CN102558280B - 一种30-卤代桦木酸的生产方法 - Google Patents
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- QGJZLNKBHJESQX-FZFNOLFKSA-N betulinic acid Chemical class C1C[C@H](O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CC[C@@H](C(=C)C)[C@@H]5[C@H]4CC[C@@H]3[C@]21C QGJZLNKBHJESQX-FZFNOLFKSA-N 0.000 title claims abstract description 55
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 16
- JYDNKGUBLIKNAM-UHFFFAOYSA-N Oxyallobutulin Natural products C1CC(=O)C(C)(C)C2CCC3(C)C4(C)CCC5(CO)CCC(C(=C)C)C5C4CCC3C21C JYDNKGUBLIKNAM-UHFFFAOYSA-N 0.000 claims abstract description 27
- FVWJYYTZTCVBKE-ROUWMTJPSA-N betulin Chemical compound C1C[C@H](O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(CO)CC[C@@H](C(=C)C)[C@@H]5[C@H]4CC[C@@H]3[C@]21C FVWJYYTZTCVBKE-ROUWMTJPSA-N 0.000 claims abstract description 27
- MVIRREHRVZLANQ-UHFFFAOYSA-N betulin Natural products CC(=O)OC1CCC2(C)C(CCC3(C)C2CC=C4C5C(CCC5(CO)CCC34C)C(=C)C)C1(C)C MVIRREHRVZLANQ-UHFFFAOYSA-N 0.000 claims abstract description 27
- 230000026030 halogenation Effects 0.000 claims abstract description 20
- 238000005658 halogenation reaction Methods 0.000 claims abstract description 20
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 10
- 239000002994 raw material Substances 0.000 claims abstract description 8
- 230000003647 oxidation Effects 0.000 claims abstract description 6
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 6
- QGJZLNKBHJESQX-UHFFFAOYSA-N 3-Epi-Betulin-Saeure Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C(O)=O)CCC(C(=C)C)C5C4CCC3C21C QGJZLNKBHJESQX-UHFFFAOYSA-N 0.000 claims description 74
- CLOUCVRNYSHRCF-UHFFFAOYSA-N 3beta-Hydroxy-20(29)-Lupen-3,27-oic acid Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C(O)=O)CCC5(C)CCC(C(=C)C)C5C4CCC3C21C CLOUCVRNYSHRCF-UHFFFAOYSA-N 0.000 claims description 74
- DIZWSDNSTNAYHK-XGWVBXMLSA-N Betulinic acid Natural products CC(=C)[C@@H]1C[C@H]([C@H]2CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@@]34C)[C@@H]12)C(=O)O DIZWSDNSTNAYHK-XGWVBXMLSA-N 0.000 claims description 74
- PZXJOHSZQAEJFE-UHFFFAOYSA-N dihydrobetulinic acid Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C(O)=O)CCC(C(C)C)C5C4CCC3C21C PZXJOHSZQAEJFE-UHFFFAOYSA-N 0.000 claims description 74
- MQYXUWHLBZFQQO-UHFFFAOYSA-N nepehinol Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C)CCC(C(=C)C)C5C4CCC3C21C MQYXUWHLBZFQQO-UHFFFAOYSA-N 0.000 claims description 74
- 125000001475 halogen functional group Chemical group 0.000 claims description 43
