CN109627274A - The preparation method of -17 beta-hydroxy -3- ketone of -17 Alpha-Methyl of androstane - Google Patents
The preparation method of -17 beta-hydroxy -3- ketone of -17 Alpha-Methyl of androstane Download PDFInfo
- Publication number
- CN109627274A CN109627274A CN201811476354.8A CN201811476354A CN109627274A CN 109627274 A CN109627274 A CN 109627274A CN 201811476354 A CN201811476354 A CN 201811476354A CN 109627274 A CN109627274 A CN 109627274A
- Authority
- CN
- China
- Prior art keywords
- hydroxy
- beta
- methyl
- alpha
- androstane
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- QZLYKIGBANMMBK-UGCZWRCOSA-N 5α-Androstane Chemical compound C([C@@H]1CC2)CCC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CCC[C@@]2(C)CC1 QZLYKIGBANMMBK-UGCZWRCOSA-N 0.000 title claims abstract description 39
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 36
- 238000000034 method Methods 0.000 claims abstract description 21
- GCKMFJBGXUYNAG-UHFFFAOYSA-N 17alpha-methyltestosterone Natural products C1CC2=CC(=O)CCC2(C)C2C1C1CCC(C)(O)C1(C)CC2 GCKMFJBGXUYNAG-UHFFFAOYSA-N 0.000 claims abstract description 15
- GCKMFJBGXUYNAG-HLXURNFRSA-N Methyltestosterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@](C)(O)[C@@]1(C)CC2 GCKMFJBGXUYNAG-HLXURNFRSA-N 0.000 claims abstract description 15
- 229960001566 methyltestosterone Drugs 0.000 claims abstract description 15
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims abstract description 11
- 230000007062 hydrolysis Effects 0.000 claims abstract description 7
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 51
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 30
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 29
- 239000005977 Ethylene Substances 0.000 claims description 28
- 239000003054 catalyst Substances 0.000 claims description 15
- 150000001875 compounds Chemical class 0.000 claims description 13
- 230000008569 process Effects 0.000 claims description 13
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 12
- 238000001914 filtration Methods 0.000 claims description 12
- SBNLPRGISFUZQE-VMXHOPILSA-N (8s,9s,10r,13s,14s)-10,13-dimethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthrene Chemical compound C1C=C2CCCC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CCC[C@@]1(C)CC2 SBNLPRGISFUZQE-VMXHOPILSA-N 0.000 claims description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-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
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 9
- 239000012046 mixed solvent Substances 0.000 claims description 8
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 claims description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 6
- 150000002576 ketones Chemical class 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims description 4
- 238000000746 purification Methods 0.000 claims description 3
- 229910015900 BF3 Inorganic materials 0.000 claims description 2
- 230000009471 action Effects 0.000 claims description 2
- 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 2
- 229960002537 betamethasone Drugs 0.000 claims description 2
- 239000012024 dehydrating agents Substances 0.000 claims description 2
- 150000004678 hydrides Chemical class 0.000 claims description 2
- NXQOQNROJJFYCJ-FZFXZXLVSA-N androst-16-ene Chemical compound C1CCC[C@]2(C)[C@H]3CC[C@](C)(C=CC4)[C@@H]4[C@@H]3CCC21 NXQOQNROJJFYCJ-FZFXZXLVSA-N 0.000 claims 1
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 claims 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims 1
- 239000007788 liquid Substances 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 16
- 239000002994 raw material Substances 0.000 abstract description 8
- 238000005516 engineering process Methods 0.000 abstract description 6
- 230000008901 benefit Effects 0.000 abstract description 3
- 239000000243 solution Substances 0.000 description 17
- 239000001257 hydrogen Substances 0.000 description 13
- 229910052739 hydrogen Inorganic materials 0.000 description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 12
- -1 rambling vigorous Chemical compound 0.000 description 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 238000007792 addition Methods 0.000 description 9
- 230000004224 protection Effects 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 239000002904 solvent Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 150000001993 dienes Chemical class 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 239000002351 wastewater Substances 0.000 description 5
- 238000001035 drying Methods 0.000 description 4
- 125000000468 ketone group Chemical group 0.000 description 4
- 235000011121 sodium hydroxide Nutrition 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- QGXBDMJGAMFCBF-UHFFFAOYSA-N Etiocholanolone Natural products C1C(O)CCC2(C)C3CCC(C)(C(CC4)=O)C4C3CCC21 QGXBDMJGAMFCBF-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000006073 displacement reaction Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000007613 environmental effect Effects 0.000 description 3
- 238000006266 etherification reaction Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000010842 industrial wastewater Substances 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- 239000001397 quillaja saponaria molina bark Substances 0.000 description 3
