CN104788529B - The preparation method of 5 α-chloro-androstane-6 β, 19-epoxy-3,17-diketone - Google Patents
The preparation method of 5 α-chloro-androstane-6 β, 19-epoxy-3,17-diketone Download PDFInfo
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- CN104788529B CN104788529B CN201510125492.1A CN201510125492A CN104788529B CN 104788529 B CN104788529 B CN 104788529B CN 201510125492 A CN201510125492 A CN 201510125492A CN 104788529 B CN104788529 B CN 104788529B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 19
- 230000032050 esterification Effects 0.000 claims abstract description 14
- 238000005886 esterification reaction Methods 0.000 claims abstract description 14
- 239000002994 raw material Substances 0.000 claims abstract description 13
- 238000007792 addition Methods 0.000 claims abstract description 11
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 11
- 230000008569 process Effects 0.000 claims abstract description 9
- 230000009467 reduction Effects 0.000 claims abstract description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 50
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 48
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 30
- 238000006243 chemical reaction Methods 0.000 claims description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 25
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 24
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 24
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 16
- 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 16
- 238000001816 cooling Methods 0.000 claims description 11
- 230000003647 oxidation Effects 0.000 claims description 11
- 238000007254 oxidation reaction Methods 0.000 claims description 11
- 230000001590 oxidative effect Effects 0.000 claims description 11
- 238000003756 stirring Methods 0.000 claims description 11
- OSVMTWJCGUFAOD-KZQROQTASA-N formestane Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1O OSVMTWJCGUFAOD-KZQROQTASA-N 0.000 claims description 10
- 238000006722 reduction reaction Methods 0.000 claims description 10
- 238000010992 reflux Methods 0.000 claims description 10
- YRIZYWQGELRKNT-UHFFFAOYSA-N 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione Chemical compound ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O YRIZYWQGELRKNT-UHFFFAOYSA-N 0.000 claims description 9
- 239000007800 oxidant agent Substances 0.000 claims description 9
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 claims description 9
- 235000019345 sodium thiosulphate Nutrition 0.000 claims description 9
- 229950009390 symclosene Drugs 0.000 claims description 9
- MENYRYNFSIBDQN-UHFFFAOYSA-N 5,5-dibromoimidazolidine-2,4-dione Chemical compound BrC1(Br)NC(=O)NC1=O MENYRYNFSIBDQN-UHFFFAOYSA-N 0.000 claims description 8
- 239000004342 Benzoyl peroxide Substances 0.000 claims description 8
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- 235000019400 benzoyl peroxide Nutrition 0.000 claims description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 8
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 8
- 239000012279 sodium borohydride Substances 0.000 claims description 8
- MECHNRXZTMCUDQ-RKHKHRCZSA-N vitamin D2 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)/C=C/[C@H](C)C(C)C)=C\C=C1\C[C@@H](O)CCC1=C MECHNRXZTMCUDQ-RKHKHRCZSA-N 0.000 claims description 8
- 239000007864 aqueous solution Substances 0.000 claims description 7
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 6
- QADHLRWLCPCEKT-UHFFFAOYSA-N Androstenediol Natural products C1C(O)CCC2(C)C3CCC(C)(C(CC4)O)C4C3CC=C21 QADHLRWLCPCEKT-UHFFFAOYSA-N 0.000 claims description 6
- QADHLRWLCPCEKT-LOVVWNRFSA-N androst-5-ene-3beta,17beta-diol Chemical compound C1[C@@H](O)CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC=C21 QADHLRWLCPCEKT-LOVVWNRFSA-N 0.000 claims description 6
- 239000011630 iodine Substances 0.000 claims description 6
- 229910052740 iodine Inorganic materials 0.000 claims description 6
- 239000012044 organic layer Substances 0.000 claims description 6
- 239000000243 solution Substances 0.000 claims description 6
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims description 4
