WO2009007995A1

WO2009007995A1 - Process for preparing zolpidem and its intermediate

Info

Publication number: WO2009007995A1
Application number: PCT/IN2008/000266
Authority: WO
Inventors: Rajendiran Chinnapillai; Ravikumar Reddy Nallamaddi; Veera Reddy Arava; Venkateswarlu Jasti
Original assignee: Suven Life Sciences Ltd
Current assignee: Suven Life Sciences Ltd
Priority date: 2007-07-09
Filing date: 2008-04-28
Publication date: 2009-01-15
Anticipated expiration: 2010-01-09

Abstract

The present invention relates to an improved process for the preparation of 6- methyl-2-[4-methylphenyl]imidazo[l,2-a]pyridine-3-N,N-dimethyl acetamide having formula (1). The compound of formula (1) has adopted name 'Zolpidem'. The present invention also relates to novel intermediate of the formula (2) and a process for its preparation.Wherein R represents methyl, ethyl, propyl, butyl, isopropyl, isobutyl or tertiary butyl group. The novel intermediate of formula (2) is used in preparation of Zolpidem having formula (1). Zolpidem is useful in the treatment of anxiety, sleep disorders and convulsion.

Description

PROCESS FOR PREPARING ZOLPIDEM AND ITS INTERMEDIATE Field of the Invention

The present invention relates to an improved process for the preparation of 6- methyl-2- [4-methylphenyl] imidazo [ 1 ,2-a]pyridine-3 -N,N-dimethyl acetamide having formula (1).

The compound of formula (1) has adopted name "Zolpidem". The present invention also relates to novel intermediate of the formula (2)

and a process for its preparation wherein R represents methyl, ethyl, propyl, butyl, isopropyl, isobutyl or tertiary butyl group.

The novel intermediate of formula (T) is used in preparation of Zolpidem having formula (V). Zolpidem is useful in the treatment of anxiety, sleep disorders and convulsion. Background of the Invention

Zolpidem disclosed in EP 50563 (equivalent to US 4382938) is assigned to synthelabo (France). It is a selective benzodiazepine receptor agonist not related chemically to benzodiazepines. Zolpidem shows both high affinity and selectivity towards non-benzodiazepine-2-receptors, which means an improved activity for the treatment of anxiety, sleep disorders and convulsion.

The basic moiety required for the synthesis of Zolpidem is 6-Methyl-2-(4- methylphenyl)imidazo[l,2-a]pyridine of the formula (T), which was known in the prior art literature using Tschitschibabin reaction as depicted in the Scheme - 1.

NaHCO₃

Scheme - 1

6-Methyl-2-(4-methylphenyl)imidazo[l,2-a]pyridine of the formula (7) was prepared by the reaction of toluene of the formula (3) with chloroacetylchloride of the formula (4) under Friedel-crafts acylation conditions followed by condensation with 2- amino-5-methylpyridine of the formula (6).

EP 50563 describes the process for the preparation of Zolpidem, using synthetic process as depicted in Scheme -2.

Scheme -2

This approach involves the preparation of key intermediate 6-methyl-2-[4- methylphenyl]imidazo[l,2-a]pyridine-3-acetonitrile of the formula (10), by using the disclosed procedures of GB 991589 and GB 1076089. The amino methylation of the imidazopyridine of the formula (7) yields the 3-dimethylamino derivative of the formula (8), which is alkylated with methyliodide to obtain the quaternary ammoinium salt of the formula (9), which is then reacted with sodium cyanide to give the corresponding nitrile of the formula (10). Amidation of the nitrile derivative with formic acid and concentrated hydrochloride to produce formula (11), which on hydrolysis using 75% ethanolic potassium hydroxide yields the carboxylic acid of the formula (12) which is activated with carbonyldiimidazole (CDI), then treated with an excess dimethylamine to obtain Zolpidem of the formula (V).

The above process suffers from several drawbacks especially from the commercial point of view, the use of highly expensive, low boiling and toxic methyl iodide. The Conversion of nitrile derivative of the formula (10) to amide, followed by hydrolysis requires passing dry hydrochloride gas into the reaction mass for long hours of heating, and using of highly sensitive and unstable carbonyldiimdazole (CDI) for amide coupling restricts the industrial application.

Another synthetic route disclosed in US 4492695 for the preparation of acetonitrile derivative of the formula (10) and the preparation of Zolpidem of the formula (V) as depicted in Scheme - 3.

Scheme - 3

The 6-methyl-2-[4-methylphenyl]irnidazo[l,2-a]pyridine of the formula (T) is formylated using oxalylchloride and dimethylformamide to obtain the aldehyde derivative of the formula (13) which is reduced with sodium borohydride to yield the corresponding alcohol of the formula (14). Alcohol derivative of the formula (14) is reacted with p-toluenesulfonylchloride in the presence of pyridine to obtain the quaternary ammonium salt of the formula (15), which is reacted with cyanide ion to yield the 6-methyl-2-[4-methylphenyl]imidazo[l,2-a]pyridine-3-acetonitrile of the formula (10). The resulting acetonitrile intermediate of the formula (10) transformed into acid of the formula (12) by base hydrolysis, which is amidated using CDI and dimethylamine to give Zolpidem of the formula Qj.

The above described process, although avoids the usage of toxic methyliodide, but involves more number of steps, longer reaction times and lower yields, and cumbersome work up procedures for the preparation of acetonitrile intermediate of the formula (10). Still involves the use of CDI in the amidation step for the preparation of

Zolpidem of the formula (T).

Further US 4794185 discloses the preparation of Zolpidem using the following synthetic route as depicted in Scheme - 4.

Scheme - 4

Zolpidem of formula (1) was prepared by the reaction of 6-methyl-2-[4- methylphenyl]imidazo[l,2-a]pyridine of the formula (T) with N,N-dimethyl-2,2- dimethoxyacetamide of the formula (16) to yield 3 -substituted hydroxy derivative of the formula (17), The hydroxyl group of formula (17) is converted into chloro derivative of the formula (18), by using thionylchloride. The chloro derivative of formula (18) is converted into formula (T), by subsequent reduction with sodiumborohydride.

The above process also suffers from the fact that it is difficult to separate the un-reacted starting material of the formula (T) from the reaction product of the formula (17). The formation of chloro derivative of the formula (18) using the thionylchloride followed by reduction using sodiumborohydride to get the 6-methyl-2-[4- methylphenyl]imidazo[l,2-a]pyridine-3-N,N-dimethylacetamide of the formula (T) led to poor yields beside the use of hazardous reagents like thionylchloride and sodiumborohydride.

Additional method for the preparation of Zolpidem is reported in US 6407240 as depicted in Scheme - 5. The 6-methyl-2-[4-methylphenyl]imidazo[l,2-a]pyridine of the formula (T) reacts with methylglyoxylate or its methylhemiacetal of the formula (19) to produce the hydroxyester of the formula (20), the hydroxyester of formula (20) is converted into hydroxyl group substituted with chloride of formula (21) by using thionylchloride followed by reduction using sodiumhydroxymethanesulfinate produce the ester of the formula (22), which on reaction with dimethylamine under pressure produce the Zolpidem. This method also needs to use thionylchloride and also suffers from the same disadvantages as mentioned in above schemes.

Scheme - 5

In conclusion, all known synthesis of Zolpidem (1) uses either reagents commercially difficult to accessible, toxic to handle or products with poor purity that should undergo repeated purification procedures. Therefore, it would be desirable and paramount important to have a process for the preparation of Zolpidem (V), by avoiding the use of the expensive and highly toxic methyliodide, sodiumborohydride and CDI and employing inexpensive, readily available, easy to handle reagents. It would also be desirable to have a process that can be readily scaled up which does not require a special purification step to obtain pure Zolpidem (V). Therefore, we developed an improved process for the preparation of Zolpidem

(V) with usage of novel intermediate of formula (2) to overcome the disadvantages mentioned above. Summary of the invention

The present invention relates to the novel intermediate of the formula (2), which is useful for the preparation of Zolpidem of the formula (1)

wherein R represents methyl, ethyl, propyl, butyl, isopropyl or tertiary butyl group.

The present invention also provides process for preparation of the novel intermediate of the formula (2),

wherein R represents methyl, ethyl, propyl, butyl, isopropyl or tertiary butyl group. which comprises : a) reacting imidazopyridine of the formula (7)

with paraformaldehyde and aqueous dimethylamine solution in the presence of acetic acid at a temperature in the range of 10 to 100 ⁰C for the period of 2 to 5 hours to get dimethylaminomethyl derivative of imidazopyridine of the formula (8)

b) reacting the dimethylaminomethyl derivative of imidazopyridine of the formula (8) with alkylchloroformate at a temperature in the range of -5 to 25 ⁰C for the period of 15 minutes to 2 hours to get a novel intermediate of the formula (2). In one aspect, the present invention provides an improved process for the preparation of Zolpidem of formula (V)

which comprises: a) reacting imidazopyridine of the formula (7)

/^^N^

7 with paraformaldehyde and aqueous dimethylamine solution in the presence of acetic acid at a temperature in the range of 10 to 100 ⁰C for the period of 2 to 5 hours to get dimethylaminomethyl derivative of imidazopyridine of the formula (8)

b) reacting the dimethylaminomethyl derivative of imidazopyridine (8) with alkylchloroformate at a temperature in the range of -5 to 25 ⁰C for the period of 15 minutes to 2 hours to get a novel intermediate of the formula (T)

wherein R represents methyl, ethyl, propyl, butyl, isopropyl or tertiary butyl group c) treating the intermediate of the formula (2) with sodium cyanide at a temperature in the range of 10 to 100 ⁰C for the period of 1 to 6 hours to get acetonitrile derivative of imidazopyridine of formula (10)

d) hydrolyzing the acetonitrile derivative of the formula (10) using dilute sulfuric acid solution at a temperature in the range of 50 to 150 ⁰C for the period of 2 hours to 8 hours to give the acid derivative of formula (12)

e) treating the acid derivative of the formula (12) with pivaloyl chloride in the presence of organic base at a temperature in the range of -10 to 20 ⁰C for the period of 10 minutes to 1 hour, followed by treatment with dimethylamine solution to produce Zolpidem of formula (1)

In another aspect, the present invention provides an improved process for the preparation of Zolpidem avoiding use of the expensive methyliodide, sodiumborohydride and CDI In another aspect, the present invention provides an improved process for the preparation of Zolpidem using inexpensive readily available and easy to handle reagents.

In yet another aspect, the present invention provides an improved process for the preparation of Zolpidem which can be readily scaled up and which does not require a special purification step to obtain pure Zolpidem.

In still yet another aspect, the present invention provides an improved process for the preparation of Zolpidem, which is simple, convenient, economical and environmentally safe. Detailed Description of the Invention Accordingly, the present invention relates to the novel intermediate of the formula (2), which is useful for the preparation of Zolpidem of the formula (1).

According to another aspect of the present invention, there is provided a process for the preparation of novel intermediate of the formula (2)

wherein R represents methyl, ethyl, propyl, butyl, isopropyl or tertiary butyl group. which comprises: a) reacting imidazopyridine of the formula (T)

with paraformaldehyde and aqueous dimethylamine solution in the presence of acetic acid at a temperature in the range of 10 to 100 ⁰C for the period of 2 to 5 hours to get dimethylaminomethyl derivative of imidazopyridine of the formula

(8)

b) reacting the dimethylaminomethyl derivative of imidazopyridine of the formula (8) with alkylchloroformate at a temperature in the range of -5 to 25 ⁰C for the period of 2 hours to 8 hours to get a novel intermediate of the formula (2} According to another aspect of the present invention there is provided an improved process for the preparation of Zolpidem of formula (1)

which comprises: a) reacting imidazopyridine of the formula (7)

GD

b) reacting the dimethylaminomethyl derivative of imidazopyridine (8) with alkylchloroformate at a temperature in the range of -5 to 25 ⁰C for the period of 15 minutes to 2 hours to get a novel intermediate of the formula (2)

d) hydrolyzing the acetonitrile derivative of the formula (10) using dilute sulfuric acid solution at a temperature in the range of 50 to 150 ⁰C for the period of 2 to 8 hours to give the acid derivative of formula (12)

d) treating the acid derivative of the formula (12) with pivaloyl chloride in the presence of organic base at a temperature in the range of -10 to 20 ⁰C for the period of 10 minutes to 1 hour, followed by treatment with dimethylamine solution to produce Zolpidem of the formula (V).

Scheme - 6 illustrates an improved process for preparation of Zolpidem of the formula (V), by the present invention.

Scheme - 6 In the first step of the preparation, 6-methyl-2-(4-methylphenyl)imidazo[l,2- ajpyridine of the formula (7) is treated with paraformaldehyde and 40% aqueous dimethylamine solution in the presence of acetic acid to obtain compound of formula (8).

The reaction temperature may range from 10 to 100 ⁰C and preferably at a temperature in the range from 50 to 55 ⁰C. The duration of the reaction may range from 2 to 5 hours, preferably from a period of 3 to 4 hours.

In the second step of the preparation, the obtained dimethylaminomethyl derivative of imidazopyridine of the formula (8) is treated with alkylchloroformate in a halogenated solvent to obtain formula (T). The alkylchloroformate used in the reaction can be selected from the methylchloroformate, ethylchloroformate or butylchloroformate and preferably using ethylchloroformate. The amount of alkylchloroformate used in the reaction may be in the range of 1.0 to 3.0 molar equivalents and preferably using 1.2 to 1.5 molar equivalents. The halogenated solvent used in the reaction can be selected from dichloromethane, dichloroethane or chloroform and preferably using dichloromethane. The reaction temperature may range from -5 to 20 ⁰C and preferably at a temperature in the range from 0 to 5 ⁰C. The duration of the reaction may range from 15 minutes to 2 hours, preferably from a period of 30 to 45 minutes.

In the third step of the preparation, the formed solid of formula (2) is dissolved in water and basified to adjust the pH around 8.0 and treated with sodium cyanide to get the nitrile derivative of formula (10). The amount of sodium cyanide used in the reaction is 1.0 to 2.0 molar equivalents of compound of formula (8) and preferably in an amount of 1.1 to 1.4 molar equivalents. The base used in the reaction can be selected from potassium carbonate, sodium bicarbonate, sodium hydride or sodium hydroxide and preferably using sodium hydroxide. The reaction temperature may range from 10 to 100 ⁰C and preferably at a temperature in the range from 50 to 55 ⁰C. The duration of the reaction may range from 1 to 6 hours, preferably from a period of 3 to 4 hours.

In fourth step of the preparation, the nitrile derivative of formula (10) is converted into corresponding acid of formula (12) by means of hydrolysis. The hydrolysis reaction is carried out in presence of dilute sulfuric acid. The percentage of sulfuric acid in the reaction is ranging from 10% to 70% and preferably about 50%. The amount of sulfuric acid used in the reaction will be in the range of 10 to 30 molar equivalents, preferably 15 to 20 molar equivalents. The reaction temperature may range from 50 to 150 ⁰C and preferably at a temperature in the range from 90 to 110 ⁰C. The duration of the reaction may range from 2 to 8 hours, preferably from a period of 4 to 5 hours.

In fifth step of the preparation, the acid of formula (12) is treated with an organic base and pivaloylchloride in suitable solvent followed by dimethylamine to get Zolpidem. The solvent used in the reaction can be selected from dichloromethane, dichloroethane or chloroform and preferably using dichloromethane. The volume of solvent used in the reaction is range of 20 to 50 volumes, preferably about 30 to 40 volumes. The organic base used in the reaction can be selected from triethylamine, diisopropylethylamine, pyridine or N-methylmorpholine, for about 1.5 molar equivalents to 3.0 molar equivalents and preferably triethylamine is used as organic base for about 2.0 molar equivalents. Pivaloylchloride is used in the reaction about 1.0 to 2.0 molar equivalents, preferably 1.5 molar equivalents for a period of about 10 to 60 minutes and preferably about 30 minutes. The amount of dimethylamine used in the reaction may be about 1.5 to 3.5 molar equivalents, preferably about 2.0 molar equivalents. The reaction temperature may range from -10 to 20 ⁰C and preferably at a temperature in the range from 5 to 10 ⁰C.

The details of the invention are given in the examples provided below, which are given to illustrate the invention only and therefore should not be construed to limit the scope of the invention

Example 1: Preparation of 6-methyl-2-(4-methylphenyl)imidazo[l,2-a]pyridine-3- acetic acid (12)

Step (i): Preparation of 6-methyI-2-(4-methylphenyI)imidazo[l,2-a]pyridine-3- N,N-dimethylmethyl amine (8)

Dissolved the 6-methyl-2-(4-methylphenyl)imidazo[l,2-a]pyridine (200 grams, 0.92 mmol) in acetic acid (985 mL) under stirring. Cooled the above reaction mass to 0 - 5 ⁰C, added 40% aqueous solution of dimethylamine (157 grams, 1.39 mmol) slowly, followed by the addition of paraformaldehyde (36.11 grams, 1.20 mmol). Stirred the above reaction mass at 50 - 55 ⁰C for a period of 3 - 4 hours and removed acetic acid under reduced pressure. Added water (1.5 L) and filtered through a pad of celite and basified the solution (pH: 8.0-8.5) by adding drop wise 30% sodium hydroxide solution. Filtered the off white solid, washed with water (500 mL) and hexane (200 mL). Dried in the oven until constant weight is reached. Dry weight of obtained 6-methyl-2-(4-methylphenyl)imidazo[l ,2-a]pyridine-3-N,N-dimethylmethyl amine (8) is 230 grams. Yield: 91.6%. Purity: 93.5%. Melting Range: 137.9 - 141.5 ⁰C; IR spectra (cm^"1): 2944, 2809, 2761, 1502, 1454, 1389, 1018, 829, 799;

¹H NMR (400 MHz, CDCl₃) : δ 2.25 (s, 6H), 2.36 (s, 3H), 2.40 (s, 3H), 3.84 (s, 2H), 7.04 (dd, J= 9.1 Hz, J= 1.6 Hz, IH), 7.25 (d, J= 7.9 Hz, 2H), 7.52 (d, J= 9.1 Hz, IH), 7.69 (d, J= 8.0 Hz, 2H), 8.10 (s, IH); Mass (m/z): 280.4 (M+H)⁺. Step (ii): Preparation of 6-methyl-2-(4-methylphenyl)imidazo[l,2-a|pyridine-3- acetonitrile (10)

Dissolved the 6-methyl-2-(4-methylphenyl)imidazo[l,2-a]pyridine-3-N,N- dimethylmethylamine (8) ( (230 grams, 0.82 mmol) (obtained from step (i)) in dichloromethane (600 mL) under stirring. Cooled the above solution to 0 - 5 ⁰C, add ethylchloroformate (98.4 grams, 0.90 mmol) slowly over a period of 30 minutes. Stirred the above reaction mass for a period of 45 minutes at the same temperature, distilled off the solvent under reduced pressure, which produced 332 grams crude carbamate salt of dimethylaminomethyl imidazopyridine (2) as yellow colored solid. Dissolved the obtained solid immediately in water (690 mL), basify the solution to pH 7.5-8.0 using 10% sodium hydroxide solution. Added sodium cyanide (48.4 grams, 0.99 mmol) to the above reaction mass and stirred at 50 - 55 ⁰C for a period of 3 hours. Cooled the above reaction mass to room temperature, extracted the solution with chloroform (300 mL, 2x200 mL). Combined organic layers and washed with water (500 mL) and brine (400 mL). Dried with anhydrous sodium sulfate, filtered and concentrated the solution until the volume reaches to 250 mL. Add methanol (1000 mL), stirred for the period of 30 minutes. Filtered the formed off white solid from the solution and dried in the oven until constant weight reached. Dry weight of obtained 6- methyl-2-(4-methylphenyl)imidazo[l,2-a]pyridine-3-acetonitrile(10) is 165.0 grams. Yield: 76% Purity: 96%

Melting Range: 176.9 - 178.0⁰C;

IR spectra (cm^"1): 2921, 2895, 2249, 1500, 1386, 1343, 824, 799;

¹H NMR (400 MHz, CDCl₃): δ 2.42(s, 6H), 4.13 (s, 2H), 7.16 (dd, J= 9.1 Hz, J= 1.5 Hz, IH), 7.31 (d, J= 7.9 Hz, 2H), 7.58 (d, J= 8.0 Hz, 2H), 7.60 (d, J= 9.6 Hz, IH), 7.80

(s, IH);

Mass (m/z): 262.5 (M+H)⁺

Step (iii): Preparation of 6-methyl-2-(4-methylpheny i)imidazo[l,2-a]pyridine-3- acetic acid (12) Dissolved the 6-methyl-2-(4-methylphenyl)imidazo[l,2-a]pyridine-3- acetonitrile (obtained in step (H)) (165 grams, 0.63 mmol) (obtained from step (ii)) in

50% sulfuric acid (1032 mL) and reflux the reaction mass at 110⁰C for a period of 4 - 5 hours. Cooled the above reaction mass to room temperature and added to a flask containing ice cold water (2.5 L). Basified the obtained white precipitate by adding 33% sodium hydroxide solution until pH: 9.0 is reached. Extracted the solution with chloroform (2x300 mL) and discarded. Added carbon (9.0 grams) to the above aqueous solution and stirred for the period of 20 to 30 minutes and filtered through a pad of celite. Acidified the solution to pH: 5.5, by adding glacial acetic acid and obtained white solid filtered. Filtered cake washed with water (500 mL) and dried in the airflow oven at 60 - 65 ⁰C until constant weight reached. Dry weight of obtained 6-methyl-2-

(4-methylphenyl)imidazo[l,2-a]pyridine-3 -acetic acid (12) is 128.0 grams.

Yield: 72%

Purity: 99.9%

Melting point: 234.2 - 235.4 ⁰C; IR spectra (cm^"1): 3427, 2919, 1701, 1508, 1183, 827, 805;

¹H NMR (400 MHz, DMSO-40 δ: δ 2.31 (s, 3H), 2.34 (s, 3H), 4.08 (s, 2H), 7.17 (dd,

J= 9.1 Hz, J= 1.5 Hz, IH), 7.28 (d, J= 8.0 Hz, 2H), 7.51 (d, J= 9.1 Hz, IH), 7.61 (d, J=

8.0 Hz, 2H), 8.22 (s, IH);

Mass (m/z): 281.2 (M+H)⁺

Example 2:Preparation of 6-methyl-2-(4-methylphenyl)imidazo[l,2-a]pyridine-3- acetic acid (12)

Dissolved the 6-methyl-2-(4-methylphenyl)imidazo[l,2-a]pyridine (9) (100 grams, 0.45 mmol) in acetic acid (500 mL) under stirring. Cooled the reaction mass to 5 - 10 ⁰C, added 40% aqueous solution of dimethylamine (76 grams) slowly, followed by addition of paraformaldehyde (17.7 grams). Stirred the reaction mass at 50 - 55 ⁰C for the period of 3 hours and removed acetic acid under reduced pressure. Added water (1000 mL), basify the solution (pH 8.0) by adding 30% sodium hydroxide solution. Extracted the solution with dichloromethane (3x300 mL), washed the organic layer with water (500 mL) and brine solution (500 mL). Dry with anhydrous sodium sulfate, filtered and distilled the solvent until the volume reaches to around 300 mL. This solution contains 6-methyl-2-(4-methylphenyl)imidazo[l ,2-a]pyridine-3-N,N- dimethylmethylamine (10), 89% purity by HPLC, and used further as it is. Cooled the above organic solution to 0 - 5 ⁰C, added ethylchloroformate (58.3 grams, 0.54 mmol) slowly over a period of 30 minutes. Stirred the reaction mass for one hour at the same temperature, distilled off the solvent under reduced pressure to obtain carbamate salt as bright yellow colored solid (2). This solid was dissolved in water (300 mL), basified the solution to pH 7.5 - 8.0 using 10% sodium hydroxide solution. Added sodium cyanide (26.5 grams, 0.54 mmol) and stirred the reaction mass at 50 - 55 ⁰C for a period of 3 hours. Cooled the reaction mass to room temperature and filtered the yellow solid and washed with water (500 mL). This crude solid contains 6- methyl-2-(4-methylphenyl)imidazo[l,2-a]pyridine-3-acetonitrile (10), 82% purity by HPLC, and used for hydrolysis without any further purification. The above crude solid was dissolved in 50% sulfuric acid (624 mL), refluxed the reaction mass at 110 ⁰C for 4 hours. Cooled the reaction mass to room temperature and added to a flask contain of ice cold water (2.5 L). Basified the white ppt solution by adding sodium hydroxide flakes portion wise until pH 9.0. Extracted the solution with dichloromethane (2 x 300 mL) and discarded. Added carbon (5.0 grams), stirred for 30 minutes and filtered through a pad of celite. Acidified the solution pH 5.5 by adding glacial acetic acid and obtained white solid filtered. Filtered cake was washed with water (500 mL) and dried in the airflow oven at 60 - 65 ⁰C until constant weight reached. 78.0 grams of 6-methyl-2-(4-methylphenyl)imidazo[l,2-a]pyridine-3- aceticacid (12) obtained as off-white solid. Yield: 62.0% Purity: 99.5 %

Melting Range: 234.0 - 235.2⁰C; IR spectra (cm ¹): 3427, 2919, 1701, 1508, 1183, 827, 805; ¹H NMR (400 MHz, DMSO-c4): δ 2.31 (s, 3H), 2.34 (s, 3H), 4.08 (s, 2H), 7.17 (dd, J=

9.1 Hz, J= 1.5 Hz, IH), 7.28 (d, J= 8.0 Hz, 2H), 7.51 (d, J= 9.1 Hz, IH), 7.61 (d, J= 8.0

Hz, 2H), 8.22 (s, lH);

Mass (m/z): 281.2 (M+H)⁺

Example 3: Preparation of 6-methyl-2-(4-methylphenyl)imidazo|l,2-a]pyridine-3-

N,N-dimethylacetamide (1)

To the suspension of 6-methyl-2-(4-methylphenyl)imidazo[l,2-a]pyridine-3- acetic acid (12) (175 grams, 0.625 mmol) (obtained in Example 1 or 2) in dichloromethane (4.3 L) was added triethylamine (87.7 grams, 0.87 mmol) keeping the temperature at 0 - 5 ⁰C. Added pivaloyl chloride (98 grams, 0.81 mmol) to the above reaction mass and stir the reaction mass for a period of 30 minutes. Added 40% aqueous solution of dimethylamine (158 mL, 1.25 mmol) in a single lot at 0 - 5 ⁰C and stir the reaction mass for 30 minutes. Charged 5% sodium hydroxide solution (1500 mL), stirred for 10 minutes and separate the organic layer. Organic layer washed with water (1 L), brine solution (1 L), dried with anhydrous sodium sulfate and filtered.

Removed the solvent under reduced pressure, added hexane (1 L) and stirred for a period of 15 minutes. Filtered the off white solid and wash with hexane (200 mL).

Dried in the oven until constant weight is reached. Dry weight of obtained 6-methyl-2- (4-methylphenyl)imidazo[l,2-a]pyridine-3-N,N-dimethylacetamide (V) is 162.0 grams

Yield: 84.3%.

Purity: 99.7%.

Melting Range: 196 - 197 ⁰C '

IR spectra (cm-¹): 3434, 3024, 2915, 1635, 1505, 1344, 1138, 825, 794; 1H NMR (400 MHz, CDCl₃) δ: 2.34 (s, 3H), 2.40 (s, 3H), 2.88 (s, 3H), 2.94 (s, 3H),

4.09 (s, 2H), 7.04 (dd, J= 9.15 Hz, J= 1.58 Hz, IH), 7.26 (d, J= 7.87 Hz, 2H), 7.55-7.52

(m, 3H), 8.00 (s, IH);

Mass (m/z): 308.5 (M+H)⁺

Example 4: Preparation of Zolpidem tartrate

To a solution of 6-methyl-2(4-methylphenyl)imidazo[l,2-a]pyridine-3-N,N- dimethyl acetamide (V) (25 grams, 81 mmol) (obtained in Example 3) in methanol (180 mL) at 55 ⁰C added a solution of natural tartaricacid (6.1 grams, 40.5 mmol) in methanol (60 mL). Stirred the reaction mass at same temperature for 30 minutes and allow to the room temperature. Cool the reaction mass to 0 to 5 ⁰C and stir for the" period of 3 hours and allow settling the crystals overnight. The resulting crystalline solid is filtered, washed with cold methanol (15 mL) and dried at 50 - 55 ⁰C to obtain Zolpidem tartrate (24 grams, 77.5 % yield). Regain 4.5 grams of Zolpidem (T) from mother solution by concentration, basifying and extraction with dichloromethane. Melting Range: 195 -196 ⁰C;

IR spectra (cm-¹): 3316, 3269, 2921, 2708, 1650, 1397, 1134, 816, 794; 1H NMR (400 MHz, DMSOd₆): δ 2.29 (s, 6H), 2.33 (s, 6H), 2.88 (s, 6H), 3.11 (s, 6H), 4.13 (s, 4H), 4.29 (s, 2H), 7.11 (dd, J= 9.15 Hz, J= 1.58 Hz, 2H), 7.25 (d, J= 7.87 Hz, 4H), 7.51-7.46 (m, 6H), 8.03 (s, 2H); Mass (m/z): 308.2 (M+H)⁺ _. Advantages of the Invention:

1. The 6-methyl-2-(4-methylphenyl)imidazo[l,2-a]pyridine-3-acetic acid of the formula (12) is prepared without isolation and purification of intermediate products thereby saving the time and increasing the productivity.

2. The conversion of acetonitrile of the formula (10) to acetic acid of the formula (12) have been done in single step rather than two steps and simply by refluxing in dilute sulphuric acid followed by neutralization and isolation the pure product having 99.5% HPLC purity. This makes the process simple and economical

3. Zolpidem is prepared from acid of the formula (12) using pivaloylchloride as a coupling reagent instead of CDI which makes the process cheaper, simple and safe

4. The total yield of the Zolpidem is 55 to 60% in two-step process from 6-methyl-2- (4-methylphenyl)imidazo[l,2-a]pyridine of formula (T) instead of five-step process with 40 - 45% yield, thereby making then process economical.

