CN109627273A - A kind of synthetic method of -17 beta-hydroxy -3- ketone of -17 Alpha-Methyl of furazabol intermediate androstane - Google Patents
A kind of synthetic method of -17 beta-hydroxy -3- ketone of -17 Alpha-Methyl of furazabol intermediate androstane Download PDFInfo
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- CN109627273A CN109627273A CN201811476349.7A CN201811476349A CN109627273A CN 109627273 A CN109627273 A CN 109627273A CN 201811476349 A CN201811476349 A CN 201811476349A CN 109627273 A CN109627273 A CN 109627273A
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- Prior art keywords
- ketone
- androstane
- methyl
- alpha
- beta
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- 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 25
- RGLLOUBXMOGLDQ-IVEVATEUSA-N Furazabol Chemical compound C([C@@H]1CC2)C3=NON=C3C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@](C)(O)[C@@]2(C)CC1 RGLLOUBXMOGLDQ-IVEVATEUSA-N 0.000 title claims abstract description 19
- 229950010710 furazabol Drugs 0.000 title claims abstract description 19
- 238000010189 synthetic method Methods 0.000 title claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 25
- 238000000034 method Methods 0.000 claims abstract description 24
- 238000007792 addition Methods 0.000 claims abstract description 17
- 230000007062 hydrolysis Effects 0.000 claims abstract description 16
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 16
- -1 3 ketone group alkene Chemical class 0.000 claims abstract description 14
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims abstract description 12
- 239000002994 raw material Substances 0.000 claims abstract description 8
- 125000000468 ketone group Chemical group 0.000 claims abstract description 7
- 238000004128 high performance liquid chromatography Methods 0.000 claims abstract description 6
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000005977 Ethylene Substances 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims description 43
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 18
- 238000006266 etherification reaction Methods 0.000 claims description 18
- 239000003054 catalyst Substances 0.000 claims description 16
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 14
- 239000011777 magnesium Substances 0.000 claims description 14
- 229910052749 magnesium Inorganic materials 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 230000015572 biosynthetic process Effects 0.000 claims description 12
- 239000012046 mixed solvent Substances 0.000 claims description 12
- 238000004321 preservation Methods 0.000 claims description 11
- 238000003786 synthesis reaction Methods 0.000 claims description 11
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 10
- 238000001914 filtration Methods 0.000 claims description 10
- 150000004678 hydrides Chemical class 0.000 claims description 10
- 230000008569 process Effects 0.000 claims description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 9
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 claims description 9
- 239000007818 Grignard reagent Substances 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- 239000003513 alkali Substances 0.000 claims description 8
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 8
- 150000004795 grignard reagents Chemical class 0.000 claims description 8
- 239000000463 material Substances 0.000 claims description 7
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 claims description 6
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 5
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 claims description 5
- 230000008034 disappearance Effects 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 5
- 238000000746 purification Methods 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- 238000007259 addition reaction Methods 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 claims description 3
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 claims description 3
- 238000006555 catalytic reaction Methods 0.000 claims description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 3
- 230000009471 action Effects 0.000 claims description 2
- 239000000706 filtrate Substances 0.000 claims description 2
- 150000002576 ketones Chemical class 0.000 claims description 2
- 238000007670 refining Methods 0.000 claims description 2
- 238000005984 hydrogenation reaction Methods 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 10
- 238000005516 engineering process Methods 0.000 abstract description 3
- 239000000243 solution Substances 0.000 description 22
- 238000003756 stirring Methods 0.000 description 18
- 229910052739 hydrogen Inorganic materials 0.000 description 14
- 239000001257 hydrogen Substances 0.000 description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 230000004224 protection Effects 0.000 description 8
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 5
- 150000001993 dienes Chemical class 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 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 4
- 239000002253 acid Substances 0.000 description 4
- 238000009413 insulation Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000002351 wastewater Substances 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000006073 displacement reaction Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 230000007613 environmental effect Effects 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
- 150000003431 steroids Chemical class 0.000 description 3
- 238000010792 warming Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- WGLPBDUCMAPZCE-UHFFFAOYSA-N Trioxochromium Chemical compound O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 239000001397 quillaja saponaria molina bark Substances 0.000 description 2
- 229930182490 saponin Natural products 0.000 description 2
- 150000007949 saponins Chemical class 0.000 description 2
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 description 2
- 229910001948 sodium oxide Inorganic materials 0.000 description 2
- MWFMGBPGAXYFAR-UHFFFAOYSA-N 2-hydroxy-2-methylpropanenitrile Chemical compound CC(C)(O)C#N MWFMGBPGAXYFAR-UHFFFAOYSA-N 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 238000006237 Beckmann rearrangement reaction Methods 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
- 240000001811 Dioscorea oppositifolia Species 0.000 description 1
- 235000003416 Dioscorea oppositifolia Nutrition 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 244000062245 Hedychium flavescens Species 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- 206010054949 Metaplasia Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 229930182558 Sterol Natural products 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 239000003263 anabolic agent Substances 0.000 description 1
- AEMFNILZOJDQLW-QAGGRKNESA-N androst-4-ene-3,17-dione Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 AEMFNILZOJDQLW-QAGGRKNESA-N 0.000 description 1
- AEMFNILZOJDQLW-UHFFFAOYSA-N androstenedione Natural products O=C1CCC2(C)C3CCC(C)(C(CC4)=O)C4C3CCC2=C1 AEMFNILZOJDQLW-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229910052804 chromium Inorganic materials 0.000 description 1
- 239000011651 chromium Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- VFLDPWHFBUODDF-FCXRPNKRSA-N curcumin Chemical compound C1=C(O)C(OC)=CC(\C=C\C(=O)CC(=O)\C=C\C=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-FCXRPNKRSA-N 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 230000000694 effects Effects 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
- JKFAIQOWCVVSKC-UHFFFAOYSA-N furazan Chemical compound C=1C=NON=1 JKFAIQOWCVVSKC-UHFFFAOYSA-N 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
- 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
- 230000015689 metaplastic ossification Effects 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 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
- ICMWWNHDUZJFDW-DHODBPELSA-N oxymetholone Chemical compound C([C@@H]1CC2)C(=O)\C(=C/O)C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@](C)(O)[C@@]2(C)CC1 ICMWWNHDUZJFDW-DHODBPELSA-N 0.000 description 1
- ICMWWNHDUZJFDW-UHFFFAOYSA-N oxymetholone Natural products C1CC2CC(=O)C(=CO)CC2(C)C2C1C1CCC(C)(O)C1(C)CC2 ICMWWNHDUZJFDW-UHFFFAOYSA-N 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 231100000004 severe toxicity Toxicity 0.000 description 1
- 239000000344 soap Substances 0.000 description 1
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 229960000912 stanozolol Drugs 0.000 description 1
- 239000003270 steroid hormone Substances 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 150000003432 sterols Chemical class 0.000 description 1
- 235000003702 sterols Nutrition 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)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The present invention provides a kind of synthetic method of -17 beta-hydroxy -3- ketone of -17 Alpha-Methyl of furazabol intermediate androstane, and this method is with 4-AD (abbreviation 4AD) for raw material, is etherified by 3 ketone group alkene, 17 ketone group grignard additions；Then the catalytic hydrogenation reaction for first carrying out 5 ethylene linkages without sour water solution after grignard addition, finally carries out 3 alkene ethers again and -17 beta-hydroxy -3- ketone of -17 Alpha-Methyl of compound androstane, 99.0% or more HPLC purity is prepared in 17 double hydrolysis.The method of the present invention route is brief, and production technology is easy to control, environmental-friendly, and production cost is low, is suitble to industrial scale production.
Description
Technical field
The present invention relates to a kind of synthetic methods of medicine intermediate, male more particularly to a kind of furazabol intermediate
The synthetic method of -17 beta-hydroxy -3- ketone of -17 Alpha-Methyl of steroid.
