FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003


PROVISIONAL SPECIFICATION (See section 10 and rule 13)
'PROCESSES FOR THE PREPARATION OF INDIPLON AND INTERMEDIATES
THEREOF"

Glenmark Generics Limited an Indian Company, registered under the Indian company's Act 1957 and having its
registered office at
Glenmark House,
HDO - Corporate Bldg, Wing -A,
B.D. Sawant Marg, Chakala, Andheri (East), Mumbai - 400 099
The following specification describes the nature of the invention:


FIELD OF THE INVENTION
The present invention relates to processes for the preparation of indiplon and intermediates thereof. The present invention also relates to a pharmaceutical composition and a method of treating primary, chronic insomnia.
BACKGROUND OF THE INVENTION
Indiplon is a GABA-A receptor modulator, which has been filed for regulatory
approval in the U.S. for treatment of primary, chronic insomnia in adult and elderly patients. Indiplon is chemically described as N-methyl-N-[3-[3-(thi^n-2-ylcarbonyl) pyrazolo[l,5-a]pyrimidin-7-yl]phenyI]acetamide and is represented by structural formula (I):

(I)
U.S. Patent No. 4,521,422 describes pyrazolopyrirnidines derivatives, including indiplon and their pharmaceutically acceptable salts, a pharmaceutical composition and method of treatment, a process for the preparation of indiplon.
U.S. Patent No. 6,399,621 (the '621 patent) discloses $ process, as illustrated below, for the preparation of indiplon, which involves an N-alkylation of enaminone intermediate compound of formula IV, that is carried out by using iodomethane in the presence of sodium hydride to give the N-methyl enaminone intermediate compound of formula III followed by condensation with aminopyrazole intermediate compound of formula II using glacial acetic acid at reflux conditions to afford indiplon of formula I.
2


U.S. Patent No.6, 472,528 (the "528 patent) describes a process for the preparation of indiplon comprising an N-alkylation of an enaminone intermediate compound of formula IV, that is carried out with the use of dimethyl sulfate, a phase transfer catalyst (tetrabutyl ammonium sulfate) in the presence of benzoflouride and dichloromethane as solvents at a temperature below 40°C, to give the N-methylenaminone intermediate compound of formula III, as illustrated below; then followed by condensation with aminopyrazole intermediate compound of formula II using glacial acetic acid at reflux conditions to afford indiplon of formula I.


In the aforementioned processes, the N-alkyiation of the enaminone intermediate compound (IV) engages differing methodologies; where one process uses sodium hydride as a base and alternately, another process uses a phase transfer catalyst The similarity of these processes affords the N-methyl enaminone compound of formula III to be produced in yields of less than about 60% and purity levels of less than about 90% , which translates to a reduction in the overall yield of indiplon (I).
Further, the usage of either sodium hydride as a base or phase transfer catalysts is disadvantageous which stems from moisture sensitivity, safety concerns, storage issues, required quenching after use, which subsequently negates the suitability and feasibility of the process on an industrial scale.
The "621 and "528 patents disclose the recovery of the target indiplon product from the reaction mixture using water and glacial acetic acid. However, neither the "621 patent or the "528 patent discloses the formation or presence of by-products; and their removal or separation from the target product, should they be formed.
Potentially in acidic conditions the isomeric regioisomer impurity of indiplon may be formed in an amount of not less than 5% . The levels of impurity would make the product unacceptable to market. Additionally, said product to be marketable would require multiple purifications steps , thus rendering the process economically not feasible.
Moreover, for a new drug product to gain marketing approval, manufacturers are mandated to submit to the regulatory authorities evidence to show that the product is
4

