CN114057819A - Method for recovering desogestrel recrystallization mother liquor - Google Patents
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- CN114057819A CN114057819A CN202111312845.0A CN202111312845A CN114057819A CN 114057819 A CN114057819 A CN 114057819A CN 202111312845 A CN202111312845 A CN 202111312845A CN 114057819 A CN114057819 A CN 114057819A
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- methyl
- desogestrel
- beta
- mother liquor
- methyleneestra
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- RPLCPCMSCLEKRS-BPIQYHPVSA-N desogestrel Chemical compound C1CC[C@@H]2[C@H]3C(=C)C[C@](CC)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 RPLCPCMSCLEKRS-BPIQYHPVSA-N 0.000 title claims abstract description 42
- 229960004976 desogestrel Drugs 0.000 title claims abstract description 42
- 239000012452 mother liquor Substances 0.000 title claims abstract description 31
- 238000001953 recrystallisation Methods 0.000 title claims abstract description 28
- 238000000034 method Methods 0.000 title claims abstract description 22
- 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 abstract description 41
- 230000009467 reduction Effects 0.000 claims abstract description 9
- 238000006722 reduction reaction Methods 0.000 claims abstract description 9
- 238000006027 Birch reduction reaction Methods 0.000 claims abstract description 6
- 230000008030 elimination Effects 0.000 claims abstract description 5
- 238000003379 elimination reaction Methods 0.000 claims abstract description 5
- 230000007062 hydrolysis Effects 0.000 claims abstract description 5
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 5
- 230000031709 bromination Effects 0.000 claims abstract description 4
- 238000005893 bromination reaction Methods 0.000 claims abstract description 4
- 230000015556 catabolic process Effects 0.000 claims abstract description 4
- 238000006731 degradation reaction Methods 0.000 claims abstract description 4
- 230000032050 esterification Effects 0.000 claims abstract description 3
- 238000005886 esterification reaction Methods 0.000 claims abstract description 3
- 239000000203 mixture Substances 0.000 claims description 25
- 238000006243 chemical reaction Methods 0.000 claims description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 20
- 239000002904 solvent Substances 0.000 claims description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 13
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 239000000010 aprotic solvent Substances 0.000 claims description 9
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 239000003513 alkali Substances 0.000 claims description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 6
- SMUQFGGVLNAIOZ-UHFFFAOYSA-N quinaldine Chemical compound C1=CC=CC2=NC(C)=CC=C21 SMUQFGGVLNAIOZ-UHFFFAOYSA-N 0.000 claims description 6
- 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 6
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 229910021529 ammonia Inorganic materials 0.000 claims description 4
- 229940125904 compound 1 Drugs 0.000 claims description 4
- 150000007530 organic bases Chemical class 0.000 claims description 4
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- JQRYUMGHOUYJFW-UHFFFAOYSA-N pyridine;trihydrobromide Chemical compound [Br-].[Br-].[Br-].C1=CC=[NH+]C=C1.C1=CC=[NH+]C=C1.C1=CC=[NH+]C=C1 JQRYUMGHOUYJFW-UHFFFAOYSA-N 0.000 claims description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 3
- 239000012279 sodium borohydride Substances 0.000 claims description 3
- 238000003786 synthesis reaction Methods 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- UTBIMNXEDGNJFE-UHFFFAOYSA-N collidine Natural products CC1=CC=C(C)C(C)=N1 UTBIMNXEDGNJFE-UHFFFAOYSA-N 0.000 claims description 2
- 229940125782 compound 2 Drugs 0.000 claims description 2
- 229940126214 compound 3 Drugs 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims description 2
- 238000005984 hydrogenation reaction Methods 0.000 claims description 2
- 238000006317 isomerization reaction Methods 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 239000007858 starting material Substances 0.000 claims description 2
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 238000002425 crystallisation Methods 0.000 abstract description 4
- 230000008025 crystallization Effects 0.000 abstract description 4
- 230000007613 environmental effect Effects 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- 239000002699 waste material Substances 0.000 abstract description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 238000003756 stirring Methods 0.000 description 6
- 229960000583 acetic acid Drugs 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000006392 deoxygenation reaction Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- KVNYZZFGXXHVMG-CAVMOMJPSA-N (8s,9s,10r,13s,14s)-13-ethyl-11-methylidene-1,2,3,6,7,8,9,10,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-17-one Chemical compound C1CC[C@@H]2[C@H]3C(=C)C[C@](CC)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 KVNYZZFGXXHVMG-CAVMOMJPSA-N 0.000 description 1
- 238000011925 1,2-addition Methods 0.000 description 1
- -1 18-methyl-11-methyleneestr-3-en-17-one Chemical compound 0.000 description 1
- DZPCYXCBXGQBRN-UHFFFAOYSA-N 2,5-Dimethyl-2,4-hexadiene Chemical group CC(C)=CC=C(C)C DZPCYXCBXGQBRN-UHFFFAOYSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N ethyl acetate Substances CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 150000002642 lithium compounds Chemical class 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 229940127234 oral contraceptive Drugs 0.000 description 1
- 239000003539 oral contraceptive agent Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000000583 progesterone congener Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 150000005691 triesters Chemical class 0.000 description 1
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Classifications
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- 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
- C07J1/0051—Estrane derivatives
- C07J1/0066—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa
- C07J1/007—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa the substituent being an OH group free esterified or etherified
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Abstract
The invention belongs to the field of organic chemistry, and particularly relates to a method for recovering desogestrel recrystallization mother liquor, aiming at the problem that the content ratio of delta 3 isomer to desogestrel in the existing crystallization mother liquor is up to 40: after 60, the desogestrel cannot be further recovered by a common recrystallization method, and the scheme is provided, wherein a single-component desogestrel intermediate is obtained by carrying out side chain degradation, reduction, esterification, bromination, elimination, hydrolysis and Birch reduction on recrystallization mother liquor. The desogestrel recrystallization mother liquor is converted into the single-component 18-methyl-11-methylene estra-4-ene-17 beta-ol with high yield, the used main raw material is the original waste mother liquor in desogestrel production, the high atom utilization rate meeting the requirement of environmental protection production is achieved, and the economic benefit is improved.
Description
Technical Field
The invention relates to the technical field of organic chemistry, in particular to a method for recovering desogestrel recrystallization mother liquor.
Background
Desogestrel is a third-generation progestogen, which was originally developed as an oral contraceptive by Ougan, the Netherlands, and has a trade name of "Mafulong", and is currently marketed in most countries around the world. There are currently three major synthetic routes for desogestrel (Recueil 1975, 35; Recueil 1988,331; Tetrahedron 1994,10709), all of which ultimately involve a 3-deoxygenation step, where a double-bond isomeric impurity, the Δ 3 isomer, is inevitably produced (impurity A in the European pharmacopoeia of desogestrel 9.0). The Δ 3 isomer content in the deoxygenated crude product is typically in the range of 8-25% after treatment with various deoxygenation means as reported. Since the structure and properties of the impurity are very similar to those of the main product, subsequent purification is difficult, and repeated recrystallization is required. In order to improve the yield, the crystallization mother liquor is recovered and recrystallized. In production practice, we found that when the content ratio of delta 3 isomer and desogestrel in the crystallization mother liquor reaches 40: after 60, no further recovery of desogestrel was possible by conventional recrystallization methods.
Disclosure of Invention
The invention aims to solve the problem that in the prior art, when the content ratio of delta 3 isomer to desogestrel in the crystallization mother liquor reaches 40: 60 later, the defect that desogestrel cannot be further recovered by a common recrystallization method is overcome, and the method for recovering the desogestrel recrystallization mother liquor is provided.
