阅读说明：本技术 1-氨基-4-取代环己基羧酸及其盐的顺式异构体的制备方法 (Process for preparing cis-isomers of 1-amino-4-substituted cyclohexyl carboxylic acids and salts thereof ) 是由 王博 田学芳 贾成国 于 2020-05-14 设计创作，主要内容包括：本发明公开了一种1-氨基-4-取代环己基羧酸及其盐的顺式异构体的制备方法,属于医药、农药及其中间体合成技术领域。所述方法包括在反应溶剂中,化合物II与氰化物、铵盐反应得到化合物III,化合物III在碱性条件下水解得到化合物I,化合物I与III均为顺式结构。本发明工艺简单,反应产物的顺式异构体与反式异构体的比例大于90:10,避免了顺/反异构体混合物的拆分工序,极大的简化了实验过程,缩短了生产工时,同时还可以节约反应原料、提高产品收率,且所需溶剂、催化剂简单易得且价格低廉,原料利用率高,生产成本低。(The invention discloses a preparation method of cis-isomer of 1-amino-4-substituted cyclohexyl carboxylic acid and salt thereof, belonging to the technical field of medicine, pesticide and intermediate synthesis thereof. The method comprises the steps of reacting a compound II with cyanide and ammonium salt in a reaction solvent to obtain a compound III, hydrolyzing the compound III under an alkaline condition to obtain a compound I, wherein the compound I and the compound III are both in cis-structures. The method has the advantages of simple process, high utilization rate of raw materials and low production cost, and the ratio of cis-isomer to trans-isomer of the reaction product is more than 90:10, so that the separation process of cis/trans isomer mixture is avoided, the experimental process is greatly simplified, the production time is shortened, reaction raw materials can be saved, the product yield is improved, and the required solvent and catalyst are simple and easy to obtain and have low price.)

1. A method for preparing cis-isomers of 1-amino-4-substituted cyclohexyl carboxylic acids and salts thereof, characterized in that: in a reaction solvent, reacting a compound II with cyanide and ammonium salt to obtain a compound III, hydrolyzing the compound III under an alkaline condition to obtain a compound I, wherein the compound I and the compound III are both in cis-structure,

wherein the structure of the compound II is shown as the following formula

The structure of the intermediate III is shown as

The product I has a structure formula of

Wherein: r is C_1-10Is alkyl or alkoxy, X is H⁺、NH₄ ⁺、Na⁺、K⁺、Li⁺Or Ca²⁺。

2. The process for producing cis-isomers of 1-amino-4-substituted cyclohexylcarboxylic acid and salts thereof according to claim 1, wherein: the reaction of compound II to compound III, the reaction solvent comprising: one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol and acetonitrile or a solution formed by the methanol, the ethanol, the n-propanol, the isopropanol, the n-butanol and the acetonitrile and water, wherein the content of the water is 0.0 to 10 percent.

3. The process for producing cis-isomers of 1-amino-4-substituted cyclohexylcarboxylic acid and salts thereof according to claim 1, wherein: reaction of compound II to compound III, the cyanide being: one of ammonium cyanide, sodium cyanide or potassium cyanide, the amount of which is 80-500% of the mole number of the compound II; the ammonium salt is ammonium carbonate or ammonium bicarbonate, and the dosage of the ammonium salt is 60 to 800 percent of the mole number of the compound II.

4. The process for producing cis-isomers of 1-amino-4-substituted cyclohexylcarboxylic acid and salts thereof according to claim 1, wherein: in the reaction from the compound II to the compound III, the reaction temperature is 0 to 80 ℃, preferably 0 to 40 ℃.

5. The process for producing cis-isomers of 1-amino-4-substituted cyclohexylcarboxylic acid and salts thereof according to claim 1, wherein: the reaction time in the reaction from the compound II to the compound III is 0.5 to 70 hours, preferably 5 to 24 hours.

6. The process for producing cis-isomers of 1-amino-4-substituted cyclohexylcarboxylic acid and salts thereof according to claim 1, wherein: the alkaline conditions in the hydrolysis of compound III to compound I are: NaOH, KOH, LiOH, Ca (OH)₂、NaHCO₃、KHCO₃、Na₂CO₃、K₂CO₃、Li₂CO₃And the concentration of the alkaline aqueous solution formed by ammonia water or ammonium carbonate is 0.05-50 percent of the weight percentage of the solute, and the preferred concentration is 1-20 percent.

