position 2, 3, 4 and 6 with respect to the position of the piperidine residue which is present in position 1, if the position of the group -CH2NH2 in a compound of the formula I or of the group derived therefrom in the other compounds of the invention is designated as position 5 (if the
5 position of the group -CH2-NH2 is designated as position 3, the group R1 can be present in position 2, 4, 5 and 6).
Salts of a compound according to or related to the present invention, i.e. any
compound which is employed into a process or which is obtained by a process or
10 which occurs as an intermediate in a process described herein, including any compound which is a subject of the present invention per se, which contains one or more basic groups, i.e. protonatable groups such as amino groups, piperidinyl groups, pyridinyl groups and/or other basic heterocyclic groups, are in particular acid
addition salts formed by the respective compound and inorganic or organic acids,
15 including mineral acids and organic carboxylic acids and suifonic acids. Examples of acids which may form such salts are hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, citric acid, trifluoroacetic acid, lactic acid, tartaric acid, fumaric acid, maleic acid, methanesulfonic acid, ethanesulfonic acid,
20 benzenesulfonic acid, p-toluenesulfonic acid, etc. Compounds which contain two or more basic groups can form acid addition salts with one acid equivalent or with two or more acid equivalents. In particular in the case of compounds of the formulae I and la which are intended for use as in the production of pharmaceutical compositions or for use—as-pharrnacologically active ingredients, preferred salts are physiologically
25 acceptable salts or pharmaceutically acceptable salts which are non-toxic and exhibit a suitable property profile for the intended use. However, the present invention includes also salts which, owing to low physiological compatibility, are not directly suitable for use in pharmaceuticals but which can be used, for example, as intermediates for chemical reactions or for the preparation of physiologically
30 acceptable salts, for example by ion exchange procedures. Salts may be obtained by any process as described herein or by customary methods which are known to the person skilled in the art such as, for example, by contacting a basic compound with
 
43
an acid in a solvent, or by ion exchange from another salt. Likewise, by applying customary methods such as contacting a salt with a base in a solvent, a salt can be converted into the free base if desired, for example if an intermediate which has been isolated as a salt is needed in a subsequent reaction step as the free base.
5
In the processes and compounds according to the present invention, and in particular
for various values of R-1 and R2, it may be advantageous or necessary to protect reactive functional groups, where these are desired in the final product, or let them be present initially in form of precursor moieties which are later converted into the
10 desired group, in order to avoid their unwanted participation in reactions according to
processes of the present invention. Conventional protecting groups and precursor
moieties and processes for introduction and their removal or conversion into the desired groups may be used in accordance with standard practice known to one skilled in the art, for example as described in T.W. Greene and P.G.M. Wuts in
15 "Protective Groups in Organic Chemistry", John Wiley and Sons, 1991.
In the processes and compounds according to the present invention R1 and Ry preferably are H, F, CF3, OCF3, (C3-C7)-cycloalkyl, phenyl, (Ci-C4)- alkoxy, phenoxy or di((ei-C4)-alkyl)amino, more preferably H, F, CF3, OCF3, (Ci-C4)-
20 alkyl, (Ci-C4)-alkoxy, or di((Ci-C4)-alkyl)amino, particularly preferably H, F, CF3, OCF3, (Ci-C4)-alkyl or (Ci-C4)-alkoxy, more particularly preferably H, F, CF3, OCF3, CH3 or OCH3, especially preferably H or F, moreover preferably H. In case that one
residue R1 or R1 is present which is F, the flourine atom is preferably present in position 2 with respect to the position of the piperidine residue which is present in
25 position 1, if the position of the group -CH2-NH2 in a compound of the formula I, or of the group derived therefrom in the other compounds of the invention, is designated as position 5. R2 and R2' preferably are H, F, CF3, OCF3, (C1-C4)-alkyl, (C3-C7)- cycloalkyl, phenyl, (C1-C4)-alkoxy, phenoxy or di((Ci-C4}-alkyl)amino, more preferably H, F, CF3, OCF3,    (Ci-C4)-alkoxy, or di((C1-C4)-alkyl)amino, particularly
30 preferably H, F, CF3, OCF3, (Ci-C4)-alkyl or (Cc-C4)-alkoxy, more particularly preferably H, F, CF3, OCF3, CH3 or OCH3, especially preferably H or F. In case that one residue R2 or R2' is present, in a moreover preferred embodiment of the present
 
44
invention R2 or le is F, in particular a fluorine atom in ortho position to the ethyne moiety.
The processes according to the present invention are usually performed in the
5 presence of a solvent (or diluent) but, depending on the individual case, may also be performed without addition of a solvent. Solvents that may be used include inorganic solvents, for example water, and organic solvents. Examples of organic solvents are hydrocarbons, including aliphatic and aromatic hydrocarbons, for example pentane, hexane, heptane, petrol ether, ligroin, cyclohexane, methylcyclohexane, benzene,
10 toluene or xylene, halogenated hydrocarbons, including halogenated aliphatic and aromatic hydrocarbons, for example dichloromethane, trichloromethane, carbon tetrachloride, dichioroethane, trichloroethane, chlorobenzene or dichlorobenzene, ethers, including aliphatic ethers and cyclic ethers, for example diethyl ether, di-n¬propylether, di-isopropyl ether, dibutylether, ethyleneglycol dimethyl ether,
15 diethyleneglycol dimethyl ether, tetrahydrofuran or dioxane, esters, for example ethyl acetate, butyl acetate or dimethyl carbonate, amides, for example dimethylform¬amide, dimethylacetamide or N-methylpyrrolidone, alcohols including aliphatic alcohols, for example methanol, ethanol, propanol including n-propanol and
isopropanol, butanol including n-butanol and isobutanol, or ethyleneglycol, acids
20 including aliphatic acids, for example formic acid, acetic acid or trifluoroacetic, and others, for example acetone, butanone, dimethyl sulfoxide or acetonitrile. The term "solvent", as used herein, includes besides a single solvent also a mixture of two or more solvents which may be miscible or partly miscible or immiscible and may form two-drindM pl•fages: The ten ''solvent" thug includes, for example, mixtures of two
25 or more organic solvents, such as mbctures of an ether and an alcohol or mixtures of an ether and a hydrocarbon, and mbctures of one or two or more organic solvents, for example methanol, tetrahydrofuran or dichloromethane, with water. The choice of a suitable solvent which is advantageously used in a specific preparation process, will be made by a person skilled in the art in view of the characteristics of the reaction,
30 the compounds which are employed and obtained, and technical and other aspects. Generally, inert solvents are used which do not undergo unwanted reactions with the employed compounds and agents and/or the obtained compounds. Depending on
 
45
the individual case, it may be preferable to use a solvent which dissolves the
employed compounds and agents and/or the obtained compounds, or a solvent which dissolves the employed compounds and agents and/or the obtained compounds to some extent, or a solvent which only slightly dissolves the employed
5 compounds and agents and/or the obtained compounds. Examples of suitable solvents are given above and below in the explanations on the processes according to the invention.
In various processes according to the present invention a base is employed, for
10 example, to produce a chemical conversion or to deprotonate a compound or liberate
a basic starting compound from its salt or to scavenge an acid formed during a
reaction. Bases that may be used include organic bases, for example amines
including tertiary amines such as triethylamine, tributylamine, ethyldiisopropylamine
or N-rnethylmorpholine, and inorganic bases. Inorganic bases usually are basic
15 compounds of the alkali metals lithium, sodium and potassium and the alkaline earth metals magnesium and calcium and include hydroxides, for example lithium hydroxide, sodium hydroxide, potassium hydroxide or calcium hydroxide, carbonates and hydrogencarbonates, for example sodium carbonate, sodium hydrogencarbonate
or potassium carbonate, alcoholates, for example sodium methanolate, sodium
20 ethanolate, sodium tert-butanolate, potassium methanolate, potassium ethanolate, potassium tert-butanolate, magnesium methanolate, magnesium ethanolate, calcium methanolate or calcium ethanolate, and others, for example sodium hydride, sodium amide, lithium diisopropylamide, Na2HPO4, Na3PO4 or sodium acetate. Besides a single base also mixtures of two or more bases may be used. The choice of a
25 suitable base that is advantageously used in a specific preparation process, will be made by a person skilled in the art in view of the characteristics of the reaction, the compounds which are employed and obtained, and technical and other aspects. Examples of suitable bases are given above and below in the explanations on the processes according to the invention.
30
 
46
In the following, further explanations on the processes according to the present invention are given. In the Schemes below groups like R1, R2, Rr and R2 are defined as above, Boc is tert-butoxycarbonyl, Ph is phenyl and nBu is n-butyl.
5 The compounds of the formula I are prepared by processes according to the present invention as shown in Scheme 1.
 
