FORM 2
THE PATENTS ACT, 1970 (39 OF 1970) THE COMPLETE SPECIFICATION
(See section 10)
1. PROCESS FOR THE PREPARATION OF ZOLPIDEM.
2. CADILA PHARMACEUTICALS LTD., "CADILA CORPORATE CAMPUS", SARKHEJ-DHOLKA ROAD, BHAT, AHMEDABAD, 382210, GUJARAT, INDIA, AN INDIAN COMPANY.
3. THE FOLLOWING SPECIFICATION DESCRIBES AND ASCERTAINS THE NATURE OF THIS INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED.


FIELD OF THE INVENTION :
Zolpidem, as a hemitartrate salt, is currently approved for the short term treatment of insomnia in the United States. Zolpidem hemitartrate is classified as a non-benzodiazepine hypnotic of the imidazopyridine class.

2-(4-methylphenyl)-6-methylimidazo[1,2-a]pyridine-3-acetic acid is an intermediate of Zolpidem and is represented by the structural formula as shown below.

Zolpidem has the chemical name N,N,6-trimethyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine-3-acetamide and has CAS Reg. No. [82626-48-0] and is represented by the structural formula as shown below.
2-(4-methylphenyl)-6-methylimidazo[1,2-a]pyridine-3-acetic acid
BACKGROUND OF THE INVENTION:
European patent EP 50563 describes the preparation of 2-(4-methylphenyl)-6-methylimidazo[1,2-a] pyridine-3-acetic acid and Zolpidem in following steps. [a]Mannich aminomethylation on substituted imidazo[1,2-a]pyridine to give 3-dimethylamino derivative.
[b] Alkylation of 3-dimethylaminoderivative with methyl iodide to give quaternary ammonium salt.
[c] Replacement of quaternary Nitrogen containing group with cyano group using sodium cyanide.
[d] Acid hydrolysis of nitrile to give 2-(4-methylphenyl)-6-methylimidazo
[1,2-a]pyridine-3-acetic acid
[e] Amidation of 2-(4-methylphenyl)-6-methylimidazo[1,2-a]pyridine-3-acetic acid
with dimethylamine involving prior activation with carbonyldiimidazole [GDI]

to give Zolpidem. These steps are described in scheme -1 as follows.
SCHEME -1
This method involves the use of methyl iodide at step-b which is highly toxic and having low boiling point and is difficult to handle on commercial scale. Use of poisonous chemical sodium cyanide limits its industrial applicability. Carbonyldiimidazole is a phosgene based intermediate and therefore is difficult to prepare indigenously and therefore its regular usage as a commercial intermediate is not favourable.
Also, the procedures, involved multistep extractive work-up and purifications to isolate the product which reduces the attraction for this method.
European patent EP 92459 describes the preparation of Zolpidem by a process which is described as follows.
(A) Vilsmeier-Haack formylation of 2-(4-methylphenyl)-6-methylimidazo[1,2-a]-pyridine to give corresponding 3-formylated derivative.
(B) Reduction of 3-formylated derivative to give a primary alcohol derivative.
(C) Reaction of primary alcohol with p-TosylChloride/Pyridine to obtain quaternary ammonium salt.


~(D) Reaction of quaternary ammonium salt with sodium cyanide to give corresponding 3-acetonitrile derivative.
(E) Hydrolysis using conventional methods to give 2-(4-methylphenyl)-6-
methylimidazo[1,2-a]pyridine-3-acetic acid
(F) Amidation using dimethylamine to give Zolpidem.
This process is described in scheme-2.
SCHEME-2

(Ma)3NOC
Zolpidem
This method involves use of sodium borohydride which is difficult to handle due to its extreme moisture sensitivity and inflammability with acidic gases. The use of sodium cyanide, which is a strong poison, is hazardous to use commercially on plant which makes this approach less attractive. Use of toxic pyridine further creates operational problems. FR 2600650 and US 4794185 describes the preparation of Zolpidem using N,N-dimethylglyoxamide which is depicted in the following scheme [Scheme-3]

