CN1073985C - Process for synthesizing 1-aminocyclopropane-1-carboxylic acid - Google Patents
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Abstract
1-氯基环丙烷-1-羧酸新型合成方法，氰乙酸乙酯为起始原料、碳酸钾为碱、PEG800为催化剂，乙酸乙酯为溶剂，与二溴乙烷进行环化得1-氰基环丙烷-1-羧酸乙酯，以过氧化氢为催化剂，乙醇为溶剂，氢氧化钠为碱进行水解，水解混合物在冷浴下交替加入溴和氢氧化钠，撤除冷浴后再加入氢氧化钠，升温，在水浴冷却下用浓盐酸调pH＝1-2，纯化得产品，工艺简便，原料易得，条件温和，产率高，适合工业化生产，具有较大实施价值和效益。A novel synthesis method of 1-chlorocyclopropane-1-carboxylic acid, ethyl cyanoacetate is used as starting material, potassium carbonate is used as base, PEG800 is used as catalyst, ethyl acetate is used as solvent, and cyclization is carried out with dibromoethane to obtain 1- Ethyl cyanocyclopropane-1-carboxylate is hydrolyzed with hydrogen peroxide as a catalyst, ethanol as a solvent, and sodium hydroxide as a base. The hydrolysis mixture is alternately added with bromine and sodium hydroxide in a cold bath, and then removed from the cold bath. Add sodium hydroxide, raise the temperature, adjust the pH to 1-2 with concentrated hydrochloric acid under water bath cooling, and purify the product. The process is simple, the raw materials are easy to obtain, the conditions are mild, and the yield is high. It is suitable for industrial production and has great practical value and benefits. .
Description
本发明属于一种非蛋白特种氨基酸的合成方法，尤其是1-氨基环丙烷-1-羧酸合成方法，适用于1-氨基环丙烷-1-羧酸人工合成的场合。The invention belongs to a method for synthesizing non-protein special amino acids, in particular to a method for synthesizing 1-aminocyclopropane-1-carboxylic acid, which is suitable for the artificial synthesis of 1-aminocyclopropane-1-carboxylic acid.
在本发明作出之前，现有技术1-氨基环丙烷-1-羧酸(ACC)人工合成方法有季铵碱热解法等20余种方法，但均未实现工业化生产，其主要缺点是工艺冗长，步骤繁复，原料难得，反应条件苛刻，产率低；ACC原本存在于植物之中，含量低，直接从植物中提取分离ACC的方法成本高，也不能形成规模生产，不能实际应用。Before the present invention was made, the prior art 1-aminocyclopropane-1-carboxylic acid (ACC) artificial synthesis method had more than 20 kinds of methods such as quaternary ammonium alkali pyrolysis method, but all did not realize suitability for industrialized production, and its main shortcoming is that process Lengthy, complicated steps, rare raw materials, harsh reaction conditions, and low yield; ACC originally exists in plants with low content, and the method of directly extracting and separating ACC from plants is costly, and it cannot be produced on a large scale and cannot be practically applied.
本发明的目的是克服现有技术的缺点，提供一种工艺简便、原料易得、反应条件温和、产率高、易于形成工业化规模生产的1-氨基环丙烷-1-羧酸合成方法。The purpose of the present invention is to overcome the shortcomings of the prior art and provide a 1-aminocyclopropane-1-carboxylic acid synthesis method with simple process, readily available raw materials, mild reaction conditions, high yield and easy industrial scale production.