- 229930182490 saponin Natural products 0.000 description 3
- 150000007949 saponins Chemical class 0.000 description 3
- 231100000004 severe toxicity Toxicity 0.000 description 3
- 240000001811 Dioscorea oppositifolia Species 0.000 description 2
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 2
- LKAJKIOFIWVMDJ-IYRCEVNGSA-N Stanazolol Chemical compound C([C@@H]1CC[C@H]2[C@@H]3CC[C@@]([C@]3(CC[C@@H]2[C@@]1(C)C1)C)(O)C)C2=C1C=NN2 LKAJKIOFIWVMDJ-IYRCEVNGSA-N 0.000 description 2
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 2
- WGLPBDUCMAPZCE-UHFFFAOYSA-N Trioxochromium Chemical compound O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 2
- MUCRYNWJQNHDJH-OADIDDRXSA-N Ursonic acid Chemical group C1CC(=O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CC[C@@H](C)[C@H](C)[C@H]5C4=CC[C@@H]3[C@]21C MUCRYNWJQNHDJH-OADIDDRXSA-N 0.000 description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical group OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000011651 chromium Substances 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- QGXBDMJGAMFCBF-LUJOEAJASA-N epiandrosterone Chemical compound C1[C@@H](O)CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC[C@H]21 QGXBDMJGAMFCBF-LUJOEAJASA-N 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 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 2
- ICMWWNHDUZJFDW-UHFFFAOYSA-N oxymetholone Natural products C1CC2CC(=O)C(=CO)CC2(C)C2C1C1CCC(C)(O)C1(C)CC2 ICMWWNHDUZJFDW-UHFFFAOYSA-N 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 229960000912 stanozolol Drugs 0.000 description 2
- 239000003270 steroid hormone Substances 0.000 description 2
- 230000003637 steroidlike Effects 0.000 description 2
- DBPWSSGDRRHUNT-UHFFFAOYSA-N 17alpha-hydroxy progesterone Natural products C1CC2=CC(=O)CCC2(C)C2C1C1CCC(C(=O)C)(O)C1(C)CC2 DBPWSSGDRRHUNT-UHFFFAOYSA-N 0.000 description 1
- MWFMGBPGAXYFAR-UHFFFAOYSA-N 2-hydroxy-2-methylpropanenitrile Chemical compound CC(C)(O)C#N MWFMGBPGAXYFAR-UHFFFAOYSA-N 0.000 description 1
- QGXBDMJGAMFCBF-HLUDHZFRSA-N 5α-Androsterone Chemical compound C1[C@H](O)CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC[C@H]21 QGXBDMJGAMFCBF-HLUDHZFRSA-N 0.000 description 1
- 238000006237 Beckmann rearrangement reaction Methods 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 1
- 235000002722 Dioscorea batatas Nutrition 0.000 description 1
- 235000006536 Dioscorea esculenta Nutrition 0.000 description 1
- 235000003416 Dioscorea oppositifolia Nutrition 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- DOMWKUIIPQCAJU-LJHIYBGHSA-N Hydroxyprogesterone caproate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)CCCCC)[C@@]1(C)CC2 DOMWKUIIPQCAJU-LJHIYBGHSA-N 0.000 description 1
- 244000061456 Solanum tuberosum Species 0.000 description 1
- 229930182558 Sterol Natural products 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 229940061641 androsterone Drugs 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000003796 beauty Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229910052804 chromium Inorganic materials 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000010411 cooking Methods 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- JMANVNJQNLATNU-UHFFFAOYSA-N glycolonitrile Natural products N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 229950000801 hydroxyprogesterone caproate Drugs 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 150000002561 ketenes Chemical class 0.000 description 1
- UXYRZJKIQKRJCF-TZPFWLJSSA-N mesterolone Chemical compound C1C[C@@H]2[C@@]3(C)[C@@H](C)CC(=O)C[C@@H]3CC[C@H]2[C@@H]2CC[C@H](O)[C@]21C UXYRZJKIQKRJCF-TZPFWLJSSA-N 0.000 description 1
- 229960005272 mesterolone Drugs 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- RECVMTHOQWMYFX-UHFFFAOYSA-N oxygen(1+) dihydride Chemical compound [OH2+] RECVMTHOQWMYFX-UHFFFAOYSA-N 0.000 description 1
- CHWRSCGUEQEHOH-UHFFFAOYSA-N potassium oxide Chemical compound [O-2].[K+].[K+] CHWRSCGUEQEHOH-UHFFFAOYSA-N 0.000 description 1
- 229910001950 potassium oxide Inorganic materials 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 1
- 150000003432 sterols Chemical class 0.000 description 1
- 235000003702 sterols Nutrition 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0003—Androstane derivatives
- C07J1/0033—Androstane derivatives substituted in position 17 alfa and 17 beta
- C07J1/0037—Androstane derivatives substituted in position 17 alfa and 17 beta the substituent in position 17 alfa being a saturated hydrocarbon group
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Steroid Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
A kind of preparation method of -17 beta-hydroxy -3- ketone of -17 Alpha-Methyl of androstane, this method are to obtain -17 beta-hydroxy -3- ketone of -17 Alpha-Methyl of androstane through ketal reaction, catalytic hydrogenation, hydrolysis using methyltestosterone as raw material.The method of the present invention has the advantages that concise in technology, production cost are low, product purity is high, is suitble to industrialized production.
