CN106748853B - 一种（s）-邻氯苯甘氨酸甲酯盐酸盐的制备方法 - Google Patents
一种（s）-邻氯苯甘氨酸甲酯盐酸盐的制备方法 Download PDFInfo
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- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Substances ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 title claims abstract description 16
- COQRGFWWJBEXRC-UHFFFAOYSA-N hydron;methyl 2-aminoacetate;chloride Chemical compound Cl.COC(=O)CN COQRGFWWJBEXRC-UHFFFAOYSA-N 0.000 title claims abstract description 13
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 39
- 238000006243 chemical reaction Methods 0.000 claims abstract description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 18
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims abstract description 16
- FPYUJUBAXZAQNL-UHFFFAOYSA-N 2-chlorobenzaldehyde Chemical compound ClC1=CC=CC=C1C=O FPYUJUBAXZAQNL-UHFFFAOYSA-N 0.000 claims abstract description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000012044 organic layer Substances 0.000 claims abstract description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims abstract description 10
- 238000000034 method Methods 0.000 claims abstract description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims abstract description 5
- 230000003197 catalytic effect Effects 0.000 claims abstract description 5
- 239000013078 crystal Substances 0.000 claims abstract description 5
- 238000000605 extraction Methods 0.000 claims abstract description 5
- 239000000706 filtrate Substances 0.000 claims abstract description 5
- 239000007789 gas Substances 0.000 claims abstract description 5
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims abstract description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 5
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000002841 Lewis acid Substances 0.000 claims abstract description 3
- VBXYAKBKJUUJDR-UHFFFAOYSA-N benzaldehyde;hydrate Chemical compound O.O=CC1=CC=CC=C1 VBXYAKBKJUUJDR-UHFFFAOYSA-N 0.000 claims abstract description 3
- 150000007517 lewis acids Chemical class 0.000 claims abstract description 3
- 239000000203 mixture Substances 0.000 claims abstract description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- 238000010792 warming Methods 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 6
- 238000001953 recrystallisation Methods 0.000 claims description 4
- 239000012043 crude product Substances 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims 3
- 125000004494 ethyl ester group Chemical group 0.000 claims 1
- 229910052938 sodium sulfate Inorganic materials 0.000 claims 1
- 235000011152 sodium sulphate Nutrition 0.000 claims 1
- 238000004821 distillation Methods 0.000 abstract description 3
- KQSSATDQUYCRGS-UHFFFAOYSA-N methyl glycinate Chemical compound COC(=O)CN KQSSATDQUYCRGS-UHFFFAOYSA-N 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000009423 ventilation Methods 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- QSMTUAJDOTXEDZ-UHFFFAOYSA-N N1C=CC=C1.[Cl] Chemical compound N1C=CC=C1.[Cl] QSMTUAJDOTXEDZ-UHFFFAOYSA-N 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- -1 amino-acid ester Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000006480 benzoylation reaction Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
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- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
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- C07F7/02—Silicon compounds
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- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
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- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/02—Acyclic radicals, not substituted by cyclic structures
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Abstract
本发明公开了一种（S）‑邻氯苯甘氨酸甲酯盐酸盐的制备方法，所述方法包括以下步骤：1）将邻氯苯甲醛和三甲基氰硅烷混合物加入反应瓶中；再加入催化量路易斯酸，搅拌15‑20分钟；继续加入摩尔比为1:1的糖胺和甲醇，加入氯仿和水，氯仿和邻氯苯甲醛的体质比为4:1；水与邻氯苯甲醛的体质比为2:1，得纯品中间体3；2）将甲醇和浓硫酸加入到反应瓶中，然后再加入中间体3反应10小时；反应结束后，蒸馏，剩余物加入水和乙酸乙酯，萃取，有机层饱和碳酸氢钠洗涤至pH8‑9，有机层无水硫酸钠干燥，过滤，滤液降温至0‑5℃，通入氯化氢气体至不再吸收为止，静置结晶，过滤，干燥得（S）‑邻氯苯甘氨酸甲酯盐酸盐。
Description
技术领域
本发明属于药品中间体制备工艺领域，具体涉及一种（S）-邻氯苯甘氨酸甲酯盐酸盐的制备方法。
背景技术
（S）-邻氯苯甘氨酸甲酯是一种非天然的具有生物活性的氨基酸酯，是合成氯吡格雷的重要中间体，其结构式如下：
（S）-邻氯苯甘氨酸甲酯的主要合成路线为邻氯苯甘氨酸甲酯化后拆分，反应路线如下：
这种动力学拆分法合成的产品光学纯度高，但是收率低，原料浪费严重。
发明内容
本发明实现上述目的所采用的技术方案是一种（S）-邻氯苯甘氨酸甲酯盐酸盐的制备方法，所述方法的工艺路线图如下：
其中光学纯糖胺的结构式如下：
(R=Ac、Bz)
所述方法包括以下步骤：
1）将摩尔比为1:1.2-1.3的邻氯苯甲醛和三甲基氰硅烷混合物加入反应瓶中；再加入催化量路易斯酸，搅拌15-20分钟；继续加入糖胺和甲醇，糖胺与邻氯苯甲醛的摩尔比为1:1，甲醇与邻氯苯甲醛的体积比为2:1，升温至40-50℃分钟搅拌反应2小时；反应结束后蒸馏，残余物中加入氯仿和水，氯仿和邻氯苯甲醛的体积比为4:1；水与邻氯苯甲醛的体积比为2:1，萃取，有机层无水硫酸钠干燥，过滤，蒸馏，得中间体3粗品，异丙醇重结晶得纯品中间体3；
2）将体积比为4:1的甲醇和浓硫酸加入到反应瓶中，然后再加入上述中间体3，甲醇与中间体3的体积比为5:1，升温至回流反应10小时；反应结束后，蒸馏，剩余物加入水和乙酸乙酯，水与乙酸乙酯的体积比为1:5，萃取，有机层饱和碳酸氢钠洗涤至pH8-9，有机层无水硫酸钠干燥，过滤，滤液降温至0-5℃，通入氯化氢气体至不再吸收为止，静置结晶，过滤，干燥得（S）-邻氯苯甘氨酸甲酯盐酸盐。
本发明的原理及有益效果是：该合成方法路线较短，收率高，避免了拆分的原料浪费。
具体实施方式
下面结合具体实施例对本发明进行进一步描述，但本发明的保护范围并不仅限于此：
实施例1：
本发明的（S）-邻氯苯甘氨酸甲酯盐酸盐的制备方法包括以下步骤：
