CN110003074A - 一种左乙拉西坦中间体的制备方法 - Google Patents
一种左乙拉西坦中间体的制备方法 Download PDFInfo
- Publication number
- CN110003074A CN110003074A CN201910328462.9A CN201910328462A CN110003074A CN 110003074 A CN110003074 A CN 110003074A CN 201910328462 A CN201910328462 A CN 201910328462A CN 110003074 A CN110003074 A CN 110003074A
- Authority
- CN
- China
- Prior art keywords
- ethyl
- oxo
- alpha
- acetic acid
- pyrrolidine acetic
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 229960004002 levetiracetam Drugs 0.000 title abstract description 11
- 238000002360 preparation method Methods 0.000 title abstract description 4
- HPHUVLMMVZITSG-ZCFIWIBFSA-N levetiracetam Chemical compound CC[C@H](C(N)=O)N1CCCC1=O HPHUVLMMVZITSG-ZCFIWIBFSA-N 0.000 title abstract 2
- IODGAONBTQRGGG-UHFFFAOYSA-N 2-(2-oxopyrrolidin-1-yl)butanoic acid Chemical compound CCC(C(O)=O)N1CCCC1=O IODGAONBTQRGGG-UHFFFAOYSA-N 0.000 claims abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 12
- 239000002253 acid Substances 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 13
- IODGAONBTQRGGG-ZCFIWIBFSA-N (2r)-2-(2-oxopyrrolidin-1-yl)butanoic acid Chemical compound CC[C@H](C(O)=O)N1CCCC1=O IODGAONBTQRGGG-ZCFIWIBFSA-N 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 239000000706 filtrate Substances 0.000 claims description 6
- 238000010792 warming Methods 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- IODGAONBTQRGGG-LURJTMIESA-N Levetiracetam acid Chemical compound CC[C@@H](C(O)=O)N1CCCC1=O IODGAONBTQRGGG-LURJTMIESA-N 0.000 claims description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 3
- 238000004061 bleaching Methods 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 239000000243 solution Substances 0.000 claims description 2
- 238000001179 sorption measurement Methods 0.000 claims description 2
- 230000006340 racemization Effects 0.000 abstract description 6
- 238000004064 recycling Methods 0.000 abstract 2
- HPHUVLMMVZITSG-LURJTMIESA-N levetiracetam Chemical compound CC[C@@H](C(N)=O)N1CCCC1=O HPHUVLMMVZITSG-LURJTMIESA-N 0.000 description 10
- 239000000047 product Substances 0.000 description 8
- 239000012452 mother liquor Substances 0.000 description 7
- 239000012535 impurity Substances 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 239000003651 drinking water Substances 0.000 description 4