- QXKRUGDXPWHXHL-FQJIPJFPSA-N [(3s,8r,9s,10r,13s,14s,17s)-17-acetyloxy-10,13-dimethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthren-3-yl] acetate Chemical compound C1C=C2C[C@@H](OC(C)=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](OC(=O)C)[C@@]1(C)CC2 QXKRUGDXPWHXHL-FQJIPJFPSA-N 0.000 claims description 4
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 claims description 4
- 230000007935 neutral effect Effects 0.000 claims description 3
- 239000002699 waste material Substances 0.000 claims description 3
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 2
- 238000000605 extraction Methods 0.000 claims 1
- 235000013311 vegetables Nutrition 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 7
- 239000000460 chlorine Substances 0.000 abstract description 5
- 229910052801 chlorine Inorganic materials 0.000 abstract description 5
- 230000007613 environmental effect Effects 0.000 abstract description 2
- 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 abstract 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 abstract 3
- 239000004593 Epoxy Substances 0.000 abstract 3
- 125000005594 diketone group Chemical group 0.000 abstract 3
- 230000009977 dual effect Effects 0.000 abstract 1
- 150000002085 enols Chemical class 0.000 abstract 1
- 238000001914 filtration Methods 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 239000012265 solid product Substances 0.000 description 6
- 238000000967 suction filtration Methods 0.000 description 5
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- DWCSNWXARWMZTG-UHFFFAOYSA-N Trigonegenin A Natural products CC1C(C2(CCC3C4(C)CCC(O)C=C4CCC3C2C2)C)C2OC11CCC(C)CO1 DWCSNWXARWMZTG-UHFFFAOYSA-N 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- WQLVFSAGQJTQCK-VKROHFNGSA-N diosgenin Chemical compound O([C@@H]1[C@@H]([C@]2(CC[C@@H]3[C@@]4(C)CC[C@H](O)CC4=CC[C@H]3[C@@H]2C1)C)[C@@H]1C)[C@]11CC[C@@H](C)CO1 WQLVFSAGQJTQCK-VKROHFNGSA-N 0.000 description 3
- WQLVFSAGQJTQCK-UHFFFAOYSA-N diosgenin Natural products CC1C(C2(CCC3C4(C)CCC(O)CC4=CCC3C2C2)C)C2OC11CCC(C)CO1 WQLVFSAGQJTQCK-UHFFFAOYSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 230000008707 rearrangement Effects 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 150000003431 steroids Chemical class 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- MZWRIOUCMXPLKV-RFOVXIPZSA-N 16-Dehydropregnenolone acetate Chemical compound C([C@@H]12)C[C@]3(C)C(C(C)=O)=CC[C@H]3[C@@H]1CC=C1[C@]2(C)CC[C@H](OC(=O)C)C1 MZWRIOUCMXPLKV-RFOVXIPZSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- 241000374766 Dioscorea panthaica Species 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- WGLPBDUCMAPZCE-UHFFFAOYSA-N Trioxochromium Chemical group O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- VKHAHZOOUSRJNA-GCNJZUOMSA-N mifepristone Chemical compound C1([C@@H]2C3=C4CCC(=O)C=C4CC[C@H]3[C@@H]3CC[C@@]([C@]3(C2)C)(O)C#CC)=CC=C(N(C)C)C=C1 VKHAHZOOUSRJNA-GCNJZUOMSA-N 0.000 description 2
- 229960003248 mifepristone Drugs 0.000 description 2
- VIKNJXKGJWUCNN-XGXHKTLJSA-N norethisterone Chemical class O=C1CC[C@@H]2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 VIKNJXKGJWUCNN-XGXHKTLJSA-N 0.000 description 2
- KIQQMECNKUGGKA-NMYWJIRASA-N norgestimate Chemical compound O/N=C/1CC[C@@H]2[C@H]3CC[C@](CC)([C@](CC4)(OC(C)=O)C#C)[C@@H]4[C@@H]3CCC2=C\1 KIQQMECNKUGGKA-NMYWJIRASA-N 0.000 description 2
- 229960000417 norgestimate Drugs 0.000 description 2
- 238000000643 oven drying Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- BTTWKVFKBPAFDK-UHFFFAOYSA-N (9beta,10alpha)-Androst-4-ene-3,17-dione Natural products OC1CCC2(C)C3CCC(C)(C(CC4)O)C4C3CCC2=C1 BTTWKVFKBPAFDK-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- JRIZOGLBRPZBLQ-QXUSFIETSA-N 19-Norandrostenedione Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 JRIZOGLBRPZBLQ-QXUSFIETSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- RVWUHFFPEOKYLB-UHFFFAOYSA-N 2,2,6,6-tetramethyl-1-oxidopiperidin-1-ium Chemical compound CC1(C)CCCC(C)(C)[NH+]1[O-] RVWUHFFPEOKYLB-UHFFFAOYSA-N 0.000 description 1
