WO2013089594A1 - PROCESS FOR OBTAINING 16α,17α-CYCLOHEX-3',4'-ENOPREGN-5-EN-3β-OL-20-ONE ACETATE - Google Patents

PROCESS FOR OBTAINING 16α,17α-CYCLOHEX-3',4'-ENOPREGN-5-EN-3β-OL-20-ONE ACETATE Download PDF

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Publication number
WO2013089594A1
WO2013089594A1 PCT/RU2012/001066 RU2012001066W WO2013089594A1 WO 2013089594 A1 WO2013089594 A1 WO 2013089594A1 RU 2012001066 W RU2012001066 W RU 2012001066W WO 2013089594 A1 WO2013089594 A1 WO 2013089594A1
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Prior art keywords
acetate
obtaining
butadiene
reaction mixture
temperature
Prior art date
Application number
PCT/RU2012/001066
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English (en)
French (fr)
Inventor
Igor Viktorovich Zavarzin
Inna Solomonovna LEVINA
Original Assignee
Limited Liability Company Izvarino Pharma
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Filing date
Publication date
Application filed by Limited Liability Company Izvarino Pharma filed Critical Limited Liability Company Izvarino Pharma
Publication of WO2013089594A1 publication Critical patent/WO2013089594A1/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J53/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by condensation with a carbocyclic rings or by formation of an additional ring by means of a direct link between two ring carbon atoms, including carboxyclic rings fused to the cyclopenta(a)hydrophenanthrene skeleton are included in this class
    • C07J53/002—Carbocyclic rings fused

Definitions

  • the present invention relates to the chemistry of natural and physiologically active substances and especially, to a process for obtaining an intermediate product in the synthesis of steroid hormones of the pregnane series, containing an additional six-membered carbocycle [M. (2004)-Quali. Synthesis of pentacyclic steroids. Steroids, 2008, 73, N 8, 775-97], condensed with the steroid skeleton in the 16a,17a-positions [A.V. Kamernitsky, I.S.Levina. Pregna-O'- pentaranes. Progestins and antiprogestins.
  • the compound according to the formula I represents the key intermediate in the synthesis of a highly efficient progestin, the 6a-methyl-16a,17a-cyclohexano-progesterone.
  • the aim of the present invention is to simplify the technology for obtaining the compound of the formula I.
  • the targeted task is achieved by the proposed process for obtaining 16a,l 7a-cyc]ohex-3',4'- enopregn-5-en-3p-ol-20-one acetate by interaction of 16-dehydropregnenolone acetate with 1,3 -butadiene in the medium of an organic solvent in the presence of Lewis acid, the characteristics of the process according to the invention consisting in the process run at the molar ratio of 16-dehydropregnenolone acetate, 1,3-butadiene and of Lewis acid within 1 : 2 - 3: 0,2 -0,4, at the temperature of -10°C, the reaction mixture temperature being further brought to room temperature, the reaction mixture being passed through a sorbing agent layer, and the desired product isolated by known processes.
  • the desired product yield is 80-85%.
  • the Lewis acid mostly anhydrous aluminum chloride (AICI 3 ) or titanium tetrachloride (TiCl 4 ) are used.
  • organic solvent mostly toluene or methylene chloride are used.
  • the sorbing agent mostly silica gel, aluminum oxide, celite are used.
  • reaction performed at the temperature of -10°C and the reaction mixture temperature brought to room temperature within a determined period allow to simplify the process, common equipment being used instead of a sealed ampoule.
  • Passing the reaction mixture through a sorbing agent without a preliminary water treatment allows to prevent the formation of stable emulsions at the decomposition of the reaction mixture with a solution of soda and water.
  • the technical result of the proposed invention is to simplify the process run thanks to the refusal to use the sealed equipment and to the treatment of the reaction mixture by passing it through a sorbing agent layer before isolating the desired product.
  • the invention corresponds to the criterion "novelty" since the known scientific and engineering literature and the patent literature do not describe the whole combination of features characterizing the proposed invention.
  • the invention satisfies the criterion "inventive level" since the fact to change the water treatment operation before isolating the desired product for an operation of passing the reaction mixture through a sorbing agent is not evident since for decomposing the obtained complex of the desired product with the Lewis acid, usually a solution of soda or water is required, see, for example [P.Yates, Ph.Eaton. Acceleration of the Diels-Alder reaction by Aluminum chloride. J.Am.Chem.Soc, 1960, 82, 4436-7; I. A. Favorskaya, E.M. Auvinen, G.V. Prilutskaya. Ethylene and acetylene ketones as dienophiles in the catalytic diene synthesis. ZhOrKh, 1970, 6, No 4, 720-23].
  • the process according to the invention is technologically effective since it does not require specific equipment, that is why it is industrially practicable.
  • Example 1 To the suspension of 20 g (56 mmol) of 16-dehydropregnenolone acetate and of 1.6 g (12 mmol) of anhydrous AICI3 in 80 ml of methylene chloride under stirring and at - 10°C, 10 ml (112 mmol) of 1,3 -butadiene are added, the stirring being continued for 3 h. After that, cooling is stopped, the reaction mass temperature is allowed to rise up to room temperature at which it is maintained for 6 h more (TCX control). The reaction mixture is passed through a layer of silica gel, a sorbing agent. The sorbing agent is washed with toluene and finally with chloroform.
  • Example 2 To the suspension of 10 g (28 mmol) of 16-dehydropregnenolone acetate and of 1.52 g (11.4 mmol) of anhydrous AICI3 in 40 ml of methylene chloride under stirring and at - 10°C, 9 ml (140 mmol) of 1,3 -butadiene are added, the stirring being continued for 3 h. After that, cooling is stopped, the reaction mass temperature is allowed to rise up to room temperature at which it is maintained for 6 h more (TCX control). After a treatment, similar to the described in the Example 1, 9.2 g (80.0 %) of compound I were obtained.
  • Example 3 To the suspension of 20 g (56 mmol) of 16-dehydropregnenolone acetate and of 1.6 g (12 mmol) of anhydrous AICI3 in 150 ml of toluene under stirring and at -10°C, 12.5 ml (140 mmol) of 1 ,3-butadiene are added, the stirring being continued for 3 h. After that, cooling is stopped, the reaction mass temperature is allowed to rise up to room temperature at which it is maintained for 10 h more (TCX control). After a treatment, similar to the described in the Example 1 , 19 g (82.7 %) of compound I were obtained.
  • Example 4 To the suspension of 20 g (56 mmol) of 16-dehydropregnenolone acetate and of 1.6 g (12 mmol) of anhydrous AICI3 in 150 ml of toluene under stirring and at -10°C, 12.5 ml (140 mmol) of 1 ,3-butadiene
  • Example 5 To the suspension of 10 g (28 mmol) of 16-dehydropregnenolone acetate and of 1.25 g (12 mmol) of TiCh . in 40 ml of methylene chloride under stirring and at -10°C, 5.4 ml (84 mmol) of 1,3-butadiene are added, the stirring being continued for 10 h. After that, cooling is stopped, the reaction mass temperature is allowed to rise up to room temperature at which it is maintained for 10 h more (TCX control). After a treatment, similar to the described in the Example 1, 9.1 g (79.2 %) of compound I were obtained.
  • Example 6 To the suspension of 10 g (28 mmol) of 16-dehydropregnenolone acetate and of 1.25 g (12 mmol) of TiCl 4 in 80 ml of toluene under stirring and at -10°C, 5.4 ml (84 mmol) of 1,3-butadiene are added, the stirring being continued for 3 h. After that, cooling is stopped, the reaction mass temperature is allowed to rise up to room temperature at which it is maintained for 10 h more (TCX control). After a treatment, similar to the described in the Example 1 , 9.0 g (78.5 %) of compound I were obtained.
  • the proposed process enables to simplify the obtaining of an intermediate product in the synthesis of steroid hormones of the pregnane series thanks to the refusal to carry out the process in a sealed equipment, which makes it economically advantageous.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Steroid Compounds (AREA)
PCT/RU2012/001066 2011-12-15 2012-12-14 PROCESS FOR OBTAINING 16α,17α-CYCLOHEX-3',4'-ENOPREGN-5-EN-3β-OL-20-ONE ACETATE WO2013089594A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
RU2011151300 2011-12-15
RU2011151300/04A RU2472802C1 (ru) 2011-12-15 2011-12-15 СПОСОБ ПОЛУЧЕНИЯ АЦЕТАТА 16α,17α-ЦИКЛОГЕКС-3',4'-ЕНОПРЕГН-5-ЕН-3β-ОЛ-20-ОНА

Publications (1)

Publication Number Publication Date
WO2013089594A1 true WO2013089594A1 (en) 2013-06-20

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PCT/RU2012/001066 WO2013089594A1 (en) 2011-12-15 2012-12-14 PROCESS FOR OBTAINING 16α,17α-CYCLOHEX-3',4'-ENOPREGN-5-EN-3β-OL-20-ONE ACETATE

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RU (1) RU2472802C1 (ru)
WO (1) WO2013089594A1 (ru)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SU273195A1 (ru) * 1969-04-26 1970-06-15 А. А. Ахрем, И. С. Левина, Л. Е. Куликова , Ю. А. Титов Институт органической химии Н. Д. Зелинского Способ получения производных прегнана

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SU1311217A1 (ru) * 1985-10-03 1990-03-15 Институт органической химии им.Н.Д.Зелинского 16 @ , 17 @ -Циклогексано-17 @ -ацетил-13-метилгона-4,9-диен-3-он, про вл ющий прогестагенную активность

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SU273195A1 (ru) * 1969-04-26 1970-06-15 А. А. Ахрем, И. С. Левина, Л. Е. Куликова , Ю. А. Титов Институт органической химии Н. Д. Зелинского Способ получения производных прегнана

Non-Patent Citations (10)

* Cited by examiner, † Cited by third party
Title
A. A. AKHREM ET AL: "Condensation of delta-5-pregnen-3.beta.-ol-20-one acetate with acyclic dienes", BULLETIN OF THE ACADEMY OF SCIENCES OF THE USSR, DIVISION OF CHEMICAL SCIENCES, vol. 19, no. 2, 1970, New York, US, pages 458, XP002695555 *
A. A. AKHREM ET AL: "Transformed steroids communication 43. Synthesis of pentacyclic analogs of progesterone with an additional ring in the 16,17-positions", BULLETIN OF THE ACADEMY OF SCIENCES OF THE USSR, DIVISION OF CHEMICAL SCIENCES, vol. 21, no. 6, 1972, New York, US, pages 1308 - 1312, XP002695556 *
A.A. AKHREM; L.E. KULIKOVA; I.S. LEVINA; YU.A. TITOV.: "Synthesis of pentacyclic analogs of progesterone with an additional ring in positions 16,17", IZVESTIA AN SSSR, SER. CHEM., vol. 6, 1972, pages 1358 - 63
A.A. AKHREM; L.E. KULIKOVA; LS. LEVINA; YU.A.: "Titov. Process for obtaining pregnane derivatives with cyclohexene rings condensed in positions 16,17. USSR Author's Certificate No 273195", BULLETIN OF INVENTIONS, 1970
A.V. KAMERNITSKY; I.S.LEVINA.: "Pregna-O'- pentaranes. Progestins and antiprogestins", BIOORGAN.KHIMIA, vol. 31, 2005, pages 115 - 227
KAMERNITSKII A V ET AL: "BIOLOGICAL ACTIVITY OF TRANSFORMED STEROIDS 25. SYNTHESIS OF 16-ALPHA 17-ALPHA CYCLOHEXANE-5-ALPHA-PREGN-1-ENE-3 20-DIONE AND STUDY OF ITS PROGESTAGENIC ACTIVITY", PHARMACEUTICAL CHEMISTRY JOURNAL, vol. 24, no. 3, 1990, New York, US, pages 181 - 184, XP002695557, ISSN: 0023-1134 *
KAMERNITZKY A V ET AL: "Pregna-D'-pentaranes-a new class of active gestagenes", JOURNAL OF STEROID BIOCHEMISTRY, PERGAMON PRESS PLC, GB, vol. 16, no. 1, 1 January 1982 (1982-01-01), pages 61 - 67, XP023413888, ISSN: 0022-4731, [retrieved on 19820101], DOI: 10.1016/0022-4731(82)90144-3 *
LA. FAVORSKAYA; E.M. AUVINEN; G.V. PRILUTSKAYA.: "Ethylene and acetylene ketones as dienophiles in the catalytic diene synthesis", ZHORKH, vol. 6, no. 4, 1970, pages 720 - 23
M. IBRAHIM-QUALI.: "Synthesis ofpentacyclic steroids", STEROIDS, vol. 73, no. 8, 2008, pages 775 - 97
P.YATES; PH.EATON: "Acceleration of the Diels-Alder reaction by Aluminum chloride", J.AM.CHEM.SOC, vol. 82, 1960, pages 4436 - 7

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