acceptable for human administration. Such a submission must include, among other things, analytical data to show the impurity profile of the product to demonstrate that the impurities are absent, or are present only at a negligible amount. Further, the U.S. Food and Drug Administration's Center for Drug Evaluation and Research (CDER) has promulgated guidelines recommending that new drug and generic drug applicants identify organic impurities of 0.1% or greater in the active ingredient. Unless an impurity is a human metabolite, has been tested for safety, or was present in a composition that was shown to be safe in clinical trials, the CDER further recommends that the drug applicant reduce the amount of the impurity in the active ingredient to below 0.1%. Thus, there is a need to isolate impurities in drug substances so that their pharmacology and toxicology can be studied.
In light of the evolving and more rigorous requirements demanded of drug manufacturers and the prevailing disadvantages present with the prior art, there is a need for an improved process for the preparation of indiplon and its intermediates, which circumvents the usage of potentially hazardous chemicals, the likely formation of isomeric and other process-related impurities; while ensuring a target indiplon product with optimum yield and purity.
The processes, herein described, for the preparation of indiplon and intermediates thereof are simple, eco-friendly and well suited on industrial scale.
SUMMARY OF THE INVENTION
The present invention relates to processes for the preparation of indiplon and intermediates thereof.
In one aspect, the present invention provides a process for preparing indiplon of formula I
5

comprising :
a) reacting a compound N-[3-[3-(dimethylamino)-l-oxo-2-propenyl]-phenyl]-acetamide of formula IV or salt thereof

with a base, capable of producing hydroxide ions and methylating agent in the presence of an organic solvent to form the compound N-[H3-(dimethylamino)-l-oxo-2-propenyl]-phenyl]-N-methylacetamide of formula III or a salt thereof

Ill
b) reacting the compound of formula III with the compound 3-amino-lH-pyrazol-4-yl)-2-thienylmethanone of formula II or a salt thereof
6


in the presence of an acid with a pka of below about 4 and an organic solvent.
In a second aspect, the present invention provides a process for purifying indiplon comprising:
(a) providing a solution of a indiplon, comprising a regioisomer impurity, in a solvent or a mixture of solvents or their aqueous mixtures and
(b) precipitating the solid from the solution, and
(c) recovering the solid to obtain indiplon substantially free of regioisomer.
In a third aspect, the present invention provides indiplon, prepared by the processes herein described, having a purity of at least about 99.8% as determined by HPLC.
In a fourth aspect, the present invention provides indiplon, prepared by the processes herein described, having a purity of at least about 99.9% as determined by HPLC.
In a fifth aspect, the present invention provides indiplon, prepared by the processes herein described, having less than about 0.15% area of regioisomer, as measured by HPLC.
In a sixth aspect, the present invention provides indiplon, prepared by the processes herein described, having less than about 0.1 % area of regioisomer, as measured by HPLC.
In another embodiment, the present invention provides indiplon, prepared by the processes herein described,has less than about 0.05% area of regioisomer, as measured by HPLC.
In a yet another aspect, the present invention provides a pharmaceutical composition comprising indiplon obtained by the processes herein described, and at least a pharmaceutically acceptable carrier.

BRIEF DESCRIPTION OF DRAWING
Fig. 1. is apicture of indiplon crystal particles obtained by the process of present invention as
observed under SEM.
DETAILED DESCRIPTION OF THE INVENTION
As mentioned above, the present invention is directed to improved processes for the synthesis of indiplon and its intermediates.
In one embodiment, the present invention provides a process for preparing indiplon of formula I

comprising :
a) reacting a compound N-[3-[3-(dimethylamino)-l-oxo-2-propenyl]-phenyI]-acetamide of formula IV or salt thereof

CH
IV
with a base capable of producing hydroxide ions and methylating agent in the presence of organic solvent to form the compound N-[3-[3-(dimethylamino)-l-oxo-2-propenyl]-phenyl]-N-methylacetamide of formula III or a salt thereof

HI b) reacting the compound of formula III with the compound 3-amino-lH-pyrazol-4-yl)-2-thienylmethanone of formula II or a salt thereof