- 238000006237 Beckmann rearrangement reaction Methods 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 235000009926 Dioscorea panthaica Nutrition 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- QXKRUGDXPWHXHL-JBBZJTNDSA-N [(8r,9s,10r,13s,14s)-17-acetyloxy-10,13-dimethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthren-3-yl] acetate Chemical compound C1C=C2CC(OC(C)=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CCC(OC(=O)C)[C@@]1(C)CC2 QXKRUGDXPWHXHL-JBBZJTNDSA-N 0.000 description 1
- 239000002253 acid 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
- 239000006227 byproduct Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 239000003433 contraceptive agent Substances 0.000 description 1
- 230000002254 contraceptive effect Effects 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 150000001993 dienes Chemical class 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- -1 terasterone Chemical compound 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
- C07J71/0005—Oxygen-containing hetero ring
- C07J71/001—Oxiranes
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Abstract
The present invention proposes a kind of 5 α chlorine androstane 6 β, the preparation method of 19 epoxy 3,17 diketone, with 4 AD as raw material, be esterified through 3 enols, reduction, 3,17 double esterifications, 5,6 additions, 6,19 cyclizations, 3,17 dual oxide six-step processes, prepare 5 α chlorine androstane 6 β, 19 epoxy 3,17 diketone.The abundant raw material source of preparation method of the present invention, environmental friendliness, and cheap, building-up process yield is higher, 5 obtained α chlorine androstane 6 β, and 19 epoxy 3,17 diketone can be applicable to produce series family planning medicine.
Description
Technical Field
The invention belongs to the technical field of organic compound preparation, relates to a preparation method of an important intermediate of a 19-hydroxy steroid and a 19-nor steroid compound, and particularly relates to a preparation method of 5 alpha-chloro-androstane-6 beta, 19-epoxy-3, 17-diketone.
Background
The compound 5 alpha-chloro-androstane-6 beta, 19-epoxy-3, 17-dione is an important intermediate for preparing 19-hydroxy steroids and 19-nor steroids, and shows important application value in the preparation of birth control medicines, such as an anti-early pregnancy medicine mifepristone, contraceptive medicines norethisterone series, terasterone, norgestimate and the like.
For past decades, most of 19-hydroxysteroids and 19-norsteroids are industrially prepared from pregna-5, 16-diene-3 β -ol acetate (commonly known as dehydropregnenolone acetate) by Beckmann rearrangement of ketoxime to obtain androst-5-ene-17-one-3 β -ol acetate (commonly known as a rearrangement).
The rearrangement substances are subjected to 5, 6-site addition to generate corresponding 5 alpha-chlorine (or bromine) -androstane-6 beta, 19-epoxy-3 beta-alcohol-17-ketone, then 5 alpha-chlorine (or bromine) -androstane-6 beta, 19-epoxy-3, 17-diketone is obtained through oxidation, and then the synthesis of 19-hydroxy steroid and series 19-nor steroid compounds can be realized through the steps of ring opening, oxidation, decarboxylation and the like.
CN101948495 reports a synthesis method of 19-nor-androst-4-ene-3, 17-dione, which relates to a step of preparing an intermediate 5 α -chloro-androst-6 β, 19-epoxy-3 β -ol-17-dione by oxidizing 5 α -chloro-androst-6 β, 19-epoxy-17-one with a catalytic amount of 2,2,6, 6-tetramethylpiperidine-N-oxide.
CN102443038, in the synthesis method of 6 beta, 19-epoxy-androst-4-ene-3, 17-dione, rearrangements are subjected to a bromoalcoholization or chlorohydrination reaction with a bromization reagent or a chlorination reagent in the presence of acid to generate 5 alpha-bromo-androst-6 beta-hydroxy-17-one-3 beta-ol acetate or 5 alpha-chloro-androst-6 beta-hydroxy-17-one-3 beta-ol acetate, and then cyclization is performed under the condition of illumination to obtain 5 alpha-bromo-androst-6 beta, 19-epoxy-3 beta-ol-17-one or 5 alpha-chloro-androst-6 beta, 19-epoxy-3 beta-ol-17-one, and further oxidation to obtain 5 alpha-bromo-androst-6 beta, 19-epoxy-3, 17-dione or 5 alpha-chloro-androstane-6 beta, 19-epoxy-3, 17-dione.