- 235000020188 drinking water Nutrition 0.000 description 4
- 238000003756 stirring Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- -1 acetyl pyrrole alkyl compound Chemical class 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 238000005194 fractionation Methods 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 238000005915 ammonolysis reaction Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003556 anti-epileptic effect Effects 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229940062717 keppra Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
Classifications
-
- 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
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyrrole Compounds (AREA)
Abstract
本发明涉及一种左乙拉西坦中间体的制备方法，提供了一种通过消旋回收获得高质量的(RS)‑α‑乙基‑2‑氧代‑1‑吡咯烷乙酸，本发明提供的方法可以显著提高消旋回收产品(RS)‑α‑乙基‑2‑氧代‑1‑吡咯烷乙酸的质量和外观，且对产品收率无影响。
Description
技术领域
本发明涉及一种左乙拉西坦中间体的制备方法，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，它是一种乙酰吡咯烷类化合物，其化学名称为(S)-α-乙基-2-氧合-1-乙酰胺吡咯烷，结构如下所示：
CN85105301A报道了左乙拉西坦通过(±)-α-乙基-2-氧代-1-吡咯烷乙酸(II)，经过拆分得到(S)-α-乙基-2-氧代-1-吡咯烷乙酸(III)，然后经酯化、氨解得到左乙拉西坦粗品，最后精制得到左乙拉西坦，合成路线如下所示：
其中式II所示的化合物α-乙基-2-氧代-1-吡咯烷乙酸为其关键中间体。拆分反应母液中存在少量的化合物III以及大量的异构体(R)-α-乙基-2-氧代-1-吡咯烷乙酸，如式V所示，专利CN101333180报道了将副产物(R)-α-乙基-2-氧代-1-吡咯烷乙酸经高温消旋回收α- 乙基-2-氧代-1-吡咯烷乙酸的方法。
但由于专利CN101333180报道的回收方法为强碱下高温消旋，会产生较多的杂质，对后续生产左乙拉西坦质量产生影响。
发明内容
本发明的目的是提供一种获得高质量的(RS)-α-乙基-2-氧代-1-吡咯烷乙酸的方法，包括以下步骤：
(a)将包含(R)-α-乙基-2-氧代-1-吡咯烷乙酸和(S)-α-乙基-2-氧代-1-吡咯烷乙酸的混合物加入到强碱水溶液中，升温至80～95℃，保温搅拌8～12小时；
(b)加适量水稀释并降温至40～60℃，滴加盐酸调节pH至6.0～8.0，
(c)继续保持40～60℃下，加入活性炭或硅藻土吸附脱色一段时间后，趁热过滤；
(d)滤液升温并控制在70～90℃下滴加盐酸调节pH至1.0～2.5；
(e)降温至0～10℃，过滤，烘干得到(RS)-α-乙基-2-氧代-1-吡咯烷乙酸。
步骤(a)所述(R)-α-乙基-2-氧代-1-吡咯烷乙酸和(S)-α-乙基-2-氧代-1-吡咯烷乙酸的混合物可以来源于(RS)-α-乙基-2-氧代-1-吡咯烷乙酸拆分母液的蒸干物。
其中步骤(a)所述强碱选自：氢氧化钠或氢氧化钾；所述强碱溶液质量百分比浓度范围 25％～40％；所述碱的用量为(R)-α-乙基-2-氧代-1-吡咯烷乙酸和(S)-α-乙基-2-氧代-1-吡咯烷乙酸的混合物总摩尔量的1～3倍；
其中步骤(b)所述水用量为(R)-α-乙基-2-氧代-1-吡咯烷乙酸和(S)-α-乙基-2-氧代 -1-吡咯烷乙酸的混合物总质量的1.5～5倍；
其中步骤(c)脱色时间优选为0.5～1.5小时。
本发明的创新点在于：通过步骤(b)在适宜温度下调节pH值至适当范围，(R)-α-乙基-2- 氧代-1-吡咯烷乙酸在强碱消旋过程中产生的未知杂质可以在体系中析出(上述未知杂质在 HPLC分析中全程不出峰，此时如果进行过滤，滤纸会出现大量黑色固体，但是滤液仍为黄色)，在步骤(b)的温度下继续步骤(c)的脱色工序；通过以上操作，所获得的消旋回收的中间体(RS)-α-乙基-2-氧代-1-吡咯烷乙酸的质量和外观非常好，同时也未影响产品收率，因此降低了未知杂质引入到左乙拉西坦成品的风险，具有很好的实用价值。
