CN102531932A - Preparation method of important intermediate of hepatitis c virus (HCV) protease inhibitor - Google Patents
Preparation method of important intermediate of hepatitis c virus (HCV) protease inhibitor Download PDFInfo
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Abstract
The invention relates to a preparation method of 2-methyl-3-amino-4-acetyl anisole (III) serving as an important intermediate of a hepatitis c virus (HCV) protease inhibitor TMC435. The preparation method utilizes 3-methoxy group-2-methyl benzamide as a raw material which is degraded to be amino compound through Hoffman, and the product is obtained through acylation of the amino compound.
Description
Technical field:
The present invention relates to the preparation method of a kind of HCV proteinase inhibitor TMC435 important intermediate 2-methyl-3-amino-4-acetylbenzene methyl ether.
Background technology:
Hepatitis C virus (HCV) is a major cause of suffering from chronic hepatopathy all over the world.After initial acute infection, most of infected individuality all can develop into chronic hepatitis, and this is because HCV preferentially duplicates in liver cell rather than cytopathy directly takes place.Chronic hepatitis possibly develop into hepatic fibrosis, causes liver cirrhosis, latter stage hepatopathy and HCC (hepatocellular carcinoma), make it become the major cause of liver transplantation.Chronic hepatitis makes HCV become the important medical research focus with accumulation patient's quantity.HCV is genomic to duplicate the mediation that receives plurality of enzymes, and HCVNS3 Tryase and relevant cofactor NS4A thereof are arranged in said enzyme, and the multiple proteolytic cleavage of its mediation HCV polyprotein causes the generation of HCV replicative enzyme.The NS3 Tryase is considered to the necessary and attractive target that become drug discovery of virus replication.
TMC435 (having another name called TMC435350) is a kind of substituted cyclopentyl Macrocyclic HCV of center quinolyl NS3/4A proteinase inhibitor that has, and day clothes once are used to treat chronic hepatitis C, are researched and developed jointly by Medivir and Tibotec.Clinical data shows that it is attractive especially aspect pharmacodynamics and pharmacokinetics, can make 1 type chronic hepatitis C patient keep higher lasting virusology to reply (SVR) rate, has treatment time weak point, security, health giving quality and tolerance than characteristics such as height.A plurality of countries carry out the clinical III phase and study in the whole world at present, and the fast passage (Fast Track) that has obtained U.S. food Drug Administration (FDA) examines qualification, estimate listing in 2013.
Compound 2-methyl-3-amino-4-acetylbenzene methyl ether (III) is the important midbody of preparation TMC435.
Document WO 2007/014919 and WO2007/014926 disclose the preparation method of compound (III); With 3-methoxyl group-2-tolyl acid is starting raw material; Through triethylamine and diphenyl phosphate azide (DPPA) and trimethyl carbinol combination; Take off BOC with trifluoroacetic acid again, obtain aminocompound, reaction obtains the acidylate product to aminocompound through Sugasawa.But this method need be used the diphenyl phosphate azide and the trifluoroacetic acid of a large amount of costlinesses, causes cost high.
Document CN101921269 discloses the another kind of preparation method of compound (III), is starting raw material with 2-methyl-3 N-methyl-p-nitroaniline, through diazotization, hydrolysis, etherificate, reduction and acidylate, obtains product.But the raw material 2-methyl-3-nitro anisidine value of this method is high, and reaction scheme is long, complicated operation, and total recovery is low.
Summary of the invention:
To the problem that above-mentioned prior art exists, the object of the invention is to provide the preparation method of a kind of compound (III), and this method has overcome the defective of prior art, has simplified the preparation process, has improved yield, has practiced thrift cost, makes it to be applicable to suitability for industrialized production.
The invention provides the preparation method of compound (III); It is characterized in that: with ordinary method preparation or commercial 3-methoxyl group-2-methyl benzamide (I) of buying is starting raw material; Through the Hoffman degraded, reaction reagent is a hypohalite solution, obtains aminocompound (II).Compound (II) carries out acylation reaction again and makes 2-methyl-3-amino-4-acetylbenzene methyl ether (III).The used hypohalite solution of the first step Hoffman degraded comprises chlorine bleach liquor, potassium hypochlorite solution, sodium hypobromite solution, potassium hypobromite solution or the like.The second step acylation reaction agents useful for same is boron trichloride and acetonitrile.
