CN111269140A - 一种拉考沙胺的制备方法 - Google Patents
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- VPPJLAIAVCUEMN-GFCCVEGCSA-N lacosamide Chemical compound COC[C@@H](NC(C)=O)C(=O)NCC1=CC=CC=C1 VPPJLAIAVCUEMN-GFCCVEGCSA-N 0.000 title claims abstract description 24
- 229960002623 lacosamide Drugs 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title abstract description 8
- 230000011987 methylation Effects 0.000 claims abstract description 20
- 238000007069 methylation reaction Methods 0.000 claims abstract description 20
- 238000006243 chemical reaction Methods 0.000 claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 14
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 13
- -1 trimethyl oxonium tetrafluoroborate Chemical compound 0.000 claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 6
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 5
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 5
- 239000007810 chemical reaction solvent Substances 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 30
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 9
- GJFNRSDCSTVPCJ-UHFFFAOYSA-N 1,8-bis(dimethylamino)naphthalene Chemical compound C1=CC(N(C)C)=C2C(N(C)C)=CC=CC2=C1 GJFNRSDCSTVPCJ-UHFFFAOYSA-N 0.000 claims description 6
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- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
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- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 3
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
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- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
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- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
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- 238000001308 synthesis method Methods 0.000 claims description 2
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
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- WPLANNRKFDHEKD-UHFFFAOYSA-N 2-amino-n-benzyl-3-methoxypropanamide Chemical compound COCC(N)C(=O)NCC1=CC=CC=C1 WPLANNRKFDHEKD-UHFFFAOYSA-N 0.000 description 2
- 206010010904 Convulsion Diseases 0.000 description 2
