CN117362226B - 一种尼可刹米的制备方法 - Google Patents
一种尼可刹米的制备方法 Download PDFInfo
- Publication number
- CN117362226B CN117362226B CN202311663760.6A CN202311663760A CN117362226B CN 117362226 B CN117362226 B CN 117362226B CN 202311663760 A CN202311663760 A CN 202311663760A CN 117362226 B CN117362226 B CN 117362226B
- Authority
- CN
- China
- Prior art keywords
- reaction
- rice
- nikko
- nicotinic acid
- preparation
- 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.)
- Active
Links
- 235000007164 Oryza sativa Nutrition 0.000 title claims abstract description 12
- 235000009566 rice Nutrition 0.000 title claims abstract description 12
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 240000007594 Oryza sativa Species 0.000 title 1
- 238000006243 chemical reaction Methods 0.000 claims abstract description 41
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims abstract description 36
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims abstract description 20
- 239000011664 nicotinic acid Substances 0.000 claims abstract description 18
- 235000001968 nicotinic acid Nutrition 0.000 claims abstract description 18
- 229960003512 nicotinic acid Drugs 0.000 claims abstract description 18
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims abstract description 14
- SUAKHGWARZSWIH-UHFFFAOYSA-N N,N‐diethylformamide Chemical compound CCN(CC)C=O SUAKHGWARZSWIH-UHFFFAOYSA-N 0.000 claims abstract description 12
- 241000209094 Oryza Species 0.000 claims abstract description 11
- 238000001816 cooling Methods 0.000 claims abstract description 7
- 238000010791 quenching Methods 0.000 claims abstract description 7
- 239000000463 material Substances 0.000 claims abstract description 6
- 239000003960 organic solvent Substances 0.000 claims abstract description 5
- 238000001914 filtration Methods 0.000 claims abstract description 3
- 238000010438 heat treatment Methods 0.000 claims abstract description 3
- 230000000171 quenching effect Effects 0.000 claims abstract description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 27
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 239000008096 xylene Substances 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 abstract description 12
- 239000003054 catalyst Substances 0.000 abstract description 7
- 239000012535 impurity Substances 0.000 abstract description 7
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 230000003197 catalytic effect Effects 0.000 abstract 1
- 238000000926 separation method Methods 0.000 abstract 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 239000012043 crude product Substances 0.000 description 8
- 239000008213 purified water Substances 0.000 description 8
- 239000008346 aqueous phase Substances 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 230000006837 decompression Effects 0.000 description 4
