CN101880241B - Method for preparing 2-(substituted phenyl) methylamino-3-nitrobenzene methyl formate by one-pot method - Google Patents
Method for preparing 2-(substituted phenyl) methylamino-3-nitrobenzene methyl formate by one-pot method Download PDFInfo
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Abstract
The invention provides a method for preparing candesartan cilexetil intermediate products of 2-(substituted phenyl) methylamino-3-nitrobenzene methyl formate by a one-pot method. The candesartan cilexetil intermediate products are 2-(4-bromophenyl) methylamino-3-nitrobenzene methyl formate and 2-[[(2'-cyano xenyl-4-pyridyl) methyl] amino]-3-nitrobenzene methyl formate. The process comprises the step of using 3-nitryl-2-carboxyphenyl methyl formate as raw materials to obtain target products through continuous reaction process. The extraction and the purification are not needed, the work intensity is reduced, the operation environment is improved, the environment pollution is reduced, the raw material and product loss is reduced, the industrial production cost is greatly reduced, and the yield is improved.
Description
Technical field
The present invention relates to the preparation method of candesartan Cilexetil important intermediate 2-(substituted-phenyl) methylamino--3-nitrobenzene methyl, belong to chemical industry and chemical field of medicaments.
Background technology
Candesartan, English Candesartan by name, the chemistry of candesartan Cilexetil is called 2-oxyethyl group-1-[[2 '-(1H-tetrazole-5-yl) [1,1 '-xenyl]-the 4-yl] methyl]-1H-benzoglyoxaline-7-formic acid-1-[[(cyclohexyloxy) carbonyl] the oxygen base] ethyl ester, its structural formula is as follows:
Candesartan Cilexetil is a kind of novel non-peptide class Angiotensin II (ATII) receptor antagonist, is used for clinically the treatment of essential hypertension, and this medicine at first went on the market in Sweden in 1997.
2-(substituted-phenyl) methylamino--3-nitrobenzene methyl is synthetic candesartan Cilexetil important intermediate, and this intermediate specifically refers to 2-(4-bromophenyl) methylamino--3-nitrobenzene methyl and 2-[[(2 '-cyanobiphenyl base-4-yl) methyl] amino]-the 3-nitrobenzene methyl.The preparation method of 2-(4-bromophenyl) methylamino--3-nitrobenzene methyl is open in patent CN101068807A; this processing method is as rising such as raw material take the 3-nitrophthalic acid; get 3-nitro-2 carboxyl methyl benzoate through mono-esterification; obtain intermediate 3-nitro-2-t-butoxycarbonyl amino methyl benzoate through acidylate, azide, amidation; through nucleophilic substitution, take off tertbutyloxycarbonyl and get 2-(4-bromophenyl) methylamino--3-nitrobenzene methyl again.See lower operational path:
The method acylation reaction is used the stronger solvent benzol of toxicity, and back flow reaction, and is big for environment pollution, and per step all be directly to obtain being used for next step reaction behind the product, make the operation complicated, increased cost; Nitrine liquid is concentrated, and trinitride is dry, preservation is all very easily dangerous.
2-[[(2 '-cyanobiphenyl base-4-yl) methyl] amino]-preparation of 3-nitrobenzene methyl is open in patent CN1204125C, under alkaline condition, DMF is solvent 3-nitro-2-t-butoxycarbonyl amino methyl benzoate and 4-brooethyl-2 '-cyanobiphenyl generation nucleophilic substitution, then takes off tertbutyloxycarbonyl and gets 2-[[2-cyanobiphenyl base)-the 4-yl] methyl] amino-3-nitrobenzene methyl.
Also there is complex operation step in this technique, and solvent load is more, and yield is not high, and contaminated wastewater is large.
Summary of the invention
The purpose of this invention is to provide the method that a kind of one kettle way prepares 2-(substituted-phenyl) methylamino--3-nitrobenzene methyl, it is few that the method is used solvent species, and reduced labour intensity, and yield is high, cost is low, environmental pollution is few, is suitable for suitability for industrialized production.
Candesartan Cilexetil intermediate 2-of the present invention (substituted-phenyl) methylamino--3-nitrobenzene methyl, its structural formula is:
Wherein, Y is bromine or 2-cyano-phenyl.
For reaching goal of the invention, the technical solution used in the present invention is:
The method that one kettle way prepares candesartan Cilexetil intermediate 2-(substituted-phenyl) methylamino--3-nitrobenzene methyl (formula I) may further comprise the steps:
(1) take 3-nitro-2-carboxyl methyl benzoate as initial main raw material, makes 3-nitro-2-t-butoxycarbonyl amino methyl benzoate (formula II) chloroformic solution through Curtius reaction one kettle way;
2) in the presence of phase-transfer catalyst and alkali, this 3-nitro-2-t-butoxycarbonyl amino methyl benzoate (formula II) chloroformic solution and 4-Bromomethyl Substituted benzene (formula III) carry out alkylation reaction and obtain 2-(tertbutyloxycarbonyl (substituted-phenyl) methyl) amino-3-nitrobenzene methyl (formula IV);
The tertbutyloxycarbonyl protecting group of (3) taking off 2-(tertbutyloxycarbonyl (substituted-phenyl) methyl) amino-3-nitrobenzene methyl (formula IV) obtains 2-(substituted-phenyl) methylamino--3-nitrobenzene methyl (formula I);
Particularly, the phase-transfer catalyst in the described step 2 is quaternary amine or crown ether, and described quaternary ammonium salt comprises Tetrabutyl amonium bromide, benzyltriethylammoinium chloride.Crown ether comprise 15-hat (ether)-5,18-hat (ether)-6, bicyclohexane also-18-is preced with (ether)-6.
Described alkali is sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood, sodium bicarbonate, saleratus;
Deprotection reaction in the described step 3 is to slough the tertbutyloxycarbonyl protecting group with haloid acid in alcohol, ester or their mixtures; Described alcohol is methyl alcohol, and ethanol, described ester are ethyl acetate, isopropyl acetate; Described haloid acid hydrochloric acid or Hydrogen bromide.
Described 2-(substituted-phenyl) methylamino--3-nitrobenzene methyl is 2-(4-bromophenyl) methylamino--3-nitrobenzene methyl and 2-[[(2 '-cyanobiphenyl base-4-yl) methyl] amino]-the 3-nitrobenzene methyl.
Wherein, Y is bromine or 2-cyano-phenyl
Further, this Curtius reaction one kettle way prepares 3-nitro-2-t-butoxycarbonyl amino methyl benzoate (formula II) chloroformic solution and may further comprise the steps:
(1) under the existence of dimethyl formamide, 3-nitro-2-carboxyl methyl benzoate and sulfur oxychloride reaction, the reaction solution that obtains is directly used in next step;
(2) add chloroform in the reaction solution that obtains in the step 1, in the presence of phase-transfer catalyst and sodium azide aqueous solution carry out the chloroformic solution that azido reaction obtains 3-nitro-2-azidocarbonyl methyl benzoate;
The chloroformic solution of the 3-nitro that (3) obtains in the step 2-2-azidocarbonyl methyl benzoate and the trimethyl carbinol carry out rearrangement reaction and obtain 3-nitro-2-t-butoxycarbonyl amino methyl benzoate (formula II) chloroformic solution;
Particularly, the azido reaction of step (2) in described this Curtius reaction, described phase-transfer catalyst is quaternary amine or crown ether, described quaternary ammonium salt comprises Tetrabutyl amonium bromide, benzyltriethylammoinium chloride; Crown ether comprise 15-hat (ether)-5,18-hat (ether)-6, bicyclohexane also-18-is preced with (ether)-6.
Further, one kettle way prepares the method for candesartan Cilexetil intermediate 2-(substituted-phenyl) methylamino--3-nitrobenzene methyl (formula I), may further comprise the steps:
(1) under the existence of dimethyl formamide, 3-nitro-2-carboxyl methyl benzoate and sulfur oxychloride reaction, the reaction solution that obtains is directly used in next step;
(2) add chloroform in the reaction solution that obtains in the step 1, in the presence of phase-transfer catalyst and sodium azide aqueous solution carry out the chloroformic solution that azido reaction obtains 3-nitro-2-azidocarbonyl methyl benzoate;
The chloroformic solution of the 3-nitro that (3) obtains in the step 2-2-azidocarbonyl methyl benzoate and the trimethyl carbinol carry out rearrangement reaction and obtain 3-nitro-2-t-butoxycarbonyl amino methyl benzoate (formula II) chloroformic solution;
(4) take 3-nitro-2-carboxyl methyl benzoate as initial main raw material, make 3-nitro-2-t-butoxycarbonyl amino methyl benzoate (formula II) chloroformic solution through Curtius reaction one kettle way;
(5) in the presence of phase-transfer catalyst and alkali, this 3-nitro-2-t-butoxycarbonyl amino methyl benzoate (formula II) chloroformic solution and 4-Bromomethyl Substituted benzene (formula III) carry out alkylation reaction and obtain 2-(tertbutyloxycarbonyl (substituted-phenyl) methyl) amino-3-nitrobenzene methyl (formula IV);
The tertbutyloxycarbonyl protecting group of (6) sloughing 2-(tertbutyloxycarbonyl (substituted-phenyl) methyl) amino-3-nitrobenzene methyl (formula IV) obtains 2-(substituted-phenyl) methylamino--3-nitrobenzene methyl (formula I);
Wherein, Y is bromine or 2-cyano-phenyl.
The present invention adopts one kettle way, carried out continuously to the reaction process of target product 2-(substituted-phenyl) methylamino--3-nitrobenzene methyl by 3-nitro-2-carboxyl methyl benzoate, do not need to extract purifying, labour intensity reduces, and operating environment is improved, reduced environmental pollution, reduce the loss of raw material and product, greatly reduced industrial production cost, improved yield.
Embodiment
The present invention is described further below in conjunction with specific embodiment, but protection scope of the present invention is not limited in this:
Example 1. preparation 2-[[(2 '-cyanobiphenyl bases)-and the 4-yl] methyl] amino-3-nitrobenzene methyl
In the 1000ml there-necked flask, add 3-nitro-2-carboxyl methyl benzoate 90g, dimethyl formamide (DMF) 150ml, water-bath drips sulfur oxychloride 70g, drips complete stirring at room 3h, adds chloroform 250ml, and Tetrabutyl amonium bromide 4g stirs molten clear.T＜0 ℃ drips first the NaN of 400g10%
3The aqueous solution, drip again 20% NaOH solution to neutral, t＜20 ℃ layered, 50ml chloroform extraction water layer.Add the 100ml trimethyl carbinol in the organic layer, slowly heat up, 65-70 ℃ of backflow 2h is chilled to t＜30 ℃, adds the 400ml water washing, standing demix, and 100ml chloroform extraction water layer merges organic layer.Add in the organic layer 4-brooethyl-2 '-cyanobiphenyl 76.2g, Tetrabutyl amonium bromide 4g, stirs molten clear, the NaOH 60g of t＜10 ℃ dropping 30%, 25-30 ℃ of stirring reaction after reaction finishes, adds water 400ml washing, standing demix, 100ml chloroform extraction water layer merges organic layer.The evaporated under reduced pressure chloroform adds methyl alcohol 500ml and stirs molten clearly, slowly adds 31%HCl 100ml, and 50～55 ℃ are stirred 2h, and t＜30 ℃ drip ammonia/water (50/100ml), and 0～5 ℃ is stirred 2h, filters the ice methanol wash filter cake of 200ml 50%.60 ℃ of constant pressure and dries.Yellow powdery crystallization, 92.9g, yield 62%, mp126～130.5 ℃.
Example 2. preparation 2-[[(2 '-cyanobiphenyl bases)-and the 4-yl] methyl] amino-3-nitrobenzene methyl
In the 1000ml there-necked flask, add 3-nitro-2-carboxyl methyl benzoate 90g, dimethyl formamide (DMF) 150ml, water-bath drips sulfur oxychloride 70g, drips complete stirring at room 3h, adds chloroform 250ml, and 4g 15-is preced with (ether)-5, stirs molten clear.T＜0 ℃ drips first the NaN of 400g10%
3The aqueous solution, drip again 20% NaOH solution to neutral, t＜20 ℃ layered, 50ml chloroform extraction water layer.Add the 100ml trimethyl carbinol in the organic layer, slowly heat up, 65-70 ℃ of backflow 2h is chilled to t＜30 ℃, adds the 400ml water washing, standing demix, and 100ml chloroform extraction water layer merges organic layer.Add in the organic layer 4-brooethyl-2 '-cyanobiphenyl 76.2g, Tetrabutyl amonium bromide 4g, stirs molten clear, the NaOH 60g of t＜10 ℃ dropping 30%, 25-30 ℃ of stirring reaction after reaction finishes, adds water 400ml washing, standing demix, 100ml chloroform extraction water layer merges organic layer.The evaporated under reduced pressure chloroform adds ethyl acetate 500ml and stirs molten clearly, slowly adds 31% hydrochloric acid 100ml, and 50～55 ℃ are stirred 2h, and t＜30 ℃ drip ammonia/water (50/100ml), and 0～5 ℃ is stirred 2h, filters the ice methanol wash filter cake of 200ml 50%.60 ℃ of constant pressure and dries.Yellow powdery crystallization, 95.9g, yield 64%, mp126～130.5 ℃.
Example 3. preparation 2-(4 '-bromophenyl) methylamino-3-nitrobenzene methyls
In the 1000ml there-necked flask, add 3-nitro-2-carboxyl methyl benzoate 90g, DMF 150ml, water-bath drips sulfur oxychloride 70g, drips complete stirring at room 3h, adds chloroform 250ml, and Tetrabutyl amonium bromide 4g stirs molten clear.T＜0 ℃ drips first the NaN of 400g10%
3The aqueous solution, drip again 20% NaOH solution to neutral, drip t＜20 ℃ layering, 50ml chloroform extraction water layer.Organic layer is used 400ml water washing once (t＜20 ℃) again.The organic layer anhydrous magnesium sulfate drying, the elimination siccative adds the 100ml trimethyl carbinol, slowly heats up 65-70 ℃ of backflow 2h.Be chilled to t＜30 ℃, add the 400ml water washing, standing demix, 100ml chloroform extraction water layer merges organic layer.Adding is to bromine bromobenzyl 70g, and Tetrabutyl amonium bromide 4g stirs molten clearly, and t＜10 ℃ drip 30% NaOH60g, and 25-30 ℃ of stirring reaction adds entry 400ml washing, standing demix, and 100ml chloroform extraction water layer merges organic layer.The evaporated under reduced pressure chloroform adds methyl alcohol 500ml and stirs molten clearly, slowly adds 31%HCl100ml, and 50～55 ℃ are stirred 2h, and t＜30 ℃ drip ammonia/water (50/100ml).0～5 ℃ is stirred 2h, filters 200ml50% ice methanol wash filter cake.60 ℃ of constant pressure and dries.Get yellow powdery crystallization, 87.6g, yield 60%.mp108～112℃。
Example 4. preparation 2-(4 '-bromophenyl) methylamino-3-nitrobenzene methyls
In the 1000ml there-necked flask, add 3-nitro-2-carboxyl methyl benzoate 90g, DMF 150ml, water-bath drips sulfur oxychloride 70g, drips complete stirring at room 3h, adds chloroform 250ml, and benzyltriethylammoinium chloride 4g stirs molten clear.T＜0 ℃ drips first the NaN of 400g10%
3The aqueous solution, drip again 20% NaOH solution to neutral, drip t＜20 ℃ layering, 50ml chloroform extraction water layer.Organic layer is used 400ml water washing once (t＜20 ℃) again.The organic layer anhydrous magnesium sulfate drying, the elimination siccative adds the 100ml trimethyl carbinol, slowly heats up 65-70 ℃ of backflow 2h.Be chilled to t＜30 ℃, add the 400ml water washing, standing demix, 100ml chloroform extraction water layer merges organic layer.Adding is to bromine bromobenzyl 70g, and Tetrabutyl amonium bromide 4g stirs molten clearly, and t＜10 ℃ drip 30% NaOH60g, and 25-30 ℃ of stirring reaction adds entry 400ml washing, standing demix, and 100ml chloroform extraction water layer merges organic layer.The evaporated under reduced pressure chloroform adds isopropyl acetate 500ml and stirs molten clearly, slowly adds Hydrogen bromide 100ml, and 50～55 ℃ are stirred 2h, and t＜30 ℃ drip ammonia/water (50/100ml).0～5 ℃ is stirred 2h, filters 200ml50% ice methanol wash filter cake.60 ℃ of constant pressure and dries.Get yellow powdery crystallization, 87.6g, yield 60%.mp108～112℃。
Claims (9)
1. one kettle way prepares the method for candesartan Cilexetil intermediate 2-(substituted-phenyl) methylamino--3-nitrobenzene methyl (formula I), may further comprise the steps:
(1) take 3-nitro-2-carboxyl methyl benzoate as initial main raw material, makes 3-nitro-2-t-butoxycarbonyl amino methyl benzoate (formula II) chloroformic solution through Curtius reaction one kettle way;
(2) in the presence of phase-transfer catalyst and alkali, this 3-nitro-2-t-butoxycarbonyl amino methyl benzoate (formula II) chloroformic solution and 4-Bromomethyl Substituted benzene (formula III) carry out alkylation reaction and obtain 2-(tertbutyloxycarbonyl (substituted-phenyl) methyl) amino-3-nitrobenzene methyl (formula IV);
The tertbutyloxycarbonyl protecting group of (3) sloughing 2-(tertbutyloxycarbonyl (substituted-phenyl) methyl) amino-3-nitrobenzene methyl (formula IV) obtains 2-(substituted-phenyl) methylamino--3-nitrobenzene methyl (formula I);
Wherein, Y is bromine or 2-cyano-phenyl, and the phase-transfer catalyst in the described step (2) is quaternary ammonium salt or crown ether; Described alkali is sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood, sodium bicarbonate, saleratus.
2. method according to claim 1 is characterized in that preparing 2-(4-bromophenyl) methylamino--3-nitrobenzene methyl.
3. method according to claim 1 is characterized in that preparing 2-[[(2 '-cyanobiphenyl base-4-yl) methyl] amino]-the 3-nitrobenzene methyl.
4. method according to claim 1, it is characterized in that the quaternary ammonium salt in the step (2) comprises Tetrabutyl amonium bromide, benzyltriethylammoinium chloride, crown ether comprise 15-hat (ether)-5,18-hat (ether)-6, bicyclohexane also-18-is preced with (ether)-6.
5. method according to claim 1 is characterized in that the deprotection reaction in the step (3) is to slough the tertbutyloxycarbonyl protecting group with haloid acid in alcohol, ester or their mixtures.
6. method according to claim 5 is characterized in that the described alcohol of deprotection reaction in the step (3) is methyl alcohol, and ethanol, described ester are ethyl acetate, and isopropyl acetate, described haloid acid are hydrochloric acid or Hydrogen bromide.
7. method according to claim 1 is characterized in that the Curtius reaction one kettle way of step (1) may further comprise the steps:
(1) under the existence of dimethyl formamide, 3-nitro-2-carboxyl methyl benzoate and sulfur oxychloride reaction, the reaction solution that obtains is directly used in next step;
(2) add chloroform in the reaction solution that obtains in the step (1), in the presence of phase-transfer catalyst and sodium azide aqueous solution carry out the chloroformic solution that azido reaction obtains 3-nitro-2-azidocarbonyl methyl benzoate;
The chloroformic solution of the 3-nitro that (3) obtains in the step (2)-2-azidocarbonyl methyl benzoate and the trimethyl carbinol carry out rearrangement reaction and obtain 3-nitro-2-t-butoxycarbonyl amino methyl benzoate (formula II) chloroformic solution.
8. method according to claim 7, the phase-transfer catalyst that it is characterized in that described step (2) be Tetrabutyl amonium bromide, 15-hat (ether)-5,18-hat (ether)-6, bicyclohexane also-18-is preced with (ether)-6.
9. one kettle way prepares the method for candesartan Cilexetil intermediate 2-(substituted-phenyl) methylamino--3-nitrobenzene methyl (formula I), may further comprise the steps:
(1) under the existence of dimethyl formamide, 3-nitro-2-carboxyl methyl benzoate and sulfur oxychloride reaction, the reaction solution that obtains is directly used in next step;
(2) add chloroform in the reaction solution that obtains in the step (1), in the presence of phase-transfer catalyst and sodium azide aqueous solution carry out the chloroformic solution that azido reaction obtains 3-nitro-2-azidocarbonyl methyl benzoate;
The chloroformic solution of the 3-nitro that (3) obtains in the step (2)-2-azidocarbonyl methyl benzoate and the trimethyl carbinol carry out rearrangement reaction and obtain 3-nitro-2-t-butoxycarbonyl amino methyl benzoate (formula II) chloroformic solution;
(4) take 3-nitro-2-carboxyl methyl benzoate as initial main raw material, make 3-nitro-2-t-butoxycarbonyl amino methyl benzoate (formula II) chloroformic solution through Curtius reaction one kettle way;
(5) in the presence of phase-transfer catalyst and alkali, this 3-nitro-2-t-butoxycarbonyl amino methyl benzoate (formula II) chloroformic solution and 4-Bromomethyl Substituted benzene (formula III) carry out alkylation reaction and obtain 2-(tertbutyloxycarbonyl (substituted-phenyl) methyl) amino-3-nitrobenzene methyl (formula IV);
The tertbutyloxycarbonyl protecting group of (6) sloughing 2-(tertbutyloxycarbonyl (substituted-phenyl) methyl) amino-3-nitrobenzene methyl (formula IV) obtains 2-(substituted-phenyl) methylamino--3-nitrobenzene methyl (formula I);
Wherein, Y is bromine or 2-cyano-phenyl, and the phase-transfer catalyst in the described step (5) is quaternary ammonium salt or crown ether; Described alkali is sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood, sodium bicarbonate, saleratus.
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| CN102911128A (en) * | 2012-09-25 | 2013-02-06 | 苏州天绿生物制药有限公司 | Synthetic method of valsartan |
| EP3312174B1 (en) * | 2015-06-05 | 2019-12-18 | Zhejiang Huahai Pharmaceutical Co., Ltd | Method for preparing trityl candesartan |
| WO2020140193A1 (en) * | 2019-01-02 | 2020-07-09 | 临海市华南化工有限公司 | Synthesis method for candesartan cilexetil intermediate |
| CN113929597A (en) * | 2020-06-29 | 2022-01-14 | 临海市华南化工有限公司 | Method for synthesizing candesartan cilexetil intermediate |
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