附图说明：
附图1：左图为对比实施例的样品外观，右图为本发明实施例一的样品外观。
具体实施方式
对比实施例：
取(RS)-α-乙基-2-氧代-1-吡咯烷乙酸拆分母液旋干物20g于四口瓶中，加入23g30％液碱调节pH至12～14，于80～95℃下搅拌反应8～10小时，加入10g水稀释并降温至60℃后加入盐酸调节pH至1.5，降温至5℃析晶得到回收(RS)-α-乙基-2-氧代-1-吡咯烷乙酸，烘干称重得19.6g，纯度为99.4％。产品颜色偏黄，参见附图1的左图。
实例一：
取(RS)-α-乙基-2-氧代-1-吡咯烷乙酸拆分母液旋干物20g于四口瓶中，加入45g25％液碱调节pH至13～14，于85～90℃下保温搅拌反应8～10小时，加入10g饮用水稀释并降温至60℃后加入盐酸调节pH至7.0，体系中出现大量黑褐色悬浮杂质，加入0.5g活性炭保温搅拌0.5h后抽滤，滤液升温至并控制温度70～90℃下继续用盐酸调节pH至1.5，降温至0～10℃析晶得到回收(RS)-α-乙基-2-氧代-1-吡咯烷乙酸，烘干称重得19.6g，纯度为99.9％。产品颜色为白色。参见附图1的右图。
实例二：
取(RS)-α-乙基-2-氧代-1-吡咯烷乙酸拆分母液旋干物20g于四口瓶中，加入30g30％液碱调节pH至＝12～14，于85～95℃下搅拌反应8～10小时，加入10g饮用水稀释并降温至60℃后加入盐酸调节pH至6.0，体系中出现大量黑褐色悬浮杂质，加入0.5g活性炭搅拌1.5h后抽滤，滤液升温至并控制温度70～90℃下继续用盐酸调节pH至2.0，降温至5℃析晶得到回收(RS)-α-乙基-2-氧代-1-吡咯烷乙酸，烘干称重得19.4g，纯度为99.9％。产品为白色。
实例三：
取(RS)-α-乙基-2-氧代-1-吡咯烷乙酸拆分母液旋干物20g于四口瓶中，加入16g35％液碱调节pH至12～14，于85～90℃下搅拌反应8～10小时，加入10g饮用水稀释并降温至60℃后加入盐酸调节pH至6.0，体系中出现大量黑褐色悬浮杂质，加入0.5g药用硅藻土搅拌1.0h 后抽滤，滤液升温至并控制温度70～90℃下继续用盐酸调节pH至1.5，降温至5℃析晶得到回收(RS)-α-乙基-2-氧代-1-吡咯烷乙酸，烘干称重得19.5g，纯度为99.7％。产品颜色为白色。
实例四：
取(RS)-α-乙基-2-氧代-1-吡咯烷乙酸拆分母液旋干物20g于四口瓶中，加入20g40％液碱调节pH至12～14，于85～95℃下搅拌反应8～10小时，加入10g饮用水稀释并降温至50℃后加入盐酸调节pH至7.0，体系中出现大量黑褐色悬浮杂质，加入0.5g药用硅藻土搅拌1.5h 后抽滤，滤液升温至并控制温度70～90℃下继续用盐酸调节pH至2.0，降温至5℃析晶得到回收(RS)-α-乙基-2-氧代-1-吡咯烷乙酸，烘干称重得19.6g，纯度为99.6％。产品颜色为白色。
Claims (6)
1.一种制备(RS)-α-乙基-2-氧代-1-吡咯烷乙酸的方法，包括以下步骤：：
(a)将包含(R)-α-乙基-2-氧代-1-吡咯烷乙酸和(S)-α-乙基-2-氧代-1-吡咯烷乙酸的混合物加入到强碱水溶液中，升温至80～95℃，保温搅拌8～12小时；
(b)加适量水稀释并降温至40～60℃，滴加盐酸调节pH至6.0～8.0；
(c)继续保持40～60℃下，加入活性炭或硅藻土吸附脱色一段时间后，趁热过滤；
(d)滤液升温并控制在70～90℃下滴加盐酸调节pH至1.0～2.5；
(e)降温至0～10℃，过滤，烘干得到(RS)-α-乙基-2-氧代-1-吡咯烷乙酸。
2.权利要求1所述的方法，其中步骤(a)所述强碱选自氢氧化钠或氢氧化钾。
3.权利要求1所述的方法，其中步骤(a)所述强碱溶液质量百分比浓度范围25％～40％。
4.权利要求1所述的方法，其中步骤(a)所述碱的用量为(R)-α-乙基-2-氧代-1-吡咯烷乙酸和(S)-α-乙基-2-氧代-1-吡咯烷乙酸混合物总摩尔量的1～3倍。
5.权利要求1所述的方法，其中步骤(b)所述水用量为(R)-α-乙基-2-氧代-1-吡咯烷乙酸和(S)-α-乙基-2-氧代-1-吡咯烷乙酸混合物总质量的1.5～5倍。
6.权利要求1所述的方法，其中步骤(c)脱色时间优选为0.5～1.5小时。
Priority Applications (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910328462.9A CN110003074A (zh) | 2019-04-23 | 2019-04-23 | 一种左乙拉西坦中间体的制备方法 |
| EP20795993.3A EP3960732A4 (en) | 2019-04-23 | 2020-04-17 | MANUFACTURING PROCESS FOR LEVETIRACETAM INTERMEDIATE |
| US17/600,535 US20220162165A1 (en) | 2019-04-23 | 2020-04-17 | Preparation method for levetiracetam intermediate |
| PCT/CN2020/085370 WO2020216146A1 (zh) | 2019-04-23 | 2020-04-17 | 一种左乙拉西坦中间体的制备方法 |
