CN107286216A - Preparation method with multiple alkene steroidal compounds - Google Patents
Preparation method with multiple alkene steroidal compounds Download PDFInfo
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- CN107286216A CN107286216A CN201610204515.2A CN201610204515A CN107286216A CN 107286216 A CN107286216 A CN 107286216A CN 201610204515 A CN201610204515 A CN 201610204515A CN 107286216 A CN107286216 A CN 107286216A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 32
- 150000001875 compounds Chemical class 0.000 title claims description 114
- 150000001336 alkenes Chemical class 0.000 title abstract description 3
- 230000003637 steroidlike Effects 0.000 title description 2
- 238000006243 chemical reaction Methods 0.000 claims description 83
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 57
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 48
- 239000000243 solution Substances 0.000 claims description 48
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 37
- 239000002994 raw material Substances 0.000 claims description 37
- 239000007864 aqueous solution Substances 0.000 claims description 35
- 238000003756 stirring Methods 0.000 claims description 34
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 33
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 31
- 238000001914 filtration Methods 0.000 claims description 31
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 24
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 24
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 22
- 229910052799 carbon Inorganic materials 0.000 claims description 22
- 150000007529 inorganic bases Chemical class 0.000 claims description 22
- 239000012895 dilution Substances 0.000 claims description 20
- 238000010790 dilution Methods 0.000 claims description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 19
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Substances [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 18
- 239000007788 liquid Substances 0.000 claims description 17
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 15
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 14
- 238000000855 fermentation Methods 0.000 claims description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 12
- 230000004151 fermentation Effects 0.000 claims description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- 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 10
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 claims description 10
- UZKWTJUDCOPSNM-UHFFFAOYSA-N 1-ethenoxybutane Chemical compound CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims description 9
- 241000203720 Pimelobacter simplex Species 0.000 claims description 9
- 150000007522 mineralic acids Chemical class 0.000 claims description 9
- MWFMGBPGAXYFAR-UHFFFAOYSA-N 2-hydroxy-2-methylpropanenitrile Chemical compound CC(C)(O)C#N MWFMGBPGAXYFAR-UHFFFAOYSA-N 0.000 claims description 8
- UJTTUOLQLCQZEA-UHFFFAOYSA-N 9h-fluoren-9-ylmethyl n-(4-hydroxybutyl)carbamate Chemical compound C1=CC=C2C(COC(=O)NCCCCO)C3=CC=CC=C3C2=C1 UJTTUOLQLCQZEA-UHFFFAOYSA-N 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 7
- 235000019270 ammonium chloride Nutrition 0.000 claims description 7
- 229940041514 candida albicans extract Drugs 0.000 claims description 7
- 238000010438 heat treatment Methods 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 7
- 239000011736 potassium bicarbonate Substances 0.000 claims description 7
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 7
- 230000004044 response Effects 0.000 claims description 7
- 229920006395 saturated elastomer Polymers 0.000 claims description 7
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 7
- 239000012138 yeast extract Substances 0.000 claims description 7
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 claims description 6
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 239000012153 distilled water Substances 0.000 claims description 6
- 239000008103 glucose Substances 0.000 claims description 6
- 150000007530 organic bases Chemical class 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 5
- UREBDLICKHMUKA-DVTGEIKXSA-N betamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-DVTGEIKXSA-N 0.000 claims description 5
- 229960002537 betamethasone Drugs 0.000 claims description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- 229920001817 Agar Polymers 0.000 claims description 4
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims description 4
- 239000007818 Grignard reagent Substances 0.000 claims description 4
- 239000008272 agar Substances 0.000 claims description 4
- -1 concentration Substances 0.000 claims description 4
- 150000004795 grignard reagents Chemical class 0.000 claims description 4
- 239000000463 material Substances 0.000 claims description 4
- 230000007935 neutral effect Effects 0.000 claims description 4
- 230000003472 neutralizing effect Effects 0.000 claims description 4
- 239000007836 KH2PO4 Substances 0.000 claims description 3
- 240000008042 Zea mays Species 0.000 claims description 3
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 claims description 3
- 235000002017 Zea mays subsp mays Nutrition 0.000 claims description 3
- 235000005822 corn Nutrition 0.000 claims description 3
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- OIXUJRCCNNHWFI-UHFFFAOYSA-N 1,2-dioxane Chemical compound C1CCOOC1 OIXUJRCCNNHWFI-UHFFFAOYSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- XOBKSJJDNFUZPF-UHFFFAOYSA-N Methoxyethane Chemical compound CCOC XOBKSJJDNFUZPF-UHFFFAOYSA-N 0.000 claims description 2
- 230000003197 catalytic effect Effects 0.000 claims description 2
- 229940125782 compound 2 Drugs 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims 2
- 239000000543 intermediate Substances 0.000 abstract description 17
- 150000003431 steroids Chemical class 0.000 abstract description 11
- 239000003814 drug Substances 0.000 abstract description 7
- 238000000034 method Methods 0.000 abstract description 6
- 239000000758 substrate Substances 0.000 abstract description 5
- 125000005594 diketone group Chemical group 0.000 abstract 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract 2
- 150000001993 dienes Chemical class 0.000 abstract 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 abstract 1
- 150000005672 tetraenes Chemical class 0.000 abstract 1
- 238000005406 washing Methods 0.000 description 19
- 235000019441 ethanol Nutrition 0.000 description 12
- 238000006356 dehydrogenation reaction Methods 0.000 description 9
- 235000011121 sodium hydroxide Nutrition 0.000 description 9
- 238000010792 warming Methods 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 239000012530 fluid Substances 0.000 description 6
- 239000002609 medium Substances 0.000 description 5
- 238000000605 extraction Methods 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 3
- WRLRISOTNFYPMU-UHFFFAOYSA-N [S].CC1=CC=CC=C1 Chemical compound [S].CC1=CC=CC=C1 WRLRISOTNFYPMU-UHFFFAOYSA-N 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- CCERQOYLJJULMD-UHFFFAOYSA-M magnesium;carbanide;chloride Chemical compound [CH3-].[Mg+2].[Cl-] CCERQOYLJJULMD-UHFFFAOYSA-M 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- FWQHRZXEQNUCSY-UHFFFAOYSA-N tert-butyl N-[2-(ethoxycarbonylamino)-5-[(4-fluorophenyl)methyl-prop-2-ynylamino]phenyl]carbamate Chemical compound CCOC(=O)NC1=C(C=C(C=C1)N(CC#C)CC2=CC=C(C=C2)F)NC(=O)OC(C)(C)C FWQHRZXEQNUCSY-UHFFFAOYSA-N 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- 206010057249 Phagocytosis Diseases 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 239000003862 glucocorticoid Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 230000008782 phagocytosis Effects 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- FRXSZNDVFUDTIR-UHFFFAOYSA-N 6-methoxy-1,2,3,4-tetrahydroquinoline Chemical compound N1CCCC2=CC(OC)=CC=C21 FRXSZNDVFUDTIR-UHFFFAOYSA-N 0.000 description 1
- 101800004538 Bradykinin Proteins 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 238000003747 Grignard reaction Methods 0.000 description 1
- QXZGBUJJYSLZLT-UHFFFAOYSA-N H-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg-OH Natural products NC(N)=NCCCC(N)C(=O)N1CCCC1C(=O)N1C(C(=O)NCC(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CO)C(=O)N2C(CCC2)C(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CCCN=C(N)N)C(O)=O)CCC1 QXZGBUJJYSLZLT-UHFFFAOYSA-N 0.000 description 1
- 102100035792 Kininogen-1 Human genes 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 239000001888 Peptone Substances 0.000 description 1
- 108010080698 Peptones Proteins 0.000 description 1
- 206010043189 Telangiectasia Diseases 0.000 description 1
- 235000009754 Vitis X bourquina Nutrition 0.000 description 1
- 235000012333 Vitis X labruscana Nutrition 0.000 description 1
- 240000006365 Vitis vinifera Species 0.000 description 1
- 235000014787 Vitis vinifera Nutrition 0.000 description 1
- 230000001780 adrenocortical effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- QXZGBUJJYSLZLT-FDISYFBBSA-N bradykinin Chemical compound NC(=N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(=O)NCC(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CO)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)CCC1 QXZGBUJJYSLZLT-FDISYFBBSA-N 0.000 description 1
- 230000003196 chaotropic effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 description 1
- 229960002986 dinoprostone Drugs 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 125000005909 ethyl alcohol group Chemical group 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 206010020718 hyperplasia Diseases 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 210000003712 lysosome Anatomy 0.000 description 1
- 230000001868 lysosomic effect Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 235000019319 peptone Nutrition 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- XEYBRNLFEZDVAW-UHFFFAOYSA-N prostaglandin E2 Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CC=CCCCC(O)=O XEYBRNLFEZDVAW-UHFFFAOYSA-N 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 208000009056 telangiectasis Diseases 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
- C07J7/0005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21
- C07J7/001—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group
- C07J7/0015—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa
- C07J7/002—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa not substituted in position 16
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
- C07J7/0005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21
- C07J7/001—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group
- C07J7/004—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group substituted in position 17 alfa
- C07J7/005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group substituted in position 17 alfa substituted in position 16
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P33/00—Preparation of steroids
- C12P33/02—Dehydrogenating; Dehydroxylating
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Health & Medical Sciences (AREA)
- Wood Science & Technology (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Zoology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Microbiology (AREA)
- General Chemical & Material Sciences (AREA)
- Biochemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Engineering & Computer Science (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to the preparation method of Steroid medicine intermediates, more particularly to androstane-14 alkene 3, the α hydroxyls of 17 diketone 9 are that substrate prepares a kind of pregnant steroid 1 of pregna medicament intermediate, 4,9 (11), the diketone of 16 (17) tetraene 3,20, pregnant steroid 4, the method of the α hydroxyls of 93,20 diketone of (11) diene 17.
Description
Technical field：
The present invention relates to the preparation method of Steroid medicine intermediates, more particularly to a kind of pregnant steroid of pregna medicament intermediate
- Isosorbide-5-Nitrae, 9 (11), 16 (17)-tetraene -3,20- diketone, pregnant steroid -4,9 (11)-diene -3,20- diketone
- 17 alpha-hydroxy preparation methods.
Background technology：
Glucocorticoid is the sterid of adrenocortical secretion, the effect of its physiological show to sugar,
Protein, fat, the influence of water and electrolyte.It can suppress bradykinin, prostaglandin E2, serotonin,
The synthesis and release of the inflammatory mediators such as histamine, reduction vasopermeability, stable lysosome membrane, suppression phagocytosis.
Have very strong antiinflammatory action to inflammation caused by a variety of causes, the oozing out of the early stage that can reduce inflammation, oedema,
Telangiectasis, leukocyte infiltration and phagocytosis reaction, can suppress inflammation later stage capillary and fibroblast
Hyperplasia, suppresses the pathological change that immune response is produced, releases the symptom of the disease.