II
in the presence of an acid with a pka of below about 4 and an organic solvent.
In a) of the process directly described above, the base that can be used which is capable of providing hydroxide ions is selected from alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; alkaline earth metal hydroxides such as magnesium hydroxide, calcium hydroxide and the like; ammonium hydroxide and mixtures thereof and their aqueous or alcoholic mixtures. The alkali and alkaline metal alkoxides, alkali and alkaline metal carbonates and bicarbonates are also contemplated, preferably potassium hydroxide.
While the organic solvents that can be used in a) include but are not limited to halogenated solvents such as dichloromethane, ethylene dichloride, chloroform and the like; esters solvent such as ethyl acetate, isopropyl acetate and the like; nitriles such as acetonitrile, propionitrile and the like; ethers such as tetrahydrofuran, 1,4-dioxane and the like; aprotic polar solvents such as N,N-dimethyl formamide, dimethyl sulfoxide, dimethyl acetamide, N-methyl-2-pyrrolidone, hexamethyl phosphoric triamide and mixtures thereof in various proportions without limitation. Preferably N,N-dimethyl formamide (DMF).
9

Further, the methylating agent that can be used include but are not limited methyl iodide, dimethyl sulphate and the like. Preferably methyl iodide.
Other methylating agents are also contemplated.
The temperatures for carrying out the reaction step a can be from 25°C to about 40°C. preferably from about 25°C to about 30° C.
The reaction time for the completion of reaction can be from about 30 minutes to about 5 hours, preferably about 30 minutes.
The amount of base employed in a) is from about an equimolar amount to about 5 times the equimolar amount with respect to the starting material of formula VI, preferably an equimolar amount.
Optionally, when an excess base, which may be either aqueous or an alcoholic mixture is employed , this, then, may additionally serve as the solvent.
The acid that can be used in b) above in the reaction of compound of formula III and compound of formula II include, but are not limited to acids having the pka of below about 4 such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, oxalic acid, maleic acid, succininc acid, benzoic acid, ascorbic acid, paratoluene sulfonic acid, methane sulfonic acid, and the like; and their aqueous mixtures thereof. Preferably, phosphoric acid or maleic acid or hydrochloric acid is being used.
The solvent in b) that can used include, but not limited to, a water miscible alcohol such as methanol, ethanol, isopropanol, n-butanol and the like; ketone such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; nitrile such as acetonitrile, propionitrile and the like; and mixtures thereof in various proportions without limitation. Preferably, methanol or ethanol is used.
The temperatures for carrying out the reaction in b) can be from about 25°C to about 50°C, preferably from about 25°C to about 35° C, more preferably 25 to 30°C.
The time required for the completion of reaction in b) can be from about 30 minutes to about 15 hours, preferably from about 5 to 10 hours.
10

Typically, the molar equivalents of compound of formula II may be about 1 to about 2 times the molar amount of the compound of formula III, preferably about 1 molar equivalent; the molar equivalents of acid used may be about 1 to about 10 times the molar amount of the compound of formula III, preferably about 5 molar equivalents.
Optionally the reaction in b) is carried out in the absence of solvents, i.e., in neat conditions by employing an excess of aqueous acid.
Optionally the reaction in b) is carried without isolation of intermediates, i.e., can be carried out by one pot synthesis.
After completion of the reaction, the desired compounds of either or both formula HI and can be obtained from the reaction mixture by conventional means known to one of skilled in the art. Should the target compounds be produced immediately in the form of crystals, these can be optionally separated by filtration. Alternatively, a suitable recovery procedure optionally comprises: adding water; neutralizing the mixture, if necessary; extracting the mixture with a water-immiscible organic solvent; drying the extract; and distilling the solvent off. The product thus obtained can be, optionally further purified by conventional means, such as recrystallization or chromatographic separation techniques, for example preparative thin layer chromatography or column chromatography, notably column chromatography. Preferably by recrystallization.
The compounds of formulae IV and II can be prepared according to the methods described in U.S. Patent Nos. 6,399,521 and 7,034,154, which are incorporated herein by reference, in their entirety.
In a preferred embodiment of the present invention, the processes are optionally carried out in situ; or by one pot synthesis.
In another embodiment of the present invention, a compound of formulae IV or I is optionally purified by re-crystallization using a solvent or mixture of solvents.
In a further embodiment of the present invention, a compound of formulae IV or I is purified optionally by converting into a pharmaceutically acceptable salt.
In another embodiment, the present invention provides a process for purifying indiplon comprising: (a) providing a solution of a indiplon comprising regioisomer in a solvent or a mixture of
11

