CN102134265A - Method for synthesizing 6-methyl-17alpha-acetoxyl-19-norpregnane-4,6-diene-3,20-diketone - Google Patents
Method for synthesizing 6-methyl-17alpha-acetoxyl-19-norpregnane-4,6-diene-3,20-diketone Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 21
- 230000002194 synthesizing effect Effects 0.000 title abstract 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 67
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims abstract description 21
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 claims abstract description 16
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims abstract description 14
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 13
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims abstract description 11
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims abstract description 11
- 150000001336 alkenes Chemical class 0.000 claims abstract description 4
- 238000005874 Vilsmeier-Haack formylation reaction Methods 0.000 claims abstract description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 36
- 229960003328 benzoyl peroxide Drugs 0.000 claims description 24
- 150000001875 compounds Chemical class 0.000 claims description 22
- 150000003431 steroids Chemical class 0.000 claims description 22
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 19
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 18
- 239000000758 substrate Substances 0.000 claims description 7
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims description 6
- CYTQBVOFDCPGCX-UHFFFAOYSA-N trimethyl phosphite Chemical compound COP(OC)OC CYTQBVOFDCPGCX-UHFFFAOYSA-N 0.000 claims description 6
- 230000000694 effects Effects 0.000 claims description 4
- 230000018044 dehydration Effects 0.000 claims description 3
- 238000006297 dehydration reaction Methods 0.000 claims description 3
- 238000006722 reduction reaction Methods 0.000 claims description 3
- 238000006027 Birch reduction reaction Methods 0.000 claims description 2
- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical compound O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 claims description 2
- 229940126657 Compound 17 Drugs 0.000 claims 5
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 claims 4
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- BCWWDWHFBMPLFQ-VXNCWWDNSA-N (8r,9s,13s,14s)-3-methoxy-13-methyl-7,8,9,11,12,14,15,16-octahydro-6h-cyclopenta[a]phenanthren-17-one Chemical compound C1C[C@]2(C)C(=O)CC[C@H]2[C@@H]2CCC3=CC(OC)=CC=C3[C@H]21 BCWWDWHFBMPLFQ-VXNCWWDNSA-N 0.000 abstract 2
- 238000006266 etherification reaction Methods 0.000 abstract 1
- JWUKZUIGOJBEPC-UHFFFAOYSA-N phenyl thiohypochlorite Chemical compound ClSC1=CC=CC=C1 JWUKZUIGOJBEPC-UHFFFAOYSA-N 0.000 abstract 1
- WVLBCYQITXONBZ-UHFFFAOYSA-N trimethyl phosphate Chemical compound COP(=O)(OC)OC WVLBCYQITXONBZ-UHFFFAOYSA-N 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 60
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 50
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 36
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 28
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 25
- 238000001035 drying Methods 0.000 description 24
- 239000007787 solid Substances 0.000 description 24
- 238000001914 filtration Methods 0.000 description 20
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 16
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- 229920006395 saturated elastomer Polymers 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 239000000047 product Substances 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 229910021529 ammonia Inorganic materials 0.000 description 8
- 235000019270 ammonium chloride Nutrition 0.000 description 8
- 238000001816 cooling Methods 0.000 description 8
- 229960004756 ethanol Drugs 0.000 description 8
- 239000000284 extract Substances 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 238000005406 washing Methods 0.000 description 8
- 229910000033 sodium borohydride Inorganic materials 0.000 description 6
- 239000012279 sodium borohydride Substances 0.000 description 6
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 5
- 239000000376 reactant Substances 0.000 description 5
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 4
- 229940040526 anhydrous sodium acetate Drugs 0.000 description 4
- TWJVNKMWXNTSAP-UHFFFAOYSA-N azanium;hydroxide;hydrochloride Chemical class [NH4+].O.[Cl-] TWJVNKMWXNTSAP-UHFFFAOYSA-N 0.000 description 4
- QQVDYSUDFZZPSU-UHFFFAOYSA-M chloromethylidene(dimethyl)azanium;chloride Chemical compound [Cl-].C[N+](C)=CCl QQVDYSUDFZZPSU-UHFFFAOYSA-M 0.000 description 4
- 230000006837 decompression Effects 0.000 description 4
- 229960000935 dehydrated alcohol Drugs 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- -1 phenolic ketone Chemical class 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 239000012265 solid product Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000010025 steaming Methods 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- 238000006073 displacement reaction Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 230000002254 contraceptive effect Effects 0.000 description 2
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- DBPWSSGDRRHUNT-UHFFFAOYSA-N 17alpha-hydroxy progesterone Natural products C1CC2=CC(=O)CCC2(C)C2C1C1CCC(C(=O)C)(O)C1(C)CC2 DBPWSSGDRRHUNT-UHFFFAOYSA-N 0.000 description 1
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical group C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- DOMWKUIIPQCAJU-LJHIYBGHSA-N Hydroxyprogesterone caproate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)CCCCC)[C@@]1(C)CC2 DOMWKUIIPQCAJU-LJHIYBGHSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- 244000061456 Solanum tuberosum Species 0.000 description 1
- 238000009098 adjuvant therapy Methods 0.000 description 1
- AFVLVVWMAFSXCK-VMPITWQZSA-N alpha-cyano-4-hydroxycinnamic acid Chemical group OC(=O)C(\C#N)=C\C1=CC=C(O)C=C1 AFVLVVWMAFSXCK-VMPITWQZSA-N 0.000 description 1
- 239000003560 cancer drug Substances 0.000 description 1
- 239000003433 contraceptive agent Substances 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000022244 formylation Effects 0.000 description 1
- 238000006170 formylation reaction Methods 0.000 description 1
- 229950000801 hydroxyprogesterone caproate Drugs 0.000 description 1
- IHLVCKWPAMTVTG-UHFFFAOYSA-N lithium;carbanide Chemical compound [Li+].[CH3-] IHLVCKWPAMTVTG-UHFFFAOYSA-N 0.000 description 1
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 230000036457 multidrug resistance Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000000583 progesterone congener Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
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Abstract
The invention relates to a method for synthesizing 6-methyl-17alpha-acetoxyl-19-norpregnane-4,6-diene-3,20-diketone. The method comprises the following steps: 1) reacting acetylene with estrone-3-methyl ether so as to obtain 17alpha-acetenyl estrone-3-methyl ether; 2) carrying out Birich reaction at a low temperature; 3) carrying out alkene etherification on the product obtained in the step 2); 4) carrying out a Vilsmeier reaction on the product obtained in the steps 3); 5) reacting the product obtained in the step 4) with benzene sulfenyl chloride; 6) reacting the product obtained in the step 5) with sodium methoxide and trimethyl phosphate; 7) reducing the formoxyl at the 6-position of the product obtained in the step 6); and 8) reacting the product obtained in the step 7) with Pd-C/cyclohexene, then reacting with acetic oxide so as to obtain the target product 6-methyl-17alpha-acetoxyl-19-norpregnane-4,6-diene-3,20-diketone. By using the method, the operation is simplified, and the production cost is reduced; and the reactions involved in the invention are simple to operate, and the yield is high.