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 27
- 239000012043 crude product Substances 0.000 claims description 23
- 239000000047 product Substances 0.000 claims description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 238000001556 precipitation Methods 0.000 claims description 14
- 230000001590 oxidative effect Effects 0.000 claims description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 12
- 235000019441 ethanol Nutrition 0.000 claims description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 8
- 238000001953 recrystallisation Methods 0.000 claims description 8
- 239000012153 distilled water Substances 0.000 claims description 7
- 239000000706 filtrate Substances 0.000 claims description 7
- 235000011194 food seasoning agent Nutrition 0.000 claims description 7
- 239000003960 organic solvent Substances 0.000 claims description 7
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 6
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 claims description 5
- OBNCKNCVKJNDBV-UHFFFAOYSA-N butanoic acid ethyl ester Natural products CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 0.000 claims description 4
- YRIZYWQGELRKNT-UHFFFAOYSA-N 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione Chemical group ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O YRIZYWQGELRKNT-UHFFFAOYSA-N 0.000 claims description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 3
- HNAGHMKIPMKKBB-UHFFFAOYSA-N 1-benzylpyrrolidine-3-carboxamide Chemical compound C1C(C(=O)N)CCN1CC1=CC=CC=C1 HNAGHMKIPMKKBB-UHFFFAOYSA-N 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 229950009390 symclosene Drugs 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 2
- 239000011203 carbon fibre reinforced carbon Chemical group 0.000 abstract 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
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- 230000001093 anti-cancer Effects 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- PVFOHMXILQEIHX-UHFFFAOYSA-N 8-[(6-bromo-1,3-benzodioxol-5-yl)sulfanyl]-9-[2-(2-bromophenyl)ethyl]purin-6-amine Chemical compound C=1C=2OCOC=2C=C(Br)C=1SC1=NC=2C(N)=NC=NC=2N1CCC1=CC=CC=C1Br PVFOHMXILQEIHX-UHFFFAOYSA-N 0.000 description 1
- 229940124321 AIDS medicine Drugs 0.000 description 1
- 241000438997 Acharis Species 0.000 description 1
- 235000018185 Betula X alpestris Nutrition 0.000 description 1
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- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 1
