CN1069485A - 琥珀酰胆碱卤化物的制备方法 - Google Patents
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- -1 succinylcholine halide Chemical class 0.000 title claims abstract description 22
- 229940032712 succinylcholine Drugs 0.000 title claims abstract description 12
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- UEEJHVSXFDXPFK-UHFFFAOYSA-N N-dimethylaminoethanol Chemical compound CN(C)CCO UEEJHVSXFDXPFK-UHFFFAOYSA-N 0.000 claims abstract description 17
- 229960002887 deanol Drugs 0.000 claims abstract description 17
- 239000003054 catalyst Substances 0.000 claims abstract description 15
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims abstract description 8
- 229910052783 alkali metal Inorganic materials 0.000 claims abstract description 7
- 150000001340 alkali metals Chemical class 0.000 claims abstract description 5
- 150000001408 amides Chemical class 0.000 claims abstract description 4
- 238000000034 method Methods 0.000 claims description 21
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 5
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical group [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 claims description 4
- 229940050176 methyl chloride Drugs 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 3
- JILPJDVXYVTZDQ-UHFFFAOYSA-N lithium methoxide Chemical group [Li+].[O-]C JILPJDVXYVTZDQ-UHFFFAOYSA-N 0.000 claims description 3
- 239000007858 starting material Substances 0.000 claims description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 2
- 150000007524 organic acids Chemical class 0.000 claims description 2
- 230000009849 deactivation Effects 0.000 claims 2
- AWZOINKDOXDOFK-UHFFFAOYSA-N 4-[2-(methylamino)ethoxy]-4-oxobutanoic acid Chemical class CNCCOC(=O)CCC(O)=O AWZOINKDOXDOFK-UHFFFAOYSA-N 0.000 claims 1
- 230000001476 alcoholic effect Effects 0.000 claims 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 1
- JSINVKLVDNFTSU-UHFFFAOYSA-N bis[2-(dimethylamino)ethyl] butanedioate Chemical compound CN(C)CCOC(=O)CCC(=O)OCCN(C)C JSINVKLVDNFTSU-UHFFFAOYSA-N 0.000 abstract description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- 239000003085 diluting agent Substances 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 6
- AXOIZCJOOAYSMI-UHFFFAOYSA-N succinylcholine Chemical compound C[N+](C)(C)CCOC(=O)CCC(=O)OCC[N+](C)(C)C AXOIZCJOOAYSMI-UHFFFAOYSA-N 0.000 description 6
- 229940120904 succinylcholine chloride Drugs 0.000 description 6
- 239000001763 2-hydroxyethyl(trimethyl)azanium Substances 0.000 description 4
- 235000019743 Choline chloride Nutrition 0.000 description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 4
