CN102617692A - Steroid compound, preparation method and use thereof - Google Patents

Steroid compound, preparation method and use thereof Download PDF

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Publication number
CN102617692A
CN102617692A CN2012100160904A CN201210016090A CN102617692A CN 102617692 A CN102617692 A CN 102617692A CN 2012100160904 A CN2012100160904 A CN 2012100160904A CN 201210016090 A CN201210016090 A CN 201210016090A CN 102617692 A CN102617692 A CN 102617692A
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compound
reaction
diene
norpregna
alpha
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王海
史学松
田卫学
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ZIZHU PHARMACEUTICAL CO Ltd BEIJING
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ZIZHU PHARMACEUTICAL CO Ltd BEIJING
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Priority to CN201610335003.XA priority patent/CN106046099B/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
    • C07J31/006—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring not covered by C07J31/003
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J21/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J21/005—Ketals
    • C07J21/006—Ketals at position 3

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  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
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Abstract

The present invention relates to a steroid compound, a preparation method and a use thereof. In the prior, the preparation method for 3,3,20,20-bis(ethylenedioxy)-17alpha-hydroxy-19-norpregna5(10),9(11)-diene has the following problems that: the starting materials are single, the cost is high, the product has poor quality, the method is not suitable for industrial production and the like. According to the present invention, a novel steroid compound, a preparation method and a use thereof are provided, wherein the steroid compound can be used for preparation of 3,3,20,20-bis(ethylenedioxy)-17alpha-hydroxy-19-norpregna5(10),9(11)-diene, the preparation method of the present invention has high yield, the product has high quality, the reaction conditions are mild, the raw materials are rich and easy to obtain, the cost is low, and the industrial production is easy to perform.

Description

Steroidal compounds
Technical field
The present invention relates to steroidal compounds 3,3,20, the preparation method and the purposes of two (ethylenedioxy)-17 Alpha-hydroxies of 20--19-norpregna-5 (10), 9 (11)-diene.
Background technology
Compound 3,3,20, two (ethylenedioxy)-17 Alpha-hydroxies of 20--19-norpregna-5 (10), 9 (11)-diene are the key intermediate of preparation acetic acid Wu Lisita.Acetic acid Wu Lisita is a kind of gestation and the active steroid of anti-cortin, is used to treat gynaecopathia, contraception, treatment hypercortisolism and glaucoma etc.And document is disclosed 3,3,20, and the preparation method of two (ethylenedioxy)-17 Alpha-hydroxies of 20--19-norpregna-5 (10), 9 (11)-diene has:
U.S. Pat 5929262, with 3,3-(ethylenedioxy)-17 Alpha-hydroxy-17 beta-cyano--female steroid-5 (10); 9 (11)-diene are that raw material obtains 3,3,20 through the reaction of 3 steps; Two (ethylenedioxy)-17 Alpha-hydroxies of 20--19-norpregna-5 (10), 9 (11)-diene, total recovery is 55%.Operational path is following:
The used starting raw material 3 of this route, 3-(ethylenedioxy)-17 Alpha-hydroxy-17 beta-cyanos-female steroid-5 (10), 9 (11)-diene need be through 3; 3-(ethylenedioxy)-female steroid-5 (10); 9 (11)-diene-17-ketone and prussiate prepared in reaction and get, and prussiate all has bigger harm for producers' Occupational health and environment, and its temperature of reaction is-70 ℃; Be not suitable for fairly large production preparation, so this route starting material is difficult to obtain.And it is husky to have used lithium in this route second step reaction, is prone to set off an explosion, dangerous higher, is not suitable for suitability for industrialized production equally.