solvents or their aqueous mixtures and
(b) precipitating the solid from the solution, and
(c) recovering the solid to obtain indiplon substantially free of regioisomer.
The solvents that can be used in a) of the process directly described above, for the dissolution of indiplon is selected from methanol, ethanol, isopropyl alcohol , diethyl ether, methyl t-butyl ether, ethyl acetate, isobutyl acetate, acetonitrile and mixtures thereof, and mixtures of said organic solvents and water. Preferably acetone and acetonitrile in combination with water.
The temperature for dissolution can range from about 25 °C to about 100°C or reflux temperatures of the solvents used, preferably at about 30°C.
The time period for dissolution can be range from about 30 minutes to about 5 hours, preferably 1 hour.
The solution obtained is optionally filtered through celite ov diatamous earth to separate the extraneous matter present or formed in the solution by using conventional filtration technique known in the art.
The precipitation of solid in b) above is achieved but not limited to evaporation, cooling, drying and the like, preferably by cooling.
The temperature range for precipitation of solid can be from about -10 °C to about 30°C, preferably about 30°C.
The time period for complete precipitation of solid can range from about 30 minutes to about 5 hours, preferably 1 hour.
The obtained indiplon of formula I can be dried can be from about 25°C to about 75°C, preferably at 50°C and at reduced pressure of about e.g. 5 to 20 mbar, for a period of about I to about 10 hours. Preferably 1 hour.
In yet another embodiment, the present invention provides indiplon having a purity at least about 99.8% as determined by HPLC.
In a still further embodiment, the present invention provides indiplon having a purity at least about 99.9% as determined by HPLC.
12

In another embodiment, the present invention provides indiplon having less than about 0.15% area of regioisomer impurity as determined by HPLC.
In yet another embodiment, the present invention provides indiplon having less than about 0.1% area of regioisomer impurity as determined by HPLC.
In a still further embodiment, the present invention provides indiplon having less than about 0.05% area of regioisomer impurity as determined by HPLC.
The processes of present invention produces pure indiplon in the highest yield currently reported. The process of present invention achieves a higher reaction rate at lower temperatures than is possible using known processes for producing indiplon.
The purity of indiplon,-as isolated, prepared by the process herein described, is unexpectedly higher than available in literature (i.e., at lest about 99.8%). However, if desired, pure incfipfon obtained by the process of the present invention and having a purity of at least 99%, as determined by HPLC, can be further recrystalljzed from a solvent, preferably from methanol, ethanol, or a reaction medium of water and a co- solvent such as methanol, ethanol, acetonitrile and the like in order to produce a drug substance that complies with regulatory requirements. The regioisomer of indiplon is represented by formula V



H,C

Indiplon

Indiplon regioisomer

13

Formation of N-(3-[3-[2-thienylcarbonyl]-pyrazol-[ 1,5-a]pyrimidin-5-yl]phenyl)N-methylacetamide of formula V, regioisomer of indiplon, has been identified as a main impurity in the synthesis of indiplon starting from 3-amino-lH-pyrazol-4-yI)-2-thienylmethanone and N-[3-[3-(dimethylamino)-1 -oxo-2-propenyl]-pheny l]-N-methylacetamide. The amount of this impurity has been found to be strongly dependent on the reaction conditions.
A part from the regio isomer described above the following process related impurites may be formed which are NMT 0.5% area by HPLC in total in the final product indiplon.

