CN106957235A - 一种他莫昔芬的制备方法 - Google Patents
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- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 81
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 26
- 238000006243 chemical reaction Methods 0.000 claims abstract description 22
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 17
- 239000001257 hydrogen Substances 0.000 claims abstract description 17
- 238000013517 stratification Methods 0.000 claims abstract description 17
- 238000000967 suction filtration Methods 0.000 claims abstract description 17
- 238000005406 washing Methods 0.000 claims abstract description 17
- 239000003054 catalyst Substances 0.000 claims abstract description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 15
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims abstract description 12
- 238000002425 crystallisation Methods 0.000 claims abstract description 12
- 230000008025 crystallization Effects 0.000 claims abstract description 12
- 239000002904 solvent Substances 0.000 claims abstract description 12
- 238000001035 drying Methods 0.000 claims abstract description 11
- 239000012074 organic phase Substances 0.000 claims abstract description 10
- 238000003756 stirring Methods 0.000 claims abstract description 10
- 229960005026 toremifene Drugs 0.000 claims abstract description 10
- XFCLJVABOIYOMF-QPLCGJKRSA-N toremifene Chemical compound C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 XFCLJVABOIYOMF-QPLCGJKRSA-N 0.000 claims abstract description 10
- 239000002002 slurry Substances 0.000 claims abstract description 8
- 239000003513 alkali Substances 0.000 claims abstract description 7
- 150000001298 alcohols Chemical class 0.000 claims abstract description 5
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 17
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 10
- 229910052763 palladium Inorganic materials 0.000 claims description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 7
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 claims description 3
- 229910052697 platinum Inorganic materials 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- DSVGQVZAZSZEEX-UHFFFAOYSA-N [C].[Pt] Chemical compound [C].[Pt] DSVGQVZAZSZEEX-UHFFFAOYSA-N 0.000 claims description 2
- 239000000347 magnesium hydroxide Substances 0.000 claims description 2
- 229910001862 magnesium hydroxide Inorganic materials 0.000 claims description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical group C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 2
- PANBYUAFMMOFOV-UHFFFAOYSA-N sodium;sulfuric acid Chemical compound [Na].OS(O)(=O)=O PANBYUAFMMOFOV-UHFFFAOYSA-N 0.000 claims 1
- 229910052938 sodium sulfate Inorganic materials 0.000 abstract 1
- 235000011152 sodium sulphate Nutrition 0.000 abstract 1
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 46
- 229960001603 tamoxifen Drugs 0.000 description 23
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- 238000000034 method Methods 0.000 description 10
- 150000002431 hydrogen Chemical class 0.000 description 8
- 238000005984 hydrogenation reaction Methods 0.000 description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 7
- 238000006073 displacement reaction Methods 0.000 description 7
- 238000010438 heat treatment Methods 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- 238000001914 filtration Methods 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000005194 fractionation Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 235000012254 magnesium hydroxide Nutrition 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 2
- 125000002524 organometallic group Chemical group 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 229940046836 anti-estrogen Drugs 0.000 description 1
- 230000001833 anti-estrogenic effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- RGLYKWWBQGJZGM-ISLYRVAYSA-N diethylstilbestrol Chemical compound C=1C=C(O)C=CC=1C(/CC)=C(\CC)C1=CC=C(O)C=C1 RGLYKWWBQGJZGM-ISLYRVAYSA-N 0.000 description 1
- 229960000452 diethylstilbestrol Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000000328 estrogen antagonist Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- VCRYGHPVKURQMM-UHFFFAOYSA-N methane;platinum Chemical compound C.