Publication number is that the one Chinese patent application of CN101466723A discloses with 3; 3-(ethylenedioxy)-female steroid-5 (10), 9 (11)-diene-17-ketone is that raw material obtains 3,3 through the reaction of 5 steps; 20; Two (ethylenedioxy)-17 Alpha-hydroxies of 20--19-norpregna-5 (10), 9 (11)-diene, operational path is following:
Figure BSA00000660069100021
Above-mentioned route is not used severe toxicity and valuable reagent, and reaction conditions is gentle, relatively is fit to industrial production, and total recovery is about 46%.But its starting material is single, and cost is higher, and more at the impurity of the 4th step and the generation of the 5th step, influences the quality of the finished product.
Summary of the invention
A kind of cost is low, yield is higher, the preparation of better quality 3,3,20 in order to provide for one of the object of the invention, the novel method of two (ethylenedioxy)-17 Alpha-hydroxies of 20--19-norpregna-5 (10), 9 (11)-diene.
The object of the invention two for new steroidal compounds to be provided, and the preparation method of this compound.
Three of the object of the invention is the purposes that new steroidal compounds is provided.
Steroidal compounds is:
Figure BSA00000660069100022
Wherein, R ' is:
Figure BSA00000660069100024
or
Figure BSA00000660069100025
R 1Be C 1～C 3Straight-chain paraffin.
Compound 2 ' obtained through the ethinylation reaction by compound 1, concrete ethynylation are employed in and add potassium acetylide reaction, preferred 35 ℃～40 ℃ under 0 ℃～50 ℃ conditions.
The structural formula of compound 2 is:
Figure BSA00000660069100031
Wherein, R does
Figure BSA00000660069100032
R 1Be C 1～C 3Straight-chain paraffin or
(d)O
Compound 2 (17 α-ethynyl-17 beta-hydroxies-female steroid-4 (5); 9 (10)-diene-3-ketone or 17 α-ethynyl-17 beta-hydroxies-female steroid-5 (10); 9 (11)-diene-3-keto acyl) obtain compound 3 at-70 ℃～10 ℃ through acylation reaction with the phenyl sulphinyl chlorine; Wherein 17 α-ethynyl-17 beta-hydroxies-female steroid-4 (5), 9 (10)-diene-3-ketone can obtain through purchase, preferred-10 ℃～0 ℃.Compound 3 is shown below:
Figure BSA00000660069100033
Wherein, R does
Figure BSA00000660069100034
R 1Be C 1～C 3Straight-chain paraffin or
(d)O
When R was a, b, c, two two keys were 5 (10), 9 (11); When R was d, two two keys were 4 (5), and 9 (10) or 5 (10), 9 (11).
Compound 3 at first generates 20-methoxyl group-21-(phenyl sulfinyl) verivate through the Michael addition, obtains compound 4 with trimethyl phosphite 30 ℃～70 ℃ reactions subsequently, preferred 60 ℃～70 ℃.Compound 4 is shown below:
Wherein, R does
Figure BSA00000660069100042
R 1Be C 1～C 3Straight-chain paraffin or
(d)：O
When R was a, b, c, two two keys were 5 (10), 9 (11); When R was d, two two keys were 4 (5), and 9 (10) or 5 (10), 9 (11).
Compound 4 and hydrochloric acid or perchloric acid and Glacial acetic acid min. 99.5 mixed solution obtain compound 50 ℃～30 ℃ hydrolysis, and the structure of compound 5 is shown below:
Figure BSA00000660069100043
It is a kind of 3,3,20 that the present invention also provides, two (ethylenedioxy)-17 Alpha-hydroxies of the 20--new preparation method of 19-norpregna-5 (10), 9 (11)-diene, and this preparation method is following:
With compound 1 is that raw material forms 17 α-ethynyl-17 beta-hydroxy thing (compound 2 ') with the potassium acetylide reaction earlier; Compound 2 obtains compound 3 with phenyl sulphinyl chlorine acylation reaction again; Compound 3 obtains compound 4 with sodium methylate and trimethyl phosphite reaction; Compound 4 usefulness hydrochloric acid or perchloric acid and the hydrolysis of Glacial acetic acid min. 99.5 mixed solution obtain compound 5; Last spent glycol obtains 3,3,20,20-pair of (ethylenedioxy)-17 Alpha-hydroxies-19-norpregna-5 (10), 9 (11)-diene to 3 of compound 5 with 20 ketone group protections.Compound 1 can obtain through purchase.Concrete reaction scheme is shown below:
Figure BSA00000660069100051
Wherein, R ' is:
Figure BSA00000660069100053
or
Figure BSA00000660069100054
R 1Be C 1～C 3Straight-chain paraffin.