7. The process for producing cis-isomers of 1-amino-4-substituted cyclohexylcarboxylic acid and salts thereof according to claim 1, wherein: the temperature in the reaction for hydrolyzing the compound III into the compound I is-10 to 100 ℃, preferably 5 to 90 ℃.

8. The process for producing cis-isomers of 1-amino-4-substituted cyclohexylcarboxylic acid and salts thereof according to claim 1, wherein: the reaction of the compound II to the compound III, the reaction conversion rate of the compound II to the compound III is improved by adding a catalyst, the used catalyst comprises one or the combination of any one of tributyl hexadecyl phosphonium bromide, hexadecyl triphenyl phosphonium bromide, hexadecyl dimethyl benzyl ammonium chloride, tetrabutyl ammonium chloride and tetrabutyl ammonium bromide, and the adding amount of the catalyst is 0.01-50% of the mole number of the compound II.

Technical Field

The invention relates to a preparation method of cis-isomer of 1-amino-4-substituted cyclohexyl carboxylic acid and salt thereof, belonging to the technical field of synthesis of medicines, pesticides and intermediates thereof.

Background

The literature (L.Munday, J.Chem.Soc.,1961, 4372-.

Patents CN103270020B and CN201980001515 both obtain cis-product by forming different salts and then separating on the basis of first preparing cis/trans isomer mixture of 1-aminocyclohexanecarbonitrile salt.

1-aminocyclohexanecarbonitrile salts

The invention discovers that: by adding the catalyst and adjusting the adding sequence of the reaction solvent and the reaction materials, the compound III and the compound I with cis-structure can be directly generated, thereby avoiding the splitting process of cis/trans isomer mixture, greatly simplifying the experimental process, shortening the production working hours, saving the reaction raw materials and improving the product yield; the solvent and the catalyst required by the invention are simple, easy to obtain and low in cost.

Aiming at the technical problems in the prior art, the invention provides a method for synthesizing cis-isomer of 1-amino-4-substituted cyclohexyl carboxylic acid and salt thereof, which has the advantages of simple and convenient operation and easily obtained raw materials, can directly generate cis-isomer products through reaction, avoids the resolution process and simplifies the experimental process.

Disclosure of Invention

The technical problem to be solved by the invention is to provide a method for preparing cis-isomer of 1-amino-4-substituted cyclohexyl carboxylic acid and salt thereof, which can directly obtain the cis-isomer of 1-amino-4-substituted cyclohexyl carboxylic acid and salt thereof, wherein the ratio of the cis-isomer to the trans-isomer of a reaction product is more than 90:10, and the separation process of cis/trans isomers can be avoided.

In order to solve the technical problems, the technical scheme adopted by the invention is as follows:

a process for preparing the cis-isomer of 1-amino-4-substituted cyclohexyl carboxylic acid or its salt includes such steps as reaction between compound II and cyanide or ammonium salt in solvent to obtain compound III, hydrolyzing under alkaline condition to obtain compound I, and preparing cis-isomer from both compounds I and III in the ratio of 90.0: 10.0.

Wherein: r is C_1-10Preferably R is C_1-5Alkyl or alkoxy of (a); x is H⁺、NH₄ ⁺、Na⁺、K⁺、Li⁺Or Ca²⁺But not limited to, these positive ions.

In the preparation method, the reaction solvent of the compounds II to III includes but is not limited to one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol and acetonitrile or a solution of any one or more of the above and water, and the content of the water is 0.0-10%.

Reacting a compound II with a compound III, wherein the cyanide is preferably one of ammonium cyanide, sodium cyanide or potassium cyanide, and the amount of the cyanide is 80-500% of the mole number of the compound II; the ammonium salt is preferably ammonium carbonate or ammonium bicarbonate, and the dosage of the ammonium salt is 60 to 800 percent of the mole number of the compound II.

The reaction temperature of the compound II to the compound III is preferably 0 to 80 ℃, and more preferably 0 to 40 ℃.

The reaction time from the compound II to the compound III is preferably 0.5 to 70 hours, and more preferably 5 to 24 hours.

The alkaline conditions in the hydrolysis of compound III to compound I are preferably, but not limited to, NaOH, KOH, LiOH, Ca (OH)₂、NaHCO₃、KHCO₃、Na₂CO₃、K₂CO₃、Li₂CO₃The concentration of the aqueous alkaline solution of ammonia or ammonium carbonate is preferably 0.05 to 50% by weight, more preferably 1 to 20% by weight.

The reaction temperature for hydrolyzing the compound III into the compound I is preferably-10-100 ℃, and more preferably 5-90 ℃.

The reaction of the compound II to the compound III can improve the reaction conversion rate by adding a catalyst, wherein the catalyst comprises but is not limited to one or a combination of any more of tributyl hexadecyl phosphonium bromide, hexadecyl triphenyl phosphonium bromide, hexadecyl dimethyl benzyl ammonium chloride, tetrabutyl ammonium chloride and tetrabutyl ammonium bromide, and the adding amount of the catalyst is preferably 0.01-50% of the mole number of the compound II.

Due to the adoption of the technical scheme, the invention has the technical progress that:

the method has simple process, avoids the splitting process of a cis/trans isomer mixture, greatly simplifies the experimental process, shortens the production working hours and simultaneously improves the product yield.

The solvent and the catalyst required by the invention are simple and easy to obtain, the price is low, the utilization rate of the raw materials is high, and the production cost is low.

The ratio of cis-isomer to trans-isomer of the reaction product of the invention is more than 90:10, not only saves reaction raw materials, but also avoids the resolution of trans-isomer.

Detailed Description

The present invention will be described in further detail with reference to specific examples below:

the invention discloses a preparation method of cis-isomer of 1-amino-4-substituted cyclohexyl carboxylic acid and salt thereof, which comprises the steps of reacting a compound II with cyanide and ammonium salt in a reaction solvent to obtain a compound III, wherein the reaction temperature is controlled to be 0-80 ℃, and preferably 0-40 ℃; and then hydrolyzing the compound III under an alkaline condition to obtain a compound I, controlling the reaction temperature to be-10-100 ℃, preferably 5-90 ℃, and obtaining the compound I and the compound III which are both in cis-structure. The main principle of the invention is as follows:

wherein: r is C_1-10Preferably R is C_1-5Alkyl or alkoxy of (a); x is H⁺、NH₄ ⁺、Na⁺、K⁺、Li⁺Or Ca²⁺But not limited to, these positive ions.

In the reaction of compound II to compound III, the reaction solvent used includes, but is not limited to: one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol and acetonitrile or a solution formed by the methanol, the ethanol, the n-propanol, the isopropanol, the n-butanol and the acetonitrile and water, wherein the content of the water is 0.0 to 10 percent.

In the reaction of compound II to compound III, the cyanide is: one of ammonium cyanide, sodium cyanide or potassium cyanide, the amount of which is 80-500% of the mole number of the compound II; the ammonium salt is ammonium carbonate or ammonium bicarbonate, and the dosage of the ammonium salt is 60 to 800 percent of the mole number of the compound II.

The reaction time in the reaction from the compound II to the compound III is 0.5 to 70 hours, preferably 5 to 24 hours.

The basic conditions in the hydrolysis of compound III to compound I are preferably, but not limited to: NaOH, KOH, LiOH, Ca (OH)₂、NaHCO₃、KHCO₃、Na₂CO₃、K₂CO₃、Li₂CO₃And the concentration of the alkaline aqueous solution formed by ammonia water or ammonium carbonate is 0.05-50 percent of the weight percentage of the solute, and the preferred concentration is 1-20 percent.

In order to improve the reaction conversion rate, a catalyst can be used for the reaction of the compound II to the compound III, the used catalyst comprises but is not limited to one or the combination of any more of tributyl hexadecyl phosphonium bromide, hexadecyl triphenyl phosphonium bromide, hexadecyl dimethyl benzyl ammonium chloride, tetrabutyl ammonium chloride and tetrabutyl ammonium bromide, and the adding amount of the catalyst is 0.01-50% of the mole number of the compound II.

The following are specific examples: