CN109734654A - 一种盐酸左布比卡因的制备方法 - Google Patents
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- SIEYLFHKZGLBNX-NTISSMGPSA-N levobupivacaine hydrochloride (anhydrous) Chemical compound [Cl-].CCCC[NH+]1CCCC[C@H]1C(=O)NC1=C(C)C=CC=C1C SIEYLFHKZGLBNX-NTISSMGPSA-N 0.000 claims abstract description 21
- 238000006243 chemical reaction Methods 0.000 claims abstract description 15
- ZTQSAGDEMFDKMZ-UHFFFAOYSA-N Butyraldehyde Chemical compound CCCC=O ZTQSAGDEMFDKMZ-UHFFFAOYSA-N 0.000 claims abstract description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 10
- -1 piperidine amides Chemical class 0.000 claims abstract description 8
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000007858 starting material Substances 0.000 claims abstract description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- 230000035484 reaction time Effects 0.000 claims description 5
- 239000012024 dehydrating agents Substances 0.000 claims description 4
- 239000000706 filtrate Substances 0.000 claims description 4
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 claims description 4
- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical group O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 claims description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 3
- 230000008859 change Effects 0.000 claims description 3
- 239000002808 molecular sieve Substances 0.000 claims description 3
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 2
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims 1
- 150000001299 aldehydes Chemical class 0.000 claims 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 1
- 239000011575 calcium Substances 0.000 claims 1
- 229910052791 calcium Inorganic materials 0.000 claims 1
- 229960000935 dehydrated alcohol Drugs 0.000 claims 1
- 229910052760 oxygen Inorganic materials 0.000 claims 1
- 239000001301 oxygen Substances 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 4
- 238000005516 engineering process Methods 0.000 abstract description 3
- 150000003839 salts Chemical class 0.000 abstract description 2
- 238000011084 recovery Methods 0.000 abstract 1
- 238000006268 reductive amination reaction Methods 0.000 abstract 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- MPPPKRYCTPRNTB-UHFFFAOYSA-N 1-bromobutane Chemical compound CCCCBr MPPPKRYCTPRNTB-UHFFFAOYSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- LEBVLXFERQHONN-UHFFFAOYSA-N 1-butyl-N-(2,6-dimethylphenyl)piperidine-2-carboxamide Chemical compound CCCCN1CCCCC1C(=O)NC1=C(C)C=CC=C1C LEBVLXFERQHONN-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 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
- 150000001408 amides Chemical class 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229960003150 bupivacaine Drugs 0.000 description 1
- BRPQOXSCLDDYGP-UHFFFAOYSA-N calcium oxide Chemical compound [O-2].[Ca+2] BRPQOXSCLDDYGP-UHFFFAOYSA-N 0.000 description 1
- 239000000292 calcium oxide Substances 0.000 description 1
- ODINCKMPIJJUCX-UHFFFAOYSA-N calcium oxide Inorganic materials [Ca]=O ODINCKMPIJJUCX-UHFFFAOYSA-N 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- KXRNYDKIPJKLTD-UHFFFAOYSA-N cyanoboron Chemical compound [B]C#N KXRNYDKIPJKLTD-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 235000021050 feed intake Nutrition 0.000 description 1
- 239000004519 grease Substances 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 238000004519 manufacturing process Methods 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
- 238000005580 one pot reaction Methods 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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Abstract
本发明涉及一种新型的盐酸左布比卡因制备方法,属于制药技术领域范畴。以左哌啶酰胺和正丁醛为起始原料,经还原胺化反应得到左布比卡因碱基,再经盐酸成盐得到盐酸左布比卡因。相对于现有的技术方法,本法反应条件极为温和,操作简单,制备总收率较高。
Description
技术领域
本发明涉及盐酸左布比卡因的制备方法,属于制药技术领域。
背景技术
盐酸左布比卡因是一种新型长效酰胺类局部麻醉药,最早由美国Purdue制药公司开发,并于2002年在美国FDA上市。国内仅珠海润都制药、江苏盛迪医药及江苏奥赛康药业有盐酸左布比卡因原料药的生产批件。盐酸左布比卡因由外消旋体盐酸布比卡因发展而来,其右旋异构体被证明具有较强的心肌抑制作用,因此分离出高纯度的盐酸左布比卡因是非常重要的。
目前,文献报道的盐酸左布比卡因主要制备方法是以左哌啶酰胺和1-溴丁烷为起始物料,以碳酸钾等无机碱为催化剂,以N,N-二甲基甲酰胺,经高温、长时间反应得到左布比卡因碱基,再用盐酸成盐得到盐酸左布比卡因。
该法反应温度较高,反应耗时长,易产生季铵盐等杂质;且1-溴丁烷易挥发,如温度、反应器等控制不好1-溴丁烷易挥发出来,造成收率不稳定,另外,1-溴丁烷作为卤代烃类基因毒性杂质,挥发后对操作人员身体健康造成威胁;再次,该反应N,N-二甲基甲酰胺等高沸点溶剂,难以去除,对药物质量产生影响。
发明内容
本发明描述了一种新型的盐酸左布比卡因制备方法,避免了上述诸多问题。
本发明技术路线如下:
(1)以左哌啶酰胺和正丁醛为起始原料,在三乙胺、脱水剂存在下,于乙醇中常温搅拌24小时后,往反应体系中加入氰基硼氢化钠,继续反应,后浓缩干,用二氯甲烷重新溶解,水洗,二氯甲烷层用无水硫酸镁干燥,过滤,滤液浓缩后得到油状左布比卡因碱基。
(2)将油状的左布比卡因碱基溶于丙酮,加入浓盐酸调节pH至4~5,冷却析晶,过滤得到盐酸左布比卡因。
本发明特征在于,步骤(1)中,左哌啶酰胺、三乙胺、正丁醛及氰基硼氢化钠的投料摩尔比为1∶1∶1~1.5∶3~8;
本发明特征在于,步骤(1)中,脱水剂为五氧化二磷、氧化钙、分子筛中的一种;
本发明特征在于,步骤(1)中,第一次反应时间为12~24小时,第二次反应时间为5~10小时。
本发明的优势如下:
以左哌啶酰胺和正丁醛为起始原料,还原胺化得到左布比卡因碱基,反应条件温和,室温即可反应,操作简单,一锅化反应,反应收率较高。
具体实施方式:
实施例1:
将左哌啶酰胺(50mmol,11.6g)、正丁醛(60mmol,3.6g)以及三乙胺(50mmol,5.1g)溶于150mL乙醇,加入35g活化过的分子筛,室温搅拌反应24小时,往反应液中加入氰基硼氢化钠(250mmol,15.7g),继续搅拌反应6小时,将反应液浓缩至干,除去溶剂和三乙胺,加入二氯甲烷约200mL重新溶解,100mL水洗涤两次,10g无水硫酸镁干燥,过滤,滤液浓缩至干,得淡黄色油状物。用80mL丙酮加热溶解油状物,浓盐酸调节pH至4~5,降温至0~5℃搅拌析晶2小时,过滤得盐酸左布比卡因12.7g。
Claims (4)
1.一种盐酸左布比卡因的制备方法,路线如下:
具体步骤为:
(1)以左哌啶酰胺和正丁醛为起始原料,在三乙胺、脱水剂存在下,于无水乙醇中常温搅拌反应完毕后,往反应体系中加入氰基硼氢化钠,继续反应,反应完毕后过滤,滤液浓缩干,用二氯甲烷重新溶解,水洗,二氯甲烷层用无水硫酸镁干燥,过滤,滤液浓缩后得到油状左布比卡因碱基。
(2)将油状的左布比卡因碱基溶于丙酮,加入浓盐酸调节pH至4~5,冷却析晶,过滤得到盐酸左布比卡因。
2.根据权利要求1所述的制备方法,其特征在于,步骤(1)中,左哌啶酰胺、三乙胺、正丁醛及氰基硼氢化钠的投料摩尔比为1∶1∶1~1.5∶3~8。
3.根据权利要求1所述的制备方法,其特征在于,步骤(1)中,脱水剂为五氧化二磷、氧化钙、分子筛中的一种。
4.根据权利要求1所述的制备方法,其特征在于,步骤(1)中,第一次反应时间为12~24小时,第二次反应时间为5~10小时。
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN111548303A (zh) * | 2020-06-28 | 2020-08-18 | 山东美泰医药有限公司 | 一种盐酸左布比卡因的杂质及其制备和分析方法 |
CN113087655A (zh) * | 2020-01-09 | 2021-07-09 | 鲁南制药集团股份有限公司 | 一种左布比卡因中间体化合物 |
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WO2001076599A1 (en) * | 2000-04-06 | 2001-10-18 | Cristália Produtos Químicos Farmacéuticos Ltda. | Process of making racemic bupivacaine's enantiomers, levobupivacaine's pharmaceutical compositions, levobupivacaine's pharmaceutical compositions formulated on its free base form or its pharmaceutical acceptable salts and use of levobupivacaine's pharmaceutical compositions formulated on its free base form |
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CN106866501A (zh) * | 2017-04-11 | 2017-06-20 | 山东百诺医药股份有限公司 | 一种盐酸左布比卡因的制备方法 |
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113087655A (zh) * | 2020-01-09 | 2021-07-09 | 鲁南制药集团股份有限公司 | 一种左布比卡因中间体化合物 |
CN113087655B (zh) * | 2020-01-09 | 2023-12-19 | 鲁南制药集团股份有限公司 | 一种左布比卡因中间体化合物 |
CN111548303A (zh) * | 2020-06-28 | 2020-08-18 | 山东美泰医药有限公司 | 一种盐酸左布比卡因的杂质及其制备和分析方法 |
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