Description
Technical field
The invention belongs to organic chemical synthesis technical fields, are related to the preparation of -17 beta-hydroxy -3- ketone of -17 Alpha-Methyl of androstane
Method.
Background technique
- 17 beta-hydroxy -3- ketone of -17 Alpha-Methyl of androstane, molecular formula C20H32O2, molecular weight 304.47, structural formula are as follows:
- 17 beta-hydroxy -3- ketone of -17 Alpha-Methyl of androstane is tens of kinds of production adroyd, mesterolone, rambling vigorous, Stanozolol of husband etc.
The key intermediate of steroid hormone class drug, market is using very extensive.
The conventional production methods of -17 beta-hydroxy -3- ketone of -17 Alpha-Methyl of androstane be using Chinese yam saponin as raw material, by open loop,
The reactions such as acylated, oxidation, hydrolysis, elimination obtain diene, and diene is through oximate, Beckmann rearrangement, sour water solution, basic hydrolysis, catalysis hydrogen
The reactions such as change obtain epiandrosterone, and target product then is prepared through grignard, addition, oxidation reaction.Conventional method step is long, work
Multistep chromic anhydride oxidation reaction can be generated containing a large amount of Cr in skill route6+And Cr3+Reluctant industrial wastewater, to production enterprise
Industry production brings very big environmental protection pressure.Importantly, as wild Chinese yam plant resources are increasingly depleted, and artificial growth potato
Chinese yam plant causes the production cost of saponin, diene to be doubled and redoubled also because of the increasingly rising of the costs such as artificial growth, subsequent extracted,
The production cost of -17 beta-hydroxy -3- ketone of -17 Alpha-Methyl of androstane is caused to increase substantially with the market price, to including adroyd, beauty
The world market of hormonal medicaments including testosterone, the rambling vigorous, Stanozolol of husband etc. produces significant impact.
It is using cheap and easy to get big with 4-AD (4AD) that saponin, diene are all steroidal compounds critical materials
Soya-bean oil by-product carries out microorganism conversion preparation.The raw material is since manufacturing enterprise is numerous, and supply is very sufficient, and price is only diene
Half or so, and avoid pollution of chromium.The inexpensive 4AD easily purchased is as steroid hormone drug critical materials using increasingly
It is taken seriously.In recent years, the new technology route using 4AD as alternative materials is successively successfully applied to 17 Alpha-hydroxy progesterone, goes
The preparation of multiple steroidal compounds such as hydrogen meter androsterone, methyltestosterone, epiandrosterone.Methyltestosterone industry generallys use 4AD as replacing at present
For raw material, first to the position the 3- ketone group etherification protection of 4-AD, then carry out 17- ketone group grignard additions, hydrolysis be made
Methyltestosterone.After methyltestosterone industry is adopted new technology, production cost is greatly reduced, and avoids generating a large amount of reluctant industry
Waste water is more advantageous to environmental protection.
Methyltestosterone synthetic route is as follows:
。
In terms of the synthesis technology of -17 beta-hydroxy -3- ketone of -17 Alpha-Methyl of key intermediate androstane, technical staff uses 4AD
Unremitting improvement has been carried out as alternative materials, and has obtained following progress:
CN107417753A, as alternative materials, must be closed using 4AD through 17 ketone groups of acetone cyanohydrin or Cymag selective protection
Key intermediate cyanalcohol object, again through ethylene ketal, basic hydrolysis, catalytic hydrogenation, grignard addition, sour water solution and etc. prepared,
Synthesis route is as follows:
Above-mentioned process route has biggish cost using being prepared by sterol through the 4-AD that microbial fermentation obtains
Advantage, process route is simple, raw material 4-AD is in liberal supply, but can generate greatly in the synthesis of key intermediate cyanalcohol object
Measure cyanide containing wastewater, the cyanide ion concentration about 500-800ppm in the industrial wastewater.Since there is severe toxicity containing cyanogen compound
The industrial wastewater containing cyanide of characteristic, formation must be handled strictly, could be discharged after up to standard.According to national emission standard, discharge
Cyanide in Waste Water ion concentration must not exceed 5ppm, processing difficulty is very big, environmental protection of enterprise processing immense pressure restrict this
Application of the process route in industrialized production.
