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Industrial process for the synthesis of 17a-acetoxy-11ss-[4-(n,n-dimethyl-amino)- phenyl]-19-norpregna-4,9-diene-3,20-dione and new intermediates of the process

A technology of dimethylamino and norpregna, which is applied in the field of antiprogesterone and antiglucocorticoid drugs, formula and compounds, and can solve the problems of industrial scale and expensive

Inactive Publication Date: 2009-06-24
RICHTER GEDEON NYRT
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Another disadvantage of this process is that the synthesized intermediates are purified by column chromatography, which is very expensive for industrial scale

Method used

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  • Industrial process for the synthesis of 17a-acetoxy-11ss-[4-(n,n-dimethyl-amino)- phenyl]-19-norpregna-4,9-diene-3,20-dione and new intermediates of the process
  • Industrial process for the synthesis of 17a-acetoxy-11ss-[4-(n,n-dimethyl-amino)- phenyl]-19-norpregna-4,9-diene-3,20-dione and new intermediates of the process
  • Industrial process for the synthesis of 17a-acetoxy-11ss-[4-(n,n-dimethyl-amino)- phenyl]-19-norpregna-4,9-diene-3,20-dione and new intermediates of the process

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Effect test

Embodiment 1

[0042] 3-(ethylenedioxy)-17α-ethynyl-17β-hydroxy-estra-5(10), 9(11)-diene(IX)

[0043] Under nitrogen, potassium tert-butoxide (60 g) was dissolved in anhydrous THF (1500 mL) and acetylene was bubbled into the solution at 20 °C for 30 minutes, then the solution was cooled to 0-(-2) °C and bubbling was continued Soak in acetylene for an additional 30 minutes. The compound of formula (X) (119.4 g, 0.38 mol) was then added while continuing to bubble acetylene. The reaction mixture was stirred for 1 hour and nitrogen gas was bubbled through the mixture in order to remove excess acetylene. Saturated ammonium chloride solution (750 mL) was added and the reaction mixture was stirred for 10 minutes. The organic layer was separated and the aqueous phase was extracted with tetrahydrofuran (300 mL). The combined organic layers were washed with saturated ammonium chloride solution (150 mL), concentrated to a volume of 600 mL and poured into ice water (4 L). The resulting mixture was s...

Embodiment 2

[0045] 3-(ethylenedioxy)-21-(phenyl-sulfinyl)-19-norpregna-5(10), 9(11)17(20), 20-tetraene(VIII)

[0046] To a suspension of compound of formula (IX) (122.5 g, 0.36 mol), triethylamine (151 mL) and acetic acid (24.6 mL) in dichloromethane (2200 mL) was added dropwise phenylsulfinyl chloride (67.9 g, 0.47mol) in chloroform (170mL) while maintaining the temperature at 0 to -5°C. The reaction mixture was stirred for 10 minutes, then water (250 mL) and methanol (100 mL) were added. The organic layer was separated, washed with 1N hydrochloric acid and water, dried over sodium sulfate and concentrated to a volume of 185 mL. Diisopropyl ether (120 mL) was added to the residue and the mixture was cooled to 5°C. Precipitated crystals were filtered off and dried below 60°C to yield 144 g (88%) of the title compound. The purity of the product is at least 95% (according to HPLC).

[0047] Melting point: 176-180°C.

Embodiment 3

[0049] 3-(ethylenedioxy)-17α-hydroxy-20-methoxy-19-norpregna-5(10), 9(11), 20-triene(VII)

[0050] To a solution of sodium methoxide (8.67 g, 0.16 mol) in methanol (4320 mL) was added compound of formula (VIII) (144 g, 0.321 mol). The reaction mixture was stirred at 62-64°C for 3 hours, then trimethyl phosphite (42 mL, 0.35 mol) was added and stirring was continued at 62-64°C for 2 hours. The reaction mixture was cooled to 20 °C and poured into a solution of sodium chloride (288 g) in water (14 L). The precipitated crystalline product was filtered off, washed with water and dried at 40°C, yielding 80.2 g (67%) of the title compound. The purity of the product is at least 95% (according to HPLC).

