CN102241589B - Synthetic method of A-nor-3,5-cracking-androstane-5-ketone-3,17 beta-diacid - Google Patents
Synthetic method of A-nor-3,5-cracking-androstane-5-ketone-3,17 beta-diacid Download PDFInfo
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- CN102241589B CN102241589B CN 201110098065 CN201110098065A CN102241589B CN 102241589 B CN102241589 B CN 102241589B CN 201110098065 CN201110098065 CN 201110098065 CN 201110098065 A CN201110098065 A CN 201110098065A CN 102241589 B CN102241589 B CN 102241589B
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- 238000010189 synthetic method Methods 0.000 title claims abstract description 6
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims abstract description 30
- 238000006243 chemical reaction Methods 0.000 claims abstract description 24
- 238000000034 method Methods 0.000 claims abstract description 21
- 239000000047 product Substances 0.000 claims abstract description 21
- 239000002253 acid Substances 0.000 claims abstract description 20
- 239000002904 solvent Substances 0.000 claims abstract description 15
- 239000003054 catalyst Substances 0.000 claims abstract description 9
- 229910052751 metal Inorganic materials 0.000 claims abstract description 9
- 239000002184 metal Substances 0.000 claims abstract description 9
- 239000007795 chemical reaction product Substances 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 25
- -1 3-carbonyl-4-androstene-17-carbonyl Chemical group 0.000 claims description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 7
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 7
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 claims description 6
- PODWXQQNRWNDGD-UHFFFAOYSA-L sodium thiosulfate pentahydrate Chemical compound O.O.O.O.O.[Na+].[Na+].[O-]S([S-])(=O)=O PODWXQQNRWNDGD-UHFFFAOYSA-L 0.000 claims description 5
- VQKFNUFAXTZWDK-UHFFFAOYSA-N 2-Methylfuran Chemical compound CC1=CC=CO1 VQKFNUFAXTZWDK-UHFFFAOYSA-N 0.000 claims description 4
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 230000002829 reductive effect Effects 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- PBYZMCDFOULPGH-UHFFFAOYSA-N tungstate Chemical compound [O-][W]([O-])(=O)=O PBYZMCDFOULPGH-UHFFFAOYSA-N 0.000 claims description 4
- ZNOKGRXACCSDPY-UHFFFAOYSA-N tungsten trioxide Chemical compound O=[W](=O)=O ZNOKGRXACCSDPY-UHFFFAOYSA-N 0.000 claims description 4
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 3
- 235000011054 acetic acid Nutrition 0.000 claims description 3
- MEFBJEMVZONFCJ-UHFFFAOYSA-N molybdate Chemical compound [O-][Mo]([O-])(=O)=O MEFBJEMVZONFCJ-UHFFFAOYSA-N 0.000 claims description 3
- 229910017604 nitric acid Inorganic materials 0.000 claims description 3
- 239000002994 raw material Substances 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 2
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 2
- 235000019260 propionic acid Nutrition 0.000 claims description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical group [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 2
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 5
- 238000000746 purification Methods 0.000 abstract description 4
- 239000003638 chemical reducing agent Substances 0.000 abstract 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- 238000000605 extraction Methods 0.000 description 14
- 238000003756 stirring Methods 0.000 description 14
- 238000002360 preparation method Methods 0.000 description 8
- 238000013019 agitation Methods 0.000 description 7
- 239000012043 crude product Substances 0.000 description 7
- 238000001035 drying Methods 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- DBEPLOCGEIEOCV-WSBQPABSSA-N finasteride Chemical compound N([C@@H]1CC2)C(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](C(=O)NC(C)(C)C)[C@@]2(C)CC1 DBEPLOCGEIEOCV-WSBQPABSSA-N 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 229910052739 hydrogen Inorganic materials 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- 238000001953 recrystallisation Methods 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- 239000012047 saturated solution Substances 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 229960004039 finasteride Drugs 0.000 description 5
- TVXXNOYZHKPKGW-UHFFFAOYSA-N sodium molybdate (anhydrous) Chemical compound [Na+].[Na+].[O-][Mo]([O-])(=O)=O TVXXNOYZHKPKGW-UHFFFAOYSA-N 0.000 description 5
- XMVONEAAOPAGAO-UHFFFAOYSA-N sodium tungstate Chemical compound [Na+].[Na+].[O-][W]([O-])(=O)=O XMVONEAAOPAGAO-UHFFFAOYSA-N 0.000 description 4
- 239000000011 acetone peroxide Substances 0.000 description 3
- NVKAWKQGWWIWPM-ABEVXSGRSA-N 17-β-hydroxy-5-α-Androstan-3-one Chemical compound C1C(=O)CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@H]21 NVKAWKQGWWIWPM-ABEVXSGRSA-N 0.000 description 2