CN107312051A is equally using 4AD as alternative materials, but changes process route and be etherified through 3- ketone groups
Protection, grignard addition, catalytic hydrogenation, sour water solution and etc. prepared, synthesis route is as follows:
3 ketone group alkene etherification protections, 17 ketone group grignard additions are passed through with 4AD raw material in above-mentioned technique road, and 5 ethylene linkage catalysis add
Prepared by hydrogen, acidolysis four-step reaction, synthetic route is avoided without the cyano protection of 17 ketone groups containing cyanide ion severe toxicity
The difficulty of discharge of wastewater and processing.But the compound containing 3 ketone group alkene etherificate structures is all unstable, to moisture, acid-sensitive, is easy
It is hydrolyzed into ketenes.3- ethyoxyl-androstane -3,5- diene -17- ketone in the drying process, places just part turn quickly in air
Turn to 4AD.It especially needs to be added hydrochloric acid in 17 ketone group grignard addition last handling processes of the process route and carries out 17 acid
Solution reaction obtains 17 hydroxyls, and very unstable in acid condition containing 3 ketone group alkene etherification protection compounds, in the acid condition
Under be difficult control only carry out 17 acidolysis reactions, and without 3 ketone group alkene etherificate deprotection reaction.Occur 17 at the same time
Acidolysis and 3 ketone group alkene are etherified in de-protected situation, are continued lower step catalytic hydrogenation and are easy in target product androstane-
The isomerism impurity with 5 β H structures, the impurity and product polarity extremely phase are introduced in -17 beta-hydroxy -3- ketone of 17 Alpha-Methyl
Closely, it is difficult to remove, to finally influence the purity of product.
Summary of the invention
The purpose of the present invention is to the defects of the prior art, provide a kind of -17 beta-hydroxy -3- of -17 Alpha-Methyl of androstane
The preparation method of ketone, the method for the present invention have concise in technology, production cost is low, product purity is high, be suitble to industrialized production it is excellent
Point.
The technical scheme is that realized using following process route:
。
The present invention specifically includes following step:
Step is (1): methyltestosterone and ethylene glycol contract in the presence of organic solvent, dehydrating agent triethyl orthoformate, ketal catalyst
- 17 beta-hydroxy -3- ethylene ketal (Betamethasone Ketal structures) of -17 Alpha-Methyl of compound 5- androstene is prepared in reactive ketone；
Step is (2): -17 beta-hydroxy -3- ethylene ketal of -17 Alpha-Methyl of 5- androstene is added dropwise to the methanol of alkali in the mixed solvent
Solution regulation system pH value, then catalytic hydrogenation reaction obtains -17 α of 5 α of compound-androstane-under the action of palladium carbon catalyst
Methyl-17 beta-hydroxy -3- ethylene ketal (hydride)；
Step is (3): the system of reacting is hydrolyzed with acid for -17 beta-hydroxy -3- ethylene ketal of -17 Alpha-Methyl of 5 α of compound-androstane
It is standby to obtain -17 beta-hydroxy -3- ketone of -17 Alpha-Methyl of androstane.
The reaction temperature of step of the present invention (1) is 20~35 DEG C, preferably 30~35 DEG C；Methyltestosterone: ethylene glycol: organic
Solvent: triethyl orthoformate: the proportion of ketal catalyst is 1W:2V~3V:4V~6V:1.5V~3V:0.05V~0.1V.Institute
Stating organic solvent is dichloromethane or chloroform.The ketal catalyst is boron trifluoride ether.
The reaction temperature of step of the present invention (2) is 20~40 DEG C, preferably 25~35 DEG C；Mixed solvent used is methanol-
The volume ratio of methylene chloride, in the mixed solvent methanol and methylene chloride is 1:0.25~0.5；Alkali used is sodium hydroxide or hydrogen
Potassium oxide, the pH value range for adding alkali to adjust are 7.5~9.0, preferably 8.0~8.5；- 17 beta-hydroxy of -17 Alpha-Methyl of 5- androstene -
3- ethylene ketal: mixed solvent: the proportion of palladium carbon catalyst is 1W:15V~20V:0.1W~0.3W.
The reaction temperature of step of the present invention (3) is 5~40 DEG C, preferably 35~40 DEG C；- 17 Alpha-Methyl -17 of 5- androstene
Beta-hydroxy -3- ethylene ketal: sour proportion is 1W:0.5W~0.8W.The acid is the essence of mass percent concentration >=35%
The aqueous sulfuric acid that salt manufacturing acid or mass percent concentration are >=10%.
(2) catalytic hydrogenation reaction terminates step of the present invention, and filtering obtains -17 α of 5 α-androstane-first after removing palladium carbon catalyst
The solution of -17 beta-hydroxy -3- ethylene ketal of base without discharge process directly with the purified salt of mass percent concentration >=35%
The aqueous sulfuric acid that acid or mass percent concentration are >=10% carries out step, and (3) hydrolysis obtains -17 β of -17 Alpha-Methyl of androstane -
Hydroxyl -3- ketone.
