WO2019097539A1 - Improved process for the preparation of levomilnacipran - Google Patents
Improved process for the preparation of levomilnacipran Download PDFInfo
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- WO2019097539A1 WO2019097539A1 PCT/IN2018/050717 IN2018050717W WO2019097539A1 WO 2019097539 A1 WO2019097539 A1 WO 2019097539A1 IN 2018050717 W IN2018050717 W IN 2018050717W WO 2019097539 A1 WO2019097539 A1 WO 2019097539A1
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- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
Definitions
- the present invention relates to cost-effective, industrially efficient and safe process for synthesis of levomilnacipran that is devoid of l-phenyl-l- diethylaminocarbonyl-2- chloromethylcyclopropane intermediate.
- Levo milnacipran in its racemic form was first disclosed in US 4,478,836.
- Levo milnacipran is chemically known as (lS,2R)-l -phenyl- 1 -Diethyl carbamoyl-2- amino methyl cyclopropane and structurally depicted as formula I.
- Levo milnacipran is useful in the management of depression.
- CN103694162B discloses the use of Chloromethylene dimethyl ammonium chloride as the chlorinating agent.
- WO 2014/203277 discloses the conversion of the alcohol ((lS,2R)-N,N-diethyl-2- (hydroxymethyl)-l-phenylcyclopropanecarboxamide) to its sulfonyloxy derivatives which is then reacted with Potassium phthalamide followed by treatment with a base to obtain the compound of formula I.
- US 2014/0343322 discloses one-pot process for preparing levo milnacipran which comprises; reacting (lS,2R)-N,N-diethyl-2-(hydroxymethyl)-l- phenylcyclopropanecarboxamide successively with the following reactants 1) triethyl orthoformate and methanesulfonic acid or triethylamine and methanesulfonyl chloride, 2) a phthalimidating agent, 3) aqueous EfNH2, wherein the reaction is carried out in toluene.
- the process is shown in scheme 2 below.
- the objective of the invention is to eliminate the reliance on the use of chloro derivative by converting amino alcohol to sulphonyloxy derivative; converting the sulphonyloxy derivative to the corresponding azide by employing aqueous sodium azide.
- Another objective of the invention is to reduce the azide to Levomilnacipran in a single solvent to enable recovery and re-use of the solvent thereby improving process economics.
- the present provides process for preparation of Levomilnacipran, which process comprises;
- the present invention provides an improved process for preparation of Levomilnacipran that will eliminate the reliance on the chloro derivative, which process comprises;
- AlCl 3 used for the preparation of 1 S,2R)-N,N-diethyl-2- (hydroxymethyl)-l-phenylcyclopropanecarboxamide in step b) is in the range of 1.8-2.0 equivalents based on the cis-(+)-l-phenyl-3-oxabicyclo[3. l.0]hexan-2-one.
- the preferred sulfonyl chloride as used in step c) is Methanesulfonyl chloride. The sulfonation reaction is conducted at a temperature of 60-65°C.
- the sodium azide used in the preparation of l-Phenyl-l- diethylaminocarbonyl-2-azidomethylcyclo propane is as an aqueous solution and the quantity of water present in aqueous sodium azide would be in the range of 2-5 ml/gm of sodium azide, wherein, the preferred quantity is 2 ml water per gm of sodium azide.
- the reaction is carried out optionally in presence of a phase transfer catalyst.
- One preferred phase transfer catalyst is Tetra butyl ammonium bromide.
- the reaction is conducted at a temperature range of 50-60°C.
- l-Phenyl-l-diethylaminocarbonyl-2-azidomethylcyclo propane is reduced in presence of Zinc/ Ammonium formate to obtain levoMilnacipran.
- the solvent used in the reduction of l-Phenyl-l-diethylaminocarbonyl-2- azidomethylcyclo propane is an alcoholic solvent selected from the group consisting of Methanol, Ethanol, Isopropanol and Butanol.