47
Scheme 1
The phenylethynylsilyl compound of the formula II, wherein G is trimethylsilyl, triethylsilyi, trt-isopropylsilyl, or dimethyl-tert-butylsilyl, is treated with an alkali metal
5 hydroxide, carbonate or alcoholate, for example the respective sodium or potassium
compound, or an alkaline earth metal alcoholate, for example a magnesium or
calcium alcoholate, preferably with potassium carbonate, in a solvent, such as an aliphatic alcohol or a mixture of an aliphatic alcohol and an ether, for example methanol or ethanol or a mixture of methanol and tetrahydrofuran, at a temperature
10 of from about 0°C to about 50°C, preferably of from about 10°C to about 30°C, to give a solution of the corresponding phenylethynyl compound of the formula Ili which phenylethynyl compound is not isolated, thus avoiding the hazards that would be associated with the handling of the unstable phenylethynyl compound. The base can be employed in a catalytic amount, for example in an amount of from about 0.02 to
15 about 0.05 mol per mol of the compound of formula II, or in a greater amount up to an about equivalent amount, for example an amount of from about 0.02 to about 1.1 mot of a monovalent base per mot of the compound of the formula II.
The solution of the phenylethynyl compound is combined with the amide of the
20 formula IV in a solvent, such as an ether, for example tetrahydrofuran, dioxane or 1,2-dimethoxyethane, or dimethyl carbonate, or a mixture of an ether with an aliphatic alcohol such as methanol or ethanol, and reacted In the presence of a homogeneous palladium catalyst, for example Pd(PPI13)2C12, a cuprous salt, for example
copper(I)iodide, copper(l)bromide, copper(l)chloride or copper(l)trifluoromethane-
25 sulfonate, where the cuprous salt can also be formed in situ from a cupric salt, for
example copper(I1)acetate, and a hindered amine, for example triethylamine,
tributylamine, ethyldiisopropylamine, diethylamine, pyrrolidine or piperidine, at a temperature of from about 30°C to about 70°C. The compound of the formula III or II, respectively, is preferably employed in a slight excess, for example in an amount of
30 from about 1 to about 1.5 mol per mol of the compound of the formula IV. The
employed amount of the palladium catalyst and the cuprous salt each preferably is from about 0.005 to about 0.2, more preferably from about 0.005 to about 0.05 mol
 
48
per mol of the compound of the formula IV, and the amount of the hindered amine preferably is from about 1 to about 10, more preferably from about 1 to about 5 mol per nal of the compound of the formula If.
5 Work-up of the reaction mixture can be performed by customary procedures, as applies to all processes of the present invention, including treatment of the organic phase with brine, dilute hydrochloric acid, and aqueous sodium carbonate, to provide the Boo-protected compound of the formula V. In a surprising aspect of the present invention the reagents present in the solution resulting from treatment of the
10 phenylethynylsilyl compound of the formula II do not interfere with the subsequent coupling reaction with the compound of the formula IV.
The Boc-protected compound of the formula V can be used as a storage form of the compound of the formula 1, for example. If it is desired to prepare the compound of
15 the formula I itself or its salt, the compound of the formula V is subsequently
deprotected by splitting off the Boc group and, if applicable, removal of any other protective groups and/or conversion of precursor moieties that may be present in R1'
and/or R2'. Preferably the compound of the formula V is deprotected under acidic conditions, in particular from a compound in which R" and R2' are R1 and R2,
20 advantageously by means of a physiologically acceptable acid such as methane,sulfonic acid, for example, in a solvent such as isopropanol, for example, at a temperature of from about 10°C to about 80°C, to yield the compound of formula I
or its salt, preferably the salt with the acid employed into the deprotection step.
25 The compound of the formula IV can be prepared as illustrated in Scheme 2. When starting from 5-bromo-2-furoic acid or 5-iodo-2-furoic acid of the formula XVIII, wherein X is bromo or iodo, the acid is first activated as outlined above to give an activated acid derivative of the formula XIX wherein Xis bromo or iodo and A is a leaving group, for example chloro or bromo, or the formula XIX represents the adduct
30 obtained form the acid and a condensing agent such as a carbodiimide, or the mixed anhydride obtained from the acid and an alkyl chlorocarbonate. Preferably the acid of the formula XVIII is treated with thionyl chloride in refluxing toluene until gas evolution
 
49
ceases to provide a solution of the acid chloride of the formula XIX wherein A is chloro, which solution may be used, if desired, in the subsequent step without isolation of the acid chloride. The activated acid derivative of the formula XIX is combined with the 4[3-(tert-butoxycarbonylaminomethyl)phenylipiperidine of the
5 formula VI in a solvent, optionally in the presence of a base, for example a tertiary
amine like triethylamine, to provide the corresponding amide of the formula IV, generally at a temperature of from about -10°C to about 40°C, preferably from about 10°C to about 30°C. The 4[3-(tart-butoxycarbonylaminomethyl)phenyllpiperidine of
the formula VI may be liberated from a salt of a compound of the formula VI, for
10 example a salt with p-toluenesulfonic acid, by treatment with a base, for example an alkali metal hydroxide or alcoholate, such as sodium hydroxide, and extracting the compound of the formula VI into a solvent such as, for example, toluene or dichloromethane, followed by drying of the solution.
,X
HO    \    XVIII
 

 
Scheme 2
Previously described processes for the preparation of compounds of the formula I 20 include the process for the preparation of the specific compound 443- (aminomethyl)phenyli-1 -[5-(2-fluorophenylethynyI)-2-furanoyl]piperidine
 
50
methanesulfonic acid salt which is described in WO 2004/060584 (international patent application PCMS2003/040853) and shown in Scheme 3.
y Br CH30 \            Pd(PPh3)2Cl2 Cul
CH30     
               
XX    H Ilia       

XXI
 

 
XXII
XXI I I
5
Scheme 3
According to the previously described process, 2-fluorophenylethyne of the formula Ilia is coupled to methyl 5-bromo-2-furoate of the formula X)( via a palladium
 
51
mediated process. Work-up and chromatography yields methyl 5-(2- fluorophenylethyny1)-2-furoate of the formula XXI, which is saponified and recrystallized to give the respective acid of the formula XXII. Conversion of the acid into the acid chloride of the formula XXIII is accomplished with oxalyl chloride.
5 Acylation of 4[3-(tentbutoxycarbonylaminomethyl)phenyl]piperidine of the formula
Vla which, according to the prior process, is prepared in a tedious process using costly reagents as outlined below, with the acid chloride gives N-Boc-protected 443- (aminomethyl)pheny4-145-(2-fluorophenylethyny1)-2-furanoyfjpiperidine of the formula Va. The crude product is purified by flash chromatography followed by
10 trituration with diethyl ether/pentane or, alternatively, recrystallization. By treatment with methanesulfonic acid the Boc group is removed and 4-[3-(aminomethyl)pheny1]- 145-(2-fluorophenylethynyl)-2-furanoylipiperidine methanesulfonic acid salt of the formula lb is obtained.
15 A substantial drawback of the earlier disclosed processes is the use of phenylethynes as starting materials which are known to be unstable. For example, 2- fluorophenylethyne decomposes violently at approximately 120°C. The use of phenylethynes thus poses a safety hazard, in particular in large scale productions.
The present invention provides advantageous processes which are useful in the
20 preparation of compounds of the formula I and are distinguished by generation of the phenylethyne from the silyl compound in situ without need for isolation of the phenylethyne, thus allowing to avoid the handling of hazardous compounds.
The 4-[3-(tert-butoxycarbonylaminomethyl)phenyl]piperidines of the formula VI useful 25 as intermediates in the processes of the present invention may be prepared by processes of the present invention, for example, as shown in Scheme 4.
 
VI
Scheme 4
5 Accordingly, a 3-iodobenzylamine or 3-bromobenzylamine of the formula VII in the form of its salt, for example the hydrochloride salt, in a solvent, for example a halogenated aliphatic hydrocarbon such as dichloromethane, is treated with an about equimolar amount of 1,2-bis(chlorodimethylsitypethane in the presence of a base, for example a tertiary amine such as triethylamine, preferably at a temperature of from
 
53
about 10°C to' bout 30°C. Work-up of the reaction mixture can be accomplished by filtration, evaporation of the filtrate, and treatment of the residue with an aliphatic or aromatic hydrocarbon, for example pentane, to remove any residual amine salt, to provide the corresponding 3-halobenzyl compound of the formula VIII, i.e., the
5 corresponding 1-(3-bromobenzyI)-2,2,5,5-tetramethy1-1-aza-2,5-disilacyclopentane or 1-(3-iodobenzyI)-2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane.
The compound of the formula VIII is then treated with an alkyllithium compound, for example n-butyllithium, sec-butyllithium, t-butyllithium or hexyllithium, in a solvent, for
10 example an ether such as diethyl ether or tetrahydrofuran, and subsequently with 1- benzy1-4-piperidone at a reduced temperature, such as a temperature of from about
-80°C to about -40°C, for example at about -80°C, to provide the corresponding alcohol of the formula IX, which may be carried forward, if desired, without further purification. The alkyllithium compound and the 1-benzyl-4-piperidone are usually
15 employed in an amount of from about 1 to about 1.2 and about 1 to about 1.1 mol, respectively, per mol of the compound of the formula V111.
The alcohol of the formula IX is then treated with an inorganic acid, for example sulfuric acid, hydrochloric acid or phosphoric acid, preferably phosphoric acid, which
20 may be dilute or concentrated, in a solvent, for example a halogenated aliphatic hydrocarbon such as dichloromethane, in the presence of water, at a temperature of
from about 10°C to about 30°C, to provide the corresponding benzylamine of the formula X as its salt with the employed acid, which may be carried forward, if desired, without further purification.
25
The salt of the benzylamine of the formula X is then dehydrated with a concentrated, non-oxidizing strong acid, for example phosphoric acid, sulfuric acid, trifluoroacetic acid, or toluenesulfonic acid, preferably phosphoric acid, at an elevated temperature, for example at a temperature of from about 70°C to about 150°C, preferably at about
30 100°C, followed by alkalinization with a base such as an alkali metal hydroxide, carbonate or alcoholate, for example sodium hydroxide, to provide the corresponding
 
54
olefin of the formula Xi, which may be carried forward, if desired, without further purification.
The compound of the formula XI is then treated with di-tert-butyl dicarbonate
5 (Boc20), which is generally employed in a slight excess of from about 1 to about 1.2 molar equivalents, in a solvent, for example an aliphatic alcohol such as methanol, ethyl acetate, an ether such as tetrahydrofuran, a halogenated hydrocarbon such as dichioromethane, a mixture of two or more of such solvents or a mixture of one or more of such solvents with water, in the presence of a base, for example an alkali
10 metal hydroxide, carbonate or alcoholate or a tertiary amine, such as sodium
hydroxide or triethylamine, preferably at a temperature of from about 0°C to about 40°C, preferably at a temperature of from about 10°C to about 30°C to provide the I3oc-protected amine of the formula XII.
15 in a favorable manner, achieving simultaneous reduction of the olefinic double bond and removal of the benzyi group, the Boc-protected amine of the formula XII can then be treated with hydrogen at a pressure of from about 200 kPa to about 3000 kPa, in a solvent, for example an aliphatic alcohol such as methanol, ethanol or isopropanol, or ethyl acetate, in the presence of a palladium catalyst, for example palladium on
20 carbon or palladium hydroxide on carbon, for example Pearlmart's catalyst, and an organic or inorganic acid, for example acetic acid, at a temperature of from about 10°C to about 40°C, to provide the corresponding piperidine of the formula VI as its salt with the employed acid. If desired, the salt can then be converted to the 443- (tert-butoxycarbonylaminomethyl)phenyl]piperidine of the forMula VI by treatment
25 with a base, for example an alkali metal hydroxide, carbonate or alcoholate.
As indicated above, in the process for the preparation of the compounds of the formulae XII and VI according to the present invention many intermediates can advantageously be taken to the next reaction step, if desired, without a separate
30 purification step and intermediary Isolation.
 