Pregnant steroid-Isosorbide-5-Nitrae, 9 (11), 16 (17)-tetraene -3,20- diketone, pregnant steroid -4,9 (11)-diene -3,
The Alpha-hydroxy of 20- diketones -17 is pregna medicament important intermediate, can prepare glucocorticoid, for example
Just described in CN200710061254.4 with pregnant steroid-Isosorbide-5-Nitrae, 9 (11), 16 (17)-tetraene -3,20- is double
Ketone is the method that substrate prepares betamethasone and its series of products.
In order to preferably prepare pregnant steroid-Isosorbide-5-Nitrae, 9 (11), 16 (17)-tetraene -3,20- diketone, researcher
Take a variety of methods.
CN201010278556.9 prepares 5ST by mould dehydrogen substance and is divided into two-step reaction：The first step takes off
Water obtains methyl dehydrate, and second step is through reducing to obtain 5ST (5ST).
CN201510090371.8 is disclosed with androstane-4-alkene-3, and the Alpha-hydroxy of 17- diketones -9 is substrate, by de-
Water, it is etherified, connects side chain, biological dehydrogenation and obtain pregnant steroid-Isosorbide-5-Nitrae, 9 (11), 16 (17)-tetraene -3,20-
Diketone.
The content of the invention
The present invention relates to the preparation method of Steroid medicine intermediates, more particularly to a kind of pregnant steroid of pregna medicament intermediate
- Isosorbide-5-Nitrae, 9 (11), 16 (17)-tetraene -3,20- diketone, pregnant steroid -4,9 (11)-diene -3,20- diketone
- 17 alpha-hydroxy preparation methods.
We are by constantly research, it has surprisingly been found that by optimizing reaction scheme, adjusting process, Ke Yixiong
Gona-4-ene-3, the Alpha-hydroxy of 17- diketones -9 is substrate, and pregnant steroid is obtained by dehydration, cyaniding, ketal, grignard reaction
The Alpha-hydroxy of -4,9 (11)-diene -3,20- diketone -17, then by biological dehydrogenation, dehydration, obtain pregnant steroid
- Isosorbide-5-Nitrae, 9 (11), 16 (17)-tetraene -3,20- diketone.
A kind of preparation method of the compound of formula 2, it is characterized in that：
Step 1：
The compound of formula 3 is put into the solution of alcohol, water and the sulfuric acid composition of aqueous sulfuric acid or 1-4 carbon
In, stirring is neutralized in pH value up to being diluted to without raw material, then by reaction solution in water with inorganic base aqueous solution
Property, it is filtrated to get the compound of formula 4；
Step 2：
The alcohol and inorganic base aqueous solution of 1-4 carbon are stirred, the compound of formula 4 is put into wherein, stirring
Uniformly.The acetone cyanohydrin added more than 2 times of mol ratios, control temperature stirring reaction between 25-40 DEG C is straight
To without raw material.Reaction solution is diluted into water again, with inorganic acid and dilution is neutral to pH value；Filtering
Obtain the compound of formula 5；
Step 3：
The compound of formula 5 is put into ethylene glycol, p-methyl benzenesulfonic acid, triethyl orthoformate is sequentially added, risen
Temperature is to 30-60 DEG C of reaction until without raw material, adding appropriate organic base and neutralizing, be then diluted into reaction solution
In water, filtering obtains the compound of Betamethasone Ketal structures formula 6；
Step 4
The ether that the dry compound of formula 6 and vinyl butyl ether are put into the 2-6 carbon containing toluenesulfonic acid is molten
In liquid, stirring reaction is extremely without raw material, the intermediate reacted；Be added dropwise to again RMgBr-methyl-magnesium-chloride/
Tetrahydrofuran, after being added dropwise to complete, is stirred at room temperature reaction to without intermediate.It is slow with saturated aqueous ammonium chloride again
Grignard reagent is quenched in dropwise addition, and the pH value for then adjusting reaction solution with inorganic acid is less than 3.Heating response liquid is extremely
40-70 DEG C is incubated 2 hours, after be cooled to 5-10 DEG C, adjust pH to neutrality with inorganic base aqueous solution, concentration,
Dilution, filtering, obtains the compound of formula 1；
Step 5
The compound of formula 1 is crushed or dissolved with the alcohol of 1-4 carbon, input has cultivated the fermentation of Arthrobacter simplex
Bioconversion is carried out in tank, compound 7 is obtained.
Step 6：
Compound 7 is put into acetic acid, the semicarbazide hydrochloride aqueous solution added, temperature reaction is until without original
Material, is cooled to room temperature, is diluted into water, filters, obtains compound 2.
4 in the compound of formula 6,5 and the 5, dotted line of 6 represent 4,5 or 5,6 there is double bond.
A kind of preparation method of the compound of formula 1, it is characterized in that：
Step 1：
The compound of formula 3 is put into the solution of alcohol, water and the sulfuric acid composition of aqueous sulfuric acid or 1-4 carbon
In, stirring is neutralized in pH value up to being diluted to without raw material, then by reaction solution in water with inorganic base aqueous solution
Property, it is filtrated to get the compound of formula 4；
Step 2：
The alcohol and inorganic base aqueous solution of 1-4 carbon are stirred, the compound of formula 4 is put into wherein, stirring
Uniformly.The acetone cyanohydrin added more than 2 times of mol ratios, control temperature stirring reaction between 25-40 DEG C is straight
To without raw material.Reaction solution is diluted into water again, with inorganic acid and dilution is neutral to pH value；Filtering
Obtain the compound of formula 5；
Step 3：
The compound of formula 5 is put into ethylene glycol, p-methyl benzenesulfonic acid, triethyl orthoformate is sequentially added, risen
Temperature is to 30-60 DEG C of reaction until without raw material, adding appropriate organic base and neutralizing, be then diluted into reaction solution
In water, filtering obtains the compound of Betamethasone Ketal structures formula 6；
Step 4
The ether that the dry compound of formula 6 and vinyl butyl ether are put into the 2-6 carbon containing toluenesulfonic acid is molten
In liquid, stirring reaction is extremely without raw material, the intermediate reacted；Be added dropwise to again RMgBr-methyl-magnesium-chloride/
Tetrahydrofuran, after being added dropwise to complete, is stirred at room temperature reaction to without intermediate.It is slow with saturated aqueous ammonium chloride again
Grignard reagent is quenched in dropwise addition, and the pH value for then adjusting reaction solution with inorganic acid is less than 3.Heating response liquid is extremely
55-65 DEG C is incubated 2 hours, after be cooled to 5-10 DEG C, adjust pH to neutrality with inorganic base aqueous solution, concentration,
Dilution, filtering, obtains the compound of formula 1；
4 in the compound of formula 6,5 and the 5, dotted line of 6 represent 4,5 or 5,6 there is double bond.
