DESC:Technical field of the Invention:
The present invention relates to an improved process for the preparation of Bethanechol Chloride.

Background of the Invention:
Bethanechol chloride, a cholinergic agent, is a parasympathomimetic choline carbamate that selectively stimulates muscarinic receptors without any effect on nicotinic receptors. It stimulates the bladder to empty used to treat urinary retention (difficulty urinating), which may occur after surgery, after delivering a baby, and in other situations. Betahnechol chloride is structurally and pharmacologically related to acetylcholine.

It is designated chemically as (2-Carbamoyloxypropyl)trimetylammonium chloride (IUPAC)
2-[(aminocarbony) oxy]-N, N, N-trimethyl-1-propanaminium chloride. Its molecular formula is C7H17CIN202 and its structural formula is:

Each tablet for oral administration contains 5 mg, 10 mg, 25 mg or 50 mg bethanechol chloride.

The earliest known synthesis of bethanechol chloride, by Major et al, is described in U.S. Pat. No. 2,322,375. The synthetic method employed is depicted in the following reaction scheme 1.

Scheme 1

The patent 007’ teaches the preparation of bethanechol chloride by reacting ß- methyl choline chloride of formula (III) at room temperature with an excess of phosgene in chloroform, for about two hours. Excess phosgene and hydrochloric acid are removed by distillation under vacuo. Additional chloroform is added to the syrup and the mixture is poured into excess ammonia dissolved in chloroform and cooled in solid carbon dioxide-acetone. The solid is filtered and extracted with hot alcohol, precipitated with ether and recrystallized from isopropanol.

The process has many disadvantages, for example:
i) The use of highly toxic phosgene as a reagent is a poisonous gas at room temperature . Exposure to dangerous concentrations of phosgene may cause coughing, burning sensation in the throat and eyes, watery eyes, blurred vision, difficulty breathing or shortness of breath, nausea and vomiting, suffocation, skin contact can result in lesions similar to those from frostbite or burns. Following exposure to high concentrations of phosgene, a person may develop fluid in the lungs (pulmonary edema) within 2 to 6 hours. Due to the toxic nature and various side effects, extreme care must be taken while handling and storing phosgene. Thus making it difficult to use on large scale synthesis.

ii) The use of chloroform as a reaction solvent is evaporates quickly. Chronic exposure to chloroform is associated with effects on the liver, kidney, and central nervous system. Breathing about 900 parts of chloroform in a million parts of air for a short time causes fatigue, dizziness, and headache.

Iii) Use of multiple solvent leads to an overall increase in the handling and production costs.
Hence , the process is not viable industrially.

A refinement of the above process is described in JP 2008150322. The synthetic method employed is depicted in the following reaction scheme 2.
Scheme 2

The process comprises reacting 1-(dimethylamino)propan-2-ol of formula (V) with 1,1'-Carbonyldiimidazole (CDI) to yield 1-(dimethylamino)propan-2-yl-1H-imidazole-1-carboxylate of formula (VI). The reaction with benzylamine for almost 10 hours followed by column chromatography yields acid 2-benzyl-carbamide - dimethylamino-1 - methyl - ethyl ester of formula ( XIII). Debenzylation with 5 % Pd/C for 24 hours at room temperature yields carbamide acid 2 - dimethylamino-1 - methyl - ethyl ester of formula (XIV). Quarterization with methyl chloride for 7 days at room temperature results in bethanecholchloride of formula (I).

The process described in the above patent involves multiple steps and longer duration of reaction, which leads to decrease in the yield and purity of the product.

Therefore, there exists a need for a more economical and efficient method of making bethanechol chloride which is suitable for industrial scale up.

The present invention provides an improved process for synthesis of bethanechol chloride which avoids all the disadvantages associated with the prior art processes.

Objects of the Invention:
One object of the present invention is to provide an improved process for preparing of bethanechol chloride.

Another object of the present invention is to provide a purification method to obtain high purity of bethanechol chloride.

Yet another object of the present invention is to provide a process for preparing of bethanechol chloride which is simple, economical and suitable for industrial scale up.

