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(11)    Patent Number: KE 600

(45)    Date of grant: 30/08/2013

(51)    Int.Cl.8: C 07D 401/12

(21) Application Number: K.E/P/ 2012/001649

(22)    Filing Date: 04/03/2011

(30)    Priority data: 1059750 25/11/2010 FR and 61/311,069 05/03/2010 us

(86)  PCT data

PCT/US20 11/027131 04/03/2011 wo 20111109680 09/09/2011
 

(73) Owner:SANOFI of 54 rue La Boetie, F-75008 Paris,France

(72) Inventors:ELENBAAS, Steven, Sanofi-Aventis 1041 Route 202-206, Mail Code D-303A, Bridgewater, New Jersey 08807 US,; FARR, Robert Allan, Sanofi-Aventis, 1041 Route 202-206, Mail Code D-303A, Bridgewater, New Jersey 08807, US and KANE, John Michael, Sanofi-Aventis 1041 Route 202-206, Mail Code D-303A, Bridgewater, New Jersey 08807, us

(74) Agent/address for correspondence:,    Kaplan & Stratton Advocates, P.O. Box 40111-00100, Nairobi
 

(54)    Title: PROCESS FOR THE PREPARATION OF 2-(CYCLOHEXYLMETHYL)-N-{2- [(2S)-1-METHYLPYRROLIDIN-2-YL]ETHYL}-1, 2, 3, 4- TETRAHYDROISOQUINOLINE-7- SULFONAMIDE

(57) Abstract:Industrially applicable process for preparing 2-( cyclohexylmethyl)-N-{2-[(2S)-1- methylpyrrolidin-2-y l]ethy1} -1 ,2,3 ,4-tetrahydroisoquino line-7 -sulfonamide, and salts thereof.

PROCESS FOR THE PREPARATION OF 2~(CYCLOHEXYLMETHYL)-N~{2~[(2S)~1~ METHYLPYRROLIDIN-2~YL]ETHYL}~1 ,2,3,4~TETRAHYDROISOQUINOLJNE-7 ~

SULFONAMIDE

5    FIELD OF THE INVENTION

The present invention relates to processes for preparing 2-(cyclohexylmethyi)-N-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1 ,2,3,4-tetrahydroisoq uinoline-7 -sulfonamide, various intermediates thereto and pharmaceutically acceptable salts thereof.

10    BACKGROUND OF THE INVENTION

The histamine H3 receptors are found in the central and peripheral nervous systems.

The administration of histamine H3 receptor ligands may influence the secretion of

neurotransmitters in the  brain  and  the  periphery and thus can  be  useful  in the

treatment of several disorders, including Alzheimer'sdisease and other dementias,

15    obesity, central nervous system disorders such as vigilance and sleep disorders, narcolepsy, Parkinson'sdisease, attention-deficit hyperactivity disorder, memory and learning disorders, epilepsy, schizophrenia, moderate cognitive disorders, depression, anxiety, cardiovascular disorders, and gastrointestinal disorders.

20    To illustrate, a number of studies in the literature have demonstrated the cognitive enhancing properties of histamine H3 receptors antagonists in rodent models (See, e.g., Giovanni et al., Behav. Brain Res., 1999, 104, 147-155). These reports further suggest that antagonists and/or inverse agonists could be useful for the treatment of

cognitive impairments in neurological diseases such  as Alzheimer's disease and

25    related neurodegenerative disorders. Alzheimer's disease is the most common cause of dementia in the elderly, and is often characterized with one or more symptoms such as memory loss, confusion, irritability and aggression, mood swings, language breakdown, long-term memory loss, withdrawal of the sufferer, and loss of
motor control.

30

2-(Cyclohexylmethyi)-N-{2-[(2S)~ 1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-

tetrahydroisoquinoline-7-sulfonamide, which has the structure of Formula (1):

is a potent histamine H3 receptor antagonist with inverse agonist properties. A preparation and the physical properties and beneficial pharmacological properties of 2-( cycl ohexylmethyi)-N-{2-[ (2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-

5    tetrahydroisoquinoline-7-sulfonamide are described in, for example~ W02005/118547 (also US2007/0105834).

W02005/118547  describes  a  general  method  of  synthesis  which  is  difficult to

transpose to the industrial scale for production in large quantities.  This method of

10    synthesis entails reacting 2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydro-isoquinoline-7-sulfonyl chloride with (+/-)-2-(2-aminoethyl)-1-methylpyrrolidine, which product is deprotected in methanol and hydrochloric acid. The enantiomers are next separated
by  chiral  chromatography.   The  resulting  N-{2-[(2S)-1-methylpyrrolidin-2-yl]ethy1}-

1,2,3,4-tetrahydroisoquinoline-7-sulfonamide  undergoes  reductive  amination  with

15    cyclohexanecarboxaldehyde in the presence of a palladium catalyst. 2-(Cyclohexylmethyi)-N-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide is isolated as the free base and converted to a-. ,. salt.

20    The present invention makes it possible to optimize the synthesis of 2-(cyclohexylmethyi)-N-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7 -sulfonamide for industrial use by avoiding the chiral chromatographic separation of the enantiomers of (+/-)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide. The present invention deals

25    with the chirality issues first, allowing the coupling of 2-(2,2,2-trifluoroacetyl)-1 ,2,3,4-tetrahydroisoquinoline-7-sulfonyl c~loride with enantiomerically pure (>99% ee) (-)-2-(2-aminoethyl)-1-methylpyrrolidine. In so doing, more of the 1,2,3,4-tetrahydroisquinoline moiety in the starting sulfonyl chloride can be incorporated into

product. Using the above-described synthesis, half of this material would have been discarded with the unwanted enantiomer of N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide.