本发明的：1-氨基环丙烷-1-羧酸合成方法，以氰乙酸乙酯为起始原料，与二溴乙烷进行环化，其特征是(1)以碳酸钾为碱，聚乙二醇800(PEG800)为催化剂，乙酸乙酯为溶剂，反应温度在70-90℃，常压下搅拌反应，反应时间2-4小时，经纯化分离得合成中间体1-氰基环丙烷-1-羧酸乙酯，其中氰乙酸乙酯∶二溴乙烷∶碳酸钾∶PEG800∶乙酸乙酯=1∶1.2-1.4∶2-2.4∶0.01-0.03∶5-15(mol比)；(2)以合成中间体1-氰基环丙烷-1-羧酸乙酯为原料，30％(重量％)过氧化氢为催化剂，95％(重量％)乙醇为溶剂，10％(重量％)氢氧化钠水溶液为碱，常温常压下进行水解得中间体环丙烷-1,1-二羧酸单酰胺反应混合物，其中1-氰基环丙烷-1-羧酸乙酯∶30％(重量％)过氧化氢∶95％(重量％)乙醇∶10％(重量％)氢氧化钠水溶液=1mol∶30ml-50ml∶40-60ml∶40-50ml，反应时间4-6小时；(3)以上反应混合物紧接着进行一锅粥反应，将环丙烷-1,1-二羧酸单酰胺反应混合物置于冷浴(-5℃-20℃)中，在搅拌下逐滴交替加入溴和10％(重量％)氢氧化钠水溶液，其中1-氰基环丙烷-1-羧酸乙酯∶溴∶10％(重量％)氢氧化钠水溶液=1mol∶1mol∶500-600ml，撤除冷浴，再一次加入10％(重量％)氢氧化钠水溶液(其中1-氰基环丙烷-1-羧酸乙酯∶10％氢氧化钠=1mol∶2000ml)后迅速升温至38-45℃，放置5-6小时，在水浴冷却下加入37％(重量％)浓盐酸至PH=1-2，经纯化分离得1-氨基环丙烷-1-羧酸白色针状晶体，总产率为55-60％。The present invention: the synthetic method of 1-aminocyclopropane-1-carboxylic acid, with ethyl cyanoacetate as starting material, carries out cyclization with dibromoethane, it is characterized in that (1) take potassium carbonate as base, polyethylene Glycol 800 (PEG800) is the catalyst, ethyl acetate is the solvent, the reaction temperature is 70-90°C, the reaction is stirred under normal pressure, the reaction time is 2-4 hours, and the synthetic intermediate 1-cyanocyclopropane- 1-ethyl carboxylate, wherein ethyl cyanoacetate: dibromoethane: potassium carbonate: PEG800: ethyl acetate=1: 1.2-1.4: 2-2.4: 0.01-0.03: 5-15 (mol ratio); ( 2) Taking synthetic intermediate 1-cyanocyclopropane-1-carboxylate ethyl ester as raw material, 30% (weight %) hydrogen peroxide as catalyst, 95% (weight %) ethanol as solvent, 10% (weight %) Sodium hydroxide aqueous solution is alkali, under normal temperature and pressure, carry out hydrolysis to obtain intermediate cyclopropane-1,1-dicarboxylic acid monoamide reaction mixture, wherein 1-cyanocyclopropane-1-carboxylic acid ethyl ester: 30% (weight %) hydrogen peroxide: 95% (weight %) ethanol: 10% (weight %) sodium hydroxide aqueous solution=1mol: 30ml-50ml: 40-60ml: 40-50ml, reaction times 4-6 hours; (3) above The reaction mixture was followed by a one-pot porridge reaction, and the cyclopropane-1,1-dicarboxylic acid monoamide reaction mixture was placed in a cold bath (-5°C-20°C), and bromine and 10% (by weight) were alternately added dropwise under stirring. %) sodium hydroxide aqueous solution, wherein 1-cyanocyclopropane-1-carboxylic acid ethyl ester: bromine: 10% (weight %) sodium hydroxide aqueous solution=1mol: 1mol: 500-600ml, remove the cold bath, add again 10% (weight%) sodium hydroxide aqueous solution (wherein 1-cyanocyclopropane-1-carboxylate ethyl ester: 10% sodium hydroxide = 1mol: 2000ml) and then rapidly heat up to 38-45°C, and place it for 5-6 hours , add 37% (weight %) concentrated hydrochloric acid to PH = 1-2 under cooling in a water bath, and obtain 1-aminocyclopropane-1-carboxylic acid white needle crystals after purification, with a total yield of 55-60%.
本发明的1-氨基环丙烷-1-羧酸合成方法，与现有技术相比，工艺简便可行，原料易得，反应条件温和，产率高，容易形成工业化规模生产，具有较大实施价值和社会经济效益。Compared with the prior art, the method for synthesizing 1-aminocyclopropane-1-carboxylic acid of the present invention has the advantages of simple and feasible process, easy-to-obtain raw materials, mild reaction conditions, high yield, easy industrial scale production, and great implementation value and socioeconomic benefits.