- -1 II) Chemical compound 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000078 anti-malarial effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000003430 antimalarial agent Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
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- 230000001472 cytotoxic effect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
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- 210000004881 tumor cell Anatomy 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
- C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J53/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by condensation with a carbocyclic rings or by formation of an additional ring by means of a direct link between two ring carbon atoms, including carboxyclic rings fused to the cyclopenta(a)hydrophenanthrene skeleton are included in this class
- C07J53/002—Carbocyclic rings fused
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Abstract
一种30-卤代桦木酸的生产方法,以桦木醇为原料,选择性氧化卤化生成30-桦木酸,选用的氧化卤化剂具有高选择性,即不会影响C-3位羟基,也不影响碳碳双键。本发明氧化与卤化一步完成工艺路线短,处理方法简单,产品纯化容易。
Description
技术领域
本发明涉及天然化合物的衍生物制备领域,尤其涉及一种从桦木醇半合成30-卤代桦木酸的生产方法。
背景技术
桦木酸(betulinic acid,II)、桦木醇(betulin,III)为五环三萜类植物次生代谢产物。桦木醇在白桦树皮中的含量很高,可达到10~35%,桦木酸可经由桦木醇半合成制得。桦木酸具抗疟、抗炎、抗HIV病毒活性,并且对一系列肿瘤细胞系显示出细胞毒活性,是一种应用开发前景广阔的抗癌和抗艾滋病药物的前体化合物。以桦木酸为先导化合物进行的结构修饰获得了生物活性优异的衍生物。根据桦木酸的结构特点,化学修饰部位主要集中于C-3位、C-19位和C-28位,而30-卤代桦木酸(I)是C-19位结构修饰的重要中间体(N.V.Uzenkova等,Bioorganic&Medicinal Chemistry Letters,2005,41:692;J.Y.Kim等,Chemistry of Natural Compounds,2001,11:2405)。
30-溴代桦木酸的合成已有报道。1976年,Achari等(Tetrahedron,1976,32(6):741)发表了题为“Studies on Indian medicinal plants.XXXIX.Reinvestigation of the lactones and bromo derivative of betulinic acid”的文章。该方法以桦木酸为原料,先对C-3位羟基和C-28位羧基进行官能团保护,然后进行30位溴代反应,最后脱保护得到30-溴代桦木酸。2008年,专利合作条约公布了题为“Preparation of betulinic acid derivatives for use inantiviral and anticancer pharmaceutical compositions.”的发明专利(WO2008127364),提供了以桦木酸为原料溴化制备30-溴代桦木酸的方法。两种方法均以桦木酸为原料,生产成本高,不适于规模化生产。
发明内容
本发明的目的在于提供一种由桦木醇选择性氧化卤化直接获得30-卤代桦木酸的生产方法,且工艺路线简单、产品易纯化。
为了实验上述目的,本发明提供了一种通过使桦木醇直接选择性氧化卤化得到30-卤代桦木酸粗品,粗品进行纯化得到30-卤代桦木酸产品的工艺路线。
其中,所述的30-卤代桦木酸可以是30-氯代桦木酸、30-溴代桦木酸。
特别是,所述的30-卤代桦木酸的生产方法,以桦木醇为原料,包括如下顺序进行的步骤:
(1)桦木醇氧化卤化制备30-卤代桦木酸粗品:将桦木醇溶于一种有机溶剂中,依次加入2,2,6,6-四甲基-1-哌啶酮、碳酸氢钠、氧化卤化剂,在40~60℃下搅拌3~5小时,加入乙醇终止反应,过滤,将滤液经盐酸酸化至pH值为3.5~4.5,减压浓缩至析出沉淀,过滤并用蒸馏水洗涤所得沉淀,自然干燥得30-卤代桦木酸粗品;
(2)30-卤代桦木酸粗品纯化得30-卤代桦木酸产品:30-卤代桦木酸粗品经重结晶得30-卤代桦木酸产品。
本发明的优点是:
1.本发明以桦木醇为原料选择性氧化卤化生成30-桦木酸,选用的氧化卤化剂具有高选择性,不需要进行官能团保护。
2.本发明氧化与卤化一步完成,工艺路线短,处理方法简单,产品纯化容易。
具体实施方式
下面结合实施例对本发明作进一步详细描述:
一种30-卤代桦木酸的生产方法,使桦木醇经过选择性卤化得到30-卤代桦木酸粗品,30-卤代桦木酸粗品经纯化得到30-卤代桦木酸产品。
其中,所述的30-卤代桦木酸的生产方法,30-卤代桦木酸可以是30-氯代桦木酸、30-溴代桦木酸。
特别是,所述的30-卤代桦木酸的生产方法,以桦木醇为原料,包括如下顺序进行的步骤:
(1)桦木醇氧化卤化制备30-卤代桦木酸粗品:将桦木醇溶于一种有机溶剂中,依次加入2,2,6,6-四甲基-1-哌啶酮、碳酸氢钠、氧化卤化剂,在40~60℃下搅拌3~5小时,加入乙醇终止反应,过滤,将滤液经盐酸酸化至pH值为3.5~4.5,减压浓缩至析出沉淀,过滤并用蒸馏水洗涤所得沉淀,自然干燥得30-卤代桦木酸粗品;
(2)30-卤代桦木酸粗品纯化得30-卤代桦木酸产品:30-卤代桦木酸粗品经重结晶得30-卤代桦木酸产品。
其中,步骤(1)中所述的桦木醇与2,2,6,6-四甲基-1-哌啶酮的摩尔比为1∶0.2~0.3,所述的桦木醇与碳酸氢钠的摩尔比为1∶2~5,所述的桦木醇与氧化卤化剂的摩尔比为1∶1~3.5,所述的有机溶剂的用量为100~200毫升/克桦木醇。
所述的步骤(1)中的有机溶剂为乙酸乙酯、丁酸乙酯。
所述的步骤(1)中的氧化卤化剂为三氯异氰尿酸、N-氯代丁二酰亚胺、1,3-二溴-5,5-二甲基海因、N-溴代邻苯二甲酰亚胺。
所述的步骤(2)中的重结晶使用的溶剂为甲醇或乙醇,重结晶的次数为2~3次。
实施例1
将44.3克(0.1moL)桦木醇溶于4430毫升乙酸乙酯中,在搅拌下依次加入3.12克(0.02moL)2,2,6,6-四甲基-1-哌啶酮、25.2克(0.3moL)碳酸氢钠、46.7克(0.35moL)N-氯代丁二酰亚胺,在60℃下搅拌反应5小时后,加入10毫升乙醇终止反应,过滤,向滤液中滴加稀盐酸酸化至pH值为3.5,减压浓缩至析出沉淀,过滤并用蒸馏水洗涤所得沉淀,自然干燥得30-氯代桦木酸粗品47.3克。将所得30-氯代桦木酸粗品经甲醇重结晶2次得30-氯代桦木酸产品40.8克,纯度95.6%,收率79.3%。
实施例2
将44.3克(0.1moL)桦木醇溶于8860毫升丁酸乙酯中,在搅拌下依次加入4.68克(0.03moL)2,2,6,6-四甲基-1-哌啶酮、42.0克(0.5moL)碳酸氢钠、42.9克(0.15moL)1,3-二溴-5,5-二甲基海因,在40℃下搅拌反应3小时后,加入10毫升乙醇终止反应,过滤,向滤液中滴加稀盐酸酸化至pH值为4.5,减压浓缩至析出沉淀,过滤并用蒸馏水洗涤所得沉淀,自然干燥得30-溴代桦木酸粗品52.6克。将所得30-溴代桦木酸粗品经乙醇重结晶3次得30-溴代桦木酸产品38.8克,纯度97.1%,收率70.3%。
实施例3
将44.3克(0.1moL)桦木醇溶于6500毫升乙酸乙酯中,在搅拌下依次加入4.68克(0.03moL)2,2,6,6-四甲基-1-哌啶酮、42.0克(0.5moL)碳酸氢钠、23.2克(0.1moL)三氯异氰尿酸,在50℃下搅拌反应3小时后,加入10毫升乙醇终止反应,过滤,向滤液中滴加稀盐酸酸化至pH值为4.5,减压浓缩至析出沉淀,过滤并用蒸馏水洗涤所得沉淀,自然干燥得30-氯代桦木酸粗品48.6克。将所得30-氯代桦木酸粗品经甲醇重结晶3次得30-氯代桦木酸产品40.1克,纯度98.1%,收率80.1%。
实施例4
将44.3克(0.1moL)桦木醇溶于8000毫升丁酸乙酯中,在搅拌下依次加入4.68克(0.03moL)2,2,6,6-四甲基-1-哌啶酮、33.6克(0.4moL)碳酸氢钠、67.5克(0.3moL)N-溴代邻苯二甲酰亚胺,在60℃下搅拌反应5小时后,加入10毫升乙醇终止反应,过滤,向滤液中滴加稀盐酸酸化至pH值为4.5,减压浓缩至析出沉淀,过滤并用蒸馏水洗涤所得沉淀,自然干燥得30-溴代桦木酸粗品48.6克。将所得30-溴代桦木酸粗品经甲醇重结晶3次得30-溴代桦木酸产品37.8克,纯度95.1%,收率77.0%。
Claims (6)
1.一种30-卤代桦木酸的生产方法,其特征在于,以桦木醇为原料,采用氧化卤化剂使桦木醇一步完成选择性氧化与卤化,从而直接得到30-卤代桦木酸粗品,30-卤代桦木酸粗品经纯化得到30-卤代桦木酸产品;
其中,所述氧化卤化剂选自三氯异氰尿酸、N-氯代丁二酰亚胺、1,3-二溴-5,5-二甲基海因和N-溴代邻苯二甲酰亚胺。
2.按照权利要求1所述的30-卤代桦木酸的生产方法,其特征在于所述的30-卤代桦木酸是30-氯代桦木酸或者30-溴代桦木酸。
3.按照权利要求1所述的30-卤代桦木酸的生产方法,其特征在于以桦木醇为原料,包括如下顺序进行的步骤:
(1)桦木醇氧化卤化制备30-卤代桦木酸粗品:将桦木醇溶于一种有机溶剂中,依次加入2,2,6,6-四甲基-1-哌啶酮、碳酸氢钠、氧化卤化剂,在40~60℃下搅拌3~5小时,加入乙醇终止反应,过滤,将滤液经盐酸酸化至pH值为3.5~4.5,减压浓缩至析出沉淀,过滤并用蒸馏水洗涤所得沉淀,自然干燥得30-卤代桦木酸粗品;
(2)30-卤代桦木酸粗品纯化得30-卤代桦木酸产品:30-卤代桦木酸粗品经重结晶得30-卤代桦木酸产品。
4.按照权利要求3所述的30-卤代桦木酸的生产方法,其特征在于步骤(1)中所述的桦木醇与2,2,6,6-四甲基-1-哌啶酮的摩尔比为1∶0.2~0.3,所述的桦木醇与碳酸氢钠的摩尔比为1∶2~5,所述的桦木醇与氧化卤化剂的摩尔比为1∶1~3.5,所述的有机溶剂的用量为100~200毫升/克桦木醇。
5.按照权利要求3所述的30-卤代桦木酸的生产方法,其特征在于步骤(1)中的有机溶剂为乙酸乙酯、丁酸乙酯。
6.按照权利要求3所述的30-卤代桦木酸的生产方法,其特征在于步骤(2)中重结晶使用的溶剂为甲醇或乙醇,重结晶的次数为2~3次。
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