- SGMZJAMFUVOLNK-UHFFFAOYSA-M choline chloride Chemical compound [Cl-].C[N+](C)(C)CCO SGMZJAMFUVOLNK-UHFFFAOYSA-M 0.000 description 4
- 229960003178 choline chloride Drugs 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000001384 succinic acid Substances 0.000 description 3
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- AOAPSSUUVWPWIA-UHFFFAOYSA-N bis(2-chloroethyl) butanedioate Chemical compound ClCCOC(=O)CCC(=O)OCCCl AOAPSSUUVWPWIA-UHFFFAOYSA-N 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000003701 inert diluent Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 229940014800 succinic anhydride Drugs 0.000 description 2
- 239000010409 thin film Substances 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- ZFFBIQMNKOJDJE-UHFFFAOYSA-N 2-bromo-1,2-diphenylethanone Chemical compound C=1C=CC=CC=1C(Br)C(=O)C1=CC=CC=C1 ZFFBIQMNKOJDJE-UHFFFAOYSA-N 0.000 description 1
- SZIFAVKTNFCBPC-UHFFFAOYSA-N 2-chloroethanol Chemical compound OCCCl SZIFAVKTNFCBPC-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- LDHMZIUMVSRSIK-UHFFFAOYSA-N 4-oxo-4-[2-(trimethylazaniumyl)ethoxy]butanoate;hydrochloride Chemical compound [Cl-].C[N+](C)(C)CCOC(=O)CCC(O)=O LDHMZIUMVSRSIK-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- MUXOBHXGJLMRAB-UHFFFAOYSA-N Dimethyl succinate Chemical compound COC(=O)CCC(=O)OC MUXOBHXGJLMRAB-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 229910013698 LiNH2 Inorganic materials 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- ZSSTVFHZFMXGGO-UHFFFAOYSA-N bis[2-(methylamino)ethyl] butanedioate Chemical compound C(CCC(=O)OCCNC)(=O)OCCNC ZSSTVFHZFMXGGO-UHFFFAOYSA-N 0.000 description 1
- IRXBNHGNHKNOJI-UHFFFAOYSA-N butanedioyl dichloride Chemical compound ClC(=O)CCC(Cl)=O IRXBNHGNHKNOJI-UHFFFAOYSA-N 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- XIXADJRWDQXREU-UHFFFAOYSA-M lithium acetate Chemical compound [Li+].CC([O-])=O XIXADJRWDQXREU-UHFFFAOYSA-M 0.000 description 1
- AZVCGYPLLBEUNV-UHFFFAOYSA-N lithium;ethanolate Chemical compound [Li+].CC[O-] AZVCGYPLLBEUNV-UHFFFAOYSA-N 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 238000000199 molecular distillation Methods 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- 235000011044 succinic acid Nutrition 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/06—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton from hydroxy amines by reactions involving the etherification or esterification of hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
- C07C225/02—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C219/02—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C219/04—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C219/06—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having the hydroxy groups esterified by carboxylic acids having the esterifying carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms of an acyclic saturated carbon skeleton