In order to achieve the purpose, the invention adopts the following technical scheme:
the method for recovering desogestrel recrystallization mother liquor comprises the following steps of preparing 18-methyl-11-methylene estra-4-ene-17 beta-alcohol (compound 1) from the desogestrel recrystallization mother liquor:
desogestrel recrystallization mother liquor (the main components are desogestrel, compound 2;. delta.)3Isomer, compound 3; 17-epimer, compound 4) as the starting material, and by side chain degradation, reduction, esterification, bromination, elimination, hydrolysis, reduction, a single-component 18-methyl-11-methyleneestra-4-ene-17 β -ol (compound 1) is obtained, which is the main intermediate of desogestrel;
the method comprises the following steps:
s1, treating desogestrel recrystallization mother liquor with a Fetizon reagent in an aprotic solvent to obtain a mixture of 18-methyl-11-methylene estr-4-en-17-one and 18-methyl-11-methylene estr-3-en-17-one;
s2, reducing the mixture of 18-methyl-11-methylene estra-4-en-17-one and 18-methyl-11-methylene estra-3-en-17-one into a mixture of 18-methyl-11-methylene estra-4-en-17 beta-ol and 18-methyl-11-methylene estra-3-en-17 beta-ol by sodium borohydride or potassium borohydride in a solvent;
s3, reacting the mixture of 18-methyl-11-methylene estra-4-ene-17 beta-ol and 18-methyl-11-methylene estra-3-ene-17 beta-ol with acetic anhydride in the presence or absence of a solvent to generate a mixture of 18-methyl-11-methylene estra-4-ene-17 beta-ol, 17-acetate and 18-methyl-11-methylene estra-3-ene-17 beta-ol, 17-acetate;
(ii) reacting a mixture of S4, 18-methyl-11-methyleneestra-4-en-17 β -ol, 17-acetate and 18-methyl-11-methyleneestra-3-en-17 β -ol, 17-acetate with bromine or pyridinium tribromide in a solvent to produce a mixture of 18-methyl-11-methyleneestra-4, 5-dibromo-17 β -ol, 17-acetate and 18-methyl-11-methyleneestra-3, 4-dibromo-17 β -ol, 17-acetate;
reacting a mixture of S5, 18-methyl-11-methyleneestra-4, 5-dibromo-17 beta-ol, 17-acetate and 18-methyl-11-methyleneestra-3, 4-dibromo-17 beta-ol, 17-acetate with an organic base in the presence of an aprotic solvent or in the absence of a solvent to form a mixture of 18-methyl-11-methyleneestra-3, 5-dien-17 beta-ol, 17-acetate and 18-methyl-11-methyleneestra-2, 4-dien-17 beta-ol, 17-acetate;
s6, 18-methyl-11-methyleneestra-3, 5-diene-17 beta-ol, 17-acetate and 18-methyl-11-methyleneestra-2, 4-diene-17 beta-ol, 17-acetate mixture in solvent using strong acid to isomerize the conjugated double bond of the latter, then using alkali to remove 17-protecting group, generating single component 18-methyl-11-methyleneestra-3, 5-diene-17 beta-ol;
s7, and carrying out 1, 4-hydrogenation reduction on conjugated double bonds by using a Birch reaction on 18-methyl-11-methylene estra-3, 5-diene-17 beta-alcohol to obtain 18-methyl-11-methylene estra-4-ene-17 beta-alcohol.
Preferably, in S1, the aprotic solvent refers to an aprotic solvent commonly used in the field of organic synthesis, such as one or more of benzene, toluene, n-hexane, cyclohexane, dimethylformamide and dimethylsulfoxide.
Preferably, in the S1, the reaction temperature is 100-120 ℃.
Preferably, in S2, the solvent refers to common ether or alcohol, such as diethyl ether, tert-butyl methyl ether, tetrahydrofuran, methanol, ethanol, isopropanol, and the reaction temperature is 0-20 ℃.
Preferably, in the S3, the solvent refers to one or more of toluene, dichloromethane, chloroform and acetic acid, and the reaction temperature is 0-20 ℃.
Preferably, in the S4, the solvent refers to one or more of dichloromethane, chloroform, carbon tetrachloride and acetic acid, and the reaction temperature is 0-20 ℃.
Preferably, in S5, the aprotic solvent such as benzene, toluene, xylene, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide and the organic base is one or more of collidine, quinoline, 2-methylquinoline and DBU, and the reaction temperature is 120-140 ℃.
Preferably, in S6, the solvent refers to one or more of methanol, ethanol and isopropanol, strong acid such as sulfuric acid, hydrochloric acid, perchloric acid and p-toluenesulfonic acid, the reaction temperature is 40-60 ℃, the alkali is inorganic alkali such as ammonia, potassium carbonate, potassium hydroxide and sodium hydroxide, the reaction temperature is 20-60 ℃, preferably, the mixture of the product 18-methyl-11-methyleneestra-3, 5-diene-17 beta-alcohol, 17-acetic ester and 18-methyl-11-methyleneestra-2, 4-diene-17 beta-alcohol in S5 does not undergo acid isomerization, the mixture obtained by removing the protection with alkali directly undergoes Birch reaction to obtain a product mainly comprising 18-methyl-11-methyleneestra-4-en-17 beta-alcohol, this is because the 4-double bond in the 2, 4-diene structure is highly hindered at its terminal position and is not likely to form a lithium compound, and thus the 4-ene structure is also formed mainly by 1, 2-addition.
Compared with the prior art, the invention has the beneficial effects that:
the desogestrel recrystallization mother liquor is converted into the single-component 18-methyl-11-methylene estra-4-ene-17 beta-ol with high yield, the used main raw material is the original waste mother liquor in desogestrel production, the high atom utilization rate meeting the requirement of environmental protection production is achieved, and the economic benefit is improved.
Drawings
FIG. 1 is a synthesis scheme of a method for recovering desogestrel recrystallization mother liquor according to the present invention.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments.
Examples side chain degradation:
desogestrel mother liquor (brown oil, dry product, containing 53% desogestrel, 34% delta 3 isomer and 9% 17-epimer, GC)30g was prepared according to the method of J.C.Chem.Comm.1972, 468 and 27.3g of brown oil (containing 57% 18-methyl-11-methyleneestr-4-en-17-one and 37% 18-methyl-11-methyleneestr-3-en-17-one, GC) was obtained.
Example two reduction:
25g of the oily substance obtained in example 1 was added to a 1000ml three-necked round-bottomed flask, 500ml of methanol was added and stirred to dissolve the oily substance, a total of 10g of sodium borohydride was added thereto in portions at room temperature, the progress of the reaction was monitored by TLC, the solution was acidified with acetic acid after the completion of the reaction, the solvent was distilled off, water and methylene chloride were added and the mixture was extracted, and the organic layer was concentrated to dryness to obtain 24.3g of a brown oily substance.
Examples triester formation:
120ml of acetic anhydride was added to the total amount of the oily substance obtained in the above reduction step, followed by stirring, 1.2g of p-toluenesulfonic acid was added thereto at room temperature, and the progress of the reaction was monitored by TLC. After the reaction, 2ml of pyridine was added thereto, and then poured into 500ml of ice water, followed by stirring for 2 hours. Extraction with dichloromethane and washing of the organic layer with water was followed by concentration to dryness to give 26.1g of a brown oil.
Example tetrabromination:
the entire amount of the oil obtained in example 3 was added to a 1000ml three-necked round-bottomed flask, 500ml of methylene chloride was added thereto and dissolved by stirring, and a total of 26g of pyridinium tribromide was added thereto in portions at room temperature, and the progress of the reaction was monitored by TLC. After the reaction was completed, the reaction solution was washed with water, and the organic layer was concentrated to dryness to obtain a semisolid 36.9 g.
Example five elimination:
adding 400ml of dimethylbenzene and 70ml of 2-methylquinoline into the semisolid obtained in the bromination step in a full amount, refluxing for two hours under the protection of nitrogen, and judging the reaction end point by using UV after sampling treatment. Adding dilute hydrochloric acid, stirring for 30 min, layering, and washing organic layer with water to neutrality. Evaporated to dryness under reduced pressure to give a light brown oil which slowly crystallizes after standing at room temperature.
Example six hydrolysis:
and (3) uniformly stirring the total amount of the semi-solid obtained in the elimination step by using 500ml of methanol, adding 6ml of concentrated hydrochloric acid, refluxing for two hours under the protection of nitrogen, and judging the reaction end point by using UV. After the reaction liquid is filtered and cooled, sodium hydroxide is added to adjust the pH value>11, stir at room temperature overnight. Neutralizing with acetic acid, diluting with 500ml water, filtering, washing with water, vacuum drying to obtain crude light brown powder 22.3g, recrystallizing with methanol to obtain white needle crystal with melting point of 145-]20 D+21 ° (c ═ 1, chloroform)
Example seven Birch reduction:
under the protection of argon, condensing ammonia by about 200ml in a 1000ml four-neck round-bottom flask, dropwise adding a tetrahydrofuran solution (10g/100ml) of a hydrolysis crude product and 40ml of tert-butyl alcohol, controlling the internal temperature to be lower than-40 ℃, adding 2g of lithium in batches, continuously reacting for 1 hour, dropwise adding ethanol to terminate the reaction, discharging ammonia, heating to room temperature, adding a glacial acetic acid aqueous solution to adjust the pH to be 5-6, decompressing and distilling the filtrate to remove an organic solvent, adding water, filtering, performing vacuum drying to obtain 9.7g of light brown powder, recrystallizing by using n-hexane to obtain 7.2g of white crystalline powder, wherein the HPLC purity is higher than 93%, and the white crystalline powder can be directly used for preparing the subsequent desogestrel.
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be considered to be within the technical scope of the present invention, and the technical solutions and the inventive concepts thereof according to the present invention should be equivalent or changed within the scope of the present invention.
Claims (9)
1. The method for recovering desogestrel recrystallization mother liquor is characterized in that the desogestrel recrystallization mother liquor is used for preparing 18-methyl-11-methylene estra-4-ene-17 beta-alcohol (compound 1):
desogestrel recrystallization mother liquor (the main components are desogestrel, compound 2;. delta.)3Isomer, compound 3; 17-epimer, compound 4) as the starting material, and by side chain degradation, reduction, esterification, bromination, elimination, hydrolysis, reduction, a single-component 18-methyl-11-methyleneestra-4-ene-17 β -ol (compound 1) is obtained, which is the main intermediate of desogestrel;
the method comprises the following steps:
s1, treating desogestrel recrystallization mother liquor with a Fetizon reagent in an aprotic solvent to obtain a mixture of 18-methyl-11-methylene estr-4-en-17-one and 18-methyl-11-methylene estr-3-en-17-one;
s2, reducing the mixture of 18-methyl-11-methylene estra-4-en-17-one and 18-methyl-11-methylene estra-3-en-17-one into a mixture of 18-methyl-11-methylene estra-4-en-17 beta-ol and 18-methyl-11-methylene estra-3-en-17 beta-ol by sodium borohydride or potassium borohydride in a solvent;
s3, reacting the mixture of 18-methyl-11-methylene estra-4-ene-17 beta-ol and 18-methyl-11-methylene estra-3-ene-17 beta-ol with acetic anhydride in the presence or absence of a solvent to generate a mixture of 18-methyl-11-methylene estra-4-ene-17 beta-ol, 17-acetate and 18-methyl-11-methylene estra-3-ene-17 beta-ol, 17-acetate;
(ii) reacting a mixture of S4, 18-methyl-11-methyleneestra-4-en-17 β -ol, 17-acetate and 18-methyl-11-methyleneestra-3-en-17 β -ol, 17-acetate with bromine or pyridinium tribromide in a solvent to produce a mixture of 18-methyl-11-methyleneestra-4, 5-dibromo-17 β -ol, 17-acetate and 18-methyl-11-methyleneestra-3, 4-dibromo-17 β -ol, 17-acetate;
reacting a mixture of S5, 18-methyl-11-methyleneestra-4, 5-dibromo-17 beta-ol, 17-acetate and 18-methyl-11-methyleneestra-3, 4-dibromo-17 beta-ol, 17-acetate with an organic base in the presence of an aprotic solvent or in the absence of a solvent to form a mixture of 18-methyl-11-methyleneestra-3, 5-dien-17 beta-ol, 17-acetate and 18-methyl-11-methyleneestra-2, 4-dien-17 beta-ol, 17-acetate;
s6, 18-methyl-11-methyleneestra-3, 5-diene-17 beta-ol, 17-acetate and 18-methyl-11-methyleneestra-2, 4-diene-17 beta-ol, 17-acetate mixture in solvent using strong acid to isomerize the conjugated double bond of the latter, then using alkali to remove 17-protecting group, generating single component 18-methyl-11-methyleneestra-3, 5-diene-17 beta-ol;
s7, and carrying out 1, 4-hydrogenation reduction on conjugated double bonds by using a Birch reaction on 18-methyl-11-methylene estra-3, 5-diene-17 beta-alcohol to obtain 18-methyl-11-methylene estra-4-ene-17 beta-alcohol.
2. The method for recovering desogestrel recrystallization mother liquor as claimed in claim 1, wherein the aprotic solvent in S1 is one or more of benzene, toluene, n-hexane, cyclohexane, dimethylformamide and dimethyl sulfoxide, and is commonly used in the field of organic synthesis.
3. The method for recovering desogestrel recrystallization mother liquor as claimed in claim 1, wherein the reaction temperature in S1 is 100-120 ℃.
4. The method for recovering desogestrel recrystallization mother liquor as claimed in claim 1, wherein the solvent in S2 is commonly used ether or alcohol, and the reaction temperature is 0-20 ℃.
5. The method for recovering desogestrel recrystallization mother liquor as claimed in claim 1, wherein the solvent in S3 is one or more of toluene, dichloromethane, chloroform and acetic acid, and the reaction temperature is 0-20 ℃.
6. The method for recovering desogestrel recrystallization mother liquor as claimed in claim 1, wherein the solvent in S4 is one or more of dichloromethane, chloroform, carbon tetrachloride and acetic acid, and the reaction temperature is 0-20 ℃.
7. The method as claimed in claim 1, wherein the aprotic solvent in S5 is one or more selected from benzene, toluene, xylene, tetrahydrofuran, dioxane, dimethylformamide, and dimethylsulfoxide, the organic base is one or more selected from collidine, quinoline, 2-methylquinoline, and DBU, and the reaction temperature is 120-140 ℃.
8. The method for recovering desogestrel recrystallization mother liquor as claimed in claim 1, wherein in S6, the solvent is one or more of methanol, ethanol and isopropanol, the strong acid is sulfuric acid, hydrochloric acid, perchloric acid and p-toluenesulfonic acid, the reaction temperature is 40-60 ℃, the alkali is inorganic alkali such as ammonia, potassium carbonate, potassium hydroxide and sodium hydroxide, and the reaction temperature is 20-60 ℃.
9. The method for recovering mother liquor for recrystallization of desogestrel according to claim 1, wherein the mixture of 18-methyl-11-methyleneestra-3, 5-dien-17 β -ol, 17-acetate and 18-methyl-11-methyleneestra-2, 4-dien-17 β -ol, 17-acetate, which is the product of S5, is not subjected to acid isomerization, and the Birch reaction is directly performed on the mixture obtained by removing the protection with alkali, so that a product mainly comprising 18-methyl-11-methyleneestra-4-en-17 β -ol can be obtained.
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