N-desmethyl indplon N-desacetyl indiplon N-desmethyl-N-desacetyl indplon
VI VII VIII
Indiplon obtained by the process of present invention has the purity of at least about 99.8 area % as measured by HPLC, preferably at least about 99.9 area % as measured by HPLC.
In another embodiment, the present invention provides indiplon of formula I characterized by HPLC having a purity of at least about 99.8% and containing total impurities of about NMT 0.2% and any other individual impurity of about NMT 0.05%.
In yet another embodiment, Indiplon obtained by the process described herein has a residual organic solvent content of less than the amount recommended for pharmaceutical products, as set forth for example in ICH guidelines and U.S. pharmacopoeia; i.e., less than about 600ppm of dichloromethane, less than about lOOOppm of N,N-dimethyI formamide, less than about 5000ppm of ethanol, less than about 3000ppm of methanol, less than about 5000ppm of acetone and less than about 400ppm of acetonitrile.
14

Crystal particles of indiplon used herein has the surface area of about 1 to about 15 m2/g as measured by B. ET (Brunauer-Emmett-Teller) preferably from about 1 to about 5 m2/gm and the mean particle size of about 5 to about 50 um, preferably of about 5 to about 20 um.

S.No. Test Results
1 Description Yellow coloured powder
2. Sulphated ash 0.05%
3 Related Impurity by HPLC * Impurity A: Not detected
**Impurity B: Below detection limit. Single
maximum impurity: 0.86%
Total impurities: 0.96% -
4 TGA 0.2725% sample weight lostupto 100°C
5 Particle size Distribution d(0.1) 4.949 um d(0.5)11.641um d(0.9) 24.325 um
6 Bulk Density As such = 0.24g/ml
After tapping (750)=0.47g/ml as per USP
method I
6 SEM (Scanning electron microscope) Plate shape crystals
7 Surface area by BET 1.41 m /gm
• Impurity A: (3-Amino-l H-pyrazole-4-yl)-2-thienylmethanone.
• Impurity B: N-[3-(3-Dimethylamino)-l-oxo-2-propenyl]phenyl]-N-methyl acetamide.
As used herein, the term "um" refers to "micrometer" which is \x\0~6 meter.
As used herein, "crystalline particles" means any combination of single crystals, aggregates and agglomerates.
As used herein "Particle Size Distribution (P.S.D.)" means the cumulative volume size distribution of equivalent spherical diameters as determined by laser diffraction at 1 bar dispersive pressure in a Sympatec Helos equipment.
"Mean particle size distribution, i.e., d(0.5)" correspondingly, means the median of said particle size distribution.
15

Specific surface area is defined in units of square meters per gram (m /g).
It is usually measured by nitrogen absorption analysis. In this analysis, nitrogen is absorbed on the surface of the substance. The amount of the absorbed nitrogen (as measured during the absorption or the subsequent desorption process) is related to the surface area via a formula known as the B. ET. formula.
Specific surface area of an active pharmaceutical ingredient may be affected by various factors. There is a general connection between Specific Surface Area and Particle Size Distribution; the smaller the Particle Size Distribution, the higher the Specific Surface Area. The available surface area for drug dissolution correlates to the rate of dissolution and solubility where a greater surface area enhances the solubility of a drug and enhances the rate of dissolution of a drug, hence may improve its bioavailability and potentially its toxicity profiles. The lack of solubility of indiplon creates a problem since bioavailability of a water insoluble active ingredient is usually poor. Thus there is a need in the art to prepare active pharmaceutical ingredients such as indiplon with a high surface area to obtain formulations with greater bioavailability, and to compensate for any loss of surface area before formulation.
The particle size can be determined by such techniques as, for example, Malvern light scattering, a laser light scattering technique, etc., using, e.g., a Malvern Mastersizer 2000 It is noted the notation Dx means that X% of the particles have a diameter less than a specified diameter D. The particle sizes of the Indiplon can be obtained by, for example, any milling, grinding, micronizing or other particle size reduction method known in the art to bring the solid state indiplon any of the foregoing desired particle size range.
In another preferred embodiment of the present invention provides a pharmaceutical composition comprising indiplon obtained by the process of present invention and suitable pharmaceutical carriers. The pharmaceutical compositions may be administered to a mammalian patient in any dosage form, e.g., liquid, powder, elixir, injectable solution, etc. Dosage forms may be adapted for administration to the patient by oral, buccal, parenteral, ophthalmic, rectal and transdermal routes. Oral dosage forms include, but are not limited to, tablets, pills, capsules, troches, sachets, suspensions, powders, lozenges, elixirs and the like.
16