[Pt] VCRYGHPVKURQMM-UHFFFAOYSA-N 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000002910 solid waste Substances 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- -1 triphenylethylene class compound Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明涉及一种他莫昔芬的制备方法,其特征在于包括下述步骤:取托瑞米芬、催化剂和碱化合物,加入到醇类溶剂中,在氢气氛围下、0.1~1.0MPa、20~150℃下搅拌反应10~24小时;然后将反应体系降至室温,抽滤,常压或减压蒸除溶剂;加入乙酸乙酯和水洗涤,静置分层,取上层有机相用无水硫酸钠干燥,过滤除去硫酸钠,减压蒸除乙酸乙酯,得到浆状物,向浆状物中加入丙酮,丙酮的体积用量与所述浆状物的重量之比为2~5ml/g,然后加热至50~56℃溶解,再冷却至0℃析出结晶;对结晶进行干燥即得到白色针状固体他莫昔芬。
Description
技术领域
本发明涉及医药化工领域,具体指一种他莫昔芬的制备方法。
背景技术
他莫昔芬(tamoxifen)为三苯乙烯类化合物,是以己烯雌酚类***为先导物发展出来的抗***药物。
他莫昔芬的合成方法较多。2012年,Haroutounian等人对他莫昔芬的合成方法作了详尽的综述,总结了他莫昔芬的8类合成策略(K.M.Kasiotis andS.A.Haroutounian.Tamoxifen:a synthetic overview.Curr.Org.Chem.2012,16,335-352)。这些方法中,多数涉及到了金属有机催化剂或有机金属试剂参与的反应,合成路线较长,立体选择性不高,操作较为繁琐。尤其是在使用具有较高活性的有机金属试剂过程中,存在着许多安全隐患。其中,适合工业化制备他莫昔芬的方法主要有以下两种:
方法一:
上述方法采用分子间的Mcmurry反应,在锌粉和四氯化钛作用下发生偶联反应得到他莫昔芬及其异构体的混合物,然后经精制拆分除去E-异构体获得他莫昔芬(EP0126470)。该方法生产工时长,分离操作极为困难,固废及液废量大,异构体的拆分导致成品收率低。
方法二:
上述方法是将三级醇脱水得到他莫昔芬及其E-异构体的混合物,也需要通过精制拆分的方法获得他莫昔芬,同样存在着工时长、收率低等问题。
发明内容
本发明所要解决的技术问题是针对现有技术的现状提供一种工艺简单、收率高且环境友好的他莫昔芬的制备方法。
本发明解决上述技术问题所采用的技术方案为:该他莫昔芬的制备方法,其特征在于包括下述步骤:
取托瑞米芬、催化剂和碱化合物,加入到醇类溶剂中,在氢气氛围下、0.1~1.0MPa、20~150℃下搅拌反应10~24小时;
所述催化剂为钯碳催化剂或铂炭催化剂,所述催化剂的用量为托瑞米芬的1%~15wt%;
所述碱化合物的用量为托瑞米芬的1~5倍摩尔量;
所述溶剂的用量为托瑞米芬质量的2~20倍;
然后将反应体系降至室温,抽滤,常压或减压蒸除溶剂;
加入乙酸乙酯和水洗涤,静置分层,取上层有机相用无水硫酸钠干燥,过滤除去硫酸钠,减压蒸除乙酸乙酯,得到浆状物,向浆状物中加入丙酮,丙酮的体积用量与所述浆状物的重量之比为2~5ml/g,然后加热至50~56℃溶解,再冷却至0℃析出结晶;对结晶进行干燥即得到白色针状固体他莫昔芬。
优选所述催化剂中钯或铂的含量为1%~20wt%。
所述溶剂优选自甲醇、乙醇、异丙醇或正丁醇。
所述碱化合物优选自氢氧化钠、氢氧化钾、碳酸钠、碳酸钾或氢氧化镁。
本发明以托瑞米芬为原料,钯炭或铂炭为催化剂,在碱性的醇类溶剂中发生高温高压的氢化反应,化学反应式如下:
工艺流程简单,溶剂可以回收套用,无副反应发生,他莫昔芬收率高,产品纯度好;且反应过程稳定、安全、选择性好,所用催化剂可以回收再利用,绿色环保,环境友好。
附图说明
图1为本发明实施例1中所得产物的核磁共振氢谱(1H NMR)图。
图2为本发明实施例1中所得产物的高效液相色谱(HPLC)图。
具体实施方式
以下结合附图实施例对本发明作进一步详细描述。
实施例1
向1L氢化反应釜中,加入40g托瑞米芬,400g甲醇,8.3g氢氧化钾,4g 10%钯炭,用0.2MPa的氮气置换3次,再用0.2MPa的氢气置换3次,保持氢气压力0.3~0.5MPa,反应温度70℃,搅拌反应14小时。降至室温,抽滤,减压蒸除甲醇,加250mL乙酸乙酯和100mL水洗涤,静置分层,乙酸乙酯层再用100mL水洗涤一次,静置分层,有机相用无水硫酸钠干燥,过滤后减压蒸除乙酸乙酯,加120mL丙酮加热溶解后置于0℃析晶过夜,抽滤,60℃鼓风烘干得白色针状固体他莫昔芬31.5g,收率86%.Mp:96.5~98℃,1H NMR(400MHz,CDCl3):δ0.93(t,J=7.6Hz,3H,CH2CH 3),2.29(s,6H,NMe 2),2.46(q,J=7.6Hz,2H,CH 2CH3),2.65(t,J=5.6Hz,2H,OCH2CH 2NMe2),3.93(t,J=7.6Hz,2H,OCH 2CH2NMe2),6.56(d,J=8.8Hz,2H,Ar-H),6.77(d,J=8.8Hz,2H,Ar-H),7.11-7.37(m,10H,Ar-H).HPLC含量99.85%。