- the preferred solvent for conducting the reduction reaction is Methanol.
- the resultant pure compound was added to the Flask along with 282 ml of Isopropyl alcohol at room temperature; slowly temperature was raised to 70-75°C and stirred for 1 hr. Then slowly cooled to room temperature and stirred 1 hr and then again cooled to 0-5°C. Stirred for 2 hrs and washed with chilled Isopropyl alcohol.
- the resultant pure compound was added to the Reactor along with Isopropyl alcohol (150 lit) at room temperature; slowly temperature was raised to 70-75°C and stirred for 1 hr. Then slowly cooled to room temperature and stirred 1 hr and then again cooled to 0-5°C. Stirred for 2 hrs and washed with chilled Isopropyl alcohol.
- Aluminium chloride 140 gm
- Toluene 800 ml
- cis-( ⁇ )-l-Phenyl-3-oxabicyclo[3.l.0]hexan-2-one 100gm
- Diethylamine 150 gm
- the temperature of the reaction mass was raised to room temperature and stirred for 1 hour.
- the reaction mass was quenched in to ice cooled water (700 ml).
- the organic layer was collected and washed with water and hydrochloric acid. This was directly taken as such for the next stage.
- Triethylamine (145 gm) was added to the above toluene layer at room temperature. The reaction mass was heated to 60-65°C, stirred for 30 min followed by the slow addition of Methane sulfonyl chloride (130 gm), and stirred for 3 hours. After completion of the reaction, water (600 ml) was added. The organic layer was separated and washed with aqueous Sodium bicarbonate and water then dried with Sodium sulphate and distilled under reduced pressure.
- Aluminium chloride 140 gm
- Toluene 800 ml
- cis-( ⁇ )-l-Phenyl-3- oxabicyclo[3.l.0]hexan-2-one 100 gm
- Diethylamine 145 gm
- the temperature of the reaction mass was raised to room temperature and stirred for 1 hour.
- the reaction mass was quenched in to ice cooled water (700 ml). The organic layer was collected and washed with water and hydrochloric acid. This was directly taken as such for the next stage.
- Triethylamine (145 gm) was added to the above toluene layer at room temperature.
- the reaction mass was heated to 60-65°C, stirred for 30 min followed by the slow addition of Methane sulfonyl chloride (130 gm), and stirred for 3 hours.
- water 600 ml was added.
- the organic layer was separated and washed with aqueous Sodium bicarbonate and water then dried with Sodium sulphate and Toluene layer was directly taken as such for next stage.
- Tetrabutylamonium bromide was added to above toluene layer at room temperature followed by addition of sodium azide aqueous solution (54 gms sodium azide dissolved in 110 ml of Water) at room temperature.
- the reaction mass was heated to 50-60°C and stirred for 1-2 hours. After completion of the reaction, the reaction mass was quenched into water (800 ml). The layers were separated and the aqueous layer was extracted with toluene (200 ml), Total organic layer was washed with water. The resultant organic layer was distilled out completely under vacuum to get the titled compound.
- Aqueous layer was washed with toluene (200x2). Aqueous layer was separated and pH was adjusted with 25% sodium hydroxide solution up to 12-12.5 below l0°C and the product was extracted with Diehl oromethane(300x2), The organic layer was separated and dried with sodium sulphate and distilled under reduced pressure. To the residual mass ethyl acetate, IPA.HC1 were added and stirred for 30 minutes at room temperature. The reaction mass was cooled to l0-l5°C, maintained for 1 hour 30 minutes then solid was separated by filtration and dried at 50-60°C for 4 hours to obtain Milnacipran hydrochloride.
- Aqueous layer was separated and pH was adjusted with 25% sodium hydroxide solution up to 12-12.5 below l0°C and the product was extracted with Diehl oromethane (150 ml X 2 times), The organic layer was separated and dried with sodium sulphate and distilled under reduced pressure. To the residual mass ethyl acetate, IPA.HC1 were added and stirred for 30 minutes at room temperature. The reaction mass was cooled to l0-l5°C, maintained for 1 hour 30 minutes then solid was separated by filtration and dried at 50-60°C for 4 hours to obtain Milnacipran hydrochloride.
- Aqueous layer was separated and pH was adjusted with 25% sodium hydroxide solution up to 12-12.5 below l0°C and the product was extracted with Diehl or omethane (150 ml X 2 times), The organic layer was separated and dried with sodium sulphate and distilled under reduced pressure. To the residual mass ethyl acetate, IPA.HC1 were added and stirred for 30 minutes at room temperature. The reaction mass was cooled to l0-l5°C, maintained for 1 hour 30 minutes then solid was separated by filtration and dried at 50-60°C for 4 hours to obtain Milnacipran hydrochloride.
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Abstract
The present invention discloses cost-effective, industrially efficient and safe process synthesis of levomilnacipran that is devoid of 1-phenyl-1- diethylaminocarbonyl-2- chloromethylcyclopropane.
Description
IMPROVED PROCESS FOR THE PREPARATION OF
LEVOMILNACIPRAN
Technical Field:
The present invention relates to cost-effective, industrially efficient and safe process for synthesis of levomilnacipran that is devoid of l-phenyl-l- diethylaminocarbonyl-2- chloromethylcyclopropane intermediate.
Back ground and prior art:
Milnacipran in its racemic form was first disclosed in US 4,478,836. Levo milnacipran is chemically known as (lS,2R)-l -phenyl- 1 -Diethyl carbamoyl-2- amino methyl cyclopropane and structurally depicted as formula I. Levo milnacipran is useful in the management of depression.
The enriched isomer was disclosed in J. chromatography 1985, 318, 398-403.
Enantioselective synthesis using (R) epichlorohydrin was developed & disclosed in several journals (Tet Lett 1996, 37, 641-644 & Chinese Journal of pharmaceuticals 2004, 35, 259-260.
CN103694162B discloses the use of Chloromethylene dimethyl ammonium chloride as the chlorinating agent.
W02014/009767 describes an improved process starting with l-phenyl-3 oxabicyclo [3.1.0] hexan -2 one. The process consists of the steps as shown in scheme-I.
Scheme-1:
WO 2014/203277 discloses the conversion of the alcohol ((lS,2R)-N,N-diethyl-2- (hydroxymethyl)-l-phenylcyclopropanecarboxamide) to its sulfonyloxy derivatives which is then reacted with Potassium phthalamide followed by treatment with a base to obtain the compound of formula I.
US 2014/0343322 discloses one-pot process for preparing levo milnacipran which comprises; reacting (lS,2R)-N,N-diethyl-2-(hydroxymethyl)-l- phenylcyclopropanecarboxamide successively with the following reactants 1) triethyl orthoformate and methanesulfonic acid or triethylamine and methanesulfonyl chloride, 2) a phthalimidating agent, 3) aqueous EfNH2, wherein the reaction is carried out in toluene. The process is shown in scheme 2 below.
Scheme 2
, .
■
¾
'
F onviiiia s
Indian patent application 4226/MUM/2014 discloses another process which is shown in Scheme-3.
SCHEME-3:
A 4-
A0
c
The major drawback of the prior art processes lies in placing reliance on the use of l-phenyl-l-diethylaminocarbonyl-2- chloromethylcyclopropane, herein after referred as chloro derivative as the substrate for the reaction with sodium azide (Scheme-l) or potassium phthalamide (Scheme-2 &3). An additional drawback of Scheme- 1 lies in the use of sodium azide in solid form which can be hazardous to the people working around in the environment of commercial manufacturing of levomilnacipran.
Therefore, there remains a need in the art to provide an improved, safe and commercially feasible process for the preparation of levomilnacipran.
Objectives of the invention:
Accordingly, the objective of the invention is to eliminate the reliance on the use of chloro derivative by converting amino alcohol to sulphonyloxy derivative; converting the sulphonyloxy derivative to the corresponding azide by employing aqueous sodium azide.
Another objective of the invention is to reduce the azide to Levomilnacipran in a single solvent to enable recovery and re-use of the solvent thereby improving process economics.
Summary of the invention:
Accordingly, in an aspect, the present provides process for preparation of Levomilnacipran, which process comprises;
a) treating the cis-(+)-l-phenyl-3-oxabicyclo[3.l.0]hexan-2-one with AlCl3/Et2NH to obtain (lS,2R)-N,N-diethyl-2-(hydroxymethyl)-l- pheny 1 cy cl opropanecarb oxami de;
b) Reacting the (lS,2R)-N,N-diethyl-2-(hydroxymethyl)-l- phenylcyclopropanecarboxamide with a compound of formula RSO2CI wherein, R is Alkyl Aryl, or Substituted aryl to obtain (1S, R)Phenyl-2- methanesulfonyloxymethyl-cyclopropane-N,N-diethylformamide;
c) Reacting the (1S, R)Phenyl-2-methanesulfonyloxymethyl-cyclopropane-N,N- diethylformamide with aqueous sodium azide to obtain l-Phenyl-l- diethylaminocarbonyl-2-azidomethylcyclo propane; and
d) Reducing the l-Phenyl-l-diethylaminocarbonyl-2-azidomethylcyclo propane in presence of a reducing agent and in an organic solvent to obtain Levomilnacipran.
Detailed description of the invention:
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be fully understood and appreciated.
The processes of prior art heavily depend on chloro compound ((lS,2R)-2- (chloromethyl)-N,N-di ethyl- 1 -phenylcyclopropanecarboxamide) as intermediate in the preparation of Levomilnacipran. This intermediate is unstable and hence difficult to store. Even if the reaction conducted in one pot synthesis also it is observed that during basification, degradation of the chloro derivative is observed leading to loss in yields of the final product, Levomilnacipran.
Therefore, the present invention provides an improved process for preparation of Levomilnacipran that will eliminate the reliance on the chloro derivative, which process comprises;
a) treating the cis-(+)-l-phenyl-3-oxabicyclo[3.l.0]hexan-2-one with AlCl3/Et2NH to obtain (lS,2R)-N,N-diethyl-2-(hydroxymethyl)-l- pheny 1 cy cl opropanecarb oxami de;
b) Reacting the (lS,2R)-N,N-diethyl-2-(hydroxymethyl)-l- phenylcyclopropanecarboxamide with a compound of formula RSO2CI wherein, R is Alkyl Aryl, or Substituted aryl to obtain (1S, R)Phenyl-2- methanesulfonyloxymethyl-cyclopropane-N,N-diethylformamide;
c) Reacting the (1S, R)Phenyl-2-methanesulfonyloxymethyl-cyclopropane-N,N- diethylformamide with aqueous sodium azide to obtain l-Phenyl-l- diethylaminocarbonyl-2-azidomethylcyclo propane; and
d) Reducing the l-Phenyl-l-diethylaminocarbonyl-2-azidomethylcyclo propane in presence of a reducing agent and in an organic solvent to obtain Levomilnacipran.
The process of the present invention is shown in scheme III below:
SCHEME-III: "" j
i
■
G¹0\¾;
In an aspect, AlCl3 used for the preparation of 1 S,2R)-N,N-diethyl-2- (hydroxymethyl)-l-phenylcyclopropanecarboxamide in step b) is in the range of 1.8-2.0 equivalents based on the cis-(+)-l-phenyl-3-oxabicyclo[3. l.0]hexan-2-one. In an aspect, the preferred sulfonyl chloride as used in step c) is Methanesulfonyl chloride. The sulfonation reaction is conducted at a temperature of 60-65°C.
In an aspect, the sodium azide used in the preparation of l-Phenyl-l- diethylaminocarbonyl-2-azidomethylcyclo propane is as an aqueous solution and the quantity of water present in aqueous sodium azide would be in the range of 2-5
ml/gm of sodium azide, wherein, the preferred quantity is 2 ml water per gm of sodium azide. The reaction is carried out optionally in presence of a phase transfer catalyst. One preferred phase transfer catalyst is Tetra butyl ammonium bromide. The reaction is conducted at a temperature range of 50-60°C.
In a further aspect, l-Phenyl-l-diethylaminocarbonyl-2-azidomethylcyclo propane is reduced in presence of Zinc/ Ammonium formate to obtain levoMilnacipran. The solvent used in the reduction of l-Phenyl-l-diethylaminocarbonyl-2- azidomethylcyclo propane is an alcoholic solvent selected from the group consisting of Methanol, Ethanol, Isopropanol and Butanol. The preferred solvent for conducting the reduction reaction is Methanol.
Other features and embodiments of the invention will become apparent by the following examples which are given for illustration of the invention rather than limiting its intended scope. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art.
Examples
Example-1:
Preparation of cis-(+)-l-phenyl-3-oxabicyclo[3.1.0]hexan-2-one or (IS, 5R) -1- Phenyl-3-oxabicyclo (3, 1, 0) hexane -2-one [(S)-Lactone] :
Sodium amide (160 gm) and toluene (1200 ml) were added to the Flask at room temperature and followed by the addition of Phenyl acetonitrile (200 gm). The reaction mass was stirred for 1 hour at 0°C. (R)-epichlorohydrin (150 gm) was added and stirred for 2 hours at room temperature. After completion of reaction, the reaction mass was quenched in to ice cooled water (4000 ml). Toluene layer was separated and distilled under reduced pressure. The resultant crude (245 gm) was taken into another Flask.
25 % Potassium hydroxide solution (800 gm) and 2% Tetrabutyl ammonium bromide was added to the crude (245 gm) at room temperature, and stirred at reflux
temp for 12 hrs, then cooled the reaction mass at room temperature, Toluene (600 ml) was added and pH was adjusted to 1.0-2.0 with cone. Hydrochloric acid. The reaction mass was stirred for 3 to 4 hours at 60-70°C. Cooled the reaction mixture at room temperature, Toluene layer was separated and washed with sodium bicarbonate. Organic layer was dried with Sodium sulphate and distilled under reduced pressure. The resultant crude (196 gm) was distilled under high vacuum to get the pure compound (168 gm). The resultant pure compound was added to the Flask along with 282 ml of Isopropyl alcohol at room temperature; slowly temperature was raised to 70-75°C and stirred for 1 hr. Then slowly cooled to room temperature and stirred 1 hr and then again cooled to 0-5°C. Stirred for 2 hrs and washed with chilled Isopropyl alcohol.
Purity: 99.82%
Yield: 46%
Example-2:
Preparation of cis-(+)-l-phenyl-3-oxabicyclo[3.1.0]hexan-2-one or (IS, 5R) -1- Phenyl-3-oxabicyclo (3, 1, 0) hexane -2-one [(S)-Lactone] :
Sodium amide (50 kg) and toluene (500 lit) were added to the Reactor at room temperature and followed by the addition of Phenyl acetonitrile (62.5 kg). The reaction mass was stirred for 1 hour at 0°C. (R)-Epichlorohydrin (47 kg) was added and stirred for 2 hours at room temperature. After completion of the reaction, the reaction mass was quenched in to ice cooled water (1250 lit). Toluene layer was separated and distilled under reduced pressure. 250 kg of 25 % Potassium hydroxide solution and 2% Tetrabutyl ammonium bromide (1 kg) was added to the resultant crude at room temperature, and stirred at reflux temp for 12 hrs, then cooled the reaction mass to room temperature, Toluene (250 lit) was added and pH was adjusted to 1.0-2.0 with cone. Hydrochloric acid. The reaction mass was heated to 60-70°C and stirred for 3 to 4 hours. After completion of reaction, cooled the reaction mixture to room temperature, and toluene layer was separated and washed with sodium bicarbonate. Toluene layer was dried with Sodium sulphate and distilled under reduced pressure. The resultant crude (60 kg) was distilled under
high vacuum to get the pure compound (51 kg). The resultant pure compound was added to the Reactor along with Isopropyl alcohol (150 lit) at room temperature; slowly temperature was raised to 70-75°C and stirred for 1 hr. Then slowly cooled to room temperature and stirred 1 hr and then again cooled to 0-5°C. Stirred for 2 hrs and washed with chilled Isopropyl alcohol.
Purity: 99.90%
Yield: 44%
Example-3:
Preparation of (IS, R)Phenyl-2-methanesulfonyloxymethyl-cyclopropane- N,N-diethylformamide:
Step I:
Aluminium chloride (140 gm) and Toluene (800 ml) were taken in the Flask at room temperature and cooled to l0°C. cis-(±)-l-Phenyl-3-oxabicyclo[3.l.0]hexan-2-one (100gm) was added and stirred for lhr, followed by the addition of Diethylamine (150 gm) and stirred for lhr. Then the temperature of the reaction mass was raised to room temperature and stirred for 1 hour. After completion of the reaction, the reaction mass was quenched in to ice cooled water (700 ml). The organic layer was collected and washed with water and hydrochloric acid. This was directly taken as such for the next stage.
Step II:
Triethylamine (145 gm) was added to the above toluene layer at room temperature. The reaction mass was heated to 60-65°C, stirred for 30 min followed by the slow addition of Methane sulfonyl chloride (130 gm), and stirred for 3 hours. After completion of the reaction, water (600 ml) was added. The organic layer was separated and washed with aqueous Sodium bicarbonate and water then dried with Sodium sulphate and distilled under reduced pressure.
HPLC Purity ³ 92%
Example-4:
Preparation of l-Phenyl-l-diethylaminocarbonyl-2-azidomethylcyclo propane:
The above crude was added to the Flask along with Dimethylformamide (400 ml) at room temperature followed by the addition of Sodium azide (54 gm) and Tetra butyl ammonium bromide (15 gm). The temperature was raised to 50-60°C and stirred for 1-2 hours. After completion of the reaction, the reaction mass was quenched into water (800 ml) and extracted with ethyl acetate (500 ml). The layers were separated and Ethyl acetate layer was washed with water. The resultant organic layer was distilled out completely under vacuum to get the titled compound. Crude wt: 123 gm
Purity: 93.2%
Example-5:
Preparation of l-Phenyl-l-diethylaminocarbonyl-2-azidomethylcyclo propane: Step I:
Aluminium chloride (140 gm) and Toluene (800 ml) were added to the Flask at room temperature. Cool the reaction to l0°C then cis-(±)-l-Phenyl-3- oxabicyclo[3.l.0]hexan-2-one (100 gm) was added, stirred for 1 hr followed by the addition of Diethylamine (145 gm) and stirred for 1 hr. The temperature of the reaction mass was raised to room temperature and stirred for 1 hour. After completion of the reaction, the reaction mass was quenched in to ice cooled water (700 ml). The organic layer was collected and washed with water and hydrochloric acid. This was directly taken as such for the next stage.
Step II:
Triethylamine (145 gm) was added to the above toluene layer at room temperature. The reaction mass was heated to 60-65°C, stirred for 30 min followed by the slow addition of Methane sulfonyl chloride (130 gm), and stirred for 3 hours. After completion of the reaction, water (600 ml) was added. The organic layer was separated and washed with aqueous Sodium bicarbonate and water then dried with Sodium sulphate and Toluene layer was directly taken as such for next stage. Step-III:
Tetrabutylamonium bromide was added to above toluene layer at room temperature followed by addition of sodium azide aqueous solution (54 gms sodium azide
dissolved in 110 ml of Water) at room temperature. The reaction mass was heated to 50-60°C and stirred for 1-2 hours. After completion of the reaction, the reaction mass was quenched into water (800 ml). The layers were separated and the aqueous layer was extracted with toluene (200 ml), Total organic layer was washed with water. The resultant organic layer was distilled out completely under vacuum to get the titled compound.
Example-6:
Preparation of Cyclopropanecarboxamide, 2-(aminomethyl)-N,N-diethyl- 1- phenyl-, cis-(±)-; [Milnacipran hydrochloride]
The above crude was added to the Flask containing Methanol (540 ml) followed by the addition of Ammonium formate (64 gm). Then Zinc (lOOgm) was slowly added at room temperature and stirred for 2-3 hrs. After completion of the reaction, the reaction mass was filtered through hyflow bed and distilled the filtrate under vacuum. Methanol (465 ml) was recovered and Water (400 ml) was added to the above crude, pH was adjusted to 12.5 with 25% Sodium hydroxide solution at below l0°C and extracted with Toluene 600ml and take the toluene layer and charge with 300ml water and PH was adjusted to 1.0 to 2.0 with hydrochloride at l0°C and separated the layers. Aqueous layer was washed with toluene (200x2). Aqueous layer was separated and pH was adjusted with 25% sodium hydroxide solution up to 12-12.5 below l0°C and the product was extracted with Diehl oromethane(300x2), The organic layer was separated and dried with sodium sulphate and distilled under reduced pressure. To the residual mass ethyl acetate, IPA.HC1 were added and stirred for 30 minutes at room temperature. The reaction mass was cooled to l0-l5°C, maintained for 1 hour 30 minutes then solid was separated by filtration and dried at 50-60°C for 4 hours to obtain Milnacipran hydrochloride.
Purity: 99.93%
Yield : 59.2% from (S)-lactone
Example-7:
Preparation of Cyclopropanecarboxamide, 2-(aminomethyl)-N,N-diethyl- 1- phenyl-, cis-(±)-; [Milnacipran hydrochloride]
l-Phenyl-l-diethylaminocarbonyl-2-azidomethylcyclo propane (60 gm) (From example-4) was added to the Flask containing Methanol (270 ml) followed by the addition of Ammonium formate (32 gm). Then Zinc (50 gm) was slowly added at room temperature and stirred for 2-3 hrs. After completion of the reaction, the reaction mass was filtered through hyflow bed and distilled the filtrate under vacuum. Methanol (210 ml) was recovered and Water (200 ml) was added to the above crude, pH was adjusted to 12.5 with 25% Sodium hydroxide solution at below l0°C and extracted with Toluene (300 ml) and take the toluene layer and charged with 300ml water and PH was adjusted to 1.0 to 2.0 with hydrochloride at l0°C and separate the layers. Aqueous layer was washed with toluene (100 ml X 2 times). Aqueous layer was separated and pH was adjusted with 25% sodium hydroxide solution up to 12-12.5 below l0°C and the product was extracted with Diehl oromethane (150 ml X 2 times), The organic layer was separated and dried with sodium sulphate and distilled under reduced pressure. To the residual mass ethyl acetate, IPA.HC1 were added and stirred for 30 minutes at room temperature. The reaction mass was cooled to l0-l5°C, maintained for 1 hour 30 minutes then solid was separated by filtration and dried at 50-60°C for 4 hours to obtain Milnacipran hydrochloride.
Purity: 99.89%;
Yield: 60% from (S)-lactone
Example-8:
Preparation of Cyclopropanecarboxamide, 2-(aminomethyl)-N,N-diethyl- 1- phenyl-, cis-(±)-; [Milnacipran hydrochloride]
l-Phenyl-l-diethylaminocarbonyl-2-azidomethylcyclo propane (60 gm) (From example-4) was added to the Flask containing recovered Methanol (270 ml) (From example 6) followed by the addition of Ammonium formate (32 gm). Then Zinc (50 gm) was slowly added at room temperature and stirred for 2-3 hrs. After
completion of the reaction, the reaction mass was filtered through hyflow bed and distilled the filtrate under vacuum. Methanol (210 ml) was recovered and Water (200 ml) was added to the above crude, pH was adjusted to 12.5 with 25% Sodium hydroxide solution at below l0°C and extracted with Toluene (300 ml) and take the toluene layer and charged with 300ml water and PH was adjusted to 1.0 to 2.0 with hydrochloride at l0°C and separated the layers. Aqueous layer was washed with toluene (100 ml X 2 times). Aqueous layer was separated and pH was adjusted with 25% sodium hydroxide solution up to 12-12.5 below l0°C and the product was extracted with Diehl or omethane (150 ml X 2 times), The organic layer was separated and dried with sodium sulphate and distilled under reduced pressure. To the residual mass ethyl acetate, IPA.HC1 were added and stirred for 30 minutes at room temperature. The reaction mass was cooled to l0-l5°C, maintained for 1 hour 30 minutes then solid was separated by filtration and dried at 50-60°C for 4 hours to obtain Milnacipran hydrochloride.
Purity: 99.85%
Yield: 59.2% from (S)-lactone
Claims
1. An improved process for preparation of Levomilnacipran that will eliminate the reliance on the chloro derivative, which process comprises;
a) treating the cis-(+)-l-phenyl-3-oxabicyclo[3. l.0]hexan-2-one with AlCl3/Et2NH to obtain (lS,2R)-N,N-diethyl-2-(hydroxymethyl)-l- pheny 1 cy cl opropanecarb oxami de;
b) Reacting the (lS,2R)-N,N-diethyl-2-(hydroxymethyl)-l- phenylcyclopropanecarboxamide with a compound of formula RSO2CI wherein, R is Alkyl Aryl, or Substituted aryl to obtain (1S, R)Phenyl-2- methanesulfonyloxymethyl-cyclopropane-N,N-diethylformamide; c) Reacting the (1S, R)Phenyl-2-methanesulfonyloxymethyl- cyclopropane-N,N-diethylformamide with aqueous sodium azide to obtain l-Phenyl-l-diethylaminocarbonyl-2-azidomethylcyclo propane; and
d) Reducing the l-Phenyl4-diethylaminocarbonyl-2-azidomethylcyclo propane in presence of a reducing agent and in an organic solvent to obtain Levomilnacipran.
2. The process as claimed in claim 1, wherein, the A1C13 used in step a) is in the range of 1.8-2.0 equivalents based on the cis-(+)-l-phenyl-3- oxabicyclo[3.1 0]hexan-2-one.
3. The process as claimed in claim 1, wherein, the preferred reagent sulfonyl chloride as used in step b) is Methanesulfonyl chloride.
4. The process as claimed in claim 1, wherein, the quantity of water presents in the aqueous sodium azide in step c) is in the range of 2-5 ml/gm of sodium azide.
5. The process as claimed in claim 1, wherein, the reaction in step c) is carried out optionally in presence of a phase transfer catalyst.
6. The process as claimed in claim 1, wherein, the phase transfer catalyst is Tetra butyl ammonium bromide.
7. The process as claimed in claim 1, wherein, the reducing agent used in step d) is Zinc/ Ammonium formate.
8. The process as claimed in claim 1, wherein, the organic solvent used in step d) is an alcohol.
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US20140343322A1 (en) * | 2013-05-20 | 2014-11-20 | Cosma S.P.A. | Process for preparing levomilnacipran hcl |
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US20140343322A1 (en) * | 2013-05-20 | 2014-11-20 | Cosma S.P.A. | Process for preparing levomilnacipran hcl |
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