Description
Technical field
The present invention relates to the synthetic field of medicine, particularly, the present invention relates to a kind of synthetic 6-methyl-17-alpha-acetoxyl group-19-norpregna-4,6-diene-3, the method for 20-diketone.
Background technology
6-methyl-17-alpha-acetoxyl group-19-norpregna-4,6-diene-3,20-diketone are a kind of new and effective oral progestogen, have that contraceptive effect is good, toxic side effect is little and characteristics such as easy to use, safe.6-methyl-17-alpha-acetoxyl group-19-norpregna-4,6-diene-3,20-diketone be Theramex company research and development and went on the market in France in 1985.In western countries, 6-methyl-17-alpha-acetoxyl group-19-norpregna-4,6-diene-3, the 20-diketone as the 4th generation contraceptive bian, widespread use.In addition, 6-methyl-17-alpha-acetoxyl group-19-norpregna-4,6-diene-3, the 20-diketone is to uterus displacement (Chinese Pharrnacological Bulletin 2004Nov; 20 (11): 1215-7), reverse mammary cancer drug-resistant cell strain multidrug resistance better curative effect (China Oncol.March 2002Vol24.No.2) is arranged, so 6-methyl-17-alpha-acetoxyl group-19-norpregna-4,6-diene-3,20-diketone are at the adjuvant therapy medicaments of a plurality of state approvals as treatment uterine displacement and mammary cancer.Because 6-methyl-17-alpha-acetoxyl group-19-norpregna-4,6-diene-3, the raw material sources of the original method of 20-diketone are induced restriction, at present 6-methyl-17-alpha-acetoxyl group-19-norpregna-4,6-diene-3, the 20-diketone does not still have and can go on the market in many countries.Therefore, research and develop a simple 6-methyl-17-alpha-acetoxyl group-19-norpregna-4,6-diene-3, the synthetic route of 20-diketone, the source that solves its bulk drug has great application value and vast market prospect.
In the prior art; mainly be a strip adoption intermediate 17 α-pregnant steroid of acetoxyl group-19-demethyl-4-alkene-3 by Jean M.Gastaund invention; 20-diketone (FR2271833; GB1515284; US4544555) be starting raw material, through five steps reaction such as 3-position alkene etherificate, the formylation of 6-position, sodium borohydride reduction, dehydration and methyne migration of the double bond, synthetic 6-methyl-17-alpha-acetoxyl group-19-norpregna-4; 6-diene-3,20-diketone (structural formula 1).Yet this starting raw material very seldom arrives, and mainly depends on the semi-synthetic of the pre-plant resources of potato both at home and abroad, altogether through the reaction of 15 steps.In addition, be converted into this step reaction of 17 Alpha-hydroxies-17 alpha-cyano at 17 carbonyls and use lithium methide/ether, and generate two isomer, wherein near half reactant has been wasted.
Patent documentation WO8501504 (Theramex S.A.) has described with 3-methoxyl group-17-ethyl androstane-3,5,17 (20)-triolefins are that intermediate obtains 6-methyl-17-alpha-acetoxyl group-19-norpregna-4,6-diene-3,20-diketone through about 10 steps reaction.This operational path mainly is that the oxidation by 17 (20) two keys obtains 17 Alpha-hydroxy progesterone, and productive rate is low, the operational requirement height.
Summary of the invention
The object of the present invention is to provide a kind of synthetic 6-methyl-17-alpha-acetoxyl group-19-norpregna-4,6-diene-3, the method for 20-diketone.
According to synthetic 6-methyl-17-alpha-acetoxyl group of the present invention-19-norpregna-4,6-diene-3, the route of 20-diketone method is:
According to synthetic 6-methyl-17-alpha-acetoxyl group of the present invention-19-norpregna-4,6-diene-3, the method for 20-diketone, this method may further comprise the steps:
1) with sodium carbide direct and female phenolic ketone-3-methyl ether react the female phenolic alcohol of 17 α-ethynyl-3-methyl ether, also acetylene gas can be passed in the tetrahydrofuran solution of sodium tert-butoxide or potassium tert.-butoxide, add female phenolic ketone-3-methyl ether then and obtain the female phenolic alcohol of 17 α-ethynyl-3-methyl ether;
2) compound that step 1) is obtained (2) carries out the Birch reduction, obtains compound (3) 17 α-ethynyl-17 beta-hydroxies-19-demethyl androstane-4-alkene-3-ketone, and temperature of reaction is-60～-70 ℃;
3) with step 2) compound (3) that obtains and triethyl orthoformate reaction carry out the alkene etherificate with the carbonyl of 3-position and obtain compound (4) 3-oxyethyl group-17 α-ethynyl-17 beta-hydroxies-19-demethyl androstane-3,5-diene;
4) compound that step 3) is obtained (4) and DMF generation Vilsmeier reaction under 0～30 ℃ obtains compound (5) 3-oxyethyl group-6-formyl radical-17 α-ethynyl-17 beta-hydroxies-19-demethyl androstane-3,5-diene;
5) compound (5) that obtains of step 4) temperature-5～10 ℃ down and benzene time SULPHURYL CHLORIDE react and obtain compound (6) 3-oxyethyl group-6-formyl radical-19-demethyl-21-benzenesulfonyl pregnant steroid-3,5,17 (20), the 20-tetraene;
6) compound (6) that obtains of step 5) and sodium methylate/trimethyl phosphite change into compound (7) 3-oxyethyl group-6-formyl radical-17 Alpha-hydroxies-19-demethyl-20-methoxyl group pregnant steroid-3,5, the 20-triolefin 55～75 ℃ of reactions down;
7) compound that step 6) is obtained (7) and sodium borohydride obtain 3-oxyethyl group-6-methylol-17 Alpha-hydroxies-19-demethyl-20-methoxyl group pregnant steroid-3 with the formyl radical reduction of 6-position, 5, the 20-triolefin, after the hydrochloric acid dehydration, obtain compound (8) 17 Alpha-hydroxies-pregnant steroid of 6-methyne-19-demethyl-4-alkene-3, the 20-diketone again;
8) compound that step 7) is obtained (8) is under the effect of Pd-C/ tetrahydrobenzene, the two keys of 6-precedence methyl are obtained 17 Alpha-hydroxies-6-methyl-19-nor base pregnant steroid-4 to the ring intrinsic displacement, 6-diene-3, the 20-diketone, and then and acetic anhydride reaction after obtain compound (9) 17 α-acetoxyl group-6-methyl-19-nor base pregnant steroid-4,6-diene-3, the 20-diketone, it is target product 6-methyl-17-alpha-acetoxyl group-19-norpregna-4,6-diene-3, the 20-diketone, wherein the mol ratio of substrate and Pd-C/ tetrahydrobenzene is 1: 0.025～0.06.