55
The 4(3-(tert-butoxycarbonylaminomethyl)phenyl]piperidines useful as intermediates in the processes of the present invention also may be prepared by processes of the present invention, for example, as shown in Scheme 5.
Scheme 5
Accordingly, a 3-(4.pyridyl)benzaldehyde of the formula XIII is treated with
10 hydroxylamine or a salt of hydroxylamine, for example hydroxylammonium chloride, sulfate or phosphate, in a solvent, for example an aliphatic alcohol such as methanol, ethanol or isopropanol, optionally in the presence of a base, for example a tertiary amine such as triethylamine, an alkali metal carbonate such as sodium carbonate, or an alkali metal hydrogencarbonate such as sodium hydrogencarbonate, at a
15 temperature of from about 0°C to about 40°C, preferably at a temperature of from about 10°C to about 30°C, to provide the corresponding oxime of the formula XIV, or its salt. The solution of the oxime may be carried forward to the next step, if desired, without further purification.
 
56
The oxime of the formula XIV or its salt, in a solvent, for example a polar organic solvent such as an aliphatic alcohol or a carboxylic acid, for example methanol, ethanol, isopropanol or acetic acid, is then treated with hydrogen at a pressure of from about 300 kPa to about 1500 kPa, for example at about 500 kPa, in the
5 presence of a palladium catalyst, for example palladium on carbon or palladium hydroxide, at a temperature of from about 20°C to about 50°C, for example at about 35°C, to provide the corresponding benzylamine of the formula XV, or its salt. Upon filtration to remove the catalyst, the solution may be used, if desired, without further purification for the next step.
10
The benzylamine of the formula XV or its salt is then treated with di-tert-butyl dicarbonate (00020), which is generally employed in a slight excess of from about 1 to about 1.2 molar equivalents, in a solvent, for example an aliphatic alcohol such as methanol, ethyl acetate, an ether such as tetrahydrofuran, a halogenated
15 hydrocarbon such as dichioromethane, a mixture of two or more of such solvents or a mixture of one or more of such solvents with water, in the presence of a base, for example an alkali metal hydroxide, carbonate or alcoholate or a tertiary amine, such as sodium hydroxide or triethylamine, preferably at a temperature of from about 0°C to about 40°C, preferably at a temperature of from about 10°C to about 30°C, to
10 provide the corresponding Boc-protected amine of the formula XVI, which may be used, if desired, without further purification for the next step.
The 3(4-pyridyl)benzylcarbamic acid tert-butyl ester of the formula XVI in a solvent,
for example an aliphatic alcohol such as ethanol or isopropanol, is then treated with
t5 hydrogen at a pressure of from about 2000 kPa to about 6000 kPa in the presence of a platinum catalyst, for example platinum on carbon or a platinum oxide, for example in the presence of 5% platinum on carbon, at a temperature of from about 20°C to
about 80°C, for example at about 50°C, in the presence of an acid, for example a mineral acid such as hydrogen chloride or sulfuric acid. In a surprising aspect of the
10 present invention, the Boo-protecting group survives the presence of acid in the
reduction mixture. When the absorption of hydrogen is complete, for work-up the
 
57
solvent can be removed in vacuo, followed by treatment of the mixture with aqueous base, for example aqueous sodium hydroxide, and extraction into an organic solvent, for example dichioromethane or toluene. The residue upon evaporation of the solvent, if desired, may then be treated with an acid, for example p-toluenesulfonic
5 acid, to provide the desired piperidine of the formula VI as its salt, for example the salt with p-toluenesulfonic acid.
As outlined above, instead of from a pyridylbenzaldehyde of the formula XIII, by converting it into the oxime and hydrogenating the oxime function, the amine of the
10 formula XV or its salt can further be prepared from a pyridylbenzonitrile of the formula XVII by reducing the nitrite function, for example by catalytic hydrogenation in the presence of a palladium catalyst such as palladium on charcoal or by means of a complex hydride reducing agent. The catalytic hydrogenation of the nitrite function is preferably performed in a solvent, for example an aliphatic alcohol such as methanol
15 or a mixture of an aliphatic alcohol and water, at a temperature of from about 10°C to about 40°C, at a hydrogen pressure of from about 2000 kPa to about 6000 kPa, in the presence of an acid, for example a mineral acid such as hydrochloric acid. The reduction of the nitrile function by means of a complex hydride is preferably performed in a solvent, such as a protic solvent, for example an aliphatic alcohol like
20 methanol or ethanol, when using a complex hydride like sodium borohydride, or an aprotic solvent, for example an ether like tetrahydrofuran, when using a complex hydride like lithium aluminium hydride, at a temperature of from about 0°C to about 50°C. The amine of the formula XV or its salt may be used, if desired, without further purification for the next step in which it is treated with di-tert-butyl dicarbonate as
25 explained above. The starting compounds of the formulae XIII and XVII are commercially available or can be prepared by or analogously to procedures
described in the literature, for example in WO 98/21210, Z.Y. Wang et al., Chin. Chem. Lett. 2003, 14, pages 13-16, or M.A. Massa et al., Bioorg. Med. Chem. Lett 2001, 11, pages 1625-1628.
30
As indicated above, in the processes for the preparation of a compound of the
formula VI from a compound of the formula XIII or XVII according to the present
 
58
invention the intermediates can in an advantageous manner be taken to the next
reaction step, if desired, without a separate purification step and intermediary isolation.
5 According to the processes of the present invention, the 4-[3-(tert-butmcarbonylaminomethyl)phenyllpiperidines of the formula VI can be prepared in a considerably simpler manner and with the use of cheaper reagents than according
to the previously described processes. Previously described processes for the preparation of 4[3-(tert-butoxyearbonylaminomethyl)phenyljpiperidines include that
10 shown in Scheme 6, disclosed in WO 2004/060884 (international patent application PCT/US2003/040653).
 
LIN (Si
\ 2
PhN(SO2CF3)2
OH
Scheme 6
 
60
The first step of the previously described process, protection of the 4-piperidone derivative of the formula XXIV as the N-Teoc (2-(trimethylsilyl)ethoxycarbonyl) derivative of the formula XXV, utilizing in situ generation of the carbamate formed from 1, V-carbonyldiimidazole (CDI) and 2-(trimethylsilyl)ethanol, requires a high
5 vacuum distillation of the product at 156-160°C, as well as the use of the expensive reagent 2-(trimethylsilyl)ethanol. Enolization of the ketone of the formula XXV requires, at a temperature of -78°C, the reaction with lithium bis(trimethylsilyl)amide in tetrahydrofuran, followed by quenching of the enolate with N-phenyl¬bis(trifiuoromethanesulfonimide), another very expensive reagent, to give the vinyl
10 trMate of the formula XXVI. The triflate of the formula XXVI is used in a Suzuki coupling with the expensive reagent 3-cyanophenylboronic acid in the presence of the expensive catalyst tetrakistriphenyiphosphine palladium(0) to give the nitrite of the formula XXVII which must be purified by chromatography. Hydrogenation of both
the nitrite function and the double bond using Pd/C in the presence of hydrogen
15 chloride gives a mixture of the desired amine hydrochloride of the formula XXVIII and the partially reduced nitrite of the formula XXIX. The amine must be washed free of the nitrite and is then converted into the Boo-protected derivative of the formula XXX in the presence of di-tert-butyl dicarbonate (Boc,20). The residual nitrite of the formula XXIX may be converted to the desired amine, and protected as the Boc derivative of
20 the formula XXX in the presence of NiCl2, a toxic reagent, Boc2O, and NaBF14. The Boc derivative of the formula )00( must be isolated and further purified by trituration
with pentane, or it can alternatively be recrystallized from cyclohexane/hexane. Removal of the N-Teoc group with tetra-n-butylammonium fluoride at 50°C gives, after trituration with diethyl ether/pentane, the desired piperidine of the formula Via,
25 i.e., the compound of formula VI wherein R1' is hydrogen.
The prior art process of preparing the piperidine of the formula Via requires low temperature reaction conditions for one step, several chromatography and
purification steps, isolation of intermediates, and the use of toxic and expensive
30 reagents. Processes of the present invention, as described herein, provide the compounds of formula VI using less toxic and less expensive reagents, isolating fewer intermediates, and requiring fewer intermediate purification steps, thereby
 
61
rendering these processes more suitable for the production of commercial quantities of such compounds under economical and technical aspects.
The invention is further explained and illustrated by the following exemplary
5 procedures. These examples should in no way be construed, however, as limiting the scope of the invention.
Example 1 4-13-(tentButoxycarbonylaminomethyfiphenylipiperidine
10
a)    1-(3-Bromobenzyl)-2,2,5,5-tetramethy1-1-aza-2,5-disilacyclopentane
To a stirred suspension of 3-bromobenzylamine hydrochloride (310 g, 1.39 mol) in dichloromethane (2 L) is added triethylamine (437 g, 4.32 mol), followed by a solution
15 of 1,2-bis(chlorodimethylsilyi)ethane (300 9, 1.39 mol) in dichloromethane (700 m4 The resulting suspension is stirred for 30 min and then filtered. The filtrate is concentrated in vacuo and pentane is added. After filtration, the solvent is removed in vacuo to yield the title compound (435 g, 95%) as a colorless oil. 1H NMR (CDCI3) 8 = 7.4-7.1 (m, 4 H), 4.0 (s, 2 H), 0.8 (t, 4 H), 0.2 (s, 12 H).
20
b)    3-(1-Benzyl-1,2,3,6-tetrahydropyridin-4-yfibenzylcarbamic acid tert-butyl ester
To a solution of 1-(3-bromobenzyI)-2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane (435 g, 1.33 mol) in tetrahydrofuran (4 L) is added a 2.5 M solution of n-butyilithium
25 (n-Buts) (609 m1_, 1.52 mol) at -60°C. After 30 min, a solution of 1-benzy1-4- piperidone (276 g, 1.46 mol) in tetrahydrofuran is added at that temperature. After
stirring for a further 30 min, the reaction is quenched by addition of methanol and allowed to warm to room temperature. The solution is concentrated in vacuo to yield the crude alcohol as a sticky brown oil.
30
The crude residue from above is dissolved in dichloromethane (1.5 L). To this solution is added concentrated phosphoric acid (H3PO4) (1 equiv.) and the mixture is
 