实施例1:1-氨基环丙烷-1-羧酸合成方法，以氰乙酸乙酯为起始原料，与二溴乙烷进行环化，其特征是(1)以碳酸钾为碱，聚乙二醇800(PEG800)为催化剂，乙酸乙酯为溶剂，反应温度在70℃，常压下搅拌反应，反应时间4小时，经纯化分离得合成中间体1-氰基环丙烷-1-羧酸乙酯，其中氰乙酸乙酯∶二溴乙烷∶碳酸钾∶PEG800∶乙酸乙酯=1∶1.4∶2.4∶0.03∶5(mol比)；(2)以合成中间体1-氰基环丙烷-1-羧酸乙酯为原料，30％(重量％)过氧化氢为催化剂，95％(重量％)乙醇为溶剂，10％(重量％)氢氧化钠水溶液为碱，常温常压下进行水解得中间体环丙烷-1,1-二羧酸单酰胺反应混合物，其中1-氰基环丙烷-1-羧酸乙酯∶30％(重量％)过氧化氢∶95％(重量％)乙醇∶10％(重量％)氢氧化钠水溶液=1mol∶30ml∶40ml∶40ml，反应时间6小时；(3)以上反应混合物紧接着进行一锅粥反应，将环丙烷-1,1-二羧酸单酰胺反应混合物置于冷浴(-5℃-20℃)中，在搅拌下逐滴交替加入溴和10％(重量％)氢氧化钠水溶液，其中1-氰基环丙烷-1-羧酸乙酯∶溴∶10％(重量％)氢氧化钠水溶液=1mol∶1mol∶500ml，撤除冷浴，再一次加入10％(重量％)氢氧化钠水溶液(其中1-氰基环丙烷-1-羧酸乙酯∶10％氢氧化钠=1mol∶2000ml)后迅速升温至38℃，放置6小时，水浴冷却下加入37％(重量％)浓盐酸至PH=1-2，经纯化分离得1-氨基环丙烷-1-羧酸白色针状晶体，总产率为55％。Embodiment 1: 1-aminocyclopropane-1-carboxylic acid synthetic method, take ethyl cyanoacetate as starting material, carry out cyclization with dibromoethane, it is characterized in that (1) take potassium carbonate as base, polyethylene Diol 800 (PEG800) was used as catalyst, ethyl acetate was used as solvent, the reaction temperature was 70°C, the reaction was stirred under normal pressure, the reaction time was 4 hours, and the synthetic intermediate 1-cyanocyclopropane-1-carboxylic acid was obtained after purification and separation Ethyl cyanoacetate: ethyl cyanoacetate: dibromoethane: potassium carbonate: PEG800: ethyl acetate=1: 1.4: 2.4: 0.03: 5 (mol ratio); (2) to synthesize intermediate 1-cyanocyclopropane -1-Carboxylic acid ethyl ester is a raw material, 30% (weight %) hydrogen peroxide is a catalyst, 95% (weight %) ethanol is a solvent, 10% (weight %) sodium hydroxide aqueous solution is alkali, carries out under normal temperature and pressure Hydrolysis to obtain the intermediate cyclopropane-1,1-dicarboxylic acid monoamide reaction mixture, wherein ethyl 1-cyanocyclopropane-1-carboxylate: 30% (weight %) hydrogen peroxide: 95% (weight %) Ethanol: 10% (weight %) sodium hydroxide aqueous solution=1mol: 30ml: 40ml: 40ml, 6 hours of reaction times; The amide reaction mixture was placed in a cold bath (-5°C-20°C), and bromine and 10% (weight %) sodium hydroxide aqueous solution were alternately added dropwise under stirring, wherein 1-cyanocyclopropane-1-carboxylic acid ethyl Esters: bromine: 10% (weight %) sodium hydroxide aqueous solution=1mol: 1mol: 500ml, remove the cold bath, add 10% (weight %) sodium hydroxide aqueous solution (wherein 1-cyanocyclopropane-1-carboxylate ethyl acetate: 10% sodium hydroxide = 1mol: 2000ml) and then rapidly heated to 38°C, left to stand for 6 hours, then added 37% (weight %) concentrated hydrochloric acid to pH = 1-2 under cooling in a water bath, and purified to obtain 1- Aminocyclopropane-1-carboxylic acid white needle crystals, the total yield is 55%.