| CN202080008317.3A CN113272275B (zh) | 2019-04-23 | 2020-04-17 | 一种左乙拉西坦中间体的制备方法 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910328462.9A CN110003074A (zh) | 2019-04-23 | 2019-04-23 | 一种左乙拉西坦中间体的制备方法 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN110003074A true CN110003074A (zh) | 2019-07-12 |
Family
ID=67173668
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910328462.9A Pending CN110003074A (zh) | 2019-04-23 | 2019-04-23 | 一种左乙拉西坦中间体的制备方法 |
| CN202080008317.3A Active CN113272275B (zh) | 2019-04-23 | 2020-04-17 | 一种左乙拉西坦中间体的制备方法 |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202080008317.3A Active CN113272275B (zh) | 2019-04-23 | 2020-04-17 | 一种左乙拉西坦中间体的制备方法 |
Country Status (4)
| Country | Link |
|---|---|
| US (1) | US20220162165A1 (zh) |
| EP (1) | EP3960732A4 (zh) |
| CN (2) | CN110003074A (zh) |
| WO (1) | WO2020216146A1 (zh) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020216146A1 (zh) * | 2019-04-23 | 2020-10-29 | 浙江华海药业股份有限公司 | 一种左乙拉西坦中间体的制备方法 |
| CN114702426A (zh) * | 2022-05-24 | 2022-07-05 | 雅本化学股份有限公司 | 一种左乙拉西坦中间体的合成方法 |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11384050B1 (en) | 2021-02-03 | 2022-07-12 | Vitaworks Ip, Llc | Method for preparing levetiracetam and intermediates thereof |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8412357D0 (en) | 1984-05-15 | 1984-06-20 | Ucb Sa | Pharmaceutical composition |
| CA2488325C (en) * | 2004-11-22 | 2010-08-24 | Apotex Pharmachem Inc. | Improved process for the preparation of (s)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide and (r)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide |
| IN2005MU01546A (zh) * | 2005-12-13 | 2007-08-24 | M.M.V. Ramana | |
| CN101333180B (zh) * | 2007-06-29 | 2011-05-18 | 浙江华海药业股份有限公司 | 一种制备左乙拉西坦中间体的方法 |
| CN101838211B (zh) * | 2009-03-16 | 2014-07-02 | 黄冈华阳药业有限公司 | 生产左乙拉西坦的中间体2-氨基丁酸的工艺方法 |
| CN104370791B (zh) * | 2014-11-28 | 2018-09-21 | 上虞京新药业有限公司 | 一种左乙拉西坦的纯化方法 |
| CN108707099B (zh) * | 2018-06-19 | 2022-12-13 | 浙江华海药业股份有限公司 | 一种左乙拉西坦中间体的制备方法 |
| CN110003074A (zh) * | 2019-04-23 | 2019-07-12 | 浙江华海药业股份有限公司 | 一种左乙拉西坦中间体的制备方法 |
-
2019
- 2019-04-23 CN CN201910328462.9A patent/CN110003074A/zh active Pending
-
2020