Summary of the Invention:
According to a first aspect of the present invention, there is provided a process for preparing of bethanechol chloride of Formula (I)
;
comprising reacting ß- methyl choline chloride of formula (III)

with 1,1'-Carbonyldiimidazole (CDI), optionally in the presence of a base to the intermediate 2-[(imidazolecarbonyl) oxy]-N, N, N-trimethyl-1-propanaminium chloride of formula (II)

and reacting intermediate imidazole ester with ammonia to bethanechol chloride of Formula (I).

The condensation reaction may be carried out by isolating intermediate ester (II). Preferably, the reaction is carried out without isolating ester (II).

This improved process results in the simplified work up procedure by avoiding extraction, using multiple organic solvents and purification of the intermediates by column chromatography. All these advantages form one aspect of the present invention.

According to yet another aspect of the present invention there is provided novel intermediate 2-[(Imidazolecarbony) oxy]-N, N, N-trimethyl-1-propanaminium chloride of formula (II). The novel intermediate may be prepared according to the process described above.

There is also provided by the present invention bethanechol chloride prepared by a process as described above.

According to another aspect of the present invention, there is provided a pharmaceutical composition comprising bethanechol chloride, prepared by a process as described above, together with one or more pharmaceutically acceptable excipients. Such excipients are well known to those skilled in the art.

According to another aspect of the present invention, there is provided the use of bethanechol chloride, prepared by a process as described above in medicine.

According to another aspect of the present invention, there is bethanechol chloride, prepared by a process as described above for use in the treatment of urinary retention -acute postoperative, postpartum and neurogenic; reflux oesophagitis.

According to another aspect of the present invention, there is provided the use of bethanechol chloride, prepared by a process as described above, in the manufacture of a medicament for treating urinary retention.

According to another aspect of the present invention, there is provided the use of bethanechol chloride, prepared by a process as described above in the treatment of urinary retention.

According to another aspect of the present invention, there is provided a method of treating urinary retention- acute postoperative, postpartum and neurogenic in a patient in need of such treatment, which method comprises administering to the patient a therapeutically effective amount of bethanechol chloride, prepared by a process as described above.

Detailed Description of the Invention:
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.

The present invention describes a practical, economical and efficient synthesis for the preparation of high purity bethanechol chloride . This process is particularly advantageous in comparison with known methods because the reaction may be carried out without isolating the intermediate formed by the preceding step. The process of the present invention eliminates the risk of handling hazardous chemicals like phosgene , the enhanced cost associated with multiple reactors, and it reduces the reaction time and cleanup, thus making the process more industrially viable.

Accordingly, an embodiment of the process for the preparation of bethanechol chloride is as shown in Scheme 3.
Scheme 3

wherein the process is carried out without isolating the intermediate of formula (II). In the context of the present invention, the term “without isolation” means that the product being referred to as not being isolated is not isolated as a solid, for example it is not isolated from the reaction mass and dried to form a solid. Thus, “without isolation” may mean that the product remains in solution and is then used directly in the next synthetic step, or it may mean that solvent is substantially removed from a solution of the product such that the product is present as a residue, but not as a solid.

In an embodiment, the step (a) is carried out without isolation of intermediate 2-[(imidazolecarbony) oxy]-N, N, N-trimethyl-1-propanaminium chloride of formula (II). In another embodiment, the process is carried out as a one-pot process. Alternatively, the process may be carried out with isolation of the imidazole-N-carboxylic ester intermediate (II).

In an embodiment ß- methyl choline chloride of formula (III) is reacted with 1,1'-Carbonyldiimidazole (CDI) in the presence of a suitable solvent to the intermediate 2-[(imidazolecarbony) oxy]-N, N, N-trimethyl-1-propanaminium chloride of formula (II) .

ß- methyl choline chloride may be added as solid or as an alcoholic solution. In an embodiment alcohol is C1-C4 alcohol such as methanol, ethanol , isopropanol and the like. Preferably, alcohol is methanol and ß- methyl choline chloride is added as a 20 % w/w solution in methanol.