R is:
Figure BSA00000660069100055
R 1Be C 1～C 3Straight-chain paraffin or
(d)O。
Beneficial effect of the present invention is:
1, the present invention has overcome the single defective of disclosed preparing method's starting material among the CN101466723A, and 3 different protection bases of starting material have been carried out detailed research, finds that the compound 1 of kinds of protect base can both prepare 3 through above-mentioned route; 3; 20, two (ethylenedioxy)-17 Alpha-hydroxies of 20--19-norpregna-5 (10), 9 (11)-diene; Make that the starting material source is more extensive, and reduced whole cost.
2, in the reaction by compound 4 preparation compounds 5, use than strong acid to make 3 and 20 of compound 4 to be hydrolyzed simultaneously and to obtain compound 5, because speed of response is fast, reaction process generation impurity is less, can obtain the higher compound of purity 5; Use compound 5 can be easier to prepare content greater than 98% 3,3,20, two (ethylenedioxy)-17 Alpha-hydroxies of 20--19-norpregna-5 (10), 9 (11)-diene.
3, route reaction mild condition of the present invention, raw material and reagent are simple and easy to, and relatively are fit to suitability for industrialized production.
Embodiment
Embodiment 1:3,3-dimethoxy-17 α-ethynyl-17 beta-hydroxies-female steroid-5 (10), 9 (11)-diene
Under nitrogen protection, in the exsiccant reaction flask, add 1.2L THF and Pottasium Hydroxide 400g, be cooled to below 5 ℃ logical acetylene gas then.Add 1L acetone, be warming up to 35 ℃～40 ℃, keep logical acetylene gas, stirring reaction 2 hours.With 100g 3,3-dimethoxy-female steroid-5 (10), 9 (11)-diene-17-ketone is dissolved in the 1L THF, is added dropwise in the reaction solution, after dropwising, is controlled at 35 ℃～40 ℃ reactions 1 hour.After reaction is accomplished, add saturated ammonium chloride solution 750mL and reaction mixture is stirred 10min.Separate organic layer, water layer extracts with THF 300mL.Merge organic layer with saturated ammonium chloride 750mL washing, be evaporated to 600mL, be poured over elutriation among the frozen water 4L, stir 30min, filter, washing obtains 105g3,3-dimethoxy-17 α-ethynyl-17 beta-hydroxies-female steroid-5 (10), 9 (11)-diene to neutral.
MS (m/z): 342 [M] + 1H-NMR (DMSO): δ 0.71 (3H, 18-CH 3), δ 3.34 (H, 20-C ≡ CH), δ 3.09-3.10 (6H ,-O-CH 3With-O-CH 3), δ 5.52-5.53 (1H, H-11); 13C-NMR:135.74 (C-5), 128.97 (C-9), 125.63 (C-10), 117.62 (C-11), 98.81 (C-3), 88.72 (C-19), 78.01 (C-17), 75.09 (C-20), 47.12 (O-CH 3With-O-CH 3).