- 238000010494 dissociation reaction Methods 0.000 description 4
- 230000005593 dissociations Effects 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- CBPYOHALYYGNOE-UHFFFAOYSA-M potassium;3,5-dinitrobenzoate Chemical compound [K+].[O-]C(=O)C1=CC([N+]([O-])=O)=CC([N+]([O-])=O)=C1 CBPYOHALYYGNOE-UHFFFAOYSA-M 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 150000001263 acyl chlorides Chemical class 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 210000001034 respiratory center Anatomy 0.000 description 3
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 2
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 206010020591 Hypercapnia Diseases 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 208000004756 Respiratory Insufficiency Diseases 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 150000001266 acyl halides Chemical class 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 210000001011 carotid body Anatomy 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 108091008690 chemoreceptors Proteins 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- FJEVKYZLIRAAKE-UHFFFAOYSA-N n,n-dimethylpyridine-3-carboxamide Chemical compound CN(C)C(=O)C1=CC=CN=C1 FJEVKYZLIRAAKE-UHFFFAOYSA-N 0.000 description 1
- NCYVXEGFNDZQCU-UHFFFAOYSA-N nikethamide Chemical compound CCN(CC)C(=O)C1=CC=CN=C1 NCYVXEGFNDZQCU-UHFFFAOYSA-N 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 201000004193 respiratory failure Diseases 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
-
- 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
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
Abstract
本发明公开了一种尼可刹米的制备方法，属于有机合成技术领域，其步骤包括：S1：在反应瓶中加入有机溶剂、烟酸、催化量N,N‑二乙基甲酰胺和二氯亚砜，加热反应；S2：将S1反应后的物料降温后，滴加二乙胺，再进行反应；S3：将S2反应后的物料经淬灭后过滤、萃取、浓缩，蒸馏即得尼可刹米；本发明采用N,N‑二乙基甲酰胺作为催化剂，解决了使用N,N‑二甲基甲酰胺带来的难以分离的杂质问题，使得产品纯度明显提高，质量更有保证。
Description
技术领域
本发明涉及有机合成技术领域，尤其涉及一种尼可刹米的制备新方法。
背景技术
尼可刹米，又名可拉明、二乙烟酰胺，学名“N，N-二乙基烟酰胺”，沸点296～300℃(0.1MPa)，外观为无色或淡黄色的澄明油状液体，放置冷处即成结晶。尼可刹米可选择性地兴奋延髓呼吸中枢，也可作用于颈动脉体和主动脉体化学感受器，反射性地兴奋呼吸中枢，使呼吸加深加快。对血管运动中枢有微弱的兴奋作用，对有高碳酸血症的呼吸衰竭，它能够拮抗二氧化碳对呼吸中枢的麻醉作用。
目前，尼可刹米的制备方法主要采用易得的烟酸和二乙胺为原料进行制备，但二者直接反应的活性较差，一般要用到活化试剂和催化剂，从而将烟酸变为活泼的中间体酰卤再与二乙胺进一步反应。目前羧酸转化为酰氯常用的活化试剂有三氯化磷、五氯化磷、光气、氯化亚砜等，其中三氯化磷法适用于制备低沸点酰氯，五氯化磷法适用于制备高沸点酰氯，光气因其剧毒对劳动防护和设备要求较高。
氯化亚砜（亦即二氯亚砜）作为应用最早的酰化试剂，比如US1403117A，因其具有反应条件温和、后处理简便、反应收率较高的优点，在科研和工业上被广泛应用。以氯化亚砜作为酰化试剂时，常用的催化剂是DMF,但具体到本发明尼可刹米试验过程中发现DMF容易分解出二甲胺，与烟酸反应生成杂质N,N-二甲基烟酰胺，N,N-二甲基烟酰胺与尼可刹米结构相似、熔点接近，蒸馏纯化时分离困难，导致所制得的尼可刹米中杂质含量较高。根据《ICH 三方协调指导原则》，原料药中杂质含量应低于0.1%，而现有的这种方法，杂质含量一般会达到0.4%以上，不能满足需求。
发明内容
本发明的目的就在于提供一种尼可刹米的制备新方法，以解决上述问题。
为了实现上述目的，本发明采用的技术方案是这样的：
一种尼可刹米的制备新方法，包括下述步骤：
S1：在反应瓶中加入有机溶剂、烟酸、N,N-二乙基甲酰胺、二氯亚砜，加热反应；其中，烟酸与二氯亚砜的摩尔比为1：（1.0～1.5），N,N-二乙基甲酰胺的添加量为烟酸质量的1～2%；
S2：将S1反应后的物料降温后，滴加二乙胺进行反应，其中，烟酸与二乙胺的摩尔比为1：（1.5～3.5）；
