CN116640177A - 雌酚酮的合成方法 - Google Patents
雌酚酮的合成方法 Download PDFInfo
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- DNXHEGUUPJUMQT-UHFFFAOYSA-N (+)-estrone Natural products OC1=CC=C2C3CCC(C)(C(CC4)=O)C4C3CCC2=C1 DNXHEGUUPJUMQT-UHFFFAOYSA-N 0.000 title claims abstract description 42
- DNXHEGUUPJUMQT-CBZIJGRNSA-N Estrone Chemical compound OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 DNXHEGUUPJUMQT-CBZIJGRNSA-N 0.000 title claims abstract description 42
- 229960003399 estrone Drugs 0.000 title claims abstract description 42
- 238000001308 synthesis method Methods 0.000 title claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims abstract description 37
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims abstract description 22
- 239000002994 raw material Substances 0.000 claims abstract description 19
- 238000001914 filtration Methods 0.000 claims abstract description 15
- 239000002253 acid Substances 0.000 claims abstract description 12
- 239000011230 binding agent Substances 0.000 claims abstract description 12
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims abstract description 12
- 238000001816 cooling Methods 0.000 claims abstract description 11
- 239000003444 phase transfer catalyst Substances 0.000 claims abstract description 11
- 238000001035 drying Methods 0.000 claims abstract description 10
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 10
- 150000002367 halogens Chemical class 0.000 claims abstract description 10
- 239000007810 chemical reaction solvent Substances 0.000 claims abstract description 8
- 239000000126 substance Substances 0.000 claims abstract description 8
- 238000003756 stirring Methods 0.000 claims abstract description 6
- 238000010438 heat treatment Methods 0.000 claims abstract description 3
- 238000002156 mixing Methods 0.000 claims abstract description 3
- 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 claims abstract 6
- 229960005471 androstenedione Drugs 0.000 claims abstract 6
- AEMFNILZOJDQLW-UHFFFAOYSA-N androstenedione Natural products O=C1CCC2(C)C3CCC(C)(C(CC4)=O)C4C3CCC2=C1 AEMFNILZOJDQLW-UHFFFAOYSA-N 0.000 claims abstract 6
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- 239000002904 solvent Substances 0.000 claims description 16
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 14
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- -1 cyclic crown ethers Chemical class 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- YWWDBCBWQNCYNR-UHFFFAOYSA-N trimethylphosphine Chemical compound CP(C)C YWWDBCBWQNCYNR-UHFFFAOYSA-N 0.000 claims description 10
- 230000002194 synthesizing effect Effects 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical group [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 claims description 8
- 238000007670 refining Methods 0.000 claims description 7
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 6
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 claims description 6
- 229910052740 iodine Inorganic materials 0.000 claims description 6
- 239000011630 iodine Substances 0.000 claims description 6
- 229920000570 polyether Polymers 0.000 claims description 6
- 238000004537 pulping Methods 0.000 claims description 6
- 150000003242 quaternary ammonium salts Chemical group 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 6
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 claims description 6
- 239000004721 Polyphenylene oxide Substances 0.000 claims description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- CYTQBVOFDCPGCX-UHFFFAOYSA-N trimethyl phosphite Chemical group COP(OC)OC CYTQBVOFDCPGCX-UHFFFAOYSA-N 0.000 claims description 5
- 239000003849 aromatic solvent Substances 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- 239000002202 Polyethylene glycol Substances 0.000 claims description 3
- 230000015572 biosynthetic process Effects 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 229920001223 polyethylene glycol Polymers 0.000 claims description 3
- 238000003786 synthesis reaction Methods 0.000 claims description 3
- 150000003990 18-crown-6 derivatives Chemical group 0.000 claims description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 2
- 150000001408 amides Chemical class 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims description 2
- 150000004982 aromatic amines Chemical class 0.000 claims description 2
- UJNZOIKQAUQOCN-UHFFFAOYSA-N methyl(diphenyl)phosphane Chemical compound C=1C=CC=CC=1P(C)C1=CC=CC=C1 UJNZOIKQAUQOCN-UHFFFAOYSA-N 0.000 claims description 2
- 150000004714 phosphonium salts Chemical class 0.000 claims description 2
- 229910052698 phosphorus Inorganic materials 0.000 claims description 2
- 239000011574 phosphorus Substances 0.000 claims description 2
- 229920000642 polymer Polymers 0.000 claims description 2
- 239000011593 sulfur Substances 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 claims description 2
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 claims description 2
- RXJKFRMDXUJTEX-UHFFFAOYSA-N triethylphosphine Chemical compound CCP(CC)CC RXJKFRMDXUJTEX-UHFFFAOYSA-N 0.000 claims description 2
- FIQMHBFVRAXMOP-UHFFFAOYSA-N triphenylphosphane oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 claims description 2
- 239000005453 ketone based solvent Substances 0.000 claims 2