62
concentrated in vacuo. The yellowish phosphate is solidified by the addition of heptane and isolated by filtration.
The dried solid from above is added to concentrated Fl3PO4 (1.5 L) and the resulting
5 mixture is heated to 100°C for two hours. After cooling to room temperature, the
solution is diluted with water and extracted with ether. The aqueous layer is then basified with sodium hydroxide. The precipitate is isolated by filtration and is used in the next step without drying.
10 The solid from above is suspended in a mixture of methanol (4 L) and water (2 1) containing sodium hydroxide (10.0 g, 0.25 mol). Boc.20 (290 g, 1.33 mol) is added and the mixture is stirred overnight at room temperature. The solid is isolated by filtration and then dried in vacuo to yield the title compound (390 g, 76%) as a light yellow solid. 1H NMR (CDCI3) 3 . 7.1-7.4 (m, 9 H), 6.03 (m, 1 H), 4.90 (m, 1 H), 4.25
15 (d, 2 H), 3.68 (s, 2 H), 3.18 (m, 2 H), 2.69 (m, 2 H), 2.57 (m, 2 H), 1.42 (s, 9 H). MS intz 379 (M + H), 380 (M + 2H).
c) 4[3-(tert-Butoxycarbonylaminomethyl)phenyl]piperidine acetic acid salt
20 A mixture of 3-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)benzylcarbamic acid tert-butyl ester (190 g, 0.50 mol), Pearlman's catalyst (Pd(01-)2/C) (9.5 g) and acetic acid (60.2 g, 1.0 mol) in methanol is hydrogenated overnight at room temperature, at 345 kPa hydrogen pressure. After filtration and evaporation, the obtained oil is dissolved in diisopropyl ether which-cm-fleas precipitation of the reaction-product. After drying in
25 vacuo, the pure title compound (159 g, 90%) is isolated as a yellowish solid.1H NMR (300 MHz, CDCI3) (m, 4 H), 4.89 (m, 1 H), 4.29 (d, 2 H), 3.42 (m, 2 H), 2.86 (m, 2 H), 2.69 (m, 1 H), 2.05 (s, 3 H), 1.97 (m, 4 H), 1.45 (s, 9 H). MS rrt/z 291 (M + H), 292 (M + 2H).
30 d) 4[3-(tert-Butoxycarbonylaminomethyl)phenApiperidine
 
63
4-0-(tert-Butoxycarbonylaminomethyl)phenyl]piperidine acetic acid salt (147 g,
0.42 mol) is dissolved in dilute hydrochloric acid and the solution extracted with ether. The aqueous phase is basified with sodium hydroxide and extracted with ether. The organic phase is concentrated in vacuo and the product is precipitated from
5 pentane/ether yielding the title compound (105 9, 86%) as an off-white solid.1H NMR (300 MHz, CDCI3) 8= 7.25 (m, 1 H), 7.07-7.13 (m, 3 H), 5.12 (m, 1 H), 4.29 (d, 2 H), 3.17 (m, 3 H), 2.72 (m, 2 H), 2.60 (m, 1 H), 1.81 (m, 2 H), 1.55-1.70 (m, 2 H), 1.46 (s, 9 H). MS (ESI) m/z 291 (M+ + 1, 100).
10 Example 2
4(3-(tert-Butoxycarbonylaminomethyl)phenyl]piperidine p-toluenesulfonic acid salt
a)    3-(4-Pyridyl)benzaldehyde oxime hydrochloride
15 3-(4-Pyridyl)benzaldehyde (100 g, 546 mmol) is dissolved in methanol (500 mL) and then added to a solution of hydroxylamine hydrochloride (402 g, 573 mmol) in methanol (260 mL). After complete conversion a small sample of the reaction mixture
is concentrated in vacuo. MS (DCI) mlz 181.1, 199.1, 200.2.1H-NMR (400 MHz, DMSO-dr) 3 = 7.56 (t, J = 7.7 Hz, 1 H), 7.70-7.75 (m, 3 H), 7.79-7.83 (m, 1 H), 7.97-
20    7.99 (m, 1 H), 8.25 (s, 1 li), 8.65-8.67 (m, 2 H), 11.4 (5, 1 H).
b)    3-(4-Pyridyl)benzylamine hydrochloride
The methanolic solution of 3-(4-pyridyl)benzaldehyde oxime hydrochloride from
25 above is added to palladium on charcoal (13.1 g, 5% Pd/C). The mixture is stirred at
35°C and 500 kPa hydrogen pressure until the consumption of hydrogen ceased.
The catalyst is filtered off. HPLC showed complete conversion. A small sample of the
reaction solution is concentrated in vacuo. MS (DCI) rrilz 185.2, 186.2. 1H-NMR (400
MHz, DMSO-d6) 6 = 4.10 (s, 2 H), 7.54-7.61 (m, 2 H), 7.74-7.77 (m, 2 H), 7.83 (dt,
30 J = 2.1, 6.6 Hz, 1 H), 8.02-8.05 (m, 1 H), 8.53 (bs, 2 H), 8.67-8.70 (m, 2 H).
 
64
c) 3-(4-Pyridyl)benzylcarbamic acid tert-butyl ester
The methanolic solution of 3-(4-pyridyt)benzylamine hydrochloride from above is added to NaHCO, (109 g, 1.30 mol). The mixture is stirred until the evolution of gas
5 ceased. A solution of di-tert-butyl dicarbonate (139 g, 623 mmol) in methanol (450 mL) is added. The mixture is stirred at room temperature until HPLC showed complete conversion. Three quarters of the methanol is distilled off in vacuo. Water (500 mL) is added and the remaining methanol is distilled off in vacuo. The aqueous
layer is extracted with dichloromethane. The solvent is removed in vacuo and the
10 residue is dissolved in ethanol (100 mL). A small sample of the reaction solution is concentrated in vacuo. MS (DCI) m/z 229.3, 285.4, 286.4, 287.4.11-I-NMR (400 MHz, CDCI3) 8 = 1.48 (s, 9 H), 4.37-4.44 (m, 2 H), 4.95 (bs, 1 H), 7.34-7.39 (m, 1 H), 7.42¬7.48 (m, 1 H), 7.48-7.51 (m, 2 H), 7.52-7.56 (m, 2 H), 8.64-8.67 (m, 2 H).
15 d) 4(3-(tert-Butoxycarbonylaminomethyl)phenylipiperidine p-toluenesulfonic acid salt
Charcoal (17 g) is added to half of the above ethanolic solution of 3-(4-pyridyl)benzyl¬carbarnic acid tert-butyl ester from above. The mixture is stirred at room temperature, filtered and the filter is washed with additional ethanol (260 ml). The obtained
20 solution is added to platinum on charcoal (44.7 g, 5% Pt/C). A mixture of conc. hydrochloric acid (31 g) and ethanol (250 mL) is added. The reaction mixture is diluted with ethanol (500 mL) and then hydrogenated at 50°C and a hydrogen pressure of 3000 kPa until the consumption of hydrogen ceased. The catalyst is filtered'off. HPLCshowed complete conversion. Three quarters'of the ethanol is
?5 removed in vacuo. A mixture of water (310 mL) and sodium hydroxide solution (33%, 33 g) is added before the remainder of ethanol is removed in vacua. The aqueous solution is extracted with dichloromethane. The solvent is removed in vacuo and the residue is dissolved in isopropanol (65 mL) and diisopropyl ether (2.8 L). The solution is cooled to 0°C and then a solution of p-toluenesulfonic acid (57.5 g) in isopropanol
30 (260 mt.) is added. The mixture is subsequently stirred at 0°C for 1 h. The precipitate is filtered off, washed with diisopropyl ether and dried in vacuo to give 94.5 g of the title compound as a white solid (overall yield over 4 steps: 77%). MS (ESI) raiz
 
65
29126, 292.28, 293.28. 11-I-NMR (400 MHz, DMSO-d.) 3 = 1.39 (s, 9 H), 1.70-1.95 (m, 4 H), 2.29 (s, 3 H), 2.76-2.85 (rn, H), 2.96-3.05 (m, 2 H), 3.25-3.40 (m, 1 H), 4.08-4.13 (m, 2 H), 7.05-7.14 (m, 4 H), 7.23-7.30 (m, 1 H), 7.36-7.40 (m, 11-1), 7.46¬7.56 (m, 2 H), 8.37 (bs, 2 H).
5
Example 3
3-(4-Pyridyl)benzylamine dihydrochloride
Hydrochloric acid (34.0 g, 30 % w/w) and palladium on charcoal (12.0 g, 10% Pd/C)
10 are added to a solution of 3-(4-pyridyl)benzonitrile (25.0 g, 139 mmol) in
methanol/water (1:1, 250 mL). The mixture is stirred at room temperature and a hydrogen pressure of 3000 kPa until the consumption of hydrogen ceases. The catalyst is filtered off. HPLC shows complete conversion. A sample of the reaction solution is concentrated In vacuo. MS (DC1) mlz 185.3.11-1-NMR (400 MHz, DMS0-
15 d.) S = 4.15 (s, 2 H), 7.62 — 7.66 (m, 1 H), 7.72 (d, J = 7.6 Hz, 1 H), 7.99 (d, J = 7.8
Hz, 1 H), 8.20 (s, 1 H), 8.41 (d, J = 6.5 Hz, 2 H), 8.92 (d, J .= 6.5 Hz, 2 H).
Example 4
413-(tert-Butoxycarbonylaminomethyl)pheny11-145-bromo-2-furanoyl]piperidine
20
To a suspension of 443-(tert-butoxycarbonylaminomethyl)phenylipiperldine p¬toluenesulfonic acid salt (185 g, 0.40 mol) in toluene is added aqueous sodium hydroxide (1.1 equiv.) and the mixture is stirred at room temperature for 30 min. The phases are separated and the toluene layer is washed with water. It is dried
25 azeotropically by distilling off part of the toluene. To this solution is added triethylamine (72 mL, 0.52 mot). This mixture is used directly in the next step.
To a refluxing suspension of 5-bromo-2-furoic acid (80.8 g, 0.44 mol) in toluene (400 mL) is added thionyl chloride (37 mL, 0.52 mol). The mixture is refluxed for a
30 further 30 min, then concentrated by distilling off part of the solvent. The obtained solution is cooled to room temperature and added to the solution of amines from above. After stirring for one hour, water is added, the organic layer is separated and
 
66
diluted with heptane. The solid is filtered off and dried in vacuo. Recrystallization of the crude product from isopropand/water yields the pure title compound (143 g, '77%) as an off-white solid. 'H NMR (400 MHz, I)MSO-d6) S = 7.34 (m, 1 H), 7.24 (t, J = 7.6 Hz, 1 1-1), 7.12 (m, 2 H), 7.06 (m, 1 H), 7.02 (d, J = 3.4 Hz, 1 H), 6.75 (d, J = 3.4 Hz, 1
5 II), 4.40 (bs, 2 H), 4.10 (d, J = 6.1 Hz, 2 H), 3.25-2.90 (bs, 2 H), 2.87-2.79 (m, 1 H), 1.83 (m, 2 H), 1.63-1.53 (m, 2 H), 1.39 (s, 9 H). MS (ESI) m/z 363 (M+ -100, 100).
Example 5 4[3-(tert-Butoxycarbonylaminomethyl)pheny1]-145-(2-fluorophenylethyny1)-2- 10 foranoylipiperidine
A solution of (2-fluorophenylethynyptrimethylsilane (68.0 g, 0.35 mol) in methanol (40 mL) is added to a suspension of K2CO3 (0.76 9, 5.51 mmol) in methanol (40 mL). The solution is stirred for 30 min at room temperature and then added to a mixture of
15 443-(tert-butoxycarbonylaminomethyl)pheny1)-145-bromo-2-furanoyl]piperldine
(126 g, 0.27 mol), Pd(PPh3)2Cl2 (3.90 g, 5.56 mmol), Cul (1.0 g, 5.25 mmol) and triethylamine (94 mL) in tetrahydrofuran (550 mL). The reaction mixture is refluxed for one hour. An aqueous solution of the trisodium salt of trimercaptotriazine (0.2 equiv.) is introduced and the mixture refluxed for an additional hour. After cooling to room
20 temperature, brine is added, the organic phase separated and washed successively with dilute hydrochloric acid and sodium carbonate solution. The organic phase is refluxed with charcoal for 30 min, filtered and concentrated in vacuo. The resulting brown oil is dissolved in dichloromethane (400 mL) and stirred overnight at room ternperaturewith Deloxans THP 11(135 g). After filtration the solvent is evaporated
25 and the product crystallized from isopropanol/diisopropyl ether to yield the title compound (74.6 g, 55%) as a yellow powder. 1H NMR (300 MHz, CDCI3) 8 = 7.53 (td, 1 H), 7.41-7.28 (m, 2 H), 7.18-7.08 (m, 5 H), 7.04 (d, 1 H, J = 3.6 Hz), 6.76 (d, 1 H, J = 3.6 Hz), 4.83 (bs, 1 H), 4.72 (bm, 2 H), 4.31 (d, 2 H, J = 5.6 Hz), 3.1 (bs, 1 H), 2.82 (m, 2 H), 1.96 (m, 2 H), 1.79 (td, 2 H, J = 12.8, 4.0 Hz), 1.46 (s, 9 H). MS (ESI) m/z
30 503 (M+ + 1, 100).
Example 6
 
67
4-[3-(Aminornethyl)pheny1]-115-(2-fluorophenylethyny)-2-furanoyfjpiperldine methanesulfonic acid sett
To a solution of 443-(tert-butoxycarbonylaminomethyflphenyli-1-[5-(2-
5 fluorophenylethynyl)-2-furanoyl]piperidine (67.4 g, 0.13 mop in isopropanol (350 mL) is added methanesulfonic acid (13.5 g, 0.14 mol) at 79°C. The mixture is stirred at that temperature for three hours and then cooled slowly to room temperature. The precipitate is filtered off, washed with acetone and dried in vacuo. Recrystallization of the crude product from aqueous isopropanolkliisopropyi ether yields the analytically
10 pure title compound (56.5 g, 84%). 1H NMR (300 MHz, DMS0-4) S = 8.12 (bs, 3 H), 7.67 (tm, 1 H, J = 7.5 Hz), 7.54 (qm, 1 H, J = 7.0 Hz), 7.42-7.26 (m, 8 H), 7.10 (m, 2 H), 4,34 (bs, 2 H), 4.02 (q, 2 H, J = 5.5 Hz), 3.5-2.7 (bs, 2 H), 2.89 (m, 1 H), 2.34 (s, 3 H), 1.87 (m, 2 H), 1.65 (m, 2 H). MS (ESI) rniz 403 (M* + 1, 100).
15 Example 7 4-(5-(tert-Butoxycarbonylaminomethyl)-2-fluorophenyl]piperidine
The title compound is prepared analogously to the preparation of 443-(tert-butoxy¬carbonylaminomethyl)phenylipiperidine described in example 1. Briefly, in step a) 3-
20 bromo-4-fluorobenzylamine hydrochloride is converted into 1-(3-bromo-4- fiuorobenzy1)-2,2,5,5-tetramethy1-1-aza-2,5-disilacyclopentane. In step b) the latter compound is reacted with n-BuLi and 1-benzy1-4-piperidone at -75°C to -70°C to give 143-(1-benzy1-4-hydroxypiperidln-4-y1)-4-fluorobenzy1]-2,2,5,5-tetramethyl-1-aza-2,5- disilacyclopentane which, by treatment with phosphoric acid, is converted into 3-(1-
25 benzyl-4-hydroxypiperidin-4-yl)-4-fluorobenzylamine (as phosphoric acid salt) and subsequently into 3-(1-benzy1-1,2,3,6-tetrahydroppidin-4-y1)-4-fluorobenzylamine. Reaction with Boc2O then gives 3-(1-benzy1-1,2,3,13-tetrahydropyridin-4-y1)-4- fluorobenzylcarbamic acid tert-butyl ester. In step c) the latter compound is hydrogenated to give 4[5-(tert-butoxycarbonylaminomethyl)-2-fluorophenyl]piperidine
30 acetic acid sett which is purified by trituration with tert-butyl methyl ether. In step d) the said acetic acid salt is converted into 4[5-(tert-butoxycarbonylaminomethyl)-2- fluorophenyllpiperldine which is precipitated from pentane as a white solid. 1H NMR
 
68
(300 MHz, CDCI3) 8 = 7.10 (m, 2 H), 6.95 (m, 1 H), 4.84 (bs, 1 H), 4.26 (d, 2 H, J = 5.6 Hz), 3.18 (d, 2 H, J = 12.0 Hz), 2.95 (m, 1 H), 2.77 (m, 2 H), 1.81 -1.48 (m, 5 H), 1.46 (s, 9 H). MS (ESI) miz 309 (M + H).
 
69
Claims
1. A process for the preparation of a compound of the formula I,
5     

wherein
Ri is H, F, CF3, OCF3, (Ci-Cs)-alkyl, (C3-Cio)-cycloalkyl, 3-membered to 10-membered heterocycloalkyl comprising 1, 2 or 3 identical or different ring
10 heteroatoms chosen from nitrogen, oxygen and sulfur, (Cs-C14)-aryl, (Ci-Cs)-alkoxy, (Cs-Cis)-cycloalkoxy, (Cs-C14)-arYloxY, di((Ci-Cs)-alkyl)amino, di((C3-C10)- cycloalkyl)amino or di((es-C14-aryl)amino; and
R2 is H, F, CF3, OCF3, (Ci-Cs)-alkyl, (C3-C1o)-cycloalkyl, 3-membered to 10-membered heterocycloalkyl comprising 1, 2 or 3 identical or different ring
15 heteroatoms chosen from nitrogen, oxygen and sulfur, (Cs-C14)-aryl, 5-membered to 10-membered heteroaryl comprising 1, 2 or 3 identical or different ring heteroatoms chosen from nitrogen, oxygen and sulfur, (Ci-Ce)-alkoxy, (C3-C10)-cycloalkoxy, (C5-
C14)-aryloxy, 5-membered to 10-membered heteroaryloxy comprising 1, 2, or 3 identical or different ring heteroatoms chosen from nitrogen, oxygen and sulfur,
20 dt((Ci-C8)-alkyl)arnino, di-((Cs-Cio)-cycloalkyl)amino or diRCe-Cis)-aryDamino; or its salt,
comprising
a) treating a phenyiethynylsilane compound of the formula II,
25
 
     G    II    70

wherein G is trimethylsilyl, triethylsilyl, tri-isopropyisilyl, or dimethyl-tert-butylsilyl, and
R2' is R2 as defined above or is a protected derivative thereof or precursor moiety
5 thereto, in a solvent with an alkali metal hydroxide, carbonate or alcoholate or an alkaline earth metal alcoholate, to form a solution of a phenylethyne of the formula Ill;
     H    Ili

10 and
b) combining the resulting solution of the phenylethyne with a compound of the formula IV,
 

 
wherein X is bromo or iodo, R1' is R1 as defined above or is a protected derivative thereof or precursor moiety thereto, and Boc is tert-butoxycarbonyl, in the presence of homogeneous palladium catalyst, a cuprous salt, and a hindered amine in a solvent to form a protected compound of the formula V,
20
 