Preparation method as described above, it is characterized in that the alcohol of the 1-4 carbon is methanol or ethanol.
Preparation method as described above, it is characterized in that aqueous sulfuric acid is that 15-50% sulfuric acid is water-soluble in the step 1
Liquid
Preparation method as described above, it is characterized in that the alcohol of 1-4 carbon, water and sulfuric acid composition in the step 1
Solution reclaimed water, sulfuric acid be 15-50% aqueous sulfuric acids.
Preparation method as described above, it is characterized in that aqueous sulfuric acid concentration is 25-40%, nothing in the step 1
Machine alkali is NaOH, KOH, Na2CO3、NaHCO3、K2CO3、KHCO3In one or more.
Preparation method as described above, it is characterized in that the alcohol of 1-4 carbon, water and sulfuric acid composition in the step 1
Solution reclaimed water, sulfuric acid be 25-40% aqueous sulfuric acids, inorganic base be NaOH, KOH, Na2CO3、
NaHCO3、K2CO3、KHCO3In one or more.
Preparation method as described above, it is characterized in that inorganic base is one in NaOH, KOH in the step 2
Plant or several, inorganic base aqueous solution concentration is 30-60%, the compound of formula 4 and inorganic base aqueous solution weighing body
Product is than being 1:0.01-0.1.
Preparation method as described above, it is characterized in that p-methyl benzenesulfonic acid is catalytic amount, formula 5 in the step 3
The w/v of compound and triethyl orthoformate is 1:One in 0.7-2, the non-pyridine of organic base or triethylamine
Kind.
Preparation method as described above, it is characterized in that the compound of step 4 Chinese style 6 and vinyl butyl ether
W/v is 1:0.5-1, the ethereal solution concentration of 2-6 carbon of toluenesulfonic acid is 0.01-1%, 2-6 carbon
Ether be ether, tetrahydrofuran, 1,2- dioxane, ethyl methyl ether, dimethyl ether, inorganic acid is hydrochloric acid, inorganic
Alkali is NaOH, KOH, Na2CO3、NaHCO3、K2CO3、KHCO3In one or more.
The preparation method of the above-mentioned compound of formula 2, it is characterized in that the compound of dissolution type 1 in step 5 bioconversion
The one kind or several of solvent in methanol, ethanol, tetrahydrofuran, dioxane, DMF
Kind, Arthrobacter simplex for AS 1.754, AS 1.94*.
The preparation method of the above-mentioned compound of formula 2, it is characterized in that in step 5 bioconversion slant medium use with
Lower proportioning：The distilled water of glucose 1.3%, yeast extract 1.3%, agar 2.0%, and surplus, uses inorganic base
Solution is adjusted to pH7.0-7.2, for inclined-plane culture.
The preparation method of the above-mentioned compound of formula 2, it is characterized in that in step 5 bioconversion slant medium use with
Lower proportioning：Yeast extract 0.5%, peptone 0.5%, grape wards off 1%, and agar 2%, running water is prepared, with nothing
Machine aqueous slkali is adjusted to pH to 7.0-7.2, for inclined-plane culture.
The preparation method of the above-mentioned compound of formula 2, it is characterized in that fermentation medium is following in step 5 bioconversion
Proportioning：Glucose 1.0, yeast extract 0.16%, KH2PO40.25%, corn steep liquor 0.1%, and surplus steaming
Distilled water, pH 7.0-7.2 are adjusted to inorganic alkali solution.
The preparation method of the above-mentioned compound of formula 2, it is characterized in that the water-soluble liquid hold-up of semicarbazide hydrochloride in step 6
For 3-10%, temperature reaction temperature is more than 60 DEG C.
The feed concentrations of the compound of substrate formula 1 are≤4% (relative to zymotic fluid volume) in steps of 5；It is preferred that
Feed concentrations are 1%~3%, and 30~34 DEG C of fermentation temperature, preferably chaotropic agent addition are 2~5% (v/v).
30~72 hours biological dehydrogenation reaction time.
Biological dehydrogenation reaction terminates rear terminating reaction, it is preferred to use zymotic fluid is warming up into 70~90 DEG C and makes thalline
After the method for inactivation, terminating reaction dehydrogenation product is extracted with the form for being preferred to use solvent extraction zymotic fluid.It is described
Solvent ethyl acetate is used in extraction.
The biological dehydrogenation uses Arthrobacter simplex, and (Latin is named：Arthrobacter simplex) preferably with
Lower several bacterial strains：AS 1.754, AS 1.94* (being provided by Institute of Microorganism, Academia Sinica).
Described biological dehydrogenation reaction can use following zymotechnique：
Inclined-plane culture-one-level culture-one-level culture-addition compound (1) fermentation carries out biological de-
Hydrogen reaction-terminating reaction.
