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(11) Patent Number: KE 416

(45) Date of grant: 07/10/2010

(21)Application Number: KElP/ 2009/ 000880

(22) Filing Date: 19/09/2007

(30) Priority data:  0608286  21109/2006  FR

(86) PCT data  PCT/FR07/001516    19/09/2007 WO  2008/034973  Al    27/03/2008
 
(73)0wner: SANOFI-AVENTIS of  174, Avenue de Fraoce, F-75013 Paris., France

(72) Inventor: DLUBALA, Alain of c/o Sanofi-aventis, Departement Brevets, 174 Avenue de France, F-75013 Paris, France.

(74) Agent/address for correspondence: Kaplan & Stratton Advocates, P .0. Box 40111-00100, Nairobi
 
(54) Title: PROCESS FOR PREPARING N-ALKYL NALTREXONE HALIDES.

(57) Abstract: The invention relates to a novel process for preparing N-methlnaltrexone bromide, comprising at least the steps consisting in: (i) reacting N-methylnaltrexone methyl sulphate in an aqueous solution with an alkaline agent chosen from the group consisting of sodium carbonate, potassium carbonate, calcium carbonate, magnesium carbonate, caesium carbonate and strontium carbonate, and mixtures thereof, for a pH of the aqueous reaction medium of between 7 and 10, and then (ii) reacting the product thus obtained with hydrobromic acid which is added for a pH of the aqueous reaction medium of between 0.5 and 5, and thus obtaining N-methylnaltrexone bromide.

PROCESS FOR PREPARING N-ALKYLNALTREXONE HALIDES

The present invention relates to a process for preparing N-alkylnaltrexone

halides.

N-Aikyl quaternary derivatives of naltrexone (a nomenclature of naltrexone

being    (5a)-17-(cyclopropylmethyl)-4,5-epoxy-3, 14-dihydroxymorphinan-6-one   or

N-cyclopropylmethylnoroxymorphone) are known for their therapeutic applications,

especially N-methylnaltrexone, the use of which makes it possible to combine a morphine treatment in a patient, significantly reducing the adverse side effects of
10    morphine and derivatives thereof, especially on the gastrointestinal tract.

The  term  "N-methylnaltrexone"  more  particularly  means  (R)-N-methyl-

naltrexone, i.e. the compound of (R) configuration relative to the nitrogen atom, it

being well known to those skilled in the art that the (S)-N-methyl compound has

activity opposite to that desired for accompanying a morphine-based treated.

15    The configuration of the quaternary ammonium of the N-methylnaltrexone

having the formula below was determined by 1H NMR of the isolated (R) and (S)

diastereoisomers:

20 (S) configuration of the ammonium (equatorial methyl): R1 represents a methyl group and R2 represents a methylcyclopropyl group, and

(R) configuration of the ammonium (axial methyl) R2 represents a methyl group and R1 represents a methylcyclopropyl group.

The chemical shifts in 1H NMR of the methyl group (reference TMS or 25 tetramethylsilane) are at 3.62 ppm for the (R) configuration and at 3.13 ppm for the

(S) configuration.

Patent US 4176 186 (Boehringer lngelheim GmbH) describes quaternary

noroxymorphone derivatives and also processes for preparing them. However, the

described  processes  comprise  conditions,  especially  of  pressure,  of  necessary

amount of reagent, and of conversion by column anion exchange, which are incompatible with the desired industrial application.

Patent application WO 2004/043 964 A2 describes a process at lower pressures, comprising the use of an anhydrous solvent system, especially 1-methyl-2-pyrrolidone, but which nevertheless still has drawbacks in terms of impurities, the imperative sufficiently low content of which inevitably leads to an unsatisfactory yield.

There was thus ever-increasing interest in having available a process for the industrial-scale production of such derivatives, under the best conditions in terms of
10    production (safety and environment) and yield.

A process has now been found, entirely surprisingly and unexpectedly, for very advantageously improving both the implementation conditions in terms of safety, not only for the personnel but also for the environment, and the yield for the desired final product, i.e. an N-alkylnaltrexone halide, in particular N-
15    methylnaltrexone bromide.

In accordance with the invention, a process comprising the steps according to Scheme 1 below may be performed.

N.-Methylnaftrexone Bromide, starting from NoroxymorphorM Hydrochloride

N~ALKYLATION

O•BENZY'LATION

QUATERNIZATION

DEBENZYLATION

!-P  PURJFICATION  orr;h./":.

'Crude'N-Melhyill!llrumeBromlde    )~"•
flO    0    o    11.0o'~0   
               
'Pura'N-~nallmoneBramlde

In the text hereinbelow, the starting compounds and the reagents mentioned

for the process according to the invention, when their mode of preparation is not

described,  are  commercially  available  or  described  in  the  literature,  or  may  be

prepared  according  to  methods  that  are described therein  or that  are  known  to

those skilled in the art.

