WO2014162230A1 - Process for the purification of norethindrone and norethindrone acetate - Google Patents

Process for the purification of norethindrone and norethindrone acetate Download PDF

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Publication number
WO2014162230A1
WO2014162230A1 PCT/IB2014/059994 IB2014059994W WO2014162230A1 WO 2014162230 A1 WO2014162230 A1 WO 2014162230A1 IB 2014059994 W IB2014059994 W IB 2014059994W WO 2014162230 A1 WO2014162230 A1 WO 2014162230A1
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Prior art keywords
norethindrone
purification
water
volume
acetate
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PCT/IB2014/059994
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French (fr)
Inventor
Amit Madanrao AGARKAR
Himanshu Madhav Godbole
Girij Pal Singh
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Lupin Limited
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Publication of WO2014162230A1 publication Critical patent/WO2014162230A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
    • C07J1/0051—Estrane derivatives
    • C07J1/0081—Substituted in position 17 alfa and 17 beta
    • C07J1/0088—Substituted in position 17 alfa and 17 beta the substituent in position 17 alfa being an unsaturated hydrocarbon group
    • C07J1/0096—Alkynyl derivatives

Definitions

  • the present invention relates to process for the purification of norethindrone and norethindroneacetate.
  • Norethindrone (I) and norethindrone acetate (Il) are first-generation progestin, chemically known as 17-hydroxy-19-nor-17a-pregn-4-en-20-yn-3-one and 17-hydroxy-19-nor-17a- pregn-4-en-20-yn-3-one acetaterespectively. These are used alone or in combination with ethinylestradiolasoral contraceptives.
  • the patent US 3,409,643 describes purification of norethindrone acetate from methanol containing a drop of pyridine.
  • the present invention provides a process forthe purification of norethindrone (I) from mixture of dimethyl formamide-water.
  • the present invention further provides two processes for purification of norethindrone acetate (II):
  • Process A It involves purification from mixture of dichloromethane- n-heptane and
  • Process B It involves purification from mixture of methanol-water.
  • a process for the purification of norethindrone comprising; i) dissolution of norethindrone in dimethyl formamide by heating, ii) addition of water, iii) cooling, and iv) isolation.
  • Norethindrone is dissolved in dimethyl formamide by heating at reflux temperature, preferably 55-60 °C.
  • the ratio of dimethyl formamide-water isl: 100 to 100: 1, preferably 20: 1 to 1 :20, more preferably 10:1 to 5: 1 (volume/volume).
  • the quantity of dimethyl formamide-water with respect to norethindrone (I) is 1-20 times (weight/volume) preferably 5-10 times (weight/volume).
  • the purity of norethindrone (I) obtained by the present invention is greater than 99%.
  • Process A Process for the purification of norethindrone acetate (II) comprising a) stirring of norethindrone acetate in dichloromethane, b) addition of n-heptane, c) cooling, and d) isolation.
  • the ratio of dichloromethane and n-heptane is 1 : 10 to 10: 1, preferably 1:5 to 5:1 (volume/volume) .
  • Process B Process for the purification of norethindrone acetate (II) comprising: a) stirring of norethindrone acetate in mixture of ethanol-water and b) isolation.
  • Stirring of norethindrone acetate in mixture of ethanol-water mixture is carried out in the temperature range of 10-70 °C, preferably 20-50 °C, more preferably 30-35 °C.
  • Norethindrone acetate in ethanol-water mixture is stirred for 30 minutes to 10 hours, preferably 1-5 hours, more preferably 1-2 hours.
  • the ratio of ethanol-water is 1 : 10 to 10: 1, preferably 1: 1 to 1 :4 (volume/volume).
  • the purity of norethindrone acetate (II) obtained by the purification process of present invention is greater than 99%.
  • the pure compounds according to the present invention can be isolated by methods known in the literature such as filtration, concentration and evaporation etc.
  • Norethindrone (4.5 g) was added to dimethyl formamide (27 ml) at 25-30 °C.
  • the slurry was heated to 55-60 °C.
  • To the solution water (23.5 ml) was added and stirred for 45 minutes at 55-60°C.
  • the slurry cooled to 20-25°C and stirred for 3 hrs. Filtered, washed with water and dried under vacuum.
  • HPLC Purity 99.01
  • Norethindrone 50 g was added to toluene (1.55 litres) containing acetic anhydride (400 ml) at 20-30 °C.
  • 4-dimethylamino pyridine 4 g was added,heated to 80-90°C then stirred for 3 hours and cooled to 10-25 °C then water (1.25 litres) was added.
  • the reaction mass further cooled to 10-15°C then pH adjusted to 5.5 to 6.5 using 5% NaOH.
  • the organic layer was separated and cyclohexane (500 ml) was added to it.
  • Second crop (8.5 g) was obtained from filtrate by cooling to 0-5 °C.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Indole Compounds (AREA)

Abstract

The present invention provides a process for the purification of norethindrone (I) from a mixture of dimethylformamide (DMF) and water. The invention further provides two processes for the purification of norethindrone acetate (II) from a mixture of dichloromethane:n-heptane (Process A) and from a mixture of ethanol:water (Process B).

Description

PROCESS FOR THE PURIFICATION OF NORETHINDRONE AND NORETHINDRONE ACETATE
FIELD OF THE INVENTION: The present invention relates to process for the purification of norethindrone and norethindroneacetate.
BACKGROUND OF THE INVENTION:
Norethindrone (I) and norethindrone acetate (Il)are first-generation progestin, chemically known as 17-hydroxy-19-nor-17a-pregn-4-en-20-yn-3-one and 17-hydroxy-19-nor-17a- pregn-4-en-20-yn-3-one acetaterespectively. These are used alone or in combination with ethinylestradiolasoral contraceptives.
Figure imgf000002_0001
(I) (Π)
The methods for the purification of norethindrone and norethindrone acetate in the prior art documents are discussed below.
The patent US 2,744, 122 describes purification of norethindrone by recrystallization from ethyl acetate.
Another patent US 3,759,961 describes crystallisation of norethindrone from acetone.
The patent US 2,964,537describespurification of norethindrone acetate using the mixture of dichloromethane-hexane solvent.
The patent US 3,408, 371describescrystallization of norethindrone acetate from solvents such as ethyl acetate and dichloromethane. The patent US 3,409,643 describes purification of norethindrone acetate from methanol containing a drop of pyridine.
SUMMARY OF THE INVENTION:
The present invention provides a process forthe purification of norethindrone (I) from mixture of dimethyl formamide-water. The present invention further provides two processes for purification of norethindrone acetate (II):
Process A: It involves purification from mixture of dichloromethane- n-heptane and
Process B : It involves purification from mixture of methanol-water.
DETAILED DESCRIPTION OF THE INVENTION: In one embodiment there is provided a process for the purification of norethindrone comprising; i) dissolution of norethindrone in dimethyl formamide by heating, ii) addition of water, iii) cooling, and iv) isolation.
Norethindrone is dissolved in dimethyl formamide by heating at reflux temperature, preferably 55-60 °C.
Slurry obtained after addition of water cooled to -10 to 30 °C, preferably 20-25°C.
The ratio of dimethyl formamide-water isl: 100 to 100: 1, preferably 20: 1 to 1 :20, more preferably 10:1 to 5: 1 (volume/volume).
The quantity of dimethyl formamide-water with respect to norethindrone (I) is 1-20 times (weight/volume) preferably 5-10 times (weight/volume).
The purity of norethindrone (I) obtained by the present invention is greater than 99%. In another embodiment there is provided two processes for purification of norethindrone acetate (II):
Process A: Process for the purification of norethindrone acetate (II) comprising a) stirring of norethindrone acetate in dichloromethane, b) addition of n-heptane, c) cooling, and d) isolation.
The solvent n-heptane addedto norethindrone acetate in dichloromethane at 10-40 °C, preferably 20-30 °C. Slurry obtained after addition of n-heptane cooled to -20 to 15 °C, preferably 0-5 °C.
The ratio of dichloromethane and n-heptane is 1 : 10 to 10: 1, preferably 1:5 to 5:1 (volume/volume) .
The quantity of dichloromethane and n-heptane with respect to norethindrone acetate (II) is 1-10 times (weight/volume) preferably 2-5 times (weight/volume) Process B: Process for the purification of norethindrone acetate (II) comprising: a) stirring of norethindrone acetate in mixture of ethanol-water and b) isolation.
Stirring of norethindrone acetate in mixture of ethanol-water mixture is carried out in the temperature range of 10-70 °C, preferably 20-50 °C, more preferably 30-35 °C. Norethindrone acetate in ethanol-water mixture is stirred for 30 minutes to 10 hours, preferably 1-5 hours, more preferably 1-2 hours.
The ratio of ethanol-water is 1 : 10 to 10: 1, preferably 1: 1 to 1 :4 (volume/volume).
The purity of norethindrone acetate (II) obtained by the purification process of present invention is greater than 99%. The pure compounds according to the present invention can be isolated by methods known in the literature such as filtration, concentration and evaporation etc.
The products dried using different techniques of drying like tray trying and rotatory drying techniques with or without application of vacuum and/or under inert condition. The present invention is described in the following examples, however it should be noted that the scope of present invention is not limited by the examples.
EXAMPLE 1:
Purification of Norethindrone:
Norethindrone (4.5 g)was added to dimethyl formamide (27 ml) at 25-30 °C. The slurry was heated to 55-60 °C. To the solution water (23.5 ml) was added and stirred for 45 minutes at 55-60°C. The slurry cooled to 20-25°C and stirred for 3 hrs. Filtered, washed with water and dried under vacuum. HPLC Purity :99.01
EXAMPLE 2:
Preparation of Norethindrone Acetate Norethindrone (50 g) was added to toluene (1.55 litres) containing acetic anhydride (400 ml) at 20-30 °C. To the reaction mass, 4-dimethylamino pyridine (4 g)was added,heated to 80-90°C then stirred for 3 hours and cooled to 10-25 °C then water (1.25 litres) was added. The reaction mass further cooled to 10-15°C then pH adjusted to 5.5 to 6.5 using 5% NaOH. The organic layer was separated and cyclohexane (500 ml) was added to it. The product was chromatographed on 300 g of alumina column and eluted with toluene/cyclohexane mixture. The elute containing the product were concentrated and passed through 0.45 micron membrane filter then n-heptane (250 ml) was added. The resulting slurry was cooled to 0-5°C, stirred, filtered and washed with n-heptane. Yield: 31 g (wet cake). Purification of Norethindrone Acetate from dichloromethane- n-heptane:
Crude norethindrone acetate (31 g) obtained above was added to dichloromethane (250 ml) at 20-30 °C. To the solution, n-heptane (100 ml) was added, stirring continued at 20- 30 °Cfor 1 ½ hour and cooled to 0-5°C. Filtered it. Purification of Norethindrone Acetate from ethanol-water:
The wet solid obtained from dichloromethane-n-heptane was stirred in mixture of ethanol (125 ml) and water (225 ml)at 30-35 °C for an hour. Solid filtered, washed with water and dried. Yield: 19.5 g. HPLCPurity:99.86
Second crop (8.5 g) was obtained from filtrate by cooling to 0-5 °C.

Claims

CLAIMS:
1. A process for the purification of norethindrone (I) comprising; i) dissolution of norethindrone in dimethyl formamide by heating, ii) addition of water, iii) cooling, and iv) isolation.
2. The process according to claim 1, wherein the dissolution is carried at reflux temperature, preferably 55-60 °C.
3. The process according to claim 1, wherein the cooling is carried out between -10 to
30 °C, preferably 20-25°C.
The process according to claim 1, wherein the ratio of dimethyl formamide-water isl 100 to 100: 1, preferably 20:1 to 1 :20, more preferably 10: 1 to 5:1 (volume/volume).
A process for the purification of norethindrone acetate (II) comprising: a) stirring of norethindrone acetate in dichloromethane, b) addition of n-heptane, c) cooling, and d) isolation.
The process according to claim 5, wherein addition of n-heptane is carried out in the temperature range of 10-40 °C, preferably 20-30 °C.
The process according to claim 5, wherein the ratio of dichloromethane- n-heptane is 1 : 10 to 10: 1, preferably 1:5 to 5:1 (volume/volume).
A process for the purification of norethindrone acetate (II) comprising: a) stirring of norethindrone acetate in mixture of ethanol-water and b) isolation.
9. The process according to claim 8, wherein stirring is carried out in the temperature range of 10-70 °C, preferably 20-50 °C, more preferably 30-35 °C.
10. The process according to claim 8, wherein the ratio of ethanol-water isl : 10 to 10:1, preferably 1: 1 to 1 :4 (volume/volume).
11. The process according to claims 1, 5 and 8, wherein the product is isolated either by filtration or concentration or evaporation.
PCT/IB2014/059994 2013-04-04 2014-03-20 Process for the purification of norethindrone and norethindrone acetate WO2014162230A1 (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111875656A (en) * 2020-06-23 2020-11-03 浙江神洲药业有限公司 Preparation method of norethindrone acetate

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2744122A (en) 1951-11-22 1956-05-01 Syntex Sa delta 4-19-nor-17alpha-ethinylandrosten-17beta-ol-3-one and process
US2964537A (en) 1956-06-16 1960-12-13 Schering Ag Therapeutically valuable carboxylic acid esters of 17-alkyl-19-nor-testosterone
US3408371A (en) 1966-06-16 1968-10-29 Syntex Corp Esterification of 17alpha-ethinyl-17beta-hydroxy steroids
US3409643A (en) 1966-03-11 1968-11-05 Schering Corp Process for the preparation of 17alpha-alkynl-17beta-alkanoyloxy steroids of the androstane and estrane series
US3759961A (en) 1970-06-13 1973-09-18 Schering Ag Process for ethinylating 17-ketosteroids
US3813418A (en) * 1972-06-29 1974-05-28 Schering Ag Process for the preparation of 6-keto-delta1,3,5(10)steroids
US4029779A (en) * 1974-10-18 1977-06-14 Schering Aktiengesellschaft 1α-Hydroxy steroids
US4244949A (en) * 1978-04-06 1981-01-13 The Population Council, Inc. Manufacture of long term contraceptive implant
US4826689A (en) * 1984-05-21 1989-05-02 University Of Rochester Method for making uniformly sized particles from water-insoluble organic compounds
DD295637A5 (en) * 1981-09-07 1991-11-07 Jenapharm Gmbh Jena,De PROCESS FOR CLEANING STEROIDS

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2744122A (en) 1951-11-22 1956-05-01 Syntex Sa delta 4-19-nor-17alpha-ethinylandrosten-17beta-ol-3-one and process
US2964537A (en) 1956-06-16 1960-12-13 Schering Ag Therapeutically valuable carboxylic acid esters of 17-alkyl-19-nor-testosterone
US3409643A (en) 1966-03-11 1968-11-05 Schering Corp Process for the preparation of 17alpha-alkynl-17beta-alkanoyloxy steroids of the androstane and estrane series
US3408371A (en) 1966-06-16 1968-10-29 Syntex Corp Esterification of 17alpha-ethinyl-17beta-hydroxy steroids
US3759961A (en) 1970-06-13 1973-09-18 Schering Ag Process for ethinylating 17-ketosteroids
US3813418A (en) * 1972-06-29 1974-05-28 Schering Ag Process for the preparation of 6-keto-delta1,3,5(10)steroids
US4029779A (en) * 1974-10-18 1977-06-14 Schering Aktiengesellschaft 1α-Hydroxy steroids
US4244949A (en) * 1978-04-06 1981-01-13 The Population Council, Inc. Manufacture of long term contraceptive implant
DD295637A5 (en) * 1981-09-07 1991-11-07 Jenapharm Gmbh Jena,De PROCESS FOR CLEANING STEROIDS
US4826689A (en) * 1984-05-21 1989-05-02 University Of Rochester Method for making uniformly sized particles from water-insoluble organic compounds

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ALARY, JOSETTE ET AL: "Study of pregn-4-ene-3,20-dione and related molecules by pulse polarography. Determination of progesterone and certain synthetic progestogens", BULLETIN DE LA SOCIETE CHIMIQUE DE FRANCE , (7-8, PT. 1), 649-52 CODEN: BSCFAS; ISSN: 0037-8968, 1977, XP008169640 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111875656A (en) * 2020-06-23 2020-11-03 浙江神洲药业有限公司 Preparation method of norethindrone acetate

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