CN114560800A - 左乙拉西坦原料药生产方法 - Google Patents
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- HPHUVLMMVZITSG-ZCFIWIBFSA-N levetiracetam Chemical compound CC[C@H](C(N)=O)N1CCCC1=O HPHUVLMMVZITSG-ZCFIWIBFSA-N 0.000 title claims abstract description 60
- 229960004002 levetiracetam Drugs 0.000 title claims abstract description 60
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 28
- 239000003814 drug Substances 0.000 title claims abstract description 9
- 229940079593 drug Drugs 0.000 title claims abstract description 7
- 239000012043 crude product Substances 0.000 claims abstract description 28
- 239000000047 product Substances 0.000 claims abstract description 23
- 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 5
- CDIIZULDSLKBKV-UHFFFAOYSA-N 4-chlorobutanoyl chloride Chemical compound ClCCCC(Cl)=O CDIIZULDSLKBKV-UHFFFAOYSA-N 0.000 claims abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 90
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- 238000003756 stirring Methods 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 17
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 15
- 239000000463 material Substances 0.000 claims description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- 238000007599 discharging Methods 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 12
- 238000010438 heat treatment Methods 0.000 claims description 12
- 238000010992 reflux Methods 0.000 claims description 12
- 238000005070 sampling Methods 0.000 claims description 12
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 12
- 238000005406 washing Methods 0.000 claims description 12
- 238000007363 ring formation reaction Methods 0.000 claims description 10
- 238000001816 cooling Methods 0.000 claims description 9
- 238000001914 filtration Methods 0.000 claims description 9
- 238000004321 preservation Methods 0.000 claims description 9
- 238000001514 detection method Methods 0.000 claims description 8
- 239000012452 mother liquor Substances 0.000 claims description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 6
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 claims description 6
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 6
- 239000004744 fabric Substances 0.000 claims description 6
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 6
- 239000011259 mixed solution Substances 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 238000005303 weighing Methods 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 238000002425 crystallisation Methods 0.000 claims description 3
- 230000008025 crystallization Effects 0.000 claims description 3
- 238000004821 distillation Methods 0.000 claims description 3
- 238000011049 filling Methods 0.000 claims description 3
- 239000012065 filter cake Substances 0.000 claims description 3
- 239000000706 filtrate Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 238000002386 leaching Methods 0.000 claims description 3
- 238000005086 pumping Methods 0.000 claims description 3
- 239000007787 solid Substances 0.000 claims description 3
- 238000000034 method Methods 0.000 claims description 2
- 239000007858 starting material Substances 0.000 abstract description 3
- 238000007670 refining Methods 0.000 description 3
- 239000012535 impurity Substances 0.000 description 2
- 239000003513 alkali Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
- C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
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- 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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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
一种左乙拉西坦原料药生产方法,该方法包括左乙拉西坦粗品的生产方法和左乙拉西坦精品的生产方法,该方法使用L‑2‑氨基丁酰胺盐酸盐、4‑氯丁酰氯作为起始物料进行生产。本发明之方法的左乙拉西坦粗品的收率≥70%,左乙拉西坦精品的收率≥70%,大大提高了左乙拉西坦的收率,提高了生产效率,降低了生产成本。
Description
技术领域
本发明属于医药生产领域,具体涉及一种左乙拉西坦原料药生产方法。
背景技术
左乙拉西坦生成反应的基本原理为:起始物料L-2-氨基丁酰胺盐酸盐(SM1)、4-氯丁酰氯(SM2)经酰胺化得到中间态产物,在强碱氢氧化钾作用下发生环合反应制得到左乙拉西坦粗品,此反应对温度要求较为苛刻。原工艺在反应时温度控制在-10℃~-5℃之间,由于温度未达到-20℃~15℃这个最佳反应温度,导致反应过程中出现副产物和异构体,一次精制后不能完全去除相关杂质及异构体,需要二次精制才能达到质量要求,但是多精制一次收率减低约为10%~20%;当把反应温度控制在-20℃~15℃时,反应过程中的杂质在经过一次精制后就能到达质量要求,因此收率能提高约10%~20%。
发明内容
本发明的目的是提供一种左乙拉西坦原料药生产方法,该方法能提高左乙拉西坦的收率。
一种左乙拉西坦原料药生产方法,该方法包括左乙拉西坦粗品的生产方法和左乙拉西坦精品的生产方法;