A  subject  of  the  present  invention  is  thus,  most  particularly,  a  novel

intennediate compound which, without wishing to be bound by any theory, is in the

form of a double ion having the formula (I) below (which may thus be referred to as an N-methy!nattnaxone double ion):

~y
~
o~-o

(I)

10    The respective diastereoisomers of (R) and (S) configurations relative to the

nitrogen  atom  of the N-methylnaltrexone double  ion,  and  also  mixtures thereof,

including racemic mixtures, form part of the invention.

Besides its anhydrous form,  the  N-methylnaltrexone double ion  may also

exist in the form of a hydrate.

15 According to the invention, the tenn uhydrate" means a form of association or combination of the compound of formula (I} with one or more molecules of water of crystallization in the crystal lattice, i.e. excluding the water of insertion into the
microchannels of the crystals (or "water of impregnation"), the hydrate possibly

being determined firstly by analysis on a monocrystal and then conf1rmed routinely

20    by comparative analysis of diffractograms (or powder diagrams) as is well known to those skilled in the art and illustrated in Example 1.

Such hydrates also form part of the invention. For example, the hemihydrate, dihydrate and trihydrate forms may be mentioned.

According to a particular embodiment of the invention,  the double ion of

25    formula (I) has an (R) configuration relative to the nitrogen atom and is in dihydrate fonn.
This novel N-methylnaltrexone double ion compound, of formula (1), may advantageously be prepared via a process comprising the step that consists in

reacting N-methylnaltrexone methyl sulfate in aqueous solution with an alkaline agent chosen from the group constituted by sodium carbonate (Na2C03), potassium carbonate, calcium carbonate, magnesium carbonate, caesium carbonate, strontium carbonate and mixtures thereof, for a pH of the aqueous solution of
between 7 and 10 and preferably between 9.5 and 9.8 and at a temperature of

between 15 and 30°C, preferably about 20°C.

A  subject  of  the  present  invention  is  also  a  process  for  preparing  N-

methylnaltrexone bromide, comprising at least the steps consisting in:

(i) reacting N-methylnaltrexone methyl sulfate in aqueous solution with an

10    alkaline agent chosen from the group constituted by sodium carbonate, potassium carbonate, calcium carbonate, magnesium carbonate, caesium carbonate, strontium carbonate and mixtures thereof, for a pH of the aqueous reaction medium of between 7 and 10 and preferably between 9.5 and 9.8 and at a temperature of between 15 and 30°C, preferably about 20°C, and then in

15    (ii) reacting the product thus obtained with hydrobromic acid, preferably of

48% concentration, which is added for a pH  of the aqueous reaction medium of

between 0.5 and 5 and preferably of about 1, and the reagents are preferably left in

contact  with  stirring  for  a  further  one  hour,  in  order  thus  to  obtain  the  N-

methylnaltrexone bromide.

20    Preferably,  the  alkaline  agent is  chosen  from  the  group  constiluted  by

sodium carbonate and potassium carbonate, and mixtures thereof.

According to one particular embodiment, methanol may be added at the end of step (ii} described above, the reaction medium is heated to a temperature of
between 20 and 80°C, for example between 50 and 70°C, preferably about 60°C,

25    until dissolution is virtually complete, and the remaining light insoluble matter is then separated out by filtration, in order subsequently to cool the methanol/water filtrate, preferably to about 0°C, in order to crystallize therefrom the desired N-
methylnaltrexone bromide.

According  to  another  particularly  preferred  embodiment,  the  insoluble

30    producl obtained at the end of step (i) described above is isolated after filtration by suction, and is then suspended in a methanol/water mixture, preferably of 4/1, thus constituting the aqueous reaction medium for step (ii) in which is performed the
reaction wfih hydrobromic acid, preferably at 48% concentration, which is added, for a pH of the aqueous reaction medium of between 0.5 and 5 and preferably of about 35    3, at a temperature of between 20 and 80°C, for example between 50 and 70°C,

preferably  60°C,  until  dissolution  is  almost  complete,  and  the  remaining  light

insoluble matter is then separated out by filtration, in order subsequently to cool the

filtrate,    preferably  to  about  O'C, to  crystallize  therefrom  the  desired  N-

methylnaltrexone bromide.

Recrystallization in a methanol/water mixture (of N-methylnaltrexone bromide) or optional washing of the isolated product (N-methylnaltrexone double

ion) with an organic solvent (for example methanol) makes it possible to remove the

lipophilic impurity 0-benzyi-N-methylnaltrexone bromide that may still be present.

The process according to the invention may advantageously include a step

10    of purification of the N-methylnaltrexone bromide thus obtained, by dissolution in an acetone/water mixture, preferably of 60/20, heating to reflux, preferably for at least about 15 minutes, and then separation by hot filtration, precipitation of the N-methylnaltrexone bromide by placing the hot filtrate in contact with warm acetone,

preferably of about 50'C,  and cooling of the reaction medium to a temperature

15    below O'C,preferably -2'C, the N-methylnaltrexone bromide thus precipitated being recovered by filtration, and dried.
This step of purification of the N-methylnaltrexone bromide may also be performed via dissolution in a methanol/water mixture or in water alone; similar
yields and qualities of the same chemical species are then obtained.