The dehydropregnenolone acetate is obtained from a natural product diosgenin, which is derived from a plant dioscorea panthaica, and the dioscorea panthaica not only requires about three years for the production period, but also causes serious environmental pollution in the process of extracting the diosgenin; with the increasing environmental pressure in recent years, the price of diosgenin is increased dramatically, and the substitution of steroid raw materials is imperative. Androst-4-ene-3, 17 dione (4-AD for short) generated by fermenting soybean oil by-product has abundant and easily available raw material source and about half of the cost of diene, so that the development of a new method for preparing steroid medicines and important intermediates thereof by using 4-AD as raw material is a key point and a hot spot of recent steroid field research.
Disclosure of Invention
The invention aims to solve the technical problem of providing a method for preparing 5 alpha-chlorine-androstane-6 beta, 19-epoxy-3, 17-diketone. The invention solves the problems of expensive raw materials and environment in the raw material obtaining process in the prior preparation of 5 alpha-chloro-androstane-6 beta, 19-epoxy-3, 17-diketone by the following technical scheme.
The invention provides a preparation method of 5 alpha-chloro-androstane-6 beta, 19-epoxy-3, 17-diketone, which takes 4-AD as a raw material to prepare the 5 alpha-chloro-androstane-6 beta, 19-epoxy-3, 17-diketone through six steps of 3-enol esterification, reduction, 3, 17-diester, 5, 6-addition, 6, 19-cyclization and 3, 17-double oxidation.
The reaction process of the above preparation method of the present invention is as follows:
the invention comprises the following steps:
1) in the step of esterifying the 3-enol, 4-AD, acetic anhydride and p-toluenesulfonic acid are added into a reaction vessel for reaction to obtain androstane-3, 5-diene-17-ketone-3 beta-alcohol acetate;
2) in the reduction step, androstane-3, 5-diene-17-ketone-3 beta-alcohol acetate and methanol obtained in the previous step are added into a reaction container, sodium borohydride is added, and androstane-5-alkene-3 beta, 17 beta-diol is obtained through reduction reaction;
3) in the step of 3, 17-site double esterification, androstane-5-ene-3 beta, 17 beta-diol, toluene, acetic anhydride and pyridine obtained in the step are added into a reaction vessel to react to obtain androstane-5-ene-3, 17-diol diacetate;
4) in the step of 5, 6-position addition, androstane-5-alkene-3 beta, 17 beta-diol diacetate, acetone and water are added into a reaction container, trichloroisocyanuric acid/acetone solution is dripped, and 5 alpha-chloro-androstane-6 beta-hydroxy-3 beta, 17 beta-diol diacetate is obtained after reaction;
5) in the 6, 19-position cyclization step, sequentially adding 5 alpha-chloro-androstane-6 beta-hydroxy-3 beta, 17 beta-diol diacetate, dibromohydantoin, anhydrous sodium carbonate, benzoyl peroxide, iodine and benzene, carrying out reflux reaction, adding an aqueous solution of sodium thiosulfate, stirring, standing for layering, adding potassium hydroxide and ethanol into an organic layer for reflux reaction, cooling to room temperature, adjusting the pH value to be neutral, and layering to obtain 5 alpha-chloro-androstane-6 beta, 19-epoxy-3 beta, 17 beta-diol;
6) and in the step of 3, 17-site double oxidation, adding 5 alpha-chloro-androstane-6 beta, 19-epoxy-3 beta, 17 beta-diol and acetone, dropwise adding an oxidant, and dropwise adding an aqueous solution of sodium bisulfite to obtain 5 alpha-chloro-androstane-6 beta, 19-epoxy-3, 17-dione.
Wherein, the source of the raw material 4-AD is as follows: the waste produced in the process of extracting natural vegetable oil is obtained by fermentation.
Wherein, in the 3-enol esterification step, 4-AD: acetic anhydride: the mass ratio of the p-toluenesulfonic acid is 150: 250-375: 7-8.
In the reduction step, the androsta-3, 5-diene-17-one-3 beta-ol acetate: methanol: the weight ratio of the sodium borohydride is 68: 900-1200: 25-28.
In the step of 3, 17-site double esterification, the androst-5-ene-3 beta, 17 beta-diol: toluene: acetic anhydride: the weight ratio of the pyridine is 5: 20-30: 5-8: 2-6.