According to synthetic 6-methyl-17-alpha-acetoxyl group of the present invention-19-norpregna-4,6-diene-3, the method for 20-diketone, preferred temperature of reaction is-5～0 ℃ in the described step 1); Preferred temperature of reaction is 5～15 ℃ in the described step 3); Preferred temperature of reaction is 0～5 ℃ in the described step 4); Preferred temperature of reaction is 60～65 ℃ in the described step 5); The preferred mol ratio of compound in the described step 7) (8) and tetrahydrobenzene is 1: 0.035～0.045.
A new method provided by the present invention is used for preparing 6-methyl-17-alpha-acetoxyl group-19-norpregna-4,6-diene-3, the 20-diketone, this method has overcome the deficiencies in the prior art, simplified operation, reduced production cost, the operation that the present invention relates to is easy, the productive rate height, per step is all more than 70%.
Description of drawings
Fig. 1 is 6-methyl-17-alpha-acetoxyl group of the present invention-19-norpregna-4,6-diene-3, the synthetic route of 20-diketone.
Embodiment
1, the female phenolic alcohol of 17 α-ethynyl-3-methyl ether (2)
The potassium tert.-butoxide powder of 60 grams are put in 3 liters the reaction flask, add THF (1.4L), acetylene gas is passed in the reaction flask up to saturated, is cooled to 0 ℃, logical again acetylene gas is after 30 minutes, add female phenolic ketone alcohol-3-methyl ether (100g, 0.35mol), reaction solution at room temperature stirred 1 hour, add saturated aqueous ammonium chloride, organic layer separates, and water layer extracts with tetrahydrofuran (THF), merges organic phase, use the saturated sodium-chloride water washing, behind the concentrating part organic solvent, be poured in ice-water, separate out solid filtering, obtain the female phenolic alcohol of 105 gram 17 α-ethynyls-3-methyl ether after the drying, productive rate 97%, TLC shows a point, can be directly used in next step reaction.
2,17 α-ethynyl-17 beta-hydroxies-19-demethyl androstane-4-alkene-3-ketone (3)
Under the dry ice-propanone cooling, collect the liquefied ammonia of 2kg, add sodium Metal 99.5 (23g, 1mol), react after 30 minutes, with the female phenolic alcohol of 17 α-ethynyl-3-methyl ether (104g, 0.335mol) tetrahydrofuran (THF) (2L) drips of solution be added in sodium-liquefied ammonia, reacted 60 minutes, and added ethanol (1L), be poured in the saturated ammonium chloride water, separate out solid filtering, obtain 82g after the drying, productive rate 82%, fusing point 205-206 ℃.
3,3-oxyethyl group-6-formyl radical-17 α-ethynyl-17 beta-hydroxies-19-demethyl androstane-3,5-diene (5)
With 17 α-ethynyl-17 beta-hydroxies-19-demethyl androstane-4-alkene-3-ketone (81g, 0.27mol) be dissolved in toluene (600mL), dehydrated alcohol (50mL), triethyl orthoformate (80mL), and tosic acid (1.5g), behind the heating reflux reaction 2 hours, cooling, add triethylamine (5mL), with the solid product that obtains after concentrating under the reactant decompression, directly be dissolved in (250mL) in the toluene, ice bath is cooled to 5～8 ℃, adds Vilsmeier reagent (the 200mL DMF+65mLPOCl of new configuration
3), be reflected between 10 ℃ to 15 ℃ and carry out.React after 2 hours, add sodium acetate, anhydrous in batches, controlled temperature is below 30 ℃; finish; reaction is 3 hours under the room temperature, adds entry, extracts with toluene; dry; obtain 3-oxyethyl group-6-formyl radical-17 α-ethynyl-17 beta-hydroxies-19-demethyl androstane-3 with recrystallizing methanol, 5-diene 68g, two step productive rates are 71%; HNMR (ppm, CDCl
3): 10.24 (s, 1H), 6.36 (s, 1H), 3.86-3.96 (q, 2H), 3.55 (s, 1H), 3.47 (s, 1H), 2.95-2.97 (t, 1H), 2.55-2.59 (dd, 1H), 2.25-2.35 (m, 2H), 2.15-2.25 (m, 2H), 1.0-2.05 (m, 15H), 0.67 (s, 3H).
4,3-oxyethyl group-6-formyl radical-19-demethyl-21-benzenesulfonyl pregnant steroid-3,5,17 (20), 20-tetraene (6)
With 3-oxyethyl group-6-formyl radical-17 α-ethynyl-17 beta-hydroxies-19-demethyl androstane-3; 5-diene (67g; 0.19mol); triethylamine (80mL), acetic acid (15mL) is dissolved in the methylene dichloride (1L); be cooled to-5 ℃ under stirring; (34g, chloroform 0.23mol) (100mL) solution, reaction solution stirred 10 minutes between-5 ℃ to 0 ℃ to be added dropwise to benzene time SULPHURYL CHLORIDE.Add entry (100mL) and methyl alcohol (50mL); tell organic phase, water, saturated aqueous ammonium chloride, saturated sodium-chloride water solution washing, drying; product obtains 3-oxyethyl group-6-formyl radical-19-demethyl-21-benzenesulfonyl pregnant steroid-3 with ethyl acetate-sherwood oil recrystallization; 5,17 (20), the 20-tetraene; 77g; productive rate 84%, HNMR (ppm, CDCl
3): 10.20 (s, 1H), 7.47-7.65 (m, 5H), 6.60 (s, 1H), 6.27 (s, 1H), 3.74-3.76 (q, 2H), 1.0-3.0 (m, 21H), 0.90 (s, 3H).
5,3-oxyethyl group-6-formyl radical-17 Alpha-hydroxies-19-demethyl-20-methoxyl group pregnant steroid-3,5,20-triolefin (7)
With 3-oxyethyl group-6-formyl radical-19-demethyl-21-benzenesulfonyl pregnant steroid-3; 5,17 (20), 20-tetraene (77g; 0.16mol) join sodium methylate (4.5g; 0.08mol) methyl alcohol (2L) solution in, 62 ℃ to 64 ℃ down reactions 3 hours, then; add trimethyl phosphite (21mL); continuation was reacted 2 hours down at 62 ℃ to 64 ℃, was cooled to 20 ℃, was poured in the water; separate out solid filtering; drying obtains 3-oxyethyl group-6-formyl radical-17 Alpha-hydroxies-19-demethyl-20-methoxyl group pregnant steroid-3,5,20-triolefin; 46g; productive rate 74%, HNMR (ppm, CDCl
3): 10.23 (s, 1H), 5.72 (s, 1H), 4.26 (s, 1H), 4.08 (s, 1H), 3.81-3.85 (q, 2H), 3.56 (t, 3H), 1.3-2.8 (m, 21H), 0.66 (s, 3H).