实施例2:1-氨基环丙烷-1-羧酸合成方法，以氰乙酸乙酯为起始原料，与二溴乙烷进行环化，其特征是(1)以碳酸钾为碱，聚乙二醇800(PEG800)为催化剂，乙酸乙酯为溶剂，反应温度在80℃，常压下搅拌反应，反应时间3.5小时，经纯化分离得合成中间体1-氰基环丙烷-1-羧酸乙酯，其中氰乙酸乙酯∶二溴乙烷∶碳酸钾∶PEG800∶乙酸乙酯=1∶1.3∶2.2∶0.02∶10(mol比)；(2)以合成中间体1-氰基环丙烷-1-羧酸乙酯为原料，30％(重量％)过氧化氢为催化剂，95％(重量％)乙醇为溶剂，10％(重量％)氢氧化钠水溶液为碱，常温常压下进行水解得中同体环丙烷-1,1-二羧酸单酰胺反应混合物，其中1-氰基环丙烷-1-羧酸乙酯∶3％(重量％)过氧化氢∶95％(重量％)乙醇∶10％(重量％)氢氧化钠水溶液=1mol∶40ml∶50ml∶45ml，反应时间5小时；(3)以上反应混合物紧接着进行一锅粥反应，将环丙烷-1,1-二羧酸单酰胺反应混合物置于冷浴(-5℃-20℃)中，在搅拌下逐滴交替加入溴和10％(重量％)氢氧化钠水溶液，其中1-氰基环丙烷-1-羧酸乙酯∶溴∶10％(重量％)氢氧化钠水溶液=1mol∶1mol∶550ml，撤除冷浴，再一次加入10％(重量％)氢氧化钠水溶液(其中1-氰基环丙烷-1-羧酸乙酯∶10％氢氧化钠=1mol∶2000ml)后迅速升温至40℃，放置5.5小时，在水浴冷却下加入37％(重量％)浓盐酸至PE=1-2，经纯化分离得1-氨基环丙烷-1-羧酸白色针状晶体，总产率为6％。Embodiment 2: 1-aminocyclopropane-1-carboxylic acid synthetic method, take ethyl cyanoacetate as starting material, carry out cyclization with dibromoethane, it is characterized in that (1) take potassium carbonate as base, polyethylene Diol 800 (PEG800) was used as catalyst, ethyl acetate was used as solvent, the reaction temperature was 80°C, the reaction was stirred under normal pressure, and the reaction time was 3.5 hours. After purification and separation, the synthetic intermediate 1-cyanocyclopropane-1-carboxylic acid was obtained. Ethyl cyanoacetate: ethyl cyanoacetate: dibromoethane: potassium carbonate: PEG800: ethyl acetate=1: 1.3: 2.2: 0.02: 10 (mol ratio); (2) to synthesize intermediate 1-cyanocyclopropane -1-Carboxylic acid ethyl ester is a raw material, 30% (weight %) hydrogen peroxide is a catalyst, 95% (weight %) ethanol is a solvent, 10% (weight %) sodium hydroxide aqueous solution is alkali, carries out under normal temperature and pressure Hydrolysis to obtain homogeneous cyclopropane-1,1-dicarboxylic acid monoamide reaction mixture, wherein 1-cyanocyclopropane-1-carboxylic acid ethyl ester: 3% (weight %) hydrogen peroxide: 95% (weight %) Ethanol: 10% (weight %) sodium hydroxide aqueous solution=1mol: 40ml: 50ml: 45ml, 5 hours of reaction times; The amide reaction mixture was placed in a cold bath (-5°C-20°C), and bromine and 10% (weight %) sodium hydroxide aqueous solution were alternately added dropwise under stirring, wherein 1-cyanocyclopropane-1-carboxylic acid ethyl Ester: bromine: 10% (weight %) sodium hydroxide aqueous solution=1mol: 1mol: 550ml, remove cold bath, add 10% (weight %) sodium hydroxide aqueous solution again (wherein 1-cyanocyclopropane-1-carboxylate Acetate ethyl ester: 10% sodium hydroxide=1mol:2000ml) then rapidly warming up to 40°C, standing for 5.5 hours, adding 37% (weight %) concentrated hydrochloric acid to PE=1-2 under water bath cooling, after purification and separation, 1 -Aminocyclopropane-1-carboxylic acid white needle crystals, the total yield is 6%.
