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WO2018185783A1 - Nouveau procédé de préparation de 19- norstéroïdes - Google Patents

Nouveau procédé de préparation de 19- norstéroïdes Download PDF

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Publication number
WO2018185783A1
WO2018185783A1 PCT/IN2018/050196 IN2018050196W WO2018185783A1 WO 2018185783 A1 WO2018185783 A1 WO 2018185783A1 IN 2018050196 W IN2018050196 W IN 2018050196W WO 2018185783 A1 WO2018185783 A1 WO 2018185783A1
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WO
WIPO (PCT)
Prior art keywords
formula
norethisterone
solution
group
acid
Prior art date
Application number
PCT/IN2018/050196
Other languages
English (en)
Inventor
Vinayak Tripathi
Rajesh Kumar
Rohit BHUWANIA
Binay Kumar BHUWANIA
Original Assignee
Coral Drugs Pvt. Ltd.
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 Coral Drugs Pvt. Ltd. filed Critical Coral Drugs Pvt. Ltd.
Publication of WO2018185783A1 publication Critical patent/WO2018185783A1/fr

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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
    • 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
    • C07J1/0059—Estrane derivatives substituted in position 17 by a keto group

Definitions

  • the present invention provides a process for the preparation of norsteroids.
  • the present invention provides a process for the preparation of 19-norsteroids.
  • Norsteroids are pharmacologically active compounds or important intermediate for pharmacologically active compounds. These have been known as xenobiotics with androgenic and anabolic properties and obligatory endogenous intermediates in the biosynthesis of estrogens from androgens in all species, including mammals.
  • Norsteroids have been found to exhibit potent progestational activities, antiestrogenic activities, and estrogenic responses in the estrogen-deficient state. Besides, depending on the specific compound produced, there are several other effects also associated with that compound such as pregnancy-maintenance, anti-estrogenic, ovulation- suppressing, androgenic and anti-androgenic activities.
  • US 2774777 discloses a process wherein, the starting material, 19-Norandrostene- 3, 17-dione is first protected with ethyl orthoformate to form enol-ether at the C-3 position as intermediate. Then, this intermediate is purified through solvent purification. Further base mediated acetylene is introduced at C-17 position followed by deprotection at the C-3 position. To obtain the final product, multiple purifications with ethyl acetate are conducted. The disadvantage of this process is protection at C-3, then deprotection in the last stage and multiple purifications at each stage to get the pure product with low yield. Therefore, due to multiple steps process with multiple purification steps and also low yield, this process is not commercially viable.
  • US 2744122 discloses a process wherein A— 19-nor-androsten-17p-ol-3-one compound, a lower alkyl ether of estrone with an alkali metal in liquid ammonia followed by hydrolysis with a mineral acid and oxidation with chromic acid to form A -19-norandrosten-3, 17-dione, selectively forming a 3-enol ether of said dione and treating said ether with acetylene in the presence of an alkali metal alkoxide, followed by hydrolysis with a mineral acid. Therefore, due to multiple steps process and also low yield, this process is not commercially viable.
  • US3655649 discloses a process wherein 9-hydroxy-3-keto-A-steroid is reacted with a secondary amine to form the corresponding 19-nor-3, 5-diene-3-amine.
  • C-3 keto group is protected through secondary amine and column chromatography is used for purification which makes the process is more complex and commercially not viable.
  • An object of the present invention is to provide a process for the preparation of 19- Norethisterone of Formula-I that addresses one or more deficiencies mentioned in the prior art documents.
  • the present invention provides a one-pot process for the preparation of 19- Norethisterone of Formula-I with high yield and high purity.
  • the one-pot process is simple, economical, user-friendly and commercially viable.
  • the process for the preparation of 19- Norethisterone of Formula-I comprises the step of:
  • the present invention discloses a single pot process for the preparation of 19- Norethisterone of Formula-I, comprising the ste s of:
  • the process of the present invention may be suitably started from the compound of formula II, known by its IUPAC name (8R,9S,10R,13S,14S)-13-methyl-l,2,6,7,8,9,10,l 1,12,13, 14,15,16- dodecahydro-lH-cyclopenta[a]phenanthrene-3,17(2H,6H)-dione and hereinafter referred to as 19-Norandrostenedione (formula II) and leads to formation of 19 -Norethisterone of Formula-I known by its IUPAC name (8R,9S,10R,13S,14S,17R)-17-ethynyl-17-hydroxy-13-methyl- 6,7,8,9,10,11,12, 14, 15, 16-dodecahydro-lH-cyclopenta[a]phenanthren-3(2H)-one.
  • IUPAC name 8R,9S,10R,13S,14S,17R
  • a solution comprising 19-Norandrostenedione of Formula II may be contacted with the solution comprising metal acetylide at temperature not exceeding 5°C, preferably between -5°C to 5°C, more preferably 0°C + 2°C, and most preferably 0°C + 1°C, to get a first stage reaction solution comprising 19-Norethisterone of Formula I and free metal.
  • the solution of 19-Norandrostenedione of Formula II comprises a solvent selected from a group consisting of tetrahydrofuran (THF), toluene, and dioxane; with tetrahydrofuran being the preferred choice.
  • THF tetrahydrofuran
  • toluene toluene
  • dioxane dioxane
  • the solution comprising metal acetylide is obtained by dissolving the metal acetylide in a solvent selected from a group consisting of tetrahydrofuran, toluene, and dioxane; with tetrahydrofuran being the preferred choice.
  • the solution comprising metal acetylide is obtained by in- situ reaction of the first base with an acetylene yielding stream.
