WO2017093980A1 - Process for preparation of testosterone - Google Patents

Process for preparation of testosterone Download PDF

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Publication number
WO2017093980A1
WO2017093980A1 PCT/IB2016/057335 IB2016057335W WO2017093980A1 WO 2017093980 A1 WO2017093980 A1 WO 2017093980A1 IB 2016057335 W IB2016057335 W IB 2016057335W WO 2017093980 A1 WO2017093980 A1 WO 2017093980A1
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Prior art keywords
testosterone
androsten
dione
mixture
iii
Prior art date
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PCT/IB2016/057335
Other languages
French (fr)
Inventor
Vishal Sukhadeo MAWALE
Naresh Daga PATIL
Dabeer Rauf Karnalkar
Pravin Raghunath Mahajan
Gurvinder Pal Singh
Purna Chandra Ray
Girij Pal Singh
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Lupin Limited
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Publication of WO2017093980A1 publication Critical patent/WO2017093980A1/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07JSTEROIDS
    • C07J1/00Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
    • C07J1/0003Androstane derivatives
    • C07J1/0011Androstane derivatives substituted in position 17 by a keto group
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07JSTEROIDS
    • C07J1/00Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
    • C07J1/0003Androstane derivatives
    • C07J1/0018Androstane derivatives substituted in position 17 beta, not substituted in position 17 alfa
    • C07J1/0022Androstane derivatives substituted in position 17 beta, not substituted in position 17 alfa the substituent being an OH group free esterified or etherified

Definitions

  • the present invention relates to a process for preparation of testosterone (I) having HPLC purity > 99 %.
  • Testosterone (I) is a steroid hormone that belongs to androgen group and is found in all vertebrates. It plays a key role in development of reproductive tissues and secondary sexual characteristics as well as prevention of osteoporosis. Testosterone is chemically known as (8R,9S,10R,13S,14S,17S)-17-hydroxy-10,13-dimethyl-
  • the present invention is directed to provide an improved synthetic process for the preparation of testosterone, having minimum amount of impurities.
  • the objective of the present invention is to provide a process for purification of 4- androsten-3,17-dione (II).
  • Another objective of the present invention relates to a process for preparing testosterone (I) having purity > 99 % as measured by HPLC, comprising purification of 4-androsten- 3,17-dione (II) from mixture of tetrahydrofuran and cyclohexane; and its conversion to testosterone (I).
  • the present invention provides testosterone (I) having purity > 99 % as measured by HPLC.
  • the testosterone (I) obtained in the present invention has total impurity content less than 1 %, preferably less than 0.5 %, more preferably less than 0.25%, measured as area percentage by HPLC.
  • the present invention further provides a process for purification of 4-androsten-3,17- dione (II) comprising the steps of:
  • step iii) cooling of step ii) to 25-35 °C
  • the present invention further provides a process for preparation of testosterone (I) having purity > 99 % when measured by HPLC comprising the steps of:
  • step ii) heating reaction mixture of step i) to 70-80°C
  • step iii) cooling of step ii) to 25-35 °C
  • Pure 4-androsten-3,17-dione (II) of the present invention can be converted to testosterone (I) by the methods known in the literature.
  • the present invention further provides a process for preparation of testosterone (I) having purity > 99 % when measured by HPLC comprising the steps of:
  • step ii) heating reaction mixture of step i) to 70-80°C
  • step iii) cooling of step ii) to 25-35 °C
  • Reaction of pure 4-androsten-3,17-dione (II) with triethyl orthoformate in alcohol using pyridine hydrochloride to obtain 17-Keto-3-enol ether (III) is carried out at 0-15°C, more preferably 5-10°C for 4-6 hrs.
  • Reaction of 17-Keto-3-enol ether (III) with reducing agent in alcohol is carried out in presence of base triethyl amine at 0-15°C, more preferably at 5-10°C for 4-6 hrs to obtain 3-enol ether (IV).
  • In situ dealkylation of 3-enol ether (IV) is carried out with inorganic acid such as hydrochloric acid or sulfuric acid at 0-5°C to obtain crude testosterone (I).
  • the alcohol used in step (v) and step (vi) is selected from group comprising of one or more methanol, ethanol, isopropyl alcohol, n-propyl alcohol, n-butanol, isobutanol and mixture thereof. More preferably methanol or ethanol is used.
  • the reducing agent used in step (vi) is selected from group comprising of one or more sodium borohydride, potassium borohydride, lithium borohydride, lithium aluminium hydride, dimethyl aluminium hydride, sodium metal, dimethyl aluminium, semicarbazide and mixture thereof. More preferably sodium borohydride or lithium borohydride is used.
  • the testosterone (I) obtained according to the present invention is optionally purified by contacting testosterone (I) with mixture of methanol and triethylamine, adding water to reaction mixture, heating the reaction mixture at 65-80°C, more preferably 70-75°C, cooling the reaction mixture to 20-30°C, followed by filtration to obtain pure testosterone (I) wherein the phytosterol content is less than 0.1% and the total impurity content is less than 1 %, preferably less than 0.5 %, more preferably less than 0.25%, measured as area percentage by HPLC.
  • the isolated testosterone may be dried using different techniques of drying like tray drying and rotatory drying techniques with or without application of vacuum and/or under inert condition.
  • testosterone may pose a problem for formulation in that impurities often affect the safety and shelf life of a formulation. Therefore, the testosterone prepared by the process of the present invention might be ideal for pharmaceutical formulation, since it is substantially pure.
  • Testosterone (I) obtained by the process of the present invention may be formulated in conventional manner using one or more pharmaceutically acceptable carriers, excipients, or diluents.
  • HPLC High Performance Liquid Chromatography Chromatographic conditions: Instrument : HPLC equipped with Pump, Injector, UV detector and
  • Testosterone 70 gm was added to mixture of 70 ml of triethylamine and 500 ml of methanol at 25-30°C, stirred for 20-30 min and filtered.

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

Abstract

The present invention relates to a process for purification of 4-androsten-3,17-dione (II) and its conversion to testosterone (I) having purity > 99 % as measured by HPLC.

Description

PROCESS FOR PREPARATION OF TESTOSTERONE
FIELD OF THE INVENTION
The present invention relates to a process for preparation of testosterone (I) having HPLC purity > 99 %.
BACKGROUND OF THE INVENTION
Testosterone (I) is a steroid hormone that belongs to androgen group and is found in all vertebrates. It plays a key role in development of reproductive tissues and secondary sexual characteristics as well as prevention of osteoporosis. Testosterone is chemically known as (8R,9S,10R,13S,14S,17S)-17-hydroxy-10,13-dimethyl-
1,2,6,7,8,9,11,12,14,15,16, 17-dodeca hydrocyclopenta[a]phenanthren-3-one and represented by formula as shown below.
Figure imgf000002_0001
(I) (ID
The synthesis of testosterone is described in several publications, some of these are:
R E Marker et al., in Journal of American chemical society (1941), 63, 777; Norymberski, J. K. and Woods, Gilbert F. in Journal of the Chemical Society (1955), 3426-30; K Morita, in Bulletin of the Chemical Society of Japan (1958), 31, 450-3. The patents relevant to synthesis of testosterone are US 2294433 and 2679502; Indian patent application IN 1483/DEL/2003; PCT applications WO 2007118644 Al and WO 2011000693 Al. Although several documents exist in literature but none of them describe process to obtain highly pure testosterone (I).
It is always desirable to prepare pharmaceutical product of a high purity having a minimum amount of impurities, in order to reduce adverse side effects and to improve the shelf life of active ingredient, as well as its formulation. In some cases it has been found that high purity also facilitates in formulation process.
Therefore, the present invention is directed to provide an improved synthetic process for the preparation of testosterone, having minimum amount of impurities. SUMMARY OF THE INVENTION
The objective of the present invention is to provide a process for purification of 4- androsten-3,17-dione (II).
Another objective of the present invention relates to a process for preparing testosterone (I) having purity > 99 % as measured by HPLC, comprising purification of 4-androsten- 3,17-dione (II) from mixture of tetrahydrofuran and cyclohexane; and its conversion to testosterone (I).
DETAILED DESCRIPTION OF THE INVENTION
In one embodiment, the present invention provides testosterone (I) having purity > 99 % as measured by HPLC. The testosterone (I) obtained in the present invention has total impurity content less than 1 %, preferably less than 0.5 %, more preferably less than 0.25%, measured as area percentage by HPLC.
The present invention further provides a process for purification of 4-androsten-3,17- dione (II) comprising the steps of:
i) contacting 4-androsten-3,17-dione (II) with mixture of tetrahydrofuran and cyclohexane,
heating reaction mixture of step i) to 70-80°C,
iii) cooling of step ii) to 25-35 °C,
iv) isolating pure 4-androsten-3,17-dione (II). Purification of 4-androsten-3,17-dione (II) is carried out by contacting it with mixture of tetrahydrofuran and cyclohexane to form the slurry. The slurry is heated to 70-80°C for 1- 2 hrs, then cooled to 30-35°C followed by filtration to obtain 4-androsten-3,17-dione (II) having purity > 98 % as measured by HPLC (phytosterol content < 0.1 %).
The present invention further provides a process for preparation of testosterone (I) having purity > 99 % when measured by HPLC comprising the steps of:
i) contacting 4-androsten-3,17-dione (II) with mixture of tetrahydrofuran and cyclohexane,
ii) heating reaction mixture of step i) to 70-80°C,
iii) cooling of step ii) to 25-35 °C,
iv) isolating pure 4-androsten-3,17-dione (II), and
v) converting pure 4-androsten-3, 17-dione (II) to testosterone (I)
Pure 4-androsten-3,17-dione (II) of the present invention can be converted to testosterone (I) by the methods known in the literature.
The present invention further provides a process for preparation of testosterone (I) having purity > 99 % when measured by HPLC comprising the steps of:
i) contacting 4-androsten-3,17-dione (II) with mixture of tetrahydrofuran and cyclohexane,
ii) heating reaction mixture of step i) to 70-80°C,
iii) cooling of step ii) to 25-35 °C,
iv) isolating pure 4-androsten-3,17-dione (II),
v) reacting pure 4-androsten-3,17-dione (II) with triethyl orthoformate in alcohol using pyridine hydrochloride to get 17-Keto-3-enol ether (III),
Figure imgf000004_0001
Etcr
(III)
reducing 17-Keto-3-enol ether (III) with reducing agent in alcohol to obtain 3 enol ether (IV),
Figure imgf000005_0001
(IV)
vii) dealkylating 3-enol ether (IV) using hydrochloric acid to testosterone (I) viii) optionally carrying out the purification of testosterone (I).
Reaction of pure 4-androsten-3,17-dione (II) with triethyl orthoformate in alcohol using pyridine hydrochloride to obtain 17-Keto-3-enol ether (III) is carried out at 0-15°C, more preferably 5-10°C for 4-6 hrs.
Reaction of 17-Keto-3-enol ether (III) with reducing agent in alcohol is carried out in presence of base triethyl amine at 0-15°C, more preferably at 5-10°C for 4-6 hrs to obtain 3-enol ether (IV). In situ dealkylation of 3-enol ether (IV) is carried out with inorganic acid such as hydrochloric acid or sulfuric acid at 0-5°C to obtain crude testosterone (I).
The alcohol used in step (v) and step (vi) is selected from group comprising of one or more methanol, ethanol, isopropyl alcohol, n-propyl alcohol, n-butanol, isobutanol and mixture thereof. More preferably methanol or ethanol is used.
The reducing agent used in step (vi) is selected from group comprising of one or more sodium borohydride, potassium borohydride, lithium borohydride, lithium aluminium hydride, dimethyl aluminium hydride, sodium metal, dimethyl aluminium, semicarbazide and mixture thereof. More preferably sodium borohydride or lithium borohydride is used.
The testosterone (I) obtained according to the present invention is optionally purified by contacting testosterone (I) with mixture of methanol and triethylamine, adding water to reaction mixture, heating the reaction mixture at 65-80°C, more preferably 70-75°C, cooling the reaction mixture to 20-30°C, followed by filtration to obtain pure testosterone (I) wherein the phytosterol content is less than 0.1% and the total impurity content is less than 1 %, preferably less than 0.5 %, more preferably less than 0.25%, measured as area percentage by HPLC. The isolated testosterone may be dried using different techniques of drying like tray drying and rotatory drying techniques with or without application of vacuum and/or under inert condition.
The presence of impurities in testosterone may pose a problem for formulation in that impurities often affect the safety and shelf life of a formulation. Therefore, the testosterone prepared by the process of the present invention might be ideal for pharmaceutical formulation, since it is substantially pure.
Testosterone (I) obtained by the process of the present invention may be formulated in conventional manner using one or more pharmaceutically acceptable carriers, excipients, or diluents.
It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention and specific examples provided herein, without deviating from the scope of the invention. Therefore, it is intended that the scope of the present invention covers the modifications and/or variations that are equivalents.
Examples:
HPLC (High Performance Liquid Chromatography) Chromatographic conditions: Instrument : HPLC equipped with Pump, Injector, UV detector and
Recorder
Column : Zorbax SB C-8 (4.6x150 mm) 3.5 μπι
Wavelength : UV at 200 nm
Flow rate : 2.0 mL/min
Injection volume : 20 μΙ,
Column oven temp : 25 °C
Auto sampler temp : 25 °C
Buffer : Not applicable.
Mobile phase : Water: Acetonitrile (10:90) v/v. Example 1: Purification of 4-androsten-3,17-dione (II)
To a slurry of 200 gm of 4-androsten-3,17-dione (HPLC purity < 97 %) in 150 ml of tetrahydrofuran was added 1000 ml of cyclohexane. The mixture was then stirred at 70- 80°C for 1.5 to 2hrs. The mixture was the cooled to 30-35°C. The solid was filtered , washed with 200 ml of cyclohexane and dried to give 182.6 gm of purified 4-androsten- 3,17-dione (HPLC purity = 99.36%, Retention time = 19.1 min).
Example 2: Purification of 4-androsten-3,17-dione (II)
To a slurry of 200 gm of 4-androsten-3,17-dione (HPLC purity < 97 %) in 150 ml of tetrahydrofuran was added 1000 ml of cyclohexane. The mixture was then stirred at 70- 80°C for 1.0 to 1.5 hrs. The mixture was the cooled to 30-35°C and maintained for 1-2 hrs. The solid was filtered , washed with 200 ml of cyclohexane and dried to give 185.6 gm of purified 4-androsten-3,17-dione (HPLC purity = 99.35 %, Retention time = 19.1 min).
Example 3: Preparation of 17-Keto-3-enol ether (III)
A mixture of 87 ml (78 gm) of triethyl orthoformate and 13 gm was prepared in 350 ml of absolute ethanol and cooled to 5-10°C. To this mixture lOOgm of purified 4-androsten- 3,17-dione was added and stirred at 5-10°C for 6 hrs. 90 ml of triethylamine was the added and mixture is stirred 5-15°C for 20 min. 300 ml of water was then added and the mixture is stirred 25-30°C for 1 hr. The solid obtained was filtered, washed with water and dried to give 98.4 gm of 17-Keto-3-enol ether (III) (HPLC purity = 98.7 %). Example 3: Preparation of testosterone (I)
90 gm of 17-Keto-3-enol ether (III) was added to a mixture of 540 ml of ethanol and 4.5 ml of triethylamine at 0-5 °C and then stirred for 10 min. 10.8 gm of sodium borohydride was then added to this mixture at 0-5°C and then the reaction was maintained at 5-10°C for 6 hrs. To this 450 ml of IN hydrochloric acid was added dropwise at 0-5 °C and after addition the mixture is stirred at 25-30°C for 4-5 hrs. 180 ml of water was added and stirred the slurry at 25-30°C for 1 hr. the solid obtained was filtered, washed with water and dried to give 73.8 gm of testosterone (off white crystalline powder) (HPLC purity = 99.92 %).
Example 4: Purification of testosterone (I)
Testosterone (70 gm) was added to mixture of 70 ml of triethylamine and 500 ml of methanol at 25-30°C, stirred for 20-30 min and filtered. To the clear filtrate 420 ml of water was added with stirring and maintained the slurry formed at 70-75 °C for 20-30 mins, cooled to 25-30°C and stirred for 1 hr. Solid obtained was filtered, washed with water and dried to give 57 gm of pure testosterone (off white crystalline solid) (HPLC purity = 99.95 %, Retention time = 16 min). Melting range = 153.6 - 154.4°C.

Claims

process for purification of 4-androsten-3,17-dione (II) comprising the steps of:
Figure imgf000009_0001
(ID
i) contacting 4-androsten-3,17-dione (II) with mixture of tetrahydrofuran and cyclohexane,
ii) heating reaction mixture of step i) to 70-80°C,
iii) cooling of step ii) to 25-35°C,
iv) isolating pure 4-androsten-3 , 17-dione (II) .
A process for preparation of testosterone (I) having purity > 99 % when measured by HPLC, comprising the step
Figure imgf000009_0002
(I)
i) contacting 4-androsten-3,l 7-dione (II) with mixture of tetrahydrofuran and cyclohexane,
ii) heating reaction mixture of step i) to 70-80°C,
iii) cooling of step ii) to 25-35°C,
iv) isolating pure 4-androsten-3,l 7-dione (II),
v) converting pure 4-androsten-3,17-dione (II) to testosterone (I).
A process for preparation of testosterone (I) having purity > 99 % when measured by HPLC, comprising the steps of:
i) contacting 4-androsten-3,l 7-dione (II) with mixture of tetrahydrofuran and cyclohexane,
ii) heating reaction mixture of step i) to 70-80°C, cooling of step ii) to 25-35°C,
isolating pure 4-androsten-3,17-dione (II),
reacting pure 4-androsten-3,17-dione (II) with triethyl orthoformate alcohol using pyridine to-3-enol ether (III),
Figure imgf000010_0001
(Hi)
reducing 17-Keto-3-enol ether (III) with reducing agent in alcohol to obtain 3-enol ether (IV),
Figure imgf000010_0002
(IV)
vii) dealkylating 3-enol ether (IV) using hydrochloric acid to testosterone (I), viii) optionally carrying out the purification of testosterone (I).
The process according to claim 3, wherein the alcohol used in step (v) and step (vi) is selected from one or more methanol, ethanol, isopropyl alcohol, n-propyl alcohol, n-butanol, isobutanol and mixture thereof.
The process according to claim 4, wherein the alcohol is methanol or ethanol.
The process according to claim 3, wherein the reducing agent used in step (vi) is selected from one or more sodium borohydride, potassium borohydride, lithium borohydride, lithium aluminium hydride, dimethyl aluminium hydride, sodium metal, dimethyl aluminium, semicarbazide and mixture thereof.
The process according to claim 6, wherein the reducing agent is sodium borohydride.
The process according to claim 3, wherein the purification of testosterone (I) in step (viii) comprising the steps of: i) Contacting testosterone (I) with mixture of trimethylamine and methanol, ii) adding water to reaction mixture of step i),
iii) heating the reaction mixture of step ii),
iv) cooling of step iii),
v) isolating testosterone (I).
The process according to claim 8, wherein the heating the reaction mixture of step ii) is carried out at 65-80°C and cooling of step iii) is carried out at 20-30°C.
Testosterone (I) obtained by the process of claim 2, claim 3 and claim 8 having total impurities less than 0.25% when measured by HPLC.
PCT/IB2016/057335 2015-12-05 2016-12-03 Process for preparation of testosterone WO2017093980A1 (en)

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IN4612MU2015 2015-12-05

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109096354A (en) * 2018-09-12 2018-12-28 湖北竹溪人福药业有限责任公司 A kind of testosterone intermediate mother liquor recycling method
CN114957367A (en) * 2022-05-27 2022-08-30 黄冈人福药业有限责任公司 Refining method for preparing testosterone by biological method

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2294433A (en) 1937-10-05 1942-09-01 Schering Corp Hydroxy ketones of the cyclopentanopolyhydrophenanthrene series and method of producing the same
US2679502A (en) 1948-11-17 1954-05-25 Ciba Pharm Prod Inc Process for the preparation of compounds of the cyclopentanopolyhydrophenanthrene series
DD295637A5 (en) * 1981-09-07 1991-11-07 Jenapharm Gmbh Jena,De PROCESS FOR CLEANING STEROIDS
WO2007118644A1 (en) 2006-04-11 2007-10-25 Iep Gmbh Process for the preparation of steroid derivatives by reduction of oxosteroid compounds or by oxidation of hydroxysteroid compounds using a hydroxysteroid dehydrogenase
WO2011000693A1 (en) 2009-07-01 2011-01-06 F.I.S. Fabbrica Italiana Sintetici S.P.A. Process for the preparation of testosterone
CN104262439A (en) * 2014-10-08 2015-01-07 常州大学 Method of synthesizing testosterone through 4-androstenedione one-step method

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2294433A (en) 1937-10-05 1942-09-01 Schering Corp Hydroxy ketones of the cyclopentanopolyhydrophenanthrene series and method of producing the same
US2679502A (en) 1948-11-17 1954-05-25 Ciba Pharm Prod Inc Process for the preparation of compounds of the cyclopentanopolyhydrophenanthrene series
DD295637A5 (en) * 1981-09-07 1991-11-07 Jenapharm Gmbh Jena,De PROCESS FOR CLEANING STEROIDS
WO2007118644A1 (en) 2006-04-11 2007-10-25 Iep Gmbh Process for the preparation of steroid derivatives by reduction of oxosteroid compounds or by oxidation of hydroxysteroid compounds using a hydroxysteroid dehydrogenase
WO2011000693A1 (en) 2009-07-01 2011-01-06 F.I.S. Fabbrica Italiana Sintetici S.P.A. Process for the preparation of testosterone
CN104262439A (en) * 2014-10-08 2015-01-07 常州大学 Method of synthesizing testosterone through 4-androstenedione one-step method

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
K MORITA, BULLETIN OF THE CHEMICAL SOCIETY OF JAPAN, vol. 31, 1958, pages 450 - 3
NORYMBERSKI, J. K.; WOODS; GILBERT F, JOURNAL OF THE CHEMICAL SOCIETY, 1955, pages 3426 - 30
R E MARKER ET AL., JOURNAL OF AMERICAN CHEMICAL SOCIETY, vol. 63, 1941, pages 777

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109096354A (en) * 2018-09-12 2018-12-28 湖北竹溪人福药业有限责任公司 A kind of testosterone intermediate mother liquor recycling method
CN114957367A (en) * 2022-05-27 2022-08-30 黄冈人福药业有限责任公司 Refining method for preparing testosterone by biological method
CN114957367B (en) * 2022-05-27 2023-12-29 黄冈人福药业有限责任公司 Refining method for preparing testosterone by biological method

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