Background technique
Furazabol (parallel (2, the 3-C) furazan of-17-5 α of beta-hydroxy of 17 Alpha-Methyl-androstane) also known as furazabol, Fu La
Miscellaneous vigorous (Furazabol), structural formula are as follows:
。
Furazabol is protein anabolic hormone class drug, can promote the synthesis of vivo protein and it is inhibited to decompose generation
It thanks, while there is effect for reducing blood fat, be suitable for hyperlipidemia and atherosclerosis.Furazabol intermediate androstane -17
The traditional synthesis technology of -17 beta-hydroxy -3- ketone of Alpha-Methyl be using Chinese yam saponin as raw material, by open loop, acylation, oxidation, hydrolysis,
The reactions such as elimination obtain diene, and diene obtains table hero through reactions such as oximate, Beckmann rearrangement, sour water solution, basic hydrolysis, catalytic hydrogenations
Then target product is prepared through grignard, addition, oxidation reaction in ketone.Conventional method step is long, multistep chromic anhydride in process route
Oxidation reaction can be generated containing a large amount of Cr6+And Cr3+Reluctant industrial wastewater, to manufacturing enterprise production bring it is very big
Environmental protection pressure.The factors such as reduction and national environmental protection policy, restraint of trade due to medicine source plant resource (yellow ginger) cultivated area influence soap
The price of element and diene constantly rises violently, and cost of material is high, status in short supply causes -17 β of -17 Alpha-Methyl of androstane -
The production cost of hydroxyl -3- ketone increases substantially with the market price, to including furazabol, adroyd, mesterolone, stanozolol
The world market of hormonal medicaments including alcohol etc. produces significant impact.
It is using cheap and easy to get with 4-AD (abbreviation 4AD) that saponin, diene are all steroidal compounds critical materials
Soybean oil by-product carry out microorganism conversion preparation.The raw material is since manufacturing enterprise is numerous, and supply is very sufficient, and price is only
Half of diene or so, and avoid pollution of chromium.The inexpensive 4AD easily purchased is got over as the application of steroid hormone drug critical materials
To be more taken seriously.
CN107417753A uses 4AD as alternative materials, 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. made
Standby, synthesis route is as follows:
。
Above-mentioned process route is had biggish using being prepared by sterol through the 4-AD that microbial fermentation obtains
Cost advantage, process route is simple, raw material 4-AD is in liberal supply, but can produce in the synthesis of key intermediate cyanalcohol object
Give birth to a large amount of cyanide containing wastewaters, the cyanide ion concentration about 500-800ppm in the industrial wastewater.Due to having containing cyanogen compound
The industrial wastewater containing cyanide of hypertoxic characteristic, formation must be handled strictly, could be discharged after up to standard.According to national emission standard,
The Cyanide in Waste Water ion concentration of discharge must not exceed 5ppm, and processing difficulty is very big, and the immense pressure of environmental protection of enterprise processing restricts
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, 5 ethylene linkage catalysis are passed through with 4AD raw material in above-mentioned technique road
Add hydrogen, prepared by acidolysis four-step reaction, synthetic route is avoided without the cyano protection of 17 ketone groups containing cyanide ion play
The difficulty of malicious discharge of wastewater and processing.But the compound containing 3 ketone group alkene etherificate structures is all unstable, to moisture, acid-sensitive, holds
Facile hydrolysis is at ketenes.3- ethyoxyl-androstane -3,5- diene -17- ketone in the drying process, places just part quickly in air
It is converted into 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
Acidolysis reaction obtains 17 hydroxyls, and very unstable in acid condition containing 3 ketone group alkene etherification protection compounds, in the acidity item
It is difficult to control under part and only carries out 17 acidolysis reactions, and the deprotection reaction without 3 ketone group alkene etherificate.Occur 17 at the same time
Position acidolysis and 3 ketone group alkene are etherified in de-protected situation, are continued lower step catalytic hydrogenation and are easy in target product hero
The isomerism impurity with 5 β H structures is introduced in -17 beta-hydroxy -3- ketone of -17 Alpha-Methyl of steroid, the impurity and product polarity are extremely
It is close, be difficult to remove, thus finally influence product purity.
Summary of the invention
The present invention provides a kind of synthetic method of -17 beta-hydroxy -3- ketone of -17 Alpha-Methyl of furazabol intermediate androstane,
So as to overcome the above-mentioned drawbacks in the prior art.Synthetic route of the invention is as follows:
。
The technical scheme is that being etherified by 3 ketone group alkene, 17 with 4-AD (abbreviation 4AD) for raw material
Ketone group grignard addition；Then the catalytic hydrogenation reaction of 5 ethylene linkages is first carried out without sour water solution after grignard addition, finally again
It carries out 3 alkene ethers and -17 beta-hydroxy -3- ketone of -17 Alpha-Methyl of compound androstane is prepared in 17 double hydrolysis.