20    In the process described below, the N-methylna~rexone methyl sulfate may

be  advantageously  obtained  by  subjecting  Q-benzyi-N-methylnaltrexone  methyl

sulfate to a hydrogenation step.

This hydrogenation step may advantageously be performed as described in

Example    1  below,  and  even  more  generally  by  subjecting  0-benzyi-N-

25    methylnaltrexone methyl sulfate, in the fomn of an aqueous solution, to a hydrogenation on 5% palladium-on-charcoal, the reaction medium being maintained at a temperature of between 30 and 50'C, preferably 40'C, under a pressure of about 2.5 bar of hydrogen, for at least about 2 hours for complete Q-debenzylation.

The reaction medium is then cooled and the catalytic system removed by filtration.

30    The product obtained may advantageously not be isolated, which makes it

possible  to  avoid  any  contact  with  the  residual  dimethyl  sulfate  (highly  toxic

product).

In  the  process  according  to  the  invention,  0-benzyi-N-methylnaltrexone

methyl sulfate may be advantageously obtained by reacting 0-benzylnaltrexone with

35    dimethyl sulfate, in acetone, in the presence of sodium hydrogen carbonate, the
 
reaction medium being refluxed for a sufficient time, preferably at least about 72 hours, for acceptable disappearance of the 0-benzylnaltrexone compound, the reaction monitoring possibly being monitored in a known manner, for example by HPLC monitoring.

A subject of the present invention is also the novel intermediate compound 0-benzyi-N-methylnaltrexone methyl sulfate, thus obtained.

The respective diastereoisomers of (R) and (S) configurations relative to the nitrogen atom of 0-benzyi-N-methylnaltrexone methyl sulfate, and also mixtures thereof, including racemic•mixtures, form part of the invention.
10 In particular, the benzyl protecting group on the phenolic oxygen most particularly has a twofold advantage:

cleavage without introduction and formation of an ionic product: only hydrogen is used, and the toluene formed is readily removed;
hydrogenation makes tt possible to reduce the amount of 7,8-didehydro-N-

15    methylnaltrexone (undesirable conjugated ketone) in the final product after hydrogenation of the double bond.

Moreover, the process according to the invention provides excellent diastereoselectivity upstream and for the isolation in N-methylnaltrexone double ion form, and for the production of the desired final product, i.e. (R)-N-

20    methylnaltrexone.

In the process according to the invention, the 0-benzylnaltrexone may be advantageously obtained by reacting naltrexone hydrochloride, or base naltrexone, with benzyl bromide, in acetone, in the presence of potassium carbonate, the reaction medium being maintained at reflux, preferably at a temperature of about

25    60°C, for about 2 hours, and then cooled to room temperature (about 20°C) in order subsequently to filter, and optionally wash with acetone, and the acetone is evaporated from the filtrate to obtain the desired compound in the form of an oil. Preferably, this oil is taken up, for example, in dichloromethane and washed, for example, with dilute (3%) sodium hydroxide.

30 This liquid extraction in basic medium makes it possible to totally remove the residual non-benzylated naltrexone and to avoid the formation of the impurity 3-0-methyi-N-methylnaltrexone in the alkylation/quaternization step.

The product may advantageously not be isolated, which makes it possible to avoid manipulating a medium containing benzyl bromide, which is a lachrymogenic

35    and toxic product.

Finally,    in  the   process  according  to  the  invention,  the  naltrexone

hydrochloride or the base naltrexone may be advantageously obtained by reacting

noroxymorphone    hydrochloride  with  bromomethylcyclopropane,   in  dimethyl-

acetamide,  in the presence of sodium hydrogen carbonate, the reaction medium

being heated to a temperature of between 60 and 75oc and preferably between 65 and 69°C, as described, for example, in step 1 of the process of Example 1.
Figure  1  represents  a  theoretical  diffractogram  (or  powder  diagram),

obtained from a monocrystal of the double ion, as described in Example 1 (part

1.5.2).

10    Figure 2  represents  an experimental  diffractogram (or powder diagram),

obtained from the double ion, as described in Example 1 (part 1.5.2).

The examples that follow are intended to illustrate the present invention, in a non-limiting manner, and should therefore not be interpreted as possibly limiting its

scope.

15 Unless otherwise mentioned, the NMR data below are obtained with TMS (tetramethylsilane) as reference.

Example 1:   Preoaration of N-methylnaltrexone bromide

20    1.1    Preparation of crude base naltrexone (Step 1; N-alkylation)

100 g (0.27 mol) of noroxymorphone hydrochloride, 80.8 g (0.96 mol; 3.55 eq.) of sodium hydrogen carbonate and 300 ml of dimethylacetamide are

successively introduced into a 500 ml reactor equipped with a condenser and a

mechanical stirrer. The reaction medium is heated to between 65°C and 69"'C.

25 At the end of the observed evolution of gas (about 10 minutes), 35 ml of bromomethylcyclopropane (0.44 mol; 1.6 eq.) are introduced over 30 minutes while keeping the temperature at 69°C.

The N-alkylation is complete in about 6 hours, and the reaction progress is monitored by HPLC analysis (residual content of noroxymorphone less than or

30    equal to 0.5%). The reaction medium is cooled to 50°C and then poured with stirring over 1 hour into a mixture of 1000 ml of water and 100 g of sodium chloride

preheated to 50°C.

The pH is adjusted to 8.6-9 by addition of 8 ml of 30% sodium hydroxide.

The product obtained is isolated by filtration at 15°C and dried in an oven under

86  g  of  crude  naltrexone  are  finally  obtained  (yield:  88.6%)  (HPLC  in

accordance with the standard and in accordance regarding the 1H and 13C NMR and

mass structures).

1H NMR: (ppm; ± O.Q1 ppm): 0.45 to 0.65 (2H, CH, (20/21 ), unresolved complex); 0.41 and 0.66 (2H, CH, (20/21), two multiplets); 1.11 (1H, CH (19), multiplet); 1.47 and 2.72 (2H, CH2(15), multiplet and dt); 1.50 and 2.05 (2H, CH2 (B),

10    two multiplets); 2.10 and 3.03 (2H, CH, (7), two multiplets); 2.48 and 3.03 (2H, CH2 (16), two multiplets); 2.97 and 3.32 (2H, CH,(1B), two multiplets); 4.02 (1H, CH (9), doublet; J = 6.0 Hz)± 0.5 Hz); 5.04 (1H, CH (5), singlet); 6.71 (1H, CH(2), doublet; J = B Hz± 0.5 Hz); 7.11 (1H, COH (14), singlet); 9.05 (1H, NH, singlet); 9.05 (1H,

COH (3), singlet).

15 "c NMR (ppm ± 0.1 ppm): 2.6 and 5.0 (C20 and C21); 5.6 (C19); 22.8 (C10); 27.1 (C15); 30.6 (CB), 35 (C7); 46 (C16); 48.5 (C13); 56.6 (C1B); 60.8 (C9); 69.7 (C14); 88.5 (C5); 118.0 (C2); 119.7 (C1); 120.4 (C11); 127.8 (C12); 140.1

(C4); 143.5 (C6).

Mass (chemical ionization (M + H)• = 342.2

20

1.2    Preparation of 0-benzylnaltrexono (Step 2; 0-Benzylation)

5.0    g (0.014 mol) of naltrexone hydrochloride (the base may be used), 5.0 g (0.036 mol; 2.58 eq.) of potassium carbonate and 25 ml of acetone are successively

added to a 50 ml reactor equipped with a condenser and a mechanical stirrer. 2.6 g

25    (0.015 mol; 1.08 eq.) of benzyl bromide are then added over 10 minutes at 2ooc with stirring. The reaction medium is refluxed (60°C) for 2 hours and then cooled to 20oc and filtered. The filter cake is washed with twice 25 ml of acetone.
The acetone is evaporated off under vacuum and the residual oil is taken up

in 40 ml of dichloromethane and then washed with 3 times 25 ml of dilute (3%)

sodium hydroxide.

This liquid extraction in basic medium makes it possible to totally remove the

residual  non-benzylated  naltrexone  and  to  avoid  the  formation  of  the  impurity

5    3-0-methyi-N-methylnaltrexone in the quatemization step 3.

After performing separations of the phases by settling and extractions, the

dichloromethane solution is concentrated until no further distillation takes place, and is then used in the following stage without further purification.
The  product  is  not  isolated,  to  avoid  manipulating  a  medium  containing

10    benzyl bromide, which is a lachrymogenic and toxic product.

Structural  analysis:  a  sample  of the  oil  obtained  is  taken  to  isolate  the

0-benzylnaltrexone product in hydrochloride fonm (the 0-benzylnaltrexone hydrochloride is obtained by dissolving the base in oil form in MTBE - or methyl

15    tert-butyl ether- and adding 35% hydrochloric acid).

1H NMR (ppm± 0.01 ppm): 1.2 (2H,CH 2 (20), multiplet J =6Hz; 0.46 and 1.20 (2H,CH2 (20'),multiplet, J =5Hz); 1.2 (1H, CH(19), multiplet, J = 7.0 Hz); 3.2 (2H,CH2, broad signals); 1.67 and 3.2 (2H, C HZ (15), dd; J = 13.8, J = 3.0 Hz,

20    broad signals); 1.84 and 2.51 (2H,C Hz (8), td, J = 3.2 Hz, broad signals); 2.33 and

3.25 (2H,CH2(7), d, J = 14.5 Hz, J = 5.0, td J = 14.6 Hz, J = 2.0 Hz); 2.51 and 3.45 (2H,CH2 (16), broad signal); 2.94 and 3.45 (2H,CH2(18), dd; J = 12.5 Hz, J = 7.2 Hz,

broad signal), 4.51  (1H, CH (9), broad singlet); 5.22 and 5.30 (2H, CH2  (21) and CH2 (21');J  = 12.1 Hz); 5.00 (1H, CH (5); broad singlet); 6.79 (1H, CH(2) and 25    CH(1), AB system; J = 8.3 Hz); 6.65 (1H, CH (1) and CH(2), AB system, J = 8.3


Hz); 6.65 (1 H, CH(23)CH(24), benzyl system) 6.65 (1 H, CH(25), benzyl system); 6.65 (1 H,CH(24),CH(23), benzyl system).

13C NMR (ppm± 0.1 ppm): 3.8 (C20); (C20');6.1 (C19); 24.2 (C10); 27.5 (C15), 31.2 (C8); 35.4 (C7); 47.0 (C16); 49.2 (C13);; 58.4 (C18); 61.2 (C9); 70.4 (C14): 72.1 (C21 and 21');89.8 (C5); 118.9 (C2 and C1); 119.9 (C1 and C2); 121.6 (C22); 127.8 (C23 and C24); 128 (C25); 128.5 (C24 and C23); 137 (C3); 142.8 (C11 and C12); 145.9 (C12 and C11); 207.1 (C6)
Mass (ionization MH')= 432.5

10    1.3 Preparation of N-methyl-0-benzylnaltrexone methyl sulfate (step 3: N-methylation, quaternization)
The oil obtained in the preceding stage is dissolved in 20 ml of acetone and

then poured at 20'C with stirring into a dry 50 ml reactor containing 1.3 g (0.015 mol; 1.08 eq.) of sodium hydrogen carbonate; 6.7 g (0.053 mol; 3.53 eq.) of

15    dimethyl sulfate are then added over 10 minutes.

The reaction medium is refluxed with stirring for a minimum of 72 hours until

the 0-benzylnaltrexone has totally disappeared (HPLC monitoring). The reaction medium is cooled to 20'Cand then filtered.

The filter cake is washed with twice 10 ml of acetone and then placed in

20    basic solution (NaHCO, or NaOH). This filtrate is stored at 20'Cfor use in the following stage without isolation.

The  product  is  not  isolated,  to  avoid  manipulating  a  product  containing

dimethyl sulfate. Similarly, the filter cake (NaHCO, + dimethyl sulfate residue) is

dissolved  on the filter without isolation, with basic medium,  so as to destroy the

25    dimethyl sulfate and form sodium methyl sulfate (non-toxic).

Structural analysis: a small amount of the product is taken up and purified by

preparative chromatography in order thus to obtain a sample analysed as follows.
 

1H NMR (ppm ± 0.01 ppm); 0.41 and 0.88 (2H, CH, (20); multiple~ J = 5.0 Hz); 1.2 (1 H, CH (19), multiplet, J = 5.0 Hz); 0.55 and 1.06 (2H CH, (20');multiplet,

J = 5.0 Hz); 1.75 and 3.0 (2H, CH2 (15), d; J = 12.5 Hz); 3.1 and 3.41 (2H, CH2 (10}, multiplet d, J = 5.5 Hz, J = 20.1 Hz); 1.63 and 2.43 (2H, CH, (8}, td, doublet of multiplets, J = 13.7 Hz, J = 3.2 Hz, J = 11.5 Hz); 2.25 and 3.16 (2H, CH2 (7), dt, unresolved complex, J = 14.9 Hz; J = 2.8 Hz); 3.66 (3H, CH, (17}, s); 2.9 and 3.15 (2H, CH,(16}, multiplet, H =3Hz); 5.03 (1H,CH(9}, d, J = 4.1 Hz) 5.20 and 5.28 (2H, CH, (21) and (21',d, J = 12.0 Hz); 2.60 and 3.77 (2H, CH2(18); dd,dd, J = 13.5

10    Hz, J = 9.4 Hz; J =13.5 Hz, J = 3.6 Hz); 5.05 (1H, CH(S), s); 6.82 (2H,CH(2) and CH(1}, AB system, J = 8.3 Hz); 6.68 (2H, CH(1) and CH(2}, AB system, J = 8.3 Hz);
7.33    (2H, CH (23) and CH(24), benzyl system) 7.33 (1H, CH (25), benzyl system;

7.33    (2H CH(23) and CH (24}, benzyl system).

13C NMR (ppm± 0.1 ppm): 3.6 (C20); 4.2 (C19}; 7.1 (C20');25 (C15); 27.9

15    (C10); 32.5 (C8); 35.3 (C7); 49.0 (C13); 53.8 (C17); 58 (C16); 71.4 (C9); 72 (C14); 7.21 (C21 and 21'),73.2 (C1B); 89.6 (C5); 119.0 (C2 and C1); 120.3 (C(1) and C(2}); 121.1 (C22); 127.8 (C23 and C24) 128.1 (C25); 128.5 (C24 and C23); 136.8 (C3); 143.3 (C11 and C12); 146.0 (C12 and C11); 206.8 (C6).

Mass (chemical ionization M')= 466

20    By HPLC analysis, the existence of the (R} and (S) respective configurations

with  respect to  the  nitrogen  atom  is  observed,  in an  R!S  configuration ratio  of

96.6/3.4.

