CN108821992A - 一种左乙拉西坦杂质以及合成方法 - Google Patents
一种左乙拉西坦杂质以及合成方法 Download PDFInfo
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- 239000012535 impurity Substances 0.000 title claims abstract description 29
- 229960004002 levetiracetam Drugs 0.000 title claims abstract description 11
- HPHUVLMMVZITSG-ZCFIWIBFSA-N levetiracetam Chemical compound CC[C@H](C(N)=O)N1CCCC1=O HPHUVLMMVZITSG-ZCFIWIBFSA-N 0.000 title claims abstract 4
- 238000010189 synthetic method Methods 0.000 title abstract description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims abstract description 20
- HTBWSCRZTSTTKF-UHFFFAOYSA-N 4,4-dichlorobutanoyl chloride Chemical compound ClC(Cl)CCC(Cl)=O HTBWSCRZTSTTKF-UHFFFAOYSA-N 0.000 claims abstract description 14
- HDBMIDJFXOYCGK-DFWYDOINSA-N (2s)-2-aminobutanamide;hydrochloride Chemical compound Cl.CC[C@H](N)C(N)=O HDBMIDJFXOYCGK-DFWYDOINSA-N 0.000 claims abstract description 13
- CDIIZULDSLKBKV-UHFFFAOYSA-N 4-chlorobutanoyl chloride Chemical compound ClCCCC(Cl)=O CDIIZULDSLKBKV-UHFFFAOYSA-N 0.000 claims abstract description 12
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-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
- 238000006243 chemical reaction Methods 0.000 claims abstract description 10
- 238000000034 method Methods 0.000 claims abstract description 8
- 150000007529 inorganic bases Chemical class 0.000 claims abstract description 7
- 239000003960 organic solvent Substances 0.000 claims abstract description 6
- 238000006482 condensation reaction Methods 0.000 claims abstract description 3
- 238000010438 heat treatment Methods 0.000 claims abstract description 3
- 238000010992 reflux Methods 0.000 claims abstract description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 229910021529 ammonia Inorganic materials 0.000 claims 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims 1
- ARUJJNVNLJPSDO-UHFFFAOYSA-N butanamide;hydrochloride Chemical compound Cl.CCCC(N)=O ARUJJNVNLJPSDO-UHFFFAOYSA-N 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- 238000005360 mashing Methods 0.000 abstract description 3
- 238000005292 vacuum distillation Methods 0.000 abstract description 3
- 230000002194 synthesizing effect Effects 0.000 abstract description 2
- 239000012065 filter cake Substances 0.000 description 9
- HPHUVLMMVZITSG-LURJTMIESA-N levetiracetam Chemical compound CC[C@@H](C(N)=O)N1CCCC1=O HPHUVLMMVZITSG-LURJTMIESA-N 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 239000007787 solid Substances 0.000 description 6
- 229920001084 poly(chloroprene) Polymers 0.000 description 4
- 230000006837 decompression Effects 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000004570 mortar (masonry) Substances 0.000 description 3
- 238000004321 preservation Methods 0.000 description 3
- -1 4- chlorobutanoylchloride Acyl chlorides Chemical class 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 150000001263 acyl chlorides Chemical class 0.000 description 2
- 239000000337 buffer salt Substances 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 238000002386 leaching Methods 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- YEJRWHAVMIAJKC-UHFFFAOYSA-N 4-Butyrolactone Chemical compound O=C1CCCO1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 0.000 description 1
- PRTPCFQVSHLFTP-MLWJPKLSSA-N CCCC(C(N[C@@H](CC)C(N)=O)=O)Cl Chemical compound CCCC(C(N[C@@H](CC)C(N)=O)=O)Cl PRTPCFQVSHLFTP-MLWJPKLSSA-N 0.000 description 1
- 0 CC[C@@](C(*)=O)N Chemical compound CC[C@@](C(*)=O)N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 230000003556 anti-epileptic effect Effects 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- DNSISZSEWVHGLH-UHFFFAOYSA-N butanamide Chemical compound CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 231100000025 genetic toxicology Toxicity 0.000 description 1
- 230000001738 genotoxic effect Effects 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 229940062717 keppra Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/14—Preparation of carboxylic acid amides by formation of carboxamide groups together with reactions not involving the carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
- C07C233/04—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C233/05—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/58—Preparation of carboxylic acid halides
- C07C51/62—Preparation of carboxylic acid halides by reactions not involving the carboxylic acid halide group
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明提供了一种左乙拉西坦的杂质及其合成方法,该方法为将4‑氯丁酰氯与氯化亚砜、盐酸、N‑氯代琥珀酰亚胺加热回流反应后减压蒸馏除去氯化亚砜后得2,4‑二氯丁酰氯;(S)‑2‑氨基丁酰胺盐酸盐和无机碱加入到有机溶剂中,然后加入2,4‑二氯丁酰氯进行缩合反应,最后经四次打浆制备得到杂质IV。本发明属于首次报道该杂质,同时合成路线工艺简单,收率良好,得到产物纯度高。
Description
技术领域:
本发明涉及一种左乙拉西坦杂质以及合成方法,属于医药化工领域。
背景技术:
左乙拉西坦(Levetiracetam,商品名为Keppra)是由比利时公司UCB研制的一种新型的抗癫痫药物,其化学名为(S)-2-(2-氧代吡咯烷-1-基)丁酰胺,日最大摄入量为3000mg,结构式如式V所示:
CN 1583721A和WO 2004069796等专利报道左乙拉西坦可由式II所示的4-氯丁酰氯和式III所示的(S)-2-氨基丁酰胺盐酸盐为原料,在碱性条件下缩合然后环合得到,合成路线如下所示:
其中左乙拉西坦杂质可能在上述制备过程中会产生,其结构式如下:
从结构上判断,该杂质是因原料4-氯丁酰氯中存在2,4-二氯丁酰氯,2,4-二氯丁酰氯和(S)-2-氨基丁酰胺盐酸盐在碱性条件下缩合得到。4-氯丁酰氯由γ-丁内酯和氯化亚砜在氯化锌催化下制备得到,由于4-氯丁酰氯α位置氢原子比较活泼,在制备过程中不可避免引入氯代杂质,即2,4-二氯丁酰氯。所以在左乙拉西坦中极有可能引入该杂质。该杂质和左乙拉西坦结构类似,在精制过程中难以去除,且该杂质含有两个氯离子,含氯片段均被认为是具有基因毒性的警示结构,因此研究该杂质的产生途径,定向合成该杂质,对左乙拉西坦原料药的质量控制有非常重要的意义。
发明内容:
本发明提供了一种左乙拉西坦合成相关杂质,其结构式如下式IV所示:
化学名为(S)-N-(1-氨基-1-酮代-2-丁基)-2,4-二氯丁酰胺,其合成路线如下所示:
具体反应步骤为:
(1)将4-氯丁酰氯与氯化亚砜、盐酸、N-氯代琥珀酰亚胺加热回流反应后减压蒸馏除去氯化亚砜后得2,4-二氯丁酰氯;
(2)(S)-2-氨基丁酰胺盐酸盐和无机碱加入到有机溶剂中,然后加入2,4-二氯丁酰氯进行缩合反应得到杂质IV。
其中步骤(1)氯化亚砜摩尔用量为4-氯丁酰氯摩尔量的0.8~1.5倍;所述N-氯代琥珀酰亚胺摩尔用量为4-氯丁酰氯摩尔量的1.5~2.5倍;所述盐酸用量摩尔用量为4-氯丁酰氯摩尔量的0.01~0.05倍。
步骤(2)所述无机碱选自:碳酸氢钠、碳酸氢钾;所述有机溶剂选自:乙腈、二氯甲烷、氯仿、四氢呋喃。
步骤(2)所述2,4-二氯丁酰氯摩尔用量为(S)-2-氨基丁酰胺盐酸盐摩尔量的0.9~1.3倍,所述无机碱的摩尔用量为(S)-2-氨基丁酰胺盐酸盐摩尔量的1.5~3.0倍,所述有机溶剂的重量为(S)-2-氨基丁酰胺盐酸盐重量的10~30倍。
本发明属于首次报道该杂质,同时合成路线工艺简单,收率良好,得到产物纯度高。
具体实施方式:
实施例1制备2,4-二氯丁酰氯
向2000mL四口瓶中加入564g 4-氯丁酰氯(4.0mol)、1068g N-氯代琥珀酰亚胺(6.0mol)、476g氯化亚砜(4.0mol)和2mL精制盐酸,加热至回流,回流反应9小时,停止反应。
反应液先控制压力-0.070~-0.080Mpa,温度30~50℃减压蒸馏除去氯化亚砜,然后控制压力大于-0.098Mpa,温度90~120℃减压蒸馏得到2,4-二氯丁酰氯604g,收率:71.2%.纯度(GC):99.0%,其它最大单杂(GC):0.08%。
实施例2制备杂质IV
向5000mL四口瓶中加入138.6g(S)-2-氨基丁酰胺盐酸盐(1.0mol)、168g碳酸氢钠(2.0mol)和2000g乙腈,控制温度20±5℃,向其中滴加175.5g2,4-二氯丁酰氯(1.0mol),滴加完毕,控制温度20±5℃继续保温2小时。然后升温至常温,继续保温搅拌2小时。
反应完毕,过滤除去固体,滤液减压蒸馏除去乙腈,得到固体用300g乙腈淋洗,滤饼加入200g乙腈中,降温至5±5℃,打浆0.5小时,过滤。滤饼用研钵研成细粉状,然后用200g乙腈打浆三次。最后将滤饼烘干,得到该杂质167g,收率69.5%,纯度(HPLC):99.7%,其它最大单杂(HPLC):0.01%。
HPLC分析方法:
仪器:高效液相色谱仪配备紫外检测器,色谱柱:YMC-pack ODS-AQ 150×4.6mm 3μm,缓冲盐:5.7g磷酸二氢钾溶于1000mL水中,用5%KOH溶液调节pH至4.5,流动相:缓冲盐:乙腈=2:3(%V/V),检测波长:205nm。
产物结构鉴定如下:
1H-NMR(CDCl3-D1 400MHz)δ(ppm):0.772-0.801(t,3H,-CH3),1.632-1.681(m,2H,-CH2Me),2.016-2.078(m,2H,-CH2-),3.790-3.835(m,2H,-CH2Cl),4.442-4.494(m,1H,-CHCl-),4.489-4.518(m,1H,-CH-NR2),6.915(s,1H,-NH2),7.164(s,1H,-NH2),8.113(s,1H,-NH-)。13C-NMR(CDCl3-D1400MHz)δ(ppm):10.432,17.754,32.165,38.773,57.952,75.482,165.983,173.947。MS-ESI[M+H+]:240.11。
实施例3制备杂质IV
向5000mL四口瓶中加入138.6g(S)-2-氨基丁酰胺盐酸盐(1.0mol)、210g碳酸氢钠(2.5mol)和4000g二氯甲烷,控制温度20±5℃,向其中滴加226.1g2,4-二氯丁酰氯(1.3mol),滴加完毕,控制温度20±5℃继续保温2小时。然后升温至常温,继续保温搅拌2小时。
反应完毕,过滤除去固体,滤液减压蒸馏除去乙腈,得到固体用200g二氯甲烷淋洗,滤饼加入200g二氯甲烷中,降温至5±5℃,打浆0.5小时,过滤。滤饼用研钵研成细粉状,然后用200g二氯甲烷打浆三次。最后将滤饼烘干,得到该杂质175g,收率73.2%,纯度(HPLC):99.5%,其它最大单杂(HPLC):0.02%。
实施例4制备杂质IV
向5000mL四口瓶中加入138.6g(S)-2-氨基丁酰胺盐酸盐(1.0mol)、150g碳酸氢钾(1.5mol)和3100g四氢呋喃,控制温度20±5℃,向其中滴加156.6g2,4-二氯丁酰氯(0.9mol),滴加完毕,控制温度20±5℃继续保温1.5小时。然后升温至常温,继续保温搅拌1.5小时。
反应完毕,过滤除去固体,滤液减压蒸馏除去乙腈,得到固体用200g四氢呋喃淋洗,滤饼加入200g四氢呋喃中,降温至5±5℃,打浆0.5小时,过滤。滤饼用研钵研成细粉状,然后用200g四氢呋喃打浆三次。最后将滤饼烘干,得到该杂质156g,收率65.0%,纯度(HPLC):99.5%,其它最大单杂(HPLC):0.01%。
Claims (5)
1.一种左乙拉西坦杂质,其结构式如下式IV所示:
2.一种制备如式IV所示左乙拉西坦杂质的方法,其特征在于该方法步骤为:
(1)将4-氯丁酰氯与氯化亚砜、盐酸、N-氯代琥珀酰亚胺加热回流反应后减压蒸馏除去氯化亚砜后得2,4-二氯丁酰氯;
(2)(S)-2-氨基丁酰胺盐酸盐和无机碱加入到有机溶剂中,然后加入2,4-二氯丁酰氯进行缩合反应得到杂质IV;
3.根据权利要求2所述其特征在于步骤(1)氯化亚砜摩尔用量为4-氯丁酰氯摩尔量的0.8~1.5倍;所述N-氯代琥珀酰亚胺摩尔用量为4-氯丁酰氯摩尔量的1.5~2.5倍;所述盐酸用量摩尔用量为4-氯丁酰氯摩尔量的0.01~0.05倍。
4.根据权利要求2所述,其特征在于步骤(2)所述无机碱选自:碳酸氢钠、碳酸氢钾;所述有机溶剂选自:乙腈、二氯甲烷、氯仿、四氢呋喃。
5.根据权利要求2所述,其特征在于步骤(2)所述2,4-二氯丁酰氯摩尔用量为(S)-2-氨基丁酰胺盐酸盐摩尔量的0.9~1.3倍,所述无机碱的摩尔用量为(S)-2-氨基丁酰胺盐酸盐摩尔量的1.5~3.0倍,所述有机溶剂的重量为(S)-2-氨基丁酰胺盐酸盐重量的10~30倍。
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CN110028434A (zh) * | 2019-05-10 | 2019-07-19 | 浙江华海致诚药业有限公司 | 一种左乙拉西坦杂质及其制备方法 |
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