5    BRIEF SUMMARY OF THE INVENTION

Accordingly, the present invention provides a process for producing 2-(cyclohexylmethyl)-N-{2-[ (2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7 -sulfonamide and salts thereof, of high purity and in a relatively high yield suitable for use on an industrial scale.

10

The present invention is also directed to synthetic intermediates, for example 2- • (2,2,2-trifluoroacetyl)-N-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2, 3,4-tetrahydroisoquinoline-7-sulfonamide, a compound of Formula (Ill), wherein Pg =
COCF3,  that are useful in the preparation of the 2-(cyclohexylmethyl)-N-{2-[(2S)-1-

15    methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7 -sulfonamide and salts thereof.

DETAILED DESCRIPTION OF THE INVENTION

20    Definitions and Abbreviations

As used above, and throughout the description of the invention, the following abbreviations, unless otherwise indicated, shall be understood to hay~ the following meanings:

25    HPLC    high performance liquid chromatography
    kg    kilogram
    L    liter
    mL    milliliter
    MTBE    methyl t-butyl ether
30       
 

The term "pharmaceutically acceptable" refers to those compounds, materials, compositions, carrier agents, bulking agents, solvents, diluents and other excipients which are, within the scope of sound medicinal judgment, suitable for

contact with humans or other mammals without undue toxicity, irritation, allergic response and the like, commensurate with a reasonable benefit/risk ratio.

A    process  of  the  invention  for  preparing  2-(cyclohexylmethyi)-N-{2-[(28)-1-

5    methylpyrrolidin-2-yl]ethyl}-1 ,2,3,4-tetrahydroisoq uinoline-7 -sulfonamide, or a pharmaceutically acceptable salt thereof, or a solvate or hydrate of a pharmaceutically acceptable salt comprises:

a)    coupling (-)-2-(2-aminoethyl)-1-methylpyrrolidine with an amine-protected

tetrahydroquinoline-7-sulfonyl chloride to give an amine-protected N-{2-[(28)-1-10 methylpyrrolidin-2-yl]ethyl}-1 ,2, 3,4-tetrahydroisoquinoline-7 -sulfonamide;
b) ' deprotecting the amine-protected N-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1 ,2,3,4-tetrahydroisoquinoline-7-sulfonamide to give N-{2-[(28)-1-methylpyrrolidin-2-yl]ethyl}-1 ,2,3,4-tetrahydroisoquinoline-7 -sulfonamide or a salt thereof;

15    c)    reductively  aminating    N-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1 ,2,3,4-
    tetrahydroisoquinoline-7-sulfonamide    or    a    salt    thereof    with
    cyclohexanecarboxaldehyde    to    form    2-( cyclohexylmethyi)-N-{2-[(2S)-1-

methylpyrrolidin-2-yl]ethyl}-1 ,2,3,4-tetrahydroisoquinoline-7 -sulfonamide;

d)    optionally reacting 2-( cyclohexylmethyi)-N-{2-[ (28)-1-methylpyrrolidin-2-

20    yl]ethyl}-1 ,2,3,4-tetrahydroisoquinoline-7-sulfonamide, with a stoichiometric amount or an excess of a salt-forming acid in a solvent to form a salt or a hydrate or solvate thereof; and
e)    optionally recrystallizing the product of step d).


25    In one aspect of the invention, processes for preparing the 2-(cyclohexylmethyi)-N-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1 ,2,3,4-tetrahydroisoquinoline-7 -sulfonamide or a pharmaceutically acceptable salt, solvate, or hydrate thereof, or a solvate or hydrate of a pharmaceutically acceptable salt and the intermediates that are useful for preparing such compounds are outlined in Scheme 1:
                       
5                                   
    The  processes  for  preparing  2-(cyclohexylmethyi)-N-{2-[(2S)-1-methylpyrrolidin-2-   
    yl]ethyl}-1 ,2,3,4-tetrahydroisoquinoline-7-sulfonamide,    or    a    pharmaceutically   
    acceptable salt thereof, or a solvate or hydrate of a pharmaceutically acceptable salt,   
1o    as outlined in Scheme 1, comprise:               
    a)    coupling  (-)-2-(2-aminoethyl)-1-methylpyrrolidine with  amine-protected   
    tetrahydroquinoline-7-sulfonyl chloride to give a compound of Formula (Ill), amine-   
    protected    N-{2-[ (2S)-1-methylpyrrolidin-2-yl}ethyl}-1,2,3,4-tetrahydroisoquinoline-7-   
    sulfonamide, wherein Pg represents an amine protecting group;           
15    b)    deprotecting the compound of Formula (Ill) to give the compound of   
    Formula (II), N-{2-[ (28)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-   
    sulfonamide or a salt thereof;                   

c)    reductively aminating the compound of Formula (II) with cyclohexanecarboxaldehyde to give a compound of Formula (1), 2-(cyclohexylmethyi)-N-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;

d)    optionally reacting the compound of Formula (I) with a stoichiometric

5    amount or an excess of a salt-forming acid in a solvent to form a salt, or a hydrate or solvate thereof, of Formula (Ia), 2-(cyclohexylmethyi)-N-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7 -sulfonamide addition salt; and

e)    optionally recrystallizing the product of step d).


10    A particular process of the invention for preparing 2-(cyclohexylmethyi)-N-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide, or a pharmaceutically acceptable salt thereof, or a solvate or hydrate of a

pharmaceutically acceptable salt, comprises:

a)    coupling (-)-2-(2-aminoethyl)-1-methylpyrrolidine with an amine-protected

15    tetrahydroquinoline-7-sulfonyl chloride in the presence of a base to give an amine-protected N-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;

b)    deprotecting   the   amine-protected   N-{2-[(2S)-1-methylpyrrolidin-2-

yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide under basic conditions and in a

20    solvent selected from an alcohol and a combination of water with an ethereal solvent, to give N-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-

sulfonamide or a salt thereof;    ,..

c)    reductively  aminating  N-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-

tetrahydroisoquinoline-7-sulfonamide    or    a    salt    thereof    with

25    cyclohexanecarboxaldehyde in the presence of a reducing agent and in a solvent selected from an alcohol and a combination of water with an ethereal solvent, to form 2-( cyclohexylmethyi)-N-{2-[ (2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7 -sulfonamide;

d)    optionally reacting 2-( cyclohexylmethyi)-N-{2-[(2S)-1-methylpyrrolidin-2-

30    yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide, or a hydrate or solvate thereof, with a stoichiometric amount or an excess of a salt-forming acid in a solvent to form a salt or a hydrate or solvate thereof; and

e)    optionally recrystallizing the product of step d).

Another particular process of the invention for preparing 2-(cyclohexylmethyi)-N-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7 -sulfonamide, or a pharmaceutically acceptable salt thereof, or a solvate or hydrate of a

5    pharmaceutically acceptable salt, comprises:

a)    coupling (-)-2-(2-aminoethyl)-1-methylpyrrolidine with 2-(2,2,2-

    trifluoroacetyl)-1 ,2,3,4-tetrahydroquinoline-7 -sulfonyl    chloride    to  give    2-(2,2,2-
    trifluoroacetyi)-N-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1 ,2,3,4-tetrahydroisoquinoline-
    7-sulfonamide;               
10    b)    deprotecting    2-(2,2,2-trifluoroacetyi)-N-{2-[(2S)-1-methylpyrrolidin-2-
    yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7 -sulfonamide    to    give    N-{2-[(28)-1:';'
    methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide,  or  a  salt
    thereof;                   

c)    reductively  aminating  N-{2-[(28)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-

15 tetrahydroisoquinoline-7 -sulfonamide, or a salt thereof with cyclohexanecarboxaldehyde to form 2-( cyclohexylmethyi)-N-{2-[(28)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;

d) optionally reacting 2-( cyclohexylmethyi)-N-{2-[(28)-1-methylpyrrolidin-2-yl]ethyl}-1 ,2,3,4-tetrahydroisoquinoline-7 -sulfonamide, with a stoichiometric amount or

20    an excess of a salt-forming acid in a solvent to form a salt, or a hydrate or ~olvate thereof; and
 

e)    optionally recrystallizing the product of step d).
 
For Scheme 1:

25 Amine-protected N-{2-[(28)-1-methylpyrrolidin-2-yl]ethyl}-1 ,2,3,4-tetrahydroisoquinoline-7-sulfonamide is prepared in step a) from a coupling between (-)-2-(2-aminoethyl}-1-methylpyrrolidine and an amine-protected 1,2,3,4-tetrahydoisoquinoline-7-sulfonyl chloride, such as 2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-7 -sulfonyl chloride or 1,2,3,4-tetrahydroisoquinoline-7 -sulfonyl

30    chloride protected with other suitable amine-protecting groups (i.e., amine-protecting groups that are stable in acid and removable under conditions that would not cleave the sulfonamide bond). In one aspect, 2-(2,2,2-trifluoroacetyi)-N-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1 ,2,3,4-tetrahydroisoquinoline-7-sulfonamide is prepared

from a coupling between (-)-2-(2-aminoethyl)-1-methylpyrrolidine and 2-(2,2,2-trifluoroacetyl)-1 ,2,3,4-tetrahydroisoquinoline-7-sulfonyl chloride in the presence of an inorganic base, such as sodium ~ydroxide, potassium hydroxide, lithium hydroxide, and the like, or an organic base, such as triethylamine and the like; in an inert

5    solvent,  for example a halogenated solvent such as dichloromethane,  chloroform,

1 ,2-dichloroethane, and the like, or an ethereal solvent such as t-butyl methyl ether or 2-methyltetrahydrofuran and the like; at temperatures preferably between about ooc and ambient temperature, for example about 25°C.

10    Accordingly, one embodiment of the invention is a process for preparing 2-(2,2,2-trifl uoroacetyi)-N-{2-[ (2 S)-1-methyl pyrroli di n-2-yl]ethyl}-1 ,2, 3 ,4-tetrahyo roisoq uin o Iine-7-sulfonamide comprising coupling 2-(2,2,2,-trifluoroacetyl)-1 ,2,3,4-

tetrahydroisoquinoline-7 -sulfonyl    chloride    and    (-)-2-(2-aminoethyl)-1-

methylpyrrolidine  in  the  presence  of  a  base  and  in  an  inert  solvent.   Another

15    embodiment of the invention is a process for preparing 2-(cyclohexylmethyi)-N-{2-[( 28)-1-methylpyrrolidin-2-yl]ethyl}-1, 2, 3,4-tetrahydroisoquinoline-7 -sulfonamide

comprising the step of coupling 2-(2,2,2-trifluoroacetyl)-1 ,2,3,4-tetrahydroisoquinoline-7 -sulfonyl chloride and (-)-2-(2-aminoethyl)-1-methylpyrrolidine in the presence of a base and in an inert solvent.
20

Amine-protected 1 ,2,3,4-tetrahydoisoquinoline-7 -sulfonyl chloride, such as 2-(2,2,2-trifluoroacetyl)-1 ,2,3,4-tetrahydroisoquinoline-7-sulfonyl chloride, may be commercially available or otherwise may be prepared according to processes known to those skilled in the art (see, for example, Blank, B.; Krog, A.J.; Weiner, G.;

25    Pendleton, R.G. J. Med. Chern. 1980, 23, 837-840). For example, amine-protected 1,2,3,4-tetrahydoisoquinoline-7-sulfonyl chlorides can be prepared by reacting the amine-protected 1,2,3,4-tetrahydroisoquinoline with an excess of chlorosulfonic acid in a halogenated solvent such as dichloromethane, chloroform or 1.2-dichloroethane. In particular, 2-(2,2,2-trifluoroacetyl)-1 ,2,3,4-tetrahydroisoquinoline-7-sulfonyl chloride

30    can prepared by reacting 2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline with excess chlorosulfonic acid in either chloroform or dichloromethane at about ooc to about 5°C for several hours and then at room temperature for several days. Quenching of the reaction into a mixture of chloroform or dichloromethane and

crushed ice affords a solution of the desired sulfonyl chloride, which following removal of the solvent, can be purified by crystallization from, for example, t-butyl methyl ether.



5    The deprotection of amine-protected N-{2-[(28)-1-methylpyrrolidin-2-yl]ethyl}-1 ,2,3,4-tetrahydroisoquinoline-7 -sulfonamide, such as 2-(2,2,2-trifluoroacetyi)-N-{2-[(28)-1-

methylpyrrolidin-2-yl]ethyl}-1 ,2,3,4-tetrahydroisoquinoline-7 -sulfonamide, in step b) may be carried out using deprotection techniques known in the art. Preferably, the protecting group may be removed under basic conditions, for example in the

10    presence of an inorganic base such as potassium hydroxide, sodium hydroxide, lithium hydroxide, and potassium carbonate. The reaction is preferably carried out in an alcohol, such as isopropanol, methanol, and the like, or combinations of water with

an ethereal solvent, such as tetrahydrofuran and dioxane, and at a temperature between about ooc and about the reflux temperature of the mixture, and, more

15    preferably, below about 100°C.


Therefore, one embodiment of the invention is the process for preparing N-{2-[(28)-1-methylpyrrolidin-2-yl]ethyl}-1 ,2,3,4-tetrahydroisoquinoline-7 -sulfonamide compnsmg deprotecti ng 2-(2, 2,2-trifluoroacetyi)-N-{2-[ (2S)-1-methyl pyrrolid in-2-yl]ethyl}-1 ,2, 3,4-

20    tetrahydroisoquinoline-7 -sulfonamide in the presence of a base. Another embodiment of the invention is the process for preparing 2-(cyclohexylmethyi)-N-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1.,2.;'3,4-tetrahydroisoquinoline-7-sulfonamide

compnsmg    the    step    of   deprotecting    2-(2,2,2-trifluoroacetyi)-N-{2-[(2S)-1-
methylpyrrolidin-2-yl]ethyl}-1 ,2,3,4-tetrahydroisoquinoline-7 -sulfonamide    in    the

25    presence of a base.


Step c) involves the formation of 2-(cyclohexylmethyl)-N-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1 ,2,3,4-tetrahydroisoquinoline-7-sulfonamide by reacting N-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1 ,2, 3,4-tetrahydroisoquinoline-7-sulfonamide and

30    cyclohexanecarboxaldehyde, in the presence of a reducing agent, such as formic acid (produced by the addition of sodium or potassium formate, and the like, for example) in an organic solvent, for example an alcohol, such as ethanol, methanol, isoorooanol, and the like, or a combination of water with an ethereal solvent, such as

tetrahydrofuran, dioxane, and the like, or a combination of acetonitrile with water or an alcohol with water. This reaction is preferably performed at temperatures between about ooc and about the reflux temperature of the mixture, and, more preferably, below about 100°C.
5

Pharmaceutically acceptable salts of 2-(cyclohexylmethyi)-N-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1 ,2,3,4-tetrahydroisoq uinoline~ 7-sulfonamide, and hydrates and solvates thereof, include conventional, non-toxic salts of 2-(cyclohexylmethyi)-N-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-

10    tetrahydroisoquinoline-7 -sulfonamide, which can be formed with either inorganic acids such as hydrochloric acid or organic acids such as benzoic acid, fumaric acid, oxalic acid and L-tartaric acid. A pharmaceutically acceptable salt can be obtained

using standard procedures well known in the art, such as by reacting the compound of Formula (I) with stoichiometric amounts or with an excess of the desired salt-
IS forming acid in a suitable solvent or various combinations of solvents. For example, an oxalate salt can be made by dissolving the compound of Formula (I) in ethanol and adding about 1.1 equivalents of oxalic acid, and allowing the salt to form. In one aspect of the invention, a fumarate salt is obtained. In a preferred aspect, the fumarate salt is a difumarate monohydrate salt.

20

The pharmaceutically acceptable salt of 2-(cyclohexylmethyi)-N-{2-[(2S)-1-methylpyrrolidin-2-yl]'ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide, or hydr:ate or solvate thereof, is optionally recrystallized. Suitable recrystallization solvents include, for example, isopropanol and ethanol in the presence of an antisolvent such

25    as toluene or acetone.


Another aspect of the invention are the processes described above further comprising the step of formulating 2-(cyclohexylmethyi)-N-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7 -sulfonamide or a pharmaceutically

30    acceptable salt thereof, or a solvate or hydrate of a pharmaceutically acceptable salt, with one or more pharmaceutically acceptable carrier agents, bulking agents, solvents, diluents and other excipients. In one aspect, the process comprises the step of formulating 2-(cyclohexylmethyi)-N-{2-[(2S)-1-methylpyrrolidin-2-

yl]ethyl}-1 ,2,3,4-tetrahydroisoquinoline-7-sulfonamide  difumarate  monohydrate  with

one or more pharmaceutically acceptable carrier agents, bulking agents, solvents,

diluents and other excipients.


