阅读说明：本技术 一种卤代环丙烷的合成方法和工艺 (Synthesis method and process of halogenated cyclopropane ) 是由 王可为 韩建国 赵文武 蔡小川 唐培昆 刘威 许汉 于 2020-12-25 设计创作，主要内容包括：本发明公开了一种卤代环丙烷的合成方法和工艺。该合成方法和工艺由两步反应组成：(1)使用环丙胺为原料,在亚硝酸酯等亚硝化试剂存在下,与卤代金属盐反应得到1,1-二卤代环丙烷；(2)将1,1-二卤代环丙烷与有机金属试剂作用发生金属化反应,再进行水解得到卤代环丙烷。该合成方法和工艺具有不使用有毒和造成环境污染的试剂,得到的产物纯度和收率较高,适合工业化生产等优势。(The invention discloses a method and a process for synthesizing halogenated cyclopropane. The synthesis method and the process consist of two steps of reactions: (1) using cyclopropylamine as a raw material, and reacting the cyclopropylamine with a halogenated metal salt in the presence of a nitrosation reagent such as nitrite to obtain 1, 1-dihalogenocyclopropane; (2) the 1, 1-dihalogenated cyclopropane and an organic metal reagent react to generate a metalation reaction, and then hydrolysis is carried out to obtain the halogenated cyclopropane. The synthesis method and the process have the advantages that toxic reagents causing environmental pollution are not used, the purity and the yield of the obtained product are high, and the method and the process are suitable for industrial production.)

1. The invention discloses a new synthesis method and a process of halogenated cyclopropane.

2. The synthesis method and the process consist of two steps of reactions: (1) using cyclopropylamine as a raw material, and reacting the cyclopropylamine with a halogenated metal salt in the presence of nitrite or nitrite to obtain 1, 1-dihalogenocyclopropane; (2) the 1, 1-dihalogenated cyclopropane and an organic metal reagent react to generate a metalation reaction, and then hydrolysis is carried out to obtain the halogenated cyclopropane.

3. The synthesis process of claim 2, wherein the first step is reaction of cyclopropylamine as material with halogeno-metal salt under the action of nitrites and other diazotizing agent; diazotization reagents comprise nitrite esters, such as tert-butyl nitrite, isopropyl nitrite, isobutyl nitrite and the like, and nitrous acid and salts thereof, such as sodium nitrite, potassium nitrite, cesium nitrite and the like; the halogenated metal salt includes cupric bromide, cupric chloride, and cupric iodide.

4. The synthesis method according to claim 3, wherein the molar ratio of the reaction materials is cyclopropylamine, nitrite or nitrous acid and salts thereof, namely halogenated metal salt =1 (1-5): 1-8, preferably cyclopropylamine, nitrite or nitrous acid and salts thereof, namely halogenated metal salt =1 (1-2.5): 1-2.2; the reaction temperature is in the range of-20 deg.C^oC～130 ^oC, preferably-10 ^oC ～80^oC; the solvent used in the reaction is alcohols such as methanol and ethanol, ethers such as diethyl ether, isopropyl ether, tetrahydrofuran, methyl tetrahydrofuran, etc., halogenated hydrocarbons such as dichloromethane or dichloroethane, esters such as ethyl acetate and acetonitrile, etc.

5. A synthesis method and process as claimed in claim 2, wherein in the second step, the 1, 1-dihalocyclopropane is metallated with an organometallic reagent and then hydrolyzed to give the halocyclopropane; organometallic reagents include methyllithium, n-butyllithium, t-butyllithium, and methylmagnesium bromide, methylmagnesium chloride, and the like.

6. The synthesis method according to claim 5, wherein the molar ratio of the reaction materials is 1, 1-dihalocyclopropane to organometallic reagent =1 (1-8), preferably 1, 1-dihalocyclopropane to organometallic reagent =1 (1-2.5); the reaction temperature is in the range of-80 deg.C ^oC～20 ^oC, preferably-78 ^oC～0^oC; the solvent used in the reaction is ethers such as diethyl ether, isopropyl ether, tetrahydrofuran, methyl tert-butyl ether, etc.; the reaction temperature range during hydrolysis is-10^oC～40 ^oC, preferably 0 ^oC～20^oC。

Technical Field

The invention relates to the field of organic chemical industry, in particular to a method and a process for synthesizing halogenated cyclopropane.

Background

The halogenated cyclopropane is an organic synthesis intermediate and a chemical raw material, is used in the fields of medicines, pesticides, new materials and the like, and has wide application prospect and market demand. The compound has the following structure:

the halogenated cyclopropane, especially bromo-cyclopropane and iodo-cyclopropane, has high chemical reactivity, can react with compounds containing amino, hydroxyl and other groups, and can also be prepared into cyclopropyl metal reagents such as cyclopropyl lithium and cyclopropyl Grignard reagent for corresponding reaction. In the field of medicine, cyclopropyl has a relatively flat structure and is an isostere of a vinyl structure, an allyl structure and the like, and can be well matched with a drug action target receptor such as a corresponding enzyme and the like, so that modification of a basic structure of a drug is usually considered as a preferred modification group in development of a new drug, so that the pharmacological activity of a candidate compound is improved, the pharmacokinetic index is improved, adverse reactions are reduced, the pharmaceutical properties are improved and the like. At present, the number of compounds containing cyclopropyl structures in new compound entities of newly developed drugs tends to increase continuously, and a plurality of varieties of the compounds have excellent clinical effects, so that the compounds become hot spots for new drug development. Resulting in a large increase in the demand for cyclopropyl compounds. In the field of pesticides, with the increasing demand for highly effective and low toxic pesticides, the development of new pesticides is often accompanied by the modification of new pesticide entities with cyclopropyl groups, and thus the demand for cyclopropyl-based compounds is increasing year by year. In the field of new materials, the cyclopropyl structure has certain stability, so that the cyclopropyl structure is also commonly used in the fields of material modification, development of novel functional materials, research and development of electronic chemicals and the like. In a word, the development of a new synthesis method and process of the halogenated cyclopropane has high practical value and wide market prospect.

The prior art for synthesizing the intermediate of halogenated cyclopropane includes the following techniques:

a process for reacting cyclopropyl carboxylic acid with a halogenated cyclopropane, as reported in Bulletin of the Chemical Society of Japan, 1971 (44), 1130 to 1133, by Asahara T, is as follows:

the method uses halogen for decarboxylation substitution, needs to use heavy metal salts with toxicity as catalysts, generates a large amount of waste water containing halogen and heavy metal salts in the reaction process, causes certain pollution to the environment, and has undesirable reaction conversion rate. The raw material cyclopropanecarboxylic acid used in the method is difficult to prepare, so that the source is limited, the market price is high, and the possibility of industrial production is limited.

A method for the synthesis of halogenated cyclopropanes from trihalopropanes is reported in angelwan nd Chemie 1963 (75) 672 by Kirmse w, the reaction is as follows:

the method has the advantages that raw materials are not easy to obtain, the source is limited, a large amount of halogen-containing wastewater is generated in the reaction process, and certain pollution is caused to the environment, so that no report of adopting the method to carry out industrial production is seen at present.

In conclusion, the prior reported method has the following technical difficulties:

1. the raw material cost is too high due to the limitation of the raw material source of the reaction;

2. a large amount of halogen-containing wastewater is generated in the reaction process, the treatment is difficult, and certain pollution is caused to the environment;

3. the resource treatment of the waste is difficult;

4. the industrial amplification technology has many difficulties, and the industrial amplification production is difficult to realize.

In order to overcome the technical difficulties in the synthesis of the halogenated cyclopropane, the patent discloses a novel method and a novel process for synthesizing the halogenated cyclopropane, which solve the technical difficulties to a certain extent.

Disclosure of Invention

The invention discloses a method and a process for synthesizing halogenated cyclopropane. The synthesis method and the process consist of two steps of reactions: (1) using cyclopropylamine as a raw material, and reacting the cyclopropylamine with a halogenated metal salt in the presence of nitrite or nitrite to obtain 1, 1-dihalogenocyclopropane; (2) the 1, 1-dihalogenated cyclopropane and an organic metal reagent react to generate a metalation reaction, and then hydrolysis is carried out to obtain the halogenated cyclopropane. The synthetic route is as follows:

in the first step of the synthetic route, cyclopropylamine is used as a raw material and reacts with a halogenated metal salt under the action of a diazotization reagent such as nitrite ester. Diazotizing agents include nitrites such as tert-butyl nitrite, isopropyl nitrite, isobutyl nitrite and the like, and nitrous acid and its salts including sodium nitrite, potassium nitrite, cesium nitrite and the like. The halogenated metal salt includes cupric bromide, cupric chloride, and cupric iodide.

The molar ratio of the reaction materials is cyclopropylamine to nitrite or nitrite and salts thereof to halogenated metal salt =1 (1-5): 1-8, and is preferably cyclopropylamine to nitrite or nitrite and salts thereof to halogenated metal salt =1 (1-2.5): 1-2.2. The reaction temperature is in the range of-20 deg.C ^oC～130 ^oCPreferably-10 ^oC～80^oC. The solvent used in the reaction is alcohols such as methanol and ethanol, ethers such as diethyl ether, isopropyl ether, tetrahydrofuran, methyl tetrahydrofuran, etc., halogenated hydrocarbons such as dichloromethane or dichloroethane, esters such as ethyl acetate and acetonitrile, etc.

In the second step, 1-dihalogenated cyclopropane reacts with an organic metal reagent to generate a metalation reaction, and then hydrolysis is carried out to obtain the halogenated cyclopropane. Organometallic reagents include methyllithium, n-butyllithium, t-butyllithium, and methylmagnesium bromide, methylmagnesium chloride, and the like.

The molar ratio of the reaction materials is 1, 1-dihalocyclopropane to organometallic reagent =1 (1 to 8), and preferably 1, 1-dihalocyclopropane to organometallic reagent =1 (1 to 2.5). The reaction temperature is in the range of-80 deg.C ^oC～20 ^oCPreferably-78 ^oC～0^oC. The solvent used in the reaction is ethers such as diethyl ether, isopropyl ether, tetrahydrofuran, methyl tert-butyl ether, etc. The reaction temperature range during hydrolysis is-10^oC～40 ^oCIs preferably 0 ^oC～20^oC。

Compared with the prior art, the synthesis method has the following advantages:

1. the raw materials are low in price and easy to obtain, and preparation is not needed;

2. the process conditions are relatively mild, and the requirements of reaction control and industrial scale-up production are facilitated;

3. the selectivity of the reaction is higher, the purity of the obtained product is higher, and the yield is higher;

4. relatively less waste and can realize resource recycling.

Detailed Description

The present invention will be further described with reference to specific examples, but the present invention is not limited to these specific examples. It will be appreciated by those skilled in the art that the present specification encompasses all alternatives, modifications and equivalents as may be included within the scope of the claims.

Examples

1. Synthesis and process of bromocyclopropane

1, 11, 1-dibromo-cyclopropane

Name (R)	Molecular weight	Number of moles	Amount of feed	Molar ratio of
					Cyclopropanamines	57.10	1	57.1 g	1
Nitrous acid tert-butyl ester	103.12	1.1	113.5 g	1.1
					Copper bromide	223.35	2.0	446.74	2.0
Tetrahydrofuran (THF)			500 mL

Adding cyclopropylamine, tetrahydrofuran and copper bromide into a three-neck flask, uniformly stirring, and heating to 50 ℃. And (3) dropwise adding tert-butyl nitrite through a dropping funnel, and reacting for 4 hours at 50 ℃ after dropwise adding. And (3) tracking the reaction process by using gas chromatography, and cooling after the reaction is finished. Filtration and concentration of the filtrate under reduced pressure gave 180 g of 1, 1-dibromocyclopropane, gas chromatography purity: 95%, yield: 90 percent.

1.2 Bromocyclopropane

Adding 1, 1-dibromocyclopropane and methyl tert-butyl ether into a three-neck flask, uniformly stirring, and cooling to-25 ℃. Adding n-butyl lithium hexane solution dropwise through a dropping funnel, controlling the reaction temperature to be lower than-20 ℃, and reacting for 4 h at-20 ℃ after the dropwise addition. The reaction progress was followed by gas chromatography, after completion of the reaction, the temperature was gradually raised to 0 ℃. 36 g of water is added dropwise through a dropping funnel, the reaction temperature is controlled to be lower than 5 ℃, and stirring is carried out for 1 hour after dripping. Standing for layering, separating out an organic layer, concentrating the filtrate under reduced pressure to distill out methyl tert-butyl ether, rectifying the residue, collecting fractions at 69-71 ℃ to obtain 58 g of bromocyclopropane, wherein the gas chromatography purity is as follows: 98%, yield: 95 percent.

2. Synthesis and process of chlorocyclopropane

1.11, 1-dichloro-cyclopropane

Name (R)	Molecular weight	Number of moles	Amount of feed	Molar ratio of
					Cyclopropanamines	57.10	1	57.1 g	1
Nitrous acid tert-butyl ester	103.12	1.1	113.5 g	1.1
					Copper chloride	134.45	2.0	268.91	2.0
Tetrahydrofuran (THF)			500 mL

Adding cyclopropylamine, tetrahydrofuran and copper chloride into a three-neck flask, uniformly stirring, and heating to 50 ℃. And (3) dropwise adding tert-butyl nitrite through a dropping funnel, and reacting for 4 hours at 50 ℃ after dropwise adding. And (3) tracking the reaction process by using gas chromatography, and cooling after the reaction is finished. Filtration and concentration of the filtrate under reduced pressure gave 102 g of 1, 1-dichlorocyclopropane, gas chromatography purity: 96%, yield: 91.9 percent.

1.2 Chlorocyclopropane

Adding 1, 1-dichlorocyclopropane and tetrahydrofuran into a three-neck flask, uniformly stirring, and cooling to-25 ℃. Adding n-butyl lithium hexane solution dropwise through a dropping funnel, controlling the reaction temperature to be lower than-20 ℃, and reacting for 4 h at-20 ℃ after the dropwise addition. The reaction progress was followed by gas chromatography, after completion of the reaction, the temperature was gradually raised to 0 ℃. 36 g of water is added dropwise through a dropping funnel, the reaction temperature is controlled to be lower than 5 ℃, and stirring is carried out for 1 hour after dripping. Standing and layering, separating out an organic layer, rectifying, and collecting fractions at 40-42 ℃ to obtain 26 g of chlorocyclopropane, wherein the gas chromatography purity is as follows: 97.4%, yield: 72.8 percent.

3. Synthesis and process of iodocyclopropane

1.11, 1-diiodocyclopropane

Name (R)	Molecular weight	Number of moles	Amount of feed	Molar ratio of
					Cyclopropanamines	57.10	1	57.1 g	1
Nitrous acid tert-butyl ester	103.12	1.1	113.5 g	1.1
					Copper iodide	317.35	2.0	634.75	2.0
Tetrahydrofuran (THF)			500 mL

Adding cyclopropylamine, tetrahydrofuran and copper chloride into a three-neck flask, uniformly stirring, and heating to 50 ℃. And (3) dropwise adding tert-butyl nitrite through a dropping funnel, and reacting for 6 hours at 50 ℃ after dropwise adding. And (3) tracking the reaction process by using gas chromatography, and cooling after the reaction is finished. Filtration and concentration of the filtrate under reduced pressure gave 274 g of 1, 1-diiodocyclopropane, gas chromatography purity: 95.8%, yield: 93.2 percent.

1.2 Iodotyclopropane

Adding 1, 1-diiodocyclopropane and methyl tert-butyl ether into a three-neck flask, uniformly stirring, and cooling to-25 ℃. Adding n-butyl lithium hexane solution dropwise through a dropping funnel, controlling the reaction temperature to be lower than-20 ℃, and reacting for 4 h at-20 ℃ after the dropwise addition. The reaction progress was followed by gas chromatography, after completion of the reaction, the temperature was gradually raised to 0 ℃. Adding water dropwise through a dropping funnel, controlling the reaction temperature to be lower than 5 ℃, and stirring for 1h after dripping. Standing for layering, separating out an organic layer, concentrating the filtrate under reduced pressure to distill out methyl tert-butyl ether, rectifying the residue, collecting fractions at 96-98 ℃ to obtain 80g of iodocyclopropane, wherein the gas chromatography purity is as follows: 98%, yield: 95.2 percent.

The foregoing examples are illustrative of the present invention and are not intended to limit the invention to the particular embodiments described. Other variations and modifications within the spirit and scope of the invention and the appended claims will occur to persons skilled in the art and are intended to be covered by the invention.