SCHEME -3
The required side chain intermediate i.e. N,N-dimethylglyoxamide is prepared according to following Scheme 3A. SCHEME -3A

Total number of steps required to prepare Zolpidem are many, as the side chain intermediate also need to be prepared, separately, thus time cycle is increased, hence unsuitable for large scale manufacture.
"Actual Chim. Ther". (1991) 18, page number:215-239, describes the synthesis of Zolpidem by Pummerer modified reaction as shown in Scheme-4.


SCHEME-4

Zolpidem
This procedure is critical due to formation of toxic gas methyl mercaptan. This method also uses a carcinogenic compound Raney Nickel which generates heavy metal waste. The yields are also poor which makes this process unattractive for large scale preparation.
PCT Publication WO 00/08021 describes the preparation of Zolpidem in four steps as outlined in scheme-5. SCHEME-5


CH.

This process uses reagents which are not readily available, and results in low yields with products of poor purity hence industrially unsuitable.
6

European Patent No. 1038875 describes the preparation of 2-(p-tolyl)-6-methylimidazo[1,2-a]pyridine-3-acetic acid by following process.
1. 2-(p-tolyl)-6-methylimidazo[1,2-a]pyridine (22 gms) was reacted with glyoxylic acid monohydrate(10 gms) in 100 ml dichloroethane at reflux for 1.5 hours to give 2-(p-tolyl)-6-methylimidazo[1,2-a]pyridine-(2'-hydroxy)acetic (28 gms).
2. 2-(p-tolyl)-6-methylimidazo[1,2-a]pyridine-(2'-hydroxy)acetic (50 gms) was dissolved in formic acid (500 ml), and 5 gms 10% Pd/C catalyst and heated at reflux for 20 hours. The reaction mixture was filtered at room temperature to remove catalyst and the filtrate was evaporated under reduced pressure, diluted with 1000 ml water, and precipitated solid was filtered and washed with 2 x 300 ml of cold water and product vacuum dried at 40°C to give 2-(p-tolyl)-6-methylimidazo[1,2-a]pyridine-3-acetic acid. Yield = 38 gms.
These reaction steps are summarized in scheme-6.
SCHEME-6

The process uses extremely corrosive and difficult to handle chemical like formic acid which also involves filtration and vacuum distillation. The process also uses precious metal catalyst i.e. Palladium on carbon which needs to be recycled after reprocessing. Due to these reasons the process is difficult to implement on a large scale.
EP 1038875 describes another process wherein, 2-(p-tolyl)-6-methylimidazo[1,2-a] pyridine(15 gms) was dissolved in 100 ml of formic acid and reacted with 6.2 gms of glyoxylic

acid mono-hydrate and refluxed for 1.5 hour. After that, 0.75 gms of Rh/C catalyst was added and the mixture was refluxed for 9 hours while 50 ml of formic acid/water mixture was distilled off. The reaction mixture was then worked up to give 15.5 gms of 2-(p-tolyl)-6-methylirnidazo[1,2-a]pyridine-3-acetic acid with HPLC purity of 99%.The reaction step is outlined in Scheme-7. SCHEME-7

2-(p-tolyl)-6-methylimidazo[1,2-a] pyridine-3-acetic acid
This process also uses toxic and corrosive chemical like formic acid and also involves the use of Rh/C catalyst which needs to be reprocessed and recycled for cost effective manufacture.
PCT Publication Number WO 02/14306 A1 describes the preparation of Zolpidem in 2 steps
as follows.
Stepl:
2-(4-methylphenyl)-6-methylimidazo[1,2-a]-pyridine, in a mixture of toluene and cyclohexane
was reacted with oxalylchloride in presence of pyridine as a base, initially at 0°C to 5°C and
then at 65°C to 70°C for 2 hours , which is then reacted with dimethylamine and the resulting
product was isolated after an aqueous work-up and filtration to give 6-methyl-N,N-dimethyl-
2-(4-methylphenyl)imidazo[1,2-a]pyridine-3-glyoxyacetamide in 80 % yield.
Step 2 :
To a slurry of product of step-1 and Zinc powder in pyridine was added a solution of acetic
anhydride in acetic acid and maintaining temperature below 45°C .The suspension was then
heated to 50°C to 55°C and stirred for 25 to 30 hours; Unreacted zinc was filtered off and the
filtrate was subjected to vacuum distillation. To the remaining oil, 25 % aqueous ammonia

solution were added. The precipitated solid was collected by filtration ana punned by recrystallization in methyl isobutyl ketone to give Zolpidem in 65.6 % yield.
The procedure described above (in step-1) uses a mixture of solvents such as toluene, cyclohexane, 2-propanol to isolate the compound. Due to mixture of these solvents, individual recovery of each solvent and recycling of the same is difficult and separate operations and facilities are required for recycling, hence is less attractive for industrial use.
In step-2 for reduction of carbonyl group to methylene group, a heavy metal like zinc is used along with toxic pyridine, acetic anhydride and acetic acid in the same pot. This method suffers from the disadvantages like toxic metal waste generation, recovery and recycling of solvents, long reaction time, low yield and recrystallization required to isolate Zolpidem.
These steps are summarized in scheme-8 as follows. SCHEME-8

PCT Publication Number WO02718303 describes the preparation of A/,A/-dimethyl-3-(4-methyQbenzoylpropionamide, which is an intermediate for the preparation of Zolpidem. The process involves following steps:
1. Reacting 3-(4-methyl)benzoyl propionic acid with alkyl chloroformate or pivaloyl chloride in a suitable solvent in presence of organic base.
2. Reacting mixed anhydride obtained in previous step with dimethylamine to yield the resultant benzoylpropionamide intermediate.
The steps in the process are outlined below in the scheme-9

Scheme-9

This process of cyclization of benzoylpropionamide intermediate with 5-methylpyridin-2-amine suffers a drawback of low yields thus making the preparation of Zolpidem unsuitable for industrial scale-up when prepared using the said benzoylpropionamide intermediate. US Patent No 6384226 describes the preparation of Zolpidem as shown in Scheme-10. SCHEME-10

This process involves separate preparation of side chain using, first, partial saponification followed by isolation of potassium mono ethyl oxalate and drying.
The dried mono potassium mono ethyl oxalate is then reacted sequentially with POCI3 for 6 hours and then with 2-(4-methylphenyl)-6-methylimidazo[1,2-a]pyridine using triethylamine as a base to give a product which is isolated by aqueous work-up and followed by distillation of solvent to give a solid residue which is crystallized in ethanol to give ethyl 2-(4-methy!phenyl)-6-methylimidazo[1,2-a]pyridine-3-glyoxalate which is isolated by filtration and drying.
This intermediate is then saponified in water-ethanol mixture as solvent and using potassium hydroxide as a base and the resulting yellow-orange solution is treated with hydrazine and refluxed for 14 hours, cooled to 60° C, potassium hydroxide is added and the reaction mass heated up to 124° C with distillation until nitrogen evolution ceases. The reaction mass is then diluted with water, cooled to room temperature filtered and dropped in acetic acid in methanol to isolate 2-(4-methylphenyl)-6-methylimidazo[1,2-a]pyridine-3-acetic acid , which is converted to Zolpidem in 90 % yield as shown in Scheme-7. This process involves a long , multistep, extractive procedure to isolate Zolpidem.

11
2 7 OCT 2008
U.S. Patent No. 6664421 describes the preparation of Zolpidem by reacting the 3-bromo-/V,Aklimethyl-4-(4-methylphenyl)-4-oxobutanamide with 5-methylpyridin-2-amine. The butanamlde intermediate is prepared by reacting A/,W-dimethyl-4-(4-methylphenyl)-4-oxobutanamide with elemental bromine. The process can be depicted as in scheme-11

This process involves extractive work-up again making the process unsuitable for the industrial scale-up. Moreover the yield obtained in the process is also poor.
U.S. Publication Number 2004/0010146 describes the preparation of Zolpidem wherein the hydroxyacetamide derivative obtained by the reaction of imidazo[1,2-a]pyridine and hemihydrate of dimethylglyoxamide, is reacted with phosphorous tribromide to get an intermediate which gets hydrolysed to yield Zolpidem. The process is depicted in the scheme-12 below.
Scheme-12

A drawback of this process is the use of Phosphorous tribromide, a harmful chemical which can cause burns and is irritating to the respiratory system thus making it difficult to handle during scale-up operations.

SUMMARY OF THE PRESENT INVENTION
The present invention relates to a process for the preparation of imidazo[1,2-a] pyridine-3-acetamide derivatives which involves a "One Pot" process for the conversion of imidazo[1,2-ajpyridine derivatives to imidazo[1,2-a]pyridine-3-acetic acid derivatives and more particularly 2-(4-methylphenyl)-6-methylimidazo[1,2-a]pyridine-3-acetic acid. The present invention also discloses for the first time, the preparation of Zolpidem from 2-(4-methylphenyl)-6-methylimidazo[1,2-a]pyridine-3-acetic acid by a mixed anhydride method using pivaloyl chloride.
DETAILED DESCRIPTION OF THE PRESENT INVENTION
In the present invention we disclose a cost effective, convenient and facile preparation of 2-phenyl-imidazo[1,2-a]pyridine derivatives having general formula [1]

wherein Z= OH.OM,

[2]
wherein X and Y have the same meaning defined above in formula [1];
with oxalyl chloride i.e.
CI-CO-CO-CI

Where M=alkali metals such as Na+, K*; any alkaline earth metals like Ca+2, Mg+2 etc. X= H, halogen, C1-4 alkyl.C1-4 alkoxy, CF3, MeS ,N02, MeS02 Y= H.halogen.C1-4 alkyl, OR where (R=C1-4alkyl).S02Me are prepared by a process which comprises reacting a 2-phenyl-imidazo[1,2-a]pyridine of formula [2]


to give an intermediate which is saponified in-situ or otherwise, using a base to give a compound of formula [3]
[3] wherein X and Y have the same meaning defined above in formula [1] and M= monovalent or divalent cation
which is then reacted with hydrazine in the presence of a base essentially alkali metal hydroxide, carbonates, alkaline earth hydroxides or carbonates, alkoxide bases etc. to generate a compound of formula [4]

[4] wherein X and Y have the same meaning defined above in formula [1] and M has the meaning defined above in formula [3]; which is then neutralized with an acid [organic or inorganic] to give a compound of formula where M=H.
The present invention also discloses the conversion of compound of formula [4] where M=H prepared by this method, to a compound of formula [1] where Z=NR2R3 Where R2 and R3 may be H or C1-4 alkyl, wherein X and Y have the meaning defined in formula [1] by a mixed anhydride method involving the use of pivaloyl chloride as a reagent.
The present invention discloses an elegant way of attaching a two carbon side chain unit to imidazo[1,2-a]pyridine moiety by reacting with a readily available two carbon containing reactive functional group incorporated by oxalyl chloride. The attached group can then be easily saponified using a "One Pof reaction to give alpha keto carboxylic acid salt which can be directly taken for reduction of ketonic carbonyl group to corresponding methylene group using environmentally safe and inexpensive reagent i.e. hydrazine hydrate (mediated by hydrazone formation) using a base at elevated temperature.

The product after reduction can then be acidified to isolate the compound of formula [1] where Z=OH. The present invention of preparing 2-(4-methylphenyl)-6-methylimidazo[1,2-a]pyridine-3-acetic acid is described in Scheme -13 as follows. SCHEME-13

[E]
2-(4-methylphenyl)-6-methyl-
imidazof 1,2-a]pyridine-3-acetic acid
The essential feature of our invention is that intermediates which are square bracketed i.e. intermediates [B], [C], [D] are not isolated but are carried forward in-situ and the final compound 2-(4-methylphenyl)-6-methylimidazo[1,2-a]pyridine-3-acetic acid is isolated by acidification. This essential feature eliminates multi-step extractive work-up procedures and makes the process convenient to follow even on plant scale affording overall high yields.
In the first step, 2-(4-methylphenyl)-6-methylimidazo[1,2-a]pyridine is reacted with oxalylchloride using a suitable solvent in the presence of a base to give intermediate [B],

the solvent can be selected from halogenated solvents like dichloromethane, chloroform,
carbon tetrachloride, most preferably dichloromethane; Aromatic hydrocarbon solvents such
as benzene, toluene, etc.
The bases used can be tertiary amines such as triethylamine, trimethylamine, tributylamine,
diisopropylethyl amine, pyridine, A/-methylmorpholine, but most preferably triethylamine.
The temperature maintained for converting [A] to [B] during the reaction can be from +5°C to
50°C preferably between +15°C to 40°C.
The preferential mode of addition is portion-wise addition of compound [A] to a solution of
oxalyl chloride in methylene chloride which Is to be kept stirred in the flask, to keep always
oxalyl chloride in excess [ to prevent probable bis-acylation]. As the compound [A] is electron
rich, the acylation is facile and needs no catalysis. The base used, preferably tertiary amines
favour the formation of acylated product by making hydrochloride salt formation thus
favouring the equilibrium to product side. After the completion of the portion wise addition of
compound [A], the reaction mixture is stirred at 35°C to 40°C for 2 to 3 hours
The progress of the reaction [ Disappearance of compound [A] ] is monitored by TLC.
After the completion of the reaction, to the very same reaction mass is added an aqueous.
solution of KOH to saponify the acid chloride to K-salt i.e. compound [C].
The solvent is distilled at this stage. This gives compound [C] in aqueous phase which is
ready for reaction with hydrazine hydrate.
At 60°C hydrazine hydrate is added and the reaction mixture is heated to 95°C to 100°C and maintained for 14 to 16 hours. Reaction mixture is then cooled to 40°C and KOH flakes are added and heated to 115°C to 130°C by distilling out water and maintained at 120°C to 130°C for complete reduction. The reaction mixture is then cooled to 40°C and diluted with water and filtered which gives an aqueous solution of compound [D]. The aqueous solution containing compound [D] is then acidified by dropping into a mixture of acetic acid and methanol at 20°C to 25°C.
The precipitated compound [E] is then cooled to 10°C and reaction mass is filtered and washed with chilled water to give compound [E] which is dried at 55°C to 60°C to give 2-(4-methylphenyl)-6-methyllmidazo[1,2-a]pyridine-3-acetic acid in 85 % overall yield with more than 96% purity.
PREPARATION OF IMIDAZO[1,2-a]PYRIDINE 3-ACETAMIDE DERIVATIVES :
This step of synthesis refers to the preparation of imidazo[1,2-a]pyridine derivatives
according to formula [1] as described in detailed description of the present invention where