6, the 17 Alpha-hydroxies-pregnant steroid of 6-methyne-19-demethyl-4-alkene-3,20-diketone (8)
With 3-oxyethyl group-6-formyl radical-17 Alpha-hydroxies-19-demethyl-20-methoxyl group pregnant steroid-3,5,20-triolefin (45g; 0.11mol) be dissolved in (2L) in the methyl alcohol, add sodium borohydride (5g, 0.13mol); reacted 30 minutes, and added concentrated hydrochloric acid (15mL), be poured in the water; the solid filtering of separating out, drying obtains the 17 Alpha-hydroxies-pregnant steroid of 6-methyne-19-demethyl-4-alkene-3; the 20-diketone, 32g, productive rate 88%; HNMR (ppm, CDCl
3): 6.12 (d, 1H), 5.20 (t, 1H), 4.97 (t, 1H), 3.49 (s, 1H), 2.93-2.99 (m, 1H), 2.45-2.50 (m, 2H), 2.25-2.30 (m, 3H), 2.12 (s, 3H), and 1.9-2.0 (m, 3H), 1.75-1.85 (m, 3H), 1.5-1.6 (m, 3H), 1.2-1.4 (m, 2H), 1.0-1.1 (m, 1H), 0.69 (s, 3H).
7,17 α-acetoxyl group-6-methyl-19-nor base pregnant steroid-4,6-diene-3,20-diketone (9)
With the 17 Alpha-hydroxies-pregnant steroid of 6-methyne-19-demethyl-4-alkene-3, and the 20-diketone (30g, 0.09mol), THF (100mL), triethylamine (15mL), acetic anhydride (100mL), reaction was stirred 5 hours, add ethanol (1L), 5%Pd-C (20g), tetrahydrobenzene (0.3g, 0.0036mol), (wherein the reaction substrate 17 Alpha-hydroxies-6-methyne-pregnant steroid 4-of 19-demethyl alkene-3, the mol ratio of 20-diketone and Pd-C/ tetrahydrobenzene is 1: 0.04) stirring and refluxing reaction half an hour, filter, the a large amount of solvents of pressure reducing and steaming, pour in the water, separate out solid filtering, drying obtains solid, obtain product 26g with recrystallizing methanol, productive rate 78%, HNMR (ppm, CDCl
3): 6.04 (d, 1H), 5.96 (s, 1H), 2.96-3.03 (td, 1H), 2.53-2.59 (dd, 1H), 2.25-2.30 (m, 3H), 2.12 (s, 3H), 2.06 (s, 3H), 2.05-2.15 (m, 2H), 1.85-1.95 (m, 6H), 1.55-1.60 (m, 3H), 1.10-1.40 (m, 3H), 0.71 (s, 3H).
1, the female phenolic alcohol of 17 α-ethynyl-3-methyl ether (2)
The potassium tert.-butoxide powder of 60 grams are put in 3 liters the reaction flask, add THF (1.4L), acetylene gas is passed in the reaction flask up to saturated, is cooled to-10 ℃, logical again acetylene gas is after 30 minutes, add female phenolic ketone alcohol-3-methyl ether (100g, 0.35mol), reaction solution at room temperature stirred 1 hour, add saturated aqueous ammonium chloride, organic layer separates, and water layer extracts with tetrahydrofuran (THF), merges organic phase, use the saturated sodium-chloride water washing, behind the concentrating part organic solvent, be poured in ice-water, separate out solid filtering, obtain the female phenolic alcohol of 105 gram 17 α-ethynyls-3-methyl ether after the drying, productive rate 96%, TLC shows a point, can be directly used in next step reaction.
2,17 α-ethynyl-17 beta-hydroxies-19-demethyl androstane-4-alkene-3-ketone (3)
Under the dry ice-propanone cooling, collect the liquefied ammonia of 2kg, add sodium Metal 99.5 (23g, 1mol), react after 30 minutes, with the female phenolic alcohol of 17 α-ethynyl-3-methyl ether (104g, 0.335mol) tetrahydrofuran (THF) (2L) drips of solution be added in sodium-liquefied ammonia, reacted 60 minutes, and added ethanol (1L), be poured in the saturated ammonium chloride water, separate out solid filtering, obtain 82g after the drying, productive rate 82%, fusing point 205-206 ℃.
3,3-oxyethyl group-6-formyl radical-17 α-ethynyl-17 beta-hydroxies-19-demethyl androstane-3,5-diene (5)
With 17 α-ethynyl-17 beta-hydroxies-19-demethyl androstane-4-alkene-3-ketone (81g, 0.27mol) be dissolved in toluene (600mL), dehydrated alcohol (50mL), triethyl orthoformate (80mL), and tosic acid (1.5g), behind the heating reflux reaction 2 hours, cooling adds triethylamine (5mL), with the solid product that obtains after concentrating under the reactant decompression, directly be dissolved in (250mL) in the toluene, ice bath is cooled to 5～8 ℃, adds the Vilsmeier reagent (200mLDMF+65mLPOCl of new configuration
3), be reflected between 5 ℃ to 10 ℃ and carry out.React after 2 hours, add sodium acetate, anhydrous in batches, controlled temperature is below 30 ℃; finish; reaction is 3 hours under the room temperature, adds entry, extracts with toluene; dry; obtain 3-oxyethyl group-6-formyl radical-17 α-ethynyl-17 beta-hydroxies-19-demethyl androstane-3 with recrystallizing methanol, 5-diene 68g, two step productive rates are 70%; HNMR (ppm, CDCl
3): 10.24 (s, 1H), 6.36 (s, 1H), 3.86-3.96 (q, 2H), 3.55 (s, 1H), 3.47 (s, 1H), 2.95-2.97 (t, 1H), 2.55-2.59 (dd, 1H), 2.25-2.35 (m, 2H), 2.15-2.25 (m, 2H), 1.0-2.05 (m, 15H), 0.67 (s, 3H).