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
式I的琥珀酰胆碱卤化物的制备方法如下：将琥
珀酸二烷基酯在碱金属醇化物或氨化物催化剂存在
下，同过量的二甲氨基乙醇反应，然后将所得的双
(2-二甲氨基乙基)琥珀酸酯同卤代甲烷反应。
Description
本发明涉及琥珀酰胆碱卤化物的一种制备方法。
琥珀酰胆碱卤化物是被用作肌肉组织松驰剂的药物活性化合物。
从文献报导已知制备琥珀酰胆碱卤化物有各种各样的方法。
The Bulletin of the Institute of Chemistry，Academia Sinica，26（1979），47-54页介绍了琥珀酰胆碱氯化物的五种制备方法：
方法Ⅰ是将琥珀酸与二甲氨基乙醇反应，先制成双（2-二甲氨基乙基）琥珀酸酯，然后再同氯代甲烷（CH3Cl）反应，生成琥珀酰胆碱氯化物。
方法Ⅱ是用双（2-氯乙基）琥珀酸酯为原料，先使它同二甲胺反应，再如上所述与氯代甲烷反应，便制得琥珀酰胆碱氯化物。
不过，这两种方法的产率都较低。
方法Ⅲ介绍了将琥珀酸同2-氯乙醇反应先制成琥珀酸双（2-氯乙酯），然后用三甲胺加以烷基化，便制得琥珀酰胆碱氯化物，其产率仍然是低。
方法Ⅳ是通过琥珀酰基二氯化物同胆碱氯化物反应制成琥珀酰胆碱氯化物。但是，该方法的缺点是，一方面原料很易吸水因此难以处理，另外还需要辅助的步骤由琥珀酸酐和亚硫酰（二）氯制备酰氯。
方法Ⅴ以琥珀酸酐为原料，以干HCl作催化剂，在苯中与胆碱氯化物反应制取。该方法也必需使用吸水性的胆碱氯化物。另一个缺点是采用苯操作。
J.Am、Chem.Soc（1949）149，Page3264，公开了脂肪二元羧酸的双（β-二甲氨基乙基）酯的一种制备方法，它是采用在少量溶解的钠存在下使甲酯或乙酸同稍为过量的二甲氨基乙醇反应制取。不过，所要求的氨基酯得率低。
出乎意料的是，现在已经发现了琥珀酰基胆碱卤化物的一种新制备方法，它用琥珀酸二烷基酯和二甲氨基乙醇为原料（后者同时作稀释剂），以碱金属醇化物或碱金属氨化物为催化剂，再将产物同卤代甲烷反应，便制得高纯度高产率的琥珀酰胆碱卤化物。
本发明因此涉及以下分子式Ⅰ的琥珀酰基胆碱卤化物的一种制备方法：
式中Ⅹ是氯、溴或碘，
其特征在于：将式Ⅱ的琥珀酸二烷基酯（其中R1为（C1-C4）烷基）：
在碱金属醇化物或氨化物催化剂存在下，用过量的二甲氨基乙醇处理，不断蒸去反应中生成的醇，回收过量的二甲氨基乙醇，然后使催化剂失活并过滤掉，再将所得的双（2-甲氨基乙基）琥珀酸酯（见式Ⅲ）与氯代甲烷反应，便制成式Ⅰ化合物，
按照本发明的方法可按如下步骤实施：在一公用N2吹洗过的反应容器中首先放入也兼用作稀释剂的二甲氨基乙醇，并同时一起加入催化剂。
每摩尔琥珀酸二烷基酯宜使用约2.5-20当量（即5-40摩尔）二甲氨基乙醇，又以7-10摩尔为佳，以8-9摩尔为更佳。使用较大量的二甲氨基乙醇对反应并无任何不利的影响，不过，反应终了时必须把更多的二甲氨基乙醇蒸掉。所用的催化剂包括碱金属醇化物或氨化物，例如甲醇锂，乙醇锂，氨基化锂，甲醇钠，氨基化钠，氨基化钾或甲醇钾。优选采用的是甲醇锂，氨基化锂或甲醇钠。催化剂的用量约占琥珀酸二烷基酯的0.5-6%（重量），又以约1-3%（重量）为佳，以约2%（重量）为更佳。
接着把混合物加热到约30-120℃（最好是约75-90℃），用约15-30分钟加入琥珀酸二烷基酯。所用的该酯的烷基链含1-4个碳原子，又以含1-2个碳原子为佳。反应压力为50-760毫巴，又以100-300毫巴为佳。降低反应压力如降到200毫巴是有益的，因为反应生成的醇随后可以被更容易和更快地蒸掉。
不断蒸去反应生成的醇，在最初15-30分钟内，大部分的醇被分离掉。
按照这种方法回收的二甲氨基乙醇可以重新用作原料化合物或稀释剂。二甲氨基乙醇被蒸掉后，放掉真空通入N2气，反应浴液中加入有机酸如醋酸，草酸，甲酸或琥珀酸，使催化剂失活，加入量相当于催化剂的含量。
为了能更容易地滤出所得的凝胶状沉淀物，宜采用在过滤出生成的碱金属盐之后能易于脱除和回收的一种惰性稀释剂处理反应混合物。可以采用的稀释剂特别是苯，甲苯或醚类如二异丙基醚。优先采用的是二异丙基醚。留下的残渣双（2-二甲基乙基）琥珀酸酯再按传统的方法精制。尤其合适的精制方法是薄膜蒸发和分子蒸馏。
为了进一步的反应，将双（2-二甲氨基乙基）琥珀酸酯悬浮在惰性稀释剂中如丙酮，四氢呋喃或二异丙基醚，需要的话，用活性炭澄清。丙酮是优先采用的稀释剂。将卤代甲烷在压力下引入悬浮液。每摩尔双（2-二甲氨基乙基）琥珀酸酯需用2摩尔卤代甲烷。优先用2.5-9摩尔，最好用2.8-3.2摩尔。然后使温度升高到约30-100℃，优选是40-60℃。反应通常在约1-20小时后完成，此时冷却反应混合物，蒸去稀释剂和过量的卤代甲烷。回收后的稀释剂和卤代甲烷可以分别被重新用作稀释剂和季铵化剂。
所得的琥珀酰胆碱卤化物可以按常规方法重结晶，例如从乙醇/水混合物重结晶。
采用本发明方法所得的琥珀酰胆碱卤化物产率高，纯度好。
实施例1
双（2-二甲氨基乙基）琥珀酸酯的制备
在用N2气吹洗过的反应容器中放入1418.56克（15.9摩尔）二甲氨基乙醇，加入10克（0.43摩尔）LiNH2，便有NH3放出。使温度升高到约70℃，压力降低到200毫巴，用20分钟加入500克（3.42摩尔）琥珀酸二甲酯。不断蒸出反应生成的甲醇，在开始15分钟内分离出了大部分的甲醇（约200毫升，甲醇的理论总量＝277毫升）。
7小时后，降压到15毫巴，蒸去过量的二甲氨基乙醇和残留的甲醇。放掉真空通入N2气，用等摩尔量的酯酸（按LiNH2计算）处理反应混合物。为了能更易过滤掉产生的凝胶状醋酸锂沉淀，在50-60℃往反应溶液里加入2000毫升二异丙基醚。
蒸去滤液中的醚，用薄膜蒸馏法处理留下的双（2-二甲氨基乙基）琥珀酸酯。
产率：806克（90.64%），纯度：99.5%
