WO2014203277A2 - Process for the preparation of (1s,2r)-2-(aminomethyl)-n,n-diethyl-1-phenylcyclopropanearboxamide hydrochloride - Google Patents

Process for the preparation of (1s,2r)-2-(aminomethyl)-n,n-diethyl-1-phenylcyclopropanearboxamide hydrochloride Download PDF

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WO2014203277A2
WO2014203277A2 PCT/IN2014/000405 IN2014000405W WO2014203277A2 WO 2014203277 A2 WO2014203277 A2 WO 2014203277A2 IN 2014000405 W IN2014000405 W IN 2014000405W WO 2014203277 A2 WO2014203277 A2 WO 2014203277A2
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formula
compound
diethyl
aminomethyl
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WO2014203277A3 (en
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Srinivasan Thirumalai Rajan
Sajja Eswaraiah
Revu Satyanarayana
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Msn Laboratories Private Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/16—Preparation of optical isomers
    • C07C231/18—Preparation of optical isomers by stereospecific synthesis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/16—Preparation of optical isomers
    • C07C231/20—Preparation of optical isomers by separation of optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/24—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
    • C07C303/28—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
    • C07C69/12—Acetic acid esters
    • C07C69/14—Acetic acid esters of monohydroxylic compounds
    • C07C69/145—Acetic acid esters of monohydroxylic compounds of unsaturated alcohols
    • C07C69/157—Acetic acid esters of monohydroxylic compounds of unsaturated alcohols containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

Definitions

  • the present invention relates to a process for the preparation of (lS,2R)-2- (aminomethyl)-N,N-diethyl- 1 -phenylcyclopropanecarboxamide represented by the structural formula- 1 , and its h drochloride salt com ound of formula- 1 a.
  • (1 S,2R)-2-(aminomethyl)-N,N-diethyl-l -phenylcyclopropanecarboxamide is an antidepressant currently under development by Forest Laboratories for the treatment of depression in the United States and Canada.
  • (lS,2R)-2-(aminomethyl)-N,N-diethyl-l- phenylcyclopropanecarboxamide is an active enantiomer of ( ⁇ )-[lR(S),2S(R)]-2-
  • the first method for obtaining this enantiomer in enriched form has been developed by the separation or resolution of enantiomers from the racemic mixture (Bonnaud B. et al., J. Chromatogr. 1985, 318, 398-403). Enantio-selective syntheses were then developed for preparing enantiomerically enriched milnacipran (Doyle M. R and Hu W. Adv. Synth. Catal. 2001, 343, 299-302; Roggen H. et al., Bioorg. Med. Chem. 2007, 17, 2834-2837; Shuto S. et al., Tetrahedron Lett. 1996, 37, 641-644; Wang X.-Q.
  • 3-oxabicyclo[3.1.0]hexane comprising of reacting 2-phenylacetonitrile with epichlorohydrin in the presence of sodium hydride in a mixture of toluene and ⁇ , ⁇ '-dimethyl imidazolidinone followed by hydrolysis.
  • the said process involves the usage of sodium hydride which is pyrophoric in nature, difficult to handle and hence not suitable for commercial purpose.
  • WO 2010/086394 Al patent disclosed a process for the preparation of (1S,2R) isomer of (Z)-2-aminomethyl- 1 -phenyl -N,N-diethylcyclopropane carboxamide hydrochloride salt starting from the reaction of 2-phenyl acetonitrile with (R)-epichlorohydrin in presence of bases like sodium hydride and sodium amide.
  • US8222454 disclosed a process for the preparation of optically pure Milnacipran using tartaric acid derivatives as resolving agents.
  • the said tartaric acid derivatives are dibenzoyl tartaric acid, di-p-toluoyl tartaric acid and di-p-anisoyl tartaric acid.
  • tartaric acid derivatives such as di-p-toluoyl tartaric acid, di-p- anisoyl tartaric acid and di-benzoyl tartaric acid as resolving agent for the resolution of cis racemic mixture to obtain optically active milnacipran may increase the cost of the reaction which is not suitable for the commercial scale process.
  • the first aspect of the present invention is to provide a one-pot process for the preparation of (lS,2R)-2-(aminomethyl)-N,N-diethyl-l-phenylcyclopropane carboxamide compound of formula- 1 and its hydrochloride salt compound of formula- la, comprising of the following steps;
  • the second aspect of the present invention is to provide a process for the preparation of compound of general formula-6, comprising of the following steps; a) Reacting 2-phenyl acetonitrile compound of formula-2 with (R)-epichlorohydrin compound of formula-3 in presence of a suitable base in a suitable solvent provides cyano compound, which on hydrolysis in presence of a suitable base in a suitable solvent followed by treating with a suitable acid provide (lS,5R)-l-phenyl-3- oxabicyclo [3.1.0]hexan-2-one compound of formula-4,
  • the third aspect of the present invention is to provide a process for the preparation of (IS, 2R)-2-(aminomethyl)-N,N-diethyl-l-phenylcyclopropanecarboxamide compound of formula- 1 and its hydrochloride salt compound of formula- la, comprising of the following steps;
  • the fourth aspect of the present invention is to provide a novel acid addition salt of (IS, 2R)-2-(aminomethyl)-N,N-diethyl-l-phenylcyclopropanecarboxamide compound of formula- lb and its process for the preparation.
  • the fifth aspect of the present invention is to provide a process for the preparation of
  • the sixth aspect the present invention is to provide crystalline form-M of of (IS, 2R)- 2-(aminomethyl)-N,N-diethyl-l -phenylcyclopropanecarboxamide (R)-2 -acetyl mandelate salt compound of formula- lb.
  • Figure 1 Illustrates the PXRD pattern of crystalline Form-M of (l S,2R)-2-(aminomethyl)- N,N-diethyl-l-phenylcyclopropane carboxamide (R)-2-acetyl mandelate compound of Formula- lb;
  • Figure 2 Illustrates the DSC thermogram of crystalline Form-M of (lS,2R)-2- (aminomethyl)-N,N-diethyl-l-phenylcyclopropane carboxamide (R)-2-acetyl mandelate compound of Formula- lb;
  • Figure 3 Illustrates the PXRD pattern of (l S,2R)-2-(aminomethyl)-N,N-diethyl-l -phenyl cyclopropane carboxamide hydrochloride of Formula- la obtained according to Example- 1 ;
  • Figure 4 Illustrates the DSC thermogram of (l S,2R)-2-(aminomethyl)-N,N-diethyl-l- phenyl cyclopropane carboxamide hydrochloride of Formula- la obtained according to Example- 1.
  • suitable solvent refers to "hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, pet ether, benzene, toluene, xylene and the like; "ether solvents” such as dimethyl ether, diethyl ether, methyl tert-butyl ether, 1,2- dimethoxy ethane, tetrahydrofuran, 1 ,4-dioxane and the like; “ester solvents” such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and the like; “polar-aprotic solvents such as dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone (NMP) and the like; "chloro solvents” such as dichloromethane, dichloroethane, chloroform and the like;
  • suitable base refers to inorganic bases selected from “alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate and the like; “alkali metal hydroxides” such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert.butoxide, potassium tert.butoxide, lithium tert.butoxide and the like; “alkali metal hydrides” such as sodium hydride, potassium hydride, lithium hydride and the like; “alkali metal amides” such as sodium amide, potassium amide, lithium amide and the like; ammonia; and organic bases like methylamine, dimethylamine, diethylamine, diisopropyl amine, di
  • alkyl refers to Ci-C 6 straight chain or branched chain alkyl group or the alkyl group is optionally substituted with halo group
  • aryl refers to phenyl or substituted phenyl
  • substituted phenyl means phenyl group optionally substituted with 1-5 substituents independently selected from C C 5 alkyl, halogen, N0 2 wherein, halogen refers to chlorine, fluorine, bromine and iodine.
  • sulfonyl derivative is selected from methanesulfonyl chloride, methane sulfonic acid, para-toluene sulfonyl chloride, para-toluene sulfonic acid, trifluoromethane sulfonyl chloride, parabromo benzene sulfonyl chloride, parabromo benzene sulfonic acid, para nitrobenzene sulfonyl chloride and paranitrobenzene sulfonic acid.
  • the first aspect of the present invention provides a one-pot process for the preparation of (IS, 2R)-2-(aminomethyl)-N,N-diethyl-l-phenylcyclopropanecarboxamide compound of formula- 1 and its hydrochloride salt compound of formula- la, comprising of the following steps:
  • 'R' is Ci-C 6 straight or branched chain alkyl; aryl or substituted aryl;
  • the suitable base used in step-a), step-c) & step-e) is selected from organic, inorganic base and organosilicon base.
  • the suitable acid used in step-a) is selected from hydrochloric acid.
  • the suitable solvent used in any of the steps, i.e., from step-a), b), d) & e) is selected from
  • polar-aprotic solvents like dimethyl acetamide, dimethylformamide, dimethyl sulphoxide, acetonitrile; ether solvents like dimethyl ether, diethyl ether, methyl tert- butyl ether, 1 ,2-dimethoxy ethane, tetrahydrofuran, 1,4-dioxane; hydrocarbon solvents like toluene, xylene, hexane, heptane and cyclohexane; polar solvents such as water or mixtures thereof.
  • the suitable lewis acid used in step-b) is selected from aluminium chloride, aluminium bromide, boron trifluoride, Iron chloride, Tin(IV) chloride, calcium chloride dihydrate, calcium chloride and zinc chloride; preferably aluminium chloride.
  • the suitable solvent used in step-f) is selected from ether solvents, alcoholic solvents, ester solvents or mixtures thereof.
  • the suitable hydrochloric acid source used in step-f) is selected from HCl gas, aqueous HCl, dry HCl, ethylacetate-HCl, IPA-HCl, ethanol-HCl, methanol-HCl, preferably ethanol- HCl
  • a preferred embodiment of the present invention provides a one-pot process for the preparation of (IS ,2R)-2-(aminomethyl)-N,N-diethyl- 1 -phenylcyclopropanecarboxamide compound of formula- 1 and its hydrochloride salt compound of formula- la, comprising of the following steps:
  • the present invention not only decreases the cost of the process, but also enhances the purity of (lS,2R)-2-(aminomethyl)-N,N-diethyl-l-phenylcyclopropane carboxamide hydrochloride salt compound of formula-la with 99.98% by HPLC without using additional purification steps.
  • Example- 1 of US20110112197 A 1 We, the present inventors have repeated the process disclosed in Example- 1 of US20110112197 A 1 and the obtained PXRD pattern is matching with crystalline Form- A.
  • the second aspect of the present invention provides a one-pot process for the preparation of compound of general formula-6 comprising of the following steps:
  • a preferred embodiment of the present invention provides a one-pot process for the preparation of ((lR,2S)-2-(diethyl carbamoyl)-2-phenylcyclopropyl)methyl methanesulfonate compound of formula-6a, comprising of the following steps:
  • the third aspect of the present invention provides a one-pot process for the preparation of (IS, 2R)-2-(aminomethyl)-N,N-diethyl-l-phenylcyclopropanecarboxamide compound of formula- 1 and its hydrochloride salt compound of formula- la, comprising of the following steps:
  • a preferred embodiment of the present invention provides a one-pot process for the preparation of (lS,2R)-2-(aminomethyl)-N,N-diethyl-l-phenylcyclopropane carboxamide compound of formula- 1 and its hydrochloride salt compound of formula- la, comprising of the following steps:
  • the fourth aspect of the present invention provides (IS, 2R)-2-(aminomethyl)-N,N- diethyl-l-phenylcyclopropanecarboxamide (R)-2-acetyl mandelate salt compound of formula- lb.
  • the fifth aspect of the present invention provides a process for the preparation of ( 1 S,2R)-2-(aminomethyl)-N,N-di ethyl- 1 -phenylcyclopropanecarboxamide compound of formula- 1 and its hydrochloride salt compound of formula- la, comprising of the following steps:
  • step-a) to step-c) is same as defined in step-a), b), d) & f) of the first aspect of the present invention.
  • the suitable resolving agent used in step-a) is selected from (R)-(-)-0-Acetyl mandelic acid and camphor sulfonic acid and the like.
  • the suitable base used in step-b) is selected from inorganic bases such as alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates and alkali metal bicarbonates.
  • the suitable hydrochloric acid source used in step-c) is same as defined in step-f) of the first aspect of present invention.
  • a preferred embodiment of the present invention provides a process for the preparation of (lS,2R)-2-(aminomethyl)-N,N-diethyl-l-phenylcyclopropane carboxamide compound of formula- 1 and its hydrochloride salt compound of formula- la, comprising of the following steps:
  • the main advantage of the above process i.e., preparation of (IS, 2R)-2- (aminomethyl)-N,N-diethyl-l-phenylcyclopropanecarboxamide (R)-2-acetyl mandelate salt compound of formula-lb, is that, the said salt enhances the purity of (lS,2R)-2- (aminomethyl)-N,N-diethyl-l -phenyl cyclopropane carboxamide compound of formula- 1.
  • the obtained compound of formula- 1 can be converted into high pure (lS,2R)-2- (aminomethyl)-N,N-diethyl-l -phenyl cyclopropane carboxamide hydrochloride compound of formula- la without proceeding additional purifications.
  • the sixth aspect of the present invention provides crystalline form-M of (lS,2R)-2- (aminomethyl)-N,N-diethyl-l-phenylcyclopropanecarboxamide (R)-2-acetyl mandelate salt compound of formula- l b, characterized by:
  • Levomilnacipran hydrochloride obtained by the present invention was analyzed by HPLC under the following conditions;
  • Apparatus A liquid chromatograph equipped with variable wavelength UV detector;
  • Wavelength 225 nm; Column temperature: 30°C; Injection volume: 10 ⁇ .,; Run time: 35 min; Elution: gradient; Mobile phase- A: Potassium dihydrogen phosphate: 1 -Octane sulfonic acid sodium saltwater (1 :1:1000, v/v/v); Mobile phase-B: Methanol (100%); Diluent: watenmethanol (50:50, v/v);
  • Levomilnacipran hydrochloride as produced by the present invention can be further micronized or milled to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements.
  • Techniques that may be used for particle size reduction include, but not limited to ball, roller and hammer mills, and jet mills. Milling or micronization may be performed before drying, or after the completion of drying of the product.
  • the present invention is schematically represented as follows.
  • Example-1 One-pot process for the preparation of (lS,2R)-2-(aminomethyl)-N,N- diethyl-l-phenylcyclopropane carboxamide hydrochloride
  • Aluminium chloride 46 g was added to pre-cooled toluene (200 ml) at 15-20°C and stirred for 15 minutes.
  • Slowly diethyl amine (52.5 g) was added to the above reaction mixture at 15-20°C and stirred for 15 minutes at the same temperature.
  • the organic layer obtained in the step-(a) or the compound obtained in example-5 was added to the reaction mixture at 15-20°C and stirred for 4 hours at the same temperature.
  • Slowly water was added to the reaction mixture at 0-10°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 30 minutes at the same temperature.
  • Step-(c) Preparation of ((lR,2S)-2-(diethylcarbamoyl)-2-phenylcyclopropyl)methyl methanesulfonate (Formula-6a)
  • Triethylamine (57.2 g) was added to the organic layer obtained in step-(b) at 25-30°C.
  • Slowly methane sulfonyl chloride (36 g) was added to the reaction mixture at 25-30°C and stirred for 3 hours at the same temperature.
  • the reaction mixture containing (( 1 R,2S)-2-(diethylcarbamoyl)-2-phenylcyclopropyl)methyl methanesulfonate compound of formula-6 was utilized in the next step without isolating the compound from the reaction mixture.
  • Step-(d) Preparation of (lS,2R)-2-((l,3-dioxoisoindolin-2-yl)methyl)-N,N-diethyI-l- phenyl cyclopropane carboxamide (Formula-7)
  • Step-(e) Preparation of (lS,2R)-2-(aminomethyl)-N,N-diethyl-l-phenylcyclopropane carboxamide (Formula- 1)
  • Methylamine 200 ml was added to the filtrate obtained in step-(d) at 25-30°C and stirred for 2 hours at the same temperature. After completion of the reaction, water was added to the reaction mixture and stirred for 20 minutes. Both the organic and aqueous layers were separated and aqueous layer was extracted with toluene. Combined organic layers and water was added. Adjusted the pH of the reaction mixture to below 2.0 by using hydrochloric acid (75 ml) at 25-30°C. Both the organic and aqueous layers were seperated and acidic carbon was added to the aqueous layer. Stirred the reaction mixture at 25-30°C for 45 minutes. Filtered the reaction mixture through hyflow bed and washed with water.
  • D(0.1) is 10.23 ⁇ ; D(0.5) is 25.59 ⁇ ; D(0.9) is 54.07 ⁇ ⁇ ; D(4,3) is 29.39.
  • Triphenyl phosphine (21 g) was added to a pre-cooled mixture of acetonitrile (300 ml) and 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ) (17.5 g) at 10-15°C and stirred for 40 minutes at the same temperature. Raised the temperature of the reaction mixture to 25- 30°C. Potassium phthalimide (45 g) was added to the reaction mixture at 25-30°C and stirred for 30 minutes at the same temperature. Cooled the reaction mixture to 10-15°C.
  • DDQ 2,3-dichloro-5,6-dicyano-l,4-benzoquinone
  • Toluene (6 ml) was added to a mixture of water (12 ml) and (lS,2R)-2- (aminomethyl)-N,N-diethyl-l-phenylcyclopropanecarboxamide (R)-2-acetyl mandelate (3 g) at 25-30°C. Cooled the reaction mixture to 0-5°C and sodium hydroxide solution was added to the reaction mixture at the same temperature. Raised the temperature of the reaction mixture to 25-30°C and stirred for 15 minutes at the same temperature. Both organic and aqueous layers were separated and aqueous layer was extracted thrice with toluene. Combined the organic layers and distilled off the solvent to get residue.
  • Potassium tertiary butoxide (16.2 g) was added to a pre-cooled solution of tetrahydrofuran (50 ml), phenyl acetonitrile (10 g) and R-(-)-epichlorohydrin at -30 to 20°C and stirred the reaction mixture for 2 hour at the same temperature.
  • Water (30 ml) was added to the reaction mixture at -30 to -20°C. Distilled off the solvent completely from the reaction mixture.
  • Sodium hydroxide (1.6 g) dissolved in water (60 ml) and dimethyl sulfoxide (50 ml) was added to the reaction mixture 25-30°C. Heated the reaction mixture to 80-85°C and stirred for 4 hours at the same temperature.
  • D(0.1) is 8.57 ⁇ ; D(0.5) is 21.35 ⁇ ; D(0.9) is 46.02 ⁇ ; D(4,3) is 24.81.

Abstract

The present invention relates to a process for the preparation of (1S,2R)-2-(aminomethyl)-N,N-diethyl-1-phenylcyclopropanecarboxamide hydrochloride compound of formula-1a, represented by the following structural formula: [Formula should be inserted here]

Description

Process for the preparation of (lS,2R)-2-(aminomethyl)-N.N- diethyl-l-phenylcvclopropanecarboxamide hydrochloride
Related Application:
This application claims the benefit of priority of our Indian patent application
2661 /CHE/2013 filed on 19th June 2013 which is incorporated herein by reference.
Field of the Invention:
The present invention relates to a process for the preparation of (lS,2R)-2- (aminomethyl)-N,N-diethyl- 1 -phenylcyclopropanecarboxamide represented by the structural formula- 1 , and its h drochloride salt com ound of formula- 1 a.
Figure imgf000003_0001
Formula- 1 Formula- la
(1 S,2R)-2-(aminomethyl)-N,N-diethyl-l -phenylcyclopropanecarboxamide is an antidepressant currently under development by Forest Laboratories for the treatment of depression in the United States and Canada. (lS,2R)-2-(aminomethyl)-N,N-diethyl-l- phenylcyclopropanecarboxamide is an active enantiomer of (±)-[lR(S),2S(R)]-2-
(aminomethyl)-N,N-diethyl-l-phenylcyclopropane carboxamide and therefore has similar effects and pharmacology, acting as a serotonin-norepinephrine reuptake inhibitor.
Background of the Invention:
The first method for obtaining this enantiomer in enriched form has been developed by the separation or resolution of enantiomers from the racemic mixture (Bonnaud B. et al., J. Chromatogr. 1985, 318, 398-403). Enantio-selective syntheses were then developed for preparing enantiomerically enriched milnacipran (Doyle M. R and Hu W. Adv. Synth. Catal. 2001, 343, 299-302; Roggen H. et al., Bioorg. Med. Chem. 2007, 17, 2834-2837; Shuto S. et al., Tetrahedron Lett. 1996, 37, 641-644; Wang X.-Q. et al., Chinese journal of Pharmaceuticals 2004, 35, 259-260; WO 2005/118 564). However, most of these syntheses use sodium azide as a reagent, which may hardly be contemplated industrially because of its toxicity and of its instability which may lead to an explosion.
US 2008/0064885 Al also disclosed a process for the preparation of 2-oxo-l -phenyl -
3-oxabicyclo[3.1.0]hexane, comprising of reacting 2-phenylacetonitrile with epichlorohydrin in the presence of sodium hydride in a mixture of toluene and Ν,Ν'-dimethyl imidazolidinone followed by hydrolysis. The said process involves the usage of sodium hydride which is pyrophoric in nature, difficult to handle and hence not suitable for commercial purpose.
WO 2010/086394 Al patent disclosed a process for the preparation of (1S,2R) isomer of (Z)-2-aminomethyl- 1 -phenyl -N,N-diethylcyclopropane carboxamide hydrochloride salt starting from the reaction of 2-phenyl acetonitrile with (R)-epichlorohydrin in presence of bases like sodium hydride and sodium amide.
Hence, there is a need in the art to develop an improved process for the preparation of (lS,2R)-2-(aminomethyl)-N,N-diethyl-l-phenylcyclopropanecarboxamide compound of formula- 1 by using simple bases that avoids the disadvantages mentioned in the prior-art processes.
US8222454 disclosed a process for the preparation of optically pure Milnacipran using tartaric acid derivatives as resolving agents. The said tartaric acid derivatives are dibenzoyl tartaric acid, di-p-toluoyl tartaric acid and di-p-anisoyl tartaric acid.
The use of expensive tartaric acid derivatives such as di-p-toluoyl tartaric acid, di-p- anisoyl tartaric acid and di-benzoyl tartaric acid as resolving agent for the resolution of cis racemic mixture to obtain optically active milnacipran may increase the cost of the reaction which is not suitable for the commercial scale process.
Therefore there is still a significant need for new methods for synthesizing (1S,2R)- milnacipran which are more secure, more economical and more efficient.
Advantages of the present invention:
• Avoids the usage of bases like sodium amide, sodium hydride, which are pyrophoric in nature, difficult to handle and not suitable for commercial scale up. • Provides a simple and safe process by using mild bases.
• Eco-friendly and economic process.
Brief Description of the Invention:
The first aspect of the present invention is to provide a one-pot process for the preparation of (lS,2R)-2-(aminomethyl)-N,N-diethyl-l-phenylcyclopropane carboxamide compound of formula- 1 and its hydrochloride salt compound of formula- la, comprising of the following steps;
a) Reacting 2-phenyl acetonitrile compound of formula-2 with (R)-epichlorohydrin compound of formula-3 in presence of a suitable base in a suitable solvent provides cyano compound, which on hydrolysis in presence of a suitable base in a suitable solvent followed by treating with a suitable acid provide (lS,5R)-l-phenyl-3- oxabicyclo [3.1.0]hexan-2-one compound of formula-4,
b) reacting the compound of formula-4 in-situ with diethylamine in presence of a suitable lewis acid in a suitable solvent to provide (lS,2R)-N,N-diethyl-2- (hydroxymethyl)-l-phenylcyclopropanecarboxamide compound of formula-5, c) reacting the compound of formula-5 in-situ with sulfonyl derivative compound of general formula-8 in presence of a suitable base to provide compound of general formula-6,
d) reacting the compound of formula-6 in-situ with potassium phthalimide in a suitable solvent to provide (1 S,2R)-2-(( 1,3 -dioxoisoindolin-2-yl)methyl)-N,N-di ethyl- 1- phenyl cyclopropanecarboxamide compound of formula-7,
e) treating the compound of formula-7 in-situ with a suitable base to provide (lS,2R)-2- (aminomethyl)-N,N-diethyl-l -phenylcyclopropanecarboxamide compound of formula- 1,
f) converting the compound of formula- 1 into its hydrochloride salt compound of formula- la by treating in-situ with a suitable hydrochloride source in a suitable solvent.
The second aspect of the present invention is to provide a process for the preparation of compound of general formula-6, comprising of the following steps; a) Reacting 2-phenyl acetonitrile compound of formula-2 with (R)-epichlorohydrin compound of formula-3 in presence of a suitable base in a suitable solvent provides cyano compound, which on hydrolysis in presence of a suitable base in a suitable solvent followed by treating with a suitable acid provide (lS,5R)-l-phenyl-3- oxabicyclo [3.1.0]hexan-2-one compound of formula-4,
b) reacting the compound of formula-4 in-situ with diethylamine in presence of a suitable lewis acid in a suitable solvent to provide (lS,2R)-N,N-diethyl-2- (hydroxymethyl)-l-phenylcyclopropanecarboxamide compound of formula-5, c) reacting the compound of formula-5 in-situ with sulfonyl derivative compound of general formula-8 in presence of a suitable base to provide compound of general formula-6.
The third aspect of the present invention is to provide a process for the preparation of (IS, 2R)-2-(aminomethyl)-N,N-diethyl-l-phenylcyclopropanecarboxamide compound of formula- 1 and its hydrochloride salt compound of formula- la, comprising of the following steps;
a) Reacting 2-phenyl acetonitrile compound of formula-2 with (R)-epichlorohydrin compound of formula-3 in presence of a suitable base in a suitable solvent provides cyano compound, which on hydrolysis in presence of a suitable base in a suitable solvent followed by treating with a suitable acid provide (1S,5R)-1 -phenyl -3- oxabicyclo [3.1.0]hexan-2-one compound of formula-4,
b) reacting the compound of formula-4 in-situ with diethylamine in presence of a suitable lewis acid in a suitable solvent to provide (lS,2R)-N,N-diethyl-2- (hydroxymethyl)-l-phenylcyclopropanecarboxamide compound of formula-5, c) reacting the compound of formula-5 in-situ with potassium phthalimide in presence of triphenyl phosphine and 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ) in a suitable solvent to provide (lS,2R)-2-((l,3-dioxoisoindolin-2-yl)m'ethyl)-N,N- diethyl-1 -phenyl cyclopropanecarboxamide compound of formula-7,
d) treating the compound of formula-7 in-situ with a suitable base to provide (lS,2R)-2- (aminomethyl)-N,N-di ethyl- 1 -phenylcyclopropanecarboxamide compound of formula- 1,
e) converting the compound of formula- 1 into its hydrochloride salt compound of formula- la by treating it in-situ with a suitable hydrochloride source in a suitable solvent.
The fourth aspect of the present invention is to provide a novel acid addition salt of (IS, 2R)-2-(aminomethyl)-N,N-diethyl-l-phenylcyclopropanecarboxamide compound of formula- lb and its process for the preparation. The fifth aspect of the present invention is to provide a process for the preparation of
(1 S,2R)-2-(aminomethyl)-N,N-diethyl- 1 -phenylcyclopropanecarboxamide compound of formula- 1 and its hydrochloride salt compound of formula- la, comprising of the following steps;
a) Resolving the (±)-[lR(S),2S(R)]-2-(aminomethyl)-N,N-diethyl-l-phenyl cyclopropane carboxamide compound of formula-I with a suitable resolving agent in a suitable solvent to provide (lS,2R)-2-(aminomethyl)-N,N-diethyl-l -phenyl cyclopropanecarboxamide (R)-2-acetyl mandelate salt compound of formula- lb, b) neutralizing the compound formula- lb with a suitable base in a suitable solvent to provide compound of formula- 1,
c) converting the compound of formula- 1 into its hydrochloride salt compound of formula- l a by treating it with a suitable hydrochloride source in a suitable solvent.
The sixth aspect the present invention is to provide crystalline form-M of of (IS, 2R)- 2-(aminomethyl)-N,N-diethyl-l -phenylcyclopropanecarboxamide (R)-2 -acetyl mandelate salt compound of formula- lb.
Brief description of figures:
Figure 1: Illustrates the PXRD pattern of crystalline Form-M of (l S,2R)-2-(aminomethyl)- N,N-diethyl-l-phenylcyclopropane carboxamide (R)-2-acetyl mandelate compound of Formula- lb;
Figure 2: Illustrates the DSC thermogram of crystalline Form-M of (lS,2R)-2- (aminomethyl)-N,N-diethyl-l-phenylcyclopropane carboxamide (R)-2-acetyl mandelate compound of Formula- lb;
Figure 3: Illustrates the PXRD pattern of (l S,2R)-2-(aminomethyl)-N,N-diethyl-l -phenyl cyclopropane carboxamide hydrochloride of Formula- la obtained according to Example- 1 ; Figure 4: Illustrates the DSC thermogram of (l S,2R)-2-(aminomethyl)-N,N-diethyl-l- phenyl cyclopropane carboxamide hydrochloride of Formula- la obtained according to Example- 1.
Detailed Description of the Invention:
The term "suitable solvent" used in the present invention refers to "hydrocarbon solvents" such as n-hexane, n-heptane, cyclohexane, pet ether, benzene, toluene, xylene and the like; "ether solvents" such as dimethyl ether, diethyl ether, methyl tert-butyl ether, 1,2- dimethoxy ethane, tetrahydrofuran, 1 ,4-dioxane and the like; "ester solvents" such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and the like; "polar-aprotic solvents such as dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone (NMP) and the like; "chloro solvents" such as dichloromethane, dichloroethane, chloroform and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; "nitrile solvents" such as acetonitrile, propionitrile, isobutyro nitrie and the like; "alcoholic solvents" such as methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso- butanol, t-butanol and the like; "polar solvents" such as water; acetic acid or mixtures thereof.
The term "suitable base" used in the present invention refers to inorganic bases selected from "alkali metal carbonates" such as sodium carbonate, potassium carbonate, lithium carbonate and the like; "alkali metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate and the like; "alkali metal hydroxides" such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; "alkali metal alkoxides" such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert.butoxide, potassium tert.butoxide, lithium tert.butoxide and the like; "alkali metal hydrides" such as sodium hydride, potassium hydride, lithium hydride and the like; "alkali metal amides" such as sodium amide, potassium amide, lithium amide and the like; ammonia; and organic bases like methylamine, dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, diisobutylamine, triethylamine, tributylamine, tert.butyl amine, pyridine, 4-dimethylaminopyridine (DMAP), N-methyl morpholine (NMM), 2,6- lutidine, lithium diisopropylamide (LDA), l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5- diazabicyclo[4.3.0]non-5-ene (DBN), l,4-diazabicyclo[2.2.2]octane (DABCO) and the like; organosilicon bases such as lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS); n-butyl lithium or mixtures thereof.
As used herein the term "alkyl" refers to Ci-C6 straight chain or branched chain alkyl group or the alkyl group is optionally substituted with halo group; the term aryl refers to phenyl or substituted phenyl; the term "substituted phenyl" means phenyl group optionally substituted with 1-5 substituents independently selected from C C5 alkyl, halogen, N02 wherein, halogen refers to chlorine, fluorine, bromine and iodine.
As used herein the term "sulfonyl derivative" is selected from methanesulfonyl chloride, methane sulfonic acid, para-toluene sulfonyl chloride, para-toluene sulfonic acid, trifluoromethane sulfonyl chloride, parabromo benzene sulfonyl chloride, parabromo benzene sulfonic acid, para nitrobenzene sulfonyl chloride and paranitrobenzene sulfonic acid.
The first aspect of the present invention provides a one-pot process for the preparation of (IS, 2R)-2-(aminomethyl)-N,N-diethyl-l-phenylcyclopropanecarboxamide compound of formula- 1 and its hydrochloride salt compound of formula- la, comprising of the following steps:
a) Reacting 2 -phenyl acetonitrile co 2
Figure imgf000009_0001
with (R)-epichlorohydrin compound of formula-3
o
Formula-3
in presence of a suitable base in a suitable solvent provides cyano compound, which on hydrolysis in presence of a suitable base in a suitable solvent followed by treating with a suitable acid provides (l S,5R)-l-phenyl-3-oxabicyclo[3.1.0]hexan-2-one compound of formula-4,
Figure imgf000010_0001
Formula-4
b) reacting the compound of formula-4 in-situ with diethylamine in presence of a suitable lewis acid in a suitable . solvent provides (l S,2R)-N,N-diethyl-2- (hydroxymethyl)-l-phenylcycl ide compound of formula-5,
Figure imgf000010_0002
Formula-5
c) reacting the compound of formula-5 in-situ with sulfonyl derivative compound of general formula-8
O
II
R-S-X
II
O
Formula-8
Wherein, 'R' is Ci-Ce straight or branched chain alkyl; aryl or substituted aryl; and X = Halogen such as CI or Br;
in presence of a suitable bas of general formula-6,
Figure imgf000010_0003
Formula-6
Wherein, 'R' is Ci-C6 straight or branched chain alkyl; aryl or substituted aryl;
d) reacting the compound of general formula-6 in-situ with potassium phthalimide in a suitable solvent provides (l S,2R)-2-((l ,3-dioxoisoindolin-2-yl)methyl)-N,N-diethyl- 1 -phenyl cyclopropanecarboxamide compound of formula-7,
Figure imgf000011_0001
Formula-7
e) treating the compound of formula-7 in-situ with a suitable base provides (lS,2R)-2- (aminomethyl)-N,N-diethyl-l-phenylcyclopropanecarboxamide compound of formula- 1,
Figure imgf000011_0002
Formula- 1
f) converting the compound of formula- 1 into its hydrochloride salt compound of formula- la by treating it in-situ with a suitable hydrochloric acid source in a suitable solvent.
Wherein, the suitable base used in step-a), step-c) & step-e) is selected from organic, inorganic base and organosilicon base.
The suitable acid used in step-a) is selected from hydrochloric acid.
The suitable solvent used in any of the steps, i.e., from step-a), b), d) & e) is selected from
polar-aprotic solvents like dimethyl acetamide, dimethylformamide, dimethyl sulphoxide, acetonitrile; ether solvents like dimethyl ether, diethyl ether, methyl tert- butyl ether, 1 ,2-dimethoxy ethane, tetrahydrofuran, 1,4-dioxane; hydrocarbon solvents like toluene, xylene, hexane, heptane and cyclohexane; polar solvents such as water or mixtures thereof.
The suitable lewis acid used in step-b) is selected from aluminium chloride, aluminium bromide, boron trifluoride, Iron chloride, Tin(IV) chloride, calcium chloride dihydrate, calcium chloride and zinc chloride; preferably aluminium chloride.
The suitable solvent used in step-f) is selected from ether solvents, alcoholic solvents, ester solvents or mixtures thereof.
The suitable hydrochloric acid source used in step-f) is selected from HCl gas, aqueous HCl, dry HCl, ethylacetate-HCl, IPA-HCl, ethanol-HCl, methanol-HCl, preferably ethanol- HCl
A preferred embodiment of the present invention provides a one-pot process for the preparation of (IS ,2R)-2-(aminomethyl)-N,N-diethyl- 1 -phenylcyclopropanecarboxamide compound of formula- 1 and its hydrochloride salt compound of formula- la, comprising of the following steps:
a) Reacting 2-phenyl acetonitrile compound of formula-2 with (R)-epichlorohydrin compound of formula-3 in presence of sodium hexamethyldisilazide in tetrahydrofuran provides cyano compound, which on hydrolysis in presence of sodium hydroxide in dimethyl sulfoxide followed by treating with hydrochloric acid provides (lS,5R)-l-phenyl-3-oxabicyclo[3.1.0]hexan-2-one compound of formula-4, b) reacting the compound of formula-4 in-situ with diethylamine in presence of aluminium chloride in toluene provides (lS,2R)-N,N-diethyl-2-(hydroxymethyl)-l- phenyl cyclopropanecarboxamide compound of formula-5,
c) reacting the compound of formula-5 in-situ with methanesulfonyl chloride compound of formula-8a in presence of triethyl amine provides ((lR,2S)-2-(diethylcarbamoyl)- 2-phenylcyclopropyl) methyl methanesulfonate compound of formula-6a,
d) reacting the compound of formula-6a in-situ with potassium phthalimide in toluene provides ( 1 S,2R)-2-(( 1 ,3-dioxoisoindolin-2-yl)methyl)-N,N-diethyl- 1 -phenyl cyclo propane carboxamide compound of formula-7,
e) treating the compound of formula-7 in-situ with methyl amine provides (lS,2R)-2- (aminomethyl)-N,N-di ethyl- 1 -phenylcyclopropanecarboxamide compound of formula- 1,
f) converting the compound of formula- 1 into its hydrochloride salt compound of formula- la by treating it in-situ with ethanolic hydrochloric acid in a mixture of methyl tertiary butyl ether and ethanol provides (lS,2R)-2-(aminomethyl)-N,N- diethyl-1 -phenyl cyclopropane carboxamide hydrochloride compound of formula- la. The main advantage with the present invention is that, as the present invention proceeds through one-pot process, it is not necessary to isolate the intermediate products formed in different stages from the reaction mixture. By adopting such process, the present inventor has avoided the yield loss at each stage during intermediate purification steps and thereby provides a highly economic process.
The present invention not only decreases the cost of the process, but also enhances the purity of (lS,2R)-2-(aminomethyl)-N,N-diethyl-l-phenylcyclopropane carboxamide hydrochloride salt compound of formula-la with 99.98% by HPLC without using additional purification steps.
We, the present inventors have repeated the process disclosed in Example- 1 of US20110112197 A 1 and the obtained PXRD pattern is matching with crystalline Form- A.
The PXRD pattern of (lS,2R)-2-(aminomethyl)-N,N-diethyl-l-phenylcyclopropane carboxamide hydrochloride salt compound of formula- la obtained from the present process is also matching with PXRD pattern of crystalline Form- A disclosed in US20110112197A1.
The second aspect of the present invention provides a one-pot process for the preparation of compound of general formula-6 comprising of the following steps:
a) Reacting 2-phenyl acetonitrile compound of formula-2 with (R)-epichlorohydrin compound of formula-3 in presence of a suitable base in a suitable solvent provides cyano compound, which on hydrolysis in presence of a suitable base in a suitable solvent followed by treating with a suitable acid provides (1 S,5R)-l-phenyl-3- oxabicyclo [3.1.0]hexan-2-one compound of formula-4,
b) reacting the compound of formula-4 in-situ with diethylamine in presence of a suitable lewis acid in a suitable solvent provides (lS,2R)-N,N-diethyl-2- (hydroxymethyl)-l-phenylcyclopropanecarboxamide compound of formula-5, c) reacting the compound of formula-5 in-situ with sulfonyl derivative compound of general formula-8 in presence of a suitable base provides compound of general formula-6.