Z=N(Me)2 from a compound of same formula where Z=OH; where X and Y have the meaning defined in formula [1].
The conversion essentially consists of preparing a mixed anhydride with pivaloyl chloride in presence of a base followed by reaction with amine to form an amide. As the mixed anhydrides are known to be moisture sensitive and generally formed at low temperatures the solvents are selected accordingly.
The solvents are selected from a halogenated solvents such as chloroform, dichloromethane, 1,2-dichloroethane etc., preferably dichloromethane. The other class of solvents include ethers such as Diethyl ether THF, dioxane, etc.
The solvents selected for the isolation of imidazo[1,2-a]pyridine 3-acetamide derivatives are n-hexane, cyciohexane, petroleum ether and toluene etc.
The bases used for the salt formation and to push the reaction in forward direction can be
tertiary amines such as triethyl amine, tri n-butyl amine diisopropylethylamine, N-
methylmorpholine, diethylamide, DMAP, DBU, DBN etc.; The bases can also be selected
from various inorganic bases like carbonates, bicarbonates of alkali metals. Out of all
available bases triethylamine is preferred over other bases due to its ease of availability and
low cost.
The temperature during mixed anhydride formation is between -20 °C and +10°C. and after
respective amine added the temperature range is from 20°C to 120°C depending on the
choice of solvent.
The detailed process for the conversion of an acid to amide is exemplified in a process below
wherein 2-(4-methylphenyl)-6-methylimidazo[1,2-a]pyridine-3-acetic acid prepared by the
method shown in scheme 10 is further converted to Zolpidem.
The preparation of Zolpidem from 2-(4-methylphenyl)-6-methylimidazo[1,2-a]pyridine-3-
acetic acid is described in the scheme 14 below.

SCHEME-14

EXAMPLES
The invention is now illustrated with representative examples and in no way limit the scope of the invention. Example -1
Preparation of 2-(4-methylphenyl)-6-methyllmidazo[1,2-a]pyrldine-3-acetic acid: Into a 500 ml four-necked round bottomed flask equipped with a stirrer, condenser, addition funnel and thermometer, were charged 125 ml dichloromethane and 17.16 gms(0.135 moles) oxalyl chloride. The solution was kept stirred at 25°C to 35°C.To it were charged 25 gms (0.1126 moles) of 2-(4-methylphenyl)-6-methylimidazo[1,2-a]pyridine, portion wise, at 25°C to 35°C taking care of the evolution of gas. To it was added drop-wise a solution of 13.64 gms (0.135 moles) of triethylamine in 25 ml of dichloromethane maintaining 25°C to 35°C. After the addition was over, the reaction mass was stirred at 35°C to 40°C for 2 to 3 hours. A solution of 18.54 gms (85 % pure) (0.2814 moles) potassium hydroxide in 250 ml water was added very slowly taking care of the foaming. The reaction mixture was then heated to 80°C to distil off completely dichloromethane(about 135 ml to 140 ml). The reaction mixture was then cooled to 60°C and to it were added 10.55 gms (80% strength)(0.1688 moles).
Aqueous hydrazine hydrate and reaction mass was heated to 95°C to 100°C and maintained same temperature for 14 to 16 hours. The reaction mixture was then cooled to 40°C, and 14.84 gms (85% pure)(0.225 moles) of potassium hydroxide were added. The reaction mass was then heated with stirring to 115°C to 130°C to distil off 245 ml of water and maintained at 120°C to 130°C for one hour under reflux. The reaction mass was then cooled to 40°C and 250 ml of water were added and the resulting solution was filtered. The filtered solution was then added to a mixture of 40 gms. (0.6754 moles) of acetic acid and 6 ml of methanol under