5. The process results in a new intermediate of .the formula (T)

Claims

Claims:

1. An improved process for the preparation of Zolpidem of formula (Ij

which comprises: a) reacting 6-methyl-2-(4-methylphenyl)imidazo[l,2-a]pyridine of the formula

⁽D

λ /

7 with paraformaldehyde and aqueous solution of dimethylamine in the presence of acetic acid at a temperature in the range of 10 to 100 ⁰C for the period of 2 to 5 hours to get dimethylaminomethyl derivative of imidazopyridine of the formula (8);

b) reacting the dimethylaminomethyl derivative of imidazopyridine (8) with alkylchloroformate in haloganated solvent at a temperature in the range of -5 to 25 ⁰C for the period of 15 minutes to 2 hours to get a novel intermediate of the formula (2);

c) treating the intermediate of the formula (2) with sodium cyanide at a temperature in then range of 10 to 100 ⁰C for the period of 1 to 6 hours to get acetonitrile derivative of imidazopyridine of formula (10);

d) hydrolyzing the acetonitrile derivative of the formula (10) using dilute sulfuric acid solution at a temperature in the range of 50 to 150 ⁰C for the period of 2 to 8 hours to give the acid derivative of formula (12);

e) treating the acid derivative of the formula (12) with pivaloyl chloride in the presence of an organic base in suitable solvent at a temperature in the range of -10 to 20 ⁰C, for the period of 10 to 60 minutes, followed by treatment with dimethylamine solution to produce Zolpidem of the formula (1).

2. The process for the preparation of intermediate of the formula (2) useful in the reparation of Zolpidem

\ /

-OR

O which comprises: a) reacting 6-methyl-2-(4-methylphenyl)imidazo[l,2-a]pyridine of the formula

(Z)

with paraformaldehyde and aqueous solution of dimethylamine in the presence of acetic acid at a temperature in the range of 10 to 100 ⁰C for the period of 2 to 5 hours to get dimethylaminomethyl derivative of imidazopyridine of the formula (8);

3. The process as claimed in claims 1 or 2, wherein in step (a) imidazopyridine of the formula (7) is treated with paraformaldehyde, aqueous dimethylamine solution and the reaction is carried out a temperature in the range of 50 to 55 ⁰C for 3 to 4 hours.

4. The process as claimed in claims 1 or 2, wherein in step (b) said dimethylaminomethyl derivative of imidazopyridine (8) is treated with alkylchloroformate in a halogenated solvent at a temperature in the range of 0 to 5⁰C for 30 to 45 minutes.

5. The process as claimed in claim 4, wherein said alkylchloroformate is selected from methylchloroformate, ethylchloroformate andr butylchloroformate.

6. The process as claimed in claim 4, wherein the amount of alkylchloroformate used in range of from 1.0 to 3.0 molar equivalents of the compound of formula

(8).

7. The process as claimed in claim 4, wherein said halogenated solvent is selected from dichloromethane, dichloroethane or chloroform.

8. The process as claimed in claim 1, wherein the amount of sodium cyanide used in step (c) ranges from 1.0 to 2.0 molar equivalents of compound of formula (8)

9. The process as claimed in claim 1, wherein the amount of sulfuric acid used in step (d) for hydrolysis is in the range of from 10% to 70%.

10. The process as claimed in claim 1 wherein the amount of sulfuric acid used in step (d) for hydrolysis is in the range of from 10.0 to 30.0 molar equivalents, said hydrolysis is carried out at a temperature in range of 90 to 110 ⁰C for a period of 4 to 5 hours.

11. A process as claimed in claim 1 wherein in step (e) the said chlorinated solvent used is selected from dichloromethane, dichloroethane and chloroform and the volume of the solvent used in the reaction is in the range of 20 to 50 volumes.

12. The process as claimed in claim 1, wherein in step (e) the said organic base used is selected from triethylamine, diisopropylethylamine, pyridine and N- methylmorpholine and the amount used ranges from about 1.5 molar equivalents to 3.0 molar equivalents.

13. The process as claimed in claim 1, wherein in step (e) the amount of pivaloylchloride used is in the range of 1 to 2 molar equivalents for amidation.

14. Intermediate of the formula (2) useful in the reparation of Zolpidem