Described bio-fermentation process can also such as be referred to using any known bio-fermentation process method《It is biological
Synthetic pharmacology》(Chemical Industry Press, publishes for 2000, Chu Zhiyi chief editors；Page 666~675) in it is public
The bio-fermentation process opened.
Culture medium used in described biological dehydrogenation is preferred to use following proportioning：
Slant medium (%)：The distilled water of glucose 1.3, yeast extract 1.3, agar 2.0, and surplus, pH7.0-7.2,
For inclined-plane culture
Fermentation medium (%)：Glucose 1.0, yeast extract 0.16, KH2PO40.25, corn steep liquor 0.1, Yi Jiyu
The distilled water of amount, pH 7.0-7.2, in one-level, two grades of cultures and final biological dehydrogenation reaction.
Embodiment
HPLC：High performance liquid chromatography
Embodiment 1
Embodiment 1-1
The compound of 10g formulas 3 is put into 50ml15% aqueous sulfuric acids, stirring at normal temperature will react to without raw material
Liquid is diluted into 200ml frozen water, with dilution to neutrality in the 5%NaOH aqueous solution.Filtering, washing.It is roasting
It is dry, obtain the compound 8.1g of formula 4.
Embodiment 1-2
The compound of 10g formulas 3 is put into 25ml25% aqueous sulfuric acids, stirring at normal temperature will react to without raw material
Liquid is diluted into 200ml frozen water, with dilution to neutrality in the 15%KOH aqueous solution.Filtering, washing.It is roasting
It is dry, obtain the compound 8.4g of formula 4.
Embodiment 1-3
The compound of 10g formulas 3 is put into 20ml40% aqueous sulfuric acids, in 10 DEG C of stirrings to without raw material, by instead
Liquid is answered to be diluted into 300ml frozen water, 20%Na2CO3With dilution to neutrality in the aqueous solution.Filtering, washing.
Dry, obtain the compound 8.3g of formula 4.
Embodiment 1-4
The compound of 10g formulas 3 is put into 15ml50% aqueous sulfuric acids, 0 DEG C of stirring is to without raw material, by reaction solution
It is diluted into 300ml frozen water, 20%KHCO3With dilution to neutrality in the aqueous solution.Filtering, washing.It is roasting
It is dry, obtain the compound 8.3g of formula 4.
Embodiment 1-5
The compound of 10g formulas 3 is put into 50ml methanol, 50ml15% aqueous sulfuric acids, stirring at normal temperature is to without original
Material, reaction solution is diluted into 200ml frozen water, with dilution to neutrality in the 5%NaOH aqueous solution.Filtering,
Washing.Dry, obtain the compound 8.1g of formula 4.
Embodiment 1-6
The compound of 10g formulas 3 is put into 40ml ethanol, 25ml25% aqueous sulfuric acids, stirring at normal temperature is to without original
Material, reaction solution is diluted into 200ml frozen water, with dilution to neutrality in the 15%KOH aqueous solution.Filtering,
Washing.Dry, obtain the compound 8.4g of formula 4.
Embodiment 1-7
The compound of 10g formulas 3 is put into 40ml absolute ethyl alcohols, 20ml40% aqueous sulfuric acids, in 10 DEG C of stirrings
To without raw material, reaction solution is diluted into 300ml frozen water, 20%Na2CO3In the aqueous solution with dilution into
Property.Filtering, washing.Dry, obtain the compound 8.3g of formula 4.
Embodiment 1-8
The compound of 10g formulas 3 is put into 50ml absolute methanols, 15ml50% aqueous sulfuric acids, 0 DEG C of stirring to nothing
Raw material, reaction solution is diluted into 300ml frozen water, 20%KHCO3With dilution to neutrality in the aqueous solution.
Filtering, washing.Dry, obtain the compound 8.3g of formula 4.
Embodiment 2
Embodiment 2-1
The compound of 10g formulas 4 is put into 30ml methanol and the 1ml 60%KOH aqueous solution, stirred.Again plus
Enter 8ml acetone cyanohydrin, stirring reaction to raw material point disappears.Reaction solution is diluted into 150ml water again, used
With dilution to neutrality in watery hydrochloric acid.Filtering, washing.Dry, obtain the compound 9.9g of formula 5.
Embodiment 2-2
The compound of 10g formulas 4 is put into 20ml methanol and the 0.5ml 50%KOH aqueous solution, stirred.Again
15ml acetone cyanohydrin is added, stirring reaction to raw material point disappears.Reaction solution is diluted into 300ml water again,
With in watery hydrochloric acid and dilution is to neutrality.Filtering, washing.Dry, obtain the compound 10.3g of formula 5.
Embodiment 2-3
The compound of 10g formulas 4 is put into 15ml methanol and the sodium hydrate aqueous solutions of 0.2ml 40%, stirred.
20ml acetone cyanohydrin is added, stirring reaction to raw material point disappears.Reaction solution is diluted into 300ml water again,
With in watery hydrochloric acid and dilution is to neutrality.Filtering, washing.Dry, obtain the compound 10.3g of formula 5.
Embodiment 2-4
The compound of 10g formulas 4 is put into 10ml methanol and the sodium hydrate aqueous solutions of 0.1ml 30%, stirred.
25ml acetone cyanohydrin is added, stirring reaction to raw material point disappears.Reaction solution is diluted into 200ml water again,
With in watery hydrochloric acid and dilution is to neutrality.Filtering, washing.Dry, obtain the compound 10.2g of formula 5.
Embodiment 3
Embodiment 3-1
The compound of 10g formulas 5 is put into 15ml ethylene glycol, 0.1g p-methyl benzenesulfonic acid, 20ml is sequentially added
Triethyl orthoformate, is warming up to 55-60 DEG C of reaction to raw material point and disappears.Appropriate pyridine is added to neutralize.Then will
Reaction solution is diluted into 100ml water, is filtered, washing.Dry, obtain the compound 10.2g of formula 6.
Embodiment 3-2
The compound of 10g formulas 5 is put into 20ml ethylene glycol, 0.2g p-methyl benzenesulfonic acid, 15ml is sequentially added
Triethyl orthoformate, is warming up to 50-55 DEG C of reaction to raw material point and disappears.Appropriate pyridine is added to neutralize.Then will
Reaction solution is diluted into 150ml water, is filtered, washing.Dry, obtain the compound 10.3g of formula 6.
Embodiment 3-3
The compound of 10g formulas 5 is put into 25ml ethylene glycol, 0.2g p-methyl benzenesulfonic acid, 10ml is sequentially added
Triethyl orthoformate, is warming up to 40-45 DEG C of reaction to raw material point and disappears.Appropriate pyridine is added to neutralize.Then will
Reaction solution is diluted into 200ml water, is filtered, washing.Dry, obtain the compound 10.4g of formula 6.
Embodiment 3-2
The compound of 10g formulas 5 is put into 30ml ethylene glycol, 0.3g p-methyl benzenesulfonic acid, 20ml is sequentially added
Triethyl orthoformate, is warming up to 30-35 DEG C of reaction to raw material point and disappears.Appropriate pyridine is added to neutralize.Then will
Reaction solution is diluted into 200ml water, is filtered, washing.Dry, obtain the compound 10.3g of formula 6.
Embodiment 4
Embodiment 4-1
Formula 6 compound 10g and 5ml vinyl butyl ether are put into 50ml and contain 0.01% pair of toluene sulphur
In the tetrahydrofuran solution of acid, stirring reaction is extremely without raw material, the intermediate reacted.
It is added dropwise in 30ml 3M RMgBr methyl-magnesium-chloride/tetrahydrofuran, after being added dropwise to complete, stirs again
Reaction is mixed to without intermediate.It is slowly added dropwise again with saturated aqueous ammonium chloride and RMgBr is quenched, then uses dense salt
Acid adjusts reaction solution pH to 1-2.Heating response liquid is incubated 1 hour to 60-70 DEG C, then is cooled to 15-20 DEG C,
Adjust pH to neutrality with 10% sodium hydrate aqueous solution, concentration removes tetrahydrofuran.It will be diluted at concentration residual night
In 100ml water.Filtering, washing.DEG C dry, obtain the compound 8.8g of formula 1.
Embodiment 4-2
Formula 6 compound 10g and 7.5ml vinyl butyl ether are put into 40ml and contain 0.1% pair of toluene sulphur
In the diethyl ether solution of acid, stirring reaction is extremely without raw material, the intermediate reacted.
It is added dropwise in 35ml 3M RMgBr methyl-magnesium-chloride/tetrahydrofuran, after being added dropwise to complete, stirs again
Reaction is mixed to without intermediate.It is slowly added dropwise again with saturated aqueous ammonium chloride and RMgBr is quenched, then uses dense salt
Acid adjusts reaction solution pH to 1-2.Heating response liquid is incubated 2 hours to 50-60 DEG C, then is cooled to 10-15 DEG C,
Adjust pH to neutrality with 20% wet chemical, concentration removes tetrahydrofuran.150ml will be diluted at concentration residual night
In water.Filtering, washing.DEG C dry, obtain the compound 9.0g of formula 1.
Embodiment 4-3
Formula 6 compound 10g and 9ml vinyl butyl ether are put into 30ml and contain 0.1% pair of toluene sulphur
In 1, the 2- dioxane solutions of acid, stirring reaction is extremely without raw material, the intermediate reacted.
It is added dropwise in 40ml 3M RMgBr methyl-magnesium-chloride/tetrahydrofuran, after being added dropwise to complete, stirs again
Reaction is mixed to without intermediate.It is slowly added dropwise again with saturated aqueous ammonium chloride and RMgBr is quenched, then uses dense salt
Acid adjusts reaction solution pH to 1-2.Heating response liquid is incubated 4 hours to 45-55 DEG C, then is cooled to 15-20 DEG C,
Adjust pH to neutrality with 30% sodium bicarbonate aqueous solution, concentration removes tetrahydrofuran.It will be diluted at concentration residual night
In 200ml water.Filtering, washing.DEG C dry, obtain the compound 9.1g of formula 1.
Embodiment 5
Embodiment 5-1
Arthrobacter simplex (AS 1.754) is carried out to inclined-plane culture, one-level culture and two grades of cultures, culture successively
Temperature is 31-33 DEG C, and the compound of 20g formulas 6 is dissolved in 20ml tetrahydrofurans input 5L fermentation tanks, fed intake
Concentration is 2%, and reaction temperature is 31 DEG C.Until the compound of formula 6 residue is less than 5%, heated up after the completion of reaction
To 70 DEG C of terminating reactions, adopt and extraction zymotic fluid is extracted with ethyl acetate, organic phase is concentrated, recrystallizing methanol
Obtain the compound 17.5g of formula 7.
Embodiment 5-2
Arthrobacter simplex (AS 1.94*) is carried out to inclined-plane culture, one-level culture and two grades of cultures, culture successively
Temperature is 29-32 DEG C, the compound of 20g formulas 6 is dissolved in 30ml methanol input 5L fermentation tanks, feed concentrations
For 3%, reaction temperature is 32 DEG C, until the compound of formula 6 residue is less than 5%, 70 DEG C are warming up to after the completion of reaction
Terminating reaction, extracts zymotic fluid using chloroform extraction, organic phase is concentrated, recrystallizing methanol obtains the chemical combination of formula 7
Thing 18.2g.
Embodiment 5-3
Arthrobacter simplex (AS 1.754) is carried out to inclined-plane culture, one-level culture and two grades of cultures, culture successively
Temperature is 30-32 DEG C, and the compound of 20g formulas 6 is dissolved in into 40mlN, dinethylformamide input 5L fermentations
In tank, feed concentrations are 4%, and reaction temperature is 32 DEG C, until the compound of formula 6 residue is less than 5%, reaction
After the completion of be warming up to 70 DEG C of terminating reactions, using dichloromethane extraction extract zymotic fluid, organic phase is concentrated,
Recrystallizing methanol obtains the compound 18.6g of formula 7.
Embodiment 6
Embodiment 6-1
The compound of 10g formulas 7 is put into 50ml acetic acid, the 10% semicarbazide hydrochloride aqueous solution is added.
Reaction mixture is heated to 60-65 DEG C of reaction to without raw material point.Room temperature is cooled to, 200ml water is diluted into
In, filtering obtains the compound of 8.9g formulas 2.
Embodiment 6-2
The compound of 10g formulas 7 is put into 100ml acetic acid, the 8% semicarbazide hydrochloride aqueous solution is added.
Reaction mixture is heated to 70-75 DEG C of reaction to without raw material point.Room temperature is cooled to, 400ml water is diluted into
In, filtering obtains the compound of 9.1g formulas 2.
Embodiment 6-3
The compound of 10g formulas 7 is put into 100ml acetic acid, the 5% semicarbazide hydrochloride aqueous solution is added.
Reaction mixture is heated to 80-85 DEG C of reaction to without raw material point.Room temperature is cooled to, 400ml water is diluted into
In, filtering obtains the compound of 9.2g formulas 2.
Embodiment 6-4
The compound of 10g formulas 7 is put into 150ml acetic acid, the 3% semicarbazide hydrochloride aqueous solution is added.
Reaction mixture is heated to 85-90 DEG C of reaction to without raw material point.Room temperature is cooled to, 500ml water is diluted into
In, filtering obtains the compound of 9.2g formulas 2.
Claims (10)
1. a kind of preparation method of the compound of formula 2, it is characterized in that：
Step 1：
In the solution of alcohol, water and sulfuric acid composition that the compound of formula 3 is put into aqueous sulfuric acid or 1-4 carbon,
Stirring is neutralized to pH value neutrality with inorganic base aqueous solution up to being diluted to without raw material, then by reaction solution in water,
It is filtrated to get the compound of formula 4；
Step 2：
The alcohol and inorganic base aqueous solution of 1-4 carbon are stirred, the compound of formula 4 is put into wherein, stirring
Uniformly.The acetone cyanohydrin added more than 2 times of mol ratios, control temperature stirring reaction between 25-40 DEG C is straight
To without raw material.Reaction solution is diluted into water again, with inorganic acid and dilution is neutral to pH value；Filtering
Obtain the compound of formula 5；
Step 3：
The compound of formula 5 is put into ethylene glycol, p-methyl benzenesulfonic acid, triethyl orthoformate is sequentially added, risen
Temperature is to 30-60 DEG C of reaction until without raw material, adding appropriate organic base and neutralizing, be then diluted into reaction solution
In water, filtering obtains the compound of Betamethasone Ketal structures formula 6；
Step 4
The ether that the dry compound of formula 6 and vinyl butyl ether are put into the 2-6 carbon containing toluenesulfonic acid is molten
In liquid, stirring reaction is extremely without raw material, the intermediate reacted；Be added dropwise to again RMgBr-methyl-magnesium-chloride/
Tetrahydrofuran, after being added dropwise to complete, is stirred at room temperature reaction to without intermediate.It is slow with saturated aqueous ammonium chloride again
Grignard reagent is quenched in dropwise addition, and the pH value for then adjusting reaction solution with inorganic acid is less than 3.Heating response liquid is extremely
40-70 DEG C is incubated 2 hours, after be cooled to 5-10 DEG C, adjust pH to neutrality with inorganic base aqueous solution, concentration,
Dilution, filtering, obtains the compound of formula 1；
Step 5
The compound of formula 1 is crushed or dissolved with the alcohol of 1-4 carbon, input has cultivated the fermentation of Arthrobacter simplex
Bioconversion is carried out in tank, compound 7 is obtained.
Step 6：
Compound 7 is put into acetic acid, the semicarbazide hydrochloride aqueous solution added, temperature reaction is until without original
Material, is cooled to room temperature, is diluted into water, filters, obtains compound 2.
4 in the compound of formula 6,5 and the 5, dotted line of 6 represent 4,5 or 5,6 there is double bond.
