CN102718720B

CN102718720B - Method for preparing 4-[(4,6-dichloro-2-pyrimidyl) amino] cyanophenyl

Info

Publication number: CN102718720B
Application number: CN201210231956.3A
Authority: CN
Inventors: 施金普; 魏天海; 韩斌; 张达
Original assignee: NINGBO CHEMGOO PHARMACEUTICAL TECHNOLOGY INNOVATION Ltd
Current assignee: NINGBO CHEMGOO PHARMACEUTICAL TECHNOLOGY INNOVATION Ltd
Priority date: 2012-07-04
Filing date: 2012-07-04
Publication date: 2015-01-07
Anticipated expiration: 2032-07-04
Also published as: CN102718720A

Abstract

The invention discloses a method for preparing a critical chloro intermediate of 4-[(4,6-dichloro-2-pyrimidyl) amino] cyanophenyl (IV) of etravirine by taking 4-aminobenzamide as starting raw materials. The method has the advantages that the 4-aminobenzamide is used as the starting raw materials, the operation is safe, the cost of the raw materials is low, and no toxicity exists; and the product purity is good, and the yield in each step is higher than 80 percent.

Description

The preparation method of 4-[(4,6-dichloro-2-pyrimidinyl) is amino] cyanophenyl

Technical field

The invention belongs to the preparing technical field of the fine chemical products such as medicine, relate to a kind of preparing technical field of chloro thing of etravirine key intermediate, particularly, the present invention relates to the preparation method of 4-[(4,6-dichloro-2-pyrimidinyl) is amino] cyanophenyl (formula IV).

Background technology

Etravirine (Etravirine) (formula V), s-generation non-nucleoside reverse transcriptase inhibitor, other antiretroviral drugs of coupling, for HIV (human immunodeficiency virus) infection patient.

The structural formula of etravirine is as (V):

The key intermediate preparing etravirine in production is 4-[(4,6-dichloro-2-pyrimidinyl) is amino] cyanophenyl, and structural formula is as (IV)

4-[(4,6-dichloro-2-pyrimidinyl) is amino] cyanophenyl (IV) is the key intermediate preparing etravirine, existing report (WO 2012001695; ChemMedChem, 20094 (9), 1537-1545; WO 2008080964 etc.) synthesis IV, be with 4-aminobenzonitrile for starting raw material, successively with mononitrile amine, diethyl malonate, phosphorus oxychloride reaction, and then obtain chloro intermediate IV, reaction formula is as follows:

Starting raw material 4-aminobenzonitrile toxicity in this route is comparatively large, has certain harm during extensive use to workman and environment; Chloro midbody product IV yield is not high, causes raw-material waste; And 4-aminobenzonitrile price is relatively high, the final drug cost of etravirine chloro intermediate and etravirine is caused to increase.

Summary of the invention

Technical problem to be solved by this invention is to provide the preparation method of 4-[(4,6-dichloro-2-pyrimidinyl) is amino] cyanophenyl, and the method 4-aminobenzamide is starting raw material, operational safety, and the prices of raw and semifnished materials are cheap, nontoxicity; Product purity is good, often walks yield higher than 80%.

The present invention solves the problems of the technologies described above adopted technical scheme: the preparation method of 4-[(4,6-dichloro-2-pyrimidinyl) is amino] cyanophenyl, comprises the steps:

The first step, makes the 4-aminobenzamide shown in formula I and mononitrile amine react, prepares the 4-guanidinobenzamides shown in formula II;

Second step, the 4-guanidinobenzamides that the described the first step is obtained reacts in the corresponding methanol solution of sodium methylate or alcohol sodium alcohol solution of dimethyl malonate or diethyl malonate, after completion of the reaction, obtain the crude product of the compound III shown in formula III, described crude product is by the sterling obtaining described compound III refining in certain solvent;

3rd step, makes described second step obtain the sterling of described compound III in organic solvent, under the existence of organic bases, with phosphorus oxychloride single step reaction, obtains 4-[(4,6-dichloro-2-pyrimidinyl) the is amino] cyanophenyl shown in product formula IV.

In the described the first step, the reaction conditions of the 4-aminobenzamide shown in described formula I and mononitrile amine is: pH3-4, temperature of reaction 80-100 DEG C, reaction times 6-20h, and preferably, described pH value controls by adding mineral acid.

It is even more preferred that in the described the first step, the reaction conditions of the 4-aminobenzamide shown in described formula I and mononitrile amine is: pH3-4, temperature of reaction 100 DEG C, reaction times 12h, and described pH value is by adding hydrochloric acid or nitric acid control.

In described second step, the crude product of described compound III uses lower alcohol/water to be refining solvent, and the volume ratio of described lower alcohol and water is 1:9 to 9:1.Wherein, lower alcohol is the address of the relative length according to alcohol carbochain, and described lower alcohol refers to the alcohols that carbochain is shorter herein, namely refers to the alcohol that carbonatoms is less than 6.Preferably, described lower alcohol is ethanol, and the volume ratio of described ethanol and water is 9:1.It is further preferred that described lower alcohol is methyl alcohol, and the volume ratio of described methyl alcohol and water is 9:1.

In described 3rd step, described organic solvent be selected from toluene, dimethylbenzene and methyl-phenoxide any one.

In described 3rd step, described temperature of reaction is 100-120 DEG C; Preferably, described temperature of reaction is 110 DEG C.

In described 3rd step, described organic bases is tertiary amine.Preferably, described organic bases is triethylamine or DIPEA.

Compared with prior art, tool has the following advantages in the present invention:

(1) inexpensive and substantially nontoxic 4-aminobenzamide is employed in the first step reaction of the present invention, namely with 4-aminobenzamide and mononitrile amine, in the certain pH aqueous solution, under certain temperature, react certain hour, prepare to higher yields 4-guanidinobenzamides (II).

(2) the method 4-aminobenzamide of the present invention is starting raw material, is also safe from harm when nontoxicity uses on a large scale to work human and environment, and therefore production operation safety is more suitable for industrialized scale operation.In addition, 4-aminobenzamide is starting material, and it is cheap; Product purity is good, and yield is high.Therefore, reduce drug cost, there is higher economic worth.

Accompanying drawing explanation

Fig. 1 is the reaction process schematic diagram of the preparation method of 4-of the present invention [(4,6-dichloro-2-pyrimidinyl) is amino] cyanophenyl.

Embodiment

In order to understand content of the present invention better, be described further below in conjunction with specific embodiment.Should be understood that these embodiments only for the present invention is further described, and be not used in and limit the scope of the invention.In addition should be understood that, after having read content of the present invention, person skilled in art makes some nonessential change or adjustment to the present invention, still belongs to protection scope of the present invention.

Embodiment 1

The first step: the preparation of 4-guanidinobenzamides (II):

Get 4-aminobenzamide (I) 15g, water 75ml, stir and be warming up to 100 DEG C, drip 50% cyanamide aqueous solution 30g in batches, drip concentrated hydrochloric acid control pH is 3-4 simultaneously, continues reaction 12h.Add sodium-chlor 15g, cooling, aqueous sodium hydroxide solution adjusts pH to be weakly alkaline, filters to obtain solid, dries, obtains 4-guanidinobenzamides (II) 18.6g, yield 95%.

Second step: preparation compound III:

10g compound ii, 10ml methyl alcohol, stirs and is warming up to backflow, add 29.4% sodium methylate/methanol solution 30.9g in batches, drips dimethyl malonate 14.9g simultaneously in batches, adds and continues insulation reaction 2h.Decompression steams methyl alcohol, adds 100ml water, stirring and dissolving in residue, adjusts pH to 5-6, and filter, filter cake dries to obtain 15.2g.Get 15g, refine by methanol/water solution, fine work 60 DEG C dries to obtain compound III 12.4g, yield 90%.Wherein, described methanol/water solution refers to the mixing solutions of first alcohol and water 9:1 mixing by volume.

3rd step: prepare chloro intermediate IV:

In reaction flask, drop into 150 grams of phosphorus oxychloride, be cooled to less than 10 DEG C, add 30 grams of starting compounds III in batches, finish in half an hour.After be slowly heated to back flow reaction, solution become clarification, react about 3-4 hour aftertreatment, underpressure distillation phosphorus oxychloride (pump vacuum pressure is 0.09Mpa for distillation temperature <65 DEG C, water-bath temperature control), steams about 85 grams.After frozen water cool about 5 DEG C and drip frozen water 150ml, continue lower sodium hydroxide 40% aqueous solution that drips of cooling and adjust pH8-9, be then heated to 60-70 DEG C, stir half an hour, be cooled to room temperature and filter, dry about 36 grams.Crude product adds 180mlTHF, after the clarification of 36ml water reflux, mends dropping 72ml and is water-cooled to 5 DEG C of crystallizatioies filtrations, dry to obtain 29.1 grams of products, yield about 83.7%.Fusing point: 237.5-240.5 DEG C, HPLC purity 99.3%.1HNMR(500MHz,DMSO):10.83(s,1H),7.85(d,2H,),7.80(d,2H),7.32(s,1H)。

Embodiment 2

The first step: the preparation of 4-guanidinobenzamides (II):

Get 4-aminobenzamide (I) 15g, water 75ml, stir and be warming up to 100 DEG C, drip 50% cyanamide aqueous solution 30g in batches, drip nitric acid control pH is 3-4 simultaneously, continues reaction 12h.Add sodium-chlor 15g, cooling, aqueous sodium hydroxide solution adjusts pH to be weakly alkaline, filters to obtain solid, dries, obtains 4-guanidinobenzamides (II) 18.4g, yield 94%.

Second step: preparation compound III:

10g compound ii, 10ml ethanol, stirs and is warming up to backflow, add 20% sodium ethylate/ethanolic soln 57.2g in batches, drips diethyl malonate 18.1g simultaneously in batches, adds and continues insulation reaction 2h.Decompression steams ethanol, adds 100ml water, stirring and dissolving in residue, adjusts pH to 5-6, and filter, filter cake dries to obtain 15.5g, and refine by ethanol/water solution, fine work 60 DEG C dries to obtain compound III 12.8g, yield 92.9%.Wherein, described ethanol/water solution refers to the mixing solutions of second alcohol and water 9:1 mixing by volume.

3rd step: prepare chloro intermediate IV:

In reaction flask, drop into 150 grams of phosphorus oxychloride, be cooled to less than 10 DEG C, add 30 grams of raw materials III in batches, finish in half an hour.After be slowly heated to back flow reaction, solution become clarification, react about 3-4 hour aftertreatment, underpressure distillation phosphorus oxychloride (pump vacuum pressure is 0.09Mpa for distillation temperature <65 DEG C, water-bath temperature control), steams about 85 grams.After frozen water cool about 5 DEG C and drip frozen water 150ml, continue lower sodium hydroxide 40% aqueous solution that drips of cooling and adjust pH8-9, be then heated to 60-70 DEG C, stir half an hour, be cooled to room temperature and filter, dry about 36 grams.Crude product adds 180mlTHF, after the clarification of 36ml water reflux, mends dropping 72ml and is water-cooled to 5 DEG C of crystallizatioies filtrations, dry to obtain 29.1 grams of products, yield about 83.7%.Fusing point: 237.5-240.5 DEG C, HPLC purity 99.3%.1HNMR(500MHz,DMSO):10.83(s,1H),7.85(d,2H,),7.80(d,2H),7.32(s,1H)。

As mentioned above, just the present invention can be realized preferably.

Claims

The preparation method of 1.4-[(4,6-dichloro-2-pyrimidinyl) is amino] cyanophenyl, is characterized in that, comprise the steps:

The first step: the preparation of 4-guanidinobenzamides II:

The reactions steps that the described the first step is concrete is: get 4-aminobenzamide 15g, water 75ml, stirs and is warming up to 100 DEG C, drip 50% cyanamide aqueous solution 30g in batches, and drip concentrated hydrochloric acid control pH is 3-4 simultaneously, continues reaction 12h; Add sodium-chlor 15g, cooling, aqueous sodium hydroxide solution adjusts pH to be weakly alkaline, filters to obtain solid, dries, obtains 4-guanidinobenzamides 18.6g, yield 95%;

Second step: preparation compound III:

The concrete reactions steps of described second step is: 10g compound ii, 10ml methyl alcohol, stirs and is warming up to backflow, add 29.4% sodium methylate/methanol solution 30.9g in batches, drips dimethyl malonate 14.9g simultaneously in batches, adds and continues insulation reaction 2h; Decompression steams methyl alcohol, adds 100ml water, stirring and dissolving in residue, adjusts pH to 5-6, and filter, filter cake dries to obtain 15.2g; Get filter cake 15g, refine by methanol/water solution, fine work 60 DEG C dries to obtain compound III 12.4g, yield 90%; Described methanol/water solution refers to the mixing solutions of first alcohol and water 9:1 mixing by volume;

3rd step: prepare chloro intermediate IV:

The reactions steps that described 3rd step is concrete is: in reaction flask, drop into 150 grams of phosphorus oxychloride, be cooled to less than 10 DEG C, add 30 grams of raw materials III in batches, finish in half an hour; After be slowly heated to back flow reaction, solution become clarification, react aftertreatment in 3-4 hour, underpressure distillation phosphorus oxychloride, distillation temperature <65 DEG C, water-bath temperature control, pump vacuum pressure is 0.09Mpa, steams 85 grams; After frozen water be cooled to 5 DEG C and drip frozen water 150ml, the aqueous sodium hydroxide solution continuing the lower dropping 40% of cooling adjusts pH8-9, is then heated to 60-70 DEG C, stirs half an hour, be cooled to room temperature to filter, dry 36 grams, crude product adds 180mlTHF, after the clarification of 36ml water reflux, mend dropping 72ml and be water-cooled to 5 DEG C of crystallizatioies filtrations, dry to obtain 4-[(4,6-dichloro-2-pyrimidinyl) is amino] the cyanophenyl product shown in 29.1 grams of formula IV, yield 83.7%.
The preparation method of 2.4-[(4,6-dichloro-2-pyrimidinyl) is amino] cyanophenyl, is characterized in that, comprise the steps:

The first step: the preparation of 4-guanidinobenzamides (II):

The reactions steps that the described the first step is concrete is: get 4-aminobenzamide 15g, water 75ml, stirs and is warming up to 100 DEG C, drip 50% cyanamide aqueous solution 30g in batches, and drip nitric acid control pH is 3-4 simultaneously, continues reaction 12h; Add sodium-chlor 15g, cooling, aqueous sodium hydroxide solution adjusts pH to be weakly alkaline, filters to obtain solid, dries, obtains 4-guanidinobenzamides 18.4g, yield 94%;

Second step: preparation compound III:

The concrete reactions steps of described second step is: 10g compound ii, 10ml ethanol, stirs and is warming up to backflow, add 20% sodium ethylate/ethanolic soln 57.2g in batches, drips diethyl malonate 18.1g simultaneously in batches, adds and continues insulation reaction 2h; Decompression steams ethanol, adds 100ml water, stirring and dissolving in residue, adjusts pH to 5-6, and filter, filter cake dries to obtain 15.5g, and refine by ethanol/water solution, fine work 60 DEG C dries to obtain compound III 12.8 grams, yield 92.9%; Wherein, described ethanol/water solution refers to the mixing solutions of second alcohol and water 9:1 mixing by volume;

3rd step: prepare chloro intermediate IV:

The reactions steps that described 3rd step is concrete is: in reaction flask, drop into 150 grams of phosphorus oxychloride, be cooled to less than 10 DEG C, add 30 grams of raw materials III in batches, finish in half an hour; After be slowly heated to back flow reaction, solution become clarification, react aftertreatment in 3-4 hour, underpressure distillation phosphorus oxychloride, distillation temperature <65 DEG C, water-bath temperature control, pump vacuum pressure is 0.09Mpa, steams 85 grams; After frozen water cool 5 DEG C and drip frozen water 150ml, the aqueous sodium hydroxide solution continuing the lower dropping 40% of cooling adjusts pH8-9, is then heated to 60-70 DEG C, stirs half an hour, is cooled to room temperature and filters, dry 36 grams; Crude product adds 180mlTHF, after the clarification of 36ml water reflux, mends dropping 72ml and is water-cooled to 5 DEG C of crystallizatioies filtrations, dry 4-[(4,6-dichloro-2-pyrimidinyl) is amino] the cyanophenyl product 29.1 grams to obtain shown in product formula IV, yield 83.7%.