- 239000005456 alcohol based solvent Substances 0.000 claims 1
- 239000004210 ether based solvent Substances 0.000 claims 1
- XTQHKBHJIVJGKJ-UHFFFAOYSA-N sulfur monoxide Chemical class S=O XTQHKBHJIVJGKJ-UHFFFAOYSA-N 0.000 claims 1
- 239000000047 product Substances 0.000 description 15
- 239000012535 impurity Substances 0.000 description 11
- 239000007858 starting material Substances 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- 238000005899 aromatization reaction Methods 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 239000003880 polar aprotic solvent Substances 0.000 description 2
- XEZNGIUYQVAUSS-UHFFFAOYSA-N 18-crown-6 Chemical compound C1COCCOCCOCCOCCOCCO1 XEZNGIUYQVAUSS-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 238000010009 beating Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 150000001993 dienes Chemical class 0.000 description 1
- 210000000750 endocrine system Anatomy 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 239000002699 waste material Substances 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
- C07J1/0051—Estrane derivatives
- C07J1/0059—Estrane derivatives substituted in position 17 by a keto group
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Abstract
雌酚酮的合成方法,包括以下步骤:1)将反应溶剂,相转移催化剂和作为原料的雄二烯二酮(ADD)加入反应容器混合后,搅拌20~60min,然后加入加入卤素单质,有机膦和缚酸剂,加热至50℃~80℃反应至原料基本消失,降温至室温,过滤、干燥得到雌酚酮。
Description
技术领域
本发明涉及一种甾体化合物的制备方法,尤其涉及雌酚酮的合成方法。
背景技术
雌酚酮是一种人体和动物体内天然的雌激素,能够维持雌性个体的第二生理特征及正常的内分泌系统。传统雌酚酮生产路线以双烯为原料,经过酮肟、重排、氯纯化、环合、环合水解、开环和生物发酵共7步反应合成。该生产路线长、原料来源困难、合成收率低,并且用到三氯氧磷等剧毒物质,产生大量三废,因此制备雌酚酮的总成本高。
申请人在先申请的中国专利CN105001293公开了利用ADD经缩酮,在金属锂和联苯中反应合成雌酚酮的制备方法。虽然此路线原料易得、步骤短,但是反应条件苛刻、收率相对较低,且由于使用到金属锂易燃辅料存在安全风险,其反应式如下:
中国专利CN107602650报道了雄二烯二酮(ADD)与有机膦和卤素在极性非质子溶剂中一步法合成雌酚酮的路线,相对CN114315942路线,反应路线简短,但有机膦和卤素结合后与反应体系形成两相影响了反应效率,且反应温度高,时间长,副产物多,由于反应体系酸度过高,容易产生异构体,产品杂质多,产物呈油性且需要过柱分离,质量不符合药物标准,也不适合工业化。
基于上述问题,改进现有以ADD为原料经芳构化一步合成雌酚酮的方法,使反应在更温和的条件进行,同时提高反底物转化率和反应的选择性,从而提高产物雌酚酮的质量和产率,并且更利于工业化生产;成为现有技术中亟待解决的问题。
发明内容
我们在研究中发现在反应体系中加入优选的相转移催化剂和缚酸剂,并优化了反应条件后,可以改进现有ADD为原料经芳构化一步合成雌酚酮的合成方法,基于此为解决现有技术中存在的上述问题,提供的技术方案为:
雌酚酮合成方法,反应式如下
所述反应包括以下步骤:
1)将反应溶剂,相转移催化剂和作为原料的ADD加入反应容器混合后,搅拌20~60min,然后加入加入卤素单质,有机膦和缚酸剂,加热反应至原料基本消失,降温至室温(20℃~25℃),过滤、干燥得到雌酚酮。
所述的雌酚酮合成方法,进一步的还包括以下步骤
2)在步骤1制备的雌酚酮中加入精制溶剂2回流打浆1~3小时,降温至10℃~20℃,过滤、干燥,得到精制的雌酚酮。
所述的雌酚酮合成方法,进一步的,所述步骤1)的反应温度为50℃~80℃;
所述的雌酚酮合成方法,进一步的,所述反应溶剂为沸点高于反应温度的极性非质子溶剂,选自芳香类溶剂,烷烃类溶剂,醚类溶剂,酮类溶剂或酰胺类溶剂,更进一步的选自N,N-二甲基甲酰胺(DMF)四氢呋喃(THF)、环己酮、甲苯或苯。
所述相转移催化剂选自季铵盐、环状冠醚、聚醚、含硫聚合物类、鏻盐、N—烷基膦酰胺、次甲基桥磷或氧硫化合物,优选自季铵盐、环状冠醚、聚醚,进一步的所述季铵盐选自苄基三乙基氯化铵或四丁基氯化铵,所述环状冠醚为18-冠-6,所述聚醚为聚乙二醇2000。
所述卤素单质选自:氯气、液溴或单质碘,优选液溴或单质碘。
所述缚酸剂选自胺类化合物,进一步的选自脂肪胺或芳香胺,更进一步的选自吡啶或三乙胺。
所述有机膦选自亚磷酸三甲酯,亚磷酸三乙酯,三甲基膦,三乙基膦,三丁基膦,三苯基膦,二甲苯基膦,二苯基甲基膦或三苯基氧膦,优选三苯基膦、三甲基膦或亚磷酸三甲酯
所述精制溶剂选自酮类溶剂、醇类溶剂或芳香类溶剂,进一步的选自丙酮、甲醇或甲苯。
所述卤素单质、有机膦和原料的摩尔比为(1.1~1.2):(1.2~1.5):1,所述相转移催化剂、缚酸剂和ADD的质量比为0.18~0.22:1.8~2.2:10,所述ADD和反应溶剂的质量体积比为1:9~11,ADD和精制溶剂和的质量体积比为1:2.8~3.5。
本发明提供的雌酚酮合成方法,通过在反应体系中加入优选的相转移催化剂和缚酸剂,意外的发现了可以在比较温和的反应条件下进行,且在相转移催化剂和缚酸剂的共同作用下,使反应始终在能在均相的反应体系中进行,并能够控制反应体系的酸性,显著提高了以ADD为原料一部芳构法合成雌酚酮的反应的收率和产物质量。当采用优选的反应条件和反应试剂时,直接得到的雌酚酮粗品含量皆可达到99%左右,经过精制溶剂回流打浆精制处理后可以达到99.5%以上。
具体实施方式
下面结合具体实施例对本发明作进一步说明,但本发明的保护范围并不限于此。
实施例1
反应罐中,加入100ml N,N-二甲基甲酰胺,0.2g苄基三乙基氯化铵,10g(35.16mmol)原料ADD,搅拌半小时,加入9.82g(38.7mmol,,以I2计)单质碘),7.39g(52.7mmol)亚磷酸三甲酯,搅拌1小时,加入2g三乙胺,于70-80度反应至原料基本消失。降温至室温,过滤,得到雌酚酮粗品9g,纯度98.8%,最大单杂≤1.0%。然后用30ml丙酮回流打浆1-3小时,降至10-20℃,过滤,干燥,得到雌酚酮精品8.7g,纯度≥99.5%,单杂≤0.1%。
实施例2
反应罐中,加入100ml四氢呋喃,0.2g四丁基氯化铵和10g(35.16mmol)原料ADD,搅拌半小时,加入6.74g(42.2mmol,以Br2计)液溴,12g(45.7mmol)三苯基膦,搅拌1小时,加入2g吡啶,于50-60度反应至原料基本消失。降温至室温,过滤,得到雌酚酮粗品9.0g,纯度99.1%,最大单杂≤1.0%。然后用30ml甲醇回流打浆1-3小时,降至10-20℃,过滤,干燥,得到雌酚酮精品8.7g,纯度≥99.5%,单杂≤0.1%。
实施例3
反应罐中,加入100ml环己酮,0.2g 18-冠-6和10g(35.16mmol)原料ADD,搅拌半小时,加入10.7g(42.2mmol,以I2计)碘,3.34g(44mmol)三甲基膦,搅拌1小时,加入2g吡啶,于60-75度反应至原料基本消失。降温至室温,过滤,得到雌酚酮粗品8.9g,纯度99%,最大单杂≤1.0%。然后用30ml甲苯70-80度打浆1-3小时,降至10-20℃,过滤,干燥,得到雌酚酮精品8.6g,纯度≥99.5%,单杂≤0.1%。
实施例4
反应罐中,加入100ml甲苯,0.2g聚乙二醇2000(average Mn 2000)和10g(35.16mmol)原料ADD,搅拌半小时,加入10.3g(40.4mmol,以I2计)碘,12.9g(49.2mmol)三苯基膦,搅拌1小时,加入2g三乙胺,于65-75度反应至原料基本消失。降温至室温,过滤,干燥,得到雌酚酮粗品粗品8.8g,纯度99.2%,最大单杂≤1.0%。然后用30ml甲苯70-80度打浆1-3小时,降至10-20度,过滤,得到雌酚酮精品8.5g,纯度≥99.5%,单杂≤0.1%。
实施例5
反应罐中,加入100ml苯,0.2g苄基三乙基氯化铵和10g(35.16mmol)原料ADD,搅拌半小时,加入10.5g(41.5mmol,以I2计)碘,12.5g(47.5mmol)三苯基膦,搅拌1小时,加入2g吡啶,于55-65度反应至原料基本消失。降温至室温,过滤,得到雌酚酮粗品8.7g,纯度99.1%,最大单杂≤1.0%。然后用30ml甲醇回流打浆1-3小时,降至10-20度,过滤,干燥,得到雌酚酮精品8.4g,纯度≥99.5%,单杂≤0.1%。
Claims (7)
1.雌酚酮的合成方法,反应式如下
其特征是包括以下步骤:
1)将反应溶剂,相转移催化剂和作为原料的雄二烯二酮(ADD)加入反应容器混合后,搅拌20~60min,然后加入加入卤素单质,有机膦和缚酸剂,加热至50℃~80℃反应至原料基本消失,降温至室温,过滤、干燥得到雌酚酮。
2.如权利要求1所述的雌酚酮的合成方法,其特征是,所述反应溶剂,选自芳香类溶剂,烷烃类溶剂,醚类溶剂,酮类溶剂或酰胺类溶剂;所述相转移催化剂选自季铵盐、环状冠醚、聚醚、含硫聚合物类、鏻盐、N—烷基膦酰胺、次甲基桥磷或氧硫化合物;所述缚酸剂选自胺类化合物;所述卤素单质选自:氯气、液溴或单质碘。
3.如权利要求2所述的雌酚酮的合成方法,其特征是所述反应溶剂选自N,N-二甲基甲酰胺、四氢呋喃、环己酮、甲苯或苯;所述相转移催化剂选自季铵盐、环状冠醚、聚醚;所述卤素单质选自液溴或单质碘;所述缚酸剂选自选自脂肪胺或芳香胺;所述有机膦选自亚磷酸三甲酯,亚磷酸三乙酯,三甲基膦,三乙基膦,三丁基膦,三苯基膦,二甲苯基膦,二苯基甲基膦或三苯基氧膦。
4.如如权利要求3所述的雌酚酮的合成方法,其特征是所述季铵盐选自苄基三乙基氯化铵或四丁基氯化铵,所述环状冠醚为18-冠-6,所述聚醚为聚乙二醇2000;所述缚酸剂选自吡啶或三乙胺,所述有机膦选自三苯基膦、三甲基膦或亚磷酸三甲酯。
5.如权利要求1~4任一所述的雌酚酮合成方法,其特征是所述卤素单质、有机膦和原料的摩尔比为(1.1~1.2):(1.2~1.5):1,所述相转移催化剂、缚酸剂和原料的质量比为0.18~0.22:1.8~2.2:10,所述ADD和反应溶剂的质量体积比为1:9~11。
6.如权利要求1~5任一所述的雌酚酮的合成方法,其特征是还包括以下步骤
2)在步骤1制备的雌酚酮中加入精制溶剂回流打浆1~3小时,降温至10℃~20℃,过滤、干燥,得到精制的雌酚酮,所述精制溶剂选自酮类溶剂、醇类溶剂或芳香类溶剂。
7.如权利要求6所述的雌酚酮合成方法,其特征是所述精制溶剂选自丙酮、甲醇或甲苯,ADD和精制溶剂的质量体积比为1:2.8~3.5。
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