CN102964418B - Preparation technology of desogestrel and new intermediate compound thereof - Google Patents
Preparation technology of desogestrel and new intermediate compound thereof Download PDFInfo
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- QDCJIPFNVBDLRH-UHFFFAOYSA-N CC1(C)COCOC1 Chemical compound CC1(C)COCOC1 QDCJIPFNVBDLRH-UHFFFAOYSA-N 0.000 description 1
- PFFLOKVAHTVSOF-UHFFFAOYSA-N NC1[O](C2)C2CCCO1 Chemical compound NC1[O](C2)C2CCCO1 PFFLOKVAHTVSOF-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention relates to a preparation technology of desogestrel or implanon. Synthetic methods of prior art have deficiencies of low yield and poor quality of prepared finish products. The technology uses a compound prepared through a Jone's oxidation as a starting material to obtain the intermediate compound which can simultaneously prepare the two object products.
Description
Technical field
The invention provides a kind of new steroidal compounds and its production and use.
Background technology
Desogestrel, has another name called desogestrel, is the medicine of first extensive clinical application of acquisition in third generation progestogen.A large amount of clinical trial shows that desogestrel is a kind of progestogen efficiently with contraceptive efficacy, has high selectivity, affects little, few side effects on human physiological metabolism, and the contraceptive bian of itself and oestrogenic hormon compatibility is a kind of contraceptive be worthy of popularization.
The synthetic method of desogestrel is a lot, wherein US Patent No. 20050234251 adopts 18-methyl female steroid-4-alkene-3,17-diketone (compd A) is starting raw material, 11-position hydroxyl is introduced by microbe transformation method, obtain compd B, carry out corresponding structural modification successively by the structure of 3-position, 11-position and 17-position subsequently and obtain target compound-desogestrel.This operational path is shorter, but total recovery is on the low side, is starting material in compd B, prepares the total recovery average out to 12.3% of desogestrel.
Application number is that the Chinese patent of CN101445542A discloses 11 Alpha-hydroxy-18-methyl-estra-4-alkene-3, 17-diketone (compd B) is starting raw material, protect through 3-position carbonyl dithioketal, dibasic alcohol ketal protection 17-position carbonyl, Birch reduction reaction eliminates 3-position contracting thioketones, Jone ' s is oxidized 11 Alpha-hydroxies, the Wittig reaction of 11-position carbonyl, 17-position hydrolysis of ketal deprotection, the carbonyl ethinylation of 17-position, obtain target compound-desogestrel, take compd B as starting raw material, desogestrel yield is 38%, yield is higher, but when Jone ' s is oxidized 11 Alpha-hydroxy, inevitably cause 17-position hydrolysis of ketal deprotection, thus affect follow-up Wittig reaction, the purity of target product and yield are all exerted a certain influence.Its preparation were established is as shown in Scheme 1:
[route 1]
Summary of the invention
An object of the present invention is for providing a kind of new steroidal compounds.
The preparation method that two of object of the present invention is the steroidal compounds that provides this new.
Object of the present invention three for the steroidal compounds that provides this new is for the preparation of the purposes of desogestrel and Org 3236.
The technical scheme realizing the object of the invention is:
New steroidal compounds, its structure is shown below:
Wherein, R
1for:
R
2for:
Work as R
2during for O, be compound V, be shown below:
Wherein, R
1for:
Compound V is obtained by the protection of 3-position ketal by compound IV, and compound IV is: 18-methyl female steroid-4-alkene-3,11,17-triketone, compound IV can commercially be buied.
Compound V ketal protection 17-position carbonyl obtains compound of the present invention.
Steroidal compounds of the present invention can be used for preparing desogestrel and Org 3236.