Specific embodiment:
Embodiment 1
The preparation of 3-methoxyl group-2-aminobenzamide (I)
In reaction flask, add 1000g water, add 105g sodium hydroxide again, stir and dissolve clearly, add 3-hydroxy-2-methyl-phenylformic acid 200g when being cooled to 40-50 ℃; Stir 0.5h, system is dissolved clear, keeps temperature-resistant; Drip methyl-sulfate 400g simultaneously, back flow reaction 2h keeps system PH＞10.Get the 130g dissolution of sodium hydroxide and in 200g water, process solution, the adding system is warming up to 90-100 ℃, and insulation reaction 12h tracks to each midbody≤0.5%, gets final product termination reaction.Reaction solution is cooled between 20-30 ℃, adds 110g ammoniacal liquor, stirring reaction 2h tracks to methyl-sulfate≤0.1%, can stop destroying methyl-sulfate.Regulate PH≤2 with hydrochloric acid soln, be cooled to 15-20 ℃, insulated and stirred 1h, suction filtration, washing, oven dry again obtains 3-methoxyl group-2-methyl-benzoic white solid 216.2g, yield 98%, HPLC purity 99%.
In reaction flask, add 700g toluene, under agitation add the 3-methoxyl group-2-methyl-phenylformic acid 216.2g that obtained in the last step, be warming up to 70-80 ℃; Slowly drip the 225g sulfur oxychloride again; At 70-75 ℃ of insulation reaction 2h, slowly be warming up to 100-110 ℃ of insulation backflow 12h then, follow the tracks of and react to raw material≤2%; Get final product termination reaction, N
2The protection drop to 25-30 ℃ for use.Get another reaction flask, add 375g ammoniacal liquor, open and stir, ice bath is cooled to 0-5 ℃, with above-mentioned prepared the acyl chlorides toluene solution use N
2Be pressed in the system, controlled temperature is not higher than 20 ℃, and a large amount of solids are separated out, and adds the back and stirs 1h in 0-10 ℃; Suction filtration is put into filter cake in the 1200g water, opens and stirs, and be warming up to 50-55 ℃; Insulation 2h is cooled to 0-5 ℃, insulated and stirred 1h, suction filtration, washing, oven dry again; Get title compound 204g, yield 93%, HPLC purity 97%.
Embodiment 2
The preparation of 3-methoxyl group-2-methyl-aniline (II)
In reaction flask, add 1000g water, open and stir, slowly add 180g sodium hydroxide, controlled temperature slowly drips the 188g bromine at 0-5 ℃, and insulation reaction 1h, sodium hypobromite prepare the back heat preservation for standby use.Get another reaction flask and add 1500g water, 9g sodium hydroxide is after stirring is dissolved clearly; Add 185.6g compound (I), and be cooled to 0-5 ℃, the sodium hypobromite solution that slow dropping has prepared in system; Solid dissolves clear gradually, is incubated 2h afterwards, follows the tracks of and reacts to raw material≤5%; Get final product termination reaction, rise to room temperature naturally, stir for use.Get another reaction flask, add 460g water and be warming up to 80-85 ℃, be added dropwise to the above-mentioned reaction solution for preparing, color becomes brown; After dripping,, follow the tracks of reaction to finishing at 90-100 ℃ of insulation reaction 12h; Be cooled to 25-30 ℃,, use the saturated common salt water washing again with methylbenzene extraction twice; Drying, suction filtration, the bullion that obtains are brown liquid.
In reaction flask, add 88g methyl alcohol, be cooled to 0-5 ℃, dripping acetyl chloride, heat release is violent, insulation reaction 0.5h, the HCl/MeOH formulations prepared from solutions finishes, and is for use.The brown bullion that obtains in the last step was added in the 377g MTBE, open and stir, and be cooled to 0-5 ℃, the HCl/MeOH drips of solution is added in this system, have solid to separate out, insulation reaction 1h, suction filtration, washing obtain the hydrochloride of (II).
In reaction flask, add entry 900g, add the hydrochloride of above-mentioned (II) again, open and stir; Add again 43g sodium hydroxide and 190g water solution, the 370g methylene dichloride stirred 30 minutes; Static layering obtains organic layer, again drying, suction filtration, concentrated; Obtain dark oil thing 138.4g, yield is 85.2%, and HPLC purity is 92%.
