阅读说明：本技术 依非韦伦中间体1-(2-氨基-5-氯苯基)-2,2,2-三氟乙酮的合成方法 (Synthesis method of efavirenz intermediate 1- (2-amino-5-chlorphenyl) -2,2, 2-trifluoroacetone ) 是由 陈志卫 唐伟 袁其亮 陈寅镐 王超 于 2021-09-30 设计创作，主要内容包括：本发明公开了依非韦伦中间体1-(2-氨基-5-氯苯基)-2,2,2-三氟乙酮的合成方法。该方法以邻卤硝基苯为起始原料,先与三氟乙酰基化合物反应得到中间化合物,随后中间化合物在氢气作用下用雷尼镍催化还原得到还原化合物,最后还原化合物在催化剂二甲基亚砜的催化作用下与N-氯代丁二酰亚胺反应制得目标产物1-(2-氨基-5-氯苯基)-2,2,2-三氟乙酮。本发明具有步骤短、工艺简单、操作简便、苯胺氯代反应条件温和、总收率高等特点,因而有较大的实施价值和社会经济效益。(The invention discloses a synthesis method of an efavirenz intermediate 1- (2-amino-5-chlorphenyl) -2,2, 2-trifluoroacetone. The method comprises the steps of taking o-halonitrobenzene as an initial raw material, firstly reacting with a trifluoroacetyl compound to obtain an intermediate compound, then carrying out catalytic reduction on the intermediate compound by using raney nickel under the action of hydrogen to obtain a reduced compound, and finally reacting the reduced compound with N-chlorosuccinimide under the catalytic action of a catalyst dimethyl sulfoxide to obtain a target product 1- (2-amino-5-chlorphenyl) -2,2, 2-trifluoroacetone. The method has the characteristics of short steps, simple process, simple and convenient operation, mild aniline chlorination reaction conditions, high total yield and the like, thereby having greater implementation value and social and economic benefits.)

1. The synthesis method of the efavirenz intermediate 1- (2-amino-5-chlorphenyl) -2,2, 2-trifluoroacetone is characterized by comprising the following steps:

(A) taking o-halonitrobenzene shown in a formula (II) as a raw material, newly prepared phenylmagnesium bromide or magnesium chloride as a Grignard reagent, adding an organic solvent A and a trifluoroacetyl compound shown in a formula (III), and stirring and reacting at-40-25 ℃ for 2-8 hours to obtain a compound (IV) shown in a formula (IV);

(B) dissolving the compound (IV) obtained in the step (A) in an organic solvent B, introducing hydrogen in the presence of a catalyst A, and stirring and reacting at the pressure of 0.1-1.5 Mpa and the temperature of 20-80 ℃ for 8-26 hours to obtain a compound (V) shown in a formula (V);

(C) dissolving the compound (V) obtained in the step (B) in an organic solvent C, in the presence of a catalyst dimethyl sulfoxide, reacting with chloro reagent N-chlorosuccinimide at 0-60 ℃ for 8-20 hours under stirring to obtain a target product 1- (2-amino-5-chlorophenyl) -2,2, 2-trifluoroacetone shown in a formula (I),

2. the method for synthesizing efavirenz intermediate 1- (2-amino-5-chlorophenyl) -2,2, 2-trifluoroacetone (i) according to claim 1, characterized in that the solvent a in step (a) is one or more of an ether solvent and an alkane solvent, and the ether solvent is one or more of tetrahydrofuran, methyl tert-butyl ether, diethyl ether or petroleum ether; the alkane solvent is one or more of pentane, hexane or heptane, preferably tetrahydrofuran, and the volume consumption of the organic solvent A is 1-12 mL/g, preferably 3-6mL/g, based on the mass of the o-halonitrobenzene shown in the formula (II); the reaction temperature in the step (A) is preferably-10 ℃ to 0 ℃.

3. The method for synthesizing efavirenz intermediate 1- (2-amino-5-chlorophenyl) -2,2, 2-trifluoroacetone according to claim 1, characterized in that in step (a), the compound containing trifluoroacetyl group a (iii), preferably ethyl trifluoroacetate.

4. The method for synthesizing efavirenz intermediate 1- (2-amino-5-chlorphenyl) -2,2, 2-trifluoroacetone according to claim 1, characterized in that in the step (A), the mass ratio of the o-halonitrobenzene shown in the formula (II), the Grignard reagent phenylmagnesium chloride or phenylmagnesium bromide and the trifluoroacetyl compound shown in the structure of the formula (III) is 1: 1-1.6: 1-1.8, preferably 1: 1.1-1.4: 1.1-1.5.

5. The method for synthesizing efavirenz intermediate 1- (2-amino-5-chlorophenyl) -2,2, 2-trifluoroacetone according to claim 1, wherein in step (B), the catalyst a is selected from one of 5% Pd/C or 10% Pd/C catalyst or raney ni, the loading amount of Pd in the Pd/C catalyst is 5% or 10%, and the catalyst a is preferably raney ni; the mass amount of the catalyst A is 0.5-12% of the mass of the compound (IV), and preferably 1-5%.

6. The method for synthesizing efavirenz intermediate 1- (2-amino-5-chlorophenyl) -2,2, 2-trifluoroacetone according to claim 1, wherein in step (B), the organic solvent B is selected from one or more of the following: toluene, ethanol, tetrahydrofuran, and the like; the organic solvent B is preferably ethanol; the volume dosage of the organic solvent B is 1-12 mL/g, preferably 3-7mL/g based on the mass of the compound (IV).

7. The method for synthesizing efavirenz intermediate 1- (2-amino-5-chlorphenyl) -2,2, 2-trifluoroacetone according to claim 1, characterized in that in the step (B), the reaction temperature is preferably 45-65 ℃, and the pressure of a reaction kettle is preferably 0.6-1.0 MPa.

8. The method for synthesizing efavirenz intermediate 1- (2-amino-5-chlorophenyl) -2,2, 2-trifluoroacetone according to claim 1, wherein in step (C), the organic solvent C is selected from one or more of the following: toluene, dichloromethane, trichloromethane, 1, 2-dichloroethane, N-dimethylformamide; the organic solvent C is preferably trichloromethane; the volume usage amount of the organic solvent C is 1-10 mL/g, preferably 3-6mL/g, based on the mass of the compound (V).

9. The method for synthesizing efavirenz intermediate 1- (2-amino-5-chlorophenyl) -2,2, 2-trifluoroacetone according to claim 1, characterized in that in step (C), the amount ratio of the compound (V) represented by formula (V), N-chlorosuccinimide and dimethyl sulfoxide as a catalyst is 1:1 to 2.1:0.01 to 0.8, preferably 1:1.2 to 1.5:0.08 to 0.3.

Technical Field

The invention relates to the technical field of pharmaceutical and chemical intermediate synthesis, in particular to a method for preparing an anti-AIDS drug namely Efavirenz key intermediate 1- (2-amino-5-chlorphenyl) -2,2, 2-trifluoroacetone (I) by taking o-halonitrobenzene (II) as an initial raw material.

Background

Efavirenz (Efavirenz) was the first non-nucleoside reverse transcriptase inhibitor developed by Merck in the united states, was first marketed in the united states in 2 months 1992, was clinically used as one of the important drug varieties for aids treatment, and has the characteristics of long half-life, good tolerance, high selectivity, good treatment effect, small adverse reaction and the like. At present, the traditional Chinese medicine composition becomes a first-line medicine for treating AIDS in China, and has a good prospect. Therefore, the research on the synthesis method of the key intermediate 1- (2-amino-5-chlorphenyl) -2,2, 2-trifluoroacetone (I) has theoretical research value and certain economic benefit.

The structural formula of the efavirenz key intermediate 1- (2-amino-5-chlorphenyl) -2,2, 2-trifluoroacetone (I) is shown as follows:

before the present invention is given, the main synthesis method of 1- (2-amino-5-chlorophenyl) -2,2, 2-trifluoroacetone (I) is as follows:

1) in 2020, patent US2020062722a1 reports that p-chloroaniline as a raw material is reacted with di-tert-butyl dicarbonate to perform amino protection, then reacted with trifluoroacetylpiperidine under the action of butyl lithium, trifluoroacetyl group is introduced at the ortho-position of amino group, and finally, a protecting group is removed under an acidic condition to obtain hydrochloride thereof, and then alkalization is performed to obtain a target substance. The synthetic route is as follows:

the method comprises four steps, wherein the price of the raw material of trifluoroacetyl piperidine used in the second step is high, equivalent butyl lithium is used (no water and no oxygen are required, and-40 ℃ reaction is required), the reaction condition is strict, and industrial production is not easy to realize.

2) In 2018, patent CN108997150A reports that o-chloroaniline as a raw material reacts with pivaloyl chloride to perform amino protection, then reacts with magnesium powder to prepare grignard reagent to perform nucleophilic substitution reaction, performs chlorination reaction under the action of chlorine, removes a protecting group under a hydrochloric acid and glacial acetic acid system to obtain hydrochloride thereof, and then alkalinizes to obtain a target substance. The synthetic route is as follows:

the method has five steps, the initiation of the Grignard reaction in the second step is difficult, and the raw materials of the trifluoroacetyl chloride in the Grignard reaction and the chlorine in the chlorination reaction in the third step are both gases, so that the method has high requirements on reaction equipment, has certain toxicity and is not easy to realize large-scale production.

3) In 2016, patent CN106518636A reported that m-bromochlorobenzene was used as a starting material and separately (a) subjected to grignard exchange reaction with isopropyl magnesium chloride; (b) performing bromine-lithium exchange under the action of butyl lithium, performing nucleophilic substitution reaction, performing nitration by nitric acid, and finally performing reduction under the action of hydrogen by catalysis of 5% Pd/C to obtain a target substance, wherein the synthetic route is as follows:

the process has three steps, namely isopropyl magnesium bromide and equivalent butyl lithium used in the Grignard exchange reaction are expensive, the corresponding harsh reaction conditions are difficult to industrialize, and the use of concentrated sulfuric acid and concentrated nitric acid causes more three wastes and does not meet the green chemical requirements.

Disclosure of Invention

Aiming at the problems in the prior art, the invention aims to provide a synthetic method of efavirenz key intermediate 1- (2-amino-5-chlorphenyl) -2,2, 2-trifluoroacetone, which is simple to operate, low in cost, mild in reaction condition and suitable for industrial production.

In order to solve the above technical problems, the technical idea of the present invention is as follows:

the synthesis method of the efavirenz intermediate 1- (2-amino-5-chlorphenyl) -2,2, 2-trifluoroacetone, which is defined by the invention, is characterized by comprising the following steps:

(A) taking o-halonitrobenzene shown in a formula (II) as a raw material, newly prepared phenylmagnesium bromide or magnesium chloride as a Grignard reagent, adding an organic solvent A and a trifluoroacetyl compound shown in a formula (III), and stirring and reacting at-40-25 ℃ for 2-8 hours to obtain a compound (IV) shown in a formula (IV);

(B) dissolving the compound (IV) obtained in the step (A) in an organic solvent B, introducing hydrogen in the presence of a catalyst A, and stirring and reacting at the pressure of 0.1-1.5 Mpa and the temperature of 20-80 ℃ for 8-26 hours to obtain a compound (V) shown in a formula (V);

(C) dissolving the compound (V) obtained in the step (B) in an organic solvent C, in the presence of a catalyst dimethyl sulfoxide, reacting with chloro reagent N-chlorosuccinimide at 0-60 ℃ for 8-20 hours under stirring to obtain a target product 1- (2-amino-5-chlorophenyl) -2,2, 2-trifluoroacetone shown in a formula (I),

in the o-halonitrobenzene shown in the formula (II), a substituent X is chlorine, bromine or iodine; in the trifluoroacetyl compound shown in the formula (III), a substituent R is chlorine, bromine, piperidyl, N-methyl, methoxyl, dimethylamino, methoxyl, diethylamino or ethoxyl.

In the step (A) of the present invention, the preparation method of the phenylmagnesium bromide or magnesium chloride Grignard reagent is a conventional method.

Further, the invention also defines that the solvent A in the step (A) is one or more of ether solvents and alkane solvents, and the ether solvents are one or more of tetrahydrofuran, methyl tert-butyl ether, diethyl ether or petroleum ether; the alkane solvent is one or more of pentane, hexane or heptane, preferably tetrahydrofuran, and the volume consumption of the organic solvent A is 1-12 mL/g, preferably 3-6mL/g, based on the mass of the o-halonitrobenzene shown in the formula (II); the reaction temperature in the step (A) is preferably-10 ℃ to 0 ℃;

further, the present invention defines the trifluoroacetyl compound in step (a) as ethyl trifluoroacetate.

Furthermore, the invention limits the mass ratio of the o-halonitrobenzene shown in the formula (II), the Grignard reagent phenylmagnesium chloride or phenylmagnesium bromide and the trifluoroacetyl compound shown in the structure of the formula (III) to be 1: 1-1.6: 1-1.8, preferably 1: 1.1-1.4: 1.1-1.5.

Further, the invention defines that catalyst a in step (B) is selected from 5% Pd/C, 10% Pd/C catalyst or Raney Ni, preferably Raney Ni; the mass amount of the catalyst A is 0.5-12%, preferably 1-5% of the mass of the compound (IV).

Further, the invention defines that the organic solvent B in the step (B) is one or more selected from toluene, ethanol and tetrahydrofuran, and ethanol is preferred; the volume dosage of the organic solvent B is 1-12 mL/g, preferably 3-7mL/g based on the mass of the compound (IV).

Furthermore, the invention limits the reaction temperature in the step (B) to be 45-65 ℃ and the reaction pressure to be 0.6-1.0 Mpa.

Further, the invention defines that the organic solvent C in the step (C) is one or more selected from toluene, dichloromethane, trichloromethane, 1, 2-dichloroethane and N, N-dimethylformamide, preferably trichloromethane; the volume usage amount of the organic solvent C is 1-10 mL/g, preferably 3-6mL/g, based on the mass of the compound (V).

Further, the invention limits the mass ratio of the compound (V), the N-chlorosuccinimide and the catalyst dimethyl sulfoxide in the step (C) to be 1: 1-2.1: 0.01-0.8, preferably 1: 1.2-1.6: 0.08-0.3.

The reaction process of the invention is as follows:

by adopting the technology, compared with the prior art, the invention has the advantages that:

1) in the reaction process of reducing the nitro group into the amino group, the reaction can be finished with high yield by adopting the catalytic amount of Raney nickel or Pd/C catalyst, and the catalyst can be recycled, so that the cost of the raw materials for production is reduced;

2) according to the invention, N-chlorosuccinimide is used as a chlorination reagent, dimethyl sulfoxide is used as a catalyst, and the intermediate compound (V) is directly chlorinated to obtain a target compound, so that the processes of amino protection and deprotection are avoided, the reaction steps are shortened, and the generation amount of three wastes is reduced;

3) the invention designs and opens up a new process route for preparing 1- (2-amino-5-chlorphenyl) -2,2, 2-trifluoroacetone by taking o-halonitrobenzene as a raw material and carrying out Grignard exchange reaction, hydrogenation catalytic nitro reduction and chlorination of aniline for 3 steps, and the new process has the characteristics of strong operability, short steps, mild reaction conditions and the like, and is suitable for industrial popularization and application.

Detailed Description

The present invention is further illustrated by the following examples, which should not be construed as limiting the scope of the invention.

The first embodiment is as follows: preparation of 1- (2-nitrophenyl) -2,2, 2-trifluoroacetone (IV)

Taking a 500mL four-mouth bottle provided with a condenser tube, a mechanical stirrer, a dropping funnel and a thermometer, adding 7.6g (320mmol) of magnesium chips, 1.79g of bromobenzene (11mmol) as an initiator and 52mL of tetrahydrofuran, heating to 65 ℃ for reflux, initiating a Grignard reagent, dropwise adding bromobenzene (40.8g, 260mmol and 180mL of tetrahydrofuran) under the reflux state for 1-2h, and continuing reflux reaction for 4h after dropwise adding to obtain the phenylmagnesium bromide Grignard reagent, wherein the preparation method of the phenylmagnesium chloride Grignard reagent is the same as that of the phenylmagnesium bromide Grignard reagent; cooling the reaction system to-20 ℃, dissolving o-iodonitrobenzene (200mmol, 49.8g) in tetrahydrofuran 40mL, dropwise adding, controlling the temperature in the dropwise adding process to be not more than-10 ℃, reacting for 30min after finishing dropwise adding, adding ethyl trifluoroacetate (240mmol, 34.2g), reacting for 30min, heating to room temperature, stirring, after complete reaction, concentrating under reduced pressure to recover tetrahydrofuran to obtain a residue, adding dichloromethane (80mL), dissolving, then adding a small amount of water for washing, concentrating under reduced pressure to recover dichloromethane, and obtaining a brown oily liquid product, namely the compound (IV) (29.8g, yield 68%).

Pattern characterization of compound (iv):

¹H NMR(400MHz,CDCl₃)δ＝8.32(d,J＝6.9Hz,1H),7.90(t,J＝8.0Hz,1H),7.82(t,J＝8.0Hz,1H),7.56(d,J＝6.0Hz,1H).¹³C NMR(100MHz,CDCl₃)δ184.1(q,J_C-F＝38Hz),146.1,135.2,132.8,130.2,128.6,124.4,115.4(q,J_C-F＝289Hz),77.3,77.0,76.7.

example two: preparation of 1- (2-aminophenyl) -2,2, 2-trifluoroacetone (V)

Taking a 500mL autoclave, sequentially adding 1- (2-nitrophenyl) -2,2, 2-trifluoroacetone (100mmol,21.9g), 95% ethanol (140mL) and Raney Ni catalyst (1.3g), introducing hydrogen, heating to 0.6-0.7 MPa, keeping the temperature and stirring at 50-60 ℃, after the reaction is completed, filtering and recovering the catalyst, concentrating the organic phase under reduced pressure to recover ethanol to dryness, recrystallizing the residue with n-octanol (60mL) to obtain a compound (V), wherein the product is a dark yellow solid (17.4g, the yield is 92%) and the melting point is 51-52 ℃.

Pattern characterization of compound (iv):

¹H NMR(400MHz,CDCl₃)δ＝7.75(d,J＝8.4Hz,1H),7.38(t,J＝7.8Hz,1H),6.71(dd,J＝13.8,8.2Hz,2H),6.41(s,2H).¹³C NMR(100MHz,CDCl₃)δ＝180.8(q,J_C-F＝30Hz),153.1,136.6,131.3,117.4,117.0(q,J_C-F＝289Hz),116.3,111.0,77.3,77.0,76.7.

example three: preparation of 1- (2-amino-5-chlorophenyl) -2,2, 2-trifluoroacetone (I)

A500 mL two-neck round-bottom reaction flask was charged with 1- (2-aminophenyl) -2,2, 2-trifluoroacetone (100mmol,19.2g), N-chlorosuccinimide (15.8g,120mmol), chloroform 150mL, dimethyl sulfoxide (0.71g,10mmol) as a catalyst, stirred at room temperature until the reaction was complete, concentrated under reduced pressure to recover the solvent, and the residue was recrystallized from N-hexane (80mL) to give compound (I) (19.3g, yield 86%) as a bright yellow solid, melting point 90-91 ℃ and purity by HPLC 98.5% (mobile phase acetonitrile: water: 70: 30, V/V).

Profile characterization of compound (I):

¹H NMR(400MHz,DMSO-d₆)δ＝7.86(s,2H),7.45(d,J＝2.8Hz,2H),6.98(d,J＝8.4Hz,1H).¹⁹F NMR(376MHz,DMSO-d₆)δ＝-68.90,-83.12.¹³C NMR(100MHz,DMSO-d₆)δ＝178.2(q,J_C-F＝30Hz),153.7,137.2,128.6,120.7,118.6,117.2(q,J_C-F＝289Hz),109.6,40.6,40.4,40.2,40.0,39.8,39.6,39.4.HRMS(ESI):m/z calcd for C₈H₅ClF₃NO[M+H]⁺224.0089,found 224.0085

example four to example fifteen:

the preparation method of 1- (2-nitrophenyl) -2,2, 2-trifluoroacetone (IV) is as shown in example one, except that certain reaction conditions (such as the type of solvent, the feeding amount and temperature of trifluoroacetyl compound (III), the type of o-halonitrobenzene (II), the molar ratio of o-halonitrobenzene (II) to phenylmagnesium bromide or magnesium chloride (a) and the feeding amount of trifluoroacetyl compound (III) and the like) are changed), and the specific changed conditions and corresponding reaction effects of each example are shown in tables 1-2 below.

TABLE 1

TABLE 2

In combination with table 1, the reaction conditions of example four were varied as the type of solvent; examples five and six, the reaction conditions varied were of the type of formula III, methyl trifluoroacetate, trifluoroacetic anhydride; examples seven and eight, the reaction conditions were varied such that the molar ratio of ortho-halonitrobenzene (II) to phenyl grignard reagent (a) was charged; examples nine and ten, the reaction conditions were changed to the type of the starting o-halonitrobenzene (II).

In combination with Table 2, examples eleven, twelve and thirteen, the reaction conditions were varied in such a way that the molar ratio of the ortho-halonitrobenzene (II) to the compound of the formula (III) was fed; in the fourteenth embodiment, the fifteenth embodiment, the sixteenth embodiment and the seventeenth embodiment, the reaction condition is the Grignard reaction temperature.

Examples seventeen to twenty-eight:

preparation of 1- (2-aminophenyl) -2,2, 2-trifluoroacetone (V), the preparation method of each example is repeated with the second example, except that certain reaction conditions (such as the type of solvent B, the type of catalyst a, the amount of catalyst, the pressure and temperature of the reaction kettle, and the like) are changed, and the specific changed reaction conditions and corresponding reaction effects of each example are shown in tables 3 to 4 below.

TABLE 3

TABLE 4

In Table 3, the 10% specification Pd/C and the 5% specification Pd/C represent catalysts in which Pd was supported at 10% Pd/C and 5% Pd/C, respectively. Eighteen, nineteen examples, the type of reaction solvent being varied; example twenty, example twenty-one, the kind of catalyst is changed; in the examples twenty-two and twenty-three, the amount of the catalyst added was changed.

In combination with table 4, the reactor temperature was changed for twenty-four, twenty-five, twenty-six, and twenty-seven examples; twenty eight, twenty nine and thirty examples, the reactor pressure was varied.

Example twenty-nine to example forty-one:

preparation of 1- (2-amino-5-chlorophenyl) -2,2, 2-trifluoroacetone (I), the preparation method of each example is repeated with the third example, except that certain reaction conditions (such as the type of solvent C, the amount of dimethyl sulfoxide (DMSO), the temperature, the feeding molar ratio of 1- (2-aminophenyl) -2,2, 2-trifluoroacetone (V) to the chlorinating reagent NCS, and the like) are changed, and the specifically changed reaction conditions and the corresponding reaction effects of each example are shown in tables 5 to 6 below.

TABLE 5

TABLE 6

In combination with table 5, examples thirty-one and thirty-two, the types of reaction solvents were changed; example thirty-three, example thirty-four, example thirty-five, example thirty-six, the amount of dimethyl sulfoxide (DMSO) added was varied.

In combination with table 6, example thirty-seven, example thirty-eight, example thirty-nine and example forty, the reaction temperature was changed; example forty-one, example forty-two and example forty-three, the molar ratio of 1- (2-aminophenyl) -2,2, 2-trifluoroacetone (V) to the chlorinating agent NCS was varied.

The statements in this specification merely set forth a list of implementations of the inventive concept and the scope of the present invention should not be construed as limited to the particular forms set forth in the examples.