[0051] Melting point: 128-132°C.

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Abstract

The present invention relates to a new industrial process for the synthesis of solvate- free 17a-acetoxy-11ss-[4-(N,N-dimethyl-amino)-phenyl]-19-norpregna-4,9-diene-3,20-dione [CDB -2914] of formula (I) which is a strong antiprogestogene and antiglucocorticoid agent. The invention also relates to compounds of formula (VII) and (VIII) used as intermediates in the process. The process according to the invention is the following: i) 3-(ethylene-dioxy)-estra-5(10),9(11)-diene-17-one of formula (X) is reacted with potassium acetilyde formed in situ in dry tetrahydrofuran by known method, ii) the obtained 3-(ethylene-dioxy)-17a-ethynyl-17ss-hydroxy-estra-5(10),9(11)-diene of formula (IX) is reacted with phenylsulfenyl chloride in dichloromethane in the presence of triethylamine and acetic acid, iii) the obtained isomeric mixture of 3-(ethylene-dioxy)-21-(phenyl-sulfinyl)-19-norpregna-5(10),9(11),17(20),20-tetraene of formula (VIII) is reacted first with sodium methoxide in methanol, then with trimethyl phosphite, iv) the obtained 3-(ethylene-dioxy)-17a-hydroxy-20-methoxy-19-norpregna-5(10),9(11),20-triene of formula (VII) is reacted with hydrogen chloride in methanol, then v) the obtained 3-(ethylene-dioxy)-17a-hydroxy-19-norpregna-5(10),9(11l); -diene-20- one of formula (VI) is reacted with ethylene glycol hi dichloromethane in the presence of trimethyl orthoformate and p-toluenesulfonic acid by known method, vi) the obtained 3,3,20,20-bis(ethylene-dioxy)-17a-hydroxy-19-norpregna- 5(10),9(11)-diene of formula (V) is reacted with hydrogen peroxide in a mixture of pyridine and dichloromethane in the presence of hexachloroacetone by known method, vii) the obtained 3,3,20,20-bis(ethylene-dioxy)-17a-hydroxy-5,10-epoxy-19-norpregn-9(11)-ene of formula (IV), containing approximately a 1:1 mixture of 5a,10a- and 5ss,10ss-epoxides, is isolated from the solution and reacted with a Grignard reagent obtained from 4-bromo-N,N-dimethyl-aniline in tetrahydrofuran.

Description

field of invention [0001] The present invention relates to the synthesis of 17α-acetoxy-11β-[4-(N,N-dimethyl-amino)-phenyl]-19-norpregna-4 of formula (I) free of solvates, A new process for the industrial production of 9-diene-3,20-dione [CDB-2914], a potent antiprogestogen and antiglucocorticoid agent. [0002] The present invention also relates to compounds of formula (VII) and (VIII) for use as intermediates in said process. [0003] The nomenclature of the compounds of the formulas represented by Roman numerals on the relevant schemes is given in the description of the process of the invention. [0004] Method of the present invention is as follows: [0005] i) 3-(ethylenedioxy)-estra-5(10),9(11)-dien-17-one of formula (X) is combined with the in situ formed in anhydrous tetrahydrofuran by known methods Potassium acetylide reaction, [0006] ii) In the presence of triethylamine and acetic acid, the resulting 3-(ethylenedioxy)-17α-ethynyl-17β-hydroxy-estro-5(10), 9(11)-...

Claims

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Application Information

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IPC IPC(8): C07J21/00C07J31/00C07J41/00C07J71/00
CPCC07J71/001C07J41/0083C07J31/006C07J21/006A61P5/24A61P5/46C07J21/00C07J31/00C07J41/00C07J71/00
Inventor L·丹克斯G·维士奇Z·图巴J·科索尔戈伊C·莫尔纳E·玛格亚利
Owner RICHTER GEDEON NYRT
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