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- 230000021736 acetylation Effects 0.000 description 2
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- JJIHLJJYMXLCOY-SCSAIBSYSA-N (2r)-2-acetamido-3-hydroxypropanoic acid Chemical compound CC(=O)N[C@H](CO)C(O)=O JJIHLJJYMXLCOY-SCSAIBSYSA-N 0.000 description 1
- FHOAKXBXYSJBGX-RXMQYKEDSA-N (2r)-3-hydroxy-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](CO)C(O)=O FHOAKXBXYSJBGX-RXMQYKEDSA-N 0.000 description 1
- WYCNJBXJCACFCM-UHFFFAOYSA-N 2-amino-n-benzyl-3-hydroxypropanamide Chemical compound OCC(N)C(=O)NCC1=CC=CC=C1 WYCNJBXJCACFCM-UHFFFAOYSA-N 0.000 description 1
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- XRKSCJLQKGLSKU-LLVKDONJSA-N O-Desmethyl-lacosamide Chemical compound CC(=O)N[C@H](CO)C(=O)NCC1=CC=CC=C1 XRKSCJLQKGLSKU-LLVKDONJSA-N 0.000 description 1
- 206010061334 Partial seizures Diseases 0.000 description 1
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- 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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Abstract
本发明提供一种拉考沙胺合成中间体的甲基化新方法，该方法包括将化合物I在合适温度的反应溶剂中，以三甲基氧鎓四氟硼酸盐为甲基化试剂，在碱性条件下，进行甲基化得到甲基化产物II。反应式如下：
Description
技术领域
本发明涉及医药化工领域，尤其涉及一种药物拉考沙胺的制备方法。
背景技术
拉考沙胺(Lacosamide)，化学名为(R)-2-乙酰胺基-N-苄基-3-甲氧基丙酰胺(其结构式如下所示)，是由University of Houston(USA)研发后许可给比利时优时比公司(UCB)治疗癫痫和神经性疼痛的药物拉考沙胺是一种新型N-甲基-D-天门冬氨酸(NMDA)受体甘氨酸位点结合拮抗剂。2017年9月欧盟批准拉考沙胺用于4岁及以上癫痫患者部分发作性癫痫的治疗。2008年10月美国FDA批准其作为一种辅助药物与其它药物联合用于癫痫部分性发作。商品名为Vimpat。Vimpat获准上市的有三种剂型：薄膜片(50、100、150和200mg/片)、注射液(10mg/ml,20ml/支)、口服溶液(10mg/ml)，当患者不宜口服时可采用推注给药。现已在全球26个国家上市。
拉考沙胺(Lacosamide,CAS:175481-36-4)，结构式如下：
文献报道拉考沙胺的合成路线主要有三条，均以D-丝氨酸为起始原料：
1)专利WO 1997033861报道了拉考沙胺的合成方法，先乙酰化再酰胺化最后甲基化。
该路线以D-丝氨酸为原料，先与乙酸酐乙酰化生成N-乙酰基-D-丝氨酸，再经氯甲酸异丁酯成混合酸酐，与苄胺缩合，最后在氧化银和碘甲烷条件下甲基化制得拉考沙胺。路线中与苄胺缩合收率只有33％，且需要低温-78℃，经柱层析纯化；甲基化步骤要用到昂贵的氧化银，不经济实用；且该步合成中会产生15％的消旋化，影响终产品的质量。
2)专利WO 1997033861和J.Med.Chem.1996,39,1907-1916报道了另一种方法制备拉考沙胺，先酰胺化再乙酰化最后甲基化。
以D-丝氨酸为原料，经甲酯化，苄胺缩合，乙酰化，最后甲基化制得拉考沙胺。路线中前两步收率只有27％，收率过低，且与苄胺缩合会有不同程度的消旋；甲基化步骤同样要用到昂贵的氧化银，不经济实用，不适合工业化生产。
3)专利CN 1989102公开了一种拉考沙胺的合成方法，先甲基化再酰胺化最后乙酰化。
D-丝氨酸经叔丁氧羰基(Boc)保护得N-Boc-D-丝氨酸，再经硫酸二甲酯甲基化，苄胺缩合，脱Boc，最后乙酰化制得拉考沙胺。该路线用硫酸二甲酯作为甲基化试剂，收率有所提高，且避免使用价格昂贵的氧化银。但该方法以基因毒性试剂硫酸二甲酯作为甲基化试剂，毒性较大，不符合绿色环保要求，在药物制备中也应该尽量避免。
针对以上问题，本发明提供了合成拉考沙胺的新方法，该方法避免使用基因毒性试剂硫酸二甲酯作为甲基化试剂，同时提高了收率和对映体选择性。
发明内容
本发明目的提供一种合成拉考沙胺的新方法，该方法避免使用基因毒性试剂硫酸二甲酯作为甲基化试剂，同时提高了收率。
本发明提供一种拉考沙胺合成中间体的甲基化新方法，该方法包括将化合物I在合适温度的反应溶剂中，以三甲基氧鎓四氟硼酸盐为甲基化试剂，在碱性条件下，进行甲基化得到甲基化产物II。反应式如下：
其中R1为N-保护基团，选自乙酰基、叔丁氧羰基或苄氧羰基；R2为羟基或C1～4烷氧基或N-苄基氨基。
本发明所述的化合物I可采用试剂级或者工业级纯度的化合物；也可采用现有或已知的方法和技术来合成；
本发明所述的甲基化试剂为三甲基氧鎓四氟硼酸盐；
本发明所述的碱为NaOH、KOH、NaHCO3、KHCO3、Et3N、四丁基氢氧化铵、1,8-双二甲氨基萘等一种或其任意组合，优选NaOH或1,8-双二甲氨基萘；
本发明所述反应溶剂为，二氯甲烷、1,2-二氯乙烷、乙腈、氯仿、甲苯、四氢呋喃及2-甲基四氢呋喃等溶剂一种或其任意组合；优选二氯甲烷；
本发明所述合适温度为0～50℃，不同的反应条件下，在此温度范围内以不破坏反应物中其他官能团和有利于反应的进行为原则，选择不同的反应温度来进行，本发明优选反应温度为10～30℃，进一步优选20～30℃。
本发明的有益的技术效果在于：本发明所提供的方法反应条件温和，后处理简单，甲基化试剂绿色，无高毒性，反应收率高，符合安全环保的绿色化学理念。不仅适合实验室小规模制备，也适合大规模工业化生产。
具体实施例
以下将结合实施例对本发明的技术方案及其所产生的技术效果作进一步说明，但并不因此将本发明限制在所述的实施例范围之中。
实施例1：(R)-2-N-Boc-氨基-3-甲氧基丙酸甲酯的制备
向100ml三口瓶中加入2g(R)-2-N-Boc-氨基-3-羟基丙酸甲酯，40ml二氯甲烷，3.9g 1,8-双二甲氨基萘，氮气保护下加入2.1g三甲基氧鎓四氟硼酸盐，20℃搅拌24h，向反应液中加入30ml冰水，搅拌30min，过滤，分液，水相二氯甲烷30ml×2提取，合并有机相，1mol/L盐酸20ml×3洗涤，饱和碳酸氢钠水溶液20ml洗涤，水30ml洗，无水硫酸钠干燥，减压浓缩得(R)-2-N-Boc-氨基-3-甲氧基丙酸甲酯1.3g，收率61.1％。
实施例2：(R)-2-乙酰胺基-N-苄基-3-甲氧基丙酰胺(拉考沙胺)
向100ml三口瓶中加入2g(R)-2-乙酰胺基-N-苄基-3-羟基丙酰胺，40ml乙腈氮气保护下加入2g三甲基氧鎓四氟硼酸盐，分三批加入0.7g NaOH粉末，10℃搅拌24h，向反应液中加入30ml水，搅拌10min，过滤，分液，水相二氯甲烷40ml×2提取，合并有机相，1mol/L盐酸20ml×3洗涤，饱和碳酸氢钠水溶液20ml洗涤，水20ml洗，无水硫酸钠干燥，减压浓缩得固体(R)-2-乙酰胺基-N-苄基-3-甲氧基丙酰胺1.6g，收率76.2.0％。
实施例3：(R)-2-N-Boc-氨基-3-甲氧基丙酸的制备
向100ml三口瓶中加入2g(R)-2-N-Boc-氨基-3-羟基丙酸，50ml二氯甲烷，4.3g 1,8-双二甲氨基萘，氮气保护下加入3.2g三甲基氧鎓四氟硼酸盐，10℃搅拌24h，向反应液中加入30ml冰水，搅拌30min，过滤，滤液用50％柠檬酸调pH至<3，分液，二氯甲烷30ml×2提取，合并有机相，1mol/L盐酸20ml×3洗涤，饱和碳酸氢钠水溶液20ml洗涤，水30ml洗，无水硫酸钠干燥，减压浓缩得(R)-2-N-Boc-氨基-3-甲氧基丙酸1.8g，收率84.7％。
实施例4：(R)-2-Boc胺基-N-苄基-3-甲氧基丙酰胺
向100ml三口瓶中加入2g(R)-2-Boc胺基-N-苄基-3-羟基丙酰胺，40ml二氯甲烷，2.9g1,8-双二甲氨基萘，氮气保护下加入1.5g三甲基氧鎓四氟硼酸盐，20℃搅拌16h，向反应液中加入30ml冰水，搅拌30min，过滤，分液，水相二氯甲烷30ml×2提取，合并有机相，1mol/L盐酸20ml×3洗涤，饱和碳酸氢钠水溶液20ml洗涤，水30ml洗，无水硫酸钠干燥，减压浓缩得(R)-2-Boc胺基-N-苄基-3-甲氧基丙酰胺1.7g，收率81.0％。
Claims (5)
1.一种拉考沙胺合成中间体的甲基化新方法，该方法包括将化合物I在合适温度的反应溶剂中，以三甲基氧鎓四氟硼酸盐为甲基化试剂，在碱性条件下，进行甲基化得到甲基化产物II。反应式如下：
其中R1为N-保护基团。
2.根据权利要求1所述的方法，R1为N-保护基团，选自乙酰基、叔丁氧羰基或苄氧羰基；R2为羟基或C1～4烷氧基或N-苄基氨基。
3.根据权利要求1所述的方法，其特征在于，所述的碱为NaOH、KOH、NaHCO3、KHCO3、Et3N、四丁基氢氧化铵、1,8-双二甲氨基萘等一种或其任意组合。
4.根据权利要求1所述的方法，其特征在于，所述溶剂选自二氯甲烷、1,2-二氯乙烷、乙腈、氯仿、甲苯、四氢呋喃及2-甲基四氢呋喃等溶剂一种或其任意组合。
5.根据权利要求1所述的合成方法，其特征在于，所述反应温度为0～50℃。
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