Compared with prior art, the invention has the following advantages that
1. the present invention, using methyltestosterone as raw material, process route, which both avoids, there is the discharge of wastewater of severe toxicity containing cyanide ion and processing
Difficulty, in turn avoid because subsequent reactions are extremely difficult caused by 3 ketone group alkene etherates of intermediate compound are unstable in technical process
The inconsistency of control；
2. when carrying out catalytic hydrogenation and ketal deprotection reaction, using technique of cooking all things in one pot.In a solvent, first in alkalescent
Under the conditions of carry out catalytic hydrogenation；After catalytic hydrogenation is complete, the 5 α-androstane obtained after palladium carbon catalyst is removed in filtering
- 17 beta-hydroxy -3- ethylene ketal solution of -17 Alpha-Methyl of alkane directly carries out the de-protected water of ketal with acid without discharging separation
Solution reaction.It is effectively guaranteed the yield concentration of present invention process route in this way；
3. present invention process route is brief, raw material methyltestosterone is cheap and easy to get, and production technology is easy to control, environmental-friendly, is produced into
This is low, is suitble to industrial scale production.
Specific embodiment
The present invention is made for example, these examples are intended to help to understand technological means of the invention of example below.But
It should be understood that these embodiments are only exemplary, the present invention is not limited thereto.Palladium carbon catalyst is common according to its effective content
Specification has 1%~5%, and the specification of the palladium carbon catalyst used in the embodiment of the present invention is 2%, if selecting other specifications can be by effective
Content converts dosage.
Embodiment one
1, -17 beta-hydroxy -3- ethylene ketal of -17 Alpha-Methyl of prepare compound 5- androstene
20g methyltestosterone, 100ml methylene chloride, 30ml triethyl orthoformate, 40ml ethylene glycol and 1ml tri- are added into reaction flask
It is fluorinated borate ether, stirs evenly and keeps the temperature 10 hours in 30 DEG C~35 DEG C and reacted；To end of reaction, be cooled to 5 DEG C hereinafter,
Triethylamine tune pH value is added dropwise to 7.0~7.5, finishes stirring 30 minutes；After all solvents of evaporated under reduced pressure, then with 20ml methanol press from both sides
Band is concentrated under reduced pressure into paste, is added 20ml methanol eddy 30 minutes；5 DEG C are cooled to hereinafter, filtering, drying obtain 22.1g5- hero
- 17 beta-hydroxy -3- ethylene ketal of -17 Alpha-Methyl of steroid alkene；
2, -17 beta-hydroxy -3- ketone of -17 Alpha-Methyl of prepare compound androstane
- 17 beta-hydroxy -3- ethylene ketal of -17 Alpha-Methyl of 20g5- androstene, 320ml methanol and 80ml are added into reaction flask
Methylene chloride, the methanol solution that potassium hydroxide is added dropwise after mixing evenly adjust pH value to 8.0~8.5,4g palladium content 2% are added
Palladium charcoal, it is with hydrogen that the air displacement in reaction flask is clean, it is passed through hydrogen in 25 DEG C~30 DEG C and reacts 6 hours；To end of reaction,
The hydrogen in reaction flask is replaced completely with nitrogen, the contracting of -17 beta-hydroxy -3- ethylene glycol of -17 Alpha-Methyl of 5 α-androstane is obtained by filtration
The solution of ketone；
The lower addition 10g mass into the solution of -17 beta-hydroxy -3- ethylene ketal of -17 Alpha-Methyl of 5 α-androstane is stirred at room temperature
The purification hydrochloric acid of percent concentration >=35.0% reacts 3 hours in 35~40 DEG C；To end of reaction, 5 DEG C are cooled to hereinafter, being added dropwise
The sodium hydrate aqueous solution of mass percent concentration 5% adjusts pH value to 6.0~7.0, after evaporated under reduced pressure solvent, be cooled to 5 DEG C with
Under, it is slowly added into 500ml pure water, continues to be cooled to 5 DEG C hereinafter, standing 2 hours or more, filtering, being washed to after stirring 30 minutes
Neutrality obtains -17 beta-hydroxy -3- ketone crude product wet feed of -17 Alpha-Methyl of androstane.Crude product is recrystallized to give 16.1g in industrial alcohol
- 17 beta-hydroxy -3- ketone of -17 Alpha-Methyl of androstane, HPLC purity 99.3%.