5    The compound of Formula (V), (-)-2-(2-aminoethyl)-1-methyipyrrolidine, may be prepared as outlined in Scheme 2.

Scheme 2:

1o    For Scheme 2:   
    Step 1) entails combining 2-(2-aminoethyl)-1-methylpyrrolidine with a chiral resolving
    agent, such as di-p-toluoyi-D-tartaric acid, in an alcohol, such as ethanol, methanol,
    isopropanol,  and  the  like,  and  combinations  thereof including  combinations  with
    water.  Preferably, the solvent is a combination of ethanol and water.  The reaction is
15    preferably  performed  at  temperatures  between  about  ooc and  about  the  reflux
    temperature of the mixture, and more preferably, below about 100°C.
    ~•~ ~,' ::;-~    '>~:J'\

Racemic 2-(2-aminoethyl)-1-methylpyrrolidine starting material is commercially available (for example, from Anichem LLC, American Custom Chemicals Inc., Acros,

20    Aldrich) or otherwise may be prepared according to procedures well known to those skilled in the art. (See Turner, S.C.; Esbenshade, T.A.; Bennani, Y.L.; Hancock, A.A. Bioorg. Med. Chern. Lett. 2003, 13, 2131-2135).

Step 2) involves removing the resolving agent by dissolving the product of step 1), for

25    example, (-)-2-(2-aminoethyl)-1-methylpyrrolidine, O,O'di-p-toluoyi-D-tartaricacid salt,

in a two-phase mixture of a strong acid, such as concentrated HCI, HBr, H2 S04 , or H3P04, and a non-polar solvent, such as t-butyl methyl ether, isopropyl acetate, and the like, at temperatures between about room temperature and about 1 00°C. In one

aspect, (-)-2-(2-aminoethyl)-1-methylpyrrolidine is isolated in aqueous solution as a salt. In another aspect, the acidic solution of (-)-2-(2-aminoethyl)-1-methylpyrrolidine salt is basified by the addition of a base, such as sodium hydroxide, allowing the isolation of (-)-2-(2-aminoethyl)-1-methylpyrrolidine as the distillable free base.

5

The following examples present typical syntheses as described in Schemes 1 and 2. These examples are understood to be illustrative only and are not intended to limit the scope of the present invention in any way.

10    Example 1

Preparation of compound of Formula (VI): (-)-2-(2-Aminoethyl)-1-methylpyrrolidine, 0, 0'-Di-p-toluoyi-D-tartaricacid salt

A stock solution of aqueous ethanol was prepared by mixing ethanol (1 0370 mL) and

15    water (2080 mL). A mixture of 0,0'-di-p-tolouyi-D-tartaricacid (1624 g, 4.203 mol) and a portion of the above-described stock solution of aqueous ethanol (9050 mL) was stirred at around 65°C under a nitrogen atmosphere. Separately, racemic 2-(2-aminoethyl)-1-methylpyrrolidine (700 g, 5.35 mol) was dissolved in a portion of the
aqueous ethanol stock solution (3400 mL).  The amine solution was then added drop-

20    wise to the tartaric acid solution so that the temperature was maintained at about 65°C and no solids formed during the addition. The reaction was held at about 65°C for no less than 30 min before being cooled to about 0°C. The precipitate was collected by filtration. A stream of nitrogen was pulled through the collected solid until no longer wet. The solid was recrystallized from ethanol (15950 mL)/water (2457 mL)

25    affording the desired product as a colorless solid:  1322.4 g (44%), >99.5% ee.


Example 2

Preparation of compound of Formula (V):  (-)-2-(2-Aminoethyl)-1-methylpyrrolidine


30    A solution of HCI (296 mL, 3.55 mol) and water (517 mL) was added to a mixture of(-)-2-(2-aminoethyl)-1-methylpyrrolidine, 0,0'-di-p-toluoyi-D-tartaric acid salt (900 g, 1.75 mol) and MTBE (3.2 L). After stirring for 45 minutes, the layers were separated. Additional MTBE (1.6 L) was added to the aqueous layer. After stirring for about 10

minutes, the layers were separated. With stirring, 50% aqueous NaOH (476 ml, 9.19 mol) was added to the aqueous acid layer over about 35 minutes. The mixture was stirred for about 35 minutes, then cooled to 10°C. The organic layer was separated and distilled at reduced pressure to provided 206 g (92%) of the desired product.

5

Example 3

Preparation of compound of Formula (Iff): 2-(2,2,2-Trifluoroacetyi)-N-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoq uinoline-7 -sulfonamide

10    A solution of (-)-2-(2-aminoethyl)-1-methylpyrrolidine (172 g, 1.345 mol) in water (400 ml) was prepared and added to a solution .pf 2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-7 -sulfonyl chloride (400 g, 1.22 mol) in 2-

methyltetrahydrofuran (1600 ml) at a controlled rate to maintain the reaction temperature between -soc and 5°C. Upon completion of the coupling, the reaction

15    mixture was washed once with an aqueous potassium carbonate solution prepared from potassium carbonate (220 g, 1.59 mol) and water (1 L) to liberate the free base

of the product. Most of the 2-methyltetrahydrofuran was removed by vacuum distillation to the minimum stirred volume and replaced with ethanol (2 L). The distillation was resumed and continued to the minimum stirred volume. The ethanolic

20    solution of 2-(2,2,2-trifluoroacetyi)-N-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1 ,2,3,4-tetrahydroisoquinoline-7-sulfonamide was diluted with ethanol (1132 ml) to obtain a 30 wt % solution of product, assum,(ng a 97% yield, and carried forward into the next step.