71
 

 
wherein R1' and R2' are RI and R2, respectively, as defined above or are a protected derivative thereof or precursor moiety thereto, and Boc is tert-butoxycarbonyl, or its 5    salt.
2. A process according to claim 'I for the preparation of 443-(aminomethyl)pheny1]-1- [5-(2-fluorophenylethynyl)-2-furanoylipiperidine of the formula la,
10         la

or its salt,
comprising
15 a) treating a (2-fluorophenylethynyl)sily1 compound of the formula lia,
 
72
wherein G is trimethylsilyl, triethylsilyl, tri-isopropylsilyl, or dimethyl-tert-butylsilyl, in a solvent with an alkali metal hydroxide, carbonate or alcoholate or an alkaline earth metal alcoholate to form a solution of 2-fluorophenylethyne; and
5 b) combining the resulting solution of 2-fluorophenylethyne with a compound of the formula IVa,
NHBoc    N    \ i
3,,c0xx
IVa
10 wherein Xis bromo or iodo, and Boc is tert-butoxycarbonyl, in the presence of homogeneous palladium catalyst, a cuprous salt, and a hindered amine in a solvent to form 4[3-(tert-butoxycarbanylaminomethAphenyl]-1[5-(2-fluomphenylethyny1)-2- furanoyl]piperidine of the formula Va,
15
wherein Boc is tert-butoxycarbonyl.
3.    A process according to claim 1 or 2 wherein G is trimethylsilyl. 20
4.    A process according to any one of claims 1 to 3 wherein Xis bromo.
5.    A process according to any one of claims 1 to 4, further comprising removal of the tert-butoxycarbonyl group and other protecting groups and/or conversion of precursor
 
73
moieties present in a compound of the formula V or Va to provide a compound of the formula I or Ia or its salt.
6. A process according to any one of claims 1 to 5, further comprising removal of the 5 tert-butoxycarbonyl group from a compound of the formula V or Va in the presence of an acid to provide a compound of the formula I or Ia or its salt.
7, A process according to any one of claims 1 to 8, further comprising removal of the tert-butoxycarbonyl group from 4[3-(tert-butoxycarbonylaminomethyl)pheny1]-145-(2-
10 fluorophenylethyny1)-2-furanoygpiperidine in the presence of methanesulfonic acid to provide the methanesuffonic acid salt of 4.-[3-(aminomethyl)phenyl]-145-(2- fluorophenylethyny1)-2-furanoyl]piperidine.
8. A process for the preparation of a compound of the formula IV,
15
 

 
wherein
FIr is H, F, CF3, OCF3,    (C3-Cio)-cycloalkyl, 3-membered to 10-
20 membered heterocycloalkyl comprising 1, 2 or 3 identical or different ring heteroatoms chosen from nitrogen, oxygen and sulfur, (Cs-GO-aryl, (Ca-CO-alkoxy, (C3-G1oycycloalkoxy, (Ce-G14)-aryloxy, di((Gi-CO-alkyl)amino, di((C3-Cio)- cycloalkyl)amino or di((C6-C14)-aryl)amino, or a protected derivative thereof or precursor moiety thereto; and
25 X is bromo or iodo,
comprising
 
74
a)    activating 5-bromo-2-furoic acid or 5-iodo-2-furoic acid to provide an activated form of 5-bromo-2-furoic acid or 5-ioclo-2-furoic acid; and
b)    combining the activated form of 5-bromo-2-furoic acid or 5-iodo-2-furoic acid with a 5 compound of the formula VI,
 

 
wherein R1 is as defined for formula IV and Boo is tert-butoxycarbonyl, in a solvent.
10
9.    A process according to claim 8 wherein R1 is hydrogen.
10.    A process according to claim 8 or 9 for the preparation of the compound of the formula Bic,
15
 

 
wherein Boc is tert-butoxycarbonyl,
20 comprising
a)    treating 5-bromo-2-furoic acid with thionyl chloride to provide 5-bromo-2-furoyl chloride, and
b)    combining the 5-bromo-2-furoyl chloride with the compound of the formula Vla
 
75
NHBoc
Vla
wherein Boc is tert-butoxycarbonyl, in a solvent in the presence of base. 11. A process for the preparation of a compound of the formula VI
 

 
10 wherein Rv is H, F, CF3, OCF3, (C1-C8)-alkyl, (C3-C10-cycloalkyl, 3-membered to 10-membered heterocycloalkyl comprising 1, 2 or 3 identical or different ring heteroatoms chosen from nitrogen, oxygen and sulfur, (Cs-C14)-aryl, (C1-C8)-alkoxy, (C3-C10)-cycloalkoxy, (CrC14)-aryfoxy, di((Ci-Cs)-alkyl)amino, di((C3-Cio)- cycloallcyl)amino or di((Cs-C14)-aryl)amino, or a protected derivative thereof or
15 precursor moiety thereto; and
Boc is tert-butoxycarbonyl,
or its salt,
comprising
20 a) treating a salt of a 3-halobenzylamine of the formula VII,
 
X'
with 1,2-bis(chlorodimethylsitypetbane in a solvent in the presence of a base to provide a 1-(3-halobenzy1)-2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentene of the 5 formula VIII;
 

 
b) treating the 1-(3-halobenzyl)-Z2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane of
10 the formula VIII in a solvent with an alkyllithium compound and 1-benzy1-4-piperidone at a temperature of from about -80°C to about -40°C to provide an alcohol of the formula IX;
 

 
15
c) treating the alcohol of the formula IX with an acid in a solvent to provide a hydroxypiperidinylbenzylamine of the formula X
 
as the salt of the acid;
5 d) treating the hydroxypiperidinylbenzylamine of the formula X or its salt with a concentrated, non-oxidizing acid at a temperature of from about 70°C to about 150°C, followed by alkalinization to provide an olefin of the formula XI;
 

 
`Ph
e) treating the olefin of the formula Xi with di-tert-butyl dicarbonate in a solvent in the presence of a base to provide a protected amine of the formula XII
 
78
wherein Boc is tert-butoxycarbonyl, and where Ph in the formulae IX, X, XI and XII is phenyl, X' in the formulae VII and VIII is bromo or iodo, and Ry in the formulae VII, VIII, IX, X, X1 and XII is as defined for formula V1.
5
12. A process according to claim 11 for the preparation of 443-(tert-butoxycarbonylaminomethyl)phenygpiperidine or its salt,
comprising
10 a) treating 3-bromobenzylamine hydrochloride or 3-iodobenzylamine hydrochloride with 1,2-bis(chlorodimethylsilyl)ethane in a halogenated aliphatic hydrocarbon in the presence of a tertiary amine to provide the corresponding 1-(3-halobenzy1)-2,2,5,5- tetramethy1-1-aza-2,5-disilacyclopentane, where halo is bromo or iodo;
15 b) treating the 1-(3-halobenzy1)-2,2,5,5-tetramethyl-l-aza-2,5-disilacyclopentane in an ether with an alkyllithium compound and 1-benzy1-4-piperidone at a temperature of from about -80°C to about -40°C to provide 143-(1-benzy1-4-hydroxypiperidin-4- yl)bertzyg-2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane;
20 c) treating the 1-[3-(1-benzy1-4-hydroxypiperidin-4-y1)benzyl]-2,2,5,5-teb-amethyl-1- aza-2,5-disilacyclopentane with an inorganic acid in a halogenated hydrocarbon to provide 3-(1-benzy1-4-hydroxypiperidin-4-Abenzylamine as the salt of the inorganic acid;
25 d) treating the 3-(1-benzyl-4-hydroxypiperidin-4-yl)benzylamine with a concentrated, non-oxidizing acid at a temperature of from about 70°C to about 150°C, followed by alkalinization to provide 3-(1-benzy1-1,2,3,6-tetrahydropyridin-4-yl)benzylamine; and
e) treating the 3-(1-benzy1-1,2,3,6-tetrahydropyridin-4-yl)benzylamine with di-tert-
30 butyl dicarbonate in an aliphatic alcohol, ethyl acetate, an ether, a halogenated hydrocarbon, a mixture of two or more of such solvents or a mixture of one or more of such solvents with water, in the presence of an alkali metal hydroxide, carbonate or
 
79
alcoholate or a tertiary amine to provide 3-(1-benzy1-1,2,3,6-tetrahydropyridin-4- Abenzylcarbamic acid tert-butyl ester.
13.    A process according to claims 11 or 12, further comprising treating the amine of 5 the formula XII with hydrogen in a solvent in the presence of a palladium catalyst and in the presence of an acid to provide a compound of the formula VI or its salt.
14.    A process for the preparation of a compound of the formula VI,
10         NHBoc    VI

wherein Rt is H, F, CF3, OCF3,    (C3-C1o)-cycloalkyl, 3-membered to 10-
membered heterocycloallwl comprising 1, 2 or 3 identical or different ring beteroatoms chosen from nitrogen, oxygen and sulfur, (CB-C14)-aryl, (CrCa)-alkoxy,
15 (GrCio)-cycloalkoxy, (C6-C14)-aryloxy, di((Ci-C8)-alkyl)amino, di((03-Cio)- cycloalkyparnino or di((C6-C14)-aryl)amino, or a protected derivative thereof or precursor moiety thereto; and
Boo is tert-butoxycarbonyl,
or its.salt,
20
comprising
a) treating a 3-(4-pyridyl)benzaidehyde of the formula XIII,
 
with hydroxylamine or a salt of hydroxylamine in a solvent to provide an oxime of the formula XIV or its salt;
5
 

 
b) treating the oxime of the formula XIV or its salt with hydrogen in a solvent in the presence of a palladium catalyst to provide a 3-(4-pyridyl)benzylamine of the formula 10 XV or its salt
 

 
c) treating the 3-(4-pyridyl)benzylamine of the formula XV or its salt with di-tert-butyl 15 Bicarbonate in a solvent in the presence of a base to provide a Boc-protected 344- pyridyl)benzylamine of the formula XVI,
 
wherein Boo is tert-butoxycar'oonyl; and
5 d) treating the Boc-protected 3-(4-pyridyhbenzylarnine of the formula XVI with hydrogen in a solvent in the presence of a platinum catalyst and in the presence of an acid to provide a compound of the formula VI or its salt;
where R1. in the formulae XIII, XIV, XV and XVI is as above defined for formula VI.
'0
15. A process according to claim 14 for the preparation of 4-13-(tert-butoxycarbonylaminomethyl)phenylipiperidine or its salt,
comprising
5 a) treating 3-(4-pyridyhbenzaldehyde with hydroxylamine or a salt thereof in an aliphatic alcohol at a temperature of from about 0°C to about 40°C to provide 3-(4- pyridyhbenzaldehyde oxime or its salt;
b)    treating the 3-(4-pyridyl)benzaldehyde oxime or its salt with hydrogen at a
D pressure of from about 300 kPa to about 1500 kPa in an aliphatic alcohol in the presence of a palladium catalyst at a temperature of from about 20°C to about 50°C to provide 3-(4-pyridyl)benzylamine or its salt;
c)    treating the 3-(4-pyridyl)benzylamine or its salt with di-tert-butyl dicarbonate in an aliphatic alcohol, ethyl acetate, an ether, a halogenated hydrocarbon, a mixture of two or more of such solvents or a mixture of one or more of such solvents with water,
 