Due to extreme sensitivity of CDI to water, and since any residual water in the solvents would result in some loss of CDI, the reaction is preferably carried out in a dry condition and under inert atmosphere. Preferably, alcoholic solvent is distilled out from the reaction, before treatment with CDI. More preferably, traces of the solvents are removed by stripping with a high boiling non polar solvent. In an embodiment non polar solvent is selected from but not limited to ethyl acetate,toluene ,xylene, hexane, heptane and the like. .

The molar ratio of ß- methyl choline chloride to the CDI varies from 1:1 to 1:5.

The condensation reaction may be carried out in the absence or presence of a base such as an organic or inorganic base. The inorganic base is preferably selected from the group consisting of alkali metal hydroxides, metal amides, metal alkoxides, alkyllithiums, amine bases, and alkali metal hydrides. Examples of suitable base are: sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, sodium methoxide, sodium ethoxide, potassium t-butoxide, potassium phosphate, potassium hydrogen phosphate, sodium carbonate, BuLi, and 1,8-diazabicyclo[5.4.0]undec-7-ene. The organic base is preferably selected from the group consisting of amines and nitrogen-containing heterocyclic compounds. Examples of suitable base are: mono methylamine, diethylamine, diisopropylamine, triethylamine, diisopropylethylamine and the like.

The base may be added to the reaction mixture to accelerate the rate of the reaction.

Preferably, the condensation reaction is carried out in the absence of a base.

In general, the activation reaction consists of reacting ß-methyl choline chloride of formula (III) with slight excess of CDI in an anhydrous solvent.

After stripping with a high boiling non polar, the reaction mixture containing ß-methyl choline chloride of formula (III) and CDI is stirred in an anhydrous solvent.

The anhydrous solvent may be selected from the group consisting of an aromatic hydrocarbon, a aprotic polar solvent such as tetrahydrofuran, methyl tertrahydrofuran; a protic polar solvent dimethylformamide, an aliphatic ether, esters such as ethyl acetate; non polar solvent such as chlorinated solvent or a mixture of one or more organic solvents. Preferably, the condensation reaction is carried out in the presence of chlorinated solvent such as dichloromethane.

The reaction is preferably carried out at a temperature of about -10°C to about 20°C, preferably about -5° C to about 10°C, more preferably about 0° C to about 5° C; for about an hour to about 8 hours, preferably about an hour to about 6 hours, most preferably about an hour to about 5 hours.

After completion of the reaction, the resulting imidazole-N-carboxylic ester intermediate (II), may be isolated as solid which is characterised by NMR and melting point. Preferably, imidazole-N-carboxylic ester intermediate (II), is used without further purification due to its sensitivity to hydrolysis.

In another embodiment, in step (b), the reaction mass containing imidazole-N-carboxylic ester intermediate (II) is treated with ammonia. The ammonia used in the amidation reaction of step (b) may be in the form of gaseous ammonia or liquid ammonia, preferably gaseous ammonia.

The reaction is preferably carried out at a temperature of about -10°C to about 20°C, preferably about -5° C to about 10°C, more preferably about 0° C to about 5° C; for about an hour to about 8 hours, preferably about an hour to about 6 hours, most preferably about an hour to about 5 hours.

After completion of reaction, the solid bethanechol chloride (I) may be isolated by cooling, chilling, distilling solvent partially or completely from the reaction mass or using any other conventional technique. Preferably, after the reaction is completed, the first solvent is removed under reduced pressure below 40°C and the residue is stirred in a suitable second solvent.

In an embodiment, first solvent is a reaction solvent . In an embodiment, the second solvent may be selected from the group comprising of a polar solvent such as alcohols, an aromatic hydrocarbon, a aprotic non-polar solvent such as ethyl acetate, n-heptane, n-hexane, toluene, xylene, diethyl ether, diisopropyl ether, and the like. Preferably, second solvent used are ethyl acetate and isopropyl alcohol.
The reaction contents are cooled to room temperature (about 25°C), stirred for about 30 mins to about 5 hours, preferably about 30 mins to about 3 hours, most preferably about 30 mins to about 1 hour. The solid may be isolated by filtration, optionally washed with a suitable solvent and then dried to obtain solid bethanechol chloride of formula (I).

In an embodiment, the process is a one-pot process. In other words, all the steps that result in solid bethanechol chloride of formula (I) in the process of the present invention are carried out in a single reaction vessel.

In still another embodiment bethanechol chloride of formula (I) is prepared by isolating the intermediate (II) obtained at preceding step.

In still another embodiment ß- methyl choline chloride of formula (III) may be prepared by reacting 1-chloropropan-2-ol of formula (IV) with triethylamine in the presence of suitable solvent as shown in scheme 4.

Scheme 4

The R and S isomers of compound (I) could be prepared using the appropriate isomer of compound (III) as a starting material.

Thus , (S)- bethanechol chloride may be prepared by using (2S)-1-chloropropan-2-ol (IV) as a starting material and following the synthetic protocol given above in the scheme 3. Similarly , (R)- bethanechol chloride may be prepared by using (2R)-1-chloropropan-2-ol (IV) as a starting material and following the synthetic protocol given above in the scheme 3.
In accordance with another aspect of the present invention, an alternate process for the synthesis of bethanechol chloride is as shown in Scheme 5, wherein 1-(dimethylamino)propan-2-ol of formula (V) is reacted with CDI to obtain 1-(dimethylamino)propan-2-yl-1H-imidazole-1-carboxylate of formula (VI) which is converted to quaternary ammonium salt by reacting with an alkyl halide preferably methyl iodide or methyl bromide to obtain 2-((1H-imidazole-1-carbonyl)oxy)-N,,N-trimethylpropan-1-ammdonium iodide/ bromide of formula (VII). The compound (VII) is then reacted with ammonia to give bethanechol iodide/ bromide of formula (VIII). The compound (VIII) is finally charged on Chloride-exchange resin column, eluted with distilled water and the combined eluent was evaporated to dryness under reduced pressure and recrystallized from a suitable solvent to give bethanechol chloride of formula (I), as colourless crystals.

Scheme 5


wherein X is iodo or bromo.

The R and S isomers of compound (I) could be prepared using the appropriate isomer of compound (V) as a starting material.

Thus , (S)- bethanechol chloride may be prepared by using (S)-( + )-1-dimethylamino-2- propanol (V) as a starting material and following the synthetic protocol given above in the scheme 5. Similarly , (R)- bethanechol chloride may be prepared by using (R)-( + )-1-dimethylamino-2- propanol (V) as a starting material and following the synthetic protocol given above in the scheme 5.

In accordance with yet another aspect of the present invention, an alternate process for the synthesis of bethanechol chloride is as shown in Scheme 6, wherein 4-methyl-1,3-dioxolan-2-one of formula (IX) is treated with aqueous ammonia to obtain 1-hydroxypropan-2-yl-carbamate of formula (X), which is chlorinated with thionyl chloride to obtain 1-chloropropan-2-yl-carbamate of formula (XI), which is then treated with triethylamine to give bethanechol chloride of formula (I), as colourless crystals.

Alternatively, hydroxy group of 1-hydroxypropan-2-yl-carbamate of formula (X), is protected with tosyl chloride to obtain 2-(carbamoyloxy)propyl-4-methyl benzenesulfonate of formula (XII), which is then treated with triethylamine to give bethanechol chloride of formula (I), as colourless crystals.

Scheme 6

While emphasis has been placed herein on the specific steps of the preferred process, it will be appreciated that many steps can be made and that many changes can be made in the preferred steps without departing from the principles of the invention. These and other changes in the preferred steps of the invention will be apparent to those skilled in the art from the disclosure herein, whereby it is to be distinctly understood that the foregoing descriptive matter is to be interpreted merely as illustrative of the invention and not as a limitation.

The details of the invention given in the examples which are provided below are for illustration only and therefore these examples should not be construed to limit the scope of the invention.

Examples:

Example 1: One pot synthesis of bethanechol chloride

A 20% w/w ß- Methyl choline chloride solution in methanol ( 1.0 Kg,1.30 moles) was charged in a flask under inert atmosphere. Methanol was distilled of under reduced pressure below 55°C. Stripped out with ethyl acetate below 55°C to residue. The reaction mixture was cooled to room temperature and the residue was stirred in dichloromethane ( 2.0 lit). The reaction mixture was further cooled to 0-5°C and N, N- Carbonyldiimidazole(CDI) ( 280 g, 1.323 moles) was added with stirring and maintaining the temperature 0-5° C. The reaction mixture was stirred for about 4-5 hours at 0-5°C. After completion of reaction, ammonia gas was purged into the reaction mixture for about 30 minutes with stirring and maintaining the temperature 0-5° C. The reaction mixture was further stirred for about 1-2 hours at 0-5°C. The solvent was distilled under reduced pressure below 40°C. Ethyl acetate ( 1.5 lit) was added and stirred further for 30min. The solid was isolated by filtration , washed and suck dried.
Yield: 85%. Purity: 95%.

Purification of bethanechol chloride

Bethanechol chloride ( 230 g ) was dissolved in methanol ( 400 ml) at 60-65°C and stirred for about 1 hour.The reaction mixture was cooled to 45-50°C and filtered hot to remove insoluble. To the clear filtrate was added IPA (1.5 lit) and the reaction mixture was heated to reflux for 30 mins. The reaction mixture was cooled to room temperature, chilled to 0-5°C and further stirred for about 1 hour. The solid was isolated by filtration , washed and dried under vacuum at 45-50°C.
Yield: 80%. Purity: 99.5%.

Example 2: Synthesis of bethanechol chloride (isolating intermediate II)

A 20% w/w ß- Methyl choline chloride solution in methanol ( 1.0 Kg,1.30 moles) was charged in a flask under inert atmosphere. Methanol was distilled of under reduced pressure below 55°C. Stripped out with ethyl acetate below 55°C to residue. The reaction mixture was cooled to room temperature and the residue was stirred in dichloromethane ( 2.0 lit). The reaction mixture was further cooled to 0-5°C and N, N- Carbonyldiimidazole(CDI) ( 280 g, 1.323 moles) was added with stirring and maintaining the temperature 0-5° C. The reaction mixture was stirred for about 4-5 hours at 0-5°C. After completion of reaction, the reaction mass was filtered, solid was isolated by filtration, washed with dichloromethane and dried
Yield : 307 g (on dried basis).
Melting point ~ 180-185° C

The solids were stirred in dichloromethane (2.0 lit) & ammonia gas was purged into the reaction mixture for about 30 minutes with stirring and maintaining the temperature 0-5° C. The reaction mixture was further stirred for about 1-2 hours at 0-5°C. The solvent was distilled under reduced pressure below 40°C. Ethyl acetate ( 1.5 lit) was added and stirred further for 30min. The solid was isolated by filtration , washed and suck dried.
Yield: 84%. Purity: 94.5%.

Purification of bethanechol chloride

Bethanechol chloride ( 230 g ) was dissolved in methanol ( 400 ml) at 60-65°C and stirred for about 1 hour.The reaction mixture was cooled to 45-50°C and filtered hot to remove insolubles. To the clear filtrate was added IPA (1.5 lit) and the reaction mixture was heated to reflux for 30 mins. The reaction mixture was cooled to room temperature, chilled to 0-5°C and further stirred for about 1 hour. The solid was isolated by filtration , washed and dried under vacuum at 45-50°C.
Yield: 80%. Purity: 99.5%.

Example 3: One pot synthesis of bethanechol chloride

A 20% w/w ß- Methyl choline chloride solution in methanol ( 1.0 Kg,1.30 moles) was charged in a flask under inert atmosphere. Methanol was distilled of under reduced pressure below 55°C. Stripped out with ethyl acetate below 55°C to residue. The reaction mixture was cooled to room temperature and the residue was stirred in dichloromethane ( 2.0 lit). The reaction mixture was further cooled to 0-5°C and N, N- Carbonyldiimidazole(CDI) ( 280 g, 1.323 moles) was added with stirring and maintaining the temperature 0-5° C. The reaction mixture was stirred for about 4-5 hours at 0-5°C. After completion of reaction, ammonia gas was purged into the reaction mixture for about 30 minutes with stirring and maintaining the temperature 0-5° C. The reaction mixture was further stirred for about 1-2 hours at 0-5°C. The solvent was distilled under reduced pressure below 40°C. Isopropyl alcohol (1.0 lit) was added and stirred further for 30 min. The solid was isolated by filtration , washed and suck dried.
Yield: 83%. Purity: 95.5%.
,CLAIMS:1. A process for preparing bethanechol chloride of Formula (I)
;
comprising
a) reacting ß- methyl choline chloride of formula (III)

with 1,1'-Carbonyldiimidazole, to the intermediate 2-[(imidazolecarbonyl) oxy]-N, N, N-trimethyl-1-propanaminium chloride of formula (II)

and
b) reacting intermediate imidazole ester (II) with ammonia to obtain bethanechol chloride of Formula (I).

2. The process according to claim 1, wherein in step a) ß- methyl choline chloride is added as solid or as an alcoholic solution, wherein alcohol is selected from methanol, ethanol, and isopropanol..

3. The process according to claim 2, wherein alcohol is methanol and ß- methyl choline chloride is in the form of a 20 % w/w solution in methanol.

4. The process according claims 2 and 3, wherein alcoholic solvent is distilled out from the reaction, before treatment with 1,1'-Carbonyldiimidazole.

5. The process according claim 4, further comprises stripping with a high boiling non polar solvent, wherein the solvent comprises ethyl acetate, toluene, xylene, hexane and heptane.

6. The process according to any one of the preceding claims, wherein the molar ratio of ß- methyl choline chloride to the 1,1'-Carbonyldiimidazole, varies from 1:1 to 1:5.

7. The process according claim 6, wherein the condensation is carried out in the absence of a base.

8. The process according any one of the preceding claims, wherein reaction mixture of ß-methyl choline chloride of formula (III) and CDI is stirred in an anhydrous solvent.

9. The process according claim 8, wherein the solvent is selected from the group consisting of an aromatic hydrocarbon, a aprotic polar solvent such as tetrahydrofuran, methyl tertrahydrofuran; a protic polar solvent such as dimethylformamide, an aliphatic ether, esters such as ethyl acetate; chlorinated solvent such as dichloromethane or a mixture of one or more organic solvents.

10. The process according claim 9, wherein the condensation reaction is carried out at a temperature of about -10°C to about 20°C.

11. The process according to any one preceding claims, wherein intermediate ester (II) is not isolated.

12. The process according to any preceding claim, wherein the ammonia used in the amidation reaction of step (b) is in the form of gaseous ammonia or liquid ammonia.

13. The process according to claim 12, wherein the amidation reaction is carried out at a temperature of about -10°C to about 20°C.

14. The process according to claim 13, wherein the first solvent is removed under reduced pressure below 40°C and the residue is stirred in a suitable second solvent, wherein the first solvent is a reaction solvent.

15. The process according to claim 14, wherein the second solvent comprising of a polar solvent such as alcohols, an aromatic hydrocarbon, a aprotic non-polar solvent such as ethyl acetate, n-heptane, n-hexane, toluene, xylene, diethyl ether and diisopropyl ether.

16. A process according to any preceding claim, wherein the process is a one-pot process.

17. A process for preparing ß- methyl choline chloride of formula (III), comprising reacting 1-chloropropan-2-ol of formula (IV)

with triethylamine in the presence of suitable solvent.

18. The process according to any preceding claims, wherein 1-chloropropan-2-ol of formula (IV) is in the form of (2S)-1-chloropropan-2-ol and the bethanechol chloride compound (I ) is in the form of (S)- bethanechol chloride.

19. The process according to claims 1 to 17, wherein 1-chloropropan-2-ol of formula (IV) is in the form of (2R)-1-chloropropan-2-ol (IV) and the bethanechol chloride compound (I ) is in the form of (R)- bethanechol chloride.

20. A compound 2-[(Imidazolecarbony) oxy]-N, N, N-trimethyl-1-propanaminium chloride of formula (II).

21. A process for preparing the compound of formula (II) of claim 20, comprising reacting ß- methyl choline chloride of formula (III) with 1,1'-Carbonyldiimidazole.

22. A pharmaceutical composition comprising bethanechol chloride (I), prepared by a process as described above, together with one or more pharmaceutically acceptable excipients.