25    Example 4

Preparation of a compound of Formula (II): N-{2-[(2S)-1-Methylpyrrolidin-2-yl]ethyl}-1 ,2,3,4-tetrahydroisoquinoline-7-sulfonamide Dihydrochloride Sesquihydrate

A 45.7% solution of potassium hydroxide (105 g, 0.855 mol) was added to a 30.66%

30    (w/w) ethanolic solution of 2-(2,2,2-trifluoroacetyi)-N-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide (1023.6, 0.748 mol) at a rate that limited the temperature to no more than 45°C. After cooling to room temperature, the reaction was monitored by HPLC. Upon completion of the

deprotection, the reaction was acidified by the dropwise addition of concentrated hydrochloric acid (194 ml, 2.35 mol). The precipitated KCl was removed by filtration at between 39-51 oc. The reactor was rinsed with ethanol (300 ml) which in turn was used to rinse the collected KCI. The ethanol filtrates were combined and returned to

5    the reactor. The reactor was heated to approximately 55°C and 2-methyltetrahydrofuran (375 ml) was added. Seed crystals of N-{2-[(2S)-1-

methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahyd roisoquinoline-7 -sulfonamide

dihydrochloride sesquihydrate (1 g) were added.  After cooling to approximately -5°C,

the  product was  collected  by filtration.   The  product was  rinsed  with  a solution

10    prepared from 2-methyltetrahydrofuran (200 ml), ethanol (200 ml) and water (5 ml). Following drying in a vacuum even at 40°C, 277 g (87%) of N-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoq uinoline-7-sulfonamide dihydrochloride sesquihydrate was isolated as a colorless solid.


15 Seed crystals of N-{2-[(2S)-1-Methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7 -sulfonamide dihydrochloride sesquihydrate can be obtained following general procedures known to those skilled in the art. Alternatively, N-{2-

[ (2S)-1-Methylpyrrolidin-2-yl]ethyl}-1 ,2,3,4-tetrahydroisoquinoline-7 -sulfonamide dihydrochloride sesquihydrate can readily be prepared as described above without
20    the use of seed crystals.


Example 5

Preparation of a compound of Formula (1): 2-(Cyclohexylmethyl)-N-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1 ,2,3,4-tetrahydroisoquinoline-7-sulfonamide

25

N-{2-[(2S)-1-Methylpyrrolidin-2-yl]ethyl}-1,2, 3,4-tetrahydroisoq uinoline-7 -sulfonamide dihydrochloride sesquihydrate (92 g, 0.217 mol) was reacted with potassium formate (33.6 g, 0.399 mol) and cyclohexanecarboxaldehyde (39 ml, 0.322 mol) in hot SDA 3C ethanol (460 mL). The reaction vessel was heated to about 72°C, with release of

30    C02 • The reaction mixture was monitored for completion by HPLC. Upon completion, the reaction was cooled to about 25°C, and ethanol was removed by vacuum distillation and azeotropic removal with added water (280 ml). The hydrochloride salt of the product was formed by the addition of concentrated

hydrochloric acid (37.3 ml, 0.451 mol), and the aqueous solution was washed with isopropyl acetate (280 ml). The aqueous layer was basified with a solution of potassium carbonate (92 g, 0.666 mol) in water (100 ml). The aqueous alkaline solution was extracted with isopropyl acetate (460 ml). The isopropyl acetate layer

5    was washed with water (3 x 460 ml), and the isopropyl acetate was removed by vacuum distillation and replaced with SDA 3C ethanol (460 mL). The resulting clear yellow-tinged solution contained 85.7 g (91 %) of 2-(cyclohexylmethyi)-N-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1 ,2,3,4-tetrahydroisoquinoline-7-sulfonamide in 120.4 g of solution.

10

Example 6

Preparation of a Compound of Formula (Ia): 2-(Cyclohexylmethyi)-N-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1 ,2, 3,4-tetrahydroisoquinoline-7 -sulfonamide difumarate monohydrate

15

A solution of 2-( cyclohexylmethyi)-N-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1 ;2,3,4-tetrahydroisoquinoline-7-sulfonamide (532 g, 1.27 mol) in SDA 3C ethanol (1056 ml) was added to a suspension of fumaric acid (302 g, 2.60 mol) in water (624 ml). The resulting solution was diluted with acetone (4 L) then cooled and seeded with milled

20    2-( cyclohexylmethyi)-N-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1 ,2,3,4-tetr~!lYdroisoquinoline-7-sulfonamide difumarate monohydrate (4.2 g). After seeding, the mixture was stirred to allow crystal growth then further diluted with acetone (1990

ml). After cooling, the product was collected by filtration and washed with acetone (1.500 L). Filtration was conducted by portionwise loading of acetone into the filter-

25    dryer. After loading of each portion of acetone (1.5L), stirring was turned on at 2.6 rpm to ensure good contact between product and acetone. The product was dried in a vacuum oven at 40°C with nitrogen purge and vacuum (residual pressure 400 mBar), then allowed to re-hydrate at room temperature in the air to yield 684.7 g (85.8
%)    of    2-(cyclohexylmethyi)-N-{2-[(28)-1-methylpyrrolidin-2-yl]ethyl}-1 ,2,3,4-

30    tetrahydroisoquinoline-7 -sulfonamide difumarate monohydrate.