Embodiment 2:3,3-dimethoxy-21-(phenyl-sulfinyl)-19-norpregna-5 (10), 9 (11), 17 (20), 20-tetraene
In the exsiccant reaction flask, add 105g 3,3-dimethoxy-17 α-ethynyl-17 beta-hydroxies-female steroid-5 (10), 9 (11)-diene, 1400mL methylene dichloride, 130mL triethylamine and 25mL Glacial acetic acid min. 99.5; Be cooled to 0～-10 ℃; Dropping comprises the dichloromethane solution 120mL of phenyl sulphinyl chlorine 63g, keeps dropping temperature to be no more than 0 ℃, after being added dropwise to complete; Add entry 210mL and methyl alcohol 105mL, stirred 30 minutes.Separate organic layer, with 1N hydrochloric acid and saturated sodium carbonate solution washing, washing at last is to neutral respectively.Organic layer is used anhydrous sodium sulfate drying, is evaporated to dried.Add isopropyl ether to residuum, be cooled to 0 ℃ and stir 30min, cross and filter 120g3,3-dimethoxy-21-(phenyl-sulfinyl)-19-norpregna-5 (10), 9 (11), 17 (20), 20-tetraene.
MS (m/z): 450 [M] + 1H-NMR (CDCl 3): δ 0.96 (3H, 18-CH 3), δ 3.13-3.18 (6H ,-O-CH 3With-O-CH 3), δ 5.57 (1H, 11-H), δ 6.10-6.14 (1H, 20-=CH-S-), δ 7.45-7.66 (5H, PhH); 13C-NMR:196.44 (=C=), 136.55 (C-5), 130.17 (C-9), 124.22 (C-10), 117.52 (C-11), 48.43 (O-CH 3With-O-CH 3), 19.91 (C-18).
Embodiment 3:3,3-dimethoxy-17 alpha-hydroxy-2 0-methoxyl group-19-norpregna-5 (10), 9 (11), 20-triolefin
In the exsiccant reaction flask, add 120g3; 3-dimethoxy-21-(phenyl-sulfinyl)-19-norpregna-5 (10), 9 (11), 17 (20); 20-tetraene, sodium methylate 7.2g and anhydrous methanol 3600mL; Be warming up to 60 ℃～65 ℃ stirring reaction 3h, add trimethyl phosphite 36mL then, continue insulated and stirred reaction 1h.Reaction is poured reaction solution in the 8L water into after accomplishing, and separates out faint yellow solid.Stir after 30 minutes, filter, get 82g 3,3-dimethoxy-17 alpha-hydroxy-2 0-methoxyl group--19-norpregna-5 (10), 9 (11), 20-triolefin.
MS (m/z): 374 [M] + 1H-NMR (CDCl 3): δ 0.81 (3H, 18-CH 3), δ 3.11-3.13 (6H ,-O-CH 3With-O-CH 3), δ 5.05-5.02 (2H, 20-=CH 2), δ 3.43 (3H ,-O-CH 3), δ 5.30 (1H, 11-H); 13C-NMR:211.64 (19-C), 136.02 (C-5), 130.06 (C-9), 126.06 (C-10), 117.68 (C-11), 98.79 (C-3), 89.76 (C-17), 48.28 (O-CH 3With-O-CH 3), 16.08 (C-18).
Embodiment 4:17 Alpha-hydroxy-19-norpregna-4 (5), 9 (10)-diene-3, the 20-diketone
In reaction flask, add 82g 3,3-dimethoxy-17 alpha-hydroxy-2 0-methoxyl group-19-norpregna-5 (10), 9 (11), 20-triolefin, 410mL Glacial acetic acid min. 99.5 and 70% perchloric acid 33mL are in 20～30 ℃ of reaction 10min.Reaction is poured in the 2500mL saturated sodium carbonate solution after accomplishing, and separates out faint yellow solid.Filter, washing gets 59g 17 Alpha-hydroxies-19-norpregna-4 (5), 9 (10)-diene-3, the 20-diketone to neutral.
MS(m/z)：314[M] +； 1H-NMR(CDCl 3)：δ0.72(3H，18-CH 3)，δ2.01-1.98(3H，20-C＝OCH 3)，δ2.92-2.886(2H，1-CH 2)，δ2.92(H，17-OH)，δ5.62-5.63(H，H-11)； 13C-NMR：211.51(C-19)，210.70(C-3)，135.57(C-5)，129.65(C-9)，127.52(C-10)，119.08(C-11)，89.64(C-17)，27.68(C-20，)，46.91(C-1)，16.51(C-18)。
Embodiment 5:3,3,20, two (ethylenedioxy)-17 Alpha-hydroxies of 20--19-norpregna-5 (10), 9 (11)-diene
In reaction flask, add 59g 17 Alpha-hydroxies-19-norpregna-4 (5), 9 (10)-diene-3,20-diketone, methylene dichloride 472mL add terepthaloyl moietie 100mL, trimethyl orthoformate 106mL and tosic acid 3.6g again.Reaction solution adds saturated sodium bicarbonate solution 350mL then at 20 ℃ of-25 ℃ of stirring reaction 3h, continues to stir 30min.Separate organic layer, use the 400mL water washing, with dried over sodium sulfate and be concentrated to the volume of 150mL.Add methyl alcohol 200mL, continue to be evaporated to the volume of 150mL so that remove methylene dichloride.With reaction cooled to 0～2 ℃, filter, obtain 62g3,3,20, two (ethylenedioxy)-17 Alpha-hydroxies of 20--19-norpregna-5 (10), 9 (11)-diene.
Embodiment 6:3,3-(2, the inferior third dioxy base of 2-dimethyl-)-17 α-ethynyl-17 beta-hydroxies-female steroid-5 (10), 9 (11)-diene
Under nitrogen protection, in the exsiccant reaction flask, add 1.2L THF and Pottasium Hydroxide 400g, be cooled to below 5 ℃ logical acetylene gas then.Add 1L acetone, be warming up to 35 ℃～40 ℃, keep logical acetylene gas, stirring reaction 2 hours.With 100g 3,3-(2, the inferior third dioxy base of 2-dimethyl-)-female steroid-5 (10), 9 (11)-diene-17-ketone is dissolved in the 1L THF, is added dropwise in the reaction solution, after dropwising, is controlled at 35 ℃～40 ℃ reactions 1 hour.After reaction is accomplished, add saturated ammonium chloride solution 750mL and reaction mixture is stirred 10min.Separate organic layer, water layer extracts with THF 300mL.Merge organic layer with saturated ammonium chloride 750mL washing, be evaporated to 600mL, be poured over elutriation among the frozen water 4L, stir 30min; Filter, washing obtains 100g 3 to neutral; 3-(2, the inferior third dioxy base of 2-dimethyl-)-17 α-ethynyl-17 beta-hydroxies-female steroid-5 (10), 9 (11)-diene.
Embodiment 7:3,3-(2, the inferior third dioxy base of 2-dimethyl-)-21-(phenyl-sulfinyl)-19-norpregna-5 (10), 9 (11), 17 (20), 20-tetraene
In the exsiccant reaction flask, add 100g 3,3-(2, the inferior third dioxy base of 2-dimethyl-)-17 α-ethynyl-17 beta-hydroxies-female steroid-5 (10); 9 (11)-diene, 1400mL methylene dichloride, 123mL triethylamine and 20mL Glacial acetic acid min. 99.5 are cooled to 0～-10 ℃, drip the dichloromethane solution 120mL that comprises phenyl sulphinyl chlorine 60g; Keep dropping temperature to be no more than 0 ℃; After being added dropwise to complete, add entry 210mL and methyl alcohol 105mL, stirred 30 minutes.Separate organic layer, with 1N hydrochloric acid and saturated sodium carbonate solution washing, washing at last is to neutral respectively.Organic layer is used anhydrous sodium sulfate drying, is evaporated to dried.Add normal heptane to residuum, be cooled to 0 ℃ and stir 30min, cross and filter 110g 3,3-(2, the inferior third dioxy base of 2-dimethyl-)-21-(phenyl-sulfinyl)-19-norpregna-5 (10), 9 (11), 17 (20), 20-tetraene.
Embodiment 8:3,3-(2, the inferior third dioxy base of 2-dimethyl-)-17 alpha-hydroxy-2 0-methoxyl group-19-norpregnas-5 (10), 9 (11), 20-triolefin
In the exsiccant reaction flask, add 110g 3,3-(2, the inferior third dioxy base of 2-dimethyl-)-21-(phenyl-sulfinyl)-19-norpregna-5 (10); 9 (11); 17 (20), 20-tetraene, sodium methylate 6.6g and methyl alcohol 3300mL are warming up to 60 ℃～65 ℃ stirring reaction 3h; Add trimethyl phosphite 33mL then, continue insulated and stirred reaction 1h.Reaction is poured reaction solution in the 8L water into after accomplishing, and separates out faint yellow solid.Stir after 30 minutes, filter, get 73g3,3-(2, the inferior third dioxy base of 2-dimethyl-)-17 alpha-hydroxy-2 0-methoxyl group-19-norpregnas-5 (10), 9 (11), 20-triolefin.
Embodiment 9:17 Alpha-hydroxy-19-norpregna-4 (5), 9 (10)-diene-3, the 20-diketone
In reaction flask, add 73g 3,3-(2, the inferior third dioxy base of 2-dimethyl-)-17 alpha-hydroxy-2 0-methoxyl group--19-norpregnas-5 (10), 9 (11), 20-triolefin, 365mL Glacial acetic acid min. 99.5 and 70% perchloric acid 29mL are in 20～30 ℃ of reaction 10min.Reaction is poured in the 2500mL saturated sodium carbonate solution after accomplishing, and separates out the off-white color solid.Filter, washing gets 51g17 Alpha-hydroxy-19-norpregna-4 (5), 9 (10)-diene-3, the 20-diketone to neutral.
Embodiment 10:3,3-(the inferior third dioxy base)-17 α-ethynyl-17 beta-hydroxies-female steroid-5 (10), 9 (11)-diene
Under nitrogen protection, in the exsiccant reaction flask, add 1.2L THF and Pottasium Hydroxide 400g, be cooled to below 5 ℃ logical acetylene gas then.Add 1L acetone, be warming up to 35 ℃～40 ℃, keep logical acetylene gas, stirring reaction 2 hours.With 100g 3,3-(the inferior third dioxy base)-female steroid-5 (10), 9 (11)-diene-17-ketone is dissolved in the 1L THF, is added dropwise in the reaction solution, after dropwising, is controlled at 35 ℃～40 ℃ reactions 1 hour.After reaction is accomplished, add saturated ammonium chloride solution 750mL and reaction mixture is stirred 10min.Separate organic layer, water layer extracts with THF 300mL.Merge organic layer with saturated ammonium chloride 750mL washing, be evaporated to 600mL, be poured over elutriation among the frozen water 4L; Stir 30min, filter, washing is to neutral; Obtain 105g3,3-(the inferior third dioxy base)-17 α-ethynyl-17 beta-hydroxies-female steroid-5 (10), 9 (11)-diene.
Embodiment 11:3,3-(the inferior third dioxy base)-21-(phenyl-sulfinyl)-19-norpregna-5 (10), 9 (11), 17 (20), 20-tetraene
In the exsiccant reaction flask, add 105g 3,3-(the inferior third dioxy base)-17 α-ethynyl-17 beta-hydroxies-female steroid-5 (10), 9 (11)-diene, 1400mL methylene dichloride, 123mL triethylamine and 20mL Glacial acetic acid min. 99.5; Be cooled to 0～-10 ℃; Dropping comprises the dichloromethane solution 120mL of phenyl sulphinyl chlorine 63g, keeps dropping temperature to be no more than 0 ℃, after being added dropwise to complete; Add entry 210mL and methyl alcohol 105mL, stirred 30 minutes.Separate organic layer, with 1N hydrochloric acid and saturated sodium carbonate solution washing, washing at last is to neutral respectively.Organic layer is used anhydrous sodium sulfate drying, is evaporated to dried.Add normal heptane to residuum, be cooled to 0 ℃ and stir 30min, cross and filter 105g3,3-(the inferior third dioxy base)-21-(phenyl-sulfinyl)-19-norpregna-5 (10), 9 (11), 17 (20), 20-tetraene.