stirring at 20°C to 25°C. The precipitated product was then cooled to 10°C and filtered and was washed twice with 25 ml of chilled water. The material was unloaded and dried at 55°C to 60°C for 10 to 12 hours to give 26.80 gms. of 2-(4-methylphenyl)-6-methylimidazo[1,2-a]pyridine-3-acetic acid with HPLC purity of 95% which amounts to an overall yield of 85 % based on 2-(4-methylphenyl)-6-methylimidazo[1,2-a]pyridine. 1HNMR : (DMSO-de, 8 ppm): 2.32(s,3H),2.35(s,3H),4.08(s,2H), 7.13-8.20 (aromatic 7H)
Example -2
Preparation of Zolpfdem from 2-{4-methylphenyl)-6-methyllmidazo[1)2-a]pyrldlne-3-
acetic acid
Into a 250 ml three-necked round bottomed flask equipped with an arrangement for cooling and heating facility and provided with a condenser, addition funnel and thermometer were charged 60 ml of dichloromethane and 10 gms(0.0357 moles) of 2-(4-methylphenyl)-6-methylimidazo[1,2-a]pyridine-3-acetic acid (prepared in example-1). The reaction mixture was then cooled to 0°C to 5°C and 5.41 gms(0.054 moles) of triethylamine was added to give a clear solution at 0°C to 5°C.
8.60 gms( 0.0714 moles) of pivaloyl chloride was added to the reaction mass under stirring and maintaining temperature at 0°C to 5°C.The reaction mixture was then stirred at 0°C to 5°C for 2 hours. To the reaction mixture were added, 20 ml of 40% aqueous solution of dimethylamine(0.1596 moles). Exothermicity was observed and the temperature reached 15°C to 20°C; The reaction mass was then stirred for 3 hours at 15°C to 20°C. The reaction mass was transferred to a separatory funnel and layers were separated. The organic layer was washed twice with 100 ml of water and was dried over anhydrous sodium sulfate. Dichloromethane, containing the compound was then filtered to remove sodium sulfate. 60 ml n-hexane(optionally cyclohexane) were added to it and then distilled. This operation was again repeated with same quantity of n-hexane. 50 ml of n-hexane was then added and the reaction mixture was cooled to room temperature.
The reaction mass was filtered and the material was unloaded and dried at 35°C to 40°C to give 8.5 gms of Zolpidem with a yield of 77.55 % based on 2-(4-methylphenyl)-6-methylimidazo[1,2-a]pyridine-3-acetic acid and had a HPLC purity of 98.88 %.
In another embodiment for the amidation step, a modified purification approach was carried out which is described in Example -3.

Example -3
Preparation of Zolpidem from 2-(-4-methylphenyl)-6-methyllmidazo[1,2-a]pyridine-3-
acetic acid.
In a 250 ml three-necked round bottomed flask equipped with an arrangement for cooling and heating facility and provided with a condenser, addition funnel and thermometer were charged 60 ml of dichloromethane and 10 gms(0.0357 moles) of 2-(4-methylphenyl)-6-methylimidazo[1,2-a]pyridine-3-acetic acid (prepared in example-"). The reaction mixture was then cooled to 0°C to 5°C . and 5.41 gms(0.054 moles) of triethylamine were added to give a clear solution at 0°C to 5°C.
8.60 gms( 0.0714 moles) of pivaloyl chloride were added to the reaction mass under stirring and maintaining temperature at 0°C to 5°C. The reaction mixture was then stirred at 0°C to 5°C for 2 hours. To the reaction mixture were added, 20 ml of 40% aqueous solution of dimethylamine (0.1596 moles). Exothermicity was observed and the temperature reached 15°C to 20°C. The reaction mass was then stirred for 3 hours at 15°C to 20°C.
The reaction mass was transferred to a separatory funnel and layers were separated. The organic layer was washed twice with 100 ml of water, and was dried over anhydrous sodium sulfate. Dichloromethane, containing the compound was then filtered to remove sodium sulfate. Dichloromethane containing the compound was taken for distillation and distilled till about 30 ml of dichloromethane was recovered up to temperature 40°C. To it were added 90 ml of toluene and applied vacuum to distil a mixture of dichloromethane and toluene at 50°C to 55°C till about 60 ml of mixture of solvents was recovered in the receiver pot. The reaction mixture was then cooled to 0°C to 5°C and stirred for 2 hours. The material was filtered washed with 10 ml toluene twice and sucked dry. The material was unloaded and dried at 45°C to 50°C under vac for 12 hours to give 7.5 gm Zolpidem with a yield of 68 % and had HPLC purity of 99.5 %