S3：将S2反应后的物料经淬灭后过滤、萃取、浓缩、蒸馏得尼可刹米。
本发明以二氯亚砜为活化剂，以N,N-二乙基甲酰胺为催化剂，N,N-二乙基甲酰胺在催化的同时，分解出二乙胺，但二乙胺与烟酸的反应产物恰好是本发明产品尼可刹米，从而巧妙地避免了其他的杂质的产生。
作为优选的技术方案，步骤S1中，所述反应温度为80～110℃，进一步优选90～100℃；反应时间进一步优选4～8h。
所述有机溶剂选自甲苯、二甲苯中的一种，进一步优选甲苯。
作为优选的技术方案，步骤S2中，所述降温在氮气保护下进行，反应时间进一步优选2～4h。
作为优选的技术方案，步骤S2中，降温至20～40℃。
与现有技术相比，本发明的优点在于：本发明采用N,N-二乙基甲酰胺作为催化剂，解决了使用DMF带来的难以分离的杂质问题，使得杂质成倍降低、纯度显著提高的同时收率也得到提高。
附图说明
图1为本发明实施例1所制得的尼可刹米的核磁共振氢谱图；
图2为本发明实施例1所制得的产品的HPLC图；
图3为对比例1所制得的产品的HPLC图。
具体实施方式
下面将结合附图对本发明作进一步说明。
实施例1：
向反应瓶中加入200g甲苯，开启搅拌；然后依次加入20g烟酸、0.4g N,N-二乙基甲酰胺、23g SOCl2；加毕，升温至80℃左右反应8小时；氮气保护下降温，控制内温低于30℃滴加38g二乙胺；加毕，30℃左右反应2小时。
控制内温低于30℃加入4.4g纯化水淬灭反应；反应液离心除去二乙胺盐酸盐，滤液加入纯化水，滴加浓盐酸使产品成盐留在水相；再用氢氧化钠水溶液游离、加入氯化钠固体饱和水相后甲苯萃取、减压浓缩得到粗品；粗品经减压蒸馏得到尼可刹米成品，收率89%，其核磁共振氢谱如图1所示；所得产品的HPLC纯度99.976%，参见图2。
实施例2：
向反应瓶中加入200g二甲苯，开启搅拌；然后依次加入20g烟酸、0.4g N,N-二乙基甲酰胺、29g SOCl2；加毕，升温至100℃左右反应8小时；氮气保护下降温，控制内温低于30℃滴加30g二乙胺；加毕，30℃左右反应2小时。
控制内温低于30℃加入4.4g纯化水淬灭反应；反应液离心除去二乙胺盐酸盐，滤液加入纯化水，滴加浓盐酸使产品成盐留在水相；再用氢氧化钠水溶液游离、加入氯化钠固体饱和水相后甲苯萃取、减压浓缩得到粗品；粗品经减压蒸馏得到尼可刹米成品，收率88%，纯度99.98% 。
实施例3：
向反应瓶中加入200g甲苯，开启搅拌；然后依次加入20g烟酸、0.4g N,N-二乙基甲酰胺、20g SOCl2；加毕，升温至110℃左右反应4小时；氮气保护下降温，控制内温低于20℃滴加70g二乙胺；加毕，30℃左右反应2小时。
控制内温低于30℃加入4.4g纯化水淬灭反应；反应液离心除去二乙胺盐酸盐，滤液加入纯化水，滴加浓盐酸使产品成盐留在水相；再用氢氧化钠水溶液游离、加入氯化钠固体饱和水相后甲苯萃取、减压浓缩得到粗品；粗品经减压蒸馏得到尼可刹米成品，收率87%，纯度99.975%。
实施例4：
向反应瓶中加入200g二甲苯，开启搅拌；然后依次加入20g烟酸、0.4g N,N-二乙基甲酰胺、25g SOCl2；加毕，升温至90℃左右反应6小时；氮气保护下降温，控制内温低于40℃滴加50g二乙胺；加毕，30℃左右反应2小时。
控制内温低于30℃加入4.4g纯化水淬灭反应；反应液离心除去二乙胺盐酸盐，滤液加入纯化水，滴加浓盐酸使产品成盐留在水相；再用氢氧化钠水溶液游离、加入氯化钠固体饱和水相后甲苯萃取、减压浓缩得到粗品；粗品经减压蒸馏得到尼可刹米成品，收率90%，纯度99.981%。
对比例1：
本对比例与上述的实施例1相比，仅催化剂由N,N-二乙基甲酰胺变更为N,N-二甲基甲酰胺，加入的量也相同，其余条件也完全一样，结果，收率为88%，纯度99.574%，如图3所示。
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本发明的保护范围之内。
Claims (6)
1.一种尼可刹米的制备方法，其特征在于，包括下述步骤：
S1：在反应瓶中加入有机溶剂、烟酸、N,N-二乙基甲酰胺、二氯亚砜，然后加热反应；其中，烟酸与二氯亚砜的摩尔比为1：（1.0～1.5），N,N-二乙基甲酰胺的添加量为烟酸质量的1～2%；
S2：将S1反应后的物料降温后，滴加二乙胺进行反应，其中，烟酸与二乙胺的摩尔比为1：（1.5～3.5）；
S3：将S2反应后的物料经淬灭后过滤、萃取、浓缩、蒸馏，得到尼可刹米。
2.根据权利要求1所述的一种尼可刹米的制备方法，其特征在于，步骤S1中，反应温度80～110℃。
3.根据权利要求2所述的一种尼可刹米的制备方法，其特征在于，步骤S1中，所述反应温度为90～100℃。
4.根据权利要求1所述的一种尼可刹米的制备方法，其特征在于，所述有机溶剂选自甲苯、二甲苯中的一种。
5.根据权利要求1所述的一种尼可刹米的制备方法，其特征在于，步骤S2中，所述降温在氮气保护下进行。
6.根据权利要求1所述的一种尼可刹米的制备方法，其特征在于，步骤S2中，降温至20～40℃。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311663760.6A CN117362226B (zh) | 2023-12-06 | 2023-12-06 | 一种尼可刹米的制备方法 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311663760.6A CN117362226B (zh) | 2023-12-06 | 2023-12-06 | 一种尼可刹米的制备方法 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN117362226A CN117362226A (zh) | 2024-01-09 |
| CN117362226B true CN117362226B (zh) | 2024-02-06 |
Family
ID=89389628
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202311663760.6A Active CN117362226B (zh) | 2023-12-06 | 2023-12-06 | 一种尼可刹米的制备方法 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN117362226B (zh) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011000459A1 (de) * | 2009-06-30 | 2011-01-06 | Clariant International Ltd | Kontinuierliches verfahren zur herstellung von amiden aromatischer carbonsäuren |