In the step of 5, 6-position addition, androstane-5-alkene-3 beta, 17 beta-diol diacetate: acetone: water: the weight ratio of trichloroisocyanuric acid is 63:1100-1500: 60-90: 16-18.
In the 6, 19-position cyclization step, the 5 alpha-chloro androstane-6 beta-hydroxy-3 beta, 17 beta-diol diacetate: dibromohydantoin: the weight ratio of the anhydrous sodium carbonate to the benzoyl peroxide to the iodine to the benzene to the sodium thiosulfate to the potassium hydroxide to the ethanol is 40: 20-22: 18-22: 3.5-4.2: 3-5: 500-600: 10-15: 13-15: 80-120.
In the step of double oxidation of 3, 17-position, the 5 alpha-chloro-androstane-6 beta, 19-epoxy-3 beta, 17 beta-diol: acetone: the weight ratio of the oxidant is 1: 9-15: 5-6.
The synthesis method of 5 alpha-chloro-androstane-6 beta, 19-epoxy-3, 17-dione of the present invention is now described in detail, comprising the following steps:
first step 3-enol esterification
Respectively adding 4-AD, acetic anhydride and p-toluenesulfonic acid into a three-neck flask, reacting for 12 hours at 35-45 ℃, and finishing the thin-layer chromatography detection reaction. Cooling to 0-5 deg.c, adding into ice water and stirring for 10 min. Filtering, drying to obtain the solid product androstane-3, 5-diene-17-ketone-3 beta-alcohol acetate.
In the first step, the 4-AD: acetic anhydride: the mass ratio of the p-toluenesulfonic acid is 150: 250-375: 7-8. Preferably, the mass ratio of the 4-AD to the acetic anhydride to the p-toluenesulfonic acid is 20:40: 1.
Second reduction
Adding androstane-3, 5-diene-17-ketone-3 beta-alcohol acetate and methanol into a three-neck flask, stirring, cooling to 0-5 ℃, adding sodium borohydride, reacting at 10-22 ℃ for 10-14 hours, recovering the solvent, adding water, stirring for 20min, performing suction filtration, and recrystallizing the methanol to obtain a white solid product androstane-5-ene-3 beta, 17 beta-diol.
In the second step, the androsta-3, 5-diene-17-one-3 β -ol acetate: methanol: the weight ratio of the sodium borohydride is 68: 900-1200: 25-28. Preferably, the weight ratio of the androst-3, 5-diene-17-one-3 beta-ol acetate to the methanol to the sodium borohydride is 23:300-350: 9.
Third step of 3, 17-position double esterification
Androstane-5-alkene-3 beta, 17 beta-diol, toluene, acetic anhydride and pyridine are respectively added into a single-mouth bottle, and reflux reaction is carried out for 3 hours. Recovering toluene, adding water, stirring for 30min, vacuum filtering, and oven drying to obtain androstane-5-ene-3 beta, 17 beta-diol diacetate.
In the third step, the androst-5-ene-3 β,17 β -diol: toluene: acetic anhydride: the weight ratio of the pyridine is 5: 20-30: 5-8: 2-6. Preferably, the androst-5-ene-3 β,17 β -diol: toluene: acetic anhydride: the weight ratio of the pyridine is 5:22-25:5-7: 2-5.
Fourth step 5, 6-bit addition
Adding androstane-5-ene-3 beta, 17 beta-diol diacetate, acetone and water into a three-necked bottle, cooling to-40 ℃, dropwise adding trichloroisocyanuric acid/acetone solution, keeping the temperature until the reaction is finished after the dropwise adding is finished, recovering the acetone, adding water, performing suction filtration, and recrystallizing ethyl acetate to obtain 5 alpha-chloro-androstane-6 beta-hydroxy-3 beta, 17 beta-diol diacetate.
In the fourth step, androst-5-ene-3 β,17 β -diol diacetate: acetone: water: the weight ratio of trichloroisocyanuric acid is 63:1100-1500: 60-90: 16-18. Preferably, the androst-5-ene-3 β,17 β -diol diacetate: acetone: water: the weight ratio of trichloroisocyanuric acid is 63:1100-1500:75: 17.
