CN104276952B - 比拉斯汀关键中间体的制备方法 - Google Patents
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- 229960004314 bilastine Drugs 0.000 title claims abstract description 10
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- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 3
- OFYSAFPKXXTYLU-UHFFFAOYSA-N ethyl 2-methyl-2-phenylpropanoate Chemical compound CCOC(=O)C(C)(C)C1=CC=CC=C1 OFYSAFPKXXTYLU-UHFFFAOYSA-N 0.000 claims description 27
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
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- YIWUAPISITUDBY-UHFFFAOYSA-N (2,3,4-trifluorophenyl)methanamine Chemical compound NCC1=CC=C(F)C(F)=C1F YIWUAPISITUDBY-UHFFFAOYSA-N 0.000 description 2
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 2
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- WMKGGPCROCCUDY-PHEQNACWSA-N dibenzylideneacetone Chemical compound C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 WMKGGPCROCCUDY-PHEQNACWSA-N 0.000 description 2
- ZOGRPOZNEZJMAR-UHFFFAOYSA-N ethyl 2-(6,6-dimethylcyclohexa-2,4-dien-1-yl)acetate Chemical compound CCOC(=O)CC1C=CC=CC1(C)C ZOGRPOZNEZJMAR-UHFFFAOYSA-N 0.000 description 2
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- BKVHNXUUAWSELQ-UHFFFAOYSA-N [Cl].ClCC(=O)Cl Chemical group [Cl].ClCC(=O)Cl BKVHNXUUAWSELQ-UHFFFAOYSA-N 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
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- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/31—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of functional groups containing oxygen only in singly bound form
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
- C07C69/732—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids of unsaturated hydroxy carboxylic acids
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- C07D301/00—Preparation of oxiranes
- C07D301/02—Synthesis of the oxirane ring
- C07D301/24—Synthesis of the oxirane ring by splitting off HAL—Y from compounds containing the radical HAL—C—C—OY
- C07D301/26—Y being hydrogen
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- C07D303/02—Compounds containing oxirane rings
- C07D303/38—Compounds containing oxirane rings with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D303/40—Compounds containing oxirane rings with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals by ester radicals
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Abstract
本发明公开了一种比拉斯汀关键中间体2-(4-羟乙基)苯基-2-甲基丙酸酯的制备方法，该方法是2-(4-卤乙酰基)苯基-2-甲基丙酸酯在催化剂作用下进行还原羰基反应，后在碱性溶液中发生成环反应、催化剂作用下发生还原反应，得到2-(4-羟乙基)苯基-2-甲基丙酸酯。该方法避免了现有技术中的苛刻条件，且原料易得，操作简单，成本较低，对环境友好，适合工业化生产。
Description
技术领域
本发明为药物制备领域，具体涉及一种2-(4-羟乙基)苯基-2-甲基丙酸酯的制备方法。
背景技术
比拉斯汀(Bilastine)，为西班牙FAES公司研发的一种第2代组胺H1受体拮抗剂，2010年在欧盟获得批准，是当年全球批准的15个新分子实体之一。作为第2代抗组胺药物，比拉斯汀主要用于治疗过敏性鼻炎、荨麻疹以及慢性哮喘，较第1代抗组胺药有较低的中枢神经系统镇静作用，且服用后嗜睡乏力等副作用小。
比拉斯汀的中文化学名为：2-[4-(2-(4-(1-(2-乙氧基乙基)-苯并咪唑-2-基)哌啶-1-基)乙基)苯基]-2-甲基丙酸，其结构式如下所示：
cas：202189-78-4。
WIPO国际公开文本第WO2009102155中报道了比拉斯汀的合成方法，其合成路线如下所示：
该方法中，关键中间体2-(4-羟乙基)苯基-2-甲基丙酸乙酯的合成是以对溴苯乙醇与1-甲氧基-1-(三甲基甲硅氧基)-2-甲基-1-丙烯为原料，在催化剂双(二亚苄基丙酮)钯、三叔丁基磷和氟化锌存在下缩合制得。
该反应主要存在以下不足：(1)原料1-甲氧基-1(三甲基甲硅氧基)-2-甲基-1-丙烯及催化剂双(二亚苄基丙酮)钯和三叔丁基磷等价格都极其昂贵，不易购得，且不易保存；(2)该反应需要奇迹严格的无水无氧条件，操作复杂，且所得产物很难纯化；(3)反应完成后剩余的钯和磷都会对环境造成严重污染。
综上所述，该路线成本较高，操作困难，污染大，很难实现工业化生产。因此，寻找成本低、操作简便、对环境友好的合成方法在医药领域有非常重要的意义。
发明内容
本发明提供了一种制备比拉斯汀重要中间体的制备方法，该方法避免了现有技术中的苛刻条件，且原料易得，操作简单，成本较低，对环境友好，适合工业化生产。
为此，本发明采用的技术方案如下：
其中，X为Cl或Br，R为C1-3烷基，
包括以下步骤：
a.在溶剂中，2-(4-卤乙酰基)苯基-2-甲基丙酸酯在催化剂作用下进行还原反应，还原羰基生成2-(4-卤-2-羟乙基)苯基-2-甲基丙酸酯；
b.碱性溶液中，2-(4-卤-2-羟乙基)苯基-2-甲基丙酸酯成环反应，得到2-(4-环丙基)苯基-2-甲基丙酸酯；
c.2-(4-环丙基)苯基-2-甲基丙酸酯在催化剂作用下发生还原反应，得到2-(4-羟乙基)苯基-2-甲基丙酸酯。
进一步的，步骤a中所述的2-(4-卤乙酰基)苯基-2-甲基丙酸酯是由2，2-二甲基苯乙酸进行酰化反应后与卤乙酰卤酰化反应得到的，其合成路线如下：
进一步地，步骤a中所述的溶剂为甲醇、乙醇、丙醇、四氢呋喃、二氯甲烷或水；所述的催化剂为硼氢化钠或铝氢化锂；步骤a的反应温度为室温，反应时间为1h-5h。
进一步地，步骤b中所述的碱性溶液为氢氧化钠或氢氧化钾溶液，步骤b的反应温度为室温，反应时间为2h-10h。
进一步地，步骤c中所述的催化剂为钯和氧化铝的组合物；步骤c是在一定的压力条件下进行还原反应，反应温度为室温，反应时间为8-14h。
优选地，所述的卤乙酰卤为氯氯乙酰氯、氯乙酰溴、溴乙酰溴或溴乙酰溴。
进一步优选地，步骤a中所述的溶剂为四氢呋喃；所述的催化剂为硼氢化钠；所述的还原反应时间为2h；步骤b中所述的碱性溶液为氢氧化钠；步骤c中所述的还原剂为5％钯-氧化铝；所述的压力条件为1M氢气压；所述的还原反应时间为12h。
具体实施方式
下面以具体的实施例对本发明的内容作进一步详细地说明，但本发明的保护范围不限于此。
实施例1：2，2-二甲基苯乙酸乙酯的合成
于10L的反应烧瓶中加入2，2-二甲基苯乙酸(500g，3.1mol)，2.5L二氯甲烷溶液，室温下搅拌，加入氯化亚砜(750g，6.3mol)，升温至体系回流状态下反应15h，再缓慢滴加400mL无水乙醇后搅拌一段时间，待TLC检测反应完成后用NaOH溶液调节pH值至9-10，分出有机层，饱和碳酸氢钠洗涤2次，饱和氯化钠洗涤2次后浓缩干燥，得到2，2-二甲基苯乙酸乙酯(560g，96％)。
实施例2：2-(4-氯乙酰基)苯基-2-甲基丙酸乙酯的合成
于5L的反应烧瓶中，加入2，2-二甲基苯乙酸乙酯(542g，2.8mol)，2L二氯甲烷溶液，搅拌，加入无水三氯化铝(600g，4.5mol)，再滴加含氯乙酰氯(318.6g，2.8mol)的500mL二氯甲烷混合液，后反应一段时间，待TLC检测反应完成后停止反应，分出有机层，对有机层分别用水、饱和碳酸氢钠溶液、饱和氯化钠溶液洗涤，后浓缩干燥，得到2-(4-氯乙酰基)苯基-2-甲基丙酸乙酯(660g，87％)。
实施例3：2-(4-溴乙酰基)苯基-2-甲基丙酸乙酯的合成
按照实施例2的操作，用溴乙酰溴替换实施例2中的氯乙酰氯，得到2-(4-溴乙酰基)苯基-2-甲基丙酸乙酯(黄色液体，86％)。
实施例4：2-(4-氯-2-羟乙基)苯基-2-甲基丙酸乙酯的合成
于5L的反应烧瓶中加入2-(4-氯乙酰基)苯基-2-甲基丙酸乙酯(656g，2.4mol)，3L四氢呋喃溶液溶液，室温下搅拌，分批次加入硼氢化钠(185g，4.9mol)后反应一段时间，待TLC检测反应完成后停止反应。浓缩至干，加入适量乙酸乙酯和水，搅拌，分出有机层，对有机层分别用水、饱和氯化钠分别洗涤，浓缩干燥，得到2-(4-氯-2-羟乙基)苯基-2-甲基丙酸乙酯(615g，93％)。
实施例5：2-(4-氯-2-羟乙基)苯基-2-甲基丙酸乙酯的合成
按照实施例4的操作，用铝氢化锂替换实施例4中的硼氢化钠，得到2-(4-氯-2-羟乙基)苯基-2-甲基丙酸乙酯(黄色液体，89％)。
实施例6：2-(4-氯-2-羟乙基)苯基-2-甲基丙酸乙酯的合成
按照实施例4的操作，用甲醇溶液替换实施例4中的四氢呋喃溶液，得到2-(4-氯-2-羟乙基)苯基-2-甲基丙酸乙酯(黄色液体，87％)。
实施例7：2-(4-氯-2-羟乙基)苯基-2-甲基丙酸乙酯的合成
按照实施例4的操作，用水替换实施例4中的四氢呋喃溶液，得到2-(4-氯-2-羟乙基)苯基-2-甲基丙酸乙酯(黄色液体，80％)。
实施例8：2-(4-氯-2-羟乙基)苯基-2-甲基丙酸乙酯的合成
按照实施例4的操作，用二氯甲烷替换实施例4中的四氢呋喃溶液，得到2-(4-氯-2-羟乙基)苯基-2-甲基丙酸乙酯(黄色液体，84％)。
实施例9：2-(4-环丙基)苯基-2-甲基丙酸乙酯的合成
于10L的反应烧瓶中，加入2L稀氢氧化钠溶液，室温搅拌，滴加含2-(4-氯-2-羟乙基)苯基-2-甲基丙酸乙酯(609g，2.9mol)的3L异丙醇混合液，反应一段时间后，待TLC检测反应完成后停止反应，滴加稀盐酸溶液调节体系pH值至弱碱性，浓缩至干，加入适量乙酸乙酯，搅拌，分出有机层后分别用水、饱和氯化钠洗涤，浓缩干燥，得到2-(4-环丙基)苯基-2-甲基丙酸乙酯(429g，81％)。
实施例10：2-(4-环丙基)苯基-2-甲基丙酸乙酯的合成
按照实施例9的操作，用氢氧化钾溶液替换实施例9中的氢氧化钠溶液，得到得到2-(4-环丙基)苯基-2-甲基丙酸乙酯(黄色溶液，73％)
实施例11：2-(4-羟乙基)苯基-2-甲基丙酸乙酯的合成
于2L的氢化釜中分别加入2-(4-环丙基)苯基-2-甲基丙酸乙酯(425g，1.8mol)、500mL乙醇溶液、42.5g5％钯-氧化铝、氢氧化钠(1.1g，27.5mmol)和22mL水，搅拌，加入1M氢气压，室温下反应一段时间，待TLC检测反应完成后滤去不溶物，滤液浓缩至干，加入4L乙酸乙酯充分溶解该浓缩物，分别用水、饱和氯化钠溶液洗涤，浓缩干燥，得到2-(4-羟乙基)苯基-2-甲基丙酸乙酯(406g，95％)。
1HNMR(d-DMSO，300MHz)：δ7.13-7.04(4H，m)，δ4.56-4.55(1H，m)，δ3.99(2H，q)，δ3.53(2H，d)，δ2.64(2H，d)，δ1.41(6H，s)，δ1.05(3H，t)。
MS(ESI)：237.3([M+H]+)。
Claims (4)
1.一种比拉斯汀关键中间体，2-（4-羟乙基）苯基-2-甲基丙酸酯的制备方法，其特征在于其制备路线如下：
其中，X为Cl，R为乙基，
包括以下步骤：
a.在溶剂中，2-（4-氯乙酰基）苯基-2-甲基丙酸乙酯在催化剂作用下进行还原反应，还原羰基生成2-（4-氯-2-羟乙基）苯基-2-甲基丙酸乙酯；
b.碱性溶液中，2-（4-氯-2-羟乙基）苯基-2-甲基丙酸乙酯成环反应，得到2-（4-环氧乙烷基）苯基-2-甲基丙酸乙酯；
c.于2L的氢化釜中分别加入2-(4-环氧乙烷基)苯基-2-甲基丙酸乙酯(425g，1.8mol)、500mL乙醇溶液、42.5g5％钯-氧化铝、氢氧化钠(1.1g，27.5mmol)和22mL水，搅拌，加入1M氢气压，室温下反应一段时间，待TLC检测反应完成后滤去不溶物，滤液浓缩至干，加入4L乙酸乙酯充分溶解该浓缩物，分别用水、饱和氯化钠溶液洗涤，浓缩干燥，得到2-(4-羟乙基)苯基-2-甲基丙酸乙酯。
2.根据权利要求1所述的方法，其特征在于：步骤a中所述的溶剂为甲醇、乙醇、丙醇、四氢呋喃、二氯甲烷或水；所述的催化剂为硼氢化钠或铝氢化锂。
3.根据权利要求1所述的方法，其特征在于：步骤b中所述的碱性溶液为氢氧化钠或氢氧化钾溶液。
4.根据权利要求1所述的方法，其特征在于：步骤a中所述的溶剂为四氢呋喃；所述的催化剂为硼氢化钠。
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