The pharmaceutical compositions comprising indiplon or its pharmaceutically acceptable salts, obtained by the process disclosed herein, and suitable pharmaceutical carriers also may be administered as suppositories, ophthalmic ointments and suspensions, and parenteral suspensions, where the most preferred route of administration is oral.
Capsule dosages will contain the indiplon or its pharmaceutically acceptable salts which may be coated with gelatin. Tablets and powders may also be coated with an enteric coating. The enteric-coated powder forms may have coatings comprising phthalic acid cellulose acetate, hydroxypropylmethyl cellulose phthalate, polyvinyl alcohol phthalate,carboxymethylethyl-cellulose, a copolymer of styrene and maleic acid, a copolymer of methacrylic acid and methyl methacrylate, and like materials, and if desired, they may be employed with suitable plasticizers and/or extending agents. A coated tablet may have a coating on the surface of the tablet or may be a tablet comprising a powder or granules with an enteric-coating.
Tableting compositions may have few or many components depending upon the tableting method used, the release rate desired and other factors. For example, the compositions of the present invention may contain diluents such as cellulose-derived materials like powdered cellulose, microcrystalline cellulose, microfine cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose salts and other substituted and unsubstituted celluloses; starch; pregelatinized starch; inorganic diluents such calcium carbonate and calcium diphosphate and other diluents known to one of ordinary skill in the art. Other suitable diluents include waxes, sugars (e.g. lactose) and sugar alcohols like mannitol and sorbitol, acrylate polymers and copolymers, as well as pectin, dextrin and gelatin.
Other excipients contemplated by the present invention include binders, such as acacia gum, pregelatinized starch, sodium alginate, glucose and other binders used in wet and dry granulation and direct compression tableting processes; disintegrants such as sodium starch glycolate, crospovidone, low-substituted hydroxypropyl cellulose and others; lubricants like magnesium and calcium stearate and sodium stearyl fumarate; flavorings; sweeteners; preservatives; pharmaceutically acceptable dyes and glidants such as silicon dioxide.
17

X 500ml methylene chloride. The combined organic layers are washed with 3 X 500 ml water , the subsequent organic layer is dried over sodium sulfate and concentrated to dryness to give a yellow colored solid, which is triturated with n-hexane (700ml) ,filtered and dried at 50°C until a constant weight to give a solid (190gm) (Purity, - >95% ,by TLC)
REFERENCE EXAMPLE 2 : PREPARATION OF INDIPLON (FORMULA I)
A mixture of (3-Amino-lH-pyrazoI-4-yl)-2-thienylmethanone (lOgm) and N-[3-(dimethylamino)-l-oxo-2-propenyl]-phenyl]-N-methyl acetamide (12.5gm) in glacial acetic acid (180ml) was refluxed for 6 hr, and the progress of the reaction was monitored by TLC. The reaction mass is concentrated to obtain a residue, which is treated with methylene chloride (45ml) and triturated with n-hexane (180ml). The precipitated product was filtered, washed with mixture of methylene chloride and n-hexane (1:1,90ml) and dried in vacuum to obtain 18 gm of the title compound . Purity by HPLC: 94.88%.
EXAMPLE 2 : PREPARATION OF INDIPLON USING PHOSPHORIC ACID
N-[3-(Dimethylamino)-l-oxo-2-propenyl]-phenyl]-N-methylacetamide (2.5gm, 0.010 mole) and (3-Amino-lH-pyrazo)-4-y])-2-thienylmethanone (2.0gm,0.0I Omole) were dissolved in a mixture of water (30 ml), ethanol (15 ml) and phosphoric acid (0.79gm,0.0081 mol) and stirred for -10 hr at room temperature , the progress of the reaction was monitored by TLC. After the completion of the reaction, the reaction mass was filtered, washed with water (10 ml) and acetone (10 ml). The wet solid obtained is further dried at 50°C under vacuum to give 2.52gm of the title compound. Purity by HPLC: 99.14%.
EXAMPLE 3 : PREPARATION OF INDIPLON USING AQEOUS METHANOL AND HYDROCHLORIC ACID
N-[3-(Dimethylamino)-l-oxo-2-propenyl]-phenyl]-N-methyl acetamide (2.5gm, 0.010 mol) and (3-Amino-lH-pyrazoI-4-yl)-2-thienylmethanone (2.0gm,0.010mol) were dissolved in a mixture of water (30 ml),methanoI (15 ml) and ~34% w/w, aq. hydrochloric acid (0.96gm,0.012 mol) and stirred for -10 hr at room temperature , the progress of the
19

reaction was monitored by TLC. After the completion of the ruction, the reaction mass was filtered, washed with water (10 ml) and acetone (10 ml).The wet solid obtained is ftirther dried at 50°C under vacuum to give 2.62gm of the title compound. Purity by HPLC : 98.79% .
EXAMPLE 4 : PREPARATION OF INDIPLON USING FORMIC ACID
N-[3-(Dimethylamino)-l-oxo-2-propenyl]-phenyl]-N-methylacetamide (2.5gm, 0.010 mol) and (3-Amino-lH-pyrazol-4-yl)-2-thienylmethanone (2.0gm,0.010mole) were dissolved in formic acid (20 ml) and stirred at reflux temperature for ~4hr , the progress of the reaction was monitored by TLC. After the completion of the reaction, the reaction mass was concentrated , the residue is triturated with acetone (20 ml) and filtered, washed with acetone (10 ml), the wet solid obtained is further dried at 45°C -50°C pnder vacuum to give 2.50gm of the title compound. Purity by HPLC: 98.82%.
EXAMPLE 5 : PREPARATION OF INDIPLON USING CITRIC ACID
N-[3-(Dimethylamino)-l-oxo-2-propenyl]-phenyl]-N-methyl acetamide (5.0gm, 0.020 mole) and (3-Amino-lH-pyrazol-4-yl)-2-thienylmethanone (4.0gm,0.020mole) were dissolved in a mixture of water (54 ml),ethanol (31 ml) and citric acid (3.84gm,0.020 mol) and stirred for about 12 hrs at room temperature progress of reaction was monitored by TLC , After completion of reaction, reaction mass was filtered, wasted with a mixture of ethanol and water (1:1,24 ml) .The wet solid obtained is further dried &t 50°C under vacuum to give 5.30 gms of the title compound. Purity by HPLC: 99.10%.
EXAMPLE 6 : PREPARATION OF INDIPLON USING MAL&IC ACID
N-[3-(Dimethylamino)-l-oxo-2-propenyl]-phenyI]-N-m^thyl acetamide (5.0gm, 0.020 mole) and (3-Amino-lH-pyrazol-4-yI)-2-thienyImethanOne (4.0gm,0.020mole) were dissolved in a mixture of water (54 mI),ethanoI (31ml) and maleic acid (2.40gm,0.020 mol) and stirred for about 12 hrs at room temperature ,progress of reaction was monitored by TLC , After completion of reaction, reaction mass was filtered, waslied with a mixture of ethanol
20

and water (1:1,24 ml) .The wet solid obtained is further dried at 50°C under vacuum to give 5.40 gms of the title compound Purity by HPLC : 99.24%.
EXAMPLE 7 : PREPARATION OF INDIPLON USING OXALIC ACID
N-[3-(Dimethylamino)-l-oxo-2-propenyl]-phenyl]-N-methyl acetamide (5.0gm, 0.020 mole) and (3-Amino-lH-pyrazol-4-yl)-2-thienylmethanone (4.0gm,0.020mole) were dissolved in a mixture of water (54 ml),ethanol (31ml) and oxalic acid dihydrate (2.60gm,0.020 mol) and stirred for -12 hr at room temperature progress of reaction was monitored by TLC , After completion of reaction, Reaction mass was filtered, washed with a mixture of Ethanol and water (1:1,24 ml).The wet solid obtained is further dried at 50°C under vacuum to afford 5.10 gms of the title compound. Purity by HPLC: 98.62%.
21