4,3-oxyethyl group-6-formyl radical-19-demethyl-21-benzenesulfonyl pregnant steroid-3,5,17 (20), 20-tetraene (6)
With 3-oxyethyl group-6-formyl radical-17 α-ethynyl-17 beta-hydroxies-19-demethyl androstane-3, and the 5-diene (67g, 0.19mol), triethylamine (80mL), acetic acid (15mL) is dissolved in the methylene dichloride (1L), is cooled to-5 under stirring.℃, (34g, chloroform 0.23mol) (100mL) solution, reaction solution stirred 10 minutes between 0 ℃ to 5 ℃ to be added dropwise to benzene time SULPHURYL CHLORIDE.Add entry (100mL) and methyl alcohol (50mL); tell organic phase, water, saturated aqueous ammonium chloride, saturated sodium-chloride water solution washing, drying; product obtains 3-oxyethyl group-6-formyl radical-19-demethyl-21-benzenesulfonyl pregnant steroid-3 with ethyl acetate-sherwood oil recrystallization; 5,17 (20), the 20-tetraene; 77g; productive rate 84%, HNMR (ppm, CDCl
3): 10.20 (s, 1H), 7.47-7.65 (m, 5H), 6.60 (s, 1H), 6.27 (s, 1H), 3.74-3.76 (q, 2H), 1.0-3.0 (m, 21H), 0.90 (s, 3H).
5,3-oxyethyl group-6-formyl radical-17 Alpha-hydroxies-19-demethyl-20-methoxyl group pregnant steroid-3,5,20-triolefin (7)
With 3-oxyethyl group-6-formyl radical-19-demethyl-21-benzenesulfonyl pregnant steroid-3; 5,17 (20), 20-tetraene (77g; 0.16mol) join sodium methylate (4.5g; 0.08mol) methyl alcohol (2L) solution in, 55 ℃ of down reactions 3 hours, then; add trimethyl phosphite (21mL); continuation was reacted 2 hours down at 55 ℃, was cooled to 20 ℃, was poured in the water; separate out solid filtering; drying obtains 3-oxyethyl group-6-formyl radical-17 Alpha-hydroxies-19-demethyl-20-methoxyl group pregnant steroid-3,5,20-triolefin; 46g; productive rate 72%, HNMR (ppm, CDCl
3): 10.23 (s, 1H), 5.72 (s, 1H), 4.26 (s, 1H), 4.08 (s, 1H), 3.81-3.85 (q, 2H), 3.56 (t, 3H), 1.3-2.8 (m, 21H), 0.66 (s, 3H).
6, the 17 Alpha-hydroxies-pregnant steroid of 6-methyne-19-demethyl-4-alkene-3,20-diketone (8)
With 3-oxyethyl group-6-formyl radical-17 Alpha-hydroxies-19-demethyl-20-methoxyl group pregnant steroid-3,5,20-triolefin (45g; 0.11mol) be dissolved in (2L) in the methyl alcohol, add sodium borohydride (5g, 0.13mol); reacted 30 minutes, and added concentrated hydrochloric acid (15mL), be poured in the water; the solid filtering of separating out, drying obtains the 17 Alpha-hydroxies-pregnant steroid of 6-methyne-19-demethyl-4-alkene-3; the 20-diketone, 32g, productive rate 88%; HNMR (ppm, CDCl
3): 6.12 (d, 1H), 5.20 (t, 1H), 4.97 (t, 1H), 3.49 (s, 1H), 2.93-2.99 (m, 1H), 2.45-2.50 (m, 2H), 2.25-2.30 (m, 3H), 2.12 (s, 3H), and 1.9-2.0 (m, 3H), 1.75-1.85 (m, 3H), 1.5-1.6 (m, 3H), 1.2-1.4 (m, 2H), 1.0-1.1 (m, 1H), 0.69 (s, 3H).
7,17 α-acetoxyl group-6-methyl-19-nor base pregnant steroid-4,6-diene-3,20-diketone (9)
With the 17 Alpha-hydroxies-pregnant steroid of 6-methyne-19-demethyl-4-alkene-3, and the 20-diketone (30g, 0.09mol), THF (100mL), triethylamine (15mL), acetic anhydride (100mL), reaction was stirred 5 hours, add ethanol (1L), 5%Pd-C (20g), tetrahydrobenzene (0.45g, 0.0054mol), (wherein the reaction substrate 17 Alpha-hydroxies-pregnant steroid of 6-methyne-19-demethyl-4-alkene-3, the mol ratio of 20-diketone and Pd-C/ tetrahydrobenzene is 1: 0.06) stirring and refluxing reaction half an hour, filter, the a large amount of solvents of pressure reducing and steaming, pour in the water, separate out solid filtering, drying obtains solid, obtain product 26g with recrystallizing methanol, productive rate 78%, HNMR (ppm, CDCl
3): 6.04 (d, 1H), 5.96 (s, 1H), 2.96-3.03 (td, 1H), 2.53-2.59 (dd, 1H), 2.25-2.30 (m, 3H), 2.12 (s, 3H), 2.06 (s, 3H), 2.05-2.15 (m, 2H), 1.85-1.95 (m, 6H), 1.55-1.60 (m, 3H), 1.10-1.40 (m, 3H), 0.71 (s, 3H).
1, the female phenolic alcohol of 17 α-ethynyl-3-methyl ether (2)
The potassium tert.-butoxide powder of 60 grams are put in 3 liters the reaction flask, add THF (1.4L), acetylene gas is passed in the reaction flask up to saturated, is cooled to-5 ℃, logical again acetylene gas is after 30 minutes, add female phenolic ketone alcohol-3-methyl ether (100g, 0.35mol), reaction solution at room temperature stirred 1 hour, add saturated aqueous ammonium chloride, organic layer separates, and water layer extracts with tetrahydrofuran (THF), merges organic phase, use the saturated sodium-chloride water washing, behind the concentrating part organic solvent, be poured in ice-water, separate out solid filtering, obtain the female phenolic alcohol of 105 gram 17 α-ethynyls-3-methyl ether after the drying, productive rate 98%, TLC shows a point, can be directly used in next step reaction.
2,17 α-ethynyl-17 beta-hydroxies-19-demethyl androstane-4-alkene-3-ketone (3)
Under the dry ice-propanone cooling, collect the liquefied ammonia of 2kg, add sodium Metal 99.5 (23g, 1mol), react after 30 minutes, with the female phenolic alcohol of 17 α-ethynyl-3-methyl ether (104g, 0.335mol) tetrahydrofuran (THF) (2L) drips of solution be added in sodium-liquefied ammonia, reacted 60 minutes, and added ethanol (1L), be poured in the saturated ammonium chloride water, separate out solid filtering, obtain 82g after the drying, productive rate 82%, fusing point 205-206 ℃.
3,3-oxyethyl group-6-formyl radical-17 α-ethynyl-17 beta-hydroxies-19-demethyl androstane-3,5-diene (5)
With 17 α-ethynyl-17 beta-hydroxies-19-demethyl androstane-4-alkene-3-ketone (81g, 0.27mol) be dissolved in toluene (600mL), dehydrated alcohol (50mL), triethyl orthoformate (80mL), and tosic acid (1.5g), behind the heating reflux reaction 2 hours, cooling, add triethylamine (5mL), with the solid product that obtains after concentrating under the reactant decompression, directly be dissolved in (250mL) in the toluene, ice bath is cooled to 5～8 ℃, adds Vilsmeier reagent (the 200mL DMF+65mL POCl of new configuration
3), be reflected between 0 ℃ to 5 ℃ and carry out.React after 2 hours, add sodium acetate, anhydrous in batches, controlled temperature is below 30 ℃; finish; reaction is 3 hours under the room temperature, adds entry, extracts with toluene; dry; obtain 3-oxyethyl group-6-formyl radical-17 α-ethynyl-17 beta-hydroxies-19-demethyl androstane-3 with recrystallizing methanol, 5-diene 68g, two step productive rates are 70%; HNMR (ppm, CDCl
3): 10.24 (s, 1H), 6.36 (s, 1H), 3.86-3.96 (q, 2H), 3.55 (s, 1H), 3.47 (s, 1H), 2.95-2.97 (t, 1H), 2.55-2.59 (dd, 1H), 2.25-2.35 (m, 2H), 2.15-2.25 (m, 2H), 1.0-2.05 (m, 15H), 0.67 (s, 3H).
4,3-oxyethyl group-6-formyl radical-19-demethyl-21-benzenesulfonyl pregnant steroid-3,5,17 (20), 20-tetraene (6)
With 3-oxyethyl group-6-formyl radical-17 α-ethynyl-17 beta-hydroxies-19-demethyl androstane-3; 5-diene (67g; 0.19mol); triethylamine (80mL), acetic acid (15mL) is dissolved in the methylene dichloride (1L); be cooled to-5 ℃ under stirring; (reaction solution stirred 10 minutes between 10 ℃ for 34g, chloroform 0.23mol) (100mL) solution to be added dropwise to benzene time SULPHURYL CHLORIDE.Add entry (100mL) and methyl alcohol (50mL); tell organic phase, water, saturated aqueous ammonium chloride, saturated sodium-chloride water solution washing, drying; product obtains 3-oxyethyl group-6-formyl radical-19-demethyl-21-benzenesulfonyl pregnant steroid-3 with ethyl acetate-sherwood oil recrystallization; 5,17 (20), the 20-tetraene; 77g; productive rate 84%, HNMR (ppm, CDCl
3): 10.20 (s, 1H), 7.47-7.65 (m, 5H), 6.60 (s, 1H), 6.27 (s, 1H), 3.74-3.76 (q, 2H), 1.0-3.0 (m, 21H), 0.90 (s, 3H).
5,3-oxyethyl group-6-formyl radical-17 Alpha-hydroxies-19-demethyl-20-methoxyl group pregnant steroid-3,5,20-triolefin (7)
With 3-oxyethyl group-6-formyl radical-19-demethyl-21-benzenesulfonyl pregnant steroid-3; 5,17 (20), 20-tetraene (77g; 0.16mol) join sodium methylate (4.5g; 0.08mol) methyl alcohol (2L) solution in, 75 ℃ of down reactions 3 hours, then; add trimethyl phosphite (21mL); continuation was reacted 2 hours down at 75 ℃, was cooled to 20 ℃, was poured in the water; separate out solid filtering; drying obtains 3-oxyethyl group-6-formyl radical-17 Alpha-hydroxies-19-demethyl-20-methoxyl group pregnant steroid-3,5,20-triolefin; 46g; productive rate 70%, HNMR (ppm, CDCl
3): 10.23 (s, 1H), 5.72 (s, 1H), 4.26 (s, 1H), 4.08 (s, 1H), 3.81-3.85 (q, 2H), 3.56 (t, 3H), 1.3-2.8 (m, 21H), 0.66 (s, 3H).
6, the 17 Alpha-hydroxies-pregnant steroid of 6-methyne-19-demethyl-4-alkene-3,20-diketone (8)
With 3-oxyethyl group-6-formyl radical-17 Alpha-hydroxies-19-demethyl-20-methoxyl group pregnant steroid-3,5,20-triolefin (45g; 0.11mol) be dissolved in (2L) in the methyl alcohol, add sodium borohydride (5g, 0.13mol); reacted 30 minutes, and added concentrated hydrochloric acid (15mL), be poured in the water; the solid filtering of separating out, drying obtains the 17 Alpha-hydroxies-pregnant steroid of 6-methyne-19-demethyl-4-alkene-3; the 20-diketone, 32g, productive rate 88%; HNMR (ppm, CDCl
3): 6.12 (d, 1H), 5.20 (t, 1H), 4.97 (t, 1H), 3.49 (s, 1H), 2.93-2.99 (m, 1H), 2.45-2.50 (m, 2H), 2.25-2.30 (m, 3H), 2.12 (s, 3H), and 1.9-2.0 (m, 3H), 1.75-1.85 (m, 3H), 1.5-1.6 (m, 3H), 1.2-1.4 (m, 2H), 1.0-1.1 (m, 1H), 0.69 (s, 3H).
7,17 α-acetoxyl group-6-methyl-19-nor base pregnant steroid-4,6-diene-3,20-diketone (9)
With the 17 Alpha-hydroxies-pregnant steroid of 6-methyne-19-demethyl-4-alkene-3, and the 20-diketone (30g, 0.09mol), THF (100mL), triethylamine (15mL), acetic anhydride (100mL), reaction was stirred 5 hours, add ethanol (1L), 5%Pd-C (20g), tetrahydrobenzene (0.1875g, 0.00225mol), (wherein the reaction substrate 17 Alpha-hydroxies-pregnant steroid of 6-methyne-19-demethyl-4-alkene-3, the mol ratio of 20-diketone and Pd-C/ tetrahydrobenzene is 1: 0.025) stirring and refluxing reaction half an hour, filter, the a large amount of solvents of pressure reducing and steaming, pour in the water, separate out solid filtering, drying obtains solid, obtain product 26g with recrystallizing methanol, productive rate 78%, HNMR (ppm, CDCl
3): 6.04 (d, 1H), 5.96 (s, 1H), 2.96-3.03 (td, 1H), 2.53-2.59 (dd, 1H), 2.25-2.30 (m, 3H), 2.12 (s, 3H), 2.06 (s, 3H), 2.05-2.15 (m, 2H), 1.85-1.95 (m, 6H), 1.55-1.60 (m, 3H), 1.10-1.40 (m, 3H), 0.71 (s, 3H).