Embodiment two
1, -17 beta-hydroxy -3- ethylene ketal of -17 Alpha-Methyl of prepare compound 5- androstene
20g methyltestosterone, 80ml chloroform, 40ml triethyl orthoformate, 60ml ethylene glycol and 2ml trifluoro are added into reaction flask
Change borate ether, stirs evenly and keep the temperature 9 hours in 30 DEG C~35 DEG C and reacted；To end of reaction, 5 DEG C are cooled to hereinafter, drop
Add triethylamine tune pH value to 7.0~7.5, finishes stirring 30 minutes；After all solvents of evaporated under reduced pressure, then with 20ml methanol carry secretly,
It is concentrated under reduced pressure into paste, is added 20ml methanol eddy 30 minutes；5 DEG C are cooled to hereinafter, filtering, drying obtain 22.3g5- androstane
- 17 beta-hydroxy -3- ethylene ketal of -17 Alpha-Methyl of alkene；
2, -17 beta-hydroxy -3- ketone of -17 Alpha-Methyl of prepare compound androstane
- 17 beta-hydroxy -3- ethylene ketal of -17 Alpha-Methyl of 20g5- androstene, 270ml methanol and 90ml are added into reaction flask
Methylene chloride, the methanol solution that potassium hydroxide is added dropwise after mixing evenly adjust pH value to 8.0~8.5,2g palladium content 2% are added
Palladium charcoal, it is with hydrogen that the air displacement in reaction flask is clean, it is passed through hydrogen in 25 DEG C~30 DEG C and reacts 9 hours；To end of reaction,
The hydrogen in reaction flask is replaced completely with nitrogen, the contracting of -17 beta-hydroxy -3- ethylene glycol of -17 Alpha-Methyl of 5 α-androstane is obtained by filtration
The solution of ketone；
The lower addition 16g mass into the solution of -17 beta-hydroxy -3- ethylene ketal of -17 Alpha-Methyl of 5 α-androstane is stirred at room temperature
The aqueous sulfuric acid of percent concentration >=10% reacts 5 hours in 35~40 DEG C；To end of reaction, 5 DEG C are cooled to hereinafter, being added dropwise
The sodium hydrate aqueous solution of mass percent concentration 5% adjusts pH value to 6.0~7.0, after evaporated under reduced pressure solvent, be cooled to 5 DEG C with
Under, it is slowly added into 500ml pure water, continues to be cooled to 5 DEG C hereinafter, standing 2 hours or more, filtering, being washed to after stirring 30 minutes
Neutrality obtains -17 beta-hydroxy -3- ketone crude product wet feed of -17 Alpha-Methyl of androstane.Crude product is recrystallized to give 15.9g in industrial alcohol
- 17 beta-hydroxy -3- ketone of -17 Alpha-Methyl of androstane, HPLC purity 99.6%.
Embodiment three
1, -17 beta-hydroxy -3- ethylene ketal of -17 Alpha-Methyl of prepare compound 5- androstene
20g methyltestosterone, 120ml methylene chloride, 60ml triethyl orthoformate, 60ml ethylene glycol and 1ml tri- are added into reaction flask
It is fluorinated borate ether, stirs evenly and keeps the temperature 9 hours in 30 DEG C~35 DEG C and reacted；To end of reaction, be cooled to 5 DEG C hereinafter,
Triethylamine tune pH value is added dropwise to 7.0~7.5, finishes stirring 30 minutes；After all solvents of evaporated under reduced pressure, then with 20ml methanol press from both sides
Band is concentrated under reduced pressure into paste, is added 20ml methanol eddy 30 minutes；5 DEG C are cooled to hereinafter, filtering, drying obtain 22.0g5- hero
- 17 beta-hydroxy -3- ethylene ketal of -17 Alpha-Methyl of steroid alkene；
2, -17 beta-hydroxy -3- ketone of -17 Alpha-Methyl of prepare compound androstane
- 17 beta-hydroxy -3- ethylene ketal of -17 Alpha-Methyl of 20g5- androstene, 200ml methanol and 100ml are added into reaction flask
Methylene chloride, the methanol solution that potassium hydroxide is added dropwise after mixing evenly adjust pH value to 8.0~8.5,6g palladium content 2% are added
Palladium charcoal, it is with hydrogen that the air displacement in reaction flask is clean, it is passed through hydrogen in 30 DEG C~35 DEG C and reacts 5 hours；To end of reaction,
The hydrogen in reaction flask is replaced completely with nitrogen, the contracting of -17 beta-hydroxy -3- ethylene glycol of -17 Alpha-Methyl of 5 α-androstane is obtained by filtration
The solution of ketone；
The lower addition 12g mass into the solution of -17 beta-hydroxy -3- ethylene ketal of -17 Alpha-Methyl of 5 α-androstane is stirred at room temperature
The purification hydrochloric acid of percent concentration >=35.0% reacts 3 hours in 35~40 DEG C；To end of reaction, 5 DEG C are cooled to hereinafter, being added dropwise
The sodium hydrate aqueous solution of mass percent concentration 5% adjusts pH value to 6.0~7.0, after evaporated under reduced pressure solvent, be cooled to 5 DEG C with
Under, it is slowly added into 500ml pure water, continues to be cooled to 5 DEG C hereinafter, standing 2 hours or more, filtering, being washed to after stirring 30 minutes
Neutrality obtains -17 beta-hydroxy -3- ketone crude product wet feed of -17 Alpha-Methyl of androstane.Crude product is recrystallized to give 16.2g in industrial alcohol
- 17 beta-hydroxy -3- ketone of -17 Alpha-Methyl of androstane, HPLC purity 99.2%.