1.4    Preparation  of  N-methylnaltrexone  methyl  sulfate  (step  4:

0-debenzylation)

The above acetone solution is concentrated to one third, 100 ml of water are then added and the distillation under vacuum is continued until the acetone has been removed.
After cooling lo 20°C, the above solution  is added lo  5%  palladium-on-

charcoal (0.3 g).

The reaction medium is then warmed lo 40°C. Purging sequences (N,IH2)

are performed, followed by establishing a pressure of 2.5 bar of hydrogen.

The 0-debenzylation  is complete after about 2 hours, with  monitoring  by

10    HPLC (content of N-methyl-0-benzylnaltrexone methyl sulfate less than 0.5%). The reaction medium is cooled to 20oc and filtered to remove the catalyst.
The aqueous solution of N-methylnaltrexone methyl sulfate thus obtained is

used directly in the following stage.

The benzyl protecting group on the phenolic oxygen has a twofold 15 advantage:

cleavage  without  introduction  and  formation  of  an  ionic  product:  only

hydrogen is used, and the toluene formed is readily removed;

hydrogenation makes it possible to reduce the amount of 7,8-didehydro-N-methylnaltrexone (conjugated ketone, thus warning structure) in the final
20    product after hydrogenation of the double bond.

The product is not isolated, to avoid contact with the residual dimethyl sulfate (highly toxic product).

1.5    Preparation   of   N-methylnaltraxone   bromide   (step   5:   methyl

25    sulfate/bromide exchange)

1.5.1    N-methylnaltrexone double ion (isolation of this compound)

The aqueous solution from  stage 4 is concentrated under vacuum  until a

residual volume of 30 ml is obtained, and 1 g of Na,CO, is then added until a pH of

about 9.5 to 9.8 is obtained (natural pH of sodium carbonate in water).

30    The reaction medium is maintained at 20oc with stirring for 1 hour.

The use of sodium carbonate in this step makes it possible in particular to

destroy the dimethyl sulfate after 1 minute of contact.

The insoluble matter fonmed is filtered off by suction, and ~ is thus seen that

an N-methylnaltrexone double ion may exist under these particular pH conditions

35    (with the use of sodium carbonate Na2CO,).

Structural analysis: a portion of the suction-filtered insoluble matter obtained above is suspended in water at a pH of about 9.5 (which makes it possible to purify the double ion before analysis by "desa/tingn) and is then isolated by suction
filtration and drying.

1H NMR (ppm± 0.01 ppm); 0.0 and 0.48 (2H, CH2(C20)); multiplet, J = 5.0 Hz, J = 4.5 Hz); 0.88 (1h, CH (19), multiplet, J = 4.0 Hz); 0.29 and 0.60 (2H, C Hz(20'),muKiplet, J = 4.8 Hz); 1.49 and 2.51 (2H, CH, (15), doublet of mu/tiplets,
J = 10.4 Hz) 2.79 and 3.29 (2H, CH,(10), d, J = 19.9 Hz); 1.57 and 1.97 (2H, CH2(8)

10    or (7); dd, doublet of multiplets, J = 13.8 Hz, J = 3.9 Hz, J = 15.2 Hz); 1.77 and 2. 71 (2H, CH2 (7) or (8), doublet of mu/tiplets, dt, J = 13.9 Hz, J = 14.9 Hz, J = 5.4 Hz);

3.38 (3H, CH,(17), s); 2.80 and 3.03 (2H, CH,(16); dd; J = 13.0 Hz, J = 3.5 Hz);

3.72    (1H, CH(9), d, J = 4.6 Hz); 2.47 and 3.60 (2H, CH2 (18); t, dd, J = 9.8 Hz, J =

13.9    Hz, J = 3.5 Hz); 4.54 (1 H, CH(5), s), 6.35 (2H, CH(2) and CH(1), AB system, 15 J = 8.2 Hz); 6.26 (2H, CH(1) and CH(2), AB system, J = 8.1 Hz).

13C NMR (ppm± 0.1 ppm)= 0.0 (C20); 1.3 (C19); 3.7 (C20');22.2 (C15); 25.4 (C10); 30.2 (C8 or C7); 30.3 (C7 or C8); 47.0 (C13); 51.0 (C17); 55.5 (C16); 69.8 (C9); 70.3 (C18); 70.5 (C14); 111.9 (C5); 118.9 (C2 and C1); 119.6 (C1 and C2); 124.1 (C3); 143.8 (C11 and C12); 147.8 (C12 and C11); 211.5 (C6).

20    Mass (chemical ionization Mff) = 356 Elemental analysis:
-   theoretical calculated values (C 60.7%; H 7.68%; N 3.37%; 0 28.24%)

experimental values (C 61.64%; H 7.6%; N 3.19%).

These two values take into account a water content of 14.45%, which may

25    be interpreted in principle as a degree of hydration of a trihydrate form (3H20).

However, the following analyses were also performed.