The fifth step is 6, 19-position cyclization
5 alpha-chlorine-androstane-6 beta-hydroxyl-3 beta, 17 beta-diol diacetate, dibromohydantoin, anhydrous sodium carbonate, benzoyl peroxide, iodine and benzene are sequentially added into a three-necked bottle. Refluxing for 5-7 h, cooling to 30 ℃ after the reaction is finished, adding a sodium thiosulfate aqueous solution, stirring for 30 minutes, standing for layering, adding potassium hydroxide and ethanol into an organic layer, refluxing for 45 minutes, cooling to room temperature, adjusting the pH value to be neutral, layering, removing a solvent from the organic layer, adding water, filtering, washing with water, and drying to obtain a solid product 5 alpha-chloro-androstane-6 beta, 19-epoxy-3 beta, 17 beta-diol.
In the fifth step, the 5 alpha-chloro-androstane-6 beta-hydroxy-3 beta, 17 beta-diol diacetate comprises dibromohydantoin, anhydrous sodium carbonate, benzoyl peroxide, iodine, benzene, sodium thiosulfate and potassium hydroxide: the weight ratio of the ethanol is 40: 20-22: 18-22: 3.5-4.2: 3-5: 500-600: 10-15: 13-15: 80-120. Preferably, the weight ratio of the 5 alpha-chloro-androstane-6 beta-hydroxy-3 beta, 17 beta-diol diacetate to the dibromohydantoin to the anhydrous sodium carbonate to the benzoyl peroxide to the iodine to the benzene to the sodium thiosulfate to the water to the potassium hydroxide to the ethanol is 20:10:10:2:2:250-300:6:7: 40-50.
Sixth step 3, 17-position double oxidation
Adding 5 alpha-chloro-androstane-6 beta, 19-epoxy-3 beta, 17 beta-diol and acetone into a three-necked bottle, cooling to 10 ℃, dropwise adding an oxidant, keeping the temperature for reaction for 1 hour after dropwise adding, and dropwise adding a sodium bisulfite aqueous solution. Recovering acetone, adding water, filtering, washing, and drying to obtain yellowish crystalline solid 5 alpha-chloro-androstane-6 beta, 19-epoxy-3, 17-dione.
In the sixth step, the 5 α -chloro-androstane-6 β, 19-epoxy-3 β,17 β -diol: acetone: the weight ratio of the oxidant is 1: 9-15: 5-6. Preferably, the 5 α -chloro-androst-6 β, 19-epoxy-3 β,17 β -diol: acetone: the weight ratio of the oxidant is 3:30-40: 15.
The raw material source of the preparation method is extremely rich, the environment is friendly, the price is low, the yield of the synthesis process is high, and the obtained 5 alpha-chloro-androstane-6 beta, 19-epoxy-3, 17-diketone can be applied to the production of series family planning medicaments such as mifepristone, norethisterone series, terasterone, norgestimate and other medicaments.
Drawings
FIG. 1 shows the NMR spectrum (400MHz, CDCl) of 5 α -chloro-androstane-6 β, 19-epoxy-3, 17-dione prepared in example3)。
FIG. 2 shows the NMR carbon spectrum (100MHz, CDCl) of 5 α -chloro-androstane-6 β, 19-epoxy-3, 17-dione prepared in example3)。
Detailed Description
The present invention will be described in further detail with reference to the following specific examples, but the present invention is not limited to the following examples. Variations and advantages that may occur to those skilled in the art may be incorporated into the invention without departing from the spirit and scope of the inventive concept, and the scope of the appended claims is intended to be protected. The procedures, conditions, reagents, experimental methods and the like for carrying out the present invention are general knowledge and common general knowledge in the art except for the contents specifically mentioned below, and the present invention is not particularly limited.
Example 1: method for preparing 5 alpha-chloro-androstane-6 beta, 19-epoxy-3, 17-dione
4-AD obtained from wastes in the process of extracting natural vegetable oil is taken as a raw material, and 5 alpha-chloro-androstane-6 beta, 19-epoxy-3, 17-diketone is prepared by six steps of esterification of 3-enol, reduction, 3, 17-diester, 5, 6-addition, 6, 19-cyclization and 3, 17-double oxidation. The method specifically comprises the following steps:
first step 3-enol esterification
120ml of acetic anhydride, 3g of p-toluenesulfonic acid and 60g of 4-AD are added into a three-neck flask, and the reaction is carried out for 12 hours at the temperature of 35-45 ℃. The temperature is reduced to 0 ℃ to 5 ℃, and the mixture is added into 240ml of ice water and stirred for 10 minutes. Filtering, drying to obtain 68g of solid product androstane-3, 5-diene-17-ketone-3 beta-alcohol acetate. The yield thereof was found to be 99%.
