CLIAMS:1. A process for the preparation of (1R, 2S)-2-(aminomethyl)-N,N-diethyl-1-phenylcyclopropanecarboxamide compound of formula-II or its salt thereof, has purity more than 99 %, as measured by HPLC,

Formula-II
the process comprises the steps of;
a) reacting phenylacetonitrile with S-epichlohydrin in presence of sodium amide in solvent and obtaining (1R, 2S)-2-(hydroxymethyl)-1-phenylcyclopropanecarbonitrile of formula III,

Formula III
b) converting (1R,2S)-2-(hydroxymethyl)-1-phenylcyclopropane carbonitrile to (1R,5S)-1-phenyl-3-oxa-bicyclo[3.1.0]hexan-2-one of formula IV in presence of base,

Formula IV
c) contacting diethylamine and 1.17- 1.2 mole of aluminium chloride to 1.0 mole of (1R,5S)-1-phenyl-3-oxa-bicyclo[3.1.0]hexan-2-one and obtaining (1R,2S)-N,N-diethyl-2-(hydroxyl methyl)-1-phenylcyclopropanecarboxamide formula V,

Formula V

d) treating (1R,2S)-N,N-diethyl-2-(hydroxymethyl)-1-phenyl cyclopropane carboxamide with suitable chlorinating agent and obtaining (1R,2S)-2-(chloromethyl)-N,N-diethyl-1-phenyl cyclopropane carboxamide of formula VI

Formula VI
e) condensing 1 mole of (1R,2S)-2-(chloromethyl)-N,N-diethyl-1-phenylcyclopropane carboxamide with 1.4-1.8 mole of potassium phthalimide in a solvent at the elevated temperature and obtaining (1S,2R)-N,N-diethyl-2-((1,3-dioxoisoindolin-2-yl)methyl)-1-phenylcyclo propane carboxamide of formula VII ,

Formula VII
as an oil,
f) reacting (1R,2S)-N,N-diethyl-2-((1,3-dioxoisoindolin-2-yl)methyl)-1-phenylcyclo propanecarboxamide with ethanolamine in solvent and obtaining Dextromilnacipran base
g) converting Dextromilnacipran base to its salts thereof.

2. The process of claim 1, wherein in step e) elevated temperature is 80C to 90C.
3. The process of claim 1, Dextromilnacipran or its salt thereof has a chiral purity of greater than 95 % by HPLC.

4. The process of claim 1, wherein intermediate compound of formula-V has a chiral purity more than 98 % area by HPLC.

5. The process of claim 1, wherein intermediate compound of formula-VII has a chiral purity more than 98 % area by HPLC.

6. The process of claim 1, wherein solvent is selected from group comprises one or more of toluene, n hexane, benzene, heptane, water and mixtures thereof.

7. The process of claim 5, wherein solvent is toluene.

8. The process of claim 1, wherein chlorinating agent is selected from the group comprising of thionyl chloride (SOCl2), sulfuryl chloride (SO2Cl2), phosphorous oxychloride (POCl3), phosphorous trichloride (PCl5) and phosphorous pentachloride (PCl5).

9. The process of claim 7, wherein chlorinating agent is thionyl chloride (SOCl2).

10. The process of claim 1, wherein Dextromilnacipran or its salt thereof used as reference standards in a qualitative analysis of Levomilnacipran.
,TagSPECI:Field of Invention

The present invention relates to a process for the preparation of Dextromilnacipran or its salt thereof, which leads to develop industrially feasible simple and cost effective manufacturing process of Dextromilnacipran or its salt thereof with the higher purity and yield. In particular, the invention further provides the use of a Dextromilnacipran or its salt thereof as reference markers and/or reference standards during the synthesis of Levomilnacipran or its salt thereof.

Background of the invention

Milnacipran is a serotonin–norepinephrine reuptake inhibitor (SNRI) used in the clinical treatment of fibromyalgia. It is not approved for the clinical treatment of major depressive disorder in the USA. Milnacipran is chemically known as (1R*,2S*)-2-(aminomethyl)-N,N-diethyl-1-phenylcyclopropanecarboxamide.

Levomilnacipran is the levo-enantiomer of milnacipran, and has similar effects and pharmacology, acting as a serotonin-norepinephrine reuptake inhibitor (SNRI). Levomilnacipran, is chemically known as (1S, 2R)-2-(aminomethyl)-N,N-diethyl-1-phenylcyclopropanecarboxamide and is structurally represented by formula (I)

Formula I

US 4,478,836 describe milnacipran or its salt thereof. The preparation of Levomilnacipran and its intermediate are described in many patents, e.g. US 7,309,799, US 8,604,241, US 5,034,541, US 7,943,785and WO 2013168002.

Dextromilnacipran is the dextro-enantiomer of milnacipran. Dextromilnacipran or its salt thereof is chemically known as (1R, 2S)-2-(aminomethyl)-N,N-diethyl-1-phenylcyclopropane carboxamide and is structurally represented by formula (II)

Formula II
Thus, an object of the present invention is to provide simple, cost effective and industrially feasible process for manufacture of Dextromilnacipran or its salt thereof. Inventors of the present invention found that Dextromilnacipran or salts thereof prepared according to process of present invention provides Dextromilnacipran or its salt thereof in enhanced yield as well as purity. The another object of the present invention is to provide the use of the Dextromilnacipran or its salt thereof as reference markers and/or reference standards to analyse their content in the final product during the synthesis of Levomilnacipran or its salt thereof.

Summary of the Invention

The present invention provides a process for the preparation of (1R, 2S)-2-(aminomethyl)-N,N-diethyl-1-phenylcyclopropanecarboxamide, has purity more than 99 %, as measured by HPLC,

Formula-II
the process includes the steps of;
a) reacting phenylacetonitrile with S-epichlohydrin in presence of sodium amide in solvent to obtain (1R, 2S)-2-(hydroxymethyl)-1-phenylcyclopropanecarbonitrile,
b) converting step a) product to (1R,5S)-1-phenyl-3-oxa-bicyclo[3.1.0]hexan-2-one in presence of base,
c) contacting diethylamine and 1.17-1.2 mole of aluminium chloride with 1 mole of step b), to obtain (1R,2S)-N,N-diethyl-2-(hydroxymethyl)-1-phenylcyclopropanecarboxamide,
d) treating step c) product with suitable chlorinating agent to obtain (1R,2S)-2-(chloromethyl)-N,N-diethyl-1-phenyl cyclopropane carboxamide,
e) condensing 1 Mole of step d) product with 1.4-1.8 mole of potassium phthalimide in a solvent at elevated temperature to obtain crystalline (1S,2R)-N,N-diethyl-2-((1,3-dioxoisoindolin-2-yl)methyl)-1-phenylcyclopropanecarboxamide,
f) reacting step e) with ethanolamine in solvent to obtain Dextromilnacipran base,
g) converting Dextromilnacipran base to its salts thereof.

The present invention provides a Dextromilnacipran or its salt thereof has a chiral purity of greater than 95 % by HPLC.

The present invention also provides (1R,2S)-N,N-diethyl-2-(hydroxymethyl)-1-phenylcyclo propanecarboxamide or its salt thereof and (1S,2R)-N,N-diethyl-2- ((1,3-dioxoisoindolin-2-yl)methyl)-1-phenylcyclopropanecarboxamide or its salt thereof have chiral purity more than 98 % area by HPLC.

The present invention is directed to the use of Dextromilnacipran or its salt thereof, as reference standards in a qualitative analysis of Levomilnacipran or its salt thereof.

Description of the Invention

As used herein, the term “reference standard” refers to a compound that may be used both for quantitative and qualitative analysis of an active pharmaceutical ingredient. A reference marker” is used only for qualitative analysis, while a reference standard may be used for quantitative or qualitative analysis, or both. Hence, a reference marker is a subset of a reference standard, and is included within the definition of a reference standard.

In one aspect of the present invention provides a process for the preparation of Dextromilnacipran compound of formula-II or its salt thereof, has purity more than 99 %, as measured by HPLC,

Formula-II
the process includes the steps of;
a) reacting phenylacetonitrile with S-epichlohydrin in presence of sodium amide in solvent to obtain (1R, 2S)-2-(hydroxymethyl)-1-phenylcyclopropanecarbonitrile of formula III,

Formula III
b) converting (1R,2S)-2-(hydroxymethyl)-1-phenylcyclopropane carbonitrile to (1R,5S)-1-phenyl-3-oxa-bicyclo[3.1.0]hexan-2-one of formula IV in presence of base,

Formula IV
c) contacting diethylamine and 1.17-1.2 mole aluminium chloride with 1 mole of (1R,5S)-1-phenyl-3-oxa-bicyclo[3.1.0]hexan-2-one to obtain (1R,2S)-N,N-diethyl-2-(hydroxymethyl)-1-phenylcyclopropanecarboxamide formula V,

Formula V
d) treating (1R,2S)-N,N-diethyl-2-(hydroxymethyl)-1-phenyl cyclopropane carboxamide with suitable chlorinating agent to obtain (1R,2S)-2-(chloromethyl)-N,N-diethyl-1-phenyl cyclopropane carboxamide of formula VI,

Formula VI
e) condensing 1 mole of (1R,2S)-2-(chloromethyl)-N,N-diethyl-1-phenylcyclopropane carboxamide with 1.4-1.8 mole of potassium phthalimide in a solvent at the elevated temperature to obtain (1S,2R)-N,N-diethyl-2-((1,3-dioxoisoindolin-2-yl)methyl)-1-phenylcyclopropanecarboxamide of formula VII

Formula VII
f) reacting (1R,2S)-N,N-diethyl-2-((1,3-dioxoisoindolin-2-yl)methyl)-1-phenylcyclo propanecarboxamide with ethanolamine in solvent to obtain Dextromilnacipran base
g) converting Dextromilnacipran base to its salts thereof

The step a) of the present invention involves drop wise addition of phenylacetonitrile to the solution of sodium amide in solvent at the temperature range of between 10°C to 15°C and stirred for 1 hour. The reaction mixture is cooled to 10°C followed by drop wise addition of S-epichlorohydrin and stirred at the room temperature for 4 hour. After completion of reaction, the reaction mixture is quenched with water and organic phase is washed with water. The organic phase is distilled off to get (1R, 2S)-2-(hydroxymethyl)-1-phenylcyclopropanecarbonitrile.

The step b) of the present invention involves the addition of 30% of sodium hydroxide solution to (1R, 2S)-2-(hydroxymethyl)-1-phenylcyclopropanecarbonitrile at the elevated temperature range of between of 90°C to 100°C and stirred for 6 hours. After completion of reaction, the reaction mixture is extracted with a solvent followed by acidification of the aqueous phase with hydrochloric acid solution pH adjusted to pH 1-2. The reaction mixture is again stirred at temperature range of between 60°C to 70°C for 4 hours. The reaction mixture is further quenched with sodium carbonate and extracted with a solvent. The organic phase is distilled off to get (1R,5S)-1-phenyl-3-oxa-bicyclo[3.1.0]hexan-2-one which is further purified with column chromatography to get (1R,5S)-1-phenyl-3-oxa-bicyclo[3.1.0]hexan-2-one as orange crystals.

The step c) of the present invention involves the drop wise addition of diethylamine to the solution of AlCl3 in a solvent, under stirring at the temperature range of between of 15°C to 25°C for 15 minutes. Further, the drop wise addition of (1R,5S)-1-phenyl-3-oxa-bicyclo[3.1.0]hexan-2-one in a solvent to the above reaction mixture at the room temperature and stirred for 4 hours, wherein the molar ratio of (1R,5S)-1-phenyl-3-oxa-bicyclo[3.1.0]hexan-2-one and AlCl3 is about 1 : 1.17-1.2. After completion of the reaction, the reaction mixture is quenched with water. The organic layer is distilled off to obtain (1R,2S)-N,N-diethyl-2-(hydroxymethyl)-1-phenylcyclopropane carboxamide.

The step d) of the present invention involves the treatment of chlorinating agent to (1R,2S)-N,N-diethyl-2-(hydroxymethyl)-1-phenylcyclopropane carboxamide under inert atmosphere at room temperature for 3 hours. After completion of the reaction, the excess of chlorinating agent is recovered under vacuum followed by addition of a solvent. The organic phase is concentrated under vacuum to get (1R,2S)-2-(chloromethyl)-N,N-diethyl-1-phenylcyclopropane carboxamide as an oil, wherein chlorinating agent is selected from the group comprising of thionyl chloride (SOCl2), sulfuryl chloride (SO2Cl2), phosphorous oxychloride (POCl3), phosphorous trichloride (PCl5) and phosphorous pentachloride (PCl5).

The step e) of the present invention involves reaction of (1R,2S)-2-(chloromethyl)-N,N-diethyl-1-phenylcyclopropane carboxamide with potassium phthalimide in a solvent at temperature range of between 80°C to 90°C for 4 hours. The reaction mixture is quenched with water and the organic phase is distilled off to get (1S,2R)-N,N-diethyl-2-((1,3-dioxoisoindolin-2-yl)methyl)-1-phenylcyclopropanecarbox amide as oil, which is further recrystallized with n-hexane to get (1S,2R)-N,N-diethyl-2-((1,3-dioxoisoindolin-2-yl)methyl)-1-phenylcyclopropanecarboxamide, wherein, (1R,2S)-2-(chloromethyl)-N,N-diethyl-1-phenylcyclopropane carboxamide and potassium phthalimide are in the molar ratio of about 1:1.4-1.8.

The step f) of the present invention involves the reaction of (1S,2R)-N,N-diethyl-2-((1,3-dioxoisoindolin-2-yl)methyl)-1-phenylcyclopropanecarboxamide with ethanolamine in solvent at elevated temperature range of between 80°C to 90°C for 4 hours. The reaction mixture is further quenched with 20% brine solution followed by acidification of the organic phase with hydrochloric acid while stirring for 30 minutes and further extraction with water. The organic phase is removed followed by adjustment of pH between 10 to 12 by 20% sodium hydroxide solution and extraction with solvent. The organic phase is distilled off to obtain Dextromilnacipran free base, wherein brine solution is statured solution of sodium chloride.

The step g) of the present invention involves the drop wise addition of hydrochloric acid (12-16% w/v) in isopropanol to the stirred solution of Dextromilnacipran free base and isopropylacetate solution at temperature 25°C. The reaction mixture is stirred at temperature 10°C for 4 hours to obtain Dextromilnacipran hydrochloride which is filtered and washed with isopropyl acetate.

Solvent is selected from group comprises one or more of toluene, n hexane, benzene, heptane, water and mixtures thereof.

In another aspect of the present invention provides a Dextromilnacipran or its salt thereof, has chiral purity more than 95%, when determined by HPLC.

In another aspect of the present invention provides a (1R,2S)-N,N-diethyl-2-(hydroxymethyl)-1-phenylcyclo propanecarboxamide has a chiral purity more than 98 % area by HPLC.

In another aspect of the present invention provides a (1S,2R)-N,N-diethyl-2-((1,3-dioxoisoindolin-2-yl)methyl)-1-phenylcyclopropanecarboxamide has a chiral purity more than 98 % area by HPLC.

Yet in one another aspect of the present invention provides the use of Dextromilnacipran or its salt thereof, as reference standards in a qualitative analysis of Levomilnacipran.

The process of Dextromilnacipran or its salt thereof is schematically presented in the following scheme 1:

Scheme 1

The present invention is further illustrated by the following example, which does not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present application.

Examples

Example-1: Preparation of (1R, 2S)-2-(hydroxymethyl)-1-phenylcyclopropane carbonitrile

Charged drop wise phenylacetonitrile (170 g, 1.45 mol) to a stirred suspension of sodium amide (56 g, 1.43 mol) and toluene (800 mL) at temperature 10 – 15oC. The reaction mixture was stirred for 1 hour at temperature 10–20oC. The reaction mixture cooled at temperature 10oC followed by drop wise addition of S- epichlorohydrin (54 g, 0.583 mol) to the reaction mixture. The reaction mixture was further stirred for 4 hour at room temperature. After completion of reaction the reaction was quenched with water (500 mL) and the organic phase was washed with water (500 mL) and recovered toluene was concentrated under vacuum to get 196 g of title compound.
Mass (m/z): 174.1 (M+)

Example-2: Preparation of (1R, 5S)-1-phenyl-3-oxa-bicyclo[3.1.0]hexan-2-one

Charged 30 % of aqueous sodium hydroxide solution (200 mL) to a stirred solution of (1R, 2S)-2-(hydroxymethyl)-1-phenylcyclopropane carbonitrile (196 g) at temperature 90–100oC and stirred for 6 h. After completion of the reaction, the reaction mixture was washed with toluene (2 x 400 mL) and the aqueous phase was recovered after adding toluene (500 mL) followed by acidification by a hydrochloric acid solution adjusting pH to 1 – 2. The reaction medium was then stirred at temperature 60–70oC for 4 h. The reaction was quenched with sodium bicarbonate solution (900 mL) and the organic phase was washed with water (500 mL) and recovered toluene was concentrated under vacuum to get 72 g of title compound as oil. The oily residue was purified by column chromatography (silica gel; ethyl acetate/hexane, 1:3) to give title compound as orange crystals.
Mass (m/z): 175.1 (M+)
HPLC purity: 99.86 %
Chiral purity: 98.037 %
SOR (c 1.42, MeOH): +78.073o
Elemental Analysis: C, 75.84; H, 5.79. Found: C, 76.23; H, 5.853.

Example-3: Preparation of (1R, 2S)-N,N-diethyl-2-(hydroxymethyl)-1-phenylcyclo propane carboxamide

Charged aluminium chloride (26.7 g, 0.20 mol) in toluene (450 mL), followed by drop wise addition of diethylamine (30.2 g, 0.41 mol) at temperature 15oC to 25oC. The reaction mixture was stirred for 15 minute, followed by drop wise addition of solution of (1R, 5S)-1-phenyl-3-oxa-bicyclo[3.1.0]hexan-2-one (30 g, 0.17 mol) in toluene (150 mL). The reaction mixture was again stirred for 4 hours at 25C to 35C. After completion of reaction, the reaction mixture was quenched with water (300 mL). The organic phase was washed with water (150 mL) and recovered organic phase was concentrated under vacuum to get 44 g of title compound as oil.
Mass (m/z): 248.2 (M+)
Yield: 1.46 % w/w

Example-4: Preparation of (1R, 2S)-2-(chloromethyl)-N,N-diethyl-1-phenylcyclo propanecarboxamide

(1R, 2S)-N,N-diethyl-2-(hydroxymethyl)-1-phenylcyclopropanecarboxamide (43 g, 0.17 mol) was treated with thionyl chloride (20 g) under inert atmosphere. The reaction mixture was stirred at room temperature for 3 hours. After completion of reaction, the excess of thionyl chloride was recovered under vacuum and was further concentrated after adding toluene to get 43 g of title compound as oil.
Mass (m/z): 266.2 (M+)

Example-5: Preparation of (1R,2S)-N,N-diethyl-2-((1,3-dioxoisoindolin-2-yl)methyl)-
1-phenylcyclopropanecarboxamide

Charged potassium phthalimide (48.2 g, 0.26 mol) to a stirred solution of (1R,2S)-2-(chloromethyl)-N,N-diethyl-1-phenylcyclopropanecarboxamide (42 g, 0.15 mol) in toluene (250 mL) and stirred at temperature 80 – 90oC for 4 hours. The reaction mixture was quenched with water (210mL). The organic phase was washed with water (84 mL) and recovered Toluene was concentrated under vacuum. The resultant crude oil was crystallized from n-hexane (84 mL) to get 46.8 g title compound.
Mass (m/z): 377.3 (M+)
Yield: 1.114 % w/w

Example-6: Preparation of Dextromilnacipran Free Base

Charged ethanolamine (58.6 g) to a solution of (1R,2S)-N,N-diethyl-2-((1,3-dioxoisoindolin-2-yl)methyl)-1-phenylcyclopropanecarboxamide (46 g, 0.12 mol) in toluene (365 mL) and stirred at temperature 80–90oC for 4 hours. The reaction mixture was quenched with 20 % brine solution (135 mL). The organic phase was acidified with concentrated HCl and again stirred for 30 min. After layer separation, the acid organic phase was extracted with water and organic phase was then removed. The aqueous phases was further extracted with toluene (225 & 90 mL) after adjusting pH to 10-12 with an aqueous 20 % sodium hydroxide solution. The organic phase was washed with water (45 mL) and toluene was concentrated under vacuum to get 19.5 g of Dextromilnacipran free base as oil and used in next stage without further purification.

Example-7: Preparation of Dextromilnacipran Hydrochloride

Charged Dextromilnacipran free base (19 g, 0.077 mol) and isopropylacetate (120 mL) at temperature 25oC to 35C, followed by drop wise hydrochloric acid solution (20 mL, 12 – 16 % w/v) in isopropanol. The reaction mixture was stirred at temperature 10oC to 15C for 4 hours. The solid suspension was filtered, washed with isopropyl acetate (100 mL) to get 18 g of title compound.
Mass (m/z): 247.3 (M+)
HPLC purity: 99.96 %
SOR (c 0.95, CHCl3): – 85.18o
1H NMR, ppm (DMSO-d6): 0.74 – 0.78 (3H, t, CH3), 1.03 – 1.06 (3H, t, CH3), 1.37 – 1.40 (1H, t, CH), 1.49 – 1.53 (1H, m, CH), 1.69 – 1.72 (1H, m, CH), 2.77 – 2.82 (1H, m, CH), 2.88 – 2.93 (1H, m, CH), 3.18 – 3.22 (2H, m, NCH2), 3.37 – 3.43 (2H, m, NCH2), 7.23 – 7.37 (5H, m, 5xArH), 8.05 (2H, s, NH2, D2O exchangeable ).
13C NMR, ppm (DMSO-d6): 12.70, 13.16, 18.97, 24.96, 34.63, 39.31, 41.40, 41.80, 126.13, 127.18, 129.18, 140.30, 169.50.
Elemental Analysis: C, 63.70; H, 8.20; N, 9.91. Found: C, 64.10; H, 8.32; N, 9.90.
Chiral purity: 99.70 %