1) 将邻氯苯甲醛（14.0g，0.1mol)和三甲基氰硅烷（11.9g，0.12mol）加入反应瓶中，再加入催化量三氯化铝（1.33g，0.01mol），搅拌20分钟，加入乙酰化糖胺（34.7g，0.1mol)和甲醇30mL，升温至40-50℃反应2小时；反应结束后，蒸馏除去溶剂，剩余物中加入氯仿56mL和水30mL，萃取分层，有机层无水硫酸钠干燥，过滤，蒸馏后产品异丙醇重结晶得中间体3（40.7g，收率约82%）。
2）将200mL甲醇和50mL浓硫酸加入反应瓶中，搅拌均匀，再加入中间体3（40g，0.08mol），升温至回流反应10小时，蒸馏，剩余物加入乙酸乙酯200mL和水40mL，萃取，有机层饱和碳酸氢钠洗涤至pH8-9，无水硫酸钠干燥，过滤，滤液降温至0-5℃，通入氯化氢气体，通气结束，静置结晶，过滤，干燥得（S）-邻氯苯甘氨酸甲酯盐酸盐（16.8g,收率88.9%）。
实施例2：
本发明的（S）-邻氯苯甘氨酸甲酯盐酸盐的制备方法包括以下步骤：
1) 将邻氯苯甲醛（14.0g，0.1mol)和三甲基氰硅烷（11.9g，0.12mol）加入反应瓶中，再加入催化量三氯化铝（1.33g，0.01mol），搅拌20分钟，加入苯甲酰化糖胺（59.6g，0.1mol)和甲醇30mL，升温至40-50℃反应2小时；反应结束后，蒸馏除去溶剂，剩余物中加入氯仿56mL和水30mL，萃取分层，有机层无水硫酸钠干燥，过滤，蒸馏后产品异丙醇重结晶得中间体3（62.7g，收率约84%）。
2）将300mL甲醇和75mL浓硫酸加入反应瓶中，搅拌均匀，再加入中间体3（60g，0.08mol），升温至回流反应10小时，蒸馏，剩余物加入乙酸乙酯300mL和水60mL，萃取，有机层饱和碳酸氢钠洗涤至pH8-9，无水硫酸钠干燥，过滤，滤液降温至0-5℃，通入氯化氢气体，通气结束，静置结晶，过滤，干燥得（S）-邻氯苯甘氨酸甲酯盐酸盐（16.4g,收率86.8%）。
Claims (1)
1.一种（S）-邻氯苯甘氨酸甲酯盐酸盐的制备方法，其特征在于：所述方法包括以下步骤：
1）将摩尔比为1:1.2-1.3的邻氯苯甲醛和三甲基氰硅烷混合物加入反应瓶中；再加入催化量路易斯酸，搅拌15-20分钟；继续加入糖胺和甲醇，糖胺与邻氯苯甲醛的摩尔比为1:1，甲醇与邻氯苯甲醛的体积比为2:1，升温至40-50℃分钟搅拌反应2小时；反应结束后蒸馏，残余物中加入氯仿和水，氯仿和邻氯苯甲醛的体积比为4:1；水与邻氯苯甲醛的体积比为2:1，萃取，有机层无水硫酸钠干燥，过滤，蒸馏，得中间体3粗品，异丙醇重结晶得纯品中间体3；
2）将体积比为4:1的甲醇和浓硫酸加入到反应瓶中，然后再加入上述中间体3，甲醇与中间体3的体积比为5:1，升温至回流反应10小时；反应结束后，蒸馏，剩余物加入水和乙酸乙酯，水与乙酸乙酯的体积比为1:5，萃取，有机层饱和碳酸氢钠洗涤至pH8-9，有机层无水硫酸钠干燥，过滤，滤液降温至0-5℃，通入氯化氢气体至不再吸收为止，静置结晶，过滤，干燥得（S）-邻氯苯甘氨酸甲酯盐酸盐。
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0971915A1 (fr) * | 1997-03-05 | 2000-01-19 | Sanofi-Synthelabo | Procede de preparation de derives de 2-thienylethylamine |
| CN104326934A (zh) * | 2014-11-21 | 2015-02-04 | 沈健芬 | 一种2-氯苯甘氨酸甲酯盐酸盐的制备方法 |
| EP3026051A1 (en) * | 2013-07-24 | 2016-06-01 | Takeda Pharmaceutical Company Limited | Heterocyclic compound |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0971915A1 (fr) * | 1997-03-05 | 2000-01-19 | Sanofi-Synthelabo | Procede de preparation de derives de 2-thienylethylamine |
| US6080875A (en) * | 1997-03-05 | 2000-06-27 | Sanofi-Synthelabo | Method for preparing 2-thienylethylamine derivatives |
| EP3026051A1 (en) * | 2013-07-24 | 2016-06-01 | Takeda Pharmaceutical Company Limited | Heterocyclic compound |
| CN104326934A (zh) * | 2014-11-21 | 2015-02-04 | 沈健芬 | 一种2-氯苯甘氨酸甲酯盐酸盐的制备方法 |
Non-Patent Citations (2)
| Title |
|---|
| Asymmetric Strecker Synthesis of r-Arylglycines;Yolanda Perez-Fuertes等;《J. Org. Chem.》;20110531;第76卷;第6039页左栏Scheme 1(c) * |
| 邻氯苯甘氨酸甲酯的拆分;丁桂俐等;《广州化工》;20071231;第35卷(第6期);第44页左栏图1 * |
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