Embodiment 12:3,3-(the inferior third dioxy base)-17 alpha-hydroxy-2 0-methoxyl group-19-norpregnas-5 (10), 9 (11), 20-triolefin
In the exsiccant reaction flask, add 105g 3; 3-(the inferior third dioxy base)-21-(phenyl-sulfinyl)-19-norpregna-5 (10), 9 (11), 17 (20); 20-tetraene, sodium methylate 6.3g and methyl alcohol 3150mL; Be warming up to 60 ℃～65 ℃ stirring reaction 3h, add trimethyl phosphite 33mL then, continue insulated and stirred reaction 1h.Reaction is poured reaction solution in the 8L water into after accomplishing, and separates out faint yellow solid.Stir after 30 minutes, filter, get 71g3,3-(the inferior third dioxy base)-17 alpha-hydroxy-2 0-methoxyl group--19-norpregnas-5 (10), 9 (11), 20-triolefin.
Embodiment 13:17 Alpha-hydroxy-19-norpregna-4 (5), 9 (10)-diene-3, the 20-diketone
In reaction flask, add 71g 3,3-(the inferior third dioxy base)-17 alpha-hydroxy-2 0-methoxyl group--19-norpregnas-5 (10), 9 (11), 20-triolefin, 710mL methyl alcohol and 24mL 6N hydrochloric acid are in 20～30 ℃ of reaction 10min.Reaction is poured in the 2500mL saturated sodium carbonate solution after accomplishing, and separates out the off-white color solid.Filter, washing gets 52g 17 Alpha-hydroxies-19-norpregna-4 (5), 9 (10)-diene-3, the 20-diketone to neutral.
Embodiment 14:21-(phenyl-sulfinyl)-19-norpregna-4 (5), 9 (10), 17 (20), 20-tetraene-3 ketone
In the exsiccant reaction flask, add 100g 17 α-ethynyl-17 beta-hydroxies-female steroid-4 (5); 9 (10)-diene-3-ketone, 1400mL methylene dichloride, 123mL triethylamine and 20mL Glacial acetic acid min. 99.5 are cooled to 0～-10 ℃, drip the dichloromethane solution 120mL that comprises phenyl sulphinyl chlorine 60g; Keep dropping temperature to be no more than 0 ℃; After being added dropwise to complete, add entry 210mL and methyl alcohol 105mL, stirred 30 minutes.Separate organic layer, with 1N hydrochloric acid and saturated sodium carbonate solution washing, washing at last is to neutral respectively.Organic layer is used anhydrous sodium sulfate drying, is evaporated to dried.Add isopropyl ether to residuum, be cooled to 0 ℃ and stir 30min, cross and filter 104g 21-(phenyl-sulfinyl)-19-norpregna-4 (5), 9 (10), 17 (20), 20-tetraene-3 ketone.
Embodiment 15:17 alpha-hydroxy-2 0-methoxyl group-19-norpregna-4 (5), 9 (10), 20-triolefin-3-ketone
In the exsiccant reaction flask, add 104g 21-(phenyl-sulfinyl)-19-norpregna-4 (5); 9 (10); 17 (20), 20-tetraene-3-ketone, sodium methylate 6.4g and methyl alcohol 3200mL are warming up to 60 ℃～65 ℃ stirring reaction 2h; Add trimethyl phosphite 32mL then, continue insulated and stirred reaction 1h.Reaction is poured reaction solution in the 8L water into after accomplishing, and separates out faint yellow solid.After stirring 30min, filter, get 67g 17 alpha-hydroxy-2 0-methoxyl group-19-norpregnas-4 (5), 9 (10), 20-triolefin-3-ketone.