Analysis by powder x-ray diffraction (XRD):

The  analysis  is  perlormed  in  a  05005  diffractometer  from  the  company

BrOker. The angular range is between 2.00 and 40.00"28 in increments of 0.02"20

and 2 seconds per increment. The generator is set at 50 kV-40 rnA for a copper

tube whose incident beam wavelength is 1.54056 A.

The  double  ion  purified  by  "desalting"  as  described  above  gives  an

experimental diffractogram (see Figure 2) that proves to be identical by comparison

with  a  theoretical  diffractogram  corresponding  to  a  dihydrate  (2H2 0)  crystal

structure.  This theoretical diffractogram  is obtained by simulation (see Figure 1;

Mercury® software) from the results of a crystal study on a monocrystal of the same 10 double ion purified by "desalting".
The difference in degree of hydration obtained on a monocrystal (2H 20) and on the elemental analysis (3H,O) is explained by the presence of two molecules of

water  of  crystallization  in  the  structure  of the  crystal  lattice  and  of  one  water

molecule  originating  from  the  water  of  insertion  into  the  microchannels  of  the

15    crystals (water of impregnation).

By HPLC analysis, the existence of the (R) and (S) respective configurations

with respect to the nitrogen atom is observed, in an R/S configuration ratio of 98/2.

1.5.2    N-methylnaltrexone bromide

20 The preceding insoluble matter is suspended in 20 ml of an MeOHiwater mixture (4/1), hydrobromic acid is added (qs pH = 3) and the reaction medium is
then maintained at 60"C until the dissolution is virtually complete.

The light insoluble matter (undissolved N-methylnaltrexone) is filtered off and the filtrate is then cooled to O"C. The crude N-methylnaltrexone bromide crystallizes
25    on cooling, and is then filtered off by suction.

Recrystallization from a methanol/water mixture (of the N-methylnaltrexone bromide) or optional washing of the isolated product ("double ion") with an organic solvent (for example methanol) allows the lipophilic impurity 0-benzyi-N-

methylnaltrexone bromide to be removed.

30

1.6    Preparation   of   pure   N-methylnaltrexone   bromide   (step   6:

recrystallization from acetone/water)

5.6 g of crude N-methylnaltrexone bromide (dry), 7.5 ml of water and 22 ml

of acetone  (i.e.  5 volumes of an  B0/20  acetone/water mixture)  are  successively

35    introduced into a 50 ml reactor equipped with a condenser. The medium is refluxed


for 15 minutes. The cloudy material  (undissolved  N-methylnaltrexone bromide) is

filtered off while hot (60°C) and the hot filtrate is poured into 10 ml of acetone at

50°C.

The product precipitates in solution, the solution is cooled to -2"C and the

precipitate is filtered off.

The product is dried under vacuum at 20"C for 48 hours.

4.3 g of pure N-methylnaltrexone bromide are finally obtained (76% yield relative to the crude N-methylnaltrexone bromide, and 70% yield relative to the starting naltrexone hydrochloride).

10


Physical characteristics:

Melting point: (DSC): 262°C

15 1H NMR (ppm,± 0.01): identical to Naltrexone except for: 3.7 (3H, C(22) singlet); "c (ppm ± 0.01) identical to Naltrexone except for: 58 (C(22)).

Mass: (chemical ionization): (M+H) = 356.3. Complies in all respects with the literature data.

20    Example 2: Preparation of N-methylnaltrexone bromide (steo 5: methyl sulfate/bromide exchange variant without isolation of the intermediate

The  aqueous  solution from  step 4  of Example  1 is  concentrated  under

vacuum until a residual volume of 30 ml is obtained, and 1 g of Na2C03  is then

introduced  until  a pH  of  about 9.5  to  9.8  is  obtained  (natural  pH  of sodium

25    carbonate in water).

The reaction medium is maintained at 20"C with stirring for 1 hour, 2.1 ml of 48% hydrobromic acid are then added over 1 hour, i.e. down to a pH of about 1,


and the reagents are left in contact with stirring for a further 1 hour.

The insoluble matter of the reaction medium is filtered off by suction and this filter cake is washed with 10m! of acetone and then dried in an oven under vacuum

(10 mmHg) at 40'Cfor 12 hours.

5    9.35 g of a mixture of crude N-methylnaltrexone bromide and of mineral salts

(NaBr  and  NaMeSO,;  titre  of  crude  N-methylnaltrexone  bromide:  50%)  are

obtained.

Example 3:   Preparation  of  N-methylnaltrexone  bromide  (step  5:  methyl

1o   sulfate/bromide exchanae, variant without isolation of the intermediate. with

MeOHl

In step 5 of the process of Example 1, after treatment wijh HBr, 40 ml of

methanol are added and the mixture is then maintained at 60°C until the dissolution

is virtually complete. The light insoluble matter (undissolved N-methylnaltrexone 15 bromide) is filtered off.

The filtrate (MeOHIH,O mixture) is cooled to O'C.The crude MNTX bromide

crystallizes on cooling, and is then filtered off by suction.

The major advantage of this variant is the solubilization of mineral salts (NaBr, NaCH3S04) in the methanol/water mixture, whereas NaBr Is slightly soluble

20    in the ethanoUwater mixture.
 
(I)

in anhydrous or hydrate form.

2.    N-methylnaltrexone double ion according to Claim 1, of (R) configuration relative to the nitrogen atom.

3.  N-methylnaltrexone  double  ion  according  to  Claim  1,  of  (S)

10    configuration relative to the nitrogen atom.

4.    N-methylnaltrexone double ion according to any one of Claims 1 to

3, in the form of a hydrate chosen from the hemihydrate, dihydrate and trihydrate fonms.
5.    (R)-N-methylnaltrexone double ion, dihydrate.

15    6. Process for preparing the N-methylnaltrexone double ion compound, as defined in any one of the preceding claims, comprising the step that consists in reacting N-methylnaltrexone methyl sulfate in

aqueous  solution  with  an  alkaline  agent  chosen  from  the  group

constituted  by  sodium  carbonate,  potassium  carbonate,  calcium

20    carbonate, magnesium carbonate, caesium carbonate, strontium carbonate and mixtures thereof, for a pH of the aqueous reaction medium of between 7 and 10.

7.    Process for preparing N-methylnaltrexone bromide, comprising at least the steps consisting in:

25    (i) reacting N-methylnaltrexone methyl sulfate in aqueous solution with an alkaline agent chosen from the group constituted by sodium carbonate, potassium carbonate, calcium carbonate, magnesium carbonate, caesium carbonate, strontium carbonate and mixtures

thereof, for a pH of the aqueous reaction medium of bet'Neen7 and

10, and then in

(ii) reacting the product thus obtained with hydrobromic acid, which is added for a pH of the aqueous reaction medium of between 0.5 and 5, in order thus to obtain the N-methylnaltrexone bromide.

8.    Process according to Claim 6 or 7, characterized in that the alkaline agent is chosen from the group constituted by sodium carbonate and potassium carbonate, and mixtures thereof.
9.    Process according to Claim 7 or 6, in which methanol is added at

10    the end of step (ii), the reaction medium is heated to a temperature of between 20 and ea~c. and the remaining insoluble matter is then

separated out by filtration, in order subsequently to cool the fiKrate, from which the desired N-methylnaltrexone bromide crystallizes.
10. Process  according  to  any  one  of Claims  7 to  9,  in  which  the

15    insoluble product obtained at the end of step (i) is isolated after filtration by suction, and is then suspended in a methanol/water mixture, thus constituting the aqueous reaction medium for step (ii) in which is performed the reaction with hydrobromic acid at a
temperature of between 20 and 80°C, and the remaining insoluble

20    matter is then separated out by filtration, in order subsequently to cool the filtrate, from which the desired N-methylnaKrexone bromide crystallizes.

11.    Process according to any one of Claims 7 to 10, in which the N-methylnaltrexone bromide thus obtained is subjected to a
25    purification step by dissolution in an acetone/water mixture, heating to reflux and then separation by hot filtration, precipitation of the N-methylnaltrexone bromide by placing the hot filtrate in contact with warm acetone, cooling of the reaction medium to a temperature
below 0°C, the N-methylnaltrexone bromide thus precipitated being

30    recovered by filtration.

12.    Process according to any one of Claims 7 to 11, in which the N-methylnaltrexone methyl sulfate is obtained by subjecting 0-benzyi-N-methylnaltrexone methyl sulfate to a hydrogenation step.
13.    Process according to Claim  12, in which the 0-benzyi-N-methyl-

35    naltrexone    methyl    sulfate    is    obtained    by    reacting
 


20

0-benzylnaltrexone  with  dimethyl  sulfate,  in  acetone,  in  the

presence of sodium hydrogen carbonate, the reaction medium being

reHuxed for a sufficient time for acceptable disappearance of the 0-

benzy\naltrexone compound.

14.    0-Benzyi-N-methylnaltrexone methyl sulfate.

15.    0-Benzyi-N-methylnaltrexone methyl sulfate according to Claim 14, of (R) configuration relative to the nitrogen atom.
16.    0-Benzyi-N-methylnaltrexone methyl sulfate according to Claim 14,

of (S) configuration relative to the nitrogen atom.

10    17. Process according to Claim 13, in which the 0-benzylnaltrexone is obtained by reacting naltrexone hydrochloride, or base naltrexone, with benzyl bromide, in acetone, in the presence of potassium carbonate, the reaction medium being maintained at reflux, and then

cooled in order subsequently to filter, and the acetone is evaporated
15    from the filtrate to obtain the desired compound in the form of an oil.

18.    Process according to Claim 17, in which the naltrexone hydrochloride or the base nattrexone is obtained by reacting noroxymorphone hydrochloride with bromomethylcyclopropane, in dimethylacetamide, in the presence of sodium hydrogen carbonate,

20    the reaction medium being heated to a temperature of bet'Neen60 and 75'C

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