WE claim:
[1] A process for the preparation of Zolpidem, optionally its acid addition salt, in steps comprising:

(a) reacting the compound of formula - (1),
Formula 1
with oxalyl chloride, in presence of base using an organic solvent to give the
compound of formula-(2),

(b) saponifying compound of formula (2), using a base gives the compound of formula-
(3)

wherein, M is monovalent or divalent cation
(c) reacting the compound of formula-(3) with hydrazine hydrate in the presence of base,
and treating the reaction mixture at elevated temperature,
(d) acidifying the reaction mixture to give compound of formula (4),

(e) reacting compound of formula-(4) in an organic solvent using pivaloyl chloride in
presence of base, at -10 to +10°C to give mixed anhydride of formula-(5),

[12] The process of preparing Zolpidem from 2-(4-methylphenyl)-6-methylimidazo[1,2-a]pyridine-3-acetic acid, involving the formation of mixed anhydride using pivaloyl chloride.
[13] The process for the preparation of 2-(4-methylphenyl)-6-methylimidazo[1,2-a]pyridine -3-acetic acid comprising the steps of:
(a) reacting the compound of formula - (1),

Formula 1
with oxalyl chloride, in presence of base using an organic solvent to give the
compound of formula-(2),
(b) saponifying compound of formula (2), using a base gives the compound of formula-
(3)
wherein, M is monovalent or divalent cation
(c) reacting the compound of formula-(3) with hydrazine hydrate in the presence of base,
and treating the reaction mixture at elevated temperature,
(d) acidifying the reaction mixture to give compound of formula (4),


Date: 24 October 2008

For, Cadila Pharmaceuticals Ltd.,
Dr. B. M. Khamar,
Executive Director - Research,

CH3
Formula 5
0
(f) reacting the compound of formula (5), in-situ with dimethyl amine or its acid addition
salt, preferably an aqueous dimethyl amine to give Zolpidem,
(g) isolating the product from an organic solvent, optionally converting Zolpidem to its
acid addition salt.
[2] The process according to claim-[1], wherein the compound of formula-(1) in step(a)
is preferably added portion-wise to the solution of oxalyl chloride, keeping oxalyl
chloride in excess during the course of reaction. [3] The process according to claim-[1], wherein the reaction in step(a) is carried out at
temperature ranging from 5'C to 50'C. [4] The process as claimed in claim-[1], wherein organic solvent in step(a), is selected
from halogenated solvents such as chloroform, dichioromethane, 1,2-dichloroethane;
ethers such as diethylether, tetrahydrofuran, dioxane; and aromatic hydrocarbons
such as benzene, toluene. [5] The process as claimed in claim-[4], wherein organic solvent is dichioromethane. [6] The process as claimed in claim-[1], wherein the base, in step(a) , is selected from
tertiary amines such as trimethylamine, triethylamine, tributylamine,
diisopropylethylamine , pyridine, N-methylmorpholine, preferably triethyl amine. [7] The process as claimed in claim-[1], wherein the saponification, in step(b), is carried
out using an aqueous alkali. [8] The process as claimed in claim-[1], wherein the base used in step-(c) is selected
from alkali metal hydroxide, carbonates, alkaline earth hydroxides or carbonates,
alkoxide bases, preferably potassium hydroxide. [9] The process as claimed in claim-[1], wherein solvent in step-(e), is selected from
halogenated solvents such as chloroform, dichioromethane, 1,2-dichloroethane;
ethers such as diethyl ether, THF, 2-methyl THF ; preferably dichioromethane. [10] The process as claimed in claim-[1], wherein the base used in step-(e), is selected
from tertiary amines such as triethyl amine, tri n-butyl amine, diisopropylethylamine,
N-methylmorpholine, diethylaniline, DMAP, DBU, DBN; preferably triethyl amine. [11] The process as claimed in claim-[1], wherein, Zolpidem in step(g), is isolated from
mixture of dichioromethane and toluene.