实施例3:1-氨基环丙烷-1-羧酸合成方法，以氰乙酸乙酯为起始原料，与二溴乙烷进行环化，其特征是(1)以碳酸钾为碱，聚乙二醇800(PEG800)为催化剂乙酸乙酯为溶剂，反应温度在90℃，常压下搅拌反应，反应时间2小时，经纯化分离得合成中间体1-氰基环丙烷-1-羧酸乙酯，其中氰乙酸乙酯∶二溴乙烷∶碳酸钾∶PEG800∶乙酸乙酯=1∶1.2∶2∶0.01∶5(mol比)；(2)以合成中间体1-氰基环丙烷-1-羧酸乙酯为原料，30％(重量％)过氧化氢为催化剂，95％(重量％)乙醇为溶剂，10％(重量％)氢氧化钠水溶液为碱，常温常压下进行水解得中间体环丙烷-1,1-二羧酸单酰胺反应混合物，其中1-氰基环丙烷-1-羧酸乙酯∶30％(重量％)过氧化氢：95％(重量％)乙醇∶10％(重量％)氢氧化钠水溶液=1mol∶50ml∶60ml∶40ml，反应时间4小时；(3)以上反应混合物紧接着进行一锅粥反应，将环丙烷-1,1-二羧酸单酰胺反应混合物置于冷浴(-5℃-20℃)中，在搅拌下逐滴交替加入溴和10％(重量％)氢氧化钠水溶液，其中1-氰基环丙烷-1-羧酸乙酯∶溴∶10％(重量％)氢氧化钠水溶液=1mol∶1mol∶600ml，撤除冷浴，再一次加入10％(重量％)氢氧化钠水溶液(其中1-氰基环丙烷-1-羧酸乙酯∶10％氢氧化钠=1mol∶2000ml)后迅速升温至45℃，放置5小时，在水浴冷却下加入37％(重量％)浓盐酸PH=1-2，经纯化分离得1-氨基环丙烷-1-羧酸白色针状晶体，总产率为57％。Embodiment 3: 1-aminocyclopropane-1-carboxylic acid synthetic method, take ethyl cyanoacetate as starting material, carry out cyclization with dibromoethane, it is characterized in that (1) take potassium carbonate as base, polyethylene Diol 800 (PEG800) is the catalyst and ethyl acetate is the solvent. The reaction temperature is 90°C and the reaction is stirred under normal pressure. The reaction time is 2 hours. After purification and separation, the synthetic intermediate 1-cyanocyclopropane-1-carboxylate ethyl Ethyl cyanoacetate: dibromoethane: potassium carbonate: PEG800: ethyl acetate=1: 1.2: 2: 0.01: 5 (mol ratio); (2) to synthesize intermediate 1-cyanocyclopropane- 1-Carboxylic acid ethyl ester is a raw material, 30% (weight %) hydrogen peroxide is a catalyst, 95% (weight %) ethanol is a solvent, 10% (weight %) sodium hydroxide aqueous solution is alkali, carries out hydrolysis under normal temperature and pressure Obtain intermediate cyclopropane-1,1-dicarboxylic acid monoamide reaction mixture, wherein 1-cyanocyclopropane-1-carboxylic acid ethyl ester: 30% (weight %) hydrogen peroxide: 95% (weight %) ethanol : 10% (weight %) sodium hydroxide aqueous solution=1mol: 50ml: 60ml: 40ml, 4 hours of reaction time; (3) above reaction mixture carries out one-pot porridge reaction immediately, cyclopropane-1,1-dicarboxylic acid monoamide The reaction mixture was placed in a cold bath (-5°C-20°C), and bromine and 10% (weight %) sodium hydroxide aqueous solution were alternately added dropwise under stirring, wherein ethyl 1-cyanocyclopropane-1-carboxylate : bromine: 10% (weight %) sodium hydroxide aqueous solution=1mol: 1mol: 600ml, remove cold bath, add 10% (weight %) sodium hydroxide aqueous solution (wherein 1-cyanocyclopropane-1-carboxylic acid Ethyl ester: 10% sodium hydroxide = 1mol: 2000ml) and then rapidly heated to 45°C, left for 5 hours, added 37% (weight %) concentrated hydrochloric acid pH = 1-2 under cooling in a water bath, purified and separated to obtain 1-amino Cyclopropane-1-carboxylic acid white needle crystals, the total yield is 57%.
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| SU1313851A1 (en) * | 1985-04-18 | 1987-05-30 | Институт Элементоорганических Соединений Им.Л.Н.Несмеянова | Method for producing 1-aminocyclopropane-1-carboxylic acid |
| US5569781A (en) * | 1994-04-06 | 1996-10-29 | Huels Aktiengesellschaft | Process for the preparation of 1-aminocyclopropanecarboxylic acid hydrochloride |
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| SU1313851A1 (en) * | 1985-04-18 | 1987-05-30 | Институт Элементоорганических Соединений Им.Л.Н.Несмеянова | Method for producing 1-aminocyclopropane-1-carboxylic acid |
| US5569781A (en) * | 1994-04-06 | 1996-10-29 | Huels Aktiengesellschaft | Process for the preparation of 1-aminocyclopropanecarboxylic acid hydrochloride |
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|---|---|
| CN1239092A (en) | 1999-12-22 |
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