CN107673973B - Preparation method of cyclopropylamine intermediate methyl cyclopropanecarboxylate - Google Patents
Preparation method of cyclopropylamine intermediate methyl cyclopropanecarboxylate Download PDFInfo
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- CN107673973B CN107673973B CN201710902486.1A CN201710902486A CN107673973B CN 107673973 B CN107673973 B CN 107673973B CN 201710902486 A CN201710902486 A CN 201710902486A CN 107673973 B CN107673973 B CN 107673973B
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- methanol
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/68—Preparation of metal alcoholates
- C07C29/70—Preparation of metal alcoholates by converting hydroxy groups to O-metal groups
Abstract
The invention discloses a preparation method of cyclopropylamine intermediate methyl cyclopropanecarboxylate, which comprises the steps of firstly, dropwise adding methanol into calcium carbide in a sealed reaction kettle to generate calcium methoxide and acetylene; and then adding gamma-chlorobutyric acid methyl ester into the calcium methoxide at the temperature of 60-120 ℃, controlling the temperature to be constant in the reaction process, collecting methanol generated in the process, and then distilling to obtain methyl cyclopropanecarboxylate. The method has the advantages of simple process, few raw material types required by production, high product yield, good quality, safety and environmental protection, and part of raw materials can be recycled.
Description
Technical Field
The invention relates to the technical field of synthesis of medical intermediates, in particular to a preparation method of cyclopropylamine intermediate methyl cyclopropanecarboxylate.
Background
At present, a plurality of process routes for producing methyl cyclopropanecarboxylate are provided, but the main production route is that the methyl gamma-chlorobutyrate is subjected to hydrogen chloride removal and cyclization through sodium methoxide to generate the methyl cyclopropanecarboxylate. The industrial sodium methoxide is low-concentration methanol solution, so that the methanol needs to be distilled during the cyclization reaction, and the sodium methoxide separated out during the treatment process is easy to adhere to the side wall of a reaction kettle, so that the reaction is incomplete, the yield is difficult to control, and the content of impurities in the product is high; when the methyl cyclopropanecarboxylate is treated by the sodium methoxide, a large amount of methanol flows in the system, and influences are brought to cooling and heating of the reaction, so that the power consumption is high, and the production cost is increased; and the sodium methoxide for cyclizing the gamma-chlorobutyric acid methyl ester is synthesized by a sodium method or an alkali method, and the synthesis has higher raw material cost. Based on the defects, a method suitable for synthesizing methyl cyclopropanecarboxylate in industrial mass production is absolutely necessary to be found.
The invention content is as follows:
the purpose of the invention is: the preparation method of cyclopropylamine intermediate methyl cyclopropanecarboxylate is characterized by taking gamma-methyl chlorobutyrate as a starting raw material and using calcium methoxide prepared from calcium carbide and methanol as strong base to remove hydrogen chloride for cyclization. The method has the advantages of simple process, few raw material types required by production, high product yield, good quality, safety and environmental protection, and part of raw materials can be recycled.
The reaction principle is as follows:
in order to solve the technical problems, the technical scheme of the invention is as follows:
a preparation method of cyclopropylamine intermediate methyl cyclopropanecarboxylate comprises the following steps:
a. and (3) synthesizing methanol calcium: dropwise adding methanol into calcium carbide in a sealed reaction kettle, wherein the molar ratio of the calcium carbide to the methanol is 1: 2-6, and generating calcium carbonate and acetylene;
b. and (3) cyclization reaction: adding gamma-methyl chlorobutyrate into calcium methoxide at the temperature of 60-120 ℃, wherein the molar ratio of the calcium methoxide to the gamma-methyl chlorobutyrate is 1: 1-2, controlling the temperature to be constant in the reaction process, collecting methanol generated in the process, and distilling to obtain methyl cyclopropanecarboxylate.
Preferably, the reaction in step a is carried out after the air in the reaction kettle is replaced by nitrogen.
Preferably, the nitrogen gas displaces the air 3 times.
Preferably, the methanol obtained in step b can be recycled to step a.