Seed crystals of 2-(cyclohexylmethyi)-N-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1 ,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate can be obtained


following general procedures known to those skilled in the art in view of the above-described procedure. Alternatively, 2-(cyclohexylmethyi)-N-{2-[(28)-1-methylpyrrolidin-2-yl]ethyl}-1 ,2,3,4-tetrahydroisoquinoline-7 -sulfonamide difumarate monohydrate can readily be prepared as described above without the use of seed
5    crystals.


CLAIMS

What is claimed is:

1.    A process for preparing 2-(cyclohexylmethyi)-N-{2-[(28)-1-methylpyrrolidin-2-

5    yl]ethyl}-1 ,2, 3,4-tetrahydroisoquinoline-7 -sulfonamide,    or    a    pharmaceutically
    acceptable salt thereof, or a solvate or hydrate of a pharmaceutically acceptable salt
    comprising:           
    a)  coupling (-)-2-(2-aminoethyl)-1-methylpyrrolidine with    an amine-protected
    tetrahydroquinoline-7-sulfonyl  chloride  to  give  an  amine-protected  N-{2-[(28)-1-
1o    methylpyrrolidin-2-yl]ethyl}-1 ,2,3,4-tetrahydroisoquinoline-7 -sulfonamide;

b)    deprotecting   the   amine-protected   N-{2-[(28)-1-methylpyrrolidin-2-

    yl]ethyl}-1 ,2,3,4-tetrahydroisoquinoline-7-sulfonamide    to    give    N-{2-[(28)-1-
    methylpyrrolidin-2-yl]ethyl}-1 ,2,3,4-tetrahydroisoquinoline-7-sulfonamide  or    a  salt
    thereof;                               
15    c)    reductively  aminating    N-{2-[(28)-1-methylpyrrolidin-2-yl]ethyl}-1 ,2,3,4-
    tetrahydroisoquinoli ne-7-sulfonamide    or    a    salt        thereof    with
    cyclohexanecarboxaldehyde    to    form    2-(cyclohexylmethyi)-N-{2-[(28)-1-

methylpyrrolidin-2-yl]ethyl}-1 ,2,3,4-tetrahydroisoquinoline-7-sulfonamide;

d)    optionally reacting 2-( cyclohexylmethyi)-N-{2-[(28)-1-methylpyrrolidin-2-

20    yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide, or a hyqrate or solvate thereof, with a stoichiometric amount or an excess of a salt-forming acid in a solvent to form a salt or a hydrate or solvate there()f; and
e)    optionally recrystallizing the product of step d).


25 2. The process according to claim 1, wherein the amine-protected tetrahydroquinoline-7 -sulfonyl chloride is 2-(2,2,2-trifluoroacetyl)-1 ,2,3,4-tetrahydroisoquinoline-7 -sulfonyl chloride and the amine-protected N-{2-[(28)-1-methylpyrrolidin-2-yl]ethyl}-1 ,2,3,4-tetrahydroisoquinoline-7 -sulfonamide is 2-(2,2,2-trifluoroacetyi)-N-{2-[ (2 S)-1-methylpyrrolidi n-2 -yl]ethyl}-1 , 2, 3,4-tetrahyd roisoq uinoline-

30    7-sulfonamide.


3.    The process according to claim 1, wherein the coupling in step a) is performed in the presence of an inorganic or organic base and in an inert solvent.
 

4.    The process  according to claim 3, wherein the base is selected from the group

consisting  of  sodium  hydroxide,  potassium  hydroxide,  lithium  hydroxide  and

triethylamine.


5    5. The process according to claim 1, wherein deprotecting in step b) is performed under basic conditions and in an alcohol.

6.    The process according to claim 1, wherein the reductive ami nation of step c) is

performed in an organic solvent in the presence of a reducing agent.

10

7.    The process according to claim 6, wherein the reducing agent is formic acid.


8.    The process according to claim 1, wherein the salt formed in step d) is a pharmaceutically acceptable salt.

15

9.    The  process  according  to  claim  1,  further  comprising  formulating  2-

(cycle hexylmethyi)~N-{2-[ (2S)~ 1-methylpyrrolidin-2~yl]ethyl}-1, 2, 3,4-

tetrahydroisoquinoline~ 7 ~sulfonamide or a pharmaceutically acceptable salt thereof, or a solvate or hydrate of a pharmaceutically acceptable salt, with one or more

20    pharmaceutically acceptable carrier agents, bulking agents, solvents, diluents and other excipients.

10.    The process according to claim 1, wherein the salt~forming acid in step d)

is  fumaric  acid  to  provide  2-(cyclohexylmethyi)-N-{2-[(2S)-1-methylpyrrolidin-2-

25    yl]ethyl}-1 ,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate.


11.    The  process  according  to  claim  10,  further  comprising  formulating  2-

(cyclohexylmethyi)-N-{2-[ (2S)~ 1-methylpyrrolidin-2-yl]ethyl}~ 1,2,3,4-

tetrahydroisoquinoline-7-sulfonamide  difumarate  monohydrate  with  one  or  more

30    pharmaceutically acceptable carrier agents, bulking agents, solvents, diluents and other excipients.