82
in the presence of an alkali metal hydroxide, carbonate or alcoholate or a tertiary amine to provide 3-(4-pyridyl)benzylcarbamic add tart-butyl ester; and
d) treating the 3-(4-pyridyl)benzylcarbamic acid tert-butyl ester with hydrogen in a 5 aliphatic alcohol at a pressure of from about 2000 kPa to about 6000 kPa in the presence of a platinum catalyst and in the presence of an acid.
16. A process for the preparation of a compound of the formula VI
10
wherein Ry is H, F, CF3, OCF3, (Ci-Cs)-alkyl, (C3-C10)-cycloalkyl, 3-membered to 10-membered heterocycloalkyl comprising 1, 2 or 3 identical or different ring heteroatoms chosen from nitrogen, oxygen and sulfur, (Cs-Ci4)-aryl, (Ci-C8)-alkoxy,
15 (C3-Cie)-cycloalkoxy, (C8-C14)-aryloxy, di((Ci-C8)-alkyl)amino, di((C3-Cio)- cycioalkyl)amino or di((C6-C14)-aryl)amino, or a protected derivative thereof or precursor moiety thereto; and
Boc is tert-butoxycarbonyl,
or its salt,
to
comprising
a) treating a 3-(4-pyridyl)benzonitrile of the formula XVII,
 
with hydrogen in the presence of a palladium catalyst and in the presence of an acid, or with a complex hydride, in a solvent to provide a 3-(4-pyridyl)benzylamine of the
5 formula XV or its salt
 

 
b) treating the 3-(4-pyridyl)benzylamine of the formula XV or its salt with di-tea-butyl 10 dicarbonate in a solvent in the presence of a base to provide a Boo-protected 344- pyridyl)benzylamine of the formula XVI,
 

 
15 wherein Boc is tert-butoxycarbonyl; and
 
84
c) treating the Boo-protected 3-(4-pyridyl)benzylamine of the formula XVI with hydrogen in a solvent in the presence of a platinum catalyst and in the presence of an acid to provide a compound of the formula VI or its salt;
5 where R1' in the formula XV, XVI and XVII is as above defined for formula VI.
17. A process according to claim 16 for the preparation of 443-(tert-butoxycarbonylaminomethyl)phenyl]piperidine or its salt,
10 comprising
a)    treating 3-(4-pyridyl)benzonitrile with hydrogen in the presence of a palladium catalyst at a pressure of from about 2000 kPa to about 6000 kPa in an aliphatic alcohol or a mixture of an aliphatic alcohol and water, or with a complex hydride in an aliphatic alcohol or an ether, at a temperature of from about 0°C to about 50°C, to
15 provide 3-(4-pyridyl)benzylamine or its salt;
b)    treating the 3-(4-pyridyl)benzylamine or Its salt with di-tert-butyl dicarbonate in an aliphatic alcohol, ethyl acetate, an ether, a halogenated hydrocarbon, a mixture of two or more of such solvents or a mixture of one or more of such solvents with water,
20 in the presence of an alkali metal hydroxide, carbonate or alcoholate or a tertiary amine, to provide 3-(4-pyridyl)benzycarbannic acid tert-butyl ester; and
c)    treating the 3-(4-pyridyl)benzylcarbamic acid tert-butyl ester with hydrogen in an aliphatic alcohol at a pressure of from about 2000 kPa to about 6000 kPa in the 25 presence of a platinum catalyst and in the presence of an acid.
18. A compound of the formula VIII,
 
wherein Ry is H, F, CF3, OCF3, (C1-CO-alkyl, (C3-Cro)-cycloalkyl, 3-membered to 10-membered heterocycloalky! comprising 1, 2 or 3 identical or different ring
5 heteroatoms chosen from nitrogen, oxygen and sulfur, (Ce-C14)-aryl, (C1-CO-alkoxy,
(C3eio)-cycloalkoxy, (Ca-C14)-arYloxY,    di((C3-CIO)-cycloalkyl)amino or dk(C8-C14)-aryDamino, or a protected derivative thereof or
precursor moiety thereto.
10 19. A compound according to claim 18 which is 1-(3-bromobenzyI)-2,2,5,5- tetramethyl-l-aza-2,5-clisilacyclopentane.
20. A compound of the formula IX,
5
wherein R1' is H, F, CF3, OCF3,    (C3-C10)-cycloalkyl, 3-membered to 10-
membered heterocycloalkyl comprising 1, 2 or 3 identical or different ring heteroatoms chosen from nitrogen, oxygen and sulfur, (C6-C14)-aryl, (C1-C8)-alkoxy,
3 (C3-Cio)-cycloalkoxy, (Cs-C14)-aryloxy, di((Gi-CO-alkyl)amino, di((C3-C10)- cycioalkyl)amino or di((Ce-C14)-aryl)amino, or a protected derivative thereof or precursor moiety thereto; and Ph is phenyl.
 
86
21.    A compound according to claim 20 which is 1-13-(1-benzy1-4-hydroxypiperidin-4- yl)benzy11-2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane.
22.    A compound of the formula X, 5
R1
NI-I2
X
wherein R1' is H, F, CF3, ocr,,    (C3-GI6)-cycloalkyl, 3-membered to 10-
membered heterocycloalkyl comprising 1, 2 or 3 identical or different ring
10 heteroatoms chosen from nitrogen, oxygen and sulfur, (C6-C14)-aryl, (C7-CO-alkoxy, (C3Cis)-cycloalkoxy, (C6-Ci4)-arYloxY, di((Ci-C8)-alkyl)amino, dff(CrGio)-
cycloalkyl)amino or dff(Ce-C14)-arypamino, or a protected derivative thereof or precursor moiety thereto; and Ph is phenyl, or its salt.
15 23. A compound according to claim 22 which is 3-(1-benzy1-4-hydroxypiperidin-4- yl)benzylannine or its salt
24. A compound of the formula XI,
 
87
 
wherein ar is H, F, CF3, 00E3,    (C3-Cio)-cycloalkyl, 3-membered to 10-
membered heterocycloalkyl comprising 1, 2 or 3 identical or different ring
heteroatoms chosen from nitrogen, oxygen and sulfur, (Cs-C14)-aryl, (Ci-Cs)-alkoxy,
5 (C3-C10)-cycloalkoxy, (C6-C14)-aryloxy, di((Ci-C8)-alicyl)amino, di((C3--Cio)- cycloalicyl)amino or di((C6-C14)-aryl)amino, or a protected derivative thereof or precursor moiety thereto; and Ph is phenyl, or its salt.
25.    A compound according to claim 24 which is 3-(1-benzy1-1,2,3,6-tetrahydropyridin¬10 4-yl)benzylamine or its salt.
26.    A compound of the formula XII,
 

 
15
wherein Fe' is H, F, CF3, OCF.,    (C3-C10)-cycloalkyl, 3-membered to 10-
membered heterocycloalkyl comprising 1, 2 or 3 identical or different ring heteroatoms chosen from nitrogen, oxygen and sulfur, (C6--C14)-aryl, (Ci-Cs)-alkoxy, (C3-C10)-cycloalkoXy, (C6-C14)-aryloxy, di((ei-C.)-alkyl)arnino, di((Cy-Cio)-
20 cycloalkyDamino or di((C6-C14)-aryl)amino, or a protected derivative thereof or precursor moiety thereto; Boc is tert-butoxycarbonyl; and Ph is phenyl, or its salt.
27.    A compound according to claim 26 which is 3-(1-benzy1-1,2,3,6-tetrahydropyridin¬4-yl)benzylcarbamic acid tert-butyl ester or its salt.
25
28.    A compound of the formula XIV,
 
wherein RT is H, F, CF3, OCF3, (C1-Cs)-alkyl, (C3-Cio)-cycloalkyl, 3-membered to 10-
5 membered heterocycloalkyl comprising 1, 2 or 3 identical or different ring heteroatoms chosen from nitrogen, oxygen and sulfur, (Cs-OW-aryl, (C1-C9)-alkoxy, (C3-Cio)-cycloalkoxy, (Ce-C14)-aryloxy, di((CI-Ca)-alkyl)amino, di((C3-C1o)-
cycloalky0amino or di((C6-C14)-aryl)amino, or a protected derivative thereof or precursor moiety thereto, or its salt.
10
29.    A compound according to claim 28 which is 3-(4-pyridyl)benzaldehyde oxime or its salt.
30.    A compound of the formula XV,
15
 

 
wherein Ftv is H, F, CF3, OCF3, (C1-C8)-alkyl, (C3-C13)-cycloalkyl, 3-membered to 10-membered heterocycloaikyl comprising 1, 2 or 3 identical or different ring
20 heteroatoms chosen from nitrogen, oxygen and sulfur, (C6-C14)-aryl, (C1-C3)-alkoxy, (C3-C10)-cycloafkoxy, (Cs-C14)-aryloxy, di((Ci-Cs)-alkyi)amino, di((C3-Cio)-
 