类似地进行一些其它的实验。数据示于表1。
表1
LiOCH3NaOCH3KOCH3
％（重量） 2 3 6
T（℃） 65－87 65－80 65－88
粗产率 96.6 87 99.9
蒸馏后的纯度 99.5 99.2 99.5
实施例2
琥珀酰基胆碱卤化物的制备
将54克（0.21摩尔）双（2-二甲氨基乙基）琥珀酸酯溶于700毫升丙酮，在压力下加入27克（0.54摩尔）CH3Cl。在60℃经约8小时后，冷却反应混合物，蒸去丙酮和和过量的CH3Cl。将所得的琥珀酰胆碱氯化物用乙醇/H2O混合物（80/20）重结晶。
产率：68（89.6%），白色结晶粉末
熔点：160℃
纯度：胆碱氯化物含量＜0.5%
琥珀酰单胆碱氯化物含量＜0.5%
Claims (7)
1、式Ⅰ的琥珀酰胆碱卤化物的制备方法：
式中X为氯，溴或碘，
其特征在于：将式Ⅱ的琥珀酸二烷基酯(其中R1为(C1-C4)烷基)：
在碱金属醇化物或氨化物催化剂存在下，用过量的二甲氨基乙醇处理，不断蒸去反应生成的醇，回收过量的二甲氨基乙醇，然后使催化剂失活并过滤掉，再将所得的双(2-甲氨基乙基)琥珀酸酯(式Ⅲ)与氯代甲烷反应，便制成式Ⅰ化合物，
2、权利要求1的一种方法，其特征在于，所用催化剂是甲醇锂或甲醇钠。
3、权利要求1的一种方法，其特征在于，所用催化剂是氨基化锂。
4、权利要求1的一种方法，其特征在于，催化剂用量占式Ⅱ的原料化合物的0.5-6%（重量），又以1-3%（重量）为佳。
5、权利要求1的一种方法，其特征在于，式Ⅱ化合物对二甲按基乙醇的摩尔比为1∶2.5-1∶40，又以1∶7-1∶10为佳。
6、权利要求1的一种方法，其特征在于，二甲氨基乙醇同式Ⅱ化合物的反应在30-120℃温度下进行，又以75-90℃为佳。
7、权利要求1的一种方法，其特征在于，采用一种有机酸使催化剂失活。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AT0159191A AT396361B (de) | 1991-08-13 | 1991-08-13 | Verfahren zur herstellung von succinylcholinhalogeniden |
| ATA1591/91 | 1991-08-13 |
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| Publication Number | Publication Date |
|---|---|
| CN1069485A true CN1069485A (zh) | 1993-03-03 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN92105860A Pending CN1069485A (zh) | 1991-08-13 | 1992-07-18 | 琥珀酰胆碱卤化物的制备方法 |
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| Country | Link |
|---|---|
| US (1) | US5206420A (zh) |
| EP (1) | EP0527364A3 (zh) |
| JP (1) | JPH05221939A (zh) |
| KR (1) | KR930004247A (zh) |
| CN (1) | CN1069485A (zh) |
| AR (1) | AR247549A1 (zh) |
| AT (1) | AT396361B (zh) |
| AU (1) | AU648920B2 (zh) |
| BR (1) | BR9203111A (zh) |
| CA (1) | CA2072735A1 (zh) |
| CZ (1) | CZ249092A3 (zh) |
| FI (1) | FI923603A7 (zh) |
| HU (1) | HU210858B (zh) |
| IL (1) | IL102231A0 (zh) |
| MX (1) | MX9204676A (zh) |
| MY (1) | MY153953A (zh) |
| NO (1) | NO922801L (zh) |
| NZ (1) | NZ243820A (zh) |
| PL (1) | PL295591A1 (zh) |
| SI (1) | SI9200169A (zh) |
| SK (1) | SK249092A3 (zh) |
| TW (1) | TW207994B (zh) |
| YU (1) | YU65092A (zh) |
| ZA (1) | ZA925011B (zh) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2002287C (en) * | 1988-11-07 | 2002-03-12 | Thomas L. Brandt | Glass container transparent coating system |
| DE19503279C2 (de) * | 1995-02-02 | 1998-11-12 | Henkel Kgaa | Kation- und/oder Amphooligomere |
| WO2014024207A1 (en) | 2012-08-06 | 2014-02-13 | Neon Laboratories Ltd. | Process for preparation of succinylcholine chloride |
| CN110776435A (zh) * | 2018-07-31 | 2020-02-11 | 上海旭东海普药业有限公司 | 一种氯化琥珀胆碱的制备方法 |
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| DE970075C (de) * | 1952-07-05 | 1958-08-21 | Asta Werke Ag Chem Fab | Verfahren zur Herstellung von Bernsteinsaeure-bis-(ª-N-dimethyl- bzw. -diaethylaminoaethylester) |
-
1991
- 1991-08-13 AT AT0159191A patent/AT396361B/de not_active IP Right Cessation
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1992
- 1992-06-17 IL IL102231A patent/IL102231A0/xx unknown
- 1992-06-24 US US07/903,324 patent/US5206420A/en not_active Expired - Fee Related
- 1992-06-24 YU YU65092A patent/YU65092A/sh unknown
- 1992-06-25 MY MYPI92001077A patent/MY153953A/en unknown
- 1992-06-27 TW TW081105085A patent/TW207994B/zh active
- 1992-06-29 CA CA002072735A patent/CA2072735A1/en not_active Abandoned
- 1992-07-06 ZA ZA925011A patent/ZA925011B/xx unknown
- 1992-07-15 NO NO92922801A patent/NO922801L/no unknown
- 1992-07-17 AR AR92322764A patent/AR247549A1/es active
- 1992-07-18 CN CN92105860A patent/CN1069485A/zh active Pending
- 1992-07-29 AU AU20665/92A patent/AU648920B2/en not_active Ceased
- 1992-08-01 EP EP19920112533 patent/EP0527364A3/de not_active Withdrawn
- 1992-08-03 NZ NZ243820A patent/NZ243820A/en unknown
- 1992-08-11 JP JP4214359A patent/JPH05221939A/ja not_active Withdrawn
- 1992-08-11 PL PL29559192A patent/PL295591A1/xx unknown
- 1992-08-11 KR KR1019920014397A patent/KR930004247A/ko not_active Withdrawn
- 1992-08-12 BR BR929203111A patent/BR9203111A/pt not_active Application Discontinuation
- 1992-08-12 HU HU9202622A patent/HU210858B/hu not_active IP Right Cessation
- 1992-08-12 FI FI923603A patent/FI923603A7/fi not_active Application Discontinuation
- 1992-08-12 SK SK2490-92A patent/SK249092A3/sk unknown
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Also Published As
| Publication number | Publication date |
|---|---|
| IL102231A0 (en) | 1993-01-14 |
| NO922801D0 (no) | 1992-07-15 |
| SK249092A3 (en) | 1994-08-10 |
| EP0527364A2 (de) | 1993-02-17 |
| FI923603L (fi) | 1993-02-14 |
| NZ243820A (en) | 1993-12-23 |
| SI9200169A (en) | 1993-03-31 |
| AU648920B2 (en) | 1994-05-05 |
| HUT62257A (en) | 1993-04-28 |
| MY153953A (en) | 2015-04-15 |
| TW207994B (zh) | 1993-06-21 |
| MX9204676A (es) | 1993-02-01 |
| AR247549A1 (es) | 1995-01-31 |
| NO922801L (no) | 1993-02-15 |
| KR930004247A (ko) | 1993-03-22 |
| ZA925011B (en) | 1993-04-28 |
| EP0527364A3 (en) | 1993-05-05 |
| FI923603A7 (fi) | 1993-02-14 |
| AU2066592A (en) | 1993-02-18 |
| ATA159191A (de) | 1992-12-15 |
| AT396361B (de) | 1993-08-25 |
| HU9202622D0 (en) | 1992-10-28 |
| CA2072735A1 (en) | 1993-02-14 |
| US5206420A (en) | 1993-04-27 |
| BR9203111A (pt) | 1993-03-16 |
| YU65092A (sh) | 1994-11-15 |
| PL295591A1 (en) | 1993-02-22 |
| HU210858B (en) | 1995-08-28 |
| FI923603A0 (fi) | 1992-08-12 |
| CZ249092A3 (en) | 1993-02-17 |
| JPH05221939A (ja) | 1993-08-31 |
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