1, the female phenolic alcohol of 17 α-ethynyl-3-methyl ether (2)
The potassium tert.-butoxide powder of 60 grams are put in 3 liters the reaction flask, add THF (1.4L), acetylene gas is passed in the reaction flask up to saturated, is cooled to 5 ℃, logical again acetylene gas is after 30 minutes, add female phenolic ketone alcohol-3-methyl ether (100g, 0.35mol), reaction solution at room temperature stirred 1 hour, add saturated aqueous ammonium chloride, organic layer separates, and water layer extracts with tetrahydrofuran (THF), merges organic phase, use the saturated sodium-chloride water washing, behind the concentrating part organic solvent, be poured in ice-water, separate out solid filtering, obtain the female phenolic alcohol of 104 gram 17 α-ethynyls-3-methyl ether after the drying, productive rate 95%, TLC shows a point, can be directly used in next step reaction.
2,17 α-ethynyl-17 beta-hydroxies-19-demethyl androstane-4-alkene-3-ketone (3)
Under the dry ice-propanone cooling, collect the liquefied ammonia of 2kg, add sodium Metal 99.5 (23g, 1mol), react after 30 minutes, with the female phenolic alcohol of 17 α-ethynyl-3-methyl ether (104g, 0.335mol) tetrahydrofuran (THF) (2L) drips of solution be added in sodium-liquefied ammonia, reacted 60 minutes, and added ethanol (1L), be poured in the saturated ammonium chloride water, separate out solid filtering, obtain 82g after the drying, productive rate 82%, fusing point 205-206 ℃.
3,3-oxyethyl group-6-formyl radical-17 α-ethynyl-17 beta-hydroxies-19-demethyl androstane-3,5-diene (5)
With 17 α-ethynyl-17 beta-hydroxies-19-demethyl androstane-4-alkene-3-ketone (81g, 0.27mol) be dissolved in toluene (600mL), dehydrated alcohol (50mL), triethyl orthoformate (80mL), and tosic acid (1.5g), behind the heating reflux reaction 2 hours, cooling, add triethylamine (5mL), with the solid product that obtains after concentrating under the reactant decompression, directly be dissolved in (250mL) in the toluene, ice bath is cooled to 5～8 ℃, adds Vilsmeier reagent (the 200mL DMF+65mL POCl of new configuration
3), be reflected between 20 ℃ to 130 ℃ and carry out.React after 2 hours, add sodium acetate, anhydrous in batches, controlled temperature is below 30 ℃; finish; reaction is 3 hours under the room temperature, adds entry, extracts with toluene; dry; obtain 3-oxyethyl group-6-formyl radical-17 α-ethynyl-17 beta-hydroxies-19-demethyl androstane-3 with recrystallizing methanol, 5-diene 65g, two step productive rates are 69%; HNMR (ppm, CDCl
3): 10.24 (s, 1H), 6.36 (s, 1H), 3.86-3.96 (q, 2H), 3.55 (s, 1H), 3.47 (s, 1H), 2.95-2.97 (t, 1H), 2.55-2.59 (dd, 1H), 2.25-2.35 (m, 2H), 2.15-2.25 (m, 2H), 1.0-2.05 (m, 15H), 0.67 (s, 3H).
4,3-oxyethyl group-6-formyl radical-19-demethyl-21-benzenesulfonyl pregnant steroid-3,5,17 (20), 20-tetraene (6)
With 3-oxyethyl group-6-formyl radical-17 α-ethynyl-17 beta-hydroxies-19-demethyl androstane-3; 5-diene (67g; 0.19mol); triethylamine (80mL), acetic acid (15mL) is dissolved in the methylene dichloride (1L); be cooled to-5 ℃ under stirring; (reaction solution stirred 10 minutes between-10 ℃ for 34g, chloroform 0.23mol) (100mL) solution to be added dropwise to benzene time SULPHURYL CHLORIDE.Add entry (100mL) and methyl alcohol (50mL); tell organic phase, water, saturated aqueous ammonium chloride, saturated sodium-chloride water solution washing, drying; product obtains 3-oxyethyl group-6-formyl radical-19-demethyl-21-benzenesulfonyl pregnant steroid-3 with ethyl acetate-sherwood oil recrystallization; 5,17 (20), the 20-tetraene; 77g; productive rate 84%, HNMR (ppm, CDCl
3): 10.20 (s, 1H), 7.47-7.65 (m, 5H), 6.60 (s, 1H), 6.27 (s, 1H), 3.74-3.76 (q, 2H), 1.0-3.0 (m, 21H), 0.90 (s, 3H).
5,3-oxyethyl group-6-formyl radical-17 Alpha-hydroxies-19-demethyl-20-methoxyl group pregnant steroid-3,5,20-triolefin (7)
With 3-oxyethyl group-6-formyl radical-19-demethyl-21-benzenesulfonyl pregnant steroid-3; 5,17 (20), 20-tetraene (77g; 0.16mol) join sodium methylate (4.5g; 0.08mol) methyl alcohol (2L) solution in, 62 ℃ to 64 ℃ down reactions 3 hours, then; add trimethyl phosphite (21mL); continuation was reacted 2 hours down at 62 ℃ to 64 ℃, was cooled to 20 ℃, was poured in the water; separate out solid filtering; drying obtains 3-oxyethyl group-6-formyl radical-17 Alpha-hydroxies-19-demethyl-20-methoxyl group pregnant steroid-3,5,20-triolefin; 46g; productive rate 74%, HNMR (ppm, CDCl
3): 10.23 (s, 1H), 5.72 (s, 1H), 4.26 (s, 1H), 4.08 (s, 1H), 3.81-3.85 (q, 2H), 3.56 (t, 3H), 1.3-2.8 (m, 21H), 0.66 (s, 3H).
6, the 17 Alpha-hydroxies-pregnant steroid of 6-methyne-19-demethyl-4-alkene-3,20-diketone (8)
With 3-oxyethyl group-6-formyl radical-17 Alpha-hydroxies-19-demethyl-20-methoxyl group pregnant steroid-3,5,20-triolefin (45g; 0.11mol) be dissolved in (2L) in the methyl alcohol, add sodium borohydride (5g, 0.13mol); reacted 30 minutes, and added concentrated hydrochloric acid (15mL), be poured in the water; the solid filtering of separating out, drying obtains the 17 Alpha-hydroxies-pregnant steroid of 6-methyne-19-demethyl-4-alkene-3; the 20-diketone, 32g, productive rate 88%; HNMR (ppm, CDCl
3): 6.12 (d, 1H), 5.20 (t, 1H), 4.97 (t, 1H), 3.49 (s, 1H), 2.93-2.99 (m, 1H), 2.45-2.50 (m, 2H), 2.25-2.30 (m, 3H), 2.12 (s, 3H), and 1.9-2.0 (m, 3H), 1.75-1.85 (m, 3H), 1.5-1.6 (m, 3H), 1.2-1.4 (m, 2H), 1.0-1.1 (m, 1H), 0.69 (s, 3H).
