WO2017009866A1

WO2017009866A1 - Novel recovery and recycling process of racemic 4-(4-dimethylamino)-1-(4'-fluorophenyl)-1-(hydroxybutyl)-3-(hydroxymethyl)-benzonitrile

Info

Publication number: WO2017009866A1
Application number: PCT/IN2016/050231
Authority: WO
Inventors: Buchi Reddy Reguri; Ashok Prasad; Ajay Singh Rawat; Sandip RAJPUT; Rohit B SANTAN
Original assignee: Ipca Laboratories Limited
Priority date: 2015-07-11
Filing date: 2016-07-11
Publication date: 2017-01-19

Abstract

Disclosed herein is a novel recovery and recycling process of racemic 4-(4- dimethylamino)-1-(4'-fluorophenyl)-1-(hydroxybutyl)-3-(hydroxymethyl)- benzonitrile (hereinafter referred as cyanodiol). The racemic cyanodiol is an intermediate useful for preparation of Citalopram, Escitalopram or pharmaceutically acceptable salts thereof.

Description

"NOVEL RECOVERY AND RECYCLING PROCESS OF RACEMIC 4-(4- DIME THYL AMINO)- 1 -(4 ' -FLUOROPHENYL)- 1 -(H YDROX YBUT YL)-3- (HYDROXYMETHYL)-BENZONITRILE"

Field of the invention:

The present invention relates to a novel recovery and recycling process of racemic 4-(4-dimethylamino)- 1 -(4' -fluorophenyl)- 1 -(hydroxybutyl)-3 -(hydroxymethyl)- benzonitrile (hereinafter referred as cyanodiol). The racemic cyanodiol is an intermediate useful for preparation of Citalopram, Escitalopram or pharmaceutically acceptable salts thereof.

Background of Invention:

Citalopram, chemically designated as l-(3-dimethylaminopropyl)-l-(4-fluoro- phenyl)-l,3-dihydroisobenzofuran-5-carbonitrile, is racemic mixture of R and S isomers. Escitalopram is the S-(+)-isomer of Citalopram which is active component. Both racemic Citalopram and Escitalopram are marketed as anti depressant agents.

Citalopram Escitalopram

Racemic Citalopram and its use were disclosed in US4136193 patent. Preparation of escitalopram & its pharmaceutical salts like oxalate were disclosed in US4943590. The '590 patent reported preparation of Escitalopram by resolution of racemic cyanodiol with optically active acids like (+) di p-toluoyl tartaric acid to obtain (- )-(S)-4-(4-dimethylamino)- 1 -(4 ' -fluorophenyl)- 1 -(hy droxybutyl)-3 - (hydroxymethyl)-benzonitrile (hereinafter referred as S-cyanodiol). The S- cyanodiol is further reacted with methanesulfonyl chloride in a dry organic solvent like toluene in presence of an organic base like triethylamine to prepare Escitalopram.

The other isomer, (+)-(R)-4-(4-dimethylamino)-l -(4 '-fluorophenyl)- 1 - (hydroxybutyl)-3-(hydroxymethyl)-benzonitrile (hereinafter referred as R- cyanodiol), which is enriched and obtained after resolution is wasted/discarded.

Other publications, WO2006106531 & WO2007012954, also disclosed resolution of the racemic cyanodiol using (+) di p-toluoyl tartaric acid to obtain S-cyanodiol. However, none of the documents, reported the recovery/reuse of the other enantiomerically enriched R-cyanodiol thereby leading to increase in cost of production and causing environmental pollution.

US7390913 reported separation of racemic cyanodiol acid addition salt from non- racemic mixture cyanodiol by dissolving the non-racemic cyanodiol mixture in a solvent, toluene, treating with acid like aq.HCl/methanesulfonic acid to obtain corresponding salt of racemic cyanodiol. This patent also reported precipitation of racemic cyanodiol from a solution of non-racemic mixture of cyanodiol. However, it is found that this process is not resulting in pure racemic mixture and the recovery also found to be very low. Further repeated purifications are necessary to obtain pure racemic cyanodiol.

Another publication, WO2005098018, reported preparation of S-cyanodiol. The WO'018 publication reported reaction of racemic cyanodiol with acetyl chloride to obtain racemic acetyl cyanodiol which is subjected for selective hydrolysis using esterase enzyme derivative in methanol solvent and 2N HC1 to obtain (-) acetyl cyanodiol. The obtained (-) acetyl cyanodiol is further hydrolysed using ammonia in methanol solvent to get (-) cyanodiol. The hydrolysed enantiomerically enriched isomer R-cyanodiol, is discarded as there is no disclosure of recovery/recycling.

Yet another publication, US20080199922, belongs to the same applicant of WO'018 publication, reported selective hydrolysis of racemic acetyl cyanodiol- EDTA complex with esterase enzyme derivative in ethanol solvent and IN HCl to obtain (-) acetyl cyanodiol. The other (+)cyanodiol is racemised by reacting with IN HCl to get racemic cyanodiol. However, this racemisation process also found to be giving impure racemic cyanodiol with low recovery. Therefore, incorporation of additional purification steps is necessary to get pure racemic cyanodiol leading to escalation of production cost.

Another patent, US7112686, reported preparation of R- and S-citalopram with more than 50% of the S-enantiomer from a mixture of R- and S diol with more than 50% of the R-enantiomer by ring closure in presence of an acid (H2SO4/PTSA/HCI) in a solvent medium (acetonitrile/toluene). The obtained citalopram is further treated with gaseous HBr in acetone to obtain racemic citalopram.HBr, which is further purified in water to obtain pure racemic citalopram HBr. This process is not useful for preparation of Escitalopram as ring closure reaction by inversion is taking place leading to citalopram. Moreover, preparation of racemic citalopram by this process also involves several purification steps leading to increase in cost of production.

Consequently there is a need to develop an improved, cost effective, recovery and recycling process of for preparation of racemic cyanodiol from the enantiomerically enriched R-cyanodiol, which is useful in the preparation of Escitalopram and Citalopram. Therefore, the object of the invention is to provide an economical and industrially applicable novel recovery and recycling process of for preparation of racemic cyanodiol, in pure form with satisfactory recovery.

While screening methods for recycling process for preparation of racemic cyanodiol from the enantiomerically enriched R-cyanodiol, unexpectedly, the present inventors have found an effective recovery and recycling process for which protection is sought.

Summary of invention:

According to one aspect of the invention, there is provided a recovery and recycling process for preparation of racemic cyanodiol, which comprises; a) reacting enantiomerically enriched R-cyanodiol of formula-I with a protecting agent to obtain a compound of formula -II wherein Rl represents a protecting group and R2 represents H or a protecting group, b) reacting the compound of formula -II with an acid to obtain acid addition salt of racemic compound of formula-Ill; and

c) deprotecting the racemic compound of formula-Ill with an acid or a base to obtain racemic cyanodiol or salts thereof.

Racemic cyanodiol

Formula -IV

The acid may be selected from organic, inorganic or sulfonic acids. Organic acids include, but not limited to, acetic acid, benzoic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, fumaric acid and maleic acid. Inorganic acids include hydrochloric, hydrobromic, sulfuric, phosphoric and nitric acids. Sulfonic acids include methanesulfonic acid, p-toluenesulfonic acid and p- bromobenzene sulfonic acid.

The protecting agent is a hydroxy group protecting agent which includes but not limited to acylating agent or a silylating agent to obtain the compound of formula -II wherein Rl represents a hydroxyl protecting group such as acyl group of formula -C(0)R3 wherein R3 represents linear or branched alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or substituted aryl; or an alkyl substituted silyl group; and R2 represents H or same as Rl .

