CN105153258A - Preparation method for 3-beta-hydroxyandrost-17-one - Google Patents
Preparation method for 3-beta-hydroxyandrost-17-one Download PDFInfo
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- CN105153258A CN105153258A CN201510463987.5A CN201510463987A CN105153258A CN 105153258 A CN105153258 A CN 105153258A CN 201510463987 A CN201510463987 A CN 201510463987A CN 105153258 A CN105153258 A CN 105153258A
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- acid
- organic solvent
- androstane
- ketone
- beta
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- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 90
- 239000003960 organic solvent Substances 0.000 claims abstract description 41
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 32
- 239000002253 acid Substances 0.000 claims abstract description 14
- 238000004128 high performance liquid chromatography Methods 0.000 claims abstract description 14
- 239000002904 solvent Substances 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 11
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000002994 raw material Substances 0.000 claims abstract description 9
- 238000007171 acid catalysis Methods 0.000 claims abstract description 7
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 5
- 150000001336 alkenes Chemical class 0.000 claims abstract description 3
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 37
- 238000006243 chemical reaction Methods 0.000 claims description 35
- 239000012065 filter cake Substances 0.000 claims description 23
- 238000005406 washing Methods 0.000 claims description 21
- 238000003756 stirring Methods 0.000 claims description 17
- 239000012043 crude product Substances 0.000 claims description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- 239000000706 filtrate Substances 0.000 claims description 14
- 239000006210 lotion Substances 0.000 claims description 14
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 238000011084 recovery Methods 0.000 claims description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 10
- 239000007787 solid Substances 0.000 claims description 10
- 238000010792 warming Methods 0.000 claims description 10
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 239000000376 reactant Substances 0.000 claims description 8
- 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 8
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
- 239000003377 acid catalyst Substances 0.000 claims description 6
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 5
- 230000003472 neutralizing effect Effects 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 239000000047 product Substances 0.000 claims description 4
- 238000001953 recrystallisation Methods 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 238000005903 acid hydrolysis reaction Methods 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 3
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 3
- 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
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 2
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 238000009835 boiling Methods 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 2
- 235000006408 oxalic acid Nutrition 0.000 claims description 2
- 230000020477 pH reduction Effects 0.000 claims description 2
- 238000004904 shortening Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 12
- 238000005516 engineering process Methods 0.000 abstract description 4
- 230000009286 beneficial effect Effects 0.000 abstract description 3
- 230000007062 hydrolysis Effects 0.000 abstract description 2
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 2
- 238000006266 etherification reaction Methods 0.000 abstract 3
- PAOWPNQOTVTCAF-OEUJLIAZSA-N (8r,9s,10r,13s,14s)-3-ethoxy-10,13-dimethyl-1,2,7,8,9,11,12,14,15,16-decahydrocyclopenta[a]phenanthren-17-one Chemical compound C1C[C@@H]2[C@](CCC(OCC)=C3)(C)C3=CC[C@H]2[C@@H]2CCC(=O)[C@]21C PAOWPNQOTVTCAF-OEUJLIAZSA-N 0.000 abstract 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 abstract 1
- AEMFNILZOJDQLW-QAGGRKNESA-N androst-4-ene-3,17-dione Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 AEMFNILZOJDQLW-QAGGRKNESA-N 0.000 abstract 1
- 229960005471 androstenedione Drugs 0.000 abstract 1
- AEMFNILZOJDQLW-UHFFFAOYSA-N androstenedione Natural products O=C1CCC2(C)C3CCC(C)(C(CC4)=O)C4C3CCC2=C1 AEMFNILZOJDQLW-UHFFFAOYSA-N 0.000 abstract 1
- 230000015572 biosynthetic process Effects 0.000 abstract 1
- 230000003197 catalytic effect Effects 0.000 abstract 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 abstract 1
- 238000002844 melting Methods 0.000 abstract 1
- 230000008018 melting Effects 0.000 abstract 1