左乙拉西坦粗品的生产方法,其步骤如下:
环合罐中加入840.00kg二氯甲烷、175.00kg无水硫酸钠和70.00kg L-2-氨基丁酰胺盐酸盐;
氮气置换3次后,继续充氮,降温至-20℃~-15℃,将氢116.20kg氧化钾投入环合罐,-20~-5℃保温反应1.5h;
分2批加入8.19kg四丁基溴化铵,加入温度为-20~-8℃,第一次加入1.19kg四丁基溴化铵,保温10min,温度无明显变化后,继续加入剩余7.0kg四丁基溴化铵,控制环合罐温度为-20~-5℃,加毕后-20~-5℃保温搅拌0.5h;
滴加78.40kg 4-氯丁酰氯和140.00kg二氯甲烷的混合溶液,控制环合罐滴加温度-20~-5℃,滴加时间不超过20h,滴加完成后在-20~-5℃下保温反应2.0h取样HPLC检测,中间态含量低于15.0%后,再向环合罐加入29.40kg氢氧化钾,若中间态含量大于15%则继续反应,每1.0h取样检测;继续在-20~-5℃下保温反应2.0h后取样HPLC检测,中间态含量低于0.2%后滴加60.20kg 的质量浓度为85%磷酸,若中间态含量大于0.2%则继续反应,每1.0h取样检测,调节pH=6~7,控制环合罐滴加温度-15~-5℃,滴加时间不超过5h;
质量浓度为85%磷酸加毕后,在-20~-5℃下保温搅拌1.0h,加入16.80kg无水硫酸钠,升温至10~20℃,过滤;210.00kg二氯甲烷淋洗滤饼,所得滤液合并进行常压蒸馏,待体系温度上升且析出大量固体时,加入70.00kg乙酸乙酯;当内温升至68~72℃时停止蒸馏,加入228.20kg乙酸乙酯,升温至回流搅拌0.5h,加入3.50kg药用活性炭和35.00kg乙酸乙酯,70~80℃回流脱色0.5h,启动打料泵将物料通过已清洁并安装好的0.45μm钛棒过滤器至结晶罐中,并用压缩空气将设备及管路中残留的液体过滤净,降温至18~22℃保温搅拌1.0h,将洁净滤布铺好,启动离心机,边放料边离心,母液排净后用56.00kg乙酸乙酯洗料,洗料后离心20min,得左乙拉西坦粗品湿品,在40~45℃干燥1~2.5 h,从干燥1小时开始每隔0.5h进行称量至恒重,得左乙拉西坦粗品。
左乙拉西坦精品的生产方法,其步骤如下:
脱色罐中加入乙酸乙酯,乙酸乙酯的加入量是左乙拉西坦粗品4倍重量,升温至60℃左右,加入左乙拉西坦粗品,升温回流搅拌0.5h,加入药用活性炭和乙酸乙酯的混合溶液,其中药用活性炭的加入量是左乙拉西坦粗品0.05倍重量,乙酸乙酯的加入量是左乙拉西坦粗品0.5倍重量,75~85℃回流脱色0.5h,启动打料泵将物料通过已清洁并安装好的0.45μm钛棒过滤器至粗品结晶罐中,并用压缩空气将设备及管路中残留的液体过滤净,缓慢降温至18~22℃保温搅拌1.0h,将洁净滤布铺好,启动离心机,边放料边离心,母液排净后用乙酸乙酯洗料,其中,乙酸乙酯的加入量是左乙拉西坦粗品0.8倍重量,洗料后离心20min,得到左乙拉西坦精品湿品,在40~45℃干燥1~2.5 h,从干燥1小时开始每隔0.5h进行称量至恒重得左乙拉西坦精品。
本发明的有益效果:
左乙拉西坦粗品的收率≥70%;左乙拉西坦精品的收率≥70%,大大提高了左乙拉西坦的收率,提高了生产效率,降低了生产成本。
具体实施方式
一种左乙拉西坦原料药生产方法,该方法包括左乙拉西坦粗品的生产方法和左乙拉西坦精品的生产方法;
左乙拉西坦粗品的生产方法,其步骤如下:
环合罐中加入840.00kg二氯甲烷、175.00kg无水硫酸钠和70.00kg L-2-氨基丁酰胺盐酸盐;
氮气置换3次后,继续充氮,降温至-20℃~-15℃,将氢116.20kg氧化钾投入环合罐,-20~-5℃保温反应1.5h;
分2批加入8.19kg四丁基溴化铵,加入温度为-20~-8℃,第一次加入1.19kg四丁基溴化铵,保温10min,温度无明显变化后,继续加入剩余7.0kg四丁基溴化铵,控制环合罐温度为-20~-5℃,加毕后-20~-5℃保温搅拌0.5h;
滴加78.40kg 4-氯丁酰氯和140.00kg二氯甲烷的混合溶液,控制环合罐滴加温度-20~-5℃,滴加时间不超过20h,滴加完成后在-20~-5℃以下保温反应2.0h取样HPLC检测,中间态含量低于15.0%后,再向环合罐加入29.40kg氢氧化钾,若中间态含量大于15%则继续反应,每1.0h取样检测;继续在-20~-5℃以下保温反应2.0h后取样HPLC检测,中间态含量低于0.2%后滴加60.20kg 的质量浓度为85%磷酸,若中间态含量大于0.2%则继续反应,每1.0h取样检测,调节pH=6~7,控制环合罐滴加温度-15~-5℃,滴加时间不超过5h;
质量浓度为85%磷酸加毕后,在-20~-5℃以下保温搅拌1.0h,加入16.80kg无水硫酸钠,升温至10~20℃,过滤;210.00kg二氯甲烷淋洗滤饼,所得滤液合并进行常压蒸馏,待体系温度上升且析出大量固体时,加入70.00kg乙酸乙酯;当内温升至68~72℃时停止蒸馏,加入228.20kg乙酸乙酯,升温至回流搅拌0.5h,加入3.50kg药用活性炭和35.00kg乙酸乙酯,70~80℃回流脱色0.5h,启动打料泵将物料通过已清洁并安装好的0.45μm钛棒过滤器至结晶罐中,并用压缩空气将设备及管路中残留的液体过滤净,降温至18~22℃保温搅拌1.0h,将洁净滤布铺好,启动离心机,边放料边离心,母液排净后用56.00kg乙酸乙酯洗料,洗料后离心20min,得左乙拉西坦粗品湿品,在40~45℃干燥1~2.5 h,从干燥1小时开始每隔0.5h进行称量至恒重,得左乙拉西坦粗品。
左乙拉西坦粗品的收率≥70%。
左乙拉西坦精品的生产方法,其步骤如下:
脱色罐中加入乙酸乙酯,乙酸乙酯的加入量是左乙拉西坦粗品4倍重量,升温至60℃左右,加入左乙拉西坦粗品,升温回流搅拌0.5h,加入药用活性炭和乙酸乙酯的混合溶液,其中药用活性炭的加入量是左乙拉西坦粗品0.05倍重量,乙酸乙酯的加入量是左乙拉西坦粗品0.5倍重量,75~85℃回流脱色0.5h,启动打料泵将物料通过已清洁并安装好的0.45μm钛棒过滤器至粗品结晶罐中,并用压缩空气将设备及管路中残留的液体过滤净,缓慢降温至18~22℃保温搅拌1.0h,将洁净滤布铺好,启动离心机,边放料边离心,母液排净后用乙酸乙酯洗料,其中,乙酸乙酯的加入量是左乙拉西坦粗品0.8倍重量,洗料后离心20min,得到左乙拉西坦精品湿品,在40~45℃干燥1~2.5 h,从干燥1小时开始每隔0.5h进行称量至恒重得左乙拉西坦精品。
左乙拉西坦精品的收率≥70%。
Claims (1)
1.一种左乙拉西坦原料药生产方法,其特征在于:该方法包括左乙拉西坦粗品的生产方法和左乙拉西坦精品的生产方法;
左乙拉西坦粗品的生产方法,其步骤如下:
环合罐中加入840.00kg二氯甲烷、175.00kg无水硫酸钠和70.00kg L-2-氨基丁酰胺盐酸盐;
氮气置换3次后,继续充氮,降温至-20℃~-15℃,将氢116.20kg氧化钾投入环合罐,-20~-5℃保温反应1.5h;
分2批加入8.19kg四丁基溴化铵,加入温度为-20~-8℃,第一次加入1.19kg四丁基溴化铵,保温10min,温度无明显变化后,继续加入剩余7.0kg四丁基溴化铵,控制环合罐温度为-20~-5℃,加毕后-20~-5℃保温搅拌0.5h;
滴加78.40kg 4-氯丁酰氯和140.00kg二氯甲烷的混合溶液,控制环合罐滴加温度-20~-5℃,滴加时间不超过20h,滴加完成后在-20~-5℃下保温反应2.0h取样HPLC检测,中间态含量低于15.0%后,再向环合罐加入29.40kg氢氧化钾,若中间态含量大于15%则继续反应,每1.0h取样检测;继续在-20~-5℃下保温反应2.0h后取样HPLC检测,中间态含量低于0.2%后滴加60.20kg 的质量浓度为85%磷酸,若中间态含量大于0.2%则继续反应,每1.0h取样检测,调节pH=6~7,控制环合罐滴加温度-15~-5℃,滴加时间不超过5h;
质量浓度为85%磷酸加毕后,在-20~-5℃下保温搅拌1.0h,加入16.80kg无水硫酸钠,升温至10~20℃,过滤;210.00kg二氯甲烷淋洗滤饼,所得滤液合并进行常压蒸馏,待体系温度上升且析出大量固体时,加入70.00kg乙酸乙酯;当内温升至68~72℃时停止蒸馏,加入228.20kg乙酸乙酯,升温至回流搅拌0.5h,加入3.50kg药用炭和35.00kg乙酸乙酯,70~80℃回流脱色0.5h,启动打料泵将物料通过已清洁并安装好的0.45μm钛棒过滤器至结晶罐中,并用压缩空气将设备及管路中残留的液体过滤净,降温至18~22℃保温搅拌1.0h,将洁净滤布铺好,启动离心机,边放料边离心,母液排净后用56.00kg乙酸乙酯洗料,洗料后离心20min,得左乙拉西坦粗品湿品,在40~45℃干燥1~2.5 h,从干燥1小时开始每隔0.5h进行称量至恒重,得左乙拉西坦粗品;
左乙拉西坦精品的生产方法,其步骤如下:
脱色罐中加入乙酸乙酯,乙酸乙酯的加入量是左乙拉西坦粗品4倍重量,升温至60℃左右,加入左乙拉西坦粗品,升温回流搅拌0.5h,加入药用炭和乙酸乙酯的混合溶液,其中药用炭的加入量是左乙拉西坦粗品0.05倍重量,乙酸乙酯的加入量是左乙拉西坦粗品0.5倍重量,75~85℃回流脱色0.5h,启动打料泵将物料通过已清洁并安装好的0.45μm钛棒过滤器至粗品结晶罐中,并用压缩空气将设备及管路中残留的液体过滤净,缓慢降温至18~22℃保温搅拌1.0h,将洁净滤布铺好,启动离心机,边放料边离心,母液排净后用乙酸乙酯洗料,其中,乙酸乙酯的加入量是左乙拉西坦粗品0.8倍重量,洗料后离心20min,得到左乙拉西坦精品湿品,在40~45℃干燥1~2.5 h,从干燥1小时开始每隔0.5h进行称量至恒重得左乙拉西坦精品。
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