In a preferred embodiment, enantiomerically enriched R-monoacyl cyanodiol wherein Rl group is acetyl, is reacted with oxalic acid to form racemic monoacetyl cyanodiol oxalate salt. According to another aspect of the invention, there is provided process for citalopram or escitalopram or pharmaceutically acceptable salts thereof, which comprises;

a) reacting enantiomerically enriched R-cyanodiol of formula-I with a protecting agent to obtain a compound of formula -II wherein Rl represents a protecting group and R2 represents H or a protecting group, b) reacting the compound of formula -II with an acid to obtain acid addition salt of racemic compound of formula-Ill; and

c) deprotecting the racemic compound of formula-Ill with an acid or a base to obtain racemic cyanodiol or salts thereof; and

d) converting the racemic cyanodiol into citalopram or escitalopram or pharmaceutically acceptable salts thereof.

Description of Invention:

The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated. Unless specified otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art, to which this invention belongs. To describe the invention, certain terms are defined herein specifically as follows.

Unless stated to the contrary, any of the words, "including", "includes", "comprising", and comprises" mean "including without limitation" and shall not be construed to limit any general statement that it follows to the specific or similar items.

The terms "enantiomer", "S" and "R" as used herein, unless specified otherwise, refer to stereoisomer resulting from the spatial arrangement of groups at a chiral centre, and in the present context, the person of ordinary skill will appreciate that the groups attached with the carbon marked with asterisk represents the plane for purposes of determining the configuration.

Mixture of enantiomers means it is mixture of R and S enantiomers in any proportion. The term 'enantiomeric excess or enatiomeric enriched' as used herein, refers generally to the concentration of one stereoisomer that exceeds the concentration of another stereoisomer. Typically, the term is used to characterize the optical purity of an optically active compound that exists in the bulk as two or more stereo isomers. For example: enantiomerically enriched R-enantiomer means the enantiomer ratio of R:S varies from 51 :49 to 100:0.

The term halogen means Iodo, bromo, chloro or fluoro group.

Accordingly in one aspect of the invention, there is provided a recovery and recycling process of enantiomerically enriched R-cyanodiol, which comprises; a) reacting enantiomerically enriched R-cyanodiol of formula-I with a protecting agent to obtain a compound of formula -II wherein Rl represents a protecting group and R2 represents H or a protecting group; b) reacting the compound of formula -II with an acid to obtain acid addition salt of racemic compound of formula-Ill; and

c) deprotecting the racemic compound of formula-Ill with an acid or a base to obtain racemic cyanodiol of salts thereof.

The protecting agent is a hydroxy group protecting agent which includes but not limited to acylating agent or a silylating agent to obtain the compound of formula -II wherein Rl represents a hydroxyl protecting group such as acyl group of formula -C(0)R3 wherein R3 represents linear or branched alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or substituted aryl; or an alkyl substituted silyl group; and R2 represents H or same as Rl . The acylating agent is having formula R3COX, wherein R3 represents as defined previously and X represents a halogen or hydrogen. Exemplary alkyl groups include but are not limited to methyl, ethyl, n-propyl, iso-propyl, n-butyl, and iso- butyl. However preferred alkyl group is methyl or ethyl. The term "aryl" refers to an aromatic, optionally fused, carbocycles having from 6 to 20 carbon atoms. Examples of C6-12-aryl include but are not limited to phenyl and naphthyl.

The silylating agent includes, but not limited to, an alkyl substituted silyl halide selected from a group consisting of chlorotrimethylsilane, chlorotriethylsilane, t- butyldimethyl silyl chloride, t-butyldiphenyl silyl chloride and trimethylsilyl triflate. The silylation reaction may take place at single or both hydroxyl positions of the cyanodiol giving rise to mono or di silyl substituted or mixture of mono and di substituted cyanodiol.

The acylation reaction using R3-COX, wherein the X refers to halogen or the silylation reaction using silylating agent with enantiomerically enriched R- cyanodiol, may be conducted without solvent or using a suitable solvent medium, optionally, in presence of a base.

The solvent medium includes, but not limited to, aliphatic or aromatic hydrocarbons, chlorinated hydrocarbons, esters, ethers, polar aprotic solvents, nitriles or mixtures thereof. Chlorinated hydrocarbons preferably include methylene dichloride, ethylene dichloride, chloroform, carbon tetrachloride, and aromatic hydrocarbons preferably include toluene, xylene, and aliphatic hydrocarbons include hexane, cyclohexane, heptane etc. Esters include ethyl acetate or butyl acetate. Ethers include tetrahydrofuran, dioxane, ethyl ether or methyl -t-butyl ether. Polar aprotic solvents include dimethylsulfoxide, dimethylacetamide or dimethylformamide. Nitriles include acetonitrile, propionitrile or butyronitrile. However, most preferred solvent is methylene dichloride, ethylene dichloride or toluene. The base used in the acylation or silylation reaction may be selected appropriately from an organic or inorganic class of compounds. The preferred organic bases are alkyl amines for example triethyl amine, diisopropyl ethylamine, tetrabutylammonium hydroxide; heterocyclic bases such as pyridine, lutidine, picoline, or imidazole; aryl amines such as aniline or the like; Alicyclic bases such as l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) or l,5-Diazabicyclo[4.3.0]non-5- ene (DBN). Inorganic bases are preferably selected from ammonia, metal hydroxides, carbonates or bicarbonates, exemplary bases include, but not limited to sodium/potassium hydroxide, sodium/potassium carbonates or sodium/potassium bicarbonate or the like. Optionally phase transfer catalysts such as tetrabutyl ammonium bromide or tetrabutyl ammonium chloride may also be employed.

Typically the reaction is conducted in the range of 0°C temperature to the boiling temperature of the solvent used. Preferably, the reaction is performed at 0°C to ambient temperature. After completion of reaction, usually the reaction is quenched with water followed by extraction of the product with solvent and distillation of the solvent to isolate the acyl or silyl substituted cyanodiol product of compound -II.

The acylation reaction using R3-COX, wherein the X refers to hydroxyl, with enantiomerically enriched R-cyanodiol may be conducted to form the enantiomerically enriched R-monoacyl cyanodiol using coupling agents such as diimidazole carbonyl or dicyclohexylcarbodiimde in presence or absence of catalyst such as 1-hydroxybenzotriazole.

The enriched acyl or silyl derivative of cyanodiol is further reacted with an acid to obtain racemic monoacyl or silyl cyanodiol-salt of corresponding acid used. The reaction is preferably conducted in a suitable solvent medium. The acid reacted with compound of formula-II may be selected from organic, inorganic or sulfonic acids. Organic acids include, but not limited to, acetic acid, benzoic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, fumaric acid and maleic acid. Inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and nitric acid. Sulfonic acids include methanesulfonic acid, p-toluenesulfonic acid and p- bromobenzene sulfonic acid.

In a preferred embodiment, enantiomerically enriched R-monoacyl/silyl cyanodiol, wherein Rl group is acetyl, benzoyl or t-butyldimethylsilyl, is reacted with oxalic acid, succinic acid, fumaric acid, benzoic acid, maleic acid to form corresponding racemic monoacyl cyanodiol acid salts.

A wide range of solvents may be used for preparation of the racemic monoacyl or silyl cyanodiol acid addition salts. The solvents include water, ketones, alcohols, ethers, aliphatic or aromatic hydrocarbons, esters and aprotic polar solvents or mixtures thereof. Ketones include acetone, methyl ethyl ketone, methyl isobutyl ketone, 3,3-dimethyl-2-butanone and cyclohexanone etc. Alcohols include methanol, ethanol, n-propanol, isopropanol, n-butanol, iso butanol and tertiary butanol etc. Ethers include tetrahydrofuran, dioxane, ethyl ether and methyl -t- butyl ether etc. Aliphatic hydrocarbons include hexane, cyclohexane, heptane etc. Aromatic hydrocarbons include toluene, xylene etc. Esters include ethyl acetate, methyl acetate, n-butyl acetate or iso butyl acetate etc. Polar aprotic solvents include dimethyl sulfoxide, dimethyl acetamide, dimethyl formamide or N- methylpyrrolidine etc. However preferred solvent is acetone, methyl ethyl ketone or methyl isobutyl ketone.