- 2020-04-17 EP EP20795993.3A patent/EP3960732A4/en active Pending
- 2020-04-17 WO PCT/CN2020/085370 patent/WO2020216146A1/zh unknown
- 2020-04-17 CN CN202080008317.3A patent/CN113272275B/zh active Active
- 2020-04-17 US US17/600,535 patent/US20220162165A1/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020216146A1 (zh) * | 2019-04-23 | 2020-10-29 | 浙江华海药业股份有限公司 | 一种左乙拉西坦中间体的制备方法 |
| CN114702426A (zh) * | 2022-05-24 | 2022-07-05 | 雅本化学股份有限公司 | 一种左乙拉西坦中间体的合成方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2020216146A1 (zh) | 2020-10-29 |
| CN113272275A (zh) | 2021-08-17 |
| EP3960732A1 (en) | 2022-03-02 |
| US20220162165A1 (en) | 2022-05-26 |
| EP3960732A4 (en) | 2022-07-13 |
| CN113272275B (zh) | 2024-01-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN110003074A (zh) | 一种左乙拉西坦中间体的制备方法 | |
| CN100410242C (zh) | 普瑞巴林中间体及其制备方法 | |
| AU2011214268A1 (en) | Process for manufacturing succinic acid | |
| CN105814020A (zh) | 用于大规模生产1-[(2-溴苯基)磺酰基]-5-甲氧基-3-[(4-甲基-1-哌嗪基)甲基]-1h-吲哚二甲磺酸盐一水合物的方法 | |
| CN105584998A (zh) | 一种采用三聚氰胺净化磷酸萃余酸制磷酸氢二钠的方法 | |
| CN107556207A (zh) | 一种间氨基乙酰苯胺盐酸盐的合成方法 | |
| CN110204437A (zh) | 一种生产l-苹果酸联产丁二酸的方法 | |
| US4215223A (en) | Process for the preparation of D(-)αphenylglycine | |
| CN108586360B (zh) | 一种6-氯-3-甲基尿嘧啶的制备方法 | |
| CN105985251B (zh) | 一种亚氨基二乙酸等氨基酸类清洁生产工艺 | |
| US8754256B2 (en) | Process for preparation of L-Arginine α-ketoglutarate 1:1 and 2:1 | |
| CN102503810B (zh) | 一种回收和循环使用l-酒石酸的方法 | |
| CN104447758B (zh) | 吡唑并[3,4‑d]嘧啶类化合物的合成工艺 | |
| JP2011098975A (ja) | キラル純ｎ−（トランス−４−イソプロピル−シクロヘキシルカルボニル）−ｄ−フェニルアラニン及びそれらの結晶構造変性体の生成方法 | |
| KR940000810B1 (ko) | 결정상태의 글루타민산을 제조하는 방법 | |
| US11603361B2 (en) | Process and salts for the preparation of 2,5-furandicarboxylic acid | |
| CN109836344B (zh) | 一种有机溶剂生产甘氨酸的方法 | |
| CN106119332A (zh) | 一种土霉素生产工艺 | |
| CN111548375A (zh) | 一种改进的三氯蔗糖氯化液后处理方法 | |
| CN110272339A (zh) | 一种分离提取高纯度苹果酸的方法 | |
| CN115433081B (zh) | 一种二丙基丙二酸二乙酯的制备方法 | |
| AU2020362582B2 (en) | Method for preparing disodium 5'-guanylate heptahydrate crystal | |
| SU452543A1 (ru) | Способ получени сульфаминокислого никел | |
| JP4614180B2 (ja) | グルタミン酸の転移再結晶による精製方法 | |
| SU1293171A1 (ru) | Способ получени @ -ацетил- @ , @ -аланина |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20190712 |