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 description 2
- 102000004316 Oxidoreductases Human genes 0.000 description 2
- 108090000854 Oxidoreductases Proteins 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 2
- 229960003473 androstanolone Drugs 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229910001385 heavy metal Inorganic materials 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 description 1
- 206010003694 Atrophy Diseases 0.000 description 1
- 0 C*C([C@@](CC1)[C@@](C)(CC2)C1C(CCC1N3)C2[C@@]1(C)C=CC3=O)=O Chemical compound C*C([C@@](CC1)[C@@](C)(CC2)C1C(CCC1N3)C2[C@@]1(C)C=CC3=O)=O 0.000 description 1
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 1
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 230000037444 atrophy Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 229910003439 heavy metal oxide Inorganic materials 0.000 description 1
- 206010020718 hyperplasia Diseases 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229910052748 manganese Inorganic materials 0.000 description 1
- 239000011572 manganese Substances 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 229940072254 proscar Drugs 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 159000000000 sodium salts Chemical group 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a synthetic method of A-nor-3,5-cracking-androstane-5-ketone-3,17 beta-diacid. The method comprises the following steps of: adding hydrogen peroxide and acid into 3-carbonyl-4-androstene-17-thiolic acid in a solvent in the presence of a metal catalyst for reacting; adding a reducing agent after reacting; and collecting A-nor-3,5-cracking-androstane-5-ketone-3,17 beta-diacid serving as a target product from a reaction product. By adopting the method, a high-purity product can be obtained at high yield and high selectivity. The used method is simple, safe and environmentally-friendly. The reaction condition is mild, the reaction is relatively complete, and the purity is over 99 percent by simple purification. All reagents used in the entire reaction are readily-available, and meanwhile, the reaction yield is high, the reaction condition is mild, the solvent can be recycled, and industrial implementation is convenient.
Description
Technical field
The present invention relates to a kind of preparation Finasteride important intermediate A-and lose carbon-3, the method for the synthetic method of 5-cracking-androstane-5-ketone-3,17 β-diacid.
Background technology
Finasteride (finasteride, trade(brand)name Proscar, code name MK-906) is the medicine of the benign prostate hyperplasia of Merck company development, in listing in 1992.Benign prostate hyperplasia (BPH) is the common disease of elderly men, also is to cause the modal cause of disease of male sex's misnicturition.The rising of discovering dihydrotestosterone content is the reason that causes BPH.The 5 inhibitor can suppress testosterone and be converted into dihydrotestosterone and reach the purpose for the treatment of BPH.Make the prostate gland of hyperplasia can not get Standone and atrophy, thereby show curative effect.This medication is imitated definite, and side effect is little.Its structural formula is as (1):
Described important intermediate A-loses carbon-3, and 5-cracking-androstane-5-ketone-3,17 β-diacid is the important intermediate of synthetic Finasteride, and its general structure is as follows:
200439 (3) 226-228 provide a kind of method for preparing Finasteride as Chinese Pharmaceutical Journal, obtain A-at its committed step 3-carbonyl-4-androstene-17-carbonyl acid oxidase and lose carbon-3,5-cracking-androstane-5-ketone-3, in the time of in the process of 17 β-diacid, used expensive sodium periodate and heavy metal oxide potassium permanganate in a large number, not only separation and purification difficulty of this method is used the reagent costliness, toxicity is big, causes problems such as heavy-metal pollution simultaneously.Be not suitable for large-scale industrial production.
Summary of the invention
The purpose of this invention is to provide a kind of A-and lose carbon-3, the synthetic method of 5-cracking-androstane-5-ketone-3,17 β-diacid is to overcome the above-mentioned defective that prior art exists.
The method of present method comprises the steps: 3-carbonyl-4-androstene-17-carbonyl acid in solvent, in the presence of metal catalyst, add hydrogen peroxide and acid-respons, reaction times is 2～24h, temperature of reaction is 20～100 ℃, collects target product A-then and lose carbon-3,5-cracking-androstane-5-ketone-3 from reaction product, 17 β-diacid, yield are 95～99.5%;
Preferably, after reaction finishes, add reductive agent, behind the destruction residue hydrogen peroxide, from reaction product, collect target product A-and lose carbon-3,5-cracking-androstane-5-ketone-3,17 β-diacid.
Reaction equation is as follows:
Described metal catalyst is tungstate, phosphomolybdate, tungstic anhydride or molybdate etc., is preferably tungstate;
Described salt is sodium salt, sylvite, as sodium wolframate, potassium wolframate, Sodium orthomolybdate or potassium molybdate etc.;
Described acid is formic acid, acetic acid, propionic acid, butyric acid, phenylformic acid, tosic acid, phosphoric acid or nitric acid etc., is preferably phosphoric acid or tosic acid;
Described solvent is acetone, tetrahydrofuran (THF), ether, 2-methyl furan, isopropyl ether, 1,4-dioxane, glycol dimethyl ether, glycol ether dme, methylene dichloride, 1, more than one of 2-ethylene dichloride, Skellysolve A, normal hexane, sherwood oil, normal heptane, toluene or dimethylbenzene;
Described reductive agent comprises S-WAT, sodium bisulfite or Sulfothiorine;
The mol ratio of raw material, hydrogen peroxide, metal catalyst and acid is in reaction:
1∶1-2∶0.01-0.1∶0.001-0.01；
Compound (2) can be according to document J.Med.Chem., and 1984,27,1690 have play-by-play, repeat no more herein.
The present invention obtains A-by 3-carbonyl-4-androstene-17-carbonyl acid oxidase and loses carbon-3, and 5-cracking-androstane-5-ketone-3,17 β-diacid can obtain the higher product of purity with higher yields and highly selective, and employed method is simple, safety, environmental protection.We's bright institute reported method has avoided the product purification difficulty, the yield that run in this compounds traditional synthesis low, problems such as the reagent that uses is expensive, greatly reduce production cost.Avoided simultaneously big, the problem such as by product heavy metal manganese mud environmental pollution is serious of the reagent toxicity that uses." three wastes " discharging reduces significantly in its production technique.This is that additive method is beyond one's reach.The A-for preparing with the method that reaches of the present invention loses carbon-3, and 5-cracking-androstane-5-ketone-3,17 β-diacid can reach more than 99% through its purity after the simple purification because its reaction conditions gentleness reacts more complete.Employed reagent all is easy to get in entire reaction, while reaction yield height, and the reaction conditions gentleness, solvent can be recycled, thereby is convenient to industrializing implementation.
Embodiment
To help to understand the present invention by following specific implementation method, but not limit content of the present invention.
Embodiment 1
A-loses carbon-3, the preparation of 5-cracking-androstane-5-ketone-3,17 β-diacid:
In being full of the 250mL there-necked flask that is equipped with constant pressure funnel, thermometer, reflux condensing tube, magnetic agitation of nitrogen, a drying adds 3-carbonyl-4-androstene-17-carbonyl acid (31.64g successively; Fw:316.43; 100mmol), add 100mL acetone and hydrogen peroxide (30wt%H subsequently
2O
2, 100mmol).Add sodium wolframate (3.3g afterwards; 10mmol), 4M phosphoric acid 0.5mL.System continues to stir 1h under the backflow situation.After treating that system is cooled to room temperature after reaction finishes, be added dropwise to the sodium bisulfite saturated solution, stir 10min subsequently, solids removed by filtration is with the filtrate evaporate to dryness, use dichloromethane extraction after adding frozen water, the extraction liquid washing is dry, and evaporate to dryness gets crude product, and this product obtains target product 31.96g through solvent recrystallization subsequently, yield:95%, HPLC content is greater than 98%.
Embodiment 2
A-loses carbon-3, the preparation of 5-cracking-androstane-5-ketone-3,17 β-diacid:
In being full of the 250mL there-necked flask that is equipped with constant pressure funnel, thermometer, reflux condensing tube, magnetic agitation of nitrogen, a drying adds 3-carbonyl-4-androstene-17-carbonyl acid (31.64g successively; Fw:316.43; 100mmol), add 100mL1 subsequently, 4-dioxane and hydrogen peroxide (30wt%H
2O
2, 150mmol).Add sodium wolframate (3.3g afterwards; 10mmol), 4M nitric acid acid 0.5mL.System continues to stir 1h under the backflow situation.After treating that system is cooled to room temperature after reaction finishes, be added dropwise to the sodium bisulfite saturated solution, stir 10min subsequently, solids removed by filtration is with the filtrate evaporate to dryness, use dichloromethane extraction after adding frozen water, the extraction liquid washing is dry, and evaporate to dryness gets crude product, and this product obtains target product 31.96g through solvent recrystallization subsequently, yield:95%, HPLC content is greater than 98%.
Embodiment 3
A-loses carbon-3, the preparation of 5-cracking-androstane-5-ketone-3,17 β-diacid:
In being full of the 250mL there-necked flask that is equipped with constant pressure funnel, thermometer, reflux condensing tube, magnetic agitation of nitrogen, a drying adds 3-carbonyl-4-androstene-17-carbonyl acid (31.64g successively; Fw:316.43; 100mmol), add 150mL1 subsequently, 2-ethylene dichloride and hydrogen peroxide (30wt%H
2O
2, 200mmol).Add sodium wolframate (3.3g afterwards; 10mmol), tosic acid (1.7g; Fw:172.20; 10mmol).System continues to stir 1h under the backflow situation.After treating that system is cooled to room temperature after reaction finishes, be added dropwise to the sodium bisulfite saturated solution, stir 10min subsequently, solids removed by filtration is with the filtrate evaporate to dryness, use dichloromethane extraction after adding frozen water, the extraction liquid washing is dry, and evaporate to dryness gets crude product, and this product obtains target product 32.97g through solvent recrystallization subsequently, yield:98%, HPLC content is greater than 98%.
Embodiment 4
A-loses carbon-3, the preparation of 5-cracking-androstane-5-ketone-3,17 β-diacid:
In being full of the 250mL there-necked flask that is equipped with constant pressure funnel, thermometer, reflux condensing tube, magnetic agitation of nitrogen, a drying adds 3-carbonyl-4-androstene-17-carbonyl acid (31.64g successively; Fw:316.43; 100mmol), add 150mL1 subsequently, 2-ethylene dichloride and hydrogen peroxide (30wt%H
2O
2, 200mmol).Add Sodium orthomolybdate (2.42g afterwards; 10mmol), tosic acid (1.7g; Fw:172.20; 10mmol).System continues to stir 1h under the backflow situation.After treating that system is cooled to room temperature after reaction finishes, be added dropwise to the sodium bisulfite saturated solution, stir 10min subsequently, solids removed by filtration is with the filtrate evaporate to dryness, use dichloromethane extraction after adding frozen water, the extraction liquid washing is dry, and evaporate to dryness gets crude product, and this product obtains target product 32.97g through solvent recrystallization subsequently, yield:98%, HPLC content is greater than 98%.
Embodiment 5
A-loses carbon-3, the preparation of 5-cracking-androstane-5-ketone-3,17 β-diacid:
In being full of the 250mL there-necked flask that is equipped with constant pressure funnel, thermometer, reflux condensing tube, magnetic agitation of nitrogen, a drying adds 3-carbonyl-4-androstene-17-carbonyl acid (31.64g successively; Fw:316.43; 100mmol), add 150mL1 subsequently, 2-ethylene dichloride and hydrogen peroxide (30wt%H
2O
2, 200mmol).Add Sodium orthomolybdate (1.21g afterwards; 5mmol), tosic acid (0.86g; Fw:172.20; 5mmol).System continues to stir 1h under the backflow situation.After treating that system is cooled to room temperature after reaction finishes, be added dropwise to the Sulfothiorine saturated solution, stir 10min subsequently, solids removed by filtration is with the filtrate evaporate to dryness, use dichloromethane extraction after adding frozen water, the extraction liquid washing is dry, and evaporate to dryness gets crude product, and this product obtains target product 32.97g through solvent recrystallization subsequently, yield:98%, HPLC content is greater than 98%.
Embodiment 6
A-loses carbon-3, the preparation of 5-cracking-androstane-5-ketone-3,17 β-diacid:
In being full of the 250mL there-necked flask that is equipped with constant pressure funnel, thermometer, reflux condensing tube, magnetic agitation of nitrogen, a drying adds 3-carbonyl-4-androstene-17-carbonyl acid (31.64g successively; Fw:316.43; 100mmol), add 150mL acetone and hydrogen peroxide (30wt%H subsequently
2O
2, 100mmol).Add Sodium orthomolybdate (0.242g afterwards; 1mmol), tosic acid (0.17g; Fw:172.20; 1mmol).System continues to stir 24h under the backflow situation.After treating that system is cooled to room temperature after reaction finishes, be added dropwise to the Sulfothiorine saturated solution, stir 10min subsequently, solids removed by filtration is with the filtrate evaporate to dryness, use dichloromethane extraction after adding frozen water, the extraction liquid washing is dry, and evaporate to dryness gets crude product, and this product obtains target product 32.30g through solvent recrystallization subsequently, yield:96%, HPLC content is greater than 98%.
Embodiment 7
A-loses carbon-3, the preparation of 5-cracking-androstane-5-ketone-3,17 β-diacid:
In being full of the 250mL there-necked flask that is equipped with constant pressure funnel, thermometer, reflux condensing tube, magnetic agitation of nitrogen, a drying adds 3-carbonyl-4-androstene-17-carbonyl acid (31.64g successively; Fw:316.43; 100mmol), add 150mL acetone and hydrogen peroxide (30wt%H subsequently
2O
2, 100mmol).Add Sodium orthomolybdate (0.242g afterwards; 1mmol), acetic acid (0.12g; Fw:60.05; 2mmol).System continues to stir 20h under the backflow situation.After treating that system is cooled to room temperature after reaction finishes, be added dropwise to the Sulfothiorine saturated solution, stir 10min subsequently, solids removed by filtration is with the filtrate evaporate to dryness, use dichloromethane extraction after adding frozen water, the extraction liquid washing is dry, and evaporate to dryness gets crude product, and this product obtains target product 31.96g through solvent recrystallization subsequently, yield:95%, HPLC content is greater than 98%.
Claims (7)
1.A-lose carbon-3, the synthetic method of 5-cracking-androstane-5-ketone-3,17 β-diacid, it is characterized in that, comprise the steps: 3-carbonyl-4-androstene-17-carbonyl acid in solvent, in the presence of metal catalyst, add hydrogen peroxide and acid-respons, after reaction finishes, add reductive agent, from reaction product, collect target product A-then and lose carbon-3,5-cracking-androstane-5-ketone-3,17 β-diacid, described metal catalyst are tungstate, phosphomolybdate, tungstic anhydride or molybdate.
2. method according to claim 1 is characterized in that, 3-carbonyl-4-androstene-17-carbonyl acid in solvent, in the presence of metal catalyst, is added hydrogen peroxide and acid-respons, and the reaction times is 2～24h, and temperature of reaction is 20～100 ° of C.
3. method according to claim 1, it is characterized in that, described solvent is acetone, tetrahydrofuran (THF), ether, 2-methyl furan, isopropyl ether, 1,4-dioxane, glycol dimethyl ether, glycol ether dme, methylene dichloride, 1, more than one of 2-ethylene dichloride, Skellysolve A, normal hexane, sherwood oil, normal heptane, toluene or dimethylbenzene.
4. method according to claim 1 is characterized in that, described reductive agent is selected from S-WAT, sodium bisulfite or Sulfothiorine.
5. according to each described method of claim 1～4, it is characterized in that described acid is formic acid, acetic acid, propionic acid, butyric acid, phenylformic acid, tosic acid, phosphoric acid or nitric acid.
6. according to each described method of claim 1～4, it is characterized in that the mol ratio of raw material, hydrogen peroxide, metal catalyst and acid is in reaction: 1:1-2:0.01-0.1:0.001-0.01.
7. method according to claim 5 is characterized in that, the mol ratio of raw material, hydrogen peroxide, metal catalyst and acid is in reaction: 1:1-2:0.01-0.1:0.001-0.01.
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Non-Patent Citations (5)
| Title |
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| SHIELDING EFFECT OF ETHER C-O BOND OBTAINED FROM PROTON CHEMICAL SHIFTS OF 4-AZA-5A- AND 4-OXA-5P-ANDROSTAN-17-ONES;Y.Y.YANG,T.HAINO;《tetrahedron》;19961231;第52卷(第7期);2325 * |
| Y.Y.YANG,T.HAINO.SHIELDING EFFECT OF ETHER C-O BOND OBTAINED FROM PROTON CHEMICAL SHIFTS OF 4-AZA-5A- AND 4-OXA-5P-ANDROSTAN-17-ONES.《tetrahedron》.1996,第52卷(第7期),2325. |
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| 臧红霞.一种4-氮甾体激素化合物的合成.《现代化工》.2009,第29卷(第12期),57-58. * |
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