- 238000003786 synthesis reaction Methods 0.000 abstract 1
- 229960000583 acetic acid Drugs 0.000 description 9
- 239000003814 drug Substances 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 6
- 230000008025 crystallization Effects 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 239000008399 tap water Substances 0.000 description 6
- 235000020679 tap water Nutrition 0.000 description 6
- 239000003270 steroid hormone Substances 0.000 description 5
- 230000000630 rising effect Effects 0.000 description 4
- 240000001811 Dioscorea oppositifolia Species 0.000 description 3
- DWCSNWXARWMZTG-UHFFFAOYSA-N Trigonegenin A Natural products CC1C(C2(CCC3C4(C)CCC(O)C=C4CCC3C2C2)C)C2OC11CCC(C)CO1 DWCSNWXARWMZTG-UHFFFAOYSA-N 0.000 description 3
- 150000001993 dienes Chemical class 0.000 description 3
- WQLVFSAGQJTQCK-VKROHFNGSA-N diosgenin Chemical compound O([C@@H]1[C@@H]([C@]2(CC[C@@H]3[C@@]4(C)CC[C@H](O)CC4=CC[C@H]3[C@@H]2C1)C)[C@@H]1C)[C@]11CC[C@@H](C)CO1 WQLVFSAGQJTQCK-VKROHFNGSA-N 0.000 description 3
- WQLVFSAGQJTQCK-UHFFFAOYSA-N diosgenin Natural products CC1C(C2(CCC3C4(C)CCC(O)CC4=CCC3C2C2)C)C2OC11CCC(C)CO1 WQLVFSAGQJTQCK-UHFFFAOYSA-N 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 239000006260 foam Substances 0.000 description 3
- 238000007710 freezing Methods 0.000 description 3
- 230000008014 freezing Effects 0.000 description 3
- 239000012362 glacial acetic acid Substances 0.000 description 3
- 239000003163 gonadal steroid hormone Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000012452 mother liquor Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 238000004064 recycling Methods 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 210000003205 muscle Anatomy 0.000 description 2
- 230000008707 rearrangement Effects 0.000 description 2
- OILXMJHPFNGGTO-UHFFFAOYSA-N (22E)-(24xi)-24-methylcholesta-5,22-dien-3beta-ol Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)C=CC(C)C(C)C)C1(C)CC2 OILXMJHPFNGGTO-UHFFFAOYSA-N 0.000 description 1
- OQMZNAMGEHIHNN-UHFFFAOYSA-N 7-Dehydrostigmasterol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)C=CC(CC)C(C)C)CCC33)C)C3=CC=C21 OQMZNAMGEHIHNN-UHFFFAOYSA-N 0.000 description 1
- WYZDXEKUWRCKOB-YDSAWKJFSA-N Mestanolone Chemical compound C([C@@H]1CC2)C(=O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@](C)(O)[C@@]2(C)CC1 WYZDXEKUWRCKOB-YDSAWKJFSA-N 0.000 description 1
- HZYXFRGVBOPPNZ-UHFFFAOYSA-N UNPD88870 Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)=CCC(CC)C(C)C)C1(C)CC2 HZYXFRGVBOPPNZ-UHFFFAOYSA-N 0.000 description 1
- 239000003263 anabolic agent Substances 0.000 description 1
- LGJMUZUPVCAVPU-UHFFFAOYSA-N beta-Sitostanol Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(C)CCC(CC)C(C)C)C1(C)CC2 LGJMUZUPVCAVPU-UHFFFAOYSA-N 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- -1 diene alcohol ketone Chemical class 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 239000003337 fertilizer Substances 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229950008604 mestanolone Drugs 0.000 description 1
- ICMWWNHDUZJFDW-DHODBPELSA-N oxymetholone Chemical compound C([C@@H]1CC2)C(=O)\C(=C/O)C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@](C)(O)[C@@]2(C)CC1 ICMWWNHDUZJFDW-DHODBPELSA-N 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000001397 quillaja saponaria molina bark Substances 0.000 description 1
- OYTJKRAYGYRUJK-FMCCZJBLSA-M rocuronium bromide Chemical compound [Br-].N1([C@@H]2[C@@H](O)C[C@@H]3CC[C@H]4[C@@H]5C[C@@H]([C@@H]([C@]5(CC[C@@H]4[C@@]3(C)C2)C)OC(=O)C)[N+]2(CC=C)CCCC2)CCOCC1 OYTJKRAYGYRUJK-FMCCZJBLSA-M 0.000 description 1
- 229930182490 saponin Natural products 0.000 description 1
- 150000007949 saponins Chemical class 0.000 description 1
- 239000010865 sewage Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- HCXVJBMSMIARIN-PHZDYDNGSA-N stigmasterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)/C=C/[C@@H](CC)C(C)C)[C@@]1(C)CC2 HCXVJBMSMIARIN-PHZDYDNGSA-N 0.000 description 1
- 229940032091 stigmasterol Drugs 0.000 description 1
- BFDNMXAIBMJLBB-UHFFFAOYSA-N stigmasterol Natural products CCC(C=CC(C)C1CCCC2C3CC=C4CC(O)CCC4(C)C3CCC12C)C(C)C BFDNMXAIBMJLBB-UHFFFAOYSA-N 0.000 description 1
- 235000016831 stigmasterol Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229960004298 vecuronium bromide Drugs 0.000 description 1
- VEPSYABRBFXYIB-PWXDFCLTSA-M vecuronium bromide Chemical compound [Br-].N1([C@@H]2[C@@H](OC(C)=O)C[C@@H]3CC[C@H]4[C@@H]5C[C@@H]([C@@H]([C@]5(CC[C@@H]4[C@@]3(C)C2)C)OC(=O)C)[N+]2(C)CCCCC2)CCCCC1 VEPSYABRBFXYIB-PWXDFCLTSA-M 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
- 229940098506 zemuron Drugs 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Steroid Compounds (AREA)
Abstract
A preparation method for 3-beta-hydroxyandrost-17-one comprises taking 4AD (androstenedione) as a raw material, performing 3-position alkene etherification on 4AD in an organic solvent, employing triethyl orthoformate as a reagent, and performing acid catalysis to prepare an etherification product 3-ethoxyandrost-3,5-diene-17-one; adding the etherification product in an organic solvent, performing palladium/carbon catalytic hydrogenation, so as to obtain an intermediate hydrogenation product 3-ethoxyandrost-17-one; and performing acid catalytic hydrolysis on the hydrogenation product in a low-carbon alcohol or other organic solvents, so as to obtain 3-beta-hydroxyandrost-17-one. The product HPLC content is 99.5% or more, the melting point is 172-176 DEG C, and the synthesis weight overall yield is 75-83%. By using the method to produce 3-beta-hydroxyandrost-17-one, the raw materials are cheap and easy to obtain, the technological operation is convenient, the product overall yield is improved by 15-20%, and the production cost is reduced by 30-40%. The solvent employed in the technology is recoverable and reusable, is economical, friendly to environment and also extremely beneficial for industrialized production.
Description
Technical field
The invention belongs to the fabricating technology of steroid hormone pharmaceutical intermediate, be specifically related to the preparation method of a kind of 3-beta-hydroxy-androstane-17-ketone.
Background technology
3-beta-hydroxy-androstane-17-ketone is a kind of versatile intermediates producing steroid hormone medicine.With it for raw material, the multiple common class steroid hormone medicine of flaccid muscles such as Zemuron, vecuronium bromide can be produced; Also the multiple common male sex hormone medicine such as mestanolone, Synasteron can be produced.The conventional production methods of 3-beta-hydroxy-androstane-17-ketone; with the diosgenin extracted from Chinese yam plant; through protection, oxicracking, elimination; key intermediate acetic acid gestation diene alcohol ketone (abbreviation diene) obtained is raw material; obtain through oximate, rearrangement, acid hydrolysis, hydrogenation, the reaction of basic hydrolysis five step, its operational path is shown in accompanying drawing 1.The technique such as oximate, rearrangement of the wherein extraction of diosgenin, oxicracking, diene, waste water is more, and not easily processes, easy contaminate environment.The more important thing is, along with wild Chinese yam plant resources is day by day exhausted, and artificial growth Chinese yam plant, also because of the rising day by day of the planting costs such as artificial, chemical fertilizer, cause saponin, the production cost of diene is doubled and redoubled, cause 3-beta-hydroxy-androstane-17-ketone production cost and market value to increase substantially, already great effect was created to the world market of multiple class steroid hormone medicine of flaccid muscles and male sex hormone medicine.Find new synthetic method, steroid hormone medicine and the intermediates thereof such as low cost production 3-beta-hydroxy-androstane-17-ketone, become the industry task of top priority.Once had bibliographical information abroad, the residue utilizing soybean oil to produce extracts Stigmasterol, through modern biotechnology fermentation technique, can obtain another key intermediate 4-AD of synthesizing steroid hormonal medicaments, is called for short 4AD.Most of male sex hormone and protein anabolic hormone medicine can be produced by 4AD.But there are no producing the bibliographical information of 3-beta-hydroxy-androstane-17-ketone with 4AD.
Summary of the invention
The object of this invention is to provide the preparation method of a kind of new 3-beta-hydroxy-androstane-17-ketone, solve in existing Technology many defects such as raw materials for production are expensive, sewage disposal is difficult, complex operation, significantly reduce the production cost of 3-beta-hydroxy-androstane-17-ketone.
Technical scheme of the present invention is: the preparation method of 3-beta-hydroxy-androstane-17-ketone take 4AD as raw material, in organic solvent, by 4AD3 position alkene etherificate, make reagent with triethyl orthoformate, acid catalysis prepares etherate 3-oxyethyl group-androstane-3,5-diene-17-ketone; This etherate in organic solvent, with palladium carbon shortening, obtains intermediate hydrogenation thing 3-oxyethyl group-androstane-17-ketone; By this hydrogenation thing in organic solvent acid-catalyzed hydrolysis obtain 3-beta-hydroxy-androstane-17-ketone.Be kept to three steps by former five-step approach to complete.
Operation steps is as follows:
The method that A, acid catalysis prepare etherate is, by 4AD in organic solvent with triethyl orthoformate under acid catalysis, 20 ~ 50 DEG C of stirring reactions 12 ~ 16 hours, after having reacted, add 0.02W weak base and be neutralized to pH7 ~ 7.5, further aftertreatment, obtain etherate 3-oxyethyl group-androstane-3,5 diene-17-ketone, its HPLC content 98.5% ~ 99.5%, weight yield 100 ~ 102%;
Described organic solvent comprises methylene dichloride, toluene, methyl alcohol, ethanol; Acid catalyst used comprises hydrochloric acid, sulfuric acid, phosphoric acid, or acetic acid, tosic acid, oxalic acid; Neutralize weak base used and comprise inorganic weak bases, organic weak base; Temperature of reaction is 20 ~ 50 DEG C; Weight proportion between reactant, 4AD: triethyl orthoformate: acid is 1:0.5 ~ 1.0:0.01 ~ 0.05, the proportioning 4AD between reactant and solvent: organic solvent is 1W:2 ~ 8V.Wherein W represents g, and V represents ml.
Preferred version, described organic solvent is ethanol; Acid catalyst is tosic acid; Neutralizing weak base used is pyridine; Temperature of reaction 20 ~ 30 DEG C; Weight proportion between reactant is 1:0.8:0.02; Proportioning between reactant and low-carbon alcohol solvent is 1W:2 ~ 2.5V, or 1W:6 ~ 8V.
The preparation of B, intermediate hydrogenation thing, above-mentioned etherate is dissolved in organic solvent, adds palladium carbon, after displaced air, pass into hydrogen, be warming up to 30 ~ 60 DEG C of reactions 8 ~ 16 hours, react rear emptying, while hot press filtration, with solvent wash, filter cake send producer to reclaim, washing lotion and filtrate merge, and elutriation after recovery organic solvent, obtains solid; This solid wet product, directly with alcohol, activated carbon decolorizing recrystallization, obtains hydrogenation thing 3 oxyethyl groups-androstane-3,5-diene-17-ketone, HPLC content more than 99.0%, weight yield 90 ~ 95%;
Organic solvent described above comprises ethyl acetate, tetrahydrofuran (THF), acetic acid, acetone, below C4 low-carbon alcohol; Catalyzer comprises 1 ~ 10% palladium carbon; Temperature of reaction is 30 ~ 60 DEG C; Weight proportion between etherate and 5% palladium carbon is 1:0.05 ~ 0.25; The proportioning of etherate and organic solvent is 1W:4 ~ 10V.
Preferred version, described organic solvent is ethanol, acetic acid; Catalyzer is the palladium carbon of 5%; Temperature of reaction 40 ~ 45 DEG C, the weight proportion of etherate and palladium carbon is 1:0.15; The proportioning of etherate and organic solvent is 1W:8V.
The acidification hydrolization of C, hydrogenation thing, dissolves in organic solvent by above-mentioned hydrogenation thing, adds acid catalyst, be warming up to 60 ~ 100 DEG C, reacts 12 ~ 18 hours, after having reacted, reclaims organic solvent, and cooling elutriation, obtains 3-beta-hydroxy-androstane-17-ketone crude product; By above-mentioned crude product with alcohol, activated carbon decolorizing recrystallization, obtain 3-beta-hydroxy-androstane-17-ketone, fusing point 129-131 degree, content > 99%, yield 80 ~ 85%;
Above-mentioned organic solvent used comprises toluene, formic acid, acetic acid, ethanol, Virahol, the trimethyl carbinol of below C6 80 ~ 140 DEG C of boiling points; Described acid comprises hydrochloric acid, Hydrogen bromide, perchloric acid, sulfuric acid, or trifluoroacetic acid, tosic acid etc.; Temperature of reaction 60 ~ 100 DEG C; Hydrogenation thing is 1:0.6 ~ 1.2 with the weight proportion of acid; The weight proportion of hydrogenation thing and organic solvent is 1W:4 ~ 6V.
Preferred version, described organic solvent is preferably acetic acid or alcohol; Described acid is hydrochloric acid; Temperature of reaction 80 ~ 90 DEG C; Hydrogenation thing is 1:0.8 with the weight proportion of acid; The proportioning of hydrogenation thing and organic solvent is 1W:5V.
The invention has the beneficial effects as follows: adopt manufacture 3-beta-hydroxy of the present invention-androstane-17-ketone, the traditional method of raw material is relatively made with diosgenin, raw material 4AD wide material sources, the economic environmental protection of synthetic route, processing condition are gentle, and production operation is easy, good product quality, total yield of products improves 15 ~ 20%, and production cost is low by 30 ~ 40%.The solvent used in technique, recyclable recycled, both economical, environmental protection again, is extremely beneficial to suitability for industrialized production.
Accompanying drawing explanation
Fig. 1 is the synthetic route chart of produced in conventional processes 3-beta-hydroxy-androstane-17-ketone.
Fig. 2 is the process route chart that the present invention produces 3 beta-hydroxies-androstane-17-ketone.
Embodiment
In order to main points of the present invention and spirit are described more easily, citing is below explained:
Embodiment one
The preparation of A, etherate
In a 1000ml there-necked flask, add 100g4AD, 200ml ethanol, 80ml triethyl orthoformate, 2g tosic acid, be incubated in 20-25 DEG C of stirring reaction 12 ~ 16 hours, TLC detection reaction terminal, after having reacted, add 3ml pyridine, stir 20-25 minute neutralizing acid, then system is cooled to-5 ~ 0 DEG C, stirred crystallization 2 ~ 3 hours, suction filtration, a small amount of washing with alcohol, washing lotion and filtrate merge, and recycling design and crude product are applied mechanically; Filter cake less than 70 DEG C oven dry, obtains etherate 101.6g, HPLC content 99.2%, weight yield 101.6%.Reaction formula is shown in the first part of accompanying drawing 2.
The preparation of B, hydrogenation thing
In a 1000ml there-necked flask, add 100g etherate, 800ml ethanol, after dissolving, add the palladium carbon of 15g5%, be warming up to 40-45 DEG C of insulated and stirred reaction 15 ~ 16 hours, TLC detection reaction terminal, after having reacted, emptying, nitrogen press filtration while hot, 50ml washing with alcohol, filter cake send producer to reclaim; Washing lotion and filtrate merge, concentrating under reduced pressure, reclaim ethanol and apply mechanically.Add 600ml tap water elutriation residual night, filter, obtain solid.Above-mentioned solid is directly added in 800ml alcohol, heating makes it dissolve, add 5g gac, reflux decolour 1-1.5 hour, filtered while hot, filter cake about 80ml alcohol foam washing, merging filtrate and washing lotion, normal pressure is concentrated into recovery about 85% alcohol, then adds 500ml pure water, continues to steam the solvent of about 150ml containing ethanol 50-60%, again system is cooled to 5 ~ 10 DEG C, stirring and crystallizing 2 ~ 3 hours, filters, and the filter cake ethanolic soln of a small amount of 50% washs, less than 70 DEG C oven dry, obtain hydrogenation thing 94.6g, HPLC content 99.2%, weight total recovery 94.6%.Reaction formula is shown in the middle portion of accompanying drawing 2.
The preparation of C, 3-beta-hydroxy-androstane-17-ketone
In a 1000ml there-necked flask, add 100g hydrogenation thing, 500ml ethanol, under stirring at normal temperature, add 80g30% hydrochloric acid, slowly be warming up to 80-84 DEG C, back flow reaction 12 ~ 16 hours, after having reacted, underpressure distillation, reclaims the ethanol of about 90-95%, then adds 600ml tap water, be cooled to 10 ~ 15 DEG C, stirring and crystallizing 2 ~ 3 hours, filters, is washed to neutrality, filter cake less than 70 DEG C oven dry, obtains 3-beta-hydroxy-androstane-17-ketone crude product.Above-mentioned 3-beta-hydroxy-androstane-17-ketone crude product is dissolved in 600ml alcohol, adds 5g gac, temperature rising reflux decolouring 1-1.5 hour, filtered while hot, 100ml ethanol wash filter cake, washing lotion and filtrate merge, the alcohol of normal pressure concentration and recovery about 90%, is then cooled to-5-0 DEG C, freezing crystallization 2 ~ 3 hours, filter, a small amount of ethanol wash of filter cake, less than 70 DEG C oven dry, obtain 3-beta-hydroxy-androstane-17-ketone 84.2g, fusing point 173.5 ~ 174.0 DEG C, HPLC content 99.7%, yield 84.2%.Disposing mother liquor solvent and crude product are applied mechanically.Reaction formula is shown in the final section of accompanying drawing 2.
Embodiment two
The preparation of A, etherate
In a 1000ml there-necked flask, add 100g4AD, 600ml methylene dichloride, 80ml triethyl orthoformate, 2g tosic acid, be incubated in 20-25 degree stirring reaction 12 ~ 16 hours, TLC detection reaction terminal, after having reacted, add 3ml pyridine, stir 20-25 minute neutralizing acid, concentrating under reduced pressure, reclaim methylene dichloride, cooling, adds 100ml ethanol, then system is cooled to-5-0 DEG C, stirred crystallization 2 ~ 3 hours, suction filtration, a small amount of washing with alcohol, washing lotion and filtrate merge, and recycling design and crude product are applied mechanically; Filter cake less than 70 DEG C oven dry, obtains etherate 100.2g, HPLC content 99.4%, weight yield 100.2%.
The preparation of B, hydrogenation thing
In a 1000ml there-necked flask, add 100g etherate, 800ml Glacial acetic acid, the palladium carbon of 15g5% is added after dissolving, be warming up to 40 ~ 45 DEG C of insulated and stirred reactions 15 ~ 16 hours, TLC detection reaction terminal, after having reacted, emptying, nitrogen press filtration while hot, 50ml Glacial acetic acid washs, and filter cake send producer to reclaim; Washing lotion and filtrate merge, concentrating under reduced pressure, reclaim Glacial acetic acid and apply mechanically.Add 600ml tap water elutriation residual night, filter, obtain solid.Above-mentioned solid is directly added in 800ml alcohol, heating makes it dissolve, add 5g gac, reflux decolour 1 ~ 1.5 hour, filtered while hot, filter cake about 80ml alcohol foam washing, merging filtrate and washing lotion, normal pressure is concentrated into recovery about 85% alcohol, then adds 500ml pure water, continues to steam the solvent of about 150ml containing ethanol 50-60%, again system is cooled to 5-10 DEG C, stirring and crystallizing 2 ~ 3 hours, filters, and the filter cake ethanolic soln of a small amount of 50% washs, less than 70 DEG C oven dry, obtain hydrogenation thing 92.5g, HPLC content 99.3%, weight total recovery 92.5%.
The preparation of C, 3-beta-hydroxy-androstane-17-ketone
In a 1000ml there-necked flask, add 100g hydrogenation thing, 500ml ethanol, under stirring at normal temperature, add 70g40% Hydrogen bromide, slowly be warming up to 80-84 DEG C, back flow reaction 12-16 hour, after having reacted, underpressure distillation, reclaims the ethanol of about 90-95%, then adds 600ml tap water, be cooled to 10 ~ 15 DEG C, stirring and crystallizing 2-3 hour, filters, is washed to neutrality, filter cake less than 70 DEG C oven dry, obtains 3-beta-hydroxy-androstane-17-ketone crude product.Above-mentioned 3-beta-hydroxy-androstane-17-ketone crude product is dissolved in 600ml alcohol, adds 5g gac, temperature rising reflux decolouring 1-1.5 hour, filtered while hot, 100ml ethanol wash filter cake, washing lotion and filtrate merge, the alcohol of normal pressure concentration and recovery about 90%, is then cooled to-5-0 degree, freezing crystallization 2-3 hour, filter, a small amount of ethanol wash of filter cake, less than 70 DEG C oven dry, obtain 3-beta-hydroxy-androstane-17-ketone 84.2g, fusing point 173.0-173.5 DEG C, HPLC content 99.7%, yield 84.2%.Disposing mother liquor solvent and crude product are applied mechanically.
Embodiment three
The preparation of A, etherate
In a 1000ml there-necked flask, add the sulfuric acid of 100g4AD, 200ml ethanol, 80ml triethyl orthoformate, 2g98%, be incubated in 20-25 DEG C of stirring reaction 12 ~ 16 hours, TLC detection reaction terminal, after having reacted, add 3ml pyridine, stir 20-25 minute neutralizing acid, then system is cooled to-5-0 DEG C, stirred crystallization 2 ~ 3 hours, suction filtration, a small amount of washing with alcohol, washing lotion and filtrate merge, and recycling design and crude product are applied mechanically; Filter cake less than 70 DEG C oven dry, obtains etherate 100.8g, HPLC content 99.0%, weight yield 100.8%.
The preparation of B, hydrogenation thing
In a 1000ml there-necked flask, add 100g etherate, 800ml ethyl acetate, the palladium carbon of 15g5% is added after dissolving, be warming up to 40 ~ 45 DEG C of insulated and stirred reactions 15 ~ 16 hours, TLC detection reaction terminal, after having reacted, emptying, nitrogen press filtration while hot, 50ml ethyl acetate is washed, and filter cake send producer to reclaim; Washing lotion and filtrate merge, concentrating under reduced pressure, reclaim ethyl acetate and apply mechanically.Add 600ml tap water elutriation residual night, filter, obtain solid.Above-mentioned solid is directly added in 800ml alcohol, heating makes it dissolve, add 5g gac, reflux decolour 1 ~ 1.5 hour, filtered while hot, filter cake about 80ml alcohol foam washing, merging filtrate and washing lotion, normal pressure is concentrated into recovery about 85% alcohol, then adds 500ml pure water, continues to steam the solvent of about 150ml containing ethanol 50-60%, again system is cooled to 5 ~ 10 DEG C, stirring and crystallizing 2 ~ 3 hours, filters, and the filter cake ethanolic soln of a small amount of 50% washs, less than 70 DEG C oven dry, obtain hydrogenation thing 91.6g, HPLC content 99.3%, weight total recovery 91.6%.
The preparation of C, 3-beta-hydroxy-androstane-17-ketone
In a 1000ml there-necked flask, add 100g hydrogenation thing, 500ml ethanol, under stirring at normal temperature, add 60g50% perchloric acid, slowly be warming up to 80-84 DEG C, back flow reaction 12-16 hour, after having reacted, underpressure distillation, reclaims the ethanol of about 90-95%, then adds 600ml tap water, be cooled to 10 ~ 15 DEG C, stirring and crystallizing 2-3 hour, filters, is washed to neutrality, filter cake less than 70 DEG C oven dry, obtains 3-beta-hydroxy-androstane-17-ketone crude product.Above-mentioned 3-beta-hydroxy-androstane-17-ketone crude product is dissolved in 600ml alcohol, adds 5g gac, temperature rising reflux decolouring 1 ~ 1.5 hour, filtered while hot, 100ml ethanol wash filter cake, washing lotion and filtrate merge, the alcohol of normal pressure concentration and recovery about 90%, is then cooled to-5-0 DEG C, freezing crystallization 2-3 hour, filter, a small amount of ethanol wash of filter cake, less than 70 DEG C oven dry, obtain 3-beta-hydroxy-androstane-17-ketone 84.5g, fusing point 172.5-173.5 DEG C, HPLC content 99.5%, yield 84.5%.Disposing mother liquor solvent and crude product are applied mechanically.
The embodiment of the present invention, for illustration of working method of the present invention, does not limit protection scope of the present invention.The improvement of all impartial effects done according to the present invention, all contain by the present patent application.
Claims (7)
- The preparation method of 1.3-beta-hydroxy-androstane-17-ketone, is characterized in that: take 4AD as raw material, in organic solvent, by 4AD3 position alkene etherificate, makes reagent with triethyl orthoformate, and acid catalysis prepares etherate 3-oxyethyl group-androstane-3,5-diene-17-ketone; This etherate in organic solvent, with palladium carbon shortening, obtains intermediate hydrogenation thing 3-oxyethyl group-androstane-17-ketone; By this hydrogenation thing in organic solvent acid-catalyzed hydrolysis obtain 3-beta-hydroxy-androstane-17-ketone.
- 2. the preparation method of 3-beta-hydroxy according to claim 1-androstane-17-ketone, it is characterized in that, the method that acid catalysis prepares etherate is, by 4AD in organic solvent, with triethyl orthoformate under acid catalysis, in 20 ~ 50 DEG C of stirring reactions 12 ~ 16 hours, after having reacted, add 0.02W weak base and be neutralized to pH7 ~ 7.5, further aftertreatment, obtain etherate 3-oxyethyl group-androstane-3,5 diene-17-ketone, its HPLC content 98.5% ~ 99.5%, weight yield 100 ~ 102%; Described organic solvent comprises methylene dichloride, toluene, methyl alcohol, ethanol; Acid catalyst used comprises hydrochloric acid, sulfuric acid, phosphoric acid, or acetic acid, tosic acid, oxalic acid; Neutralize weak base used and comprise inorganic weak bases, organic weak base; Temperature of reaction is 20 ~ 50 DEG C; Weight proportion between reactant, 4AD: triethyl orthoformate: acid is 1: 0.5 ~ 1.0: 0.01 ~ 0.05, the proportioning 4AD between reactant and solvent: organic solvent is 1W: 2 ~ 8V, and wherein W represents g, and V represents ml.
- 3. the preparation method of 3-beta-hydroxy according to claim 2-androstane-17-ketone, is characterized in that, described organic solvent is ethanol; Acid catalyst is tosic acid; Neutralizing weak base used is pyridine; Temperature of reaction 20 ~ 30 DEG C; Weight proportion between reactant is 1: 0.8: 0.02; Proportioning between reactant and solvent, 4AD: low-carbon alcohol is 1W: 2 ~ 2.5V, or 1W: 6 ~ 8V.