| CN108947897A (zh) * | 2018-08-22 | 2018-12-07 | 浙江金伯士药业有限公司 | 一种尼可刹米的制备新方法 |
| CN109748866A (zh) * | 2018-12-13 | 2019-05-14 | 杭州金仕源医药化工有限公司 | 一种n,n-二乙基烟酰胺的制备方法 |
| WO2022105482A1 (zh) * | 2020-11-18 | 2022-05-27 | 山东金城医药化工有限公司 | 一种高光学纯度烟碱的制备方法 |
-
2023
- 2023-12-06 CN CN202311663760.6A patent/CN117362226B/zh active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011000459A1 (de) * | 2009-06-30 | 2011-01-06 | Clariant International Ltd | Kontinuierliches verfahren zur herstellung von amiden aromatischer carbonsäuren |
| CN108947897A (zh) * | 2018-08-22 | 2018-12-07 | 浙江金伯士药业有限公司 | 一种尼可刹米的制备新方法 |
| CN109748866A (zh) * | 2018-12-13 | 2019-05-14 | 杭州金仕源医药化工有限公司 | 一种n,n-二乙基烟酰胺的制备方法 |
| WO2022105482A1 (zh) * | 2020-11-18 | 2022-05-27 | 山东金城医药化工有限公司 | 一种高光学纯度烟碱的制备方法 |
Non-Patent Citations (2)
| Title |
|---|
| Metal-Free Amidation of Acids with Formamides and T3P;Linda Bannwart ，等;《Synthesis》;2069-2078 * |
| 尼可刹米生产工艺改进;袁文福，等;《安徽医药》;74-75 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN117362226A (zh) | 2024-01-09 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| DE69736847T2 (de) | Herstellung von Laktamen aus aliphatischen Alpha,Omega-Dinitrilen | |
| CN104447443B (zh) | 一种阿普斯特及其中间体的制备方法 | |
| DE69907943T2 (de) | Verfahren zur herstellung von methionin | |
| US10144687B2 (en) | Method for producing 1,4-butanediol | |
| CA3029325A1 (en) | Method for producing aniline or an aniline derivative | |
| CN117362226B (zh) | 一种尼可刹米的制备方法 | |
| EP2730566B1 (en) | Method for producing tetrahydrofuran | |
| US9102589B2 (en) | Reactive distillation process for preparation of acetaminophen | |
| CN103804267B (zh) | 一种维达列汀的合成工艺 | |
| JP3110459B2 (ja) | ｐ−アミノフェノール組成物の精製及びＮ−アセチル−ｐ−アミノフェノールへの直接転化 | |
| EP2509937A1 (de) | Verfahren zur herstellung von 2,2-difluorethylamin sowie seiner salze ausgehend von difluoracetonitril | |
| KR20150095930A (ko) | 시클로헥사논 옥심의 베크만 재배열로부터 정제된 카프로락탐을 제조하는 방법 | |
| JPS5840543B2 (ja) | ピリジンカルボン酸の製造法 | |
| CN110563699A (zh) | 一种氟呐普拉赞中间体的后处理纯化方法 | |
| CN1083532A (zh) | 酶法生产没食子酸的工艺 | |
| US3359260A (en) | Purification of epsilon-caprolactams | |
| CN1155581C (zh) | 5－甲基吡嗪－2－羧酸的制备方法 | |
| CN102603594A (zh) | （s）-奥拉西坦的制备方法 | |
| CN115010647B (zh) | 一种双环内酰胺类化合物的制备方法 | |
| CN102603595A (zh) | （s）-奥拉西坦的制备方法 | |
| JPH01186864A (ja) | Ｎ−アルキル置換ラクタムの製造方法 | |
| UA83663C2 (ru) | Непрерывный способ получения капролактама | |
| CN112195203B (zh) | 一种酶法合成(s)-2-氨基丁酰胺的方法 | |
| DE60030428T2 (de) | 4-cyano-3-hydroxy-butanoyl hydrazine, derivate und verfahren zu ihrer herstellung | |
| KR940005567A (ko) | 고순도 카프로락탐의 제조방법 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |