CN1425654A - Process for preparing 2-alkoxybenzimidazole compound - Google Patents

Process for preparing 2-alkoxybenzimidazole compound Download PDF

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CN1425654A
CN1425654A CN03112622A CN03112622A CN1425654A CN 1425654 A CN1425654 A CN 1425654A CN 03112622 A CN03112622 A CN 03112622A CN 03112622 A CN03112622 A CN 03112622A CN 1425654 A CN1425654 A CN 1425654A
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methyl
group
biphenyl
benzoglyoxaline
tetrazole
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苏国强
郭涤亮
刘宇
朱兰
边军
朱崇泉
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Jiangsu Provincial Institute of Materia Medica Co Ltd
Disha Pharmaceutical Group Co Ltd
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Jiangsu Provincial Institute of Materia Medica Co Ltd
Disha Pharmaceutical Group Co Ltd
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    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
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  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

The present invention relates to the preparation process of 2-alkoxybenzimidazole compound. The present invention features that through the dewatering condensation of carbonyl group inside carbamate molecule and ortho amino group, 2-alkoxybenzimidazole compound is prepared. This kinds of compounds includes candixatan as antihypertensive and candixatan ester as the precursor medicine of candixatan.

Description

A kind of preparation method of 2-alkoxyl group benzo glyoxaline compound
Technical field
The present invention relates to a kind of preparation method of 2-alkoxyl group benzo glyoxaline compound, this compounds has very strong biological activity, particularly 2-oxyethyl group-1-[[2 '-(1H-tetrazole-5-yl) biphenyl-4-yl] methyl] benzoglyoxaline-7-carboxylic acid 1-(hexamethylene oxygen methanoyl) ethyl ester (Candesartan prodrug) is present clinical application one of the most long lasting antihypertensive drug.
Background technology
Candesartan is a kind of non-peptide class angiotensin II receptor antagonists, because of its specificity and selectivity that has increased the recycle system and organized the nervous plain II receptor level blocking-up of medium vessels, have than the more superior characteristics of angiotensin-converting enzyme (ACE) inhibitor, rate of side effects is littler.
The common preparation method of 2-alkoxyl group benzo glyoxaline compound makes carbonylation agent condensations such as O-Phenylene Diamine compounds and orthocarbonic ester.
Summary of the invention
The object of the invention provides a kind of preparation method of 2-alkoxyl group benzo glyoxaline compound.
Purpose of the present invention can reach by following measure:
Preparation method of the present invention makes 2-alkoxyl group benzo glyoxaline compound by the amino dehydrating condensation of intramolecularly carboxylamine ester carbonyl group and ortho position, sees reaction formula II. Wherein R is alkyl and substituted alkyl such as methyl, ethyl, the tertiary butyl, benzyl etc. among the reaction formula II; R 1For the substituting group of any position of phenyl ring, can be alkyl or halogen substituted alkyl such as methyl or halogen substituent methyl, carboxyl or its ester group and amide group, aldehyde radical or acetal radical, ketone group or ketal group etc.; R 2Be alkyl, aromatic alkyl such as methyl, ethyl, Biphenylmethyl or substituted biphenyl methyl etc., wherein R ' is the tetrazole base of cyano group, tetrazole base or protection in the biphenyl substituting group.
Figure A0311262200051
For specific compound, radicals R 2Must be synthetic earlier, otherwise may produce imidazoles 1 or 3 mixtures that replace because of the change of imidazoles nitrogen proton, see the reaction formula III.So just make some compounds
Figure A0311262200052
Synthetic step preface more, as being raw material Synthetic 2-oxyethyl group-1-[[(2 '-cyano group with 3-nitro-2-nitrine acyl group methyl benzoate) biphenyl-4-yl] methyl] benzoglyoxaline-7-carboxylate methyl ester (Candesartan intermediate) has the reaction of five steps, sees reaction formula IV.
Figure A0311262200053
By the inventive method, be synthetic this intermediate of raw material with 3-nitro-2-nitrine acyl group methyl benzoate equally, then reaction had only for four steps.The present invention has avoided usual method deaminize manthanoate, re-uses carbonylation agents such as tetraethyl orthocarbonate, makes Curtius rearrangement product carbamate be fully used, and sees reaction formula V.
Except that Curtius resets, amino formate compounds can also make with the chloro-formic ester reaction by amino, as 2-oxyethyl group-7-methyl isophthalic acid-[[(2 '-cyano group) biphenyl-4-yl] methyl] benzoglyoxaline, see reaction formula VI, 7 methyl of this compound can advance-go on foot to make Candesartan after being oxidized to carboxylic acid.
When the present invention can also pass through the reduction nitro, the amino of generation and the synthetic step preface of ortho position urethane ester carbonyl group dehydrating condensation generation 2-oxyethyl group benzo glyoxaline compound are further reduced, reaction just can be synthesized Candesartan as being starting raw material with the 3-nitrophthalic acid through 7 steps, sees reaction formula VII.
The present invention has following advantage compared to existing technology:
The present invention makes 2-alkoxyl group benzo glyoxaline compound by the amino dehydrating condensation of intramolecularly carboxylamine ester carbonyl group and ortho position, avoided usual method deaminize manthanoate, re-use carbonylation agents such as tetraethyl orthocarbonate, reduced raw materials consumption, shorten operational path.
Adopt the 2-alkoxyl group benzo glyoxaline compound of the inventive method preparation, comprise following compound, but it can not be used to limit the scope of the invention:
A) biphenyl-4-yl 2-oxyethyl group-1-[[(2 '-cyano group)] methyl] benzoglyoxaline-7-carboxylic acid.
B) biphenyl-4-yl 2-oxyethyl group-1-[[(2 '-cyano group)] methyl] benzoglyoxaline-7-carboxylate methyl ester.
C) biphenyl-4-yl 2-oxyethyl group-1-[[(2 '-cyano group)] methyl] benzoglyoxaline-7-carboxylic acid, ethyl ester.
D) biphenyl-4-yl 2-oxyethyl group-1-[[(2 '-cyano group)] methyl] benzoglyoxaline-7-carboxylic acid 1-(hexamethylene oxygen methanoyl) ethyl ester.
E) 2-oxyethyl group-1-[[2 '-(1H-tetrazole-5-yl) biphenyl-4-yl] methyl] benzoglyoxaline-7-carboxylic acid (Candesartan).
F) 2-oxyethyl group-1-[[2 '-(1H-tetrazole-5-yl) biphenyl-4-yl] methyl] benzoglyoxaline-7-carboxylic acid 1-(hexamethylene oxygen methanoyl) ethyl ester.
G) 2-oxyethyl group-1-[[2 '-(1-trityl-tetrazole-5-yl) biphenyl-4-yl] methyl] benzoglyoxaline-7-carboxylic acid.
H) 2-oxyethyl group-1-[[2 '-(1-trityl-tetrazole-5-yl) biphenyl-4-yl] methyl] benzoglyoxaline-7-carboxylate methyl ester.
I) 2-oxyethyl group-1-[[2 '-(1-trityl-tetrazole-5-yl) biphenyl-4-yl] methyl] benzoglyoxaline-7-carboxylic acid, ethyl ester.
G) 2-oxyethyl group-1-[[2 '-(1-trityl-tetrazole-5-yl) biphenyl-4-yl] methyl] benzoglyoxaline-7-carboxylic acid 1-(hexamethylene oxygen methanoyl) ethyl ester.
Embodiment
Reference example 1
3-nitro-2-carboxyl methyl benzoate
Methyl alcohol 1500ml, 3-nitrophthalic acid 400g stirs and feeds hydrogen chloride gas (sodium-chlor 200g down, vitriol oil 250ml preparation, vitriol oil drying), heating reflux reaction 6h, reaction finishes, pour in the 2000g frozen water, place crystallization, filter, washing, get crystallization 337g, mp156-159 ℃, yield 79%.
3-nitro-2-acid azide methyl benzoate
Benzene 300ml, 3-nitro-2-carboxyl methyl benzoate 225g (1mol), sulfur oxychloride 160ml, back flow reaction 2h boils off solvent to doing, and it is standby that cooling adds acetone 500ml.
Sodium azide 100g, water 850ml, acetone 350ml, the ice bath cooling drips above-mentioned reserve liquid down, finishes, and continues reaction 1h, adds frozen water 300ml, filter, washing, room temperature vacuum-drying gets product 218g, yield 87%.
Embodiment 1
3-nitro-2-ethoxycarbonyl Methyl anthranilate
3-nitro-2-acid azide methyl benzoate 100g (0.4mol); dehydrated alcohol 400ml; slowly be heated to back flow reaction 1h; boil off solvent to doing, add methyl alcohol 100ml, crystallisation by cooling; filter; methanol wash gets 3-nitro-2-ethoxycarbonyl Methyl anthranilate 92g, yield 86%, 113～115mp ℃.
3-nitro-2-(N-2 '-cyanobiphenyl methyl-ethoxycarbonyl amino) methyl benzoate
3-nitro-2-ethoxycarbonyl Methyl anthranilate 107g (0.4mol), DMF300ml, 2 '-cyano group-4-bromomethylbiphenyl 110g (0.4mol), salt of wormwood 55g at 60～70 ℃ of reaction 6h, pours in the 1500g frozen water, filter, get 3-nitro-2-(N-2 '-cyanobiphenyl methyl-ethoxycarbonyl amino) methyl benzoate 165g with recrystallizing methanol, mp137～141 ℃, yield 90%.
3-amino-2-(N-2 '-cyanobiphenyl methyl-ethoxycarbonyl amino) methyl benzoate
Anhydrous tetrahydro furan 350ml, sodium borohydride 7.4g (0.2mol), the ice bath cooling adds sulphur powder 16g (0.5mol) down, at 0 ℃ of stirring reaction 1h, slowly drip the anhydrous tetrahydrofuran solution of 3-nitro-2-(N-2 '-cyanobiphenyl methyl-ethoxycarbonyl amino) methyl benzoate 45.9g (0.1mol), equality of temperature reaction 6h, boil off solvent, handle with frozen water, recrystallizing methanol gets 3-amino-2-(N-2 '-cyanobiphenyl methyl-ethoxycarbonyl amino) methyl benzoate 28g, yield 65%, mp115～120 ℃.
1-[(2 '-cyanobiphenyl-4-yl) methyl]-2-oxyethyl group benzo imidazoles-7-carboxylate methyl ester
3-amino-2-(N-2 '-cyanobiphenyl methyl-ethoxycarbonyl amino) methyl benzoate 42.9g (0.1mol), Glacial acetic acid 150ml, at 105 ℃ of stirring reaction 3h, boil off solvent under the decompression, ethyl acetate/chloroform recrystallization gets 1-[(2 '-cyanobiphenyl-4-yl) methyl]-2-oxyethyl group benzo imidazoles-7-carboxylate methyl ester 34.5g, yield 84%, mp168-170 ℃ (169～170 ℃ in document).
Embodiment 2
3-methyl-2-ethoxycarbonyl amino-oil of mirbane
3-methyl-2-amino-oil of mirbane (by the preparation of " organic synthesis " method) 30.4g (0.2mol), methylene dichloride 300ml, Vinyl chloroformate 33g (0.3mol), heating reflux reaction 6h, boil off solvent, recrystallizing methanol gets 3-methyl-2-ethoxycarbonyl amino-oil of mirbane 42.5g, yield 95%, mp129～131 ℃.
3-methyl-2-[N-(2 '-cyanobiphenyl-4-yl) methyl] ethoxycarbonyl amino-oil of mirbane
3-methyl-2-ethoxycarbonyl amino-oil of mirbane 22.4g (0.1mol), DMF150ml, 2 '-cyano group-4-bromomethylbiphenyl 27.5g (0.1mol), salt of wormwood 14g at 60～70 ℃ of reaction 6h, pours in the 500g frozen water, filter, get 3-methyl-2-[N-(2 '-cyanobiphenyl-4-yl) methyl with recrystallizing methanol] ethoxycarbonyl amino-oil of mirbane 35.6g, mp137～139 ℃, yield 86%.
7-methyl-2-oxyethyl group-1-[2 '-(cyanobiphenyl-4-yl) methyl] benzoglyoxaline
3-methyl-2-[N-(2 '-cyanobiphenyl-4-yl) methyl] ethoxycarbonyl amino-oil of mirbane 50g (0.13mol), Glacial acetic acid 200ml, at 105 ℃ of stirring reaction 3h, boil off solvent under the decompression, ethyl acetate/chloroform recrystallization gets 7-methyl-2-oxyethyl group-1-[2 '-(cyanobiphenyl-4-yl) methyl] benzoglyoxaline 41g, yield 86%.
Embodiment 3
3-nitro-2-[N-[2 '-(1H-tetrazole-5-yl)] the ethoxycarbonyl Methyl anthranilate
3-nitro-2-(N-2 '-cyanobiphenyl methyl-ethoxycarbonyl amino) methyl benzoate 46g (0.1mol), dimethylbenzene 500ml, nitrine tributyl tin 100g is at 125 ℃ of reaction 18h, boil off solvent under the decompression, cold 50% methyl alcohol is handled, and filters, behind stirring at room 2h, filter, ethyl acetate/chloroform recrystallization gets 3-nitro-2-[N-[2 '-(1H-tetrazole-5-yl)] ethoxycarbonyl Methyl anthranilate 34g, mp142～144 ℃, yield 68%.
1-[2 '-[(1H-tetrazole-5-yl) biphenyl-4-yl] methyl]-2-oxyethyl group benzo imidazoles-7-carboxylate methyl ester
3-nitro-2-[N-[2 '-(1H-tetrazole-5-yl)] ethoxycarbonyl Methyl anthranilate 50g (0.1mol), Glacial acetic acid 300ml, 5% palladium carbon 4g, 5atm hydrogenation, concentrating under reduced pressure is handled with frozen water, filter, ethyl acetate/chloroform recrystallization gets 1-[2 '-[(1H-tetrazole-5-yl) biphenyl-4-yl] methyl]-2-oxyethyl group benzo imidazoles-7-carboxylate methyl ester 38g, yield 84%, mp191～193 ℃ (document: mp191～193 ℃).
Get Candesartan by the usual method hydrolysis, yield 88%, mp180～182 ℃ (document mp181～182 ℃).

Claims (2)

1. the preparation method of a 2-alkoxyl group benzo glyoxaline compound is characterized in that making 2-alkoxyl group benzo glyoxaline compound by the amino dehydrating condensation of intramolecularly carboxylamine ester carbonyl group and ortho position;
R is alkyl and substituted alkyl such as methyl, ethyl, the tertiary butyl, benzyl among the formula II; R 1For the substituting group of any position of phenyl ring, can be alkyl or halogen substituted alkyl such as methyl or halogen substituent methyl, carboxyl or its ester group and amide group, aldehyde radical or acetal radical, ketone group or ketal group; R 2Be alkyl, aromatic alkyl such as methyl, ethyl, Biphenylmethyl or substituted biphenyl methyl, wherein in the biphenyl substituting group R ' be cyano group, The tetrazole base of tetrazole base or protection.
2. the prepared 2-alkoxyl group of preparation method according to claim 1 benzo glyoxaline compound comprises:
A) biphenyl-4-yl 2-oxyethyl group-1-[[(2 '-cyano group)] methyl] benzoglyoxaline-7-carboxylic acid;
B) biphenyl-4-yl 2-oxyethyl group-1-[[(2 '-cyano group)] methyl] benzoglyoxaline-7-carboxylate methyl ester;
C) biphenyl-4-yl 2-oxyethyl group-1-[[(2 '-cyano group)] methyl] benzoglyoxaline-7-carboxylic acid, ethyl ester;
D) biphenyl-4-yl 2-oxyethyl group-1-[[(2 '-cyano group)] methyl] benzoglyoxaline-7-carboxylic acid 1-(hexamethylene oxygen methanoyl) ethyl ester;
E) 2-oxyethyl group-1-[[2 '-(1H-tetrazole-5-yl) biphenyl-4-yl] methyl] benzoglyoxaline-7-carboxylic acid (Candesartan);
F) 2-oxyethyl group-1-[[2 '-(1H-tetrazole-5-yl) biphenyl-4-yl] methyl] benzoglyoxaline-7-carboxylic acid 1-(hexamethylene oxygen methanoyl) ethyl ester;
G) 2-oxyethyl group-1-[[2 '-(1-trityl-tetrazole-5-yl) biphenyl-4-yl] methyl] