CN112679328A

CN112679328A - Industrial production method of 3-trifluoromethyl-2-cyclohexene-1-ketone

Info

Publication number: CN112679328A
Application number: CN201910987122.7A
Authority: CN
Inventors: 辛茂树; 张树强; 陈志华; 朱经伟
Original assignee: Pharmablock Sciences (nanjing) Inc
Current assignee: Pharmablock Sciences (nanjing) Inc
Priority date: 2019-10-17
Filing date: 2019-10-17
Publication date: 2021-04-20
Anticipated expiration: 2039-10-17
Also published as: CN112679328B

Abstract

The invention relates to an industrial production method of 3-trifluoromethyl-2-cyclohexene-1-ketone, which is prepared by iodination and trifluoromethylation of 1, 3-cyclohexanedione, the yield is obviously improved compared with the prior art, special reaction conditions such as high temperature and high pressure are not needed, heavy metal pollution reagents are not used, the reaction and post-treatment are simple, the product is easy to purify, and the method is suitable for industrial production.

Description

Industrial production method of 3-trifluoromethyl-2-cyclohexene-1-ketone

Technical Field

The invention relates to the field of synthesis of medical intermediates, in particular to an industrial production method of 3-trifluoromethyl-2-cyclohexene-1-ketone.

Background

Fluorine atoms are often applied to the structural optimization of compounds due to strong electronegativity and small atomic radius, so that the physicochemical properties of the compounds, the drug effects, toxicity, metabolic processes and the like of drug molecules are improved, trifluoromethylated products occupy a large proportion in the fluorine atoms, and the introduction of trifluoromethyl can possibly improve the polarity, dipole moment, stability and lipophilicity of target products. 3-trifluoromethyl-2-cyclohexene-1-ketone as a medical intermediate can be used for preparing 3- (trifluoromethyl) cyclohexyl-1-alcohol, 3- (trifluoromethyl) phenol and the like so as to further synthesize various clinical candidate compounds or drug molecules.

There are two main methods for preparing 3-trifluoromethyl-2-cyclohexene-1-one reported in the prior literature.

Route 1(Journal of Fluorine Chemistry,101 (2); 199. sup. -; 202; 2000)

In the route 1, 2-cyclohexene-1-ketone is used as an initial raw material, and a target compound is obtained through trifluoromethylation and rearrangement. In the third step, the reaction conversion is incomplete, and the yield is only 28%; and pyridinium chlorochromate (PCC, containing heavy metal chromium) is used, chromium is a heavy metal with high toxicity, easily enters human cells, damages internal organs and DNA such as liver and kidney, accumulates in human body, has carcinogenicity, possibly induces gene mutation, and also causes serious pollution to the environment, so that the amplification use of the chromium is limited, and the chromium can only be used for synthesis at laboratory level.

Route 2(Tetrahedron Letters, (42), 4071-2; 1979)

Route 2 uses 3-bromo-2-cyclohexene-1-one as raw material, copper powder, hexamethylphosphoramide and trifluoroiodomethane are synthesized into CuCF₃Then synthesizing a target compound with 3-bromo-2-cyclohexene-1-ketone; CuCF₃The method is unstable, needs to be prepared at present, is gas trifluoroiodomethane, needs to be carried out under the conditions of sealing and high temperature of 120 ℃, has high requirements on reaction equipment, has certain safety risk, is not suitable for amplification operation, and has the yield of 40%.

Therefore, the development of an industrial production method of 3-trifluoromethyl-2-cyclohexene-1-ketone with safety, environmental protection, low equipment requirement and good yield is still needed.

Disclosure of Invention

In order to solve the problems in the prior art, the invention provides the preparation method of the 3-trifluoromethyl-2-cyclohexene-1-ketone, which has the advantages of easily obtained raw materials of the reagent, safety, environmental protection, no need of special reaction conditions such as high temperature and high pressure, no use of heavy metal pollution reagents, simple reaction and post-treatment, easy purification of the product, higher yield than the route reported by the literature, and suitability for industrial production.

The preparation method of the 3-trifluoromethyl-2-cyclohexene-1-ketone comprises the following steps:

the method comprises the following steps: 1, 3-cyclohexanedione is used as a starting material,

preparing 3-iodine-2-cyclohexene-1-ketone by iodination;

step two: 3-iodine-2-cyclohexene-1-ketone reacts under the condition of a fluorination reagent to prepare 3-trifluoromethyl-2-cyclohexene-1-ketone, wherein the fluorination reagent is fluorosulfonyl difluoroacetic acid methyl ester, fluorosulfonyl difluoroacetic acid ethyl ester or trimethylsilyl 2- (fluorosulfonyl) difluoroacetic acid ester

Preferably, the reaction solvent in step one is toluene.

The inventor unexpectedly finds that in the solvent screening of the first step, compared with acetonitrile generally used in the reaction of the type in the prior art, toluene is used as a reaction solvent, so that the post-reaction treatment operation is simple, the operation of column chromatography can be avoided, the impurity content of the product in the first step can be remarkably reduced, and the method is more suitable for industrial production. Other materials such as dichloromethane and tetrahydrofuran have good solubility, but have low boiling points, so that the reaction is slow; n-heptane has poor solubility for raw materials, auxiliary materials and products; the temperature rise is very obvious in the process of feeding DMF as a solvent, and the temperature is not easy to control in the operation process.

Preferably, the reaction system of the iodination reaction in the step one is elementary iodine/triphenylphosphine/triethylamine or N-iodosuccinimide/triphenylphosphine/triethylamine.

Preferably, the reaction temperature in step one is 70-85 ℃.

Preferably, the fluorinating agent in the second step is methyl fluorosulfonyl difluoroacetate.

Preferably, the reaction solvent in the second step is N, N-dimethylformamide, and the catalyst is cuprous iodide or cupric iodide.

Preferably, the first step further comprises post-treatment, wherein the post-treatment is specifically quenching and washing after the reaction is finished, adding toluene for azeotropy after the solvent is dried by rotation, adding methyl tert-butyl ether into the residue, stirring and filtering, adding anhydrous magnesium chloride into the obtained filtrate for complexation, filtering again, and evaporating the obtained filtrate to dryness to obtain the 3-iodo-2-cyclohexen-1-one.

The preparation method provided by the invention has the advantages that the total yield of two steps is about 50%, compared with the prior art, the preparation method is obviously improved, special reaction conditions such as high temperature and high pressure are not required, the use of heavy metal pollution reagents is not involved, the reaction and post-treatment are simple, the product is easy to purify, and the preparation method is suitable for industrial production.

Detailed Description

EXAMPLE 13 preparation of iodo-2-cyclohexen-1-one

Toluene (16kg) was added to a double glass kettle (50L), triphenylphosphine (5.0kg,19.0mol,1.1eq.) was added with stirring, iodine solid (5.0kg,19.2mol,1.1eq.) was added in portions at 5-10 deg.C, stirring was carried out for 20min, and triethylamine (1.9kg,19.0mol,1.1eq.) was added. Then 1, 3-cyclohexanedione (1.8kg,16.5mol,1.0eq.) was added at 5-10 ℃ and after addition the temperature was slowly raised to 75-80 ℃ and maintained at this temperature for 16h of reaction.

And (3) post-treatment: adding saturated sodium bisulfite aqueous solution (10L) into the system after cooling, stirring for 10 minutes for liquid separation, removing solvent by organic phase under reduced pressure and azeotropically removing water by toluene (100kg), adding methyl tert-butyl ether (10L) after cooling to dryness, stirring for 1 hour, filtering, washing filter cake with methyl tert-butyl ether (5L), mixing filtrates, transferring into a kettle, adding anhydrous magnesium chloride (1.2kg), complexing for 2 hours, filtering, washing filter cake with methyl tert-butyl ether (10L), mixing filtrates, concentrating to dryness to obtain light yellow liquid (2.6kg), and purifying>98％。¹HNMR(400MHz):6.81～6.82(s,1H),2.90～2.94(m,2H),2.42～2.45(m,2H),2.07～2.00)m,2H)；GCMS:222.9。

EXAMPLE 23 preparation of trifluoromethyl-2-cyclohexen-1-one

Adding DMF (16kg) into a double-layer glass kettle (50L), and adding 3-iodo-2-cyclohexen-1-one (3.0kg,11.7mol,1.00eq.) and cuprous iodide (0.4kg, 2.3mol, 0.02eq.) with stirring; methyl fluorosulfonyl difluoroacetate (2.8kg,14.7mol,1.25eq.) was added in one portion, and the mixture was heated to 75-80 ℃ for reaction for 12 h. After the reaction is finished, the temperature is reduced to 20-25 ℃, methyl tert-butyl ether (10L multiplied by 3) is extracted for three times, and the organic phase is concentrated, desolventized and rectified to obtain 3-trifluoromethyl-2-cyclohexene-1-ketone (1.35kg) with the purity of 99%.¹HNMR(400MHz):6.38-6.39(m,1H),2.49-2.52(m,4H),2.11-2.18(m,2H)；

¹⁹FNMR(400MHz):71.15；GCMS:165.1。

EXAMPLE 3 preparation of 3-iodo-2-cyclohexen-1-one post-treatment screening

Referring to the preparation method of example 1, the reaction solvent was toluene or acetonitrile, and the post-treatment mode was selected, and the operation and results are shown in table 1.

TABLE 1

Claims

1. A preparation method of 3-trifluoromethyl-2-cyclohexene-1-ketone is characterized by comprising the following steps:

preparing 3-iodine-2-cyclohexene-1-ketone by iodination;

2. The method of claim 1, wherein: the reaction solvent in the first step is toluene.

3. The method of claim 1, wherein: in the first step, the reaction system of the iodination reaction is elementary iodine/triphenylphosphine/triethylamine or N-iodosuccinimide/triphenylphosphine/triethylamine.

4. The method of claim 1, wherein: the reaction temperature in the first step is 70-85 ℃.

5. The method of claim 1, wherein: the fluorinating reagent in the second step is methyl fluorosulfonyl difluoroacetate.

6. The method of claim 1, wherein: and the reaction solvent in the second step is N, N-dimethylformamide, and the catalyst is cuprous iodide or copper iodide.

7. The method of claim 1, wherein: the first step also comprises post-treatment.

8. The preparation method according to claim 7, wherein the post-treatment is specifically quenching and washing after the reaction is finished, adding toluene for azeotropy after the solvent is dried by rotation, adding methyl tert-butyl ether to the residue, stirring and filtering, adding anhydrous magnesium chloride to the obtained filtrate for complexing, filtering again, and evaporating the obtained filtrate to dryness to obtain the 3-iodo-2-cyclohexen-1-one.

9. The method according to claim 8, wherein the purity of the 3-iodo-2-cyclohexen-1-one obtained in step one is greater than or equal to 98%.

10. The method according to claim 1, characterized by comprising the steps of:

taking methylbenzene as a reaction solvent, and carrying out iodination reaction in a reaction system of elementary iodine/triphenylphosphine/triethylamine or N-iodosuccinimide/triphenylphosphine/triethylamine, wherein the reaction temperature is 70-85 ℃; quenching and washing after the reaction is finished, adding toluene for azeotropy after the solvent is dried, adding methyl tert-butyl ether into the residue, stirring and filtering, adding anhydrous magnesium chloride into the obtained filtrate for complexing, filtering again, evaporating the obtained filtrate to dryness to obtain 3-iodine-2-cyclohexene-1-one;

step two: 3-iodine-2-cyclohexene-1-ketone reacts under the condition of fluorosulfonyl difluoroacetic acid methyl ester to prepare 3-trifluoromethyl-2-cyclohexene-1-ketone, DMF is used as a reaction solvent, and cuprous iodide or copper iodide is used as a catalyst