A preferred embodiment of the present invention provides a one-pot process for the preparation of ((lR,2S)-2-(diethyl carbamoyl)-2-phenylcyclopropyl)methyl methanesulfonate compound of formula-6a, comprising of the following steps:
a) Reacting 2-phenyl acetonitrile compound of formula-2 with (R)-epichlorohydrin compound of formula-3 in presence of sodium hexamethyldisilazide in tetrahydrofuran provides cyano compound, which on hydrolysis in presence of sodium hydroxide in dimethyl sulfoxide followed by treating with hydrochloric acid provides (lS,5R)-l-phenyl-3-oxabicyclo[3.1.0]hexan-2-one compound of formula-4, b) reacting the compound of formula-4 in-situ with diethylamine in presence of aluminium chloride in toluene provides (lS,2R)-N,N-diethyl-2-(hydroxymethyl)-l- phenylcyclo propanecarboxamide compound of formula-5,
c) reacting the compound of formula-5 in-situ with methanesulfonyl chloride compound of formula-8a in presence of triethyl amine provides ((lR,2S)-2-(diethylcarbamoyl)- 2-phenylcyclopropyl) methyl methanesulfonate compound of formula-6a.
The third aspect of the present invention provides a one-pot process for the preparation of (IS, 2R)-2-(aminomethyl)-N,N-diethyl-l-phenylcyclopropanecarboxamide compound of formula- 1 and its hydrochloride salt compound of formula- la, comprising of the following steps:
a) Reacting 2-phenyl acetonitrile compound of formula-2 with (R)-epichlorohydrin compound of formula-3 in presence of a suitable base in a suitable solvent provides cyano compound, which on hydrolysis in presence of a suitable base in a suitable solvent followed by treating with a suitable acid provides (lS,5R)-l-phenyl-3- oxabicyclo [3.1.0]hexan-2-one compound of formula-4,
b) reacting the compound of formula-4 in-situ with diethylamine in presence of a suitable lewis acid in a suitable solvent provides (lS,2R)-N,N-diethyl-2- (hydroxymethyl)-l-phenylcyclopropanecarboxamide compound of formula-5, c) reacting the compound of formula-5 in-situ with potassium phthalimide in presence of triphenyl phosphine and 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ) in a suitable solvent provides (lS,2R)-2-((l,3-dioxoisoindolin-2-yl)methyl)-N,N-diethyl- 1-phenylcyclopropanecarboxamide compound of formula-7, d) treating the compound of formula-7 in-situ with a suitable base provides (lS,2R)-2- (aminomethyl)-N,N-diethyl-l-phenylcyclopropanecarboxamide compound of formula- 1,
e) converting the compound of formula- 1 into its hydrochloride salt compound of formula- la by treating it in-situ with a suitable hydrochloride source in a suitable solvent;
A preferred embodiment of the present invention provides a one-pot process for the preparation of (lS,2R)-2-(aminomethyl)-N,N-diethyl-l-phenylcyclopropane carboxamide compound of formula- 1 and its hydrochloride salt compound of formula- la, comprising of the following steps:
a) Reacting 2-phenyl acetonitrile compound of formula-2 with (R)-epichlorohydrin compound of formula-3 in presence of sodium hexamethyldisilazide in tetrahydrofuran provides cyano compound, which on hydrolysis in presence of sodium hydroxide in dimethyl sulfoxide followed by treating with a hydrochloric acid provides (lS,5R)-l-phenyl-3-oxabicyclo[3.1.0]hexan-2-one compound of formula-4,
b) reacting the compound of formula-4 in-situ with diethylamine in presence of aluminium chloride in toluene provides (lS,2R)-N,N-diethyl-2-(hydroxymethyl)-l- phenylcyclo propanecarboxamide compound of formula-5,
c) reacting the compound of formula-5 in-situ with potassium phthalimide in presence of triphenyl phosphine and 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ) in acetonitrile provides (lS,2R)-2-((l,3-dioxoisoindolin-2-yl)methyl)-N,N-diethyl-l- phenylcyclopropanecarboxamide compound of formula-7,
d) treating the compound of formula-7 in-situ with methyl amine provides (lS,2R)-2- (aminomethyl)-N,N-diethyl-l-phenylcyclopropanecarboxamide compound of formula- 1,
e) converting the compound of formula- 1 to its hydrochloride salt compound of formula- la by treating it in-situ with ethanolic hydrochloric acid in a mixture of methyl tertiary butyl ether and ethanol. The fourth aspect of the present invention provides (IS, 2R)-2-(aminomethyl)-N,N- diethyl-l-phenylcyclopropanecarboxamide (R)-2-acetyl mandelate salt compound of formula- lb.
Figure imgf000016_0001
Formula- lb
The fifth aspect of the present invention provides a process for the preparation of ( 1 S,2R)-2-(aminomethyl)-N,N-di ethyl- 1 -phenylcyclopropanecarboxamide compound of formula- 1 and its hydrochloride salt compound of formula- la, comprising of the following steps:
a) Resolving the (±)-[lR(S),2S(R)]-2-(aminomethyl)-N,N-diethyl-l-phenyl cyclopropane carboxamide co
Figure imgf000016_0002
Formula-I
with a suitable resolving agent in a suitable solvent provides (lS,2R)-2- (aminomethyl)-N,N-diethyl- 1 -phenylcyclopropanecarboxamide (R)-2-acetyl mandelate salt compound of formula- lb,
b) neutralizing the compound of formula- lb with a suitable base in a suitable solvent provides compound of formula- 1 ,
c) converting the compound of formula- 1 into its hydrochloride salt compound of formula- la by treating it in-situ with a suitable hydrochloric acid source in a suitable solvent.
Wherein, the suitable solvent used in step-a) to step-c) is same as defined in step-a), b), d) & f) of the first aspect of the present invention.
The suitable resolving agent used in step-a) is selected from (R)-(-)-0-Acetyl mandelic acid and camphor sulfonic acid and the like. The suitable base used in step-b) is selected from inorganic bases such as alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates and alkali metal bicarbonates.
The suitable hydrochloric acid source used in step-c) is same as defined in step-f) of the first aspect of present invention.
A preferred embodiment of the present invention provides a process for the preparation of (lS,2R)-2-(aminomethyl)-N,N-diethyl-l-phenylcyclopropane carboxamide compound of formula- 1 and its hydrochloride salt compound of formula- la, comprising of the following steps:
a) Resolving the (±)-[lR(S),2S(R)]-2-(aminomethyl)-N,N-diethyl-l-phenyl cyclopropane carboxamide compound of formula-I with (R)-(-)-0-Acetyl mandelic acid in a mixture of ethyl acetate and water provides (lS,2R)-2-(aminomethyl)-N,N- diethyl-l-phenylcyclo propane carboxamide (R)-2-acetyl mandelate salt compound of formula- lb,
b) neutralizing the compound of formula- lb with sodium hydroxide in a mixture of toluene and water provides compound of formula- 1,
c) converting the compound of formula- 1 into its hydrochloride salt compound of formula- la by treating it in-situ with ethanolic hydrochloric acid in a mixture of methyl tertiary butyl ether and ethanol provides (lS,2R)-2-(aminomethyl)-N,N- diethyl-1 -phenyl cyclopropane carboxamide hydrochloride compound of formula- la.
The main advantage of the above process i.e., preparation of (IS, 2R)-2- (aminomethyl)-N,N-diethyl-l-phenylcyclopropanecarboxamide (R)-2-acetyl mandelate salt compound of formula-lb, is that, the said salt enhances the purity of (lS,2R)-2- (aminomethyl)-N,N-diethyl-l -phenyl cyclopropane carboxamide compound of formula- 1. Further, the obtained compound of formula- 1 can be converted into high pure (lS,2R)-2- (aminomethyl)-N,N-diethyl-l -phenyl cyclopropane carboxamide hydrochloride compound of formula- la without proceeding additional purifications.
The sixth aspect of the present invention provides crystalline form-M of (lS,2R)-2- (aminomethyl)-N,N-diethyl-l-phenylcyclopropanecarboxamide (R)-2-acetyl mandelate salt compound of formula- l b, characterized by:
a) Its powder X-ray diffractogram having peaks at 6.4, 7.8, 9.4, 10.3, 11.0, 12.9, 14.2, 14.6, 16.0, 1.7.4, 18.9, 19.5, 20.8, 21.0, 22.3, 23.4, 23.8, 24.9, 25.2, 26.2, 28.8, 29.5, 31.3, 31.8, and 33.5 ± 0.2 degrees of two-theta as illustrated in figure-1 ;
b) its DSC thermogram showing endotherm at 172.21 as illustrated in figure-2;
HPLC Method of Analysis:
Levomilnacipran hydrochloride obtained by the present invention was analyzed by HPLC under the following conditions;
Apparatus: A liquid chromatograph equipped with variable wavelength UV detector;
Column: Zorbax SB-CN, 250><4.6 mm, 5μπι (or) equivalent; Flow rate: 1.0 mL/min;
Wavelength: 225 nm; Column temperature: 30°C; Injection volume: 10 μΐ.,; Run time: 35 min; Elution: gradient; Mobile phase- A: Potassium dihydrogen phosphate: 1 -Octane sulfonic acid sodium saltwater (1 :1:1000, v/v/v); Mobile phase-B: Methanol (100%); Diluent: watenmethanol (50:50, v/v);
The PXRD analysis of compound of formula- la of the present invention was carried out using BRUKER/AXS X-Ray diffractometer using Cu Ka radiation of wavelength 1.5406 A° and continuous scan speed of 0.03°/min.
Levomilnacipran hydrochloride as produced by the present invention can be further micronized or milled to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited to ball, roller and hammer mills, and jet mills. Milling or micronization may be performed before drying, or after the completion of drying of the product.
The present invention is schematically represented as follows.
Scheme-I:
Figure imgf000019_0001
Levomilnacipran
Formula-la
Scheme-II:
1
Figure imgf000019_0002
The best mode of carrying out the present invention is illustrated by the below mentioned examples. These examples are provides as illustration only and hence should not be construed as limitation of the scope of the invention. Examples:
Example-1: One-pot process for the preparation of (lS,2R)-2-(aminomethyl)-N,N- diethyl-l-phenylcyclopropane carboxamide hydrochloride
Step-(a): Preparation of (lS,5R)-l-phenyl-3-oxabicyclo[3.1.0]hexan-2-one (Formula-4) Sodium hexamethyldisilazide (360 ml) was added to a pre cooled mixture of tetrahydrofuran (250 ml), benzyl cyanide (50 g) and R-(-)epichlorohydrin (43.5 g) at -25 to - 20°C under nitrogen atmosphere and stirred the reaction mixture for 3 hours at the same temperature. Water (150 ml) was added to the reaction mixture at -25 to -20°C. Distilled off the solvent from the reaction mixture to obtain residue. Dimethyl sulfoxide (250 ml) and sodium hydroxide (34 g) dissolved in water (300 ml) was added to the obtained residue at 25- 30°C. Heated the reaction mixture to 80-85°C and stirred for 4 hours at the same temperature. Cooled the reaction mixture to 20-30°C and washed with toluene. Both organic and aqueous layer were seperated and toluene was added to the aqueous layer. Adjusted the pH of the reaction mixture to 2.0 by using hydrochloric acid (150 ml) at 25-30°C and stirred the reaction mixture for 4 hours at the same temperature. After completion of the reaction, both organic and aqueous layer were seperated and aqueous layer is extracted with toluene. Combined organic layers were washed with sodium bicarbonate solution followed by sodium chloride solution. The resulting organic layer containing (lS,5R)-l-phenyl-3- oxabicyclo[3.1.0]hexan-2-one compound of formula-4 was utilized in the next step without isolating the compound from the reaction mixture.
Step-(b): Preparation of (lS,2R)-N,N-diethyl-2-(hydroxymethyI)-l-phenyl cyclopropane carboxamide (Formula-5)
Aluminium chloride (46 g) was added to pre-cooled toluene (200 ml) at 15-20°C and stirred for 15 minutes. Slowly diethyl amine (52.5 g) was added to the above reaction mixture at 15-20°C and stirred for 15 minutes at the same temperature. The organic layer obtained in the step-(a) or the compound obtained in example-5 was added to the reaction mixture at 15-20°C and stirred for 4 hours at the same temperature. After completion of the reaction, cooled the reaction mixture to 0-10°C. Slowly water was added to the reaction mixture at 0-10°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 30 minutes at the same temperature. Both organic and aqueous layers were seperated and aqueous layer was extracted with toluene. Combined organic layer were washed with sodium chloride solution and the resulting organic layer containing (lS,2R)-N,N-diethyl-2- (hydroxymethyl)-l-phenylcyclopropane carboxamide compound of formula-5 was utilized in the next step without isolating the compound from the reaction mixture.
Step-(c): Preparation of ((lR,2S)-2-(diethylcarbamoyl)-2-phenylcyclopropyl)methyl methanesulfonate (Formula-6a)
Triethylamine (57.2 g) was added to the organic layer obtained in step-(b) at 25-30°C. Slowly methane sulfonyl chloride (36 g) was added to the reaction mixture at 25-30°C and stirred for 3 hours at the same temperature. After completion of the reaction, the reaction mixture containing (( 1 R,2S)-2-(diethylcarbamoyl)-2-phenylcyclopropyl)methyl methanesulfonate compound of formula-6 was utilized in the next step without isolating the compound from the reaction mixture.
Step-(d): Preparation of (lS,2R)-2-((l,3-dioxoisoindolin-2-yl)methyl)-N,N-diethyI-l- phenyl cyclopropane carboxamide (Formula-7)
Potassium phthalimide (49 gm) and toluene (100 ml) were added to the organic layer obtained in step-(c) at 25-30°C. Heated the reaction mixture to 100-105°C and stirred for 4 hours at the same temperature. After completion of the reaction, the reaction mixture was cooled to 25-30°C. Filtered the unwanted solid and washed with toluene. The filtrate containing (lS,2R)-2-((l,3-dioxoisoindolin-2-yl)methyl)-N,N-diethyl-l-phenyl cyclopropane carboxamide compound of formula-7 was utilized in the next step without isolating the compound from the reaction mixture.
Step-(e): Preparation of (lS,2R)-2-(aminomethyl)-N,N-diethyl-l-phenylcyclopropane carboxamide (Formula- 1)
Methylamine (200 ml) was added to the filtrate obtained in step-(d) at 25-30°C and stirred for 2 hours at the same temperature. After completion of the reaction, water was added to the reaction mixture and stirred for 20 minutes. Both the organic and aqueous layers were separated and aqueous layer was extracted with toluene. Combined organic layers and water was added. Adjusted the pH of the reaction mixture to below 2.0 by using hydrochloric acid (75 ml) at 25-30°C. Both the organic and aqueous layers were seperated and acidic carbon was added to the aqueous layer. Stirred the reaction mixture at 25-30°C for 45 minutes. Filtered the reaction mixture through hyflow bed and washed with water. Cooled the obtained filtrate to 0-5 °C and toluene was added. Adjusted the pH of the reaction mixture to 12-13 by using sodium hydroxide (22 g) dissolved in water (22 ml) and stirred the reaction mixture for 15 minutes. Both the organic and aqueous layers were separated. Extracted the aqueous layer thrice with toluene and combined organic layers were dried over sodium sulphate. Distilled off the solvent completely to get the title compound.
Yield: 32 gms.
Step-(f): Preparation of (lS,2R)-2-(aminomethyl)-N,N-diet yl-l-phenylcyclopropane carboxamide hydrochloride (Formula-la)
Ethanol (30 ml) and methyl tertiary butyl ether (15 ml) were added to (lS,2R)-2- (aminomethyl)-N,N-diethyl-l-phenylcyclopropanecarboxamide compound of formula- 1 obtained in step-(e) at 25-30°C. Cooled the reaction mixture to 15-20°C. Slowly ethanolic hydrochloric acid (20 ml) was added to the reaction mixture at 15-20°C and stirred for 45 minutes at the same temperature. Filtered the solid, washed with methyl tertiary butyl ether and dried to get the title compound.
Yield: 27 gm; Pthalimido impurity: Not detectable; (1R, 2S)-isomer impurity: 0.02%.
Purity by HPLC: 99.98%; Chiral purity By HPLC: 99.94%;
Particle Size Distribution: D(0.1) is 10.23 μπι; D(0.5) is 25.59 μιη; D(0.9) is 54.07 μιη; D(4,3) is 29.39.
The PXRD of compound of formula- la matches with the prior art crystalline Form- A of Levomilnacipran hydrochloride as depicted in figure-3.
The DSC thermogram of compound of formula- la is depicted in figure-4.
ExampIe-2: Preparation of (lS,2R)-2-((l,3-dioxoisoindolin-2-yl)methyl)-N,N-diethyl-l- phenyl cyclopropanecarboxamide (Formula-7)
Triphenyl phosphine (21 g) was added to a pre-cooled mixture of acetonitrile (300 ml) and 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ) (17.5 g) at 10-15°C and stirred for 40 minutes at the same temperature. Raised the temperature of the reaction mixture to 25- 30°C. Potassium phthalimide (45 g) was added to the reaction mixture at 25-30°C and stirred for 30 minutes at the same temperature. Cooled the reaction mixture to 10-15°C. Slowly (1 S,2R)-N,N-diethyl-2-(hydroxymethyl)-l -phenylcyclopropanecarboxamide compound of formula-5 obtained in step-(b) of example- 1 dissolved in acetonitrile (50 ml) was added to the above reaction mixture at 10-15°C and stirred for 30 minutes at the same temperature. Raised the temperature of the reaction mixture to 20-25°C and stirred for 6 hours at the same temperature. After completion of the reaction, filtered the unwanted material and washed with acetonitrile. Distilled off the solvent completely from the filtrate and toluene was added to the concentrated filtrate. Filtered the reaction mixture to remove the unwanted solid and washed with toluene. The filtrate was washed thrice with water followed by 10% sodium chloride and then dried over sodium sulphate. The filtrate containing (lS,2R)-2-((l,3-dioxoisoindolin-2-yl)methyl)-N,N-diethyl-l-phenyl cyclopropane carboxamide compound of formula-7 was utilized in the next step for the preparation of compound of formula- 1.
Example-3: Preparation of (lS,2R)-2-(aminomethyl)-N,N-diethyl-l-phenyl.cyclopropane carboxamide (R)-2-acetyl mandelate: (Formula-lb)
(R)-(-)-0-Acetyl mandelic acid (8.6 g) was added to a mixture of (±)-[lR(S),2S(R)]- 2-(aminomethyl)-N,N-diethyl-l -phenylcyclopropanecarboxamide (40 g) and ethylaceate (400 ml) and water (8 ml) at 25-30°C. Heated the reaction mixture to 60-65°C and stirred for 30 minutes at the same temperature. Slowly cooled the reaction mixture to 0-5 °C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with ethyl aceate and dried to get the title compound. Yield: 15 gms. Chiral purity By HPLC: 91.68%;
The PXRD of the obtained compound of formula- 1 b is depicted in figure- 1.
The DSC thermogram of the obtained compound of formula- lb is depicted in figure-2.
Example-4:
Preparation of (lS,2R)-2-(aminomethyl)-N,N-diethyl-l-phenylcyclopropane carboxamide hydrochloride: (formula-la)
Toluene (6 ml) was added to a mixture of water (12 ml) and (lS,2R)-2- (aminomethyl)-N,N-diethyl-l-phenylcyclopropanecarboxamide (R)-2-acetyl mandelate (3 g) at 25-30°C. Cooled the reaction mixture to 0-5°C and sodium hydroxide solution was added to the reaction mixture at the same temperature. Raised the temperature of the reaction mixture to 25-30°C and stirred for 15 minutes at the same temperature. Both organic and aqueous layers were separated and aqueous layer was extracted thrice with toluene. Combined the organic layers and distilled off the solvent to get residue. To the obtained residue, ethanol (7.5 ml) and methyl tertiary butyl ether (15 ml) were added at 25-30°C. Ethanolic hydrochloric acid (1 ml) was added to the reaction mixture. Heated the reaction mixture to 50-55°C and stirred for 20 minutes at the same temperature. Slowly cooled the reaction mixture to 20-25°C and stirred for 1 hour at the same temperature. Filtered the precipitated solid, washed with methyl tertiary butyl ether and dried to get the title compound. Yield: 0.9 gms. Chiral purity By HPLC: 99.99%; Purity by HPLC: 99.93%.
Example-5:
Preparation of (lS,2R)-2-Oxo-l-phenyl-3-oxabicyclo{3.1.0}hexane (formula-4):
Potassium tertiary butoxide (16.2 g) was added to a pre-cooled solution of tetrahydrofuran (50 ml), phenyl acetonitrile (10 g) and R-(-)-epichlorohydrin at -30 to 20°C and stirred the reaction mixture for 2 hour at the same temperature. Water (30 ml) was added to the reaction mixture at -30 to -20°C. Distilled off the solvent completely from the reaction mixture. Sodium hydroxide (1.6 g) dissolved in water (60 ml) and dimethyl sulfoxide (50 ml) was added to the reaction mixture 25-30°C. Heated the reaction mixture to 80-85°C and stirred for 4 hours at the same temperature. After completion of the reaction, cooled the reaction mixture to 25-30°C and toluene was added. Both aqueous and organic layers were separated and toluene was added to aqueous layer. Adjusted the pH of the reaction mixture by using con. hydrochloric acid at 25-30°C and stirred for 4 hours at the same temperature. Both organic and aqueous layers were separated and aqueous layer was extracted with toluene. Combined organic layers were washed with sodium bicarbonate solution followed by sodium chloride solution. Dried the organic layer with sodium sulphate and distilled off the solvent completely to get the title compound.
Yield: 6 gms. Chiral purity: 84.66%. Example-6:
Purification of (lS,2R)-2-(aminomethyl)-N,N-diethyl-l-phenyl cyclopropane
carboxamide hydrochloride (Formula-la)
Ethanol (200 ml) and methyl tertiary butyl ether (425 ml) were added to (lS,2R)-2- (aminomethyl)-N,N-diethyl-l-phenylcyclopropanecarboxamide hydrochloride compound of formula-la (50 gm) at 25-30°C. Heated the reaction mixture to 50-55°C and stirred for 30 minutes at the same temperature. Cooled the reaction mixture to 20-25°C. Filtered the solid, washed with methyl tertiary butyl ether and dried to get the title compound.
Yield: 38 gm; Pthalimido impurity: Not detectable; (1R, 2S)-isomer impurity: 0.02%.
Purity by HPLC: 99.98%; Chiral purity By HPLC: 99.94%;
Particle Size Distribution: D(0.1) is 8.57 μπι; D(0.5) is 21.35 μηι; D(0.9) is 46.02 μπι; D(4,3) is 24.81.
The PXRD of compound of formula- la matches with the prior art crystalline Form- A of Levomilnacipran hydrochloride and is depicted in figure-3.
The DSC thermogram of compound of formula- la is depicted in figure-4.

Claims

We Claim:
1. A process for the preparation of (IS, 2R)-2-(aminomethyl)-N,N-diethyl-l- phenylcyclopropanecarboxamide compound of formula- 1 and its hydrochloride salt compound of formula- la, comprising of the following steps;
a) Reacting 2-phenyl acetonitrile compound of formula-2
Figure imgf000026_0001
Formula-2
with (R)-epichlorohydrin compound of formula-3
Figure imgf000026_0002
Formula-3
in presence of a suitable base in a suitable solvent provides cyano compound, which on hydrolysis in presence of a suitable base in a suitable solvent followed by treating with a suitable acid provides (lS,5R)-l-phenyl-3-oxabicyclo[3.1.0]hexan-2-one compound of formula-4,
Figure imgf000026_0003
Formula-4
b) reacting the compound of formula-4 in-situ with diethylamine in presence of suitable lewis acid in a suitable solvent provides (lS,2R)-N,N-diethyl-2-(hydroxymethyl)-l- phenylcyclopropanecarboxamide compound of formula-5,
Figure imgf000026_0004
Formula-5
c) reacting the compound of formula-5 in-situ with sulfonyl derivative compound of general formula- 8
O
II
R-S-X
II
o
Formula-8 Wherein, 'R' is Ci-C6 straight or branched chain alkyl; aryl or substituted aryl; and X = Halogen such as CI or Br;
in presence of a suitable bas of general formula-6,
Figure imgf000027_0001
Formula-6
Wherein, 'R' is Ci-C6 straight or branched chain alkyl; aryl or substituted aryl;
d) reacting the compound of general formula-6 in-situ with potassium phthalimide in a suitable solvent provides (lS,2R)-2-((l,3-dioxoisoindolin-2-yl)methyl)-N,N-diethyl- 1 -phenyl cyclopropanecarb rmula-7,
Figure imgf000027_0002
Formula-7
e) treating the compound of formula-7 in-situ with a suitable base provides (lS,2R)-2- (aminomethyl)-N,N-di ethyl- 1 -phenylcyclopropanecarboxamide compound of formula- 1,
Figure imgf000027_0003
Formula- 1
f) converting the compound of formula- 1 into its hydrochloride salt compound of formula- la by treating it in-situ with a suitable hydrochloric acid source in a suitable solvent.
2. Process according to claim- 1, wherein,
The suitable base used in step-a), step-c) & step-e) is selected from organic, inorganic base and organosilicon bases; The suitable acid used in step-a) is hydrochloric acid;
The suitable solvent used in step-a), b), d) & e) is selected from polar-aprotic solvents like dimethyl acetamide, dimethylformamide, dimethyl sulphoxide, acetonitrile; ether solvents like dimethyl ether, diethyl ether, methyl tert-butyl ether, 1 ,2-dimethoxy ethane, tetrahydrofuran, 1,4-dioxane; hydrocarbon solvents like toluene, xylene, hexane, heptane and cyclohexane; polar solvents such as water or mixtures thereof.
The suitable lewis acid used in step-b) is selected from aluminium chloride, aluminium
bromide, boron trifluoride, Iron chloride, Tin(IV) chloride, calcium chloride dihydrate, calcium chloride and zinc chloride; preferably aluminium chloride.
The suitable solvent used in step-f) is selected from ether solvents, alcohol solvents, ester
solvents or their mixtures.
The suitable "sulfonyl derivative" is selected from methanesulfonyl chloride, methanesulfonic acid, para-toluenesulfonyl chloride, para-toluenesulfonic acid, trifluoromethane sulfonyl chloride, trifluoromethane sulfonic acid, para bromobenzene sulfonyl chloride, para bromobenzene sulfonic acid, para nitrobenzenesulfonyl chloride and para nitrobenzenesulfonic acid.
The suitable hydrochloric acid source used in step-f) is selected from HC1 gas, aqueous HC1, dry HC1, ethylacetate-HCl, IPA-HC1, ethanol-HCl, methanol-HCl, preferably ethanol-HCl.
3. A process for the preparation of ( 1 S,2R)-2-(aminomethyl)-N,N-diethyl- 1 -phenylcyclo propanecarboxamide compound of formula- 1 and its hydrochloride salt compound of formula- la, comprising of the following steps;
a) Reacting 2-phenyl acetonitrile compound of formula-2 with (R)-epichlorohydrin compound of formula-3 in presence of sodium hexamethyldisilazide in tetrahydrofuran provides cyano compound, which on hydrolysis in presence of sodium hydroxide in dimethyl sulfoxide followed by treating with hydrochloric acid provides (lS,5R)-l-phenyl-3-oxabicyclo[3.1.0]hexan-2-one compound of formula-4, b) reacting the compound of formula-4 in-situ with diethylamine in presence of aluminium chloride in toluene provides (lS,2R)-N,N-diethyl-2-(hydroxymethyl)-l- phenyl cyclopropanecarboxamide compound of formula-5,
c) reacting the compound of formula-5 in-situ with methanesulfonyl chloride compound of formula-8a in presence of triethyl amine provides ((lR,2S)-2-(diethylcarbamoyl)- 2-phenylcyclopropyl)methyl methanesulfonate compound of formula-6a,
d) reacting the compound of formula-6 in-situ with potassium phthalimide in toluene provides (lS,2R)-2-((l,3-dioxoisoindolin-2-yl)methyl)-N,N-diethyl-l-phenylcyclo propanecarboxamide compound of formula-7,
e) treating the compound of formula-7 in-situ with methyl amine provides (lS,2R)-2- (aminomethyl)-N,N-diethyl- 1 -phenylcyclopropanecarboxamide compound of formula- 1,
f) converting the compound of formula- 1 into its hydrochloride salt compound of formula- la by treating it in-situ with ethanolic hydrochloric acid in a mixture of methyl tertiary butyl ether and ethanol provides (lS,2R)-2-(aminomethyl)-N,N- diethyl-1 -phenyl cyclopropane carboxamide hydrochloride compound of formula- la.
4. A process for the preparation of (lS,2R)-2-(aminomethyl)-N,N-diethyl-l-phenylcyclo propanecarboxamide compound of formula- 1 and its hydrochloride salt compound of formula- la, comprising of the following steps;
a) Resolving (±)- [ 1 R(S),2S(R)]-2-(aminomethyl)-N,N-diethyl- 1 -phenylcyclopropane carboxamide compound of formula-I
Figure imgf000029_0001
Formula-I
with (R)-(-)-0-acetyl mandelic acid in a suitable solvent provides (lS,2R)-2-
(aminomethyl)-N,N-diethyl- 1 -phenylcyclopropanecarboxamide (R)-2-acetyl mandelate salt compound of formula- lb,
b) neutralizing the compound of formula- lb with a suitable base in a suitable solvent provides compound of formula- 1,
c) converting the compound of formula- 1 into its hydrochloride salt compound of formula- la by treating it in-situ with a suitable hydrochloric acid source in a suitable solvent.
5. A process for the preparation of (lS,2R)-2-(aminomethyl)-N,N-diethyl-l -phenyl cyclopropane carboxamide compound of formula- 1 and its hydrochloride salt compound of formula- la comprising of the following steps:
a) Treating (±)-[lR(S),2S(R)]-2-(aminomethyl)-N,N-diethyl-l-phenylcyclopropane carboxamide compound of formula-I with (R)-(-)-0-Acetyl mandelic acid in a mixture of ethyl acetate and water provides (lS,2R)-2-(aminomethyl)-N,N-diethyl-l- phenylcyclopropanecarboxamide (R)-2-acetyl mandelate salt compound of formula- lb,
b) treating the compound of formula- lb with sodium hydroxide in a mixture of toluene and water provides compound of formula- 1,
c) converting the compound of formula- 1 into its hydrochloride salt compound of formula- la by treating it in-situ with ethanolic hydrochloric acid in a mixture of methyl tertiary butyl ether and ethanol provides (lS,2R)-2-(aminomethyl)-N,N- diethyl-1 -phenyl cyclopropane carboxamide hydrochloride compound of formula- la.
6. Crystalline form-M of (lS,2R)-2-(aminomethyl)-N,N-diethyl-l-phenylcyclopropane carboxamide (R)-2-acetyl mandelate salt compound of formula- lb, characterized by: a) Its powder X-ray diffractogram having peaks at 6.4, 7.8, 9.4, 10.3, 11.0, 12.9, 14.2, 14.6, 16.0, 17.4, 18.9, 19.5, 20.8, 21.0, 22.3, 23.4, 23.8, 24.9, 25.2, 26.2, 28.8, 29.5, 31.3, 31.8, and 33.5 ± 0.2 degrees of two-theta as illustrated in figure-1;
b) its DSC thermogram showing endotherm at 172.21 as illustrated in figure-2;
7. A one-pot process for the preparation of (IS, 2R)-2-(aminomethyl)-N,N-diethyl-l- phenylcyclopropanecarboxamide compound of formula- 1 and its hydrochloride salt compound of formula- la, comprising of the following steps;
a) Reacting 2rphenyl acetonitrile compound of formula-2 with (R)-epichlorohydrin compound of formula-3 in presence of .a suitable base in a suitable solvent provides cyano compound, which on hydrolysis in presence of a suitable base in a suitable solvent followed by treating with a suitable acid provides (lS,5R)-l-phenyl-3- oxabicyclo [3.1.0]hexan-2-one compound of formula-4,
b) reacting the compound of formula-4 in-situ with diethylamine in presence of a suitable lewis acid in a suitable solvent provides (lS,2R)-N,N-diethyl-2- (hydroxymethyl)-l-phenylcyclopropanecarboxamide compound of formula-5 * c) reacting the compound of formula-5 in-situ with potassium phthalimide in presence of triphenyl phosphine and 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ) in a suitable solvent provides (lS,2R)-2-((l,3-dioxoisoindolin-2-yl)methyl)-N,N-diethyl- 1 -phenyl cyclopropanecarboxamide compound of formula-7,
d) treating the compound of formula-7 in-situ with a suitable base provides (lS,2R)-2- (aminomethyl)-N,N-diethyl- 1 -phenylcyclopropanecarboxamide compound of formula- 1,
e) converting the compound of formula- 1 into its hydrochloride salt compound of formula- la by treating it in-situ with a suitable hydrochloric acid source in a suitable solvent.
8. A one-pot process for the preparation of (lS,2R)-2-(aminomethyl)-N,N-diethyl-l- phenylcyclopropane carboxamide compound of formula- 1 and its hydrochloride salt compound of formula- la, comprising of the following steps;
a) Reacting 2-phenyl acetonitrile compound of formula-2 with (R)-epichlorohydrin compound of formula-3 in presence of sodium hexamethyldisilazide in tetrahydrofuran provides cyano compound, which on hydrolysis in presence of sodium hydroxide in dimethyl sulfoxide followed by treating with a hydrochloric acid provides (lS,5R)-l-phenyl-3-oxabicyclo[3.1.0]hexan-2-one compound of formula-4,
b) reacting the compound of formula-4 in-situ with diethylamine in presence of aluminium chloride in toluene provides (lS,2R)-N,N-diethyl-2-(hydroxymethyl)-l- phenylcyclo propanecarboxamide compound of formula-5,
c) reacting the compound of formula-5 in-situ with potassium phthalimide in presence of triphenyl phosphine and 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ) in acetonitrile provides (lS,2R)-2-((l,3-dioxoisoindolin-2-yl)methyl)-N,N-diethyl-l- phenyl cyclopropanecarboxamide compound of formula-7,
d) treating the compound of formula-7 in-situ with methyl amine provides (lS,2R)-2- (aminomethyl)-N,N-diethyl- 1 -phenylcyclopropanecarboxamide compound of formula- 1,
e) converting the compound of formula- 1 to its hydrochloride salt compound of formula- la by treating it in-situ with ethanolic hydrochloric acid in a mixture of methyl tertiary butyl ether and ethanol.
9. A process for the preparation of (lS,5R)-l-phenyl-3-oxabicyclo[3.1.0]hexan-2-one compound of formula-4, comprising of reacting 2-phenyl acetonitrile compound of formula-2 with (R)-epichlorohydrin compound of formula-3 in the presence of a suitable base in a suitable solvent followed by hydrolyzing the obtained compound with a suitable base in presence or absence of a phase transfer catalyst, then treating it with a suitable acid to provide compound of formula-4, characterized in that the suitable base used for the condensation of compounds of formula-2 and formula-3 is selected from alkali metal hydroxides, alkali metal carbonates/ bicarbonates, alkali metal alkoxides, LiHMDS and NaHMDS.
10. (IS, 2R)-2-(aminomethyl)-N,N-diethyl-l -phenyl cyclopropane carboxamide (R)-2- acetyl mandelate having the structural formula:
Figure imgf000032_0001
11. Use of (lS,2R)-2-(aminomethyl)-N,N-diethyl-l-phenylcyclopropane carboxamide (R)-2-acetyl mandelate salt compound of formula-lb for the preparation of (IS, 2R)- 2-(aminomethyl)-N,N-diethyl-l -phenylcyclopropanecarboxamide compound of formula- 1 and its hydrochloride salt compound of formula- la.
12. Use of crystalline Form-M of (lS,2R)-2-(aminomethyl)-N,N-diethyl-l -phenyl cyclopropane carboxamide (R)-2-acetyl mandelate salt compound of formula- lb for the preparation of pure (I S, 2R)-2-(aminomethyl)-N,N-diethyl-l-phenylcyclopropane carboxamide compound of formula- 1 and its hydrochloride salt compound of formula- la.
13. Use of ((lR,2S)-2-(diethylcarbamoyl)-2-phenylcyclopropyl) methyl alkylsulfonate compound of general formula-6,
Figure imgf000033_0001
Formula-6
Wherein, 'R' is Ci-Ce straight or branched chain alkyl; aryl or substituted aryl;
in the preparation of (I S, 2R)-2-(aminomethyl)-N,N-diethyl-l-phenylcyclo propanecarboxamide compound of formula- 1 and its hydrochloride salt compound of formula- la.
14. Use of ((lR,2S)-2-(diethylcarbamoyl)-2-phenylcyclopropyl) methyl methanesulfonate compound of formula-6a,
Figure imgf000033_0002
Formula-6a
in the preparation of (IS, 2R)-2-(aminomethyl)-N,N-diethyl-l-phenylcyclo propanecarboxamide compound of formula- 1 and its hydrochloride salt compound of formula- la.
15. The process according to any of the preceding claims, wherein the (IS, 2R)-2- (aminomethyl)-N,N-diethyl-l-phenylcyclopropane carboxamide hydrochloride compound of formula- la having purity greater than 99.8 % by HPLC.
16. The process according to any of the preceding claims, wherein the (IS, 2R)-2- (aminomethyl)-N,N-diethyl- 1 -phenylcyclopropane carboxamide hydrochloride compound of formula-la having chiral purity > 99.5%, preferably > 99.75 %, more preferably > 99.9 % by HPLC. -
17. (IS, 2R)-2-(aminomethyl)-N,N-diethyl- 1 -phenylcyclopropane carboxamide
hydrochloride having particle size distribution of D90 less than or equal to 200 μπι.
18. (IS, 2R)-2-(aminomethyl)-N,N-diethyl-l -phenylcyclopropane carboxamide
hydrochloride having particle size distribution of D90 less than or equal to 100 μπι, preferably less than or equal to 60 μπι.
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FR2508035A1 (en) * 1981-06-23 1982-12-24 Fabre Sa Pierre ARYL-1-AMINOMETHYL-2 CYCLOPROPANES CARBOXAMIDE (Z) DERIVATIVES, THEIR PREPARATION AND THEIR USE AS MEDICAMENTS USEFUL IN THE TREATMENT OF CENTRAL NERVOUS SYSTEM DISORDERS
FR2640972B1 (en) * 1988-12-28 1991-04-19 Pf Medicament
JP4712320B2 (en) * 2004-06-16 2011-06-29 住友化学株式会社 Process for producing 2-oxo-1-phenyl-3-oxabicyclo [3.1.0] hexane
FR2941454B1 (en) * 2009-01-29 2011-04-01 Pf Medicament PROCESS FOR THE SYNTHESIS OF (1S, 2R) -MILNACIPRAN
WO2011158249A1 (en) * 2010-06-16 2011-12-22 Glenmark Generics Limited Process for preparation of milnacipran intermediate and its use in preparation of pure milnacipran
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CN108948247A (en) * 2017-05-27 2018-12-07 北京化工大学 A kind of polybutadiene of low molecular weight epoxy base sealing end, preparation method and application
CN108948247B (en) * 2017-05-27 2021-12-21 北京化工大学 Low-molecular-weight epoxy-terminated polybutadiene, and preparation method and application thereof

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