Claims (7)
1. the preparation method of -17 beta-hydroxy -3- ketone of -17 Alpha-Methyl of androstane, it is characterised in that the described method comprises the following steps:
Step is (1): methyltestosterone and ethylene glycol contract in the presence of organic solvent, dehydrating agent triethyl orthoformate, ketal catalyst
- 17 beta-hydroxy -3- ethylene ketal (Betamethasone Ketal structures) of -17 Alpha-Methyl of compound 5- androstene is prepared in reactive ketone；
Step is (2): -17 beta-hydroxy -3- ethylene ketal of -17 Alpha-Methyl of 5- androstene is added dropwise to the methanol of alkali in the mixed solvent
Solution regulation system pH value, then catalytic hydrogenation reaction obtains -17 α of 5 α of compound-androstane-under the action of palladium carbon catalyst
Methyl-17 beta-hydroxy -3- ethylene ketal (hydride)；
Step is (3): the system of reacting is hydrolyzed with acid for -17 beta-hydroxy -3- ethylene ketal of -17 Alpha-Methyl of 5 α of compound-androstane
It is standby to obtain -17 beta-hydroxy -3- ketone of -17 Alpha-Methyl of androstane；
Wherein, the reaction temperature of the step (1) is 20~35 DEG C, preferably 30~35 DEG C；Methyltestosterone: ethylene glycol: organic solvent:
Triethyl orthoformate: the proportion of ketal catalyst is 1W:2V~3V:4V~6V:1.5V~3V:0.05V~0.1V；
The reaction temperature of the step (2) is 20~40 DEG C, and the pH value range for adding the methanol solution of alkali to adjust is 7.5~9.0,5-
- 17 beta-hydroxy -3- ethylene ketal of -17 Alpha-Methyl of androstene: mixed solvent: the proportion of palladium carbon catalyst is 1W:15V~20V:
0.1W~0.3W；
The reaction temperature of the step (3) is 5~40 DEG C, -17 beta-hydroxy -3- ethylene ketal of -17 Alpha-Methyl of 5- androstene: acid
Proportion be 1W:0.5W~0.8W.
2. the preparation method of -17 beta-hydroxy -3- ketone of -17 Alpha-Methyl of androstane according to claim 1, it is characterised in that: institute
Stating organic solvent in step (1) is dichloromethane or chloroform.
3. the preparation method of -17 beta-hydroxy -3- ketone of -17 Alpha-Methyl of androstane according to claim 1, it is characterised in that: institute
Stating ketal catalyst in step (1) is boron trifluoride ether.
4. the preparation method of -17 beta-hydroxy -3- ketone of -17 Alpha-Methyl of androstane according to claim 1, it is characterised in that: institute
State step (2) in mixed solvent be methanol dichloromethane, the volume ratio of in the mixed solvent methanol and methylene chloride be 1:0.25~
0.5。
5. the preparation method of -17 beta-hydroxy -3- ketone of -17 Alpha-Methyl of androstane according to claim 1, it is characterised in that: institute
Stating step, (2) middle alkali is sodium hydroxide or potassium hydroxide.
6. the preparation method of -17 beta-hydroxy -3- ketone of -17 Alpha-Methyl of androstane according to claim 1, it is characterised in that: institute
State step (3) in acid be mass percent concentration >=35% to refine hydrochloric acid or mass percent concentration water-soluble for >=10% sulfuric acid
Liquid.
7. the preparation method of -17 beta-hydroxy -3- ketone of -17 Alpha-Methyl of androstane according to claim 1, it is characterised in that: step
Suddenly (2) catalytic hydrogenation reaction terminates, and filtering obtains -17 beta-hydroxy -3- second of -17 Alpha-Methyl of 5 α-androstane after removing palladium carbon catalyst
The solution of glycol ketal is directly dense with the purification hydrochloric acid or mass percent of mass percent concentration >=35% without discharge process
The aqueous sulfuric acid that degree is >=10% carries out step, and (3) hydrolysis obtains -17 beta-hydroxy -3- ketone of -17 Alpha-Methyl of androstane.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811476354.8A CN109627274A (en) | 2018-12-05 | 2018-12-05 | The preparation method of -17 beta-hydroxy -3- ketone of -17 Alpha-Methyl of androstane |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811476354.8A CN109627274A (en) | 2018-12-05 | 2018-12-05 | The preparation method of -17 beta-hydroxy -3- ketone of -17 Alpha-Methyl of androstane |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN109627274A true CN109627274A (en) | 2019-04-16 |
Family
ID=66070906
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811476354.8A Pending CN109627274A (en) | 2018-12-05 | 2018-12-05 | The preparation method of -17 beta-hydroxy -3- ketone of -17 Alpha-Methyl of androstane |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109627274A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN112609203A (en) * | 2020-12-28 | 2021-04-06 | 浙江工业大学 | Method for preparing 7 alpha-methyl-19-aldehyde-4-androstene-3, 17-diketone by electrocatalytic oxidation |