Method of the invention specifically includes the following steps:
Step is (1): 4-AD and triethyl orthoformate, dehydrated alcohol are subjected to etherification reaction in the presence of catalyst for etherification,
Compound 3- ethyoxyl-androstane -3,5- diene -17- ketone is prepared；
Step is (2): magnesium chips being put into tetrahydrofuran, ether or 2- methyltetrahydrofuran and is heated up, is then slowly added into methyl halogenated
Grignard Reagent is made until magnesium chips reacts disappearance completely in alkane, cools down spare；By 3- ethyoxyl-androstane -3,5- diene -17- ketone
It is dissolved in organic solvent, then the solution is added dropwise in aforementioned Grignard Reagent and brings it about grignard addition reaction, after dripping,
Heat preservation addition reaction is carried out, most of solvent is removed, water is added dropwise, filters, wash, being dried to obtain grignard object；
Step is (3): grignard object being added dropwise to the methanol solution regulation system pH value of alkali in the mixed solvent, then in palladium carbon catalyst
Under the action of carry out catalytic hydrogenation reaction, end of reaction filters out catalyst, and gained filtrate is the solution of hydride.Without out
Material process, the purification hydrochloric acid that mass percent concentration >=35% is added dropwise into the solution of hydride carry out heat preservation hydrolysis, water again
Solution reaction terminates, and removes solvent, and filtering washes, is dry, being refining to obtain -17 beta-hydroxy -3- ketone of -17 Alpha-Methyl of androstane, and HPLC is pure
99.0% or more degree.
A kind of synthetic method of -17 beta-hydroxy -3- ketone of -17 Alpha-Methyl of furazabol intermediate androstane, it is characterized in that:
Step (1) described in catalyst for etherification be pyridine hydrochloride or bromine hydracid pyridine, etherification reaction temperature be 30~50 DEG C；4-
Androstenedione: triethyl orthoformate: dehydrated alcohol: the proportion of catalyst for etherification is 1W:0.5V~1.0V:0.9V~1.2V:
0.015W~0.020W, wherein W represents g, V and represents ml；
Step (2) described in methyl halogenated alkane select chloromethanes, bromomethane or iodomethane, dissolved compound 3- ethyoxyl-hero
Organic solvent selection tetrahydrofuran, toluene or the 2- methyltetrahydrofuran of steroid -3,5- diene -17- ketone, 3- ethyoxyl-androstane -3,
5- diene -17- ketone: the proportion of magnesium chips is 1W:0.4W~0.6W；
Step (3) described in mixed solvent be methanol dichloromethane, the volume ratio of in the mixed solvent methanol and methylene chloride is
1V:0.2~0.3V, alkali are sodium hydroxide or potassium hydroxide, and the pH value range for adding alkali to adjust is 7.5~9.0；Catalytic hydrogenation reaction
Temperature is 25~40 DEG C；Hydrolysis holding temperature is 30~40 DEG C；Grignard object: mixed solvent: palladium carbon catalyst: sour proportion
For 1W:25V~30V:0.1W~0.3W:0.5W~1.0W, wherein W represents g, V and represents ml.
Further, the preferable technical solution of the present invention is:
(1) middle etherification reaction temperature is 35~45 DEG C to step；4-AD: triethyl orthoformate: dehydrated alcohol: etherificate catalysis
The proportion of agent is 1W:0.6V:1.0V:0.020W, and wherein W represents g, V and represents ml；
Step (2) in methyl halogenated alkane be chloromethanes, dissolved compound 3- ethyoxyl-androstane -3,5- diene -17- ketone is organic molten
Agent is tetrahydrofuran, and 3- ethyoxyl-androstane -3,5- diene -17- ketone: the proportion of magnesium chips is 1W:0.45W；
Step (3) in mixed solvent methanol dichloromethane the volume ratio of methanol and methylene chloride be 1V:0.2V, add alkali to adjust
PH value range is 8.0~8.5, and catalytic hydrogenation reaction temperature is 30~35 DEG C；Hydrolysis holding temperature is 35~40 DEG C；Grignard
Object: mixed solvent: palladium carbon catalyst: sour proportion is 1W:30V:0.2W:0.8W, and wherein W represents g, V and represents ml.