实施例2
向1L氢化反应釜中,加入40g托瑞米芬,400g乙醇,7.1g氢氧化钠,4g 10%铂炭,用0.2MPa的氮气置换3次,再用0.2MPa的氢气置换3次,保持氢气压力0.3~0.5MPa,反应温度90℃,搅拌反应12小时。降至室温,抽滤,减压蒸除乙醇,加250mL乙酸乙酯和100mL水洗涤,静置分层,乙酸乙酯层再用100mL水洗涤一次,静置分层,有机相用无水硫酸钠干燥,过滤后减压蒸除乙酸乙酯,加120mL丙酮加热溶解后置于0℃析晶过夜,抽滤,60℃鼓风烘干得白色针状固体他莫昔芬31.1g,收率84.9%。Mp:96.3~97.8℃。
实施例3
向1L氢化反应釜中,加入40g托瑞米芬,400g乙醇,8.3g碳酸钾,3g 10%钯炭,用0.2MPa的氮气置换3次,再用0.2MPa的氢气置换3次,保持氢气压力0.5~0.7MPa,反应温度90℃,搅拌反应12小时。降至室温,抽滤,减压蒸除乙醇,加250mL乙酸乙酯和100mL水洗涤,静置分层,乙酸乙酯层再用100mL水洗涤一次,静置分层,有机相用无水硫酸钠干燥,过滤后减压蒸除乙酸乙酯,加120mL丙酮加热溶解后置于0℃析晶过夜,抽滤,60℃鼓风烘干得白色针状固体他莫昔芬32g,收率87.5%。Mp:96~97.5℃。
实施例4
向1L氢化反应釜中,加入40g托瑞米芬,600g异丙醇,9g氢氧化钠,4g 10%钯炭,用0.2MPa的氮气置换3次,再用0.2MPa的氢气置换3次,保持氢气压力0.3~0.5MPa,反应温度80℃,搅拌反应15小时。降至室温,抽滤,减压蒸除异丙醇,加250mL乙酸乙酯和100mL水洗涤,静置分层,乙酸乙酯层再用100mL水洗涤一次,静置分层,有机相用无水硫酸钠干燥,过滤后减压蒸除乙酸乙酯,加120mL丙酮加热溶解后置于0℃析晶过夜,抽滤,60℃鼓风烘干得白色针状固体他莫昔芬31.7g,收率86.5%。Mp:96.2~98℃。
实施例5
向1L氢化反应釜中,加入40g托瑞米芬,300g甲醇,9g碳酸钠,4g 10%钯炭,用0.2MPa的氮气置换3次,再用0.2MPa的氢气置换3次,保持氢气压力0.3~0.5MPa,反应温度80℃,搅拌反应15小时。降至室温,抽滤,减压蒸除甲醇,加250mL乙酸乙酯和100mL水洗涤,静置分层,乙酸乙酯层再用100mL水洗涤一次,静置分层,有机相用无水硫酸钠干燥,过滤后减压蒸除乙酸乙酯,加120mL丙酮加热溶解后置于0℃析晶过夜,抽滤,60℃鼓风烘干得白色针状固体他莫昔芬32g,收率87.5%。Mp:96.5~98℃。
实施例6
向1L氢化反应釜中,加入40g托瑞米芬,400g正丁醇,8.3g氢氧化钾,5g 5%钯炭,用0.2MPa的氮气置换3次,再用0.2MPa的氢气置换3次,保持氢气压力0.8~1.0MPa,反应温度70℃,搅拌反应14小时。降至室温,抽滤,减压蒸除正丁醇,加250mL乙酸乙酯和100mL水洗涤,静置分层,乙酸乙酯层再用100mL水洗涤一次,静置分层,有机相用无水硫酸钠干燥,过滤后减压蒸除乙酸乙酯,加120mL丙酮加热溶解后置于0℃析晶过夜,抽滤,60℃鼓风烘干得白色针状固体他莫昔芬31.7g,收率86.5%。Mp:96.3~97.8℃。
实施例7
向1L氢化反应釜中,加入40g托瑞米芬,400g乙醇,8.3g氢氧化镁,5g 5%钯炭,用0.2MPa的氮气置换3次,再用0.2MPa的氢气置换3次,保持氢气压力0.5~0.7MPa,反应温度90℃,搅拌反应12小时。降至室温,抽滤,减压蒸除乙醇,加250mL乙酸乙酯和100mL水洗涤,静置分层,乙酸乙酯层再用100mL水洗涤一次,静置分层,有机相用无水硫酸钠干燥,过滤后减压蒸除乙酸乙酯,加120mL丙酮加热溶解后置于0℃析晶过夜,抽滤,60℃鼓风烘干得白色针状固体他莫昔芬32.3g,收率88.1%。Mp:96.2~97.5℃。
Claims (4)
1.一种他莫昔芬的制备方法,其特征在于包括下述步骤:
取托瑞米芬、催化剂和碱化合物,加入到醇类溶剂中,在氢气氛围下、0.1~1.0MPa、20~150℃下搅拌反应10~24小时;
所述催化剂为钯碳催化剂或铂炭催化剂,所述催化剂的用量为托瑞米芬的1%~15wt%;
所述碱化合物的用量为托瑞米芬的1~5倍摩尔量;
所述溶剂的用量为托瑞米芬质量的2~20倍;
然后将反应体系降至室温,抽滤,常压或减压蒸除溶剂;
加入乙酸乙酯和水洗涤,静置分层,取上层有机相用无水硫酸钠干燥,过滤除去硫酸钠,减压蒸除乙酸乙酯,得到浆状物,向浆状物中加入丙酮,丙酮的体积用量与所述浆状物的重量之比为2~5ml/g,然后加热至50~56℃溶解,再冷却至0℃析出结晶;对结晶进行干燥即得到白色针状固体他莫昔芬。
2.根据权利要求1所述的他莫昔芬的制备方法,其特征在于所述催化剂中钯或铂的含量为1%~20wt%。
3.根据权利要求1或2所述的他莫昔芬的制备方法,所述溶剂选自甲醇、乙醇、异丙醇或正丁醇。
4.根据权利要求3所述的他莫昔芬的制备方法,其特征在于所述碱化合物选自氢氧化钠、氢氧化钾、碳酸钠、碳酸钾或氢氧化镁。
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