Second reduction
68g of androstane-3, 5-diene-17-ketone-3 beta-alcohol acetate and 1220ml of methanol are added into a three-neck flask, the temperature is reduced to 0-5 ℃ under stirring, and 27g of sodium borohydride is added. Reacting at 10-22 ℃ for 10-14 hours, recovering the solvent, adding 600ml of water, stirring for 20min, carrying out suction filtration, adding 290ml of methanol into the obtained crude product, and recrystallizing to obtain 50g of a white solid product androst-5-ene-3 beta, 17 beta-diol. The yield thereof was found to be 83%.
Third step of 3, 17-position double esterification
50g of androst-5-ene-3 beta, 17 beta-diol, 250ml of toluene, 50ml of acetic anhydride and 25ml of pyridine are added into a single-mouth bottle, and reflux reaction is carried out for 3 hours. Recovering toluene, adding 300ml water, stirring for 30min, filtering, and oven drying to obtain 62.8g androst-5-ene-3 beta, 17 beta-diol diacetate. The yield thereof was found to be 97%.
Fourth step 5, 6-bit addition
Adding 62.8g of androstane-5-ene-3 beta, 17 beta-diol diacetate, 1400ml of acetone and 75ml of water into a three-necked bottle, cooling to-40 ℃, dropwise adding trichloroisocyanuric acid/acetone solution (17g of trichloroisocyanuric acid/160 ml of acetone), keeping the temperature for 2.5-5 h after dropwise adding, recovering the acetone, adding 640ml of water, performing suction filtration, and recrystallizing the obtained solid with ethyl acetate to obtain 50g of 5 alpha-chloro-androstane-6 beta-hydroxy-3 beta, 17 beta-diol diacetate. Yield: 70 percent.
The fifth step is 6, 19-position cyclization
40g of 5 alpha-chlorine-androstane-6 beta-hydroxy-3 beta, 17 beta-diol diacetate, 20g of dibromohydantoin, 20g of anhydrous sodium carbonate, 4g of benzoyl peroxide, 4g of iodine and 600ml of benzene are sequentially added into a three-necked bottle. Refluxing for 5-7 hours, cooling to 30 ℃ after the reaction is finished, adding a sodium thiosulfate aqueous solution (12g of sodium thiosulfate/200 ml of water) and stirring for 30 minutes, standing for layering, adding 14g of potassium hydroxide and 100ml of ethanol into an organic layer, refluxing for reaction for 45 minutes, cooling to room temperature, layering, removing a solvent from the organic layer, adding water, filtering, washing with water, and drying a filter cake to obtain 31g of a solid product, namely 5 alpha-chloro-androstane-6 beta, 19-epoxy-3 beta, 17 beta-diol. Yield: 97 percent.
Sixth step 3, 17-position double oxidation
30g of 5 α -chloro-androstane-6 β, 19-epoxy-3 β,17 β -diol and 450ml of acetone are added into a three-mouth bottle, the temperature is reduced to 10 ℃, 150g of oxidant (the proportion of the oxidant is chromic anhydride/water/sulfuric acid is 1/2.7/1.67) is dripped, after the dripping is finished, the heat preservation reaction is carried out for 1h, 20% of sodium bisulfite water solution is dripped until the reaction solution does not change blue through potassium iodide starch test paper detection, the acetone is concentrated, water is added for suction filtration, water washing and drying are carried out, and 27g of light yellow crystalline solid 5 α -chloro-androstane-6 β, 19-epoxy-3, 17-diketone are obtained, wherein the yield is 91%.1HNMR(400MHz,CDCl3):4.16(d,1H,J＝8.8Hz),4.04-4.01(m,2H),3.15(d,1H,J＝15.1Hz),2.67(d,1H,J＝15.1Hz),2.51-2.38(m,3H),2.17-1.76(m,9H),1.62-1.54(m,3H),1.39-1.23(m,2H),0.94(s,3H).13C NMR(100MHz,CDCl3):219.68,206.10,81.38,76.72,68.13,50.55,49.33,48.13,46.80,46.25,36.66,35.66,32.86,31.36,30.47,25.10,21.66,21.30,14.15.HRMS(ESI):calcd C19H26ClO3337.1570[M+H]+,found 337.1563。
Claims (8)