- 4. the preparation method of 3-beta-hydroxy according to claim 1-androstane-17-ketone, is characterized in that, the preparation of intermediate hydrogenation thing, above-mentioned etherate is dissolved in organic solvent, adds palladium carbon, after displaced air, pass into hydrogen, be warming up to 30 ~ 60 DEG C of reactions 8 ~ 16 hours, react rear emptying, while hot press filtration, with solvent wash, filter cake send producer to reclaim, washing lotion and filtrate merge, and elutriation after recovery organic solvent, obtains solid; This solid wet product, directly with alcohol, activated carbon decolorizing recrystallization, obtains hydrogenation thing 3 oxyethyl groups-androstane-3,5-diene-17-ketone, HPLC content more than 99.0%, weight yield 90 ~ 95%; Organic solvent described above comprises ethyl acetate, tetrahydrofuran (THF), acetic acid, acetone, below C4 low-carbon alcohol; Catalyzer comprises 1 ~ 10% palladium carbon; Temperature of reaction is 30 ~ 60 DEG C; Weight proportion between etherate and 5% palladium carbon is 1: 0.05 ~ 0.25; The proportioning of etherate and organic solvent is 1W: 4 ~ 10V.
- 5. the preparation method of 3-beta-hydroxy according to claim 4-androstane-17-ketone, is characterized in that, described organic solvent is ethanol, acetic acid; Catalyzer is the palladium carbon of 5%; Temperature of reaction 40 ~ 45 DEG C, the weight proportion of etherate and palladium carbon is 1: 0.15; The proportioning of etherate and organic solvent is 1W: 8V.
- 6. the preparation method of 3-beta-hydroxy according to claim 1-androstane-17-ketone, it is characterized in that, the acidification hydrolization of hydrogenation thing, dissolves in organic solvent by above-mentioned hydrogenation thing, adds acid catalyst, be warming up to 60 ~ 100 DEG C, react 12 ~ 18 hours, after having reacted, reclaim organic solvent, cooling elutriation, obtains 3-beta-hydroxy-androstane-17-ketone crude product; By above-mentioned crude product with alcohol, activated carbon decolorizing recrystallization, obtain 3-beta-hydroxy-androstane-17-ketone, fusing point 129-131 degree, content > 99%, yield 80-85%;Above-mentioned organic solvent used comprises toluene, formic acid, acetic acid, ethanol, Virahol, the trimethyl carbinol of below C6 80 ~ 140 DEG C of boiling points; Described acid comprises hydrochloric acid, Hydrogen bromide, perchloric acid, sulfuric acid, or trifluoroacetic acid, tosic acid etc.; Temperature of reaction 60 ~ 100 DEG C; Hydrogenation thing is 1: 0.6 ~ 1.2 with the weight proportion of acid; The weight proportion of hydrogenation thing and organic solvent is 1W: 4 ~ 6V.
- 7. the preparation method of 3-beta-hydroxy according to claim 6-androstane-17-ketone, is characterized in that, described organic solvent is acetic acid or alcohol; Described acid is hydrochloric acid; Temperature of reaction 80 ~ 90 DEG C; Hydrogenation thing is 1: 0.8 with the weight proportion of acid; The proportioning of hydrogenation thing and organic solvent is 1W: 5V.
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| CN109627273A (en) * | 2018-12-05 | 2019-04-16 | 华中药业股份有限公司 | A kind of synthetic method of -17 beta-hydroxy -3- ketone of -17 Alpha-Methyl of furazabol intermediate androstane |
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| CN109627273A (en) * | 2018-12-05 | 2019-04-16 | 华中药业股份有限公司 | A kind of synthetic method of -17 beta-hydroxy -3- ketone of -17 Alpha-Methyl of furazabol intermediate androstane |
| CN109651473A (en) * | 2019-02-18 | 2019-04-19 | 湖南科瑞生物制药股份有限公司 | A kind of preparation method of androstane -2- alkene -17- ketone |
| CN110563788A (en) * | 2019-09-24 | 2019-12-13 | 华中药业股份有限公司 | preparation method of 5 alpha-androstane-3, 17-dione |
| CN113045400A (en) * | 2021-03-23 | 2021-06-29 | 湖北共同药业股份有限公司 | Preparation method of oxandrolone intermediate |
| CN113045400B (en) * | 2021-03-23 | 2023-06-09 | 湖北共同药业股份有限公司 | Preparation method of oxaandrosane intermediate |
| CN113651866A (en) * | 2021-08-02 | 2021-11-16 | 上海敏韬医药科技有限公司 | Novel method for synthesizing cholesterol by taking 21-hydroxy-20-methyl pregn-4-ene-3-one as raw material |
| CN113651866B (en) * | 2021-08-02 | 2023-07-04 | 王涛 | Novel method for synthesizing cholesterol by taking 21-hydroxy-20-methyl pregna-4-en-3-one as raw material |
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