CN102532233A - Preparation process for desogestrel and novel intermediate compound thereof - Google Patents
Preparation process for desogestrel and novel intermediate compound thereof Download PDFInfo
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- CN102532233A CN102532233A CN2010105922163A CN201010592216A CN102532233A CN 102532233 A CN102532233 A CN 102532233A CN 2010105922163 A CN2010105922163 A CN 2010105922163A CN 201010592216 A CN201010592216 A CN 201010592216A CN 102532233 A CN102532233 A CN 102532233A
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Abstract
The invention relates to a preparation process for desogestrel and a novel intermediate compound thereof. In the prior art, 11-bit methylene is introduced through a wittig reaction in the preparation process of desogestrel, and a large quantity of environmental pollutants are produced in the reaction. In the preparation process for desogestrel and the novel intermediate compound thereof provided by the invention, the 11-bit methylene is introduced through an addition reaction, so that the problem of excessive discharge of pollutants is solved, reaction time is shortened, yield is increased, and industrial production is facilitated.
Description
Affiliated technical field
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 radical-18, pregnant steroid-4 alkene-20-alkynes-17 β-alcohol falls in 19-two.As a kind of progestogen, because it does not have male sex hormone and estrogen activity, and have good ovulation restraining effect, be widely used clinically.
The compound method of desogestrel is a lot, but its crucial synthesis technique main points mainly concentrate on the introducing of 11 methylene radical and 17 ethynyls in its structure.U.S. Pat 20050234251 adopts 18-methyl androstane-4-alkene-3; 17-diketone (compd A) is a starting raw material, introduces 11 hydroxyls through microbe transformation method, obtains compd B; Adopt the Wittig reaction to introduce 11 methylene radical through transforming the back, finally obtain the target compound desogestrel.Though this operational path is shorter, total recovery is on the low side, is starting material in the compd B, prepares the total recovery average out to 12% of desogestrel, and the Wittig reaction produces more environmental pollutant.Its preparation were established is shown in route 1.
[route 1]
Application number is that the Chinese patent of CN101445542A discloses with 11 Alpha-hydroxies-18-methyl-female steroid-4-alkene-3, and 17-diketone (compd B) prepares the operational path of desogestrel for starting raw material, adopts 3 carbonyl diurethane sulfo-ketals protections in the route; 17 carbonyls of divalent alcohol ketal protection, the Birch reduction reaction is eliminated 3 thioketones that contract, Jone ' s oxidation 11 α hydroxyls; The Wittig reaction of 11 carbonyls; 17 ketal hydrolysis deprotections, 17 carbonyl ethinylations obtain the target compound desogestrel.In the compd B is starting raw material, and the desogestrel yield is 38%, and yield is higher.This operational path is similar with U.S. Pat 20050234251, takes the Wittig reaction to introduce 11 methylene radical, the same problem that produces more environmental pollutant that exists.Its preparation were established is shown in route 2.
[route 2]
Summary of the invention
The object of the invention is that a kind of new steroidal compounds is provided.
Two of the object of the invention is preparation method and the purposes that this steroidal compounds is provided.
The object of the invention three for a kind of preparation technology of new desogestrel is provided.
Steroidal compounds of the present invention is:
Wherein R is:
Compound I I is obtained through addition reaction by compound I and addition reagent, and wherein addition reagent is trimethyl silicane lithium methide reagent or trimethyl silicane methylmagnesium-chloride reagent, preferred trimethyl silicane lithium methide reagent.Compound I can obtain through purchase.Compound I is:
Wherein R is:
Compound I I hydrolysis can obtain compound III, and compound III is the midbody of preparation desogestrel.Compound III is:
New desogestrel preparation technology provided by the invention is:
1) compound I and addition reagent react prepare compound I I, and wherein addition reagent is trimethyl silicane lithium methide reagent or trimethyl silicane methylmagnesium-chloride reagent, preferred trimethyl silicane lithium methide reagent;
2) compound I I obtains compound III through hydrolysis reaction;
3) compound III obtains desogestrel through the ethinylation reaction.
The concrete operational path of preparation desogestrel is shown in route 3:
[route 3]
The technology that specifically prepares desogestrel is:
1) compound I and addition reagent react prepare compound I I:
In solvent, add compound I and addition reagent, the oil bath reacting by heating, the reaction times is 1～3 hour.After reaction finishes, with adding water in the reaction system, separatory, the organic phase dehydration concentrates, and gained solid recrystallization gets compound I I.Yield is 85～90%.Wherein, said addition reagent optional trimethyl silicane lithium methide reagent or trimethyl silicane methylmagnesium-chloride reagent, preferred trimethyl silicane lithium methide reagent; The optional normal hexane of said solvent, hexanaphthene, THF or normal heptane, preferred normal hexane.Optional methyl alcohol of said recrystallization solvent or ethanol, particular methanol.
2) compound I I obtains compound III through hydrolysis reaction:
Compound I I and organic solvent are joined in the reaction vessel, add an amount of acid, stirring reaction 1～2 hour after reaction finishes, neutralizes reaction solution with alkali, filter, and filtrating concentrates, gained solid recrystallization, compound III.Yield 92～97%.Wherein: the optional methyl alcohol of said reaction solvent, ethanol and acetone, particular methanol; Optional methyl alcohol of recrystallization solvent or ethanol, particular methanol.Said acid is: hydrochloric acid or sulfuric acid or tosic acid or perchloric acid, preferred hydrochloric acid.
3) compound III obtains desogestrel through the ethinylation reaction:
Under the nitrogen protection, metallic lithium is suspended in the ethylenediamine solution, feeds acetylene gas, prepared in reaction acetylene lithium 1～1.5 hour, cooling; Add compound III, ethynylation 3 hours, elutriation, normal hexane extraction; Separatory, the organic phase dehydration concentrates, and gained solid recrystallization gets desogestrel.Yield 70～80%.Optional normal hexane of said recrystallization solvent or normal heptane, preferred normal hexane.
Beneficial effect of the present invention is:
1, steroidal compounds provided by the invention can be used for preparing desogestrel; The introducing of 11 methylene radical is introduced with addition reaction in this route; Only use 5 hours with the wittig reacting phase than addition reaction, and the wittig reaction is used 40 hours, addition reaction has been shortened the reaction times greatly.
2, steroidal compounds II synthesis technique of the present invention is simple, be easy to industriallization, and pollutant emission is less.
3, the present invention prepares the operational path of desogestrel, and yield is high.
Embodiment
Embodiment 1:11 beta-hydroxy-11 α-(trimethyl silicane methyl)-17,17-ethylenedioxy-18-methyl-female steroid-4 alkene
In there-necked flask, and adding compound I a (20.0g, 60.6mmol), normal hexane (470mL), logical nitrogen protection; Under the stirring at room, (130mL 0.546mol/L) adds in the above-mentioned system oil bath reacting by heating 1.5 hours to slow hexane solution with the trimethyl silicane lithium methide; Cooling adds entry 200mL termination reaction, separatory, and water extracts twice with normal hexane 200mL; Merge the normal hexane phase, with saturated aqueous common salt 200mL washed twice, anhydrous magnesium sulfate (20.0g) dehydration is filtered; Filtrating be concentrated into dried, with recrystallizing methanol get white solid compound I I a (22.0g, 52.6mmol), yield 86.8%.MS(m/z)：418[M]
+；
1H-NMR，δ0.10(9H，s，-S
i(CH
3)
3)，δ1.08(3H，t，18-CH
3)，δ5.41(1H，d，4-H)；
13C-NMR，120.2(C
4)，141.7(C
5)，120.7(C
17)。
Embodiment 2:11 beta-hydroxy-11 α-(trimethyl silicane methyl)-17,17-(1, the 3-third dioxy base)-18-methyl-female steroid-4 alkene
In there-necked flask, add hexanaphthene (600m L), compound I b (20.0g, 58.1mmol), trimethyl silicane methylmagnesium-chloride tetrahydrofuran solution (140mL, 1.3mol/L), oil bath reacting by heating 2 hours.Cooling adds entry 200mL termination reaction, separatory; Water extracts twice with hexanaphthene 200mL, merges the hexanaphthene phase, with saturated aqueous common salt 200mL washed twice; Anhydrous magnesium sulfate (20.0g) dehydration is filtered, and filtrating is concentrated into dried; With ethyl alcohol recrystallization get white solid IIb (22.5g, 52.0mmol), yield 89.5%.
Embodiment 3:11-methylene radical-18-methyl-female steroid-4 alkene-17-ketone
In there-necked flask, (20.0g, 47.8mmol), methyl alcohol (400mL) under the stirring at room, adds concentrated hydrochloric acid 2.4mL, heating in water bath for reaction 1.5h to add compound I I a.Cooling adds 2.4g sodium hydrogencarbonate neutralization reaction liquid, and reaction solution is added in the 800mL water, filters, and filter cake is drained, with recrystallizing methanol get white solid compound 3 (13.0g, 45.8mmol), yield 95.8%.MS(m/z)：284[M]
+；
1H-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)。
13C-NMR，218(C
17)146(C
11)，139(C
5)，121(C
4)，110(＝CH
2)。
Embodiment 4:11-methylene radical-18-methyl-female steroid-4 alkene-17-ketone
In there-necked flask, (20.0g, 46.2mmol), ethanol (400mL) under the stirring at room, adds 10% dilute sulphuric acid 2.4mL, heating in water bath insulation reaction 2h to add compound I I b.Cooling adds 2.4g sodium hydrogencarbonate neutralization reaction liquid, and reaction solution is added in the 800mL water, filters, and filter cake is drained, with ethyl alcohol recrystallization get white solid compound 3 (12.5g, 44.0mmol), yield 95.2%.
Embodiment 5: desogestrel
Under the nitrogen protection, in four-hole bottle, add quadrol (120mL), add lithium bar (6.0g; 0.865mol), room temperature is led to acetylene gas, and oil bath adds hot preparation acetylene lithium reaction 1h; Cooling; (8.0g, anhydrous tetrahydro furan 28.1mmol) (40mL) solution joined in the above-mentioned reaction solution, in 35～40 ℃ of ethynylations 3 hours with compound III.Reaction solution is slowly dripped in the 360mL frozen water, elutriation, water is with normal hexane (3 * 120mL) extractions.Organic phase again with saturated sodium-chloride water solution washing to neutral, anhydrous magnesium sulfate drying filters, be evaporated to dried, with the desogestrel of normal hexane recrystallization (6.4g, 20.65mmol), yield 73.5%.MS(m/z)：310[M]
+；
1H-NMR，δ1.06(3H，t，18-CH
3)，2.60(1H，s，17-C≡CH)，δ4.77(1H，s，＝CH
2)，δ4.97(1H，s，＝CH
2)，δ5.46(1H，d，4-H)；
13C-NMR，147(C
11)139(C
5)，124(C
4)，108(＝CH
2)。
Claims (10)
1. steroidal compounds is:
Wherein R is:
2. the described steroidal compounds of claim 1 is characterized by: compound I I is obtained through addition reaction by compound I and addition reagent, and compound I is:
Wherein R is:
3. steroidal compounds according to claim 2 is characterized by: addition reagent is trimethyl silicane lithium methide or trimethyl silicane methylmagnesium-chloride.
4. steroidal compounds according to claim 2 is characterized by: addition reagent is the trimethyl silicane lithium methide.
5. the above-mentioned any described steroidal compounds compound I of claim I hydrolysis can obtain compound III, and compound III is:
6. a new desogestrel preparation technology comprises the steps:
1) compound I and addition reagent react prepare compound I I;
2) compound I I obtains compound III through hydrolysis reaction;
3) compound III obtains desogestrel through the ethinylation reaction,
Its operational path is shown in the following figure:
7. preparation technology according to claim 6 is characterized by: addition reagent is trimethyl silicane lithium methide or trimethyl silicane methylmagnesium-chloride.
8. preparation technology according to claim 7 is characterized by: addition reagent is the trimethyl silicane lithium methide.
9. according to claim 6 or 7 or 8 described preparation technologies, it is characterized by: the solvent that recrystallization is used step 1) and 2) is methyl alcohol or ethanol.
10. preparation technology according to claim 9 is characterized by: the step 1) solvent for use is normal hexane, hexanaphthene, THF or normal heptane.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010592216.3A CN102532233B (en) | 2010-12-17 | 2010-12-17 | The preparation technology of desogestrel and new midbody compound thereof |
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|---|---|---|---|
| CN201010592216.3A CN102532233B (en) | 2010-12-17 | 2010-12-17 | The preparation technology of desogestrel and new midbody compound thereof |
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| CN102532233A true CN102532233A (en) | 2012-07-04 |
| CN102532233B CN102532233B (en) | 2016-07-06 |
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|---|---|---|---|
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN104496872A (en) * | 2014-12-29 | 2015-04-08 | 华润紫竹药业有限公司 | Separating and purifying method for steroid ethyl hydroxide |
| CN105906680A (en) * | 2016-04-27 | 2016-08-31 | 华润紫竹药业有限公司 | Desogestrel preparation method and midbody compound |
-
2010
- 2010-12-17 CN CN201010592216.3A patent/CN102532233B/en active Active
Non-Patent Citations (1)
| Title |
|---|
| LUTZ F. TIETZE ET AL.: "Enantioselective Total Synthesis of the Oral Contraceptive Desogestrel by a Double Heck Reaction", 《CHEM. EUR. J.》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN104496872A (en) * | 2014-12-29 | 2015-04-08 | 华润紫竹药业有限公司 | Separating and purifying method for steroid ethyl hydroxide |
| 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 |
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| Publication number | Publication date |
|---|---|
| CN102532233B (en) | 2016-07-06 |
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