The invention provides the preparation method of a kind of new desogestrel and Org 3236, the method adopts 18-methyl female steroid-4-alkene-3,11,17-triketone (compound IV) to be starting raw material, prepares desogestrel and Org 3236 successively through following steps:
1) 3 carbonyls of compound IV are through the protection of dithio alcohol, obtain compound V;
2) compound V dibasic alcohol ketal protects 17 carbonyls, obtains compound VI;
3) compound VI 11 carbonyls Wittig reaction or Peterson reaction and 17 hydrolysis of ketal deprotections, obtain compound VI I;
4) ethynylation of compound VI I 17 carbonyls, obtains compound VI II;
5) Birch reduction reaction eliminates 3 contracting thioketones of compound VI II, obtains desogestrel (Compound I);
6) compound VI II3 position contracting thioketones oxidizing reaction, obtains Org 3236 (Compound II per).
The operational path of above-mentioned preparation method is as shown in Scheme 2:
[route 2]
Specifically, above-mentioned steps of the present invention can be realized by following reaction:
1) 3 carbonyls are through the protection of dithio alcohol, obtain compound V:
Protect 3 carbonyls with binary mercaptan: in a solvent by 18-methyl female steroid-4-alkene-3,11,17-triketone (compound IV) and binary thiol reactant, take boron trifluoride diethyl etherate as catalyzer, temperature of reaction is 25 ~ 30 DEG C, and the reaction times is 4 ~ 6 hours.After completion of the reaction, reaction solution is poured into alkaline aqueous solution neutralization, elutriation, then filter, filter cake is washed to neutrality, recrystallizing methanol, and dry 18-methyl female steroid-4-alkene-11,17-diketone-3-contracting thioketones (compound V), yield is 98 ~ 100%.Wherein, the optional dithioglycol of binary mercaptan or 1,3-dimercaptopropane, preferred dithioglycol; The weightmeasurement ratio of compound IV and binary mercaptan is 1: 0.3 ~ 0.5; The weightmeasurement ratio of compound IV and boron trifluoride diethyl etherate is 1: 0.25 ~ 0.45; The optional methyl alcohol of described solvent, tetrahydrofuran (THF) or Glacial acetic acid, particular methanol.
2) dibasic alcohol ketal protects 17 carbonyls, obtains compound VI:
By compound V, dibasic alcohol and organic solvent join in reaction vessel, then add catalyzer tosic acid, 35 ~ 45 DEG C of reactions 3 ~ 6 hours, after reaction terminates, by the basic solution neutralization of reaction solution with about 0 DEG C, add water elutriation, product is separated out, then filters, filter cake is washed to neutrality, ethyl alcohol recrystallization, 40 DEG C of constant pressure and dries obtain 18-methyl female steroid-4-alkene-11,17-diketone-3-contracting thioketones-17-contracting ethylidene glycol (compound VI), yield 95 ~ 97%.Wherein, the weight ratio of compound V and dibasic alcohol is 1: 2.0 ~ 3.5, one or both mixed solvent (blending ratio is 2: 1) in the selected optional triethyl orthoformate of organic solvent and methylene dichloride, preferred triethyl orthoformate, described dibasic alcohol is ethylene glycol, 1,3-PD or 2,2-dimethyl-1, ammediol, preferred ethylene glycol.
3) Wittig of 11 carbonyls reacts and 17 hydrolysis of ketal deprotections, obtains compound VI I;
The preparation of Wittig reagent: add solvent in reactor, the air in nitrogen replacement reactor, adds highly basic and methyl triphenylphosphonium bromide phosphorus, adds rear oil bath and is warming up to reflux state, keeps reaction about 1 ~ 2 hour.Wherein said highly basic has: sodium hydride, sodium amide, n-Butyl Lithium or potassium tert.-butoxide, preferred potassium tert.-butoxide; Reaction solvent is: tetrahydrofuran (THF), methyltetrahydrofuran, methyl-sulphoxide or ether, preferred tetrahydrofuran (THF).
Wittig reacts: be cooled to room temperature after the preparation of Wittig reagent completes, and drop into compound VI, react 20 ~ 40 hours at reflux, wherein Wittig is methylene triphenyl phosphorus, is obtained by highly basic and methyl triphenylphosphonium bromide phosphorus reaction.