Due to the adoption of the technical scheme, the invention has the beneficial effects that:
1. the invention adopts a brand new synthetic route to prepare the methyl cyclopropanecarboxylate, compared with other synthetic methods, the methyl cyclopropanecarboxylate is synthesized by utilizing the byproduct of generating high-value acetylene by calcium carbide, and strong alkali which is necessary to be used in the ring forming process in other synthetic methods is omitted, so the raw material cost of the strong alkali is removed, and the raw material cost is greatly reduced.
2. The methanol calcium directly participates in the reaction, so that the solid alkali is prevented from attaching to the wall of the reaction kettle, and the condition that the utilization rate of raw materials is influenced in other synthesis methods is overcome.
3. The methanol in the production process can be reused, so that the environmental pressure caused by discharge is avoided, and the method is environment-friendly and economical.
In a word, the method has the advantages of simple process, few raw material types required by production, high product yield, good quality, safety and environmental protection, and part of raw materials can be recycled.
Detailed Description
The technical solution of the present invention is further described below with reference to examples:
the first embodiment is as follows:
1mol of calcium carbide is added into a 1000ml reaction kettle, after the reaction kettle is sealed, air is replaced by nitrogen for 3 times, 4mol of methanol is added dropwise, and acetylene gas is collected until the reaction is finished. Then 1.8mol of gamma-chlorobutyric acid methyl ester is dripped into the reaction kettle, the dripping speed is controlled, the temperature is kept constant at 100 ℃, meanwhile, methanol fractions generated in the dripping process are collected, after the reaction is finished, the fractions are collected through heating distillation, 170.3g of methyl cyclopropanecarboxylate is obtained, and the yield is 94.5%.
Example two:
1mol of calcium carbide is added into a 1000ml reaction kettle, after the reaction kettle is sealed, air is replaced by nitrogen for 3 times, 2mol of methanol is added dropwise, and acetylene gas is collected until the reaction is finished. Then 1.8mol of gamma-chlorobutyric acid methyl ester is dripped into the reaction kettle, the dripping speed is controlled, the temperature is kept constant at 100 ℃, simultaneously, methanol fractions generated in the dripping process are collected, after the reaction is finished, the fractions are collected through heating distillation, 150.1g of methyl cyclopropanecarboxylate is obtained, and the yield is 83.3%.
Example three:
1mol of calcium carbide is added into a 1000ml reaction kettle, after the reaction kettle is sealed, air is replaced by nitrogen for 3 times, 6mol of methanol is added dropwise, and acetylene gas is collected until the reaction is finished. Then 1.8mol of gamma-chlorobutyric acid methyl ester is dripped into the reaction kettle, the dripping speed is controlled, the temperature is kept constant at 100 ℃, meanwhile, methanol fractions generated in the dripping process are collected, after the reaction is finished, the fractions are collected through heating distillation, 120.5g of methyl cyclopropanecarboxylate is obtained, and the yield is 66.9%.
Example four:
1mol of calcium carbide is added into a 1000ml reaction kettle, after the reaction kettle is sealed, air is replaced by nitrogen for 3 times, 4mol of methanol is added dropwise, and acetylene gas is collected until the reaction is finished. Then 1.8mol of gamma-chlorobutyric acid methyl ester is dripped into the reaction kettle, the dripping speed is controlled, the temperature is kept constant at 60 ℃, simultaneously, methanol fractions generated in the dripping process are collected, after the reaction is finished, the fractions are collected through heating distillation, 98.2g of methyl cyclopropanecarboxylate is obtained, and the yield is 54.5%.
Example five:
1mol of calcium carbide is added into a 1000ml reaction kettle, after the reaction kettle is sealed, air is replaced by nitrogen for 3 times, 4mol of methanol is added dropwise, and acetylene gas is collected until the reaction is finished. Then 1.8mol of gamma-chlorobutyric acid methyl ester is dripped into the reaction kettle, the dripping speed is controlled, the temperature is kept constant at 120 ℃, meanwhile, methanol fractions generated in the dripping process are collected, and after the reaction is finished, the fractions are collected through heating distillation to obtain 166.5g of methyl cyclopropanecarboxylate, wherein the yield is 92.4%.