Embodiment 16:17 Alpha-hydroxy-19-norpregna-4 (5), 9 (10)-diene-3, the 20-diketone
In reaction flask, add 67g 17 alpha-hydroxy-2 0-methoxyl group-19-norpregnas-4 (5), 9 (10), 20-triolefin-3-ketone, 670ml methyl alcohol and 15ml 1N hydrochloric acid are in 20～30 ℃ of reaction 1h.After reaction is accomplished, add 700mL water, separate out the off-white color solid.Filter, washing gets 46g17 Alpha-hydroxy-19-norpregna-4 (5), 9 (10)-diene-3, the 20-diketone to neutral.

Claims (10)

1. one kind prepares 3,3,20; The method of two (ethylenedioxy)-17 Alpha-hydroxies of 20--19-norpregna-5 (10), 9 (11)-diene is characterized by: protect 17 Alpha-hydroxies-19-norpregna-4 (5) through spent glycol; 9 (10)-diene-3,3 of the 20-diketone and 20 ketone groups obtain.
2. described 17 Alpha-hydroxies of claim 1-19-norpregna-4 (5), 9 (10)-diene-3, the 20-diketone obtains through compound 4 hydrolysis, and compound 4 is:
Figure FSA00000660069000011
Wherein, R does
Figure FSA00000660069000012
R 1Be C 1～C 3Straight-chain paraffin or
(d)：O
When R was a, b, c, two two keys were 5 (10), 9 (11); When R was d, two two keys were 4 (5), and 9 (10) or 5 (10), 9 (11).
3. the described compound 4 of claim 2 through the Michael addition of compound 3, obtains with the trimethyl phosphite reaction earlier again, and compound 3 is:
Wherein, R does
Figure FSA00000660069000022
R 1Be C 1～C 3Straight-chain paraffin or
(d)：O
When R was a, b, c, two two keys were 5 (10), 9 (11); When R was d, two two keys were 4 (5), and 9 (10) or 5 (10), 9 (11).
4. the described compound 3 of claim 3 obtains through compound 2 acidylates, and compound 2 is:
Wherein, R is:
Figure FSA00000660069000024
R 1Be C 1～C 3Straight-chain paraffin or
(d)O。
The described compound 2 of claim 4 when R be (a) and (b) or (c) time be compound 2 ', compound 2 ' obtain through the ethinylation reaction by compound 1, compound 1 is:
Figure FSA00000660069000031
Wherein, R is
Figure FSA00000660069000032
or
Figure FSA00000660069000034
R 1Be C 1～C 3Straight-chain paraffin.
6. steroidal compounds is:
Figure FSA00000660069000035
7. steroidal compounds is:
Wherein, R does R 1Be C 1～C 3Straight-chain paraffin or
(d)：O
When R was a, b, c, two two keys were 5 (10), 9 (11); When R was d, two two keys were 4 (5), and 9 (10) or 5 (10), 9 (11).
8. steroidal compounds is:
Figure FSA00000660069000041
Wherein, R does
Figure FSA00000660069000042
R 1Be C 1～C 3Straight-chain paraffin or
(d)：O
When R was a, b, c, two two keys were 5 (10), 9 (11); When R was d, two two keys were 4 (5), and 9 (10) or 5 (10), 9 (11).
9. steroidal compounds is:
Figure FSA00000660069000043
Wherein, R is:
Figure FSA00000660069000044
or
Figure FSA00000660069000051
R 1Be C 1～C 3Straight-chain paraffin.
10. claim 7 or 8 described steroidal compounds, it is characterized by: R is a, b or c.
CN2012100160904A 2011-01-31 2012-01-19 Steroid compound, preparation method and use thereof Pending CN102617692A (en)

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