| CN114002442A (en) * | 2021-10-29 | 2022-02-01 | 南京岚煜生物科技有限公司 | Testosterone detection kit and preparation method thereof |
| CN114957367A (en) * | 2022-05-27 | 2022-08-30 | 黄冈人福药业有限责任公司 | Refining method for preparing testosterone by biological method |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2763670A (en) * | 1954-03-04 | 1956-09-18 | Syntex Sa | Preparation of 17alpha-methyl-androstane-17beta-ol-3-one |
| CN107417753A (en) * | 2017-06-10 | 2017-12-01 | 浙江圃瑞药业有限公司 | A kind of preparation method of Mestanlone |
-
2018
- 2018-12-05 CN CN201811476354.8A patent/CN109627274A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2763670A (en) * | 1954-03-04 | 1956-09-18 | Syntex Sa | Preparation of 17alpha-methyl-androstane-17beta-ol-3-one |
| CN107417753A (en) * | 2017-06-10 | 2017-12-01 | 浙江圃瑞药业有限公司 | A kind of preparation method of Mestanlone |
Non-Patent Citations (1)
| Title |
|---|
| L. KOLLAR等: "《Stereoselective reduction of steroids with in situ prepared phosphine rhodium catalysts》", 《JOURNAL OF MOLECULAR CATALYSIS》, vol. 47, no. 1, pages 33 - 39 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN112609203A (en) * | 2020-12-28 | 2021-04-06 | 浙江工业大学 | Method for preparing 7 alpha-methyl-19-aldehyde-4-androstene-3, 17-diketone by electrocatalytic oxidation |
| CN112609203B (en) * | 2020-12-28 | 2022-02-15 | 浙江工业大学 | Method for preparing 7 alpha-methyl-19-aldehyde-4-androstene-3, 17-diketone by electrocatalytic oxidation |
| CN114002442A (en) * | 2021-10-29 | 2022-02-01 | 南京岚煜生物科技有限公司 | Testosterone detection kit and preparation method thereof |
| CN114957367A (en) * | 2022-05-27 | 2022-08-30 | 黄冈人福药业有限责任公司 | Refining method for preparing testosterone by biological method |
| CN114957367B (en) * | 2022-05-27 | 2023-12-29 | 黄冈人福药业有限责任公司 | Refining method for preparing testosterone by biological method |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN109627274A (en) | The preparation method of -17 beta-hydroxy -3- ketone of -17 Alpha-Methyl of androstane | |
| CN109438538A (en) | A kind of synthetic method of -17 beta-hydroxy -3- ketone of -17 Alpha-Methyl of Stanozolol intermediate androstane | |
| CN105348351A (en) | Method for preparing tetraene methyl CAS | |
| US9593073B2 (en) | Method for the preparation of diazoalkanes | |
| CN112246441B (en) | Flotation composite collecting agent and preparation method and application thereof | |
| CN110156718A (en) | A method of using liquid chlorine as oxidant continuous production accelerator D CBS | |
| CN109503691A (en) | A kind of synthetic method of 5 α-androstane -3,17- diketone | |
| CN108752415A (en) | A kind of Finasteride chiral impurity（5 β-Finasterides）Synthesis and purification process | |
| CN109627273A (en) | A kind of synthetic method of -17 beta-hydroxy -3- ketone of -17 Alpha-Methyl of furazabol intermediate androstane | |
| CN110698527B (en) | Preparation method of high-purity hydrocortisone-17-valerate | |
| CN110563787A (en) | preparation method of 5 alpha-androstane-17-hydroxy-3-ketone | |
| CN110015974B (en) | Preparation method of cyclododecanone oxime | |
| CN110563788A (en) | preparation method of 5 alpha-androstane-3, 17-dione | |
| CN106008660A (en) | Method for preparing deflazacort | |
| EP2576584A1 (en) | Methods and compounds for the preparation of monofluoromethylated biologically active organic compounds | |
| CN114195844A (en) | Preparation method of dehydroepiandrosterone | |
| CN113024411A (en) | Preparation method of tralkoxydim | |
| CN109575098B (en) | Synthetic method of norgestimate | |
| US20220024860A1 (en) | Method for continuously preparing citalopram diol | |
| CN109503692A (en) | A kind of synthetic method of -17 beta-hydroxy -3- ketone of -17 Alpha-Methyl of androstane | |
| CN110862430A (en) | Preparation method of 5 α -androstane-3, 17-dione | |
| CN110981750A (en) | Method for synthesizing 2-pentanone oxime from 2-pentanone through ammoxidation | |
| CN108752176A (en) | A kind of trichloroacetone production technology | |
| US3470217A (en) | Process for the preparation of alkynyl carbinols | |
| CN111349677A (en) | Biocatalysis preparation method of steroid C1, 2-position dehydrogenation drug intermediate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20190416 |