The present invention particularly provides: A) A process for preparing indiplon of formula I

CH3

comprising :
a) reacting a compound N-[3-[3-(dimethylamino)-]-oxo-2-propenyl]-phenyl]-acetamide of formula IV or salt thereof


H*C,

IV with a base capable of producing hydroxide ions and methylating agent in the presence of organic solvent to form the compound N-[3-[3-(dimethylaniino)-I-oxo-2-propenyl]-phenyl]-N-methylacetamide of formula III or a salt thereof


H,C,

III
22

b) reacting the compound of formula III with the compound 3-amino-lH-pyrazol-4-yI)-2-thienylmethanone of formula II or a salt thereof

N-NH H2N
II in the presence of an acid with a pka of below about 4 in an organic solvent.
Al) The process as described in A, wherein the base capable of providing hydroxide ions is selected from the group comprising of alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or lithium hydroxide, and alkaline earth metal hydroxides such as magnesium hydroxide, calcium hydroxide and mixtures thereof.
A2) The process as described in A, wherein the methylating agent is methyl iodide or dimethyl sulphate.
A3) The process as described in A, wherein the acid with a pka of below about 4 is selected from group consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, oxalic acid, maleic acid, succininc acid, benzoic acid, ascorbic acid, paratoluene sulfonic acid, methane sulfonic acid, and the like; and their aqueous mixtures thereof.
A4) The process as described in A, wherein the organic solvent used in the reaction of compound of formula III with the compound of formula II is a water miscible solvent selected from alcoholic solvents, ketones, nitriles, and mixtures thereof.
A5) The process as described in A4, wherein the solvent is an alcohol solvent.
A6) The process as described in A, wherein the organic solvent used in the reaction of compound of formula IV with the base is a selected from halogenated solvents dichloromethane, ethylene dichloride, chloroform, esters solvents ethyl acetate, isopropyl
23

acetate, nitriles acetonitriie, propionitrile , ethers tetrahydrofuran, 1,4-dioxane, aprotic polar solvents N,N-dimethyl formamide, dimethyl sulfoxide, dimethyl acetamide, N-methyl-2-pyrrolidone, hexamethyl phosphoric triamide and mixtures thereof.
A7) The process as described in A, wherein the reaction of compound of formula III and compound of formula II is carried out at about 25°C to about 35°C.
A8) The process as described in A, wherein the reaction of compound of formula IV with the base is carried out at about 25°C to about 30°C.
B) A process for purifying indiplon comprising:
(a) providing a solution of a indiplon comprising regioisomer in a solvent or a mixture of solvents or their aqueous mixtures and
(b) precipitating the solid from the solution, and
(c) recovering the solid to obtain indiplon substantially free of regioisomer.
Bl) The process as described in B wherein the solvent is selected from methanol, ethanol, isopropyl alcohol, diethyl ether, methyl t-butyl ether, ethyl acetate, isobutyl acetate, acetonitriie and mixtures thereof, and mixtures of said organic solvents and water.
C. The process as described in B, wherein the indiplon obtained contains less than about
0.15% area of regioisomer impurity as measured by HPLC.
D. The process of C, wherein the indiplon has less than 0.1% area of regioisomer impurity as
measured by HPLC.
E. The process of D, wherein the indiplon has less than 0.05% area of regioisomer impurity
as measured by HPLC.
F. Indiplon having at least about 99.8% purity as measured by HPLC.
24

25
G. The process as described in F, wherein indiplon has purity at least about 99.9% purity as measured by HPLC.