WO2014162230A1 - Procédé de purification de la noréthindrone et de l'acétate de noréthindrone - Google Patents

Procédé de purification de la noréthindrone et de l'acétate de noréthindrone Download PDF

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
norethindrone
purification
water
volume
acetate
Prior art date
Application number
PCT/IB2014/059994
Other languages
English (en)
Inventor
Amit Madanrao AGARKAR
Himanshu Madhav Godbole
Girij Pal Singh
Original Assignee
Lupin Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Lupin Limited filed Critical Lupin Limited
Publication of WO2014162230A1 publication Critical patent/WO2014162230A1/fr

Links

Classifications

    • 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.

Landscapes

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

Abstract

La présente invention concerne un procédé de purification de la noréthindrone (I) à partir d'un mélange de diméthylformamide (DMF) et d'eau. La présente invention concerne en outre deux procédés de purification de l'acétate de noréthindrone (II) à partir d'un mélange de dichlorométhane-n-heptane (procédé A) et à partir d'un mélange de méthanol-eau (procédé B).
PCT/IB2014/059994 2013-04-04 2014-03-20 Procédé de purification de la noréthindrone et de l'acétate de noréthindrone WO2014162230A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1313/MUM/2013 2013-04-04
IN1313MU2013 IN2013MU01313A (fr) 2013-04-04 2014-03-20

Publications (1)

Publication Number Publication Date
WO2014162230A1 true WO2014162230A1 (fr) 2014-10-09

Family

ID=50390155

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2014/059994 WO2014162230A1 (fr) 2013-04-04 2014-03-20 Procédé de purification de la noréthindrone et de l'acétate de noréthindrone

Country Status (2)

Country Link
IN (1) IN2013MU01313A (fr)
WO (1) WO2014162230A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111875656A (zh) * 2020-06-23 2020-11-03 浙江神洲药业有限公司 一种炔诺酮醋酸酯的制备方法

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 (de) * 1981-09-07 1991-11-07 Jenapharm Gmbh Jena,De Verfahren zur reinigung von steroiden

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 (de) * 1981-09-07 1991-11-07 Jenapharm Gmbh Jena,De Verfahren zur reinigung von steroiden
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 (zh) * 2020-06-23 2020-11-03 浙江神洲药业有限公司 一种炔诺酮醋酸酯的制备方法

Also Published As

Publication number Publication date
IN2013MU01313A (fr) 2015-04-10

Similar Documents

Publication Publication Date Title
AU2017236669B2 (en) An improved process for the preparation of sugammadex
CN106256824B (zh) 一种高纯度德拉沙星葡甲胺盐的制备方法
WO2017080520A1 (fr) Procédé d'extraction d'avermectine b2 d'onguent à base d'avermectine
WO2014187364A1 (fr) Procede de preparation de trihydroxyethyl rutoside
WO2022237689A1 (fr) Procédé de préparation de dihydroquercétine
CN102775387B (zh) 一种盐酸法舒地尔的精制方法
WO2014162230A1 (fr) Procédé de purification de la noréthindrone et de l'acétate de noréthindrone
US8765196B2 (en) Method for separating and purifying Ginkgolide C from root bark of ginkgo
WO2020182228A1 (fr) Procédé de raffinage de taurocholate de sodium
EP2675820A1 (fr) Procédé de préparation amélioré du lévonorgestrel
CN112341416A (zh) 一种制备苯并含氧脂杂环衍生物的方法
CN103724288A (zh) 原甲酸三乙酯法制备1h-四氮唑乙酸的后处理方法
CN101270124B (zh) 一种提纯制备高纯度荧光素及荧光素盐的新方法
CN106674142A (zh) 一种帕瑞昔布钠及其中间体的制备方法
US9206099B2 (en) Method for producing hydrogenated biphenol
JP5203950B2 (ja) ベツリン酸の改良された抽出方法
CN107033114A (zh) 一种二氢杨梅素的分离纯化方法
CN103570619B (zh) 一种孟鲁司特钠衍生物的制备方法
EP3474847B1 (fr) Méthodes de préparation d'oxazoldinone.
WO2014170909A2 (fr) Procédé de préparation de pomalidomide
CN106565807B (zh) 一种分离DHEA及其α‑异构体的方法
JP7018840B2 (ja) フェニルピペラジンピリジンメチルアセテートの製造方法
WO2018154516A1 (fr) Procédé de préparation de pomalidomide
CN104761603B (zh) 曲氟尿苷晶型b及其制备方法
US20110137035A1 (en) Preparation of microbiologically produced ergot alkaloids

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 14713599

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 14713599

Country of ref document: EP

Kind code of ref document: A1