Preparation technology of desogestrel and its new intermediate compound

Abstract

The invention relates to a preparation process of desogestrel and a new intermediate compound thereof. In the prior art, the 11-position methylene group is introduced by the wittig reaction during the preparation of desogestrel, and this reaction produces more environmental pollutants. The invention provides a new preparation process of desogestrel and its new intermediate compound. The process introduces the 11-position methylene through an addition reaction, overcomes the problem of excessive discharge of pollutants, and shortens the The reaction time is shortened, the yield is improved, and industrial production is easy.

Description

Technical field

[0001] The invention relates to a preparation process of desogestrel and a new intermediate compound thereof. Background technique

[0002] The chemical name of desogestrel is 13β-ethyl-11-methylene-18,19-two norpregna-4en-20-yne-17β-ol. As a progestogen, it has good ovulation inhibitory effect due to its lack of androgen and estrogen activity, and is widely used clinically.

[0003] There are many synthetic methods of desogestrel, but its key synthetic process points mainly focus on the introduction of the 11-position methylene group and the 17-position ethynyl group in its structure. U.S. Patent US20050234251 uses 18-methylandrost-4-ene-3,17-dione (compound A) as the starting material, introduces the 11-position hydroxyl group through microbial transformation method, and obtains compound B, which is introduced by Wittig reaction after transformation The 11-position methylene group finally obtains the target compound desogestrel. Although the process rout...

Examples

Embodiment 1

[0038] Example 1: 11β-Hydroxy-11α-(trimethylsilylmethyl)-17,17-ethylenedioxy-18-methyl-estr-4ene

[0039]

[0040] In the there-necked flask, add compound Ia (20.0g, 60.6mmol), n-hexane (470mL), pass nitrogen protection, under stirring at room temperature, slowly dissolve the n-hexane solution of trimethylsilylmethyllithium (130mL, 0.546mol / L ) into the above system, heated in an oil bath for 1.5 hours, lowered the temperature, added 200 mL of water to terminate the reaction, separated the liquids, extracted the water phase twice with 200 mL of n-hexane, combined the n-hexane phase, washed twice with 200 mL of saturated brine, Magnesium sulfate (20.0 g) was dehydrated, filtered, the filtrate was concentrated to dryness, and recrystallized from methanol to obtain compound IIa (22.0 g, 52.6 mmol) as a white solid with a yield of 86.8%. MS(m / z): 418[M] + ; 1 H-NMR, δ0.10(9H, s, -S i (CH 3 ) 3 ), δ1.08 (3H, t, 18-CH 3 ), δ5.41(1H, d, 4-H); 13 C-NMR, 120.2 (C 4 ), 141.7 ...

Embodiment 2

[0041] Example 2: 11β-Hydroxy-11α-(trimethylsilylmethyl)-17,17-(1,3-propanedioxy)-18-methyl-estr-4ene

[0042]

[0043] In a three-neck flask, add cyclohexane (600 mL), compound Ib (20.0 g, 58.1 mmol), trimethylsilylmethylmagnesium chloride tetrahydrofuran solution (140 mL, 1.3 mol / L), and heat the reaction in an oil bath for 2 hours. Lower the temperature, add 200 mL of water to terminate the reaction, separate the liquids, extract the water phase twice with 200 mL of cyclohexane, combine the cyclohexane phase, wash twice with 200 mL of saturated brine, dehydrate with anhydrous magnesium sulfate (20.0 g), filter, and the filtrate Concentrate to dryness and recrystallize from ethanol to obtain white solid IIb (22.5 g, 52.0 mmol), yield 89.5%.

Embodiment 3

[0044] Example 3: 11-methylene-18-methyl-estr-4-en-17-one

[0045]

[0046] In a three-necked flask, compound IIa (20.0 g, 47.8 mmol) and methanol (400 mL) were added, under stirring at room temperature, 2.4 mL of concentrated hydrochloric acid was added, and the reaction was heated in a water bath for 1.5 h. Cool down, add 2.4 g of sodium bicarbonate to neutralize the reaction solution, add the reaction solution to 800 mL of water, filter, drain the filter cake, and recrystallize from methanol to obtain white solid compound 3 (13.0 g, 45.8 mmol), with a yield of 95.8%. MS(m / z): 284[M] + ; 1 H-NMR, δ0.76 (3H, t, 18-CH 3 ), δ4.83 (1H, s, =CH 2 ), δ4.92 (1H, s, =CH 2 ), δ5.48 (1H, d, 4-H). 13 C-NMR, 218 (C 17 )146(C 11 ), 139 (C 5 ), 121(C 4 ), 110 (=CH 2 ).