Hydrolysis deprotection reaction: Wittig after completion of the reaction; be cooled to room temperature; add saturated aqueous ammonium chloride termination reaction; stir; add concentrated hydrochloric acid again and adjust system pH=1 ~ 2; stirring reaction 18 ~ 24 hours at 20 ~ 25 DEG C; then neutrality is adjusted to saturated sodium carbonate solution; reaction solution is transferred in separating funnel; separatory, extraction, merging organic phase, dehydration, decolouring, crystallization, filtration, drying obtain 18-methyl female steroid-4-alkene-11-methylene radical-17-ketone-3-contracting thioketones (compound VI I), yield 63 ~ 66%.
The Peterson reaction of 11 carbonyls and 17 hydrolysis of ketal deprotections, obtain compound VI I;
Peterson reacts: in reaction flask, add solvent, metal magnesium chips and chloromethyl trimethyl silicane, the air in nitrogen replacement reactor, then stirs 2 ~ 3 hours at 30 ~ 35 DEG C, obtained Peterson reagent.Then compound VI is added, react 13 ~ 15 hours at reflux, wherein the weight ratio of compound VI and metal magnesium chips is 1: 1.0 ~ 1.5, the weightmeasurement ratio of compound VI and chloromethyl trimethyl silicane is 1: 5.0 ~ 7.0, reaction solvent is: tetrahydrofuran (THF), methyltetrahydrofuran, methyl-sulphoxide or ether, preferred tetrahydrofuran (THF).
Peterson hydrolysis and deprotection reaction: Peterson are after completion of the reaction; be cooled to 0 ~ 5 DEG C; add purified water termination reaction; stir; add concentrated hydrochloric acid again and adjust system pH=1 ~ 2; stirring reaction 5 ~ 8 hours at 20 ~ 25 DEG C; then neutrality is adjusted to saturated sodium carbonate solution; reaction solution is transferred in separating funnel; separatory, extraction, merging organic phase, dehydration, decolouring, crystallization, filtration, drying obtain 18-methyl female steroid-4-alkene-11-methylene radical-17-ketone-3-contracting thioketones (compound VI I), yield 64 ~ 66%.
4) ethynylation of 17 carbonyls, obtains compound VI I;
In reactor, add quadrol, nitrogen replacement reaction air wherein, add lithium bar, room temperature leads to acetylene gas 2 ~ 4h, compound VI I is dissolved in organic solvent and joins in above-mentioned reaction solution, 30 ~ 35 DEG C of ethynylation 2 ~ 4h hour.Be added to the water only reaction, separatory, extraction, merging organic phase, dehydration, crystallization, filtration, dry 13 β-ethyl-11-methylene radical-18,19-dinor--17 α-pregnant steroid-4-alkene-20-ethynyl-17-alcohol-3-thio ketal ization (compound VI II), yield 83 ~ 85%.Wherein, the weight ratio of compound VI I and lithium bar is 1: 0.7 ~ 1.5, the weightmeasurement ratio of compound VI I and quadrol is 1: 20 ~ 30, the theoretical amount of acetylene is 2 ~ 6 times, described organic solvent is the mixture of tetrahydrofuran (THF), methyltetrahydrofuran, dimethyl sulfoxide (DMSO) or ether and tetrahydrofuran (THF), preferred tetrahydrofuran (THF).
5) Birch reduction reaction eliminates 3 contracting thioketones, obtains desogestrel (Compound I);
Joined by sodium Metal 99.5 in the liquefied ammonia of-40 ~-60 DEG C, then add the solution of compound VI II ,-40 ~-60 DEG C of reaction 2 ~ 3h, slowly add acetonitrile termination reaction, steam liquefied ammonia.In residuum impouring frozen water, with n-hexane extraction, saturated sodium-chloride water solution is washed till neutrality, dehydration, concentrated to obtain crude product, and normal hexane is refined, and obtains desogestrel (Compound I), yield 70 ~ 74%.Reactant wherein used in Birch reduction reaction is sodium Metal 99.5 and liquefied ammonia, the weight ratio of compound VI II and sodium Metal 99.5 is 1: 0.3 ~ 0.4, the weightmeasurement ratio of compound VI II and liquefied ammonia is 1: 12 ~ 16, organic solvent used in compound VI II solution is one or both the mixed solvent (blending ratio is 1: 1) in tetrahydrofuran (THF) and ether, preferred tetrahydrofuran (THF).
6) 3 contracting thioketones oxidizing reactions, obtain Org 3236 (Compound II per).
In four-hole bottle, add cupric oxide, anhydrous cupric chloride and organic solvent, under stirring, be heated to backflow, add compound VI II and DMF, back flow reaction 1 ~ 2 hour, cooling, filter, insolubles extracts with ethanol/dichloromethane solution respectively, and alkali lye washes organic phase, dehydration, filter, concentrating under reduced pressure obtains Org 3236 (Compound II per), yield 81 ~ 85.0%.Wherein the weight ratio of compound VI II and cupric oxide is 1: 0.2 ~ 0.3, the weight ratio of compound VI II and anhydrous cupric chloride be 1: 0.7 ~ 1, compound VI II and the weightmeasurement ratio of DMF be 1: 0.5 ~ 1, described organic solvent is acetone or methylene dichloride, preferred acetone.
Beneficial effect of the present invention is:
The present invention obtains two products by an operational path, and whole piece operational path does not have obvious side reaction, and target product purity is high.Whole piece route Org 3236 and desogestrel total recovery can reach 31.9%, 37.6% respectively.In addition, the inventive method is simple to operate equally, is suitable for industrialization.
Embodiment
Following examples for illustration of the present invention, but are not used in and limit the scope of the invention.As nothing specializes, the weightmeasurement ratio related in embodiment refers to the ratio (1: 1 for 1g solid is to 1mL liquid) of solid weight and liquid volume.
Embodiment 1:18-methyl female steroid-4-alkene-11,17-diketone-3-contracting thioketones (compound V)
In there-necked flask, add methyl alcohol (75mL), 18-methyl female steroid-4-alkene-3,11,17-triketone (compound IV, 15g, 49.60mmol) (compound IV is that purchase obtains) and dithioglycol (5.0mL, 59.66mmol), control temperature is 30 DEG C, drip boron trifluoride diethyl etherate (6.0mL), add rear 30 DEG C of reaction 5h.Carry out elutriation with 450mL 10% aqueous sodium hydroxide solution, filter, filter cake is washed to neutrality, drains, and recrystallizing methanol obtains compound V (18.3g, 49.60mmol, yield 100%).MS(m/z)：376[M]
+，
1H-NMR(CDCl
3)，δ0.81(3H，t，18-CH
3)，δ5.67(1H，t，H-4)；
13C-NMR，210.1(C-11)，216.0(C-17)，139.78(C-5)，127.9(C-4)。
Embodiment 2:18-methyl female steroid-4-alkene-11,17-diketone-3-contracting thioketones-17-contracting ethylidene glycol (compound VI)
Compound V (13.1g is added in the there-necked flask of drying, 34.9mmol), ethylene glycol (10.7mL, 192mmol) with triethyl orthoformate (20mL, 120mmol), stir 5min, warming-in-water to 40 DEG C, drop into tosic acid monohydrate (0.6g, 3.15mmol), be then incubated 40 DEG C ± 2 DEG C reaction 5h.Be cooled to less than 25 DEG C after reacting completely, slowly added by reaction solution in the sodium bicarbonate aqueous solution (sodium bicarbonate of 120g is dissolved in 2.4L water) of 0 ~ 5 DEG C in 30min, stir 1h, static 10 ~ 12h, filter, filter cake washes with water to neutrality.Recrystallization from ethyl acetate/petroleum ether obtains compound as white solid VI (14.0g, 33.2mmol, yield 95.1%).
MS(m/z)：420[M]
+，
1H-NMR(CDCl
3)，δ0.96(3H，t，18-CH
3)，δ5.37(1H，t，H-4)；
13C-NMR，211.5(C-11)，115.9(C-17)，140.0(C-5)，124.2(C-4)。
Embodiment 3:18-methyl female steroid-4-alkene-11-methylene radical-17-ketone-3-contracting thioketones (compound VI I)
In reaction vessel, add tetrahydrofuran (THF) (280ml), logical nitrogen 15min, adds potassium tert.-butoxide (21g, 187.17mmol), stirs 30min, adds methyl triphenylphosphonium bromide phosphorus (63g, 176.37mmol), back flow reaction 1h.Be cooled to 25 ~ 30 DEG C, add compound VI (9.2g, 21.18mmol), be warming up to 66 DEG C, keep reaction 40h, be cooled to 25 ~ 30 DEG C, add saturated ammonium chloride solution (120ml), stir 10min, add concentrated hydrochloric acid (7.7ml) in reaction vessel, 22 DEG C are stirred 12h.Be neutral with saturated sodium carbonate adjust pH.Separatory, aqueous phase tetrahydrofuran (THF) extracts, and merges organic phase, is concentrated into dry.Add water (50ml), stir 10min, extract with sherwood oil (35ml × 6), merge petroleum ether extract, with anhydrous magnesium sulfate drying, filter, be concentrated into dry, ethyl acetate/normal hexane recrystallization obtains white crystalline compound VII (5.1g, 13.71mmol, 64.7%).MS(m/z)：374[M]
+；
1H-NMR，δ1.04(3H，t，18-CH
3)，δ3.324H，m，-S-CH
2-CH
2-S-)，δ4.81(1H，s，＝CH
2)，δ4.92(1H，s，＝CH
2)，δ5.66(1H，s，4-H)。
Embodiment 4:18-methyl female steroid-4-alkene-11-methylene radical-20-ethynyl-17-alcohol-3-contracting thioketones (compound VI II)
Quadrol (200mL) is added in four-hole bottle, with gas in nitrogen replacement three bottles, add lithium bar (7.44g, 1.071mol), room temperature leads to acetylene gas, controls 90 ~ 95 and reacts about 15min, then 80 DEG C of reaction 30min are incubated, reaction solution becomes white thick shape from blueness, Temperature fall to 35 DEG C, and after about 2h, reaction solution becomes transparent thick shape solid.Joined in above-mentioned reaction solution by anhydrous tetrahydro furan (80ml) solution of compound VI I (8.2g, 22.0mmol), about 10min added, in 30 ~ 35 DEG C of ethynylations 2.5 hours.Ice-water bath is cooled to 0 ~ 5 DEG C, and slowly drip 100ml water stopped reaction, two-phase laminated flow, aqueous phase ethyl acetate (3 × 100ml) extracts.Organic phase is extremely neutral with saturated sodium-chloride water solution washing again, anhydrous sodium sulfate drying.Concentrating under reduced pressure separates out solids, filters, obtains compound as white solid VIII (7.4g, 18.5mmol, 84.1%).
MS(m/z)：400[M]
+；
1H-NMR，δ1.03(3H，t，18-CH
3)，2.60(1H，s，17-C≡CH)，δ3.36(4H，m，-S-CH
2-CH
2-S-)，δ4.75(1H，s，＝CH
2)，δ4.98(1H，s，＝CH
2)，δ5.42(1H，s，4-H)；
13C-NMR，147.0(C
11) 141.5(C
5)，126.2(C
4)，108.6(＝CH
2)，181.61(C
3)。
Embodiment 5: desogestrel
Add liquefied ammonia (170mL) to reactor, temperature adjustment is to-45 ~-50 DEG C, and within 10min, metal Na (3.9g, 170mmol) adds in reactor by gradation, adds and stirs 40min.By compound VI II (12..2g, 30.5mmol) be dissolved in anhydrous tetrahydro furan (45ml) wiring solution-forming, then in 30min, this solution is added drop-wise in sodium ammono-system, dropwise and keep reaction 2h in-45 ~-50 DEG C, then by acetonitrile (6mL) slowly instillation reaction vessel, time for adding 10min, dropwise and continue to stir 30min, reaction vessel is placed in the water-bath of 40 ~ 45 DEG C, catch up with ammonia 35min, vacuum catches up with ammonia 2h to make material be thick again, adds in the aqueous sodium hydroxide solution (30mL) of 10%, stirs 20min.Feed liquid is slowly poured in frozen water in (300mL) under stirring, stir 30min.Concentrate to obtain crude product with n-hexane extraction, ethyl acetate/normal hexane recrystallization obtains compound as white solid I (6.9g, 22.2mmol, yield 72.8%).
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，147.4(C
11)139.9(C
5)，124.4(C
4)，108.6(＝CH
2)。
Embodiment 6: Org 3236
Cupric oxide (4.8g is added in the four-hole bottle of a 1000mL, 60mmol), anhydrous cupric chloride (16.1g, 120mmol) and acetone (400mL), backflow is heated under mechanical stirring, drip compound VI II (20.4g, acetone soln (90mL) 50.8mmol) and N, dinethylformamide (10mL), dropwise in 20min, then back flow reaction 90min, Temperature fall is to room temperature, filter, gained insolubles extracts three times with 10% ethanol/dichloromethane solution of 20mL heat respectively, merge organic phase, aqueous sodium carbonate (1M, 50mL) wash organic phase, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure obtains crude product, white compound II (the 14.0g of methylene dichloride/normal hexane mixing solutions recrystallization, 43.2mmol, 85.0%).
MS(m/z)：324[M]
+；
1H-NMR，δ1.06(3H，t，18-CH
3)，2.62(1H，s，17-C≡CH)，δ4.83(1H，s，＝CH
2)，δ5.06(1H，s，＝CH
2)，δ5.88(1H，d，4-H)；
13C-NMR，200.0(C
3)，166.5(C
5)146.3(C
11)，125.5(C
4)，108.7(＝CH
2)。
Embodiment 7:18-methyl female steroid-4-alkene-11,17-diketone-3-contracting thioketones-17-contract-2 ', 2 '-dimethylpropylidene base glycol (compound VI ')
Compound V (13.1g is added in the there-necked flask of drying, 34.9mmol), neopentyl glycol (20g, 192mmol) and triethyl orthoformate (20mL, 120mmol), open stirring, drop into and stir 5min, control temperature to 40 DEG C ± 2 DEG C, drop into tosic acid (0.6g, 3.15mmol), insulation reaction 6h.Be cooled to less than 25 DEG C, slowly added by reaction solution in 2.4L 5% sodium bicarbonate aqueous solution, stir 1h, static 10 ~ 12h, filter, filter cake is washed to neutrality.Ethyl alcohol recrystallization obtains compound as white solid VI (15.4g, 33.2mmol, yield 95.1%).
MS(m/z)：462[M]
+，
1H-NMR(CDCl
3)，δ0.96(3H，t，18-CH
3)，δ0.69(3H，S，-CH
3)，δ1.06(3H，S，-CH
3)，δ5.62(1H，t，H-4)；
13C-NMR，212.8(C-11)，216.0(C-17)，139.78(C-5)，127.9(C-4)。
Embodiment 8:18-methyl female steroid-4-alkene-11-methylene radical-17-ketone-3-contracting thioketones (compound VI I)
Tetrahydrofuran (THF) (280ml) is added, metal magnesium chips (5.5g, 229.17mmol), chloromethyl trimethyl silicane (33mL, 234.04mmol), logical nitrogen 15min, stirred at ambient temperature 2.5 hours in reaction vessel.Then add compound VI (5.0g, 11.51mmol), be warming up to 66 DEG C, keep reaction 14h, be cooled to 0 ~ 5 DEG C, add purified water (10ml), stir 10min, add concentrated hydrochloric acid (10.0ml) in reaction vessel, 22 DEG C are stirred 7h.Be neutral with saturated sodium carbonate adjust pH.Separatory, aqueous phase tetrahydrofuran (THF) extracts, and merges organic phase, is concentrated into dry.Ethyl acetate/normal hexane recrystallization obtains white crystalline compound VII (2.8g, 7.50mmol, 65.2%).