89
 
cycloalkyl)amino or diqC6-C14)-aryl)amino, or a protected derivative thereof or precursor moiety thereto, or its salt.
31.    A compound according to claim 30 which is 3-(4-pyridyl)benzylamine or its salt. 5
32.    A compound of the formula XVI,
 

 
10 wherein R1 is H, F, CF3, OCF3, (Ci-C3)-alkyl, (C3-C10)-cycloalkyl, 3-membered to 10-membered heterocycloalkyl comprising 1, 2 or 3 identical or different ring heteroatoms chosen from nitrogen, oxygen and sulfur, (Cs-C14)-aryl, (C1-C8)-alkoxy, (C3-Coo)-cycloalkoxy, (Cs-C14)-aryloxy, di((ei-C8)-alkyl)amino, di((C3-C1o)- cydoalkyl)amino or di((C5-C14)-aryl)amino, or a protected derivative thereof or
15 precursor moiety thereto; and Boc is tert-butoxycarbonyl, or its salt
33. A compound according to claim 32 which is 3-(4-pyridyl)benzylcarbamic acid tart-butyl ester or its salt.
20 34. A compound of the formula IVb,
 
90
wherein R1' is H, F, CF3, OCF3, (C1-G3)-alkyl, (C3-C,o)-cycloalkyl, 3-membered to 10-membered heterocycloalkyl comprising 1, 2 or 3 identical or different ring heteroatoms chosen from nitrogen, oxygen and sulfur, (C8-C14)-aryl, (C1-C8)-alkoxy, (C3-C10)-cycloalkoxy, (CG-C14)-aryloxy, di((CI-C8)-alkyl)amino, di((C3-C1o)-
5
cycloalkyl)amino or di((C6-C14)-aryl)amino, or a protected derivative thereof or precursor moiety thereto;
and Boc is tert-butoxycarbonyl,
or its salt.
10 35. A compound according to claim 34 which is 443-(tert-butoxycarbonylaminomethyl)pheny1]-145-bromo-2-furanoyfJpiperidine.
38. The use of a compound as claimed in any one of claims 18 to 35 as an Intermediate for the preparation of a compound of the formula I,
15
 
wherein
R1 is H, F, CF3, OCF3, (Cy-CO-alkyl, (C3-C10)-cycloalkyl, 3-membered to 10-
20 membered heterocycloalkyl comprising 1, 2 or 3 identical or different ring heteroatoms chosen from nitrogen, oxygen and sulfur, (Cs-C14)-aryl, (C1-C8)-alkoxy, (C3-C13)-cycloalkoxy, (C6-C14)-aryloxy, di((C1-C3)-alkyl)amino, di((C3-C10- cycloalkyl)amino or di((C6-C14)-aryl)amino; and
R2 is H, F, CF3, OCF3, (C1-C3)-alkyl, (C3-C10)-cycloalkyl, 3-membered to 10-
25 membered heterocycloalkyl comprising 1, 2 or 3 identical or different ring heteroatoms chosen from nitrogen, oxygen and sulfur, (C6-C14)-aryl, 5-membered to 10-membered heteroaryl comprising 1, 2 or 3 identical or different ring heteroatoms
 
91
 
chosen from nitrogen, oxygen and sulfur, (C1-C8)-alkoxy, (Cs-Cio)--cycloalkoxy, (C6¬C14)-aryloxy, 5-membered to 10-membered heteroaryloxy comprising 1, 2, or 3 identical or different ring heteroatoms chosen from nitrogen, oxygen and sulfur, di((Ci-CO-alkyl)amino, di-((C3-C10)-cyc.loalkyl)amino or di((Cn-C14)-aryl)amino;
5    or its salt.
 
indexation.Ist tags.Ist
 
(11) Patent Number: ICE 274 (45) Dan of grant 04/09/2008
-01111111111
(19) Kenya Industrial Property Institute.
(12) PATENT
(51) Int.C1.: CO7D 405/10

(21)Application    KE/P/ 2005/ 000393
Number:
(22) Filing Date:    18/02/2005
(31) Priority Number: 04004799.5 02/03/2004 EP and 60/585,745 06/07/2004 US    (84) WO No. 2005/095385 Al
13/10/2005
(32) Date: (33) Country:
(73) Owner(s): Aventis Pharnia Deutschland GMBH of Bruningstrasse 50, 95929 Frankfurt, Germany
(72) Inventor(s)    GRAF, Claus-Dieter; TAPPERTZHOFEN, Christoph
and SLEDESKI, Adam, W
(74)Agent/address for correspondence: Kaplan & Stratton Advocates,  (54) Tide:    PROCESS FOR THE PREPARATION OF TRYPTASE INHIBITORS
(57) Abstract: This invention is directed to processes for the preparation of compounds of the
formula (1) and their salts, formular (1) which are useful as trytase inhibitors, to
intermediates useful in the preparation of such compounds, to processes for the
preparation of such intermediates for the preparation of such compounds.
 
1
Process for the preparation of tryptase inhibitors
This invention is directed to processes for the preparation of compounds which are useful as tryptase inhibitors, to intermediates useful in the preparation of such
5 compounds, to processes for the preparation of such intermediates, and to the use of such intermediates for the preparation of such compounds.
Background of the invention
10 Mast cell mediated inflammatory conditions, in particular asthma, are a growing public health concern. Asthma is frequently characterized by progressive development of hyper-responsiveness of the trachea and bronchi to both immunospecific allergens and generalized chemical or physical stimuli, which lead to the onset of chronic inflammation. Leukocytes containing IgE receptors, notably mast
15 cells and basophils, are present in the epithelium and underlying smooth muscle
tissues of bronchi. These leukocytes initially become activated by the binding of specific inhaled antigens to the IgE receptors and then release a number of chemical mediators. For example, degranulation of mast cells leads to the release of proteoglycans, peroxidase, aryisuffatase B, chymase, and tryptase, which results in
20 bronchiole constriction.
Tryptase is stored in the mast cell secretory granules and is the major secretory protease of human mast cells. Tryptase has been implicated in a variety of biological processes, including degradation of vasodilating and bronchorelaxing neuropeptides
25 (Caughey et al„ J. Pharmacol. Exp. Ther., 1988, 244, pages 133-137; Franconi et al., J. Pharmacol. Exp. Then, 1988, 248, pages 947-951; and Tam et al., Am. J. Respir. Cell Mot Biol., 1990, 3, pages 27-32) and modulation of bronchial responsiveness to histamine (Sekizawa et al., J. Clin. Invest, 1989, 83, pages 175-179).
30 As a result, tryptase inhibitors are regarded as useful as anti-inflammatory agents (K Rice, P.A. Sprengler, Current Opinion in Drug Discovery and Development, 1999, 2, pages 463-474) particularly in the treatment of chronic asthma (M. Q. Zhang, H.
 
2
Timmerman, Mediators Inflamm., 1997, 112, pages 311-317), and may also be useful in treating or preventing allergic rhinitis (S. J. Wilson at al., Clin. Exp. Allergy, 1998, 28, pages 220-227), inflammatory bowel disease (S.C. Bischoff et al.,
Histopathology, 1996, 28, pages 1-13), psoriasis (A. Naukkarinen at al., Arch.
5 Dermatol. Res., 1993, 285, pages 341-346), conjunctivitis (A.A.Irani at al., J. Allergy Clin. Immunol., 1990, 86, pages 34-40), atonic dermatitis (A. Jarvikallio et al., Br. J. Dermatol., 1997, 136, pages 871-877), rheumatoid arthritis (L.0 Tetlow at al., Ann. Rheum. Dis., 1998, 54, pages 549-555), osteoarthritis (M.G. Buckley at al., J. Pathol., 1998, 186, pages 67-74), gouty arthritis, rheumatoid spondylitis, and diseases of joint
10 cartilage destruction.
In addition, tryptase has been shown to be a potent inkogen for fibroblasts,
suggesting its involvement in the pulmonary fibrosis in asthma and interstitial lung diseases (Ruoss et al., J. Clin. Invest., 1991, 88, pages 493-499).
Therefore, tryptase inhibitors are regarded as useful in treating or preventing fibrotic conditions (J.A. Cairns, A.F. Walls, J. Clin. Invest, 1997, 99, pages 1313-1321) for example, fibrosis, scieroderma, pulmonary fibrosis, liver cirrhosis, myocardial fibrosis, neurofibromas and hypertrophic scars.
Additionally, tryptase inhibitors are regarded as useful in treating or preventing myocardial infarction, stroke, angina and other consequences of atherosclerotic plaque rupture (M. Jeziorska et al., J. Pathol., 1997, 182, pages 115-122).
-•-
-Y,    ••-•.y.
25 Tryptase has also been discovered to activate prostromelysin that in turn activates collagenase, thereby initiating the destruction of cartilage and periodontal connective tissue, respectively.
Therefore, tryptase inhibitors are regarded as useful in the treatment or prevention of
30 arthritis, periodontal disease, diabetic retinopathy, and tumor growth (W.J. Bail et al., Exp. Hematol., 1998, 26, pages 158-169). Also, tryptase inhibitors are regarded as useful in the treatment of anaphylaxis (LB. Schwarz et al., J. Ulm Invest., 1995, 96,
 
3
pages 2702-2710), multiple sclerosis (M. Steinhoff et al., Nat. Med. (N. Y.), 2000, 6, pages 151-158), peptic ulcers and syncytial viral infections.
Compounds of formula I
5
 
have been disclosed as being useful as tryptase inhibitors, for example, in WO 01/90101 and WO 2004/060884 (international patent application
10 PCTMS2003/040653). Processes for preparing compounds of formula I are also disclosed therein, however, they suffer from substantial drawbacks and hazards, in particular when it is desired to prepare a compound of the formula i on a large scale.
The present invention provides advantageous processes which are useful in the preparation of compounds of the formula I and allow to overcome the drawbacks and
15 avoid the hazards of the prior art processes.
Summary of the invention
This invention is directed to processes for the preparation of compounds of formula 1,
20

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