7,17 α-acetoxyl group-6-methyl-19-nor base pregnant steroid-4,6-diene-3,20-diketone (9)
With the 17 Alpha-hydroxies-pregnant steroid of 6-methyne-19-demethyl-4-alkene-3, and the 20-diketone (30g, 0.09mol), THF (100mL), triethylamine (15mL), acetic anhydride (100mL), reaction was stirred 5 hours, add ethanol (1L), 5%Pd-C (20g), tetrahydrobenzene (0.2625g, 0.00315mol), (wherein the reaction substrate 17 Alpha-hydroxies-pregnant steroid of 6-methyne-19-demethyl-4-alkene-3, the mol ratio of 20-diketone and Pd-C/ tetrahydrobenzene is 1: 0.035) stirring and refluxing reaction half an hour, filter, the a large amount of solvents of pressure reducing and steaming, pour in the water, separate out solid filtering, drying obtains solid, obtain product 27g with recrystallizing methanol, productive rate 80%, HNMR (ppm, CDCl
3): 6.04 (d, 1H), 5.96 (s, 1H), 2.96-3.03 (td, 1H), 2.53-2.59 (dd, 1H), 2.25-2.30 (m, 3H), 2.12 (s, 3H), 2.06 (s, 3H), 2.05-2.15 (m, 2H), 1.85-1.95 (m, 6H), 1.55-1.60 (m, 3H), 1.10-1.40 (m, 3H), 0.71 (s, 3H).
Claims (6)
1. synthetic 6-methyl-17-alpha-acetoxyl group-19-norpregna-4,6-diene-3, the method for 20-diketone is characterized in that, described method may further comprise the steps:
1) obtain the female phenolic alcohol of 17 α-ethynyl-3-methyl ether with acetylene and female phenolic ketone-3-methyl ether reaction, temperature of reaction is-10～5 ℃;
2) the female phenolic alcohol of the compound 17 α-ethynyl that step 1) is obtained-3-methyl ether carries out the Birch reduction at low temperatures, obtains compound 17 α-ethynyl-17 beta-hydroxies-19-demethyl androstane-4-alkene-3-ketone;
3) with step 2) compound 17-ethynyl-17 beta-hydroxies-19-demethyl androstane-4-alkene-3-ketone of obtaining carries out the alkene etherificate and obtains compound 3-oxyethyl group-17 α-ethynyl-17 beta-hydroxies-19-demethyl androstane-3,5-diene;
4) compound 3-oxyethyl group-17 α-ethynyl-17 beta-hydroxies that step 3) obtained-19-demethyl androstane-3, the Vilsmeier reaction takes place down at 0～30 ℃ and obtains compound 3-oxyethyl group-6-formyl radical-17 α-ethynyl-17 beta-hydroxies-19-demethyl androstane-3,5-diene in the 5-diene;
5) compound 3-oxyethyl group-6-formyl radical-17 α-ethynyl-17 beta-hydroxies-19-demethyl androstane-3 of obtaining of step 4), the 5-diene temperature-5～10 ℃ down and benzene time SULPHURYL CHLORIDE react and obtain compound 3-oxyethyl group-6-formyl radical-19-demethyl-21-benzenesulfonyl pregnant steroid-3,5,17 (20), the 20-tetraene;
6) compound 3-oxyethyl group-6-formyl radical-19-demethyl-21-benzenesulfonyl pregnant steroid-3 of obtaining of step 5), 5,17 (20), 20-tetraene and sodium methylate and trimethyl phosphite react down at 55～75 ℃ and change into compound 3-oxyethyl group-6-formyl radical-17 Alpha-hydroxies-19-demethyl-20-methoxyl group pregnant steroid-3,5, the 20-triolefin;
7) compound 3-oxyethyl group-6-formyl radical-17 Alpha-hydroxies that step 6) obtained-19-demethyl-20-methoxyl group pregnant steroid-3,5, the formyl radical reduction of the 6-position of 20-triolefin obtains 3-oxyethyl group-6-methylol-17 Alpha-hydroxies-19-demethyl-20-methoxyl group pregnant steroid-3,5, the 20-triolefin further obtains the compound 17 Alpha-hydroxies-pregnant steroid of 6-methyne-19-demethyl-4-alkene-3, the 20-diketone after the dehydration;
8) compound 17 Alpha-hydroxies that the step 7) obtained-pregnant steroid of 6-methyne-19-demethyl-4-alkene-3, the 20-diketone obtains 17 Alpha-hydroxies-6-methyl-19-nor base pregnant steroid-4 under the effect of Pd-C/ tetrahydrobenzene, 6-diene-3, the 20-diketone, and then and acetic anhydride reaction after obtain compound 17 α-acetoxyl group-6-methyl-19-nor base pregnant steroid-4,6-diene-3, the 20-diketone, it is target product 6-methyl-17-alpha-acetoxyl group-19-norpregna-4,6-diene-3, the 20-diketone, the reaction substrate 17 Alpha-hydroxies-pregnant steroid of 6-methyne-19-demethyl-4-alkene-3 wherein, the mol ratio of 20-diketone and Pd-C/ tetrahydrobenzene is 1: 0.025～0.06.
2. synthetic 6-methyl-17-alpha-acetoxyl group according to claim 1-19-norpregna-4,6-diene-3, the method for 20-diketone is characterized in that, temperature of reaction is-5～0 ℃ in the described step 1).
3. synthetic 6-methyl-17-alpha-acetoxyl group according to claim 1-19-norpregna-4,6-diene-3, the method for 20-diketone is characterized in that, temperature of reaction is 5～15 ℃ in the described step 4).
4. synthetic 6-methyl-17-alpha-acetoxyl group according to claim 1-19-norpregna-4,6-diene-3, the method for 20-diketone is characterized in that, temperature of reaction is 0～5 ℃ in the described step 5).
5. synthetic 6-methyl-17-alpha-acetoxyl group according to claim 1-19-norpregna-4,6-diene-3, the method for 20-diketone is characterized in that, temperature of reaction is 60～65 ℃ in the described step 6).
6. synthetic 6-methyl-17-alpha-acetoxyl group according to claim 1-19-norpregna-4,6-diene-3, the method of 20-diketone, it is characterized in that, in described step 8), the reaction substrate 17 Alpha-hydroxies-pregnant steroid of 6-methyne-19-demethyl-4-alkene-3, the mol ratio of 20-diketone and tetrahydrobenzene is 1: 0.035～0.045.
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