Example six:
1mol of calcium carbide is added into a 1000ml reaction kettle, after the reaction kettle is sealed, air is replaced by nitrogen for 3 times, 4mol of methanol is added dropwise, and acetylene gas is collected until the reaction is finished. And then dropwise adding 1mol of gamma-chlorobutyric acid methyl ester into the reaction kettle, controlling the dropwise adding speed and keeping the temperature constant at 120 ℃, simultaneously collecting methanol fractions generated in the dropwise adding process, and after the reaction is finished, heating and distilling to collect the fractions to obtain 90.6g of methyl cyclopropanecarboxylate with the yield of 90.5%.
Example seven:
1mol of calcium carbide is added into a 1000ml reaction kettle, after the reaction kettle is sealed, air is replaced by nitrogen for 3 times, 4mol of methanol is added dropwise, and acetylene gas is collected until the reaction is finished. Then, 2mol of gamma-chlorobutyric acid methyl ester is dropwise added into the reaction kettle, the dropwise adding speed is controlled, the temperature is kept constant at 120 ℃, meanwhile, methanol fractions generated in the dropwise adding process are collected, and after the reaction is finished, the fractions are collected through heating distillation to obtain 172.2g of methyl cyclopropanecarboxylate, wherein the yield is 86.0%.
Claims (4)
1. A preparation method of cyclopropylamine intermediate methyl cyclopropanecarboxylate is characterized by comprising the following steps:
a. and (3) synthesizing methanol calcium: dropwise adding methanol into calcium carbide in a sealed reaction kettle, wherein the molar ratio of the calcium carbide to the methanol is 1: 2-6, and generating calcium carbonate and acetylene;
b. and (3) cyclization reaction: adding gamma-methyl chlorobutyrate into calcium methoxide at the temperature of 60-120 ℃, wherein the molar ratio of the calcium methoxide to the gamma-methyl chlorobutyrate is 1: 1-2, controlling the temperature to be constant in the reaction process, collecting methanol generated in the process, and distilling to obtain methyl cyclopropanecarboxylate.
2. The process for the preparation of cyclopropylamine intermediate methyl cyclopropanecarboxylate of claim 1 wherein: the reaction in the step a is carried out after the air in the reaction kettle is replaced by nitrogen.
3. The process for the preparation of cyclopropylamine intermediate methyl cyclopropanecarboxylate of claim 2, which comprises: the nitrogen displaced the air 3 times.
4. The process for the preparation of cyclopropylamine intermediate methyl cyclopropanecarboxylate of claim 1 wherein: and (c) recycling the methanol obtained in the step (b) to the step (a).
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1125715A (en) * | 1995-09-28 | 1996-07-03 | 金旭虎 | Industrial production method of cyclopropylamine |
| CN102249949A (en) * | 2011-05-13 | 2011-11-23 | 奇凯（大连）化工有限公司 | Preparation method of cyclopropyl fenpropathin derivative |
| CN104003841A (en) * | 2013-02-21 | 2014-08-27 | 中国石油大学(华东) | Method for preparing alkoxide of calcium |
| CN106854157A (en) * | 2016-11-30 | 2017-06-16 | 浙江大学 | The method for synthesizing cyclopropane ester in low-alcohols solubility solvent |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6979751B2 (en) * | 2002-12-23 | 2005-12-27 | Eastman Chemical Company | Processes for the preparation of higher molecular weight ketones |
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- 2017-09-29 CN CN201710902486.1A patent/CN107673973B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1125715A (en) * | 1995-09-28 | 1996-07-03 | 金旭虎 | Industrial production method of cyclopropylamine |
| CN102249949A (en) * | 2011-05-13 | 2011-11-23 | 奇凯（大连）化工有限公司 | Preparation method of cyclopropyl fenpropathin derivative |
| CN104003841A (en) * | 2013-02-21 | 2014-08-27 | 中国石油大学(华东) | Method for preparing alkoxide of calcium |
| CN106854157A (en) * | 2016-11-30 | 2017-06-16 | 浙江大学 | The method for synthesizing cyclopropane ester in low-alcohols solubility solvent |
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