CN102532233B - The preparation technology of desogestrel and new midbody compound thereof - Google Patents
The preparation technology of desogestrel and new midbody compound thereof Download PDFInfo
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- CN102532233B CN102532233B CN201010592216.3A CN201010592216A CN102532233B CN 102532233 B CN102532233 B CN 102532233B CN 201010592216 A CN201010592216 A CN 201010592216A CN 102532233 B CN102532233 B CN 102532233B
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Abstract
The present invention relates to the preparation technology of desogestrel and new midbody compound thereof.Preparing 11 methylene of introducing in desogestrel process in prior art all to introduce with wittig reaction, the environmental contaminants that this reaction produces are more.The present invention provides the preparation technology of a kind of new desogestrel and new midbody compound thereof, this technique is introduced by additive reaction to 11 methylene, overcomes the problem that pollutant emission is too much, and shortens the response time, improve productivity, it is easy to industrialized production.
Description
Art
The present invention relates to the preparation technology of desogestrel and new midbody compound thereof.
Background technology
Desogestrel (Desogestrel) chemical name 13 β-ethyl-11-methylene-18, pregnant steroid-4 alkene-20-alkynes-17 β-ol drops in 19-bis-.As a kind of progestogen, owing to it does not have androgen and estrogen activity, and there is good ovulation inhibitory action, be widely used clinically.
The synthetic method of desogestrel is a lot, but the synthesis technique main points of its key focus primarily upon the introducing of 11 methylene and 17 acetenyls in its structure.US Patent No. 20050234251 adopts 18-methyl androstane-4-alkene-3,17-diketone (compound A) is initiation material, 11 hydroxyls are introduced by microbe transformation method, obtain compound B, by adopting Wittig reaction to introduce 11 methylene after transforming, finally give target compound desogestrel.Although this process route is shorter, but total recovery is on the low side, counts with compound B for starting material, prepares the total recovery average out to 12% of desogestrel, and Wittig reaction produces more environmental contaminants.Its preparation technology route is as shown in Scheme 1.
[route 1]
The Chinese patent that application number is CN101445542A discloses with 11 Alpha-hydroxy-18-methyl-estra-4-alkene-3; 17-diketone (compound B) prepares the process route of desogestrel for initiation material; route adopts 3 carbonyl dithioketal protections; dihydroxylic alcohols ketal 17 carbonyls of protection; Birch reduction reaction eliminates 3 contracting thioketone; Jone ' s aoxidizes 11 α hydroxyls; the Wittig reaction of 11 carbonyls; 17 hydrolysis of ketal deprotections; 17 carbonyl ethinylations, obtain target compound desogestrel.Counting with compound B for initiation material, desogestrel yield is 38%, and yield is higher.This process route is similar to US Patent No. 20050234251, takes Wittig reaction to introduce 11 methylene, equally exists the problem producing more environmental contaminants.Its preparation technology route is as shown in Scheme 2.
[route 2]
Summary of the invention
The purpose of the present invention is for providing a kind of new steroidal compounds.
The two of the purpose of the present invention are for providing preparation method and the purposes of this steroidal compounds.
The three of the purpose of the present invention are for providing the preparation technology of a kind of new desogestrel.
The steroidal compounds of the present invention is:
Wherein R is:
Compound II per is obtained through additive reaction with addition reagent by compound I, and wherein addition reagent is trimethyl silicane lithium methide reagent or trimethyl silicane methyl chloride azoviolet, it is preferable that trimethyl silicane lithium methide reagent.Compound I can pass through to be commercially available.Compound I is:
Wherein R is:
It is the intermediate preparing desogestrel that Compound II per hydrolysis can obtain Compound II per I, Compound II per I.Compound II per I is:
New desogestrel preparation technology provided by the invention is:
1) compound I and addition reagent reacting prepare Compound II per, and wherein addition reagent is trimethyl silicane lithium methide reagent or trimethyl silicane methyl chloride azoviolet, it is preferable that trimethyl silicane lithium methide reagent；
2) Compound II per obtains Compound II per I through hydrolysis；
3) Compound II per I obtains desogestrel through ethynylation.
Prepare the concrete technology route of desogestrel as shown in Scheme 3:
[route 3]
The technique specifically preparing desogestrel is:
1) compound I and addition reagent reacting prepare Compound II per:
Adding compound I and addition reagent, oil bath reacting by heating in a solvent, the response time is 1～3 hour.After completion of the reaction, adding water in reaction system, separatory, organic facies dehydration, concentration, gained solid recrystallization obtains Compound II per.Yield is 85～90%.Wherein, the optional trimethyl silicane lithium methide reagent of described addition reagent or trimethyl silicane methyl chloride azoviolet, it is preferable that trimethyl silicane lithium methide reagent；The optional normal hexane of described solvent, hexamethylene, oxolane or normal heptane, it is preferable that normal hexane.The optional methanol of described recrystallization solvent or ethanol, it is preferable that methanol.