2. a kind of preparation method of the compound of formula 1, it is characterized in that：
Step 1：
In the solution of alcohol, water and sulfuric acid composition that the compound of formula 3 is put into aqueous sulfuric acid or 1-4 carbon,
Stirring is neutralized to pH value neutrality with inorganic base aqueous solution up to being diluted to without raw material, then by reaction solution in water,
It is filtrated to get the compound of formula 4；
Step 2：
The alcohol and inorganic base aqueous solution of 1-4 carbon are stirred, the compound of formula 4 is put into wherein, stirring
Uniformly.The acetone cyanohydrin added more than 2 times of mol ratios, control temperature stirring reaction between 25-40 DEG C is straight
To without raw material.Reaction solution is diluted into water again, with inorganic acid and dilution is neutral to pH value；Filtering
Obtain the compound of formula 5；
Step 3：
The compound of formula 5 is put into ethylene glycol, p-methyl benzenesulfonic acid, triethyl orthoformate is sequentially added, risen
Temperature is to 30-60 DEG C of reaction until without raw material, adding appropriate organic base and neutralizing, be then diluted into reaction solution
In water, filtering obtains the compound of Betamethasone Ketal structures formula 6；
Step 4
The ether that the dry compound of formula 6 and vinyl butyl ether are put into the 2-6 carbon containing toluenesulfonic acid is molten
In liquid, stirring reaction is extremely without raw material, the intermediate reacted；Be added dropwise to again RMgBr-methyl-magnesium-chloride/
Tetrahydrofuran, after being added dropwise to complete, is stirred at room temperature reaction to without intermediate.It is slow with saturated aqueous ammonium chloride again
Grignard reagent is quenched in dropwise addition, and the pH value for then adjusting reaction solution with inorganic acid is less than 3.Heating response liquid is extremely
55-65 DEG C is incubated 2 hours, after be cooled to 5-10 DEG C, adjust pH to neutrality with inorganic base aqueous solution, concentration,
Dilution, filtering, obtains the compound of formula 1；
4 in the compound of formula 6,5 and the 5, dotted line of 6 represent 4,5 or 5,6 there is double bond.
3. the preparation method as described in claim 1,2, it is characterized in that aqueous sulfuric acid is in the step 1
15-50% aqueous sulfuric acids.
4. the preparation method as described in claim 1,2, it is characterized in that described in the step 1 in step 1
Alcohol, the solution reclaimed water of water and sulfuric acid composition, the sulfuric acid of 1-4 carbon are 25-40% aqueous sulfuric acids, and inorganic base is
NaOH、KOH、Na2CO3、NaHCO3、K2CO3、KHCO3In one or more.
5. preparation method as claimed in claim 1, it is characterized in that in the step 2 inorganic base be NaOH,
One or more in KOH, inorganic base aqueous solution concentration is 30-60%, and the compound of formula 4 and inorganic base are water-soluble
The w/v of liquid is 1:0.01-0.1.
6. the preparation method as described in claim 1,2, it is characterized in that p-methyl benzenesulfonic acid is in the step 3
The w/v of catalytic amount, the compound of formula 5 and triethyl orthoformate is 1:0.7-2, organic base is pyridine
Or one kind in triethylamine.
7. the preparation method as described in claim 1,2, it is characterized in that the compound of step 4 Chinese style 6 with
The w/v of vinyl butyl ether is 1:0.5-1, the ethereal solution concentration of 2-6 carbon of toluenesulfonic acid is
The ether of 0.01-1%, 2-6 carbon is ether, tetrahydrofuran, 1,2- dioxane, ethyl methyl ether, dimethyl ether, nothing
Machine acid is hydrochloric acid, and inorganic base is NaOH, KOH, Na2CO3、NaHCO3、K2CO3、KHCO3In
It is one or more of.
8. preparation method as claimed in claim 1, it is characterized in that dissolution type 1 is changed in step 5 bioconversion
The solvent of compound in methanol, ethanol, tetrahydrofuran, dioxane, DMF one
Kind or it is several, Arthrobacter simplex for AS 1.754, AS 1.94*.
9. preparation method as claimed in claim 1, it is characterized in that slant medium in step 5 bioconversion
Using following proportioning：The distilled water of glucose 1.3%, yeast extract 1.3%, agar 2.0%, and surplus, is used
Inorganic alkali solution is adjusted to pH7.0-7.2, for inclined-plane culture.
10. preparation method as claimed in claim 1, it is characterized in that fermentation medium in step 5 bioconversion
For following proportioning：Glucose 1.0, yeast extract 0.16%, KH2PO40.25%, corn steep liquor 0.1%, Yi Jiyu
The distilled water of amount, pH 7.0-7.2 are adjusted to inorganic alkali solution.
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| CN112608359A (en) * | 2020-12-31 | 2021-04-06 | 台州仙琚药业有限公司 | Process for the preparation of 17 alpha-hydroxyandrosta-4, 9-diene-3, 20-dione |
| CN112940062A (en) * | 2021-02-23 | 2021-06-11 | 浙江神洲药业有限公司 | Preparation method of 16-dehydroprogesterone |
| CN113980818A (en) * | 2021-09-13 | 2022-01-28 | 丽江映华生物药业有限公司 | Fungus dehydrogenation seed liquid culture method |
| CN114437166A (en) * | 2022-01-27 | 2022-05-06 | 台州仙琚药业有限公司 | Synthesis method of 17 beta-cyano-17 alpha-hydroxy-9-dehydroandrostenedione |
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| CN112940062A (en) * | 2021-02-23 | 2021-06-11 | 浙江神洲药业有限公司 | Preparation method of 16-dehydroprogesterone |
| CN112940062B (en) * | 2021-02-23 | 2022-09-06 | 浙江神洲药业有限公司 | Preparation method of 16-dehydroprogesterone |
| CN113980818A (en) * | 2021-09-13 | 2022-01-28 | 丽江映华生物药业有限公司 | Fungus dehydrogenation seed liquid culture method |
| CN114437166A (en) * | 2022-01-27 | 2022-05-06 | 台州仙琚药业有限公司 | Synthesis method of 17 beta-cyano-17 alpha-hydroxy-9-dehydroandrostenedione |
| CN114437166B (en) * | 2022-01-27 | 2023-11-21 | 台州仙琚药业有限公司 | Synthesis method of 17 beta-cyano-17 alpha-hydroxy-9-dehydroandrostenedione |
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