Embodiment 3
The preparation of 3-methoxyl group-2-methyl-aniline (II)
In reaction flask, add 1000g water, open and stir, slowly add 252g Pottasium Hydroxide, controlled temperature slowly drips the 188g bromine at 0-5 ℃, and insulation reaction 1h, sodium hypobromite prepare the back heat preservation for standby use.Get another reaction flask and add 1500g water, 12.6g Pottasium Hydroxide is after stirring is dissolved clearly; Add 185.6g compound (I), and be cooled to 0-5 ℃, the potassium hypobromite solution that slow dropping has prepared in system; Solid dissolves clear gradually, is incubated 2h afterwards, tracks to raw material≤5%; Get final product termination reaction, be warming up to room temperature naturally, stir for use.Get another reaction flask, add 460g water and be warming up to 80-85 ℃, be added dropwise to the above-mentioned reaction solution for preparing, color becomes brown; After dripping,, follow the tracks of reaction to finishing at 90-100 ℃ of insulation reaction 12h; Be cooled to 25-30 ℃,, use the saturated common salt water washing again with methylbenzene extraction twice; Drying, suction filtration, the bullion that obtains are brown liquid.
In reaction flask, add 88g methyl alcohol, be cooled to 0-5 ℃, dripping acetyl chloride, heat release is violent, insulation reaction 0.5h, the HCl/MeOH formulations prepared from solutions finishes, and is for use.The brown bullion that obtains in the last step was added in the 377g MTBE, open and stir, and be cooled to 0-5 ℃, the HCl/MeOH drips of solution is added in this system, have solid to separate out, insulation reaction 1h, suction filtration, washing obtain the hydrochloride of (II).
In reaction flask, add entry 900g, add the hydrochloride of above-mentioned (II) again, open and stir; Add again 60g Pottasium Hydroxide and 190g water solution, the 370g methylene dichloride stirred 30 minutes; Static layering obtains organic layer, again drying, suction filtration, concentrated; Obtain dark oil thing 137.7g, yield is 84.5%, and HPLC purity is 91.7.
Embodiment 4
The preparation of 3-methoxyl group-2-methyl-aniline (II)
In reaction flask, add 1000g water, open and stir, slowly add 252g Pottasium Hydroxide, controlled temperature slowly feeds chlorine at 0-5 ℃, and insulation reaction 1h, potassium hypochlorite prepare the back heat preservation for standby use.Get another reaction flask and add 1500g water, 12.6g Pottasium Hydroxide is after stirring is dissolved clearly; Add 185.6g compound (I), and be cooled to 0-5 ℃, the potassium hypochlorite solution that slow dropping has prepared in system; Solid dissolves clear gradually, is incubated 2h afterwards, tracks to raw material≤5%; Get final product termination reaction, be warming up to room temperature naturally, stir for use.Get another reaction flask, add 460g water and be warming up to 80-85 ℃, be added dropwise to the above-mentioned reaction solution for preparing, color becomes brown; After dripping,, follow the tracks of reaction to finishing at 90-100 ℃ of insulation reaction 12h; Be cooled to 25-30 ℃,, use the saturated common salt water washing again with methylbenzene extraction twice; Drying, suction filtration, the bullion that obtains are brown liquid.
In reaction flask, add 88g methyl alcohol, be cooled to 0-5 ℃, dripping acetyl chloride, heat release is violent, insulation reaction 0.5h, the HCl/MeOH formulations prepared from solutions finishes, and is for use.The brown bullion that obtains in the last step was added in the 377g MTBE, open and stir, and be cooled to 0-5 ℃, the HCl/MeOH drips of solution is added in this system, have solid to separate out, insulation reaction 1h, suction filtration, washing obtain the hydrochloride of (II).
In reaction flask, add entry 900g, add the hydrochloride of above-mentioned (II) again, open and stir; Add again 60g Pottasium Hydroxide and 190g water solution, the 370g methylene dichloride stirred 30 minutes; Static layering has obtained basic unit, again drying, suction filtration, concentrated; Obtain dark oil thing 137.2g, yield is 84%, and HPLC purity is 91.5%.
Embodiment 5
The preparation of 3-methoxyl group-2-methyl-aniline (II)
In reaction flask, add 1000g water, open and stir, slowly add 180g sodium hydroxide, controlled temperature slowly feeds chlorine at 0-5 ℃, and insulation reaction 1h, Youxiaolin prepare the back heat preservation for standby use.Get another reaction flask and add 1500g water, 9g sodium hydroxide is after stirring is dissolved clearly; Add 185.6g compound (I), and be cooled to 0-5 ℃, the chlorine bleach liquor that slow dropping has prepared in system; Solid dissolves clear gradually, is incubated 2h afterwards, tracks to raw material≤5%; Get final product termination reaction, be warming up to room temperature naturally, stir for use.Get another reaction flask, add 460g water and be warming up to 80-85 ℃, be added dropwise to the above-mentioned reaction solution for preparing, color becomes brown; After dripping,, follow the tracks of reaction to finishing at 90-100 ℃ of insulation reaction 12h; Be cooled to 25-30 ℃,, use the saturated common salt water washing again with methylbenzene extraction twice; Drying, suction filtration, the bullion that obtains are brown liquid.