MS(m/z)：374[M]
+；
1H-NMR，δ1.04(3H，t，18-CH
3)，δ3.324H，m，-S-CH
2-CH
2-S-)，δ4.81(1H，s，＝CH
2)，δ4.92(1H，s，＝CH
2)，δ5.66(1H，s，4-H)。
Claims (10)
1. the preparation method of desogestrel or Org 3236 intermediate, is characterized by this preparation method for following reaction:
Wherein, R
2for:
A:-(CH
2)
2-, or
B：-CH
2C(CH
3)
2CH
2-。
2. preparation method according to claim 1, to it is characterized by reaction and with an organic solvent add dibasic alcohol with catalyzer, wherein, organic solvent is a kind of in triethyl orthoformate and methylene dichloride or the mixed solvent in 2:1 ratio, and catalyzer was tosic acid, 35 ~ 45 DEG C of reactions 3 ~ 6 hours, the weight ratio of compound and dibasic alcohol is 1:2.0 ~ 3.5, described dibasic alcohol is ethylene glycol or 2，2-dimethyl-1，3-propanediol.
3. the preparation method of desogestrel or Org 3236 intermediate, is characterized by this preparation method for following reaction:
Wherein, R
1for:
A:-(CH
2)
2-, or
b：-(CH
2)
3-，
R
2for:
A:-(CH
2)
2-, or
B:-CH
2c (CH
3)
2cH
2-, or
C：-(CH
2)
3-。
4. preparation method according to claim 3, is characterized by R
1for a, R
2for A or B.
5. the preparation method according to claim 3 or 4, is characterized by 11 carbonyl Wittig and reacts and 17 hydrolysis of ketal deprotections.
6. preparation method according to claim 5, it is characterized by Wittig reaction and add highly basic, highly basic used is sodium hydride, sodium amide, n-Butyl Lithium or potassium tert.-butoxide.
7. preparation method according to claim 5, it is characterized by reaction solvent is tetrahydrofuran (THF), methyltetrahydrofuran, methyl-sulphoxide or ether.
8. the preparation method according to claim 3 or 4, is characterized by 11 carbonyl Peterson and reacts and 17 hydrolysis of ketal deprotections.
9. preparation method according to claim 8, it is characterized by reaction solvent is tetrahydrofuran (THF), methyltetrahydrofuran, methyl-sulphoxide or ether.
10. the preparation method of desogestrel or Org 3236, is characterized by this preparation method and comprises following reaction:
Wherein, R
1for:
A:-(CH
2)
2-, or
b：-(CH
2)
3-。
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| CN101440112A (en) * | 2008-12-19 | 2009-05-27 | 北京紫竹药业有限公司 | Steroid compound and use thereof |
| CN101445542A (en) * | 2008-12-25 | 2009-06-03 | 北京市科益丰生物技术发展有限公司 | Process for preparing desogestrel |
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|---|---|---|---|---|
| US3927046A (en) * | 1972-12-09 | 1975-12-16 | Akzona Inc | Novel 11,11-alkylidene steroids |
| US5831104A (en) * | 1993-09-10 | 1998-11-03 | Jenapharm Gmbh | Steroid intermediate products and method of their production |
| CN101440112A (en) * | 2008-12-19 | 2009-05-27 | 北京紫竹药业有限公司 | Steroid compound and use thereof |
| CN101445542A (en) * | 2008-12-25 | 2009-06-03 | 北京市科益丰生物技术发展有限公司 | Process for preparing desogestrel |
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