Technical field

[0001] The invention relates to a preparation process of desogestrel and a new intermediate compound thereof. Background technique

[0002] The chemical name of desogestrel is 13β-ethyl-11-methylene-18,19-two norpregna-4en-20-yne-17β-ol. As a progestogen, it has good ovulation inhibitory effect due to its lack of androgen and estrogen activity, and is widely used clinically.

[0003] There are many synthetic methods of desogestrel, but its key synthetic process points mainly focus on the introduction of the 11-position methylene group and the 17-position ethynyl group in its structure. U.S. Patent US20050234251 uses 18-methylandrost-4-ene-3,17-dione (compound A) as the starting material, introduces the 11-position hydroxyl group through microbial transformation method, and obtains compound B, which is introduced by Wittig reaction after transformation The 11-position methylene group finally obtains the target compound desogestrel. Although the process rout...

Examples

Embodiment 1

[0038] Example 1: 11β-Hydroxy-11α-(trimethylsilylmethyl)-17,17-ethylenedioxy-18-methyl-estr-4ene

[0039]

[0040] In the there-necked flask, add compound Ia (20.0g, 60.6mmol), n-hexane (470mL), pass nitrogen protection, under stirring at room temperature, slowly dissolve the n-hexane solution of trimethylsilylmethyllithium (130mL, 0.546mol / L ) into the above system, heated in an oil bath for 1.5 hours, lowered the temperature, added 200 mL of water to terminate the reaction, separated the liquids, extracted the water phase twice with 200 mL of n-hexane, combined the n-hexane phase, washed twice with 200 mL of saturated brine, Magnesium sulfate (20.0 g) was dehydrated, filtered, the filtrate was concentrated to dryness, and recrystallized from methanol to obtain compound IIa (22.0 g, 52.6 mmol) as a white solid with a yield of 86.8%. MS(m / z): 418[M] + ; 1 H-NMR, δ0.10(9H, s, -S i (CH 3 ) 3 ), δ1.08 (3H, t, 18-CH 3 ), δ5.41(1H, d, 4-H); 13 C-NMR, 120.2 (C 4 ), 141.7 ...

Embodiment 2

[0041] Example 2: 11β-Hydroxy-11α-(trimethylsilylmethyl)-17,17-(1,3-propanedioxy)-18-methyl-estr-4ene

[0042]

[0043] In a three-neck flask, add cyclohexane (600 mL), compound Ib (20.0 g, 58.1 mmol), trimethylsilylmethylmagnesium chloride tetrahydrofuran solution (140 mL, 1.3 mol / L), and heat the reaction in an oil bath for 2 hours. Lower the temperature, add 200 mL of water to terminate the reaction, separate the liquids, extract the water phase twice with 200 mL of cyclohexane, combine the cyclohexane phase, wash twice with 200 mL of saturated brine, dehydrate with anhydrous magnesium sulfate (20.0 g), filter, and the filtrate Concentrate to dryness and recrystallize from ethanol to obtain white solid IIb (22.5 g, 52.0 mmol), yield 89.5%.

Embodiment 3

[0044] Example 3: 11-methylene-18-methyl-estr-4-en-17-one

[0045]

[0046] In a three-necked flask, compound IIa (20.0 g, 47.8 mmol) and methanol (400 mL) were added, under stirring at room temperature, 2.4 mL of concentrated hydrochloric acid was added, and the reaction was heated in a water bath for 1.5 h. Cool down, add 2.4 g of sodium bicarbonate to neutralize the reaction solution, add the reaction solution to 800 mL of water, filter, drain the filter cake, and recrystallize from methanol to obtain white solid compound 3 (13.0 g, 45.8 mmol), with a yield of 95.8%. MS(m / z): 284[M] + ; 1 H-NMR, δ0.76 (3H, t, 18-CH 3 ), δ4.83 (1H, s, =CH 2 ), δ4.92 (1H, s, =CH 2 ), δ5.48 (1H, d, 4-H). 13 C-NMR, 218 (C 17 )146(C 11 ), 139 (C 5 ), 121(C 4 ), 110 (=CH 2 ).

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