In reaction flask, add 88g methyl alcohol, be cooled to 0-5 ℃, dripping acetyl chloride, heat release is violent, insulation reaction 0.5h, the HCl/MeOH formulations prepared from solutions finishes, and is for use.The brown bullion that obtains in the last step was added in the 377g MTBE, open and stir, and be cooled to 0-5 ℃, the HCl/MeOH drips of solution is added in this system, have solid to separate out, insulation reaction 1h, suction filtration, washing obtain the hydrochloride of (II).
In reaction flask, add entry 900g, add the hydrochloride of above-mentioned (II) again, open and stir; Add again 43g sodium hydroxide and 190g water solution, the 370g methylene dichloride stirred 30 minutes; Static layering has obtained basic unit, again drying, suction filtration, concentrated; Obtain dark oil thing 139.2g, yield is 84.7%, and HPLC purity is 91%.
Embodiment 6
The preparation of 2-methyl-3-amino-4-acetylbenzene methyl ether (III)
In reaction flask, add 500g1, the 2-ethylene dichloride is opened stirring and is cooled to 0 ℃, closes stirring; Feed boron trichloride gas, maintain the temperature at 0-5 ℃, slowly drip 138.4g compound (II) (HPLC purity is 92%) and 780g1, the mixing solutions of 2-ethylene dichloride; Insulated and stirred 1h, Dropwise 5 1g acetonitrile again, after finishing, insulation reaction 0.5h; Be warming up to 80-85 ℃ of back flow reaction 12h then, follow the tracks of react to raw material less than below 5%, but termination reaction.Cooling reaction liquid slowly drips 15% hydrochloric acid soln to 0-5 ℃, can produce a large amount of solids, and insulation reaction to midbody can stop hydrolysis reaction less than 2%.Drip 40% sodium hydroxide solution regulation system PH=6-7, suction filtration has obtained basic unit then, is concentrated into driedly, obtains the beige solid crude product.Bullion is used recrystallizing methanol, obtains title compound 100.1g, and yield is 60%, and HPLC purity is 99.7%.
Claims (5)
1. the preparation method of a formula (II) compound,
This method comprises: compound shown in the formula (I) is carried out the Hoffman degraded,
2. method according to claim 1, compound is a hydrochloride shown in the formula (II).
3. according to the described method of claim 1-2, it is characterized in that the used reagent of Hoffman degraded is hypohalite solution.
4. method according to claim 3 is characterized in that the used hypohalite solution of Hoffman degraded is a kind of in Youxiaolin, potassium hypochlorite, sodium hypobromite or the potassium hypobromite solution.
5. the preparation method of a formula (III) compound,
This method comprises: the compound (II) of the described method of claim 1-4 preparation is carried out acidylate prepare compound (III).
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109846883A (en) * | 2017-11-30 | 2019-06-07 | 常州寅盛药业有限公司 | Benzofuran derivatives and TMC435 combination medicine |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101921269A (en) * | 2009-06-12 | 2010-12-22 | 中国中化股份有限公司 | Method for preparing HCV (Hepatitis C Virus) inhibitor |
| CN101987825A (en) * | 2009-07-31 | 2011-03-23 | 上海开拓者医药发展有限公司 | Method for preparing 2-amino-3-methyl-4-methoxy acetophenone |
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- 2011-11-04 CN CN201110346652.7A patent/CN102531932B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101921269A (en) * | 2009-06-12 | 2010-12-22 | 中国中化股份有限公司 | Method for preparing HCV (Hepatitis C Virus) inhibitor |
| CN101987825A (en) * | 2009-07-31 | 2011-03-23 | 上海开拓者医药发展有限公司 | Method for preparing 2-amino-3-methyl-4-methoxy acetophenone |
Non-Patent Citations (1)
| Title |
|---|
| 姜艳 等: "2-硝基-3-氯苯胺的合成", 《精细石油化工》, no. 4, 31 July 2005 (2005-07-31), pages 8 - 9 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109846883A (en) * | 2017-11-30 | 2019-06-07 | 常州寅盛药业有限公司 | Benzofuran derivatives and TMC435 combination medicine |
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