  • the first base is taken in form of a solution comprising a solvent selected from a group consisting of tetrahydrofuran, toluene and dioxane; with tetrahydrofuran being the preferred choice; and the first base is selected from the group consisting of potassium t-butoxide, potassium hydroxide, lithium hydroxide, sodium t-butoxide and sodium hydroxide; with potassium t-butoxide being the preferred choice.
  • the acetylene yielding stream is acetylene.
  • the method further comprising adding an acetylene yielding stream to the first stage reaction solution to convert the free metal thus formed to further metal acetylide, wherein the further metal acetylide reacts with 19-Norandrostenedione to form 19- norethisterone of Formula-I.
  • the addition of acetylene yielding stream is carried out until 19-Norandrostenedione gets depleted to at least 50%, preferably gets depleted to at least 75%, more preferably gets depleted to at least 90%, most preferably gets depleted to at least 99.5% of the original amount added.
  • an acid is added to the first stage reaction solution to obtain a second stage reaction solution.
  • the acid is added to the first stage reaction solution at a temperature of not exceeding 20°C, preferably between 10°C to 20°C, more preferably 15°C + 3°C, and most preferably 15°C + 1°C.
  • the temperature of the second stage reaction solution is increased to a temperature not exceeding 45°C, preferably between 35°C to 45°C, more preferably 40°C + 2°C, and most preferably 40°C + 1°C.
  • the acid is selected from a group consisting of hydrochloric acid, acetic acid, and trifluoro acetic acid.
  • hydrochloric acid is the acid.
  • the extraction of 19-Norethisterone of Formula I is done from the second stage reaction solution by use of an organic solvent selected from the group consisting of methyl isobutyl ketone, dichloromethane (DCM), ethyl acetate and toluene.
  • the organic solvent is preferably methyl isobutyl ketone.
  • a pH value of mother liquor that comprises the second stage reaction solution and the organic solvent
  • a second base may be used.
  • the second base may be selected from a group consisting of sodium bicarbonate, potassium bicarbonate, potassium carbonate and sodium carbonate.
  • sodium bicarbonate is the second base.
  • step (ii) wherein in step (ii), the purification of 19- Norethisterone of Formula-I is performed in presence of an organic solvent selected from a group consisting of methanol, ethanol and isopropanol; with methanol being the preferred organic solvent.
  • an organic solvent selected from a group consisting of methanol, ethanol and isopropanol; with methanol being the preferred organic solvent.
  • the compound of formula I may be used as important starting material/ intermediate for the synthesis of active materials.
  • the compound of formula I may be optionally purified to obtain a pure compound. Such purification may be done by means of refluxing and subsequently washing with alcohol.
  • single pot process for the preparation of 19- norethisterone of Formula-I comprises of:
  • the process for the preparation of 19- Norethisterone of Formula-I comprises of sequential steps of:
  • step (iii) adding an acetylene yielding stream to the solution of step (ii) to form metal acetylide therein;
  • step (iv) adding 19-Norandrostenedione to the solution of step (iii) while maintaining the temperature at not more than 5°C such that 19-Norandrostenedione reacts with the metal acetylide to form 19-norethisterone of Formula-I and free metal;
  • step (v) adding an acetylene yielding stream to the solution of step (iv) to convert the free metal thus formed to further metal acetylide, wherein the further metal acetylide reacts with 19- Norandrostenedione to form 19-norethisterone of Formula-I, the addition of acetylene yielding stream is carried out until 19-Norandrostenedione gets depleted to at least 50%, preferably gets depleted to at least 75%, more preferably gets depleted to at least 90%, most preferably gets depleted to at least 99.5% of the original amount added;
  • step (vi) gradually adding acid to a solution of step (v) and raising the temperature to not more than 45°C;
  • step (vii) adding an organic solvent to a solution of step (vi), stir and separate an organic layer thus formed;
  • the process for the preparation of 19- Norethisterone of Formula- 1 comprises of sequential steps of:
  • step (ii) adding an acetylene yielding stream to the solution of step (i) to convert the free metal thus formed to further metal acetylide, wherein the further metal acetylide reacts with 19- Norandrostenedione to form 19-norethisterone of Formula-I, the addition of acetylene yielding stream is carried out until 19-Norandrostenedione gets depleted to at least 50%, preferably gets depleted to at least 75%, more preferably gets depleted to at least 90%, most preferably gets depleted to at least 99.5% of the original amount added;
  • step (iii) gradually adding acid to a solution of step (ii) and raising the temperature to not more than 45°C;
  • step (iv) adding an organic solvent to a solution of step (iii), stir and separate an organic layer thus formed;
  • the amount of metal acetylide needed can be substantially lesser than the stoichimetric amount needed for conversion of 19-Norandrostenedione to the compound of formula I.
  • the amount of the first base needed can be substantially lesser than the stoichiometric ratio needed for conversion of 19-Norandrostenedione to the compound of formula I.
  • the process of the present invention is single pot and avoids multiple steps.
  • the process of the present invention involves th e use of economic and environment- friendly reagents that will give highly pure material and cost-effective process.
  • Example-1 Process for the preparation of Norethisterone of Formula-1
  • 19-Norandrostenedione should be less than 0.50%, added 10L of purified water at 5°C+ (5°C), added 30L of hydrochloric acid at 15°C+ (5°C), raised the temperature up to 40°C+ (5°C), stir for 30min., added 100L of methyl isobutyl ketone (10 volume) and 100L of purified water(10 volume), stir and separate organic layer.

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

Abstract

La présente invention concerne un procédé en pot unique pour la synthèse de 19-Noréthistérone de formule (I), comprenant la mise en contact de 19-Norandostene-3,17-dione de formule (II) avec une première base, un gaz/solution organique et un acide pour obtenir la 19-Noréthistérone de formule (I); et la purification de la 19-Noréthistérone de formule (I) ainsi obtenue par reflux et ensuite lavage avec un solvant organique.
PCT/IN2018/050196 2017-04-06 2018-04-06 Nouveau procédé de préparation de 19- norstéroïdes WO2018185783A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN201711012365 2017-04-06
IN201711012365 2017-04-06

Publications (1)

Publication Number Publication Date
WO2018185783A1 true WO2018185783A1 (fr) 2018-10-11

Family

ID=63712771

Family Applications (1)

Application Number Title Priority Date Filing Date
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5371052A (en) * 1976-12-07 1978-06-24 Mitsubishi Chem Ind Ltd Purification of 19-norethisterone
JPS588096A (ja) * 1981-07-08 1983-01-18 Mitsubishi Chem Ind Ltd １９−ノルエチステロンの製法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5371052A (en) * 1976-12-07 1978-06-24 Mitsubishi Chem Ind Ltd Purification of 19-norethisterone
JPS588096A (ja) * 1981-07-08 1983-01-18 Mitsubishi Chem Ind Ltd １９−ノルエチステロンの製法

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