2) Compound II per obtains Compound II per I through hydrolysis:
Joining in reaction vessel by Compound II per and organic solvent, add appropriate acid, stirring reaction 1～2 hour, after reaction terminates, neutralized by reactant liquor alkali, filter, filtrate concentrates, and gained solid recrystallization obtains Compound II per I.Yield 92～97%.Wherein: the optional methanol of described reaction dissolvent, ethanol and acetone, it is preferable that methanol；The optional methanol of recrystallization solvent or ethanol, it is preferable that methanol.Described acid is: hydrochloric acid or sulphuric acid or p-methyl benzenesulfonic acid or perchloric acid, it is preferable that hydrochloric acid.
3) Compound II per I obtains desogestrel through ethynylation:
Under nitrogen protection, being suspended in ethylenediamine solution by lithium metal, pass into acetylene gas, reaction prepares acetylene lithium 1～1.5 hour, cooling; add Compound II per I, ethynylation 3 hours, elutriation, normal hexane extraction; separatory, organic facies dehydration, concentration, gained solid recrystallization obtains desogestrel.Yield 70～80%.The optional normal hexane of described recrystallization solvent or normal heptane, it is preferable that normal hexane.
The invention have the benefit that
1, steroidal compounds provided by the invention can be used for preparing desogestrel, in this route, the introducing additive reaction of 11 methylene introduces, with wittig reacting phase than additive reaction only with 5 little time, and wittig react with 40 hours, additive reaction substantially reduces the response time.
2, the steroidal compounds II synthesis technique of the present invention is simple, it is easy to industrialization, and pollutant emission is less.
3, the present invention prepares the process route of desogestrel, and yield is high.
Detailed description of the invention
Embodiment 1:11 beta-hydroxy-11 α-(trimethyl silicane methyl)-17,17-ethylenedioxy-18-methyl-estra-4 alkene
In there-necked flask, add compound Ia (20.0g, 60.6mmol), normal hexane (470mL), logical nitrogen protection, it is stirred at room temperature down, slowly by the hexane solution (130mL of trimethyl silicane lithium methide, 0.546mol/L) add in above-mentioned system, oil bath reacting by heating 1.5 hours, cooling, add water 200mL and terminate reaction, separatory, aqueous phase extracts twice with normal hexane 200mL, merge normal hexane phase, wash twice with saturated aqueous common salt 200mL, anhydrous magnesium sulfate (20.0g) dehydration, filter, filtrate is concentrated into dry, compound as white solid IIa (22.0g is obtained with recrystallizing methanol, 52.6mmol), yield 86.8%.MS (m/z): 418 [M]+；1H-NMR, δ 0.10 (9H, s ,-Si(CH3)3), δ 1.08 (3H, t, 18-CH3), δ 5.41 (1H, d, 4-H)；13C-NMR, 120.2 (C4), 141.7 (C5), 120.7 (C17)。
Embodiment 2:11 beta-hydroxy-11 α-(trimethyl silicane methyl)-17,17-(1,3-third dioxy base)-18-methyl-estra-4 alkene
In there-necked flask, add hexamethylene (600mL), compounds ib (20.0g, 58.1mmol), trimethyl silicane methyl-magnesium-chloride tetrahydrofuran solution (140mL, 1.3mol/L), oil bath reacting by heating 2 hours.Cooling, adding water 200mL and terminate reaction, separatory, aqueous phase extracts twice with hexamethylene 200mL, merge hexamethylene phase, wash twice with saturated aqueous common salt 200mL, anhydrous magnesium sulfate (20.0g) dehydration, filter, filtrate is concentrated into dry, white solid IIb (22.5g, 52.0mmol), yield 89.5% is obtained with ethyl alcohol recrystallization.
Embodiment 3:11-methylene-18-methyl-estra-4 alkene-17-ketone
In there-necked flask, add Compound II per a (20.0g, 47.8mmol), methanol (400mL), be stirred at room temperature down, add concentrated hydrochloric acid 2.4mL, heating in water bath for reaction 1.5h.Cooling, adds in 2.4g sodium bicarbonate and reactant liquor, is added by reactant liquor in 800mL water, filter, and filter cake is drained, and obtains compound as white solid 3 (13.0g, 45.8mmol), yield 95.8% with recrystallizing methanol.MS (m/z): 284 [M]+；1H-NMR, δ 0.76 (3H, t, 18-CH3), δ 4.83 (1H, s ,=CH2), δ 4.92 (1H, s ,=CH2), δ 5.48 (1H, d, 4-H).13C-NMR, 218 (C17)146(C11), 139 (C5), 121 (C4), 110 (=CH2)。
Embodiment 4:11-methylene-18-methyl-estra-4 alkene-17-ketone
In there-necked flask, add Compound II per b (20.0g, 46.2mmol), ethanol (400mL), be stirred at room temperature down, add 10% dilute sulfuric acid 2.4mL, heating in water bath insulation reaction 2h.Cooling, adds in 2.4g sodium bicarbonate and reactant liquor, is added by reactant liquor in 800mL water, filter, and filter cake is drained, and obtains compound as white solid 3 (12.5g, 44.0mmol), yield 95.2% with ethyl alcohol recrystallization.