The beneficial effects of the present invention are: using 4-AD cheap and easy to get for raw material, both avoided in process route
Largely severe toxicity containing cyanide ion discharge of wastewater and processing are not easy problem up to standard, do not in turn avoid originally in acid condition very not
Stable should be in acid condition without this technique extremely rambunctious of reaction containing 3 ketone group alkene etherificate structural compounds
Route defect.The method of the present invention route is brief, and production technology is easy to control, environmental-friendly, and production cost is low, is suitble to commercial scale
Metaplasia produces.
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, prepare compound 3- ethyoxyl-androstane -3,5- diene -17- ketone
100g 4-AD, 60ml triethyl orthoformate, 100ml dehydrated alcohol are added into reaction flask, finishes 30 points of stirring
Then 2.0g bromine hydracid pyridine is added in clock, heat up in 35 DEG C~45 DEG C heat preservations, 6 hours progress etherification reactions；To end of reaction, drop
Temperature is to 5 DEG C hereinafter, dropwise addition triethylamine tune pH value finishes stirring 1 hour to 7.0~7.5；0 DEG C is cooled to hereinafter, filtering, drying
Obtain 104.9g compound 3- ethyoxyl-androstane -3,5- diene -17- ketone.
2, grignard object is prepared
600ml tetrahydrofuran, 47.2g magnesium chips, 0.2g iodine grain are added into reaction flask, stirring is warming up to 40 DEG C, starts from 40 DEG C
~45 DEG C are slowly passed through chloromethanes until magnesium chips reacts disappearances completely, continue at 40 DEG C~45 DEG C insulation reaction 1 hour, obtained lattice
Family name's reagent, be cooled to 10 DEG C or less it is spare；
300ml tetrahydrofuran is added in the 104.9g compound 3- ethyoxyl that upper step is reacted-androstane -3,5- diene -17- ketone
In, it stirs 5 minutes and dissolves, 3- ethyoxyl-androstane -3,5- diene -17- ketone tetrahydrofuran solution is added dropwise to above-mentioned format and is tried
In agent, 10 DEG C~15 DEG C of dropping temperature are controlled.After dripping, 40 DEG C~45 DEG C progress additions insulation reaction 12 hours are continued at,
End of reaction, normal pressure concentration, the residual paste being concentrated to get cool down, are added into concentrated residues paste and are cooled in advance
0 DEG C~5 DEG C of water finishes and continues stirring 2 hours, stand 2 hours or more, it filters, wash, being dried to obtain 120.0g grignard object.
3, -17 beta-hydroxy -3- ketone of -17 Alpha-Methyl of prepare compound androstane
25g grignard object, 625ml methanol, 125ml methylene chloride are added into reaction flask, potassium hydroxide is added dropwise after mixing evenly
Methanol solution adjusts pH value to 8.0~8.5, and the palladium charcoal of 5g palladium content 2% is added, is done the air displacement in reaction flask with hydrogen
Only, hydrogen is passed through in 30 DEG C~35 DEG C to react 10 hours；To end of reaction, the hydrogen in reaction flask is replaced completely with nitrogen,
The solution of hydride is obtained by filtration；
The purification hydrochloric acid that 20g mass percent concentration >=35.0% is added in the lower solution to hydride is stirred at room temperature, in 35 DEG C
~40 DEG C carry out heat preservation hydrolysis 3 hours；To end of reaction, 5 DEG C are cooled to hereinafter, the hydrogen of mass percent concentration 5% is added dropwise
It aoxidizes aqueous solutions of potassium and adjusts pH value to 6.0~7.0, after evaporated under reduced pressure solvent, be cooled to 5 DEG C hereinafter, to be slowly added into 800ml pure
Water continues to be cooled to 5 DEG C hereinafter, standing 2 hours or more, filtering, washing, obtaining -17 Alpha-Methyl -17 of androstane after stirring 30 minutes
Beta-hydroxy -3- ketone crude product wet feed.Crude product is recrystallized to give to -17 beta-hydroxy of -17 Alpha-Methyl of 17.2g androstane-in industrial alcohol
3- ketone, HPLC purity 99.6%.
Embodiment two
1, prepare compound 3- ethyoxyl-androstane -3,5- diene -17- ketone
100g 4-AD, 50ml triethyl orthoformate, 120ml dehydrated alcohol are added into reaction flask, finishes 30 points of stirring
Then 1.5g bromine hydracid pyridine is added in clock, heat up in 40 DEG C~50 DEG C heat preservations, 7 hours progress etherification reactions；To end of reaction, drop
Temperature is to 5 DEG C hereinafter, dropwise addition triethylamine tune pH value finishes stirring 1 hour to 7.0~7.5；0 DEG C is cooled to hereinafter, filtering, drying
Obtain 103.5g compound 3- ethyoxyl-androstane -3,5- diene -17- ketone.
2, grignard object is prepared
560ml2- methyltetrahydrofuran, 62.1g magnesium chips, 0.2g iodine grain are added into reaction flask, stirring is warming up to 40 DEG C, starts
Slowly be passed through in 40 DEG C~45 DEG C bromomethane until magnesium chips react disappearance completely, continue at 40 DEG C~45 DEG C insulation reaction 1 hour,
Be made Grignard Reagent, be cooled to 10 DEG C or less it is spare；
300ml2- methyl four is added in the 103.5g compound 3- ethyoxyl that upper step is reacted-androstane -3,5- diene -17- ketone
In hydrogen furans, stirs 5 minutes and dissolve, 3- ethyoxyl-androstane -3,5- diene -17- ketone 2- methyltetrahydrofuran solution is added dropwise
Enter in above-mentioned grignard reagent, controls 10 DEG C~15 DEG C of dropping temperature.After dripping, 40 DEG C~45 DEG C progress addition heat preservations are continued at
Reaction 10 hours, end of reaction, normal pressure concentration, the residual paste being concentrated to get cools down, into concentrated residues paste
The preparatory water for being cooled to 0 DEG C~5 DEG C is added, finishes and continues stirring 2 hours, stand 2 hours or more, it filters, wash, be dried to obtain
117.6g grignard object.
3, -17 beta-hydroxy -3- ketone of -17 Alpha-Methyl of prepare compound androstane
30g grignard object, 600ml methanol, 150ml methylene chloride are added into reaction flask, sodium hydroxide is added dropwise after mixing evenly
Methanol solution adjusts pH value to 8.5~9.0, and the palladium charcoal of 9g palladium content 2% is added, is done the air displacement in reaction flask with hydrogen
Only, hydrogen is passed through in 25 DEG C~30 DEG C to react 9 hours；To end of reaction, the hydrogen in reaction flask is replaced to clean, mistake with nitrogen
Filter obtains the solution of hydride；
The purification hydrochloric acid that 15g mass percent concentration >=35.0% is added in the lower solution to hydride is stirred at room temperature, in 35 DEG C
~40 DEG C carry out heat preservation hydrolysis 3 hours；To end of reaction, 5 DEG C are cooled to hereinafter, the hydrogen of mass percent concentration 5% is added dropwise
Aqueous solution of sodium oxide adjusts pH value to 6.0~7.0, after evaporated under reduced pressure solvent, is cooled to 5 DEG C hereinafter, to be slowly added into 800ml pure
Water continues to be cooled to 5 DEG C hereinafter, standing 2 hours or more, filtering, washing, obtaining -17 Alpha-Methyl -17 of androstane after stirring 30 minutes
Beta-hydroxy -3- ketone crude product wet feed.Crude product is recrystallized to give to -17 beta-hydroxy of -17 Alpha-Methyl of 20.6g androstane-in industrial alcohol
3- ketone, HPLC purity 99.3%.
Embodiment three
1, prepare compound 3- ethyoxyl-androstane -3,5- diene -17- ketone
100g 4-AD, 100ml triethyl orthoformate, 90ml dehydrated alcohol are added into reaction flask, finishes 30 points of stirring
Then 2g pyridine hydrochloride is added in clock, heat up in 30 DEG C~40 DEG C heat preservations, 9 hours progress etherification reactions；To end of reaction, it is cooled to
5 DEG C hereinafter, dropwise addition triethylamine tune pH value finishes stirring 1 hour to 7.0~7.5；0 DEG C is cooled to hereinafter, filtering, being dried to obtain
102.0g compound 3- ethyoxyl-androstane -3,5- diene -17- ketone.
2, grignard object is prepared
600ml ether, 40.8g magnesium chips are added into reaction flask, stirring is warming up to 30 DEG C, starts from 30 DEG C~32 DEG C and be slowly added dropwise
Iodomethane continues back flow reaction 1 hour, obtained Grignard Reagent until magnesium chips reacts disappearances completely, be cooled to 10 DEG C or less it is spare；
The 102.0g compound 3- ethyoxyl that upper step is reacted-androstane -3,5- diene -17- ketone is added in 400ml toluene,
It stirs 5 minutes and dissolves, 3- ethyoxyl-androstane -3,5- diene -17- ketone toluene solution is added dropwise in above-mentioned grignard reagent, control
10 DEG C~15 DEG C of dropping temperature processed.After dripping, 30 DEG C~35 DEG C progress additions insulation reaction 24 hours are continued at, have been reacted
Finish, normal pressure concentration, the residual paste being concentrated to get cools down, and is added into concentrated residues paste and is cooled to 0 DEG C~5 in advance
DEG C water, finish and continue stirring 2 hours, stand 2 hours or more, filter, wash, being dried to obtain 116.5g grignard object.
3, -17 beta-hydroxy -3- ketone of -17 Alpha-Methyl of prepare compound androstane
25g grignard object, 625ml methanol, 125ml methylene chloride are added into reaction flask, potassium hydroxide is added dropwise after mixing evenly
Methanol solution adjusts pH value to 7.5~8.0, and the palladium charcoal of 2.5g palladium content 2% is added, with hydrogen by the air displacement in reaction flask
Completely, hydrogen is passed through in 35 DEG C~45 DEG C to react 12 hours；To end of reaction, the hydrogen in reaction flask is replaced with nitrogen and is done
Only, the solution of hydride is obtained by filtration；
The purification hydrochloric acid that 25g mass percent concentration >=35.0% is added in the lower solution to hydride is stirred at room temperature, in 30 DEG C
~35 DEG C carry out heat preservation hydrolysis 3 hours；To end of reaction, 5 DEG C are cooled to hereinafter, the hydrogen of mass percent concentration 5% is added dropwise
Aqueous solution of sodium oxide adjusts pH value to 6.0~7.0, after evaporated under reduced pressure solvent, is cooled to 5 DEG C hereinafter, to be slowly added into 800ml pure
Water continues to be cooled to 5 DEG C hereinafter, standing 2 hours or more, filtering, washing, obtaining -17 Alpha-Methyl -17 of androstane after stirring 30 minutes
Beta-hydroxy -3- ketone crude product wet feed.Crude product is recrystallized to give to -17 beta-hydroxy of -17 Alpha-Methyl of 17.0g androstane-in industrial alcohol
3- ketone, HPLC purity 99.5%.
Claims (7)
1. a kind of synthetic method of -17 beta-hydroxy -3- ketone of -17 Alpha-Methyl of furazabol intermediate androstane, which is characterized in that
With 4-AD (abbreviation 4AD) for raw material, it is etherified by 3 ketone group alkene, 17 ketone group grignard additions；Then in grignard
The catalytic hydrogenation reaction for first carrying out 5 ethylene linkages after addition without sour water solution finally carries out 3 alkene ethers and 17 double hydrolysis again
- 17 beta-hydroxy -3- ketone of -17 Alpha-Methyl of compound androstane is prepared；
Step is (1): 4-AD and triethyl orthoformate, dehydrated alcohol are subjected to etherification reaction in the presence of catalyst for etherification,
Compound 3- ethyoxyl-androstane -3,5- diene -17- ketone is prepared；
Step is (2): magnesium chips being put into tetrahydrofuran, ether or 2- methyltetrahydrofuran and is heated up, is then slowly added into methyl halogenated
Grignard Reagent is made until magnesium chips reacts disappearance completely in alkane, cools down spare；By 3- ethyoxyl-androstane -3,5- diene -17- ketone
It is dissolved in organic solvent, then the solution is added dropwise in aforementioned Grignard Reagent and brings it about grignard addition reaction, after dripping,
Heat preservation addition reaction is carried out, most of solvent is removed, water is added dropwise, filters, wash, being dried to obtain grignard object；
Step is (3): grignard object being added dropwise to the methanol solution regulation system pH value of alkali in the mixed solvent, then in palladium carbon catalyst
Under the action of carry out catalytic hydrogenation reaction, end of reaction filters out catalyst, and gained filtrate is the solution of hydride, without going out
Material process, the purification hydrochloric acid that mass percent concentration >=35% is added dropwise into the solution of hydride carry out heat preservation hydrolysis, water again
Solution reaction terminates, and removes solvent, and filtering washes, is dry, being refining to obtain -17 beta-hydroxy -3- ketone of -17 Alpha-Methyl of androstane, and HPLC is pure
99.0% or more degree.
2. a kind of synthesis side of -17 beta-hydroxy -3- ketone of -17 Alpha-Methyl of furazabol intermediate androstane according to claim 1
Method, which is characterized in that step (1) described in catalyst for etherification be pyridine hydrochloride or bromine hydracid pyridine, etherification reaction temperature 30
~50 DEG C；4-AD: triethyl orthoformate: dehydrated alcohol: the proportion of catalyst for etherification is 1W:0.5V~1.0V:0.9V
~1.2V:0.015W~0.020W, wherein W represents g, V and represents ml.
3. a kind of synthesis side of -17 beta-hydroxy -3- ketone of -17 Alpha-Methyl of furazabol intermediate androstane according to claim 2
Method, which is characterized in that (1) middle etherification reaction temperature is 35~45 DEG C to step；4-AD: triethyl orthoformate: anhydrous second
Alcohol: the proportion of catalyst for etherification is 1W:0.6V:1.0V:0.020W, and wherein W represents g, V and represents ml.
4. a kind of synthesis side of -17 beta-hydroxy -3- ketone of -17 Alpha-Methyl of furazabol intermediate androstane according to claim 1
Method, which is characterized in that step (2) described in methyl halogenated alkane select chloromethanes, bromomethane or iodomethane, dissolved compound 3-
Ethyoxyl-androstane -3,5- diene -17- ketone organic solvent selects tetrahydrofuran, toluene or 2- methyltetrahydrofuran, 3- ethoxy
Base-androstane -3,5- diene -17- ketone: the proportion of magnesium chips is 1W:0.4W~0.6W.
5. a kind of synthesis side of -17 beta-hydroxy -3- ketone of -17 Alpha-Methyl of furazabol intermediate androstane according to claim 4
Method, which is characterized in that step (2) in methyl halogenated alkane be chloromethanes, dissolved compound 3- ethyoxyl-androstane -3,5- diene -17-
The organic solvent of ketone is tetrahydrofuran, and 3- ethyoxyl-androstane -3,5- diene -17- ketone: the proportion of magnesium chips is 1W:0.45W.
6. a kind of synthesis side of -17 beta-hydroxy -3- ketone of -17 Alpha-Methyl of furazabol intermediate androstane according to claim 1
Method, which is characterized in that step (3) described in mixed solvent be methanol dichloromethane, in the mixed solvent methanol and methylene chloride
Volume ratio be 1V:0.2~0.3V, alkali be sodium hydroxide or potassium hydroxide, add alkali adjust pH value range be 7.5~9.0；It urges
Changing hydrogenation reaction temperature is 25~40 DEG C；Hydrolysis holding temperature is 30~40 DEG C；Grignard object: mixed solvent: palladium charcoal catalysis
Agent: sour proportion is 1W:25V~30V:0.1W~0.3W:0.5W~1.0W, and wherein W represents g, V and represents ml.
7. a kind of synthesis side of -17 beta-hydroxy -3- ketone of -17 Alpha-Methyl of furazabol intermediate androstane according to claim 6
Method, which is characterized in that step (3) in mixed solvent methanol dichloromethane the volume ratio of methanol and methylene chloride be 1V:0.2V,
The pH value range for adding alkali to adjust is 8.0~8.5, and catalytic hydrogenation reaction temperature is 30~35 DEG C；Hydrolysis holding temperature is 35
~40 DEG C；Grignard object: mixed solvent: palladium carbon catalyst: sour proportion is 1W:30V:0.2W:0.8W, and wherein W represents g, V representative
ml。
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