Usually reaction of salt formation is conducted at 10°C to boiling temperature of the solvent used. Preferably, the reaction is performed in the temperature range of about 20°C to ambient temperature. Most preferred temperature is ambient temperature. After completion of salt formation, the reaction mass is cooled to 5°C, filtered the mass to isolate the racemic monoacyl or silyl cyanodiol-salt leaving mixture of R and S-cyanodiol in filtrate (2). The filtrate (2) containing mixture of R and S- cyanodiol may further be subjected for treatment with acylating agent or silylating agent to recover racemic cyanodiol as per the present invention leaving filtrate (3) containing mixture of R and S-cyanodiol. By employing the above method, the filtrates obtained sequentially can be subjected for recovery of racemic cyanodiol according the present invention.

The obtained racemic monoacyl or silyl cyanodiol salt is further subjected for deprotection to obtain racemic cyanodiol using a base or acid. The racemic monoacyl cyanodiol salt is subjected for deprotection using a base to liberate racemic cyanodiol free base in suitable solvent.

The base used in the deprotection (deacylation) reaction may be selected from organic or inorganic bases. Inorganic bases include ammonia, sodium/potassium hydroxide, whereas, organic bases include triethylamine, diethylamine, methylamine, diisopropyl ethylamine or pyridine. However, preferred base is sodium hydroxide.

The solvents used for hydrolysis include water, alcohols, polar aprotic solvents or mixtures thereof. Alcohols include methanol, ethanol, n-propanol, isopropanol, n- butanol, iso butanol and tertiary butanol etc. Polar aprotic solvents include dimethyl sulfoxide, dimethyl acetamide, dimethyl formamide or N- methylpyrrolidine etc.

Typically the hydrolysis reaction is conducted at ambient temperature to liberate the racemic cyanodiol free base. The racemic cyanodiol free base is extracted with suitable solvent followed by removal of the solvent by distillation to isolate the product. Usually, the racemic cyanodiol is obtained as an oil. Optionally, the isolated racemic cyanodiol may be subjected for crystallization using suitable solvent such as toluene. Alternately, the racemic cyanodiol may be converted into suitable inorganic or organic salts.

In case of racemic silyl cyanodiol salt, the deprotection is preferably conducted using an acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid or p-toluenesulfonic acid.

The racemic cyanodiol obtained as per the present invention may be used for the preparation of Citalopram or Escitalopram by the known procedures. Usually, in the preparation of Escitalopram, the obtained racemic cyanodiol is resolved using optically active acids like (+) di p-toluoyl tartaric acid to obtain S-cyanodiol-(+) DPTTA salt and enriched R-Cyanodiol in filtrate. The S-cyanodiol-(+)DPTTA is treated with base to liberate S-cyanodiol which is further reacted with p- toluenesulfonyl chloride, p-toluenesulfonyl bromide, methanesulfonylchloride, methanesulfonylchloride, methanesulfonylbromide or camphor sulfonylchloride in solvent in presence of an organic base like triethylamine. Whereas, for preparation of citalopram, the same procedure can be practiced starting from racemic cyanodiol instead of S-cyanodiol. The enriched R-cyanodiol from filtrate recycled/reused as per the present invention. The R-cyanodiol from filtrate may be isolated by standard known procedures or it may be recycled/reused without isolation. Usually R-cyanodiol from filtrate is isolated by concentrating the mother liquor to obtain residue. The residue is dissolved in suitable solvent such as methyl enedi chloride and washed with aq. ammonia. The organic layer is then concentrated to obtain enriched R-Cyanodiol as oil.

The present invention is depicted in Scheme-1 : Scheme- 1

Formula -I

Formula -II Formula -I

Enriched R-cyanodiol (racemic)

Deprotection

+DPPTA

Neutralisation

R-Cyanodiol(+)DPPTA salt Resolusion

in mother liquor

Formula -V (+) DPTTA

Neutralisation Citalopra

ormu a -

S-Cyanodiol(+)DPPTA salt

-VI

S-Cyanodiol

Escitalopram free base Escitalopram Oxalate Formula -VII

Formula -VIII Formula -IX

Wherein Rl represents a protecting group and R2 represents H or a protecting group. The following examples are presented to further explain the invention with experimental conditions, which are purely illustrative and are not intended to limit the scope of the invention.

Example 1. Preparation of (S)-Cyanodiol-(+)-DPTTA salt (VI)

To a solution of Racemic cyanodiol (300g, 0.88 moles) in isopropyl alcohol (1800 ml) at 25-35°C (+)-Di-p-toluoyl-D-tartaric acid (169.2g, 0.44 mole) was added. The reaction mixture was then heated and maintained at 60-70° C for lhour. After maintaining was over the reaction mass was cooled and maintained at 28- 32° C for 2-4 hours. The precipitated solid was then filtered, washed with isopropyl alcohol (300 ml) and suck dried for 30minutes. The filtrate was preserved for the recovery of Racemic cyanodiol and (+)-Di-p-toluoyl-D-tartaric acid. The obtained wet cake of (S)-cyanodiol - (+)-DPTTA was suspended in isopropyl alcohol (1200 ml), heated and maintained at 55-65°C for 60 minutes. After maintaining was over the reaction mass was cooled to 28-32°C where it was maintained for 60 minutes. The precipitated solid was then filtered, washed with isopropyl alcohol (300 ml) and finally dried under vacuum at 60-70° C which provided the title compound (VI) as a white solid. The obtained filtrate was combined with the earlier obtained filtrate for the recovery of Racemic cyanodiol and (+)-Di-p-toluoyl-D-tartaric acid.

Yield: 145g (61.96% by Theory)

Purity by HPLC: 99.71%

Chiral Purity: S-Isomer - 99.59%

R-Isomer - 0.41%

Example 2. Recovery of R-enriched cyanodiol (I)

The mother liquor collected in Example-!, was concentrated under vacuum at 45- 5()°C to a residue (375g). This obtained residue was then dissolved in dichloromethane (900ml) at 25-30° C whereupon water (1500ml) was added and the biphasic mass was stirred for 10-1.5minutes at 25-30° C. The bi hasic mass was then cooied to 10-20°C after which the pH was adjusted at 9-11 with aqueous ammonia solution. After stirring the obtained biphasic mixture for 30 minutes at 10-20°C, the organic layer and aqueous layer were separated. The aqueous layer was preserved for the recovery of (-i-)-Di-p-to!uoyl-D-tartarie acid while the separated organic layer was concentrated under vacuum at 35-40°C which provided title compound (I) as a yellowish color viscous oi l .

Weight of oil of R-enriched cyanodiol 208.7g.

Purity by HPLC: 90 42%

Chiral Purity: S-Isomer - 26 25%;

R-Isomer - 73.75%

Example 3 Preparation of Monoacetylcyanodiol ester oxalate salt (Ilia) from R-enriched cyanodiol (I)

R-enriched cyanodiol (IV) as obtained in Example-2 was dissolved in dichloromethane (900 ml) at 20-40°C. Then a solution of acetyl chloride (144.4g, 1.84 moles) in dichloromethane (210 ml) was added at 20-40°C. After addition was over the reaction mass was maintained at 20-40°C for 4 hours. After completion of reaction water (600ml) was added to the reaction mixture and the pH was adjusted above 9 at 15-25°C with aqueous ammonia solution. After pH adjustment the biphasic reaction mass was stirred at 15-25°C for 30 minutes. The organic layer was then separated and concentrated under vacuum at 35-40°C to an oily residue. Traces of dichloromethane was removed by its co-distillation with acetone (150 ml) under vacuum at 35-40° C which provided an orange to yellowish colored viscous oil of Mono acetyl cyanodiol ester. The Mono acetyl cyanodiol ester oil (Ila) was dissolved in acetone (450ml) at 20-40°C to provide a clear solution. To this obtained clear solution a solution of oxalic acid dihydrate (38.66g, 0.31 moles) in acetone (110ml) was added in 1 hour and the obtained reaction mass was maintained for 1-2 hours at 30-40°C. After maintaining was over the reaction mass cooled to 0-5°C whereupon the precipitated solid was filtered, washed with acetone (90 ml) and dried under vacuum at 50-60°C which afforded Mono acetyl cyanodiol ester oxalate salt (Ilia) as a white solid.

Weight of Moiioacetyl cyanodiol ester oxalate (Ilia): 102g. Purity by HPLC: 92.95%

Example 4 Preparation of Monoacetylcyanodiol ester oxalate salt (Ilia) without isolating R-enriched cyanodiol (I)

Mother liquor obtained after filtration of (S)-Cyanodiol~(+)-DPPTA salt was concentrated under vacuum at 45-50°C to yield a residue (330g, 0.96 moles). The obtained residue was then dissolved in dichl or om ethane (900rnl) at 28-30° C after which water (1500ml) was added and the obtained biphasic mass was stirred at 25-30°C for 10-15 min. The biphasic mass was then cooled to 10-20°C whereupon its pH was adjusted between 9 and 11 with aqueous ammonia solution. After stirring the reaction mass at 1G-20°C for 15 minutes the lower organic layer containing R-Enriched cyanodiol was separated while the upper aqueous layer was preserved for the recovery of (+)-Di-p-toluoyl-D-tartaric acid. To the separated upper organic layer a solution of acetyl chloride (144.4g, 1 .84 moles) in dichloromethane (210 ml) was added at 20-40°C. After complete addition of acetyl chloride the reaction mass was maintained at 20-40°€ for 2 hours. After maintaining water (600mi ) was added and its pH was adjusted above 9 with aqueous ammonia. After stirring the biphasic mass at. 1.5-25° C for 30 minutes the organic layer was separated and concentrated under vacuum at 35-40° C to an oily residue. Traces of dichloromethane were removed from the oil by its co- distillation with acetone (150 ml) under vacuum at 35-40° C which afforded Mono acetyl cyanodiol ester (Ha) as an oily mass. The obtained Mono acetyl cyanodiol ester (Ha) oi l was then dissolved in Acetone (450ml) at 30-40° C after which a solution of oxalic acid dihydrate (38.66g, 0.31 moles) in acetone (1 10ml) was added and the reaction mass maintained further at 30-40°C for 1-2 hours. After maintaining was over the reaction mass was cooled to 0-5°C whereupon the precipitated solid was ^"filtered, washed with acetone (90 ml) and dried under vacuum at 50-60°C which afforded Mono acetyl cyanodiol ester oxalate (Ilia) as a solid.

Weight of MonoacetyS cyanodiol ester oxalate: 134.5g. ¹H-NMR in CDCb at 400MHz (ppm): 1.27-1.29 (m, 2H), 1.44-1.76 (m, 2H), 1.93(s, 3H), 2.24 (s, 6H), 4.58-4.61 (dd, 2H), 6.67-7.51 (m,7H-aromatic)

FT-IR as such (cm^"1): 3196, 2954, 2229, 1750, 1601, 1505, 1457, 1234, 1158, 830

Mass Analysis (ESI, +ve mode): Molecular ion peak observed at 385.42 a.m.u which corresponds to (M+H)⁺ peak of the free base of the title compound

XRPD Analysis (Observed 2Θ values): 5.91, 6.90, 8.38, 9.85, 10.36, 10.83, 12.05, 12.88, 14.12, 14.81, 15.88, 16.15, 16.59, 17.11, 17.89, 18.28, 19.00, 19.40, 20.19, 20.66, 20.99, 21.81, 22.64, 23.11, 23.76, 24.22, 25.00, 25.76, 26.30, 27.49, 27.81, 28.40, 29.06, 29.90, 30.94, 31.66, 32.47, 33.46, 34.79, 36.23, 37.72, 38.61, 39.31, 40.88, 43.03, 45.45

DSC Analysis: Endotherm peaks observed at 205.46°C

Purity by HPLC : 95 88%

Example 5 Preparation of Mono acetyl cyanodiol ester oxalate salt (Ilia) without isolating R-enriched cyanodiol (I) (using triethylamine)

Mother liquor obtained after filtration of (S)-Cyanodiol-(+)-DPPTA salt [equivalent to racemic cyanodiol (lOOg) input] was concentrated under vacuum at 45-50°C to a residue. The obtained residue was dissolved in a mixture of dichloromethane (40Gml) and water (500ml) at 25-30° C. The obtained biphasic mass was then stirred at 25-30° C for 10-15 minutes and further cooled to 10- 20°C whereupon its pH was adjusted above 9 with aqueous ammonia solution. After stirring the obtained biphasic mixture further for 15 minutes at 10-20°C the organic layer containing R-Enriched cyanodiol was separated. To this separated organic layer containing R-Enriched cyanodiol, triethylamine (88.6g, 0.87 moles) followed by a solution of acetyl chloride (34.4g, 0.44 moles) in dichloromethane (100 ml) was added sequentially at 20-40°C. After additions were complete the reaction mass was stirred for another 2 hours at 20-40°C after which water (200ml) was added and its pH adjusted above 9 at 15-25°C with aqueous ammonia solution. Then after stirring the biphasic mass at 15-25°C for further 30 minutes the organic layer was separated and concentrated under vacuum at 35- 40°C to provide an oily residue. The traces of dichloromethane was removed by its co-distillation with acetone (50 ml) under vacuum at 35-40° C to afford HOg of mono acetyl cyanodiol ester (Ila) as an orange to yellowish colored viscous oil. This obtained (Ila) oil was then dissolved in acetone (200ml) at 20-40° C to which a solution of oxalic acid dihydrate (1.8.03g, 0, 14 moles) in acetone (11.0ml) was added and the reaction mass maintained at 30-40°C for 1-2 hours. After maintaining was over the reaction mass was cooled to 0-5°C whereupon the precipitated solid was filtered, washed with acetone (55 ml) and dried under vacuum at 50~60°C which afforded Mono acetyl cyanodiol ester oxalate salt (Ilia) as an white solid. Weight of Monoacetyl cyanodiol ester oxalate salt (Ilia): 53g.

Example 6. Preparation of Mono acetyl diol ester succinate salt (Illb)

To a solution of Mono acetyl cyanodiol ester oil (Ila) (10. Og, 0.026 moles) prepared as per example 3 or 4 in Acetone (10ml) a solution of succinic acid (1.53g, 0.013 moles) in acetone (40ml) was added in 1 hours at 20-40° C. After addition was complete the reaction mass was stirred for 1-2 hours at 20-40° C. Then the reaction mass was cooled to 0-5°€ whereupon the precipitated solid was filtered, washed with acetone (5 ml) and dried under vacuum at 50-60° C which afforded Mo o acetyl cyanodiol succinate salt (Illb) as a white solid.

Weight of Monoacetyl cyanodiol ester succinate salt (Illb): 4.0g.

1H-NMR in DMSO at 300MHz (ppm): 1.25-1.27 (m,lH), 1.43-1.50 (m,lH), 1.96 (s,3H), 2.14 (s,6H), 2.50-2.51 (d,3H), 4.78-4.83 (dd, lH), 5.17-5.21 (dd, lH), 7.08- 7.7.14 (t,2H), 7.23-7.28 (q,2H), 7.75-7.78 (d, lH), 7.79-7.88 (t, 2H)

FT-IR as such (cm^"1): 3234, 2230, 1737, 1564, 1505, 1377, 1157, 1031, 974, 830 Mass Analysis (ESI, +ve mode): Molecular ion peak observed at 385.34 a.m.u which corresponds to (M+H)⁺ peak of the free base of the title compound

DSC Analysis: Two Endotherm peaks observed at 105.23 and 127.92°C

Purity by HPLC: 97 22% Example 7. Preparation of Mono acetyl diol ester fumarate salt (IIIc)

A solution of Fumaric acid (1.5gm) dissolved in Methanol (20ml) was added slowly into a solution of Monoacetyl cyanodiol ester (lO.Ogm, 0.026moles) (prepared as per example 3 or 4) in Methanol (10ml) at 25-30°C. After complete addition the obtained slurry mass was stirred at 25-30°C for 30min. Then the mass was further cooled and maintained at 0-5° C for 1-2 hours. After maintaining was over the solid was filtered, washed with chilled acetone and dried under vacuum at 50-60° C which provided 4.5gm of the title compound (IIIc) as a off-white solid.

¹H-NMR in DMSO at 300MHz (ppm): 1.26-1.50 (m, 2H), 1.96 (s, 3H), 2.2 (s,

6H), 4.77-4.82 (dd, lH), 5.16-5.21 (dd, lH), 6.49-7.88 (7H, Aromatic)

FT-IR as such (cm^"1): 3470, 2225, 1740, 1602, 1568, 1506, 1359

Mass Analysis (ESI, +ve mode): Molecular ion peak observed at 385.35 a.m.u which corresponds to (M+H)⁺ peak of the free base of the title compound

XRPD Analysis (Observed 2Θ values):6.57, 7.36, 7.75, 8.09, 9.92, 10.88, 12.41,

12.55, 13.07, 13.56, 14.34, 14.74, 15.69, 16.11, 16.60, 16.88, 17.40, 17.95, 18.98,

19.73, 20.31, 20.62, 20.96, 21.30, 22.06, 22.38, 23.05, 23.28, 23.69, 24.24, 24.67,

24.93, 25.58, 25.90, 26.23, 26.87, 27.55, 27.78, 28.13, 28.61, 29.00, 29.91, 30.20,

31.28, 31.84, 32.15, 32.93, 33.54, 33.92, 34.92, 35.65, 36.84, 37.56, 38.54, 40.18,

41.19, 41.73, 43.83, 45.52, 48.49

DSC Analysis: Two Endotherm peaks observed at 112.52 and 142.79°C

Purity by HPLC: 93.63%

Example 8 Preparation of Mono acetyl diol ester benzoate salt (Hid)

To a solution of Mono acetyl cyanodiol ester oil (10. Og, 0.026 moles) prepared as per example 3 or 4 in Acetone (10ml) a solution of benzoic acid (1.5g, 0.0.12 moles) in acetone (10ml) was added in 1 hours. The resulting mass was maintained further for 1-2 hours at 20-40°C. After maintaining was over the reaction mass was cooled to 0-5°C whereupon the precipitated solid was fi ltered, washed with acetone (5 ml) and dried under vacuum at 50-60° C which afforded 2.4g Mono acetyl cyanodioi ester benzoate salt as a white solid.

¹H-NMR in DMSO at 300MHz (ppm): 1.22-1.485 (m,2H), 1.96 (s,3H),2.16 (s,6H), 2.28-2.36 (m,3H),4.78-4.82 (dd, lH), 5.17-5.21 (dd,2H), 7.06-7.13 (t,2H),7.21-7.27 (q,2H),7.44-7.49 (t,2H),7.55-7.60 (t, lH),7.7.74 (s, lH),7.81-7.85 (d,2H),7.92-7.95 (t,2H)

FT-IR as such (cm^"1): 3178, 2230, 1748, 1733, 1600, 1566, 1505, 1374, 1241 Mass Analysis (ESI, +ve mode): Molecular ion peak observed at 385.34 a.m.u which corresponds to (M+H)⁺ peak of the free base of the title compound

DSC Analysis: Two Endotherm peaks observed at 103.01 and 119.72°C

Purity by HPLC: 97 39%

Example 9. Preparation of Mono acetyl diol ester maleic acid salt (Hie)

To a solution of Mono acetyl cyanodioi ester oil (10. Og, 0.026 moles) prepared as per Example 3 in Ethyl acetate (30ml) maleic acid (1 .51 g, 0,013 moles) was added and the reaction mass heated up to 60-70°C. After maintaining the reaction mass at 60-70° C for 2 hours the reaction mass was cooled to 0-5°C whereupon the precipitated solid was filtered, washed with ethyl acetate (5 ml) and dried at 50-60° C under vacuum which afforded 3.7g of title compound (Hie) as a white solid.

¹H-NMR in DMSO at 300MHz (ppm): 1.30-1.36 (m, lH), 1.59-1.63 (m, lH), 1.96 (s,3H), 2.21-2.24 (t,2H), 2.69 (s,6H) 2.92- 3.08 (m,2H), 4.74-4.79 (dd, lH), 5.14- 5.19 (dd,lH), 7.11-7.17 (t,3H), 7.23-7.28 (q,2H),7.77-7.78 ( d, lH), 7.85-7.935 (m,2H)

FT-IR as such (cnr^^SS, 2225, 1746, 1558, 1540, 1506, 1464, 1355, 1241, 1224, 1045

DSC Analysis: Endotherm peaks observed at 138.83 °C XRPD Analysis (Observed 2Θ values): 5.94, 7.98, 8.80, 9.11, 9.64, 11.88, 12.75, 13.80, 15.97, 16.41, 16.59, 17.28, 17.68, 17.85, 18.11, 19.41, 19.98, 20.28, 20.51, 21.40, 21.80, 22.47, 22.64, 23.47, 23.91, 24.48, 24.80, 25.21, 25.69, 25.91, 26.40, 26.82, 27.40, 28.17, 28.52, 29.99, 30.97, 31.67, 32.23, 32.49, 32.90, 33.85, 34.95, 35.91, 36.49, 36.97, 38.40, 39.47, 40.62, 41.35, 42.29, 43.06, 43.46, 45.25, 46.27 Purity by HPLC: 96 82%

Example 10. Preparation of Benzoyl cyanodiol ester oxalate salt (Illf)

R-enriched cyanodiol (I) (lOg, 0.292 moles) prepared as per example 2 was dissolved in dichloromethane (40ml) at 20-40° C and cooled to 0-5°C. Then triethylamine (4.4g; 0.043 moles) followed by a solution of benzoyl chloride (4.5g, 0.03 mole) in dichloromethane (10ml) was added at 0-5°C. The reaction mass was maintained further at 0-5° C for 2 hours. After maintaining 10% sodium chloride solution was added and the resulting biphasic mixture was stirred at 10- 20° C for 10-20min. Then the organic layer was separated and concentrated under vacuum at 35-40°C which afforded 13.2 g of mono benzoyl cyanodiol ester as an oil. To this obtained mono benzoyl cyanodiol ester, acetone (35ml) followed by a solution of oxalic acid dihydrate (3.6g, 0.03rnoles) in acetone (23ml) was added. Then the reaction mass was maintained at 30-40° C for 1-2 hours. After maintaining was over the reaction mass was cooled to 0-5°C whereupon the precipitated solid was filtered, washed with acetone (12 ml) and dried under vacuum at 50-60°C which afforded 6.0g title compound (lllf) as a white solid. ¹H-NMR in CDC1₃ at 400MHz (ppm): 1.24-1.60 (d, 2H), 2.03-2.31 (d, 2H), 2.48 (s, 6H), 2.79-2.84 (dd, 2H), 4.73-4.77 (d, 1H), 5.27-5.31 (d, 2H), 6.66-7.67 (m, 12H- Aromatic)

Mass Analysis (ESI, +ve mode): Molecular ion peak observed at 447.47 a.m.u which corresponds to the freebase of the title compound.