Embodiment 5: desogestrel
Under nitrogen protection; four-hole bottle adds ethylenediamine (120mL); add lithium bar (6.0g; 0.865mol), room temperature leads to acetylene gas, and oil bath adds hot preparation acetylene lithium reaction 1h; cooling; anhydrous tetrahydro furan (40mL) solution of Compound II per I (8.0g, 28.1mmol) is joined in above-mentioned reactant liquor, in 35～40 DEG C of ethynylations 3 hours.Being slowly added dropwise by reactant liquor in 360mL frozen water, elutriation, aqueous phase normal hexane (3 × 120mL) extracts.Organic facies is extremely neutral with saturated sodium-chloride water solution washing again, and anhydrous magnesium sulfate dries, and filters, is evaporated to dry, with the desogestrel (6.4g, 20.65mmol) of normal hexane recrystallization, yield 73.5%.MS (m/z): 310 [M]+；1H-NMR, δ 1.06 (3H, t, 18-CH3), 2.60 (1H, s, 17-C ≡ CH), δ 4.77 (1H, s ,=CH2), δ 4.97 (1H, s ,=CH2), δ 5.46 (1H, d, 4-H)；13C-NMR, 147 (C11)139(C5), 124 (C4), 108 (=CH2)。
Claims (9)
1. steroidal compounds, it is:
2. the preparation method of the steroidal compounds described in claim 1, is characterized by: compound Ia, Ib or Ic obtain Compound II per a, IIb or IIc described in claim 1 with addition reagent through additive reaction respectively, and compound Ia, Ib and Ic be:
3. preparation method according to claim 2, is characterized by: addition reagent is trimethyl silicane lithium methide or trimethyl silicane methyl-magnesium-chloride.
4. preparation method according to claim 2, is characterized by: addition reagent is trimethyl silicane lithium methide.
5. the preparation method of Compound II per I, is characterized by: Compound II per a, IIb or IIc hydrolysis described in claim 1 obtains Compound II per I, Compound II per I and is:
6. a preparation method for desogestrel, comprises the steps:
1) compound Ia and addition reagent reacting prepare Compound II per a；
2) Compound II per a obtains Compound II per I through hydrolysis；
3) Compound II per I obtains desogestrel through ethynylation,
Its syntheti c route is as follows:
1) compounds ib and addition reagent reacting prepare Compound II per b；
2) Compound II per b obtains Compound II per I through hydrolysis；
3) Compound II per I obtains desogestrel through ethynylation,
Its syntheti c route is as follows:
1) compound Ic and addition reagent reacting prepare Compound II per c；
2) Compound II per c obtains Compound II per I through hydrolysis；
3) Compound II per I obtains desogestrel through ethynylation,
Its syntheti c route is as follows:
7. preparation method according to claim 6, is characterized by: addition reagent is trimethyl silicane lithium methide or trimethyl silicane methyl-magnesium-chloride.
8. preparation method according to claim 7, is characterized by: addition reagent is trimethyl silicane lithium methide.
9. preparation method according to claim 8, is characterized by: step 1) solvent for use is normal hexane, hexamethylene, oxolane or normal heptane.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103804454A (en) * | 2012-11-14 | 2014-05-21 | 上海信谊药厂有限公司 | Desogestrel crystal form and preparation method thereof |
| CN104496872B (en) * | 2014-12-29 | 2018-04-20 | 华润紫竹药业有限公司 | A kind of isolation and purification method of steroidal ethyl hydroxylate |
| CN105906680A (en) * | 2016-04-27 | 2016-08-31 | 华润紫竹药业有限公司 | Desogestrel preparation method and midbody compound |
| CN115974951A (en) * | 2023-01-05 | 2023-04-18 | 湖南科益新生物医药有限公司 | Refining method of desogestrel |
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Non-Patent Citations (1)
| Title |
|---|
| Enantioselective Total Synthesis of the Oral Contraceptive Desogestrel by a Double Heck Reaction;Lutz F. Tietze et al.;《Chem. Eur. J.》;20071123;第14卷;第1541-1551页 * |
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