1. A preparation method of 5 alpha-chloro-androstane-6 beta, 19-epoxy-3, 17-diketone is characterized in that 4-AD is used as a raw material, and the 5 alpha-chloro-androstane-6 beta, 19-epoxy-3, 17-diketone is prepared through six steps of esterification of 3-enol, reduction, double esterification of 3, 17-position, addition of 5, 6-position, 6, 19-cyclization and double oxidation of 3, 17-position; the reaction process is as follows:
wherein,
1) in the step of esterifying the 3-enol, 4-AD, acetic anhydride and p-toluenesulfonic acid are added into a reaction vessel for reaction to obtain androstane-3, 5-diene-17-ketone-3 beta-alcohol acetate;
2) in the reduction step, androstane-3, 5-diene-17-ketone-3 beta-alcohol acetate and methanol obtained in the previous step are added into a reaction container, sodium borohydride is added, and androstane-5-alkene-3 beta, 17 beta-diol is obtained through reduction reaction;
3) in the step of 3, 17-site double esterification, androstane-5-alkene-3 beta, 17 beta-diol, toluene, acetic anhydride and pyridine obtained in the step are added into a reaction vessel to react to obtain androstane-5-alkene-3 beta, 17 beta-diol diacetate;
4) in the step of 5, 6-position addition, androstane-5-alkene-3 beta, 17 beta-diol diacetate, acetone and water are added into a reaction container, trichloroisocyanuric acid/acetone solution is dripped, and 5 alpha-chloro-androstane-6 beta-hydroxy-3 beta, 17 beta-diol diacetate is obtained after reaction;
5) in the 6, 19-position cyclization step, sequentially adding 5 alpha-chloro-androstane-6 beta-hydroxy-3 beta, 17 beta-diol diacetate, dibromohydantoin, anhydrous sodium carbonate, benzoyl peroxide, iodine and benzene, carrying out reflux reaction, adding a sodium thiosulfate aqueous solution, stirring, standing for layering, adding potassium hydroxide and ethanol into an organic layer for reflux reaction, cooling to room temperature, adjusting the pH value to be neutral, and layering to obtain 5 alpha-chloro-androstane-6 beta, 19-epoxy-3 beta, 17 beta-diol;
6) and in the step of 3, 17-site double oxidation, adding 5 alpha-chloro-androstane-6 beta, 19-epoxy-3 beta, 17 beta-diol and acetone, dropwise adding an oxidant, and dropwise adding an aqueous solution of sodium bisulfite to obtain 5 alpha-chloro-androstane-6 beta, 19-epoxy-3, 17-dione.
2. The method according to claim 1, wherein the raw material 4-AD is 4-AD obtained from waste in a natural vegetable oil-and-fat extraction process.
3. The process according to claim 1, wherein in the 3-enol esterification step, the ratio of 4-AD: acetic anhydride: the mass ratio of the p-toluenesulfonic acid is 150: 250-375: 7-8.
4. The method of claim 1, wherein in the reducing step, the ratio of androsta-3, 5-dien-17-one-3 β -ol acetate: methanol: the weight ratio of the sodium borohydride is 68: 900-1200: 25-28.
5. The process of claim 1, wherein in the step of di-esterifying at the 3, 17-position, the ratio of androst-5-ene-3 β,17 β -diol: toluene: acetic anhydride: the weight ratio of the pyridine is 5: 20-30: 5-8: 2-6.
6. The method of claim 1, wherein in the 5, 6-position addition step, androst-5-ene-3 β,17 β -diol diacetate: acetone: water: the weight ratio of trichloroisocyanuric acid is 63:1100-1500: 60-90: 16-18.
7. The method according to claim 1, wherein in the 6, 19-position cyclization step, the 5 α -chloro-androst-6 β -hydroxy-3 β,17 β -diol diacetate, dibromohydantoin, anhydrous sodium carbonate, benzoyl peroxide, iodine, benzene, sodium thiosulfate, potassium hydroxide: the weight ratio of the ethanol is 40: 20-22: 18-22: 3.5-4.2: 3-5: 500-600: 10-15: 13-15: 80-120.
8. The method of claim 1, wherein in the step of double oxidizing the 3, 17-position, the ratio of 5 α -chloro-androstane-6 β, 19-epoxy-3 β,17 β -diol: acetone: the weight ratio of the oxidant is 1: 9-15: 5-6.
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