Example 11 Preparation of Monosilyl cyanodiol (lib)

R-enriched cyanodiol (lOg, 0.029 moles) was dissolved in MDC (30ml) at 20-40° C. To the obtained clear reaction mass imidazole (5.96g, 0.0438 moles) followed by a solution of t-butyldimethylsilylchloride (TBDMSC1) (6.60g, 0.04 moles) in dichloromethane (10ml) was added at 20-40° C and the reaction mass stirred further at 20-30°C for 1-2 hours. Then the reaction mass was directly washed with water (30ml x 3) after which the lower organic layer was separated and concentrated under vacuum at 35-40° C which yielded l l .Ogm title compound ( lib) as a off white solid.

¹H-NMR in DMSO at 300MHz (ppm):0.23-0.24 (d,3H), 0.17-0.18(d,3H), 0.76- 0.77 (s, 9H), 0.83-0.85 (d, lH), 1.17-1.22 (m,lH), 1.41-1.45 (m,lH), 2.03 (s,6H), 2.08-2.25 (m,4H), 4.27-4.33 (dd,lH), 4.74-4.79 (dd,lH), 7.07-7.13 (t,2H), 7.23- 7.27 (m,2H),7.80-7.83 (d,3H)

FT-IR as such (cm^"1): 2952, 2855, 2227, 1599, 1506, 1470, 1253, 1216, 1160, 1122, 1109, 1092, 1035, 1016, 958, 897

Mass Analysis (ESI, +ve mode): Molecular ion peak observed at 457.47 a.m.u which corresponds to (M+H)⁺ peak of title compound

DSC Analysis: Two Endotherm peaks observed at 124.89 and 136.30 °C

XRPD Analysis (Observed 2Θ values):8.09, 9.32, 10.45, 11.44, 12.34, 13.29,

14.02, 15.57, 16.26, 16.87, 17.51, 18.18, 18.71, 19.34, 19.87, 20.39, 20.99, 21.47, 22.13, 22.49, 23.01, 23.29, 24.49, 24.87, 25.33, 25.74, 26.29, 26.78, 27.03, 27.52, 28.26, 28.69, 29.05, 29.41, 29.61, 30.13, 31.44, 32.09, 32.37, 32.86, 33.17, 33.77, 34.78, 35.16, 35.81, 36.74, 37.54, 38.33, 38.64, 39.45, 40.16, 41.24, 41.59, 42.24,

43.03, 44.29, 45.79, 47.81, 48.49

Purity by HPLC : 91 27%

Example 12 Preparation of Monosilylcyanodiol oxalate salt (Illg)

Monosilyl cyanodiol (lib) (lOg, 0.022moles) prepared as per example 11 was dissolved in acetone (40ml) at 40-45°C. Then a solution of oxalic acid dihydrate (1.38g, 0.011 moles) in acetone (10ml) was added after which the reaction mass was stirred at 40-45°C for 1 hour. The obtained slurry was then cooled to 0-5° C where upon the solid was filtered, washed with chilled acetone (5ml) and dried at 50-60° C under vacuum which provided 5.8g of title compound (Illg) as an off- white solid. ¹H-NMR in DMSO at 300MHz (ppm):0.17-0.23 (d,6H), 0.77 (s,9H), 1.24 (s,lH),1.54 (s,lH), 2.35 (s,6H), 2.51-2.60 (d,2H), 4.25-4.31 (d,2H), 4.73-4.79 (d,2H), 7.09-7.15 (t,2H), 7.23-7.28 (m,2H), 7.8-7.85 (m,3H)

FT-IR as such (cm^"1): 3168, 2951, 2930, 2857, 2358, 2228, 1622, 1506, 1462, 1407, 1380, 1360, 1298, 1250, 1180, 1061, 1016, 894, 225

Mass Analysis (ESI, +ve mode): Molecular ion peak observed at 457.41 a.m.u which corresponds to (M+H)⁺ peak of freebase of the title compound (as free base)

XRPD Analysis (Observed 2Θ values):4.62, 7.68, 8.43, 9.21, 9.46, 11.19, 12.75, 13.81, 14.12, 14.88, 15.77, 16.68, 16.87, 17.44, 18.48, 19.13, 19.43, 20.46, 20.94, 21.66, 22.67, 23.05, 23.83, 24.25, 25.19, 25.68, 26.07, 27.82, 28.38, 29.25, 30.98, 32.10, 33.52, 34.05, 34.74, 37.34, 38.95, 40.65, 44.58, 47.54

Purity by HPLC: 95 03%

Example 13 Preparation of Monosilylcyanodiol maleic acid salt (Illh)

Monosilyl cyanodiol (lib) (lOg, 0.022 moles) prepared as per example 11 was dissolved in Ethyl acetate (30ml) at 65-75°C. Then Maleic acid (1.27g, 0.011 moles) was added and the reaction mass stirred at 65-75°C for 1 hour. The reaction mass was then cooled to 0-5° C and the precipitated solid was filtered, washed with chilled ethyl acetate (5ml) and dried at 50-60° C under vacuum which afforded 5g of title compound.

¹H-NMR in DMSO at 300MHz (ppm):0.17-0.23 (d,6H), 0.77 (s,9H), 1.28-1.30 (m,lH), 1.60-1.62 (m,lH), 2.19-2.22 (t,2H), 2.63 (s,6H), 2.90-3.05 (m,2H), 6.03- 6.04 (d,2H), 7.11-7.17 (t,2H), 7.24-7.28 (q,2H), 7.8-7.9 (m,3H)

FT-IR as such (cm^"1): 3340, 2953, 2857, 2709, 2226, 1578, 1506, 1470, 1352, 1253, 1222, 1074

Mass Analysis (ESI, +ve mode): Molecular ion peak observed at 457.55 a.m.u which corresponds to (M+H)⁺ peak of freebase of the title compound (as free base)

DSC Analysis: Endotherm peaks observed at 133.47 °C

Purity by HPLC: 95 3% Example 14 Preparation of Monosilylcyanodiol succinate salt (Illi)

A solution of succinic acid (1.30g) in acetone (10 ml) was added into a solution of monosilyl

cyanodiol (lib) (lOg, 0.011) (prepared as per example 11) in acetone (30 ml) at 40-45°C. After addition was complete the reaction mass was maintained at 40- 45°C for 1 hour. The obtained slurry was then cooled to 0-5°C wherein the solid was filtered, washed with chilled acetone (5ml) and dried under vacuum at 50-60° C which afforded 2.4g of the title compound (Illi) as a off-white solid.

1H-NMR in DMSO at 300MHz (ppm):0.04 -0.18 (d,6H), 0.76-0.78 (s,9H), 1.18- 1.21 (m,lH), 1.43-1.46 (m,lH), 2.09 (s,6H), 2.15-2.19 (m. lH), 2.21-2.25 (t,3H), 2.30 (s,2H), 4.27-4.33 (dd,lH), 4.74-4.79 (dd,lH), 7.08-7.14 (t,2H), 7.23-7.28 (q,2H), 7.81-7.83 (d,3H)

FT-IR as such (cm^"1): 3294, 2929, 2856, 2224, 1563, 1507, 1469, 1382, 1252, 1226, 1074, 1057

Mass Analysis (ESI, +ve mode): Molecular ion peak observed at 457.47 a.m.u which corresponds to (M+H)⁺ peak of freebase of the title compound

Purity by HPLC: 98 03%

Example 15. Preparation of Monosilylcyanodiol fumarate salt (Illj)

Charged Monosilylcyanodiol (lib) (lOg, 0.022 moles) prepared as per example 11, in absolute alcohol (40ml) and heated the reaction mass to 65-75°C. Then fumaric acid (1.27g, 0.011 moles) was added and the reaction mass was maintained at 65- 75°C for 1 hour. After maintaining, the mass was cooled and maintained at 0-5° C for 1-2 hours. The precipitated solid was then filtered, washed with chilled absolute (5ml) and dried under vacuum at 50-60° C which afforded 4.4g of the title compound (Illj) as an off-white solid.

¹H-NMR in DMSO at 300MHz (ppm):0. 17-0.23 (dd,6H), 0.77 (s,9H), 1 .21 -1.24 On. H i ), 1.50 (m,lH), 2.22 (s,8H), 2.35-2.45 (i,3H), 4.26-4.31 (dd. H i ), 4.73-4.78 iddJH), 7.08-7.14 (t,3H), 7.22-7.27 (q,3H), 7.77-7.88 (m,3H)

FT-IR as such (cm^"1): 2953, 2930, 2853, 2226, 1571, 1504, 1470, 1360, 1297, 1253, 1156, 1070, 1005, 893

Mass Analysis (ESI, +ve mode): Molecular ion peak observed at 457.45 a.m.u which corresponds to (M+H)⁺ peak of freebase of the title compound

DSC Analysis: Two Endotherm peaks observed at 105.07 and 142.95 °C

Purity by HPLC: 92.82%

Example 16 Preparation of Monosilylcyanodiol benzoate salt (Illk)

Monosilylcyanodiol (lib) (lOg, 0.022 moles) prepared as per example 11 was dissolved in acetone (30ml) at 40-45°C after which a solution of benzoic acid (1.33g, 0.011 moles) in acetone (10ml) was added into it. Then the obtained reaction mass was stirred at 40-45°C for 1 hour and cooled to 0-5°C. The precipitated solid was then filtered, washed with chilled acetone (5ml) and dried at 50-60° C under vacuum which afforded 3.2g of the title compound as an off-white solid

¹H-NMR in DMSO at 300MHz (ppm): 0.17-0.23 (dd,6H), 0.77 (s,9H), 1.20- 1.23 (m, lH), 1.44-1.47 (m, lH), 2.13 (s,lH), 2.25-2.28 (t,3H), 4.02-4.07 (dd,lH), 4.22-4.32 (dd, lH), 4.55-4.60 (dd, lH), 4.79-4.74 (1H), 7.07-7.13 (t,3H), 7.22-7.27 (q,3H), 7.45-7.50 (t,3H), 7.56-7.61 (t,3H), 7.71-7.83 (m,4H), 7.92-7.95 (t,3H) FT-IR as such (cm^"1): 2963, 2852, 2228, 1599, 1552, 1461, 1384, 1257, 1234, 1156, 1116, 1067, 1022, 903, 833

Mass Analysis (ESI, +ve mode): Molecular ion peak observed at 457.55 a.m.u which corresponds to (M+H)⁺ peak of freebase of the title compound.

DSC Analysis: Endotherm peaks observed at 101.03 °C

Purity by HPLC: 90.16%

Example 17 Preparation of Racemic cyanodiol (IV) from Monoacetylcyanodiol ester oxalate salt (Ilia)

Charged Monoacetylcyanodiol ester oxalate salt (Ilia) (68 g, 0.14moles) into methanol (272ml) at 25-35°C. To this obtained reaction mass a solution of sodium hydroxide (21.3g, 0.53 moles) in water (210 ml) was added and the reaction mass was maintained at 25-35° C for 1-2 hours. After maintaining was over the reaction mass was concentrated under vacuum at 40-50° C to a residue. Traces of methanol were co-distilled with toluene (68ml) at 40-50° C under vacuum. To the obtained viscous mass toluene (340ml) followed by water (410ml) was added whereupon the obtained biphasic mixture was heated and maintained at 60-70°C for 30-60 minutes. After maintaining was over the organic layer was separated and washed with water (476 ml) at 60-70°C after which the organic layer was concentrated under vacuum at 40-50°C till ~140ml was left. The resulting slurry was then cooled to 0-5°C whereupon the precipitated solid was filtered, washed with toluene (35 ml) and dried under vacuum at 40-45° C which afforded crude racemic cyanodiol as an off-white solid. This obtained crude racemic cyanodiol was then suspended in water (272 ml), heated and maintained at 40-45°C for 1 hr. After maintaining was over the solid was filtered at 40-45°C, washed with water (68ml) and dried under vacuum at 40-45° C which provided 47g of the title compound (IV) as an off white solid.

¹H-NMR in CDCb at 400MHz (ppm): 1.68-1.70 (m, 2H), 2.24 is, 6H), 2,37 2.48 (in, SB), 4.17-4.20 uk! . 1 H), 4.42~4.45(dd,IH), 6.98-6-7.62 (7RAr-H)

FT-IR as such (cm^"1): 3304, 2995, 2979, 2950, 2226, 1600, 1465, 1403, 1223, 1047, 1012, 829, 819

Mass Analysis (ESI, +ve mode): Molecular ion peak observed at 343.38 a.m.u which corresponds to (M+H)⁺ peak of title compound

XRPD Analysis (Observed 2Θ values):7.37, 8.44, 9.33, 9.68, 10.68, 11.49, 13.41, 14.23, 14.75, 14.95, 15.18, 16.91, 17.97, 18.41, 19.44, 19.98, 20.54, 21.19, 21.53, 22.19, 22.92, 23.18, 23.50, 25.05, 25.46, 26.18, 27.06, 27.50, 27.89, 28.23, 28.66, 29.09, 29.32, 29.75, 30.65, 31.54, 32.05, 32.75, 34.33, 34.91, 35.25, 36.69, 37.41, 38.35, 39.26, 39.90, 40.68, 41.29, 41.89, 42.36, 42.81, 43.53, 45.02, 46.02, 46.74, 48.01, 49.27

DSC Analysis: Endotherm peaks observed at 77.29°C

Purity by HPLC: 99.51%

Chiral Purity: S-Isomer - 49.61%

R-Isomer - 50.39% Example 18. Preparation of Racemic cyanodiol (IV) from Monosilylcyanodiol oxalate salt (Illg)

Charged aqueous hydrochloric acid solution (2g, 0.02 moles) into a mixture of monosilyl cyanodiol oxalate salt (Illg) (3g, 0.0055 moles) and methanol (18ml) at 0-5° C and maintained the mass at 0-5° C for 1 hour. Then the reaction mass was concentrated under vacuum at 45-50° C to a residue. To the obtained residue toluene (15ml) followed by water (15ml) was added and the resulting biphasic mixture was stirred for 15 minutes at 25-35° C. The pH of the biphasic mixture was adjusted above 9 with aqueous ammonia solution and the resulting mass was maintained for 30 minutes at 25-35° C. After maintaining was over the organic layer was separated and concentrated under vacuum at 45-50° C which provided 2.3g of the title compound (IV).

Chiral Purity: S-Isomer - 48.30%

R-Isomer - 51.70%

Example 19 Preparation of (S)-Cyanodiol-(+)-DPTTA salt (VI) from Recovered Racemic cyanodiol (IV)

Racemic cyanodiol (70g, 0.204 moles) as obtained in Example 17 was charged into isopropyl alcohol (420 ml) after which (+)-Di-p-toluoyl-D-tartaric acid (39.5g,0.102 mole) was added at 25-35° C. The obtained reaction mass was then heated and maintained at 60-70° C for lhour. After maintaining was over, the reaction mass was cooled to 28-32° C where it was further maintained for 2-4 hours. The precipitated solid was then filtered, washed with isopropyl alcohol (70 ml) and suck dried for 30minutes. This obtained wet cake of (S)-cyanodiol-(+)- DPTTA was suspended in isopropyl alcohol (210 ml), heated and maintained at 55-65°C for 60 minutes. Then the reaction mass was cooled and maintained at 28- 32°C for 60 minutes. The solid was then filtered, washed with isopropyl alcohol (70 ml) and dried under vacuum at 60-70° C which afforded (S)- cyanodiol - (+)- DPTTA salt as white solid.

Yield: 36g (65.93% by Theory)

Purity by HPLC: 99.52% Chiral Purity: S-Isomer - 99.29%

R-Isomer - 0.71%

Example 20. Preparation of Escitalopram oxalate (IX) from (S)-Cyanodiol- (+)-DPTTA salt (VI) generated from Recovered Racemic cyanodiol

S-Cyanodiol-(+)-DPTTA salt (VI) (30g, 0.056 moles) prepared in Example 19 was charged into a biphasic mixture of dichloromethane (120ml) and water (150ml) at 25-30° C and cooled to 5-15° C. Then aqueous ammonia (8g, 0.112 moles) was added to the biphasic reaction mixture which was stirred further at 5- 15° C for 1 hour. Then the lower organic layer was separated and dried over sodium sulfate (6g) which provided S-Cyanodiol (VII) as a dichloromethane solution. To this obtained dried S-Cyanodiol solution triethyl amine (15.87g, 0.156 moles) followed by p-toluene sulfonyl chloride (11.75g, 0.061 moles) was added at -5 to 5°C and the reaction mass maintained further at the same temperature for 1-2 hours. After maintaining was over the reaction mass was sequentially washed with 10% brine solution (98 ml), water (96ml) and then dried over sodium sulfate (6g). The obtained organic layer was then concentrated under vacuum at 25-35°C to an oily residue. Traces of dichloromethane was removed by its co-distillation with acetone (18 ml) under vacuum at 25-35° C which provided escitalopram base (VIII) as a yellow colored oil. To this obtained escitalopram base (VIII) acetone (36ml) followed by a solution of oxalic acid dihydrate (7.77g, 0.062moles) in acetone (36ml) was added at 20-30°C. After maintaining the reaction mass for 1-2 hours at 20-40° C the reaction mass was cooled to 0-5°C whereupon the precipitated solid was filtered and washed with acetone (9 ml) wherein crude escitalopram oxalate (IX) was isolated as a white solid. The obtained crude escitalopram oxalate (IX) was then suspended in acetone (60ml) and stirred for 1 hour at 25-40°C. The slurry obtained was then further cooled and maintained at 0-5° C for 1 hour. The solid was then filtered, washed with acetone (9 ml) and finally dried at 50-60° C under vacuum which afforded the title compound as a white solid.

Yield: 14.5g (62.44% by Theory) ¹H-NMR in DMSO-d6 at 300MHz (ppm): 1.34-1.35 (m, 2H), 2 20-2 25 (t, 2H), 2.62 (s, 6H), 2.95 - 3.00 (t, 2H), 5.13 - 5.26 (q, 2H), 7.12 - 7.19 (t, 2H), 7.56 - 7.60 (m, 2H), 7.73 - 7.76 (m, 3H)

¹³C-NMR in DMSO-d6 at 75MHz (ppm): 19.57, 37.42, 42.51, 56.88, 71.61, 90.75, 111.11, 115.53-115.81, 119.25, 126.24, 127.36-127.47, 132.57, 140.31- 140.53, 149.31, 160.18, 163.41, 165.22

FT-IR as such (cm^"1): 3022, 2856, 2232, 1666, 1036

Mass Analysis (ESI, +ve mode): Molecular ion peak observed at 325.22a.m.u which corresponds to (M+H)⁺ peak of freebase of the title compound

XRPD Analysis (Observed 2Θ values):7.07, 9.02, 10.89, 13.49, 14.12, 16.39,

17.65, 18.62, 19.22, 19.54, 21.24, 22.82, 24.33, 24.56, 25.46, 27.42,

DSC Analysis: Endotherm peaks observed at 152.16°C

Purity by HPLC : 99.8%

Chiral Purity: S-Isomer - 99.36%

R-Isomer - 0.64%

Claims

We Claim,

1) A recovery and recycling process for preparation of racemic cyanodiol, which comprises;

a) reacting enantiomerically enriched R-cyanodiol of formula-I with a protecting agent to obtain a compound of formula -II wherein Rl represents a protecting group and R2 represents H or a protecting gro

b) reacting the compound of formula -II with an acid to obtain acid addition salt of racemic compound of formula-Ill; and

F orov.it a -I f FoTETWiia -If c) deprotecting the racemic compound of formula-Ill with an acid or a base to obtain racemic cyanodiol or salts thereof.

formula -iff R acsmie cyaosdioi

2) The process according to claim 1, wherein the protecting agent is an acylating agent or a silylating agent; and the protecting group is acyl group of formula -C(0)R3 wherein R3 represents linear or branched alkyl, alkenyl, alkynyl, cycloalkyl, aiyl, heteroaiyl or substituted aiyl; or an alkyl substituted silyl group.

3) The process according to claim 2, wherein the acylating agent is having formula R3COX, wherein R3 represents methyl, ethyl, n-propyl, iso- propyl, n-butyl, iso-butyl, phenyl and naphthyl; and X represents a halogen or hydrogen.

4) The process according to claim 3, wherein the acylating agent is acetyl chloride or benzoyl chloride.

5) The process according to claim 2, wherein the silylating agent is selected from a group consisting of chlorotrimethylsilane, chlorotriethylsilane, t- butyldimethyl silyl chloride, t-butyldiphenylsilyl chloride and trimethyl silyl triflate.

6) The process according to claim 1, wherein the acid used in step b) is organic acid, inorganic acid or sulfonic acid.

7) The process according to claim 6, wherein the organic acid is selected from a group consisting of acetic acid, benzoic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, fumaric acid and maleic acid.

8) The process according to claim 1, wherein the acid used in step c) is selected from a group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid and p-toluenesulfonic acid. 9) The process according to claim 1, wherein the base used in step c) is selected from a group consisting of ammonia, sodium hydroxide, potassium hydroxide, triethylamine, diethylamine, methylamine, diisopropyl ethylamine and pyridine.

10) The process according to claim 1, wherein the step a) reaction is performed in a solvent medium, optionally, in presence of a base.

11) The process according to claim 10, wherein the solvent medium is selected from a group consisting of aliphatic hydrocarbons, aromatic hydrocarbons, chlorinated hydrocarbons, esters, ethers, polar aprotic solvents, nitriles or mixtures thereof.

12) The process according to claim 11, wherein the solvent is methylene dichloride or ethylene dichloride.

13) The process according to claim 1, wherein the step b) reaction is performed in a solvent selected from a group consisting of water, ketones, alcohols, ethers, aliphatic hydrocarbons, aromatic hydrocarbons, esters, aprotic polar solvents and mixtures thereof.

14) The process according to claim 13, wherein the solvent is selected from a group consisting of acetone, ethanol, methanol and ethylacetate.

15) The process according to claim 1, wherein the step c) reaction is performed in a solvent selected from a group consisting of water, alcohols, polar aprotic solvents and mixtures thereof.

16) The process according to claim 15, wherein the alcohol is methanol or ethanol.

17) A process for citalopram or escitalopram or pharmaceutically acceptable salts thereof, which comprises;

a) reacting enantiomerically enriched R-cyanodiol of formula-I with a protecting agent to obtain a compound of formula -II wherein Rl represents a protecting group and R2 represents H or a protecting group;

b) reacting the compound of formula -II with an acid to obtain acid addition salt of racemic compound of formula-Ill; and c) deprotecting the racemic compound of formula-Ill with an acid or a base to obtain racemic cyanodiol or salts thereof; and

18) The process according to claim 17, wherein the racemic cyanodiol is reacted with p-toluenesulfonyl chloride, p-toluenesulfonyl bromide, methane sulf ony 1 chl ori de, methane sulf ony 1 chl ori de, methanesulfonylbromide or camphor sulfonylchloride to obtain citalopram or pharmaceutically acceptable salts thereof.

19) The process according to claim 17, wherein the racemic cyanodiol is resolved with (+)-di-p-toluoyltartaric acid to obtain S-cyanodiol; and the S-cyanodiol further reacted with p-toluenesulfonyl chloride, p- toluenesulfonyl bromide, methanesulfonylchloride, methanesulfonylchloride, methanesulfonylbromide or camphor sulfonylchloride to obtain Escitalopram or pharmaceutically acceptable salts thereof.