12.    The process according to claim 1, comprising:

a)    coupling (-)-2-(2-aminoethyl)-1-methylpyrrolidine with 2-(2,2,2-

trifluoroacetyl)-1 ,2,3,4-tetrahydroquinoline-7 -sulfonyl   chloride   to   give   2-(2,2,2-

trifl uoroacetyl)-N-{2-[ (2S)-1-methyl pyrrol idi n-2-yl] ethyl}-1 ,2, 3 ,4-tetrahyd roisoq ui no Iine-

5    7 -sulfonamide;

b)    deprotecti ng 2-(2,2,2-trifluoroacetyi)-N-{2-[(2S)-1-methylpyrrolidin-2-

yl]ethyl}-1 ,2,3,4-tetrahydroisoquinoline-7-sulfonamide to give N-{2-[(28)-1-methylpyrrolidin-2-yl]ethyl}-1 ,2,3,4-tetrahydroisoquinoline-7-sulfonamide, or a salt

    thereof;                       
10    c)    reductively  aminating    N-{2-[(28)-1-methylpyrrolidin-2-yl]ethyl}-1 ,2,3,4-
    tetrahydroisoquinoline-7-sulfonamide,    or    a    salt    thereof  ,.   with
    cyclohexanecarboxaldehyde    to    form    2-( cyclohexylmethyl)-N-{2-[(28)-1-

methylpyrrolidin-2-yl]ethyl}-1 ,2,3,4-tetrahydroisoq ui noline-7-sulfonamide;

d)    optionally reacting 2-(cyclohexylmethyl)-N-{2-[(28)-1-methylpyrrolidin-2-

15    yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide with a stoichiometric amount or an excess of a salt-forming acid in a solvent to form a salt, or a hydrate or solvate thereof; and
e)    optionally recrystallizing the product of step d).


20    13. The process according to claim 12, further comprising formulating 2-(cyclohexylmethyl)-N-{2-[ (28)-1-methylpyrrolidin-2-yl]ethyl}-1 ,2, 3,4-tetrahydroisoquinoline-7-sulfonamide or a pharmaceutically:;acceptable salt, or• a

solvate or hydrate of a pharmaceutically acceptable salt, with one or more pharmaceutically acceptable carrier agents, bulking agents, solvents, diluents

25    and other excipients.


14. The process according to claim 12, wherein the salt-forming acid in step d~ is fumaric acid to provide 2-(cyclohexylmethyi)-N-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2, 3,4-tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate .

. 30
 

15. The process according to claim 14, further comprising formulating 2-(cyclohexylmethyi)-N-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1 ,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate with one or more


pharmaceutically acceptable carrier agents, bulking agents, solvents, diluents and other excipients.

16.    The process according to claim 1, comprising:

5 a) coupling (-)-2-(2-aminoethyl)-1-methylpyrrolidine with an amine-protected tetrahydroquinoline-7 -sulfonyl chloride in the presence of a base to give an amine-protected N-{2-[ (2S)-1-methylpyrrolidin-2-yl]ethyl}-1 ,2,3,4-tetrahydroisoquinoline-7-sulfonamide;

b)    deprotecting   the   amine-protected   N-{2-[(2S)-1-methylpyrrolidin-2-

10    yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfona under basic conditions and in a solvent selected from an alcohol and a combination of water with an ethereal solvent, to give N-{2-[(2 S)-1-methyl pyrroli din-2-yl]ethyl}-1 ,2, 3 ,4-tetra hyd roisoq uin ali ne-7-sulfonamide or a salt thereof;

c)    reductively  aminating  N-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1 ,2,3,4-

15 tetrahydroisoquinoline-7 -sulfonamide or a salt thereof with cyclohexanecarboxaldehyde in the presence of a reducing agent and in a solvent selected from an alcohol and a combination of water with an ethereal solvent, to form 2-( cyclohexylmethyi)-N-{2-[(28)-1-methylpyrrolidin-2-yl]ethyl}-1 ,2, 3,4-tetrahydroisoquinoli ne-7 -sulfonamide;

20 d) optionally reacting 2-(cyclohexylmethyi)-N-{2-[(28)-1-methylpyrrolidin-2-yl]ethyl}-1 ,2,3,4-tetrahydroisoquinoline-7-sulfonamide with a stoichiometric amount or an excess of a salt-forming acid in a solvent t9 form a salt or a hydrate or solvate thereof; and

e)    optionally recrystallizing the product of step d).

25
17.    The compound 2-(2,2, 2-trifluoroacetyi)-N-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1 ,2, 3,4-tetrahydroisoquinoline-7 -sulfonamide.

18.    A process for preparing 2-(2,2,2-trifluoroacetyl)-N-{2-[(2S)-1-methylpyrrolidin-30 2-yl]ethyl}-1 ,2,3,4-tetrahydroisoquinoline-7 -sulfonamide comprising coupling 2-(2,2,2-

trifluoroacetyl)-1 ,2,3,4-tetrahydroisoquinoline-7 -sulfonyl   chloride   and    (-)-2-(2-

aminoethyl)-1-methylpyrrolidine in the presence of a base and in an inert solvent.


19.    A process for preparing 2-(cyclohexylmethyi)-N-{2-[(2S)-1-methylpyrrolidin-2-

yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide, comprising the step of coupling 2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl chloride and (-)-2-(2-aminoethyl)-1-methylpyrrolidine in the presence of a base and in an inert

5   solvent.           
20.    A  process   for  preparing    N-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-
tetrahydroisoquinoline-7 -sulfonamide    compnsmg    de protecting    2-(2,2,2-

trifl uoroacetyi)-N-{2-[ (2 S)-1-methyl pyrrolidi n-2 -yl]ethyl}-1,2,3,4-tetrahyd roisoq uinol ine-10 7 -sulfonamide in the presence of a base.

21.    A process for preparing 2-( cyclohexylmethyi)-N-{2-[(2S)-1-methylpyrrolidin-2-

yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide,    comprising   the  step  of

deprotecting  2-(2,2,2-trifluoroacetyi)-N-{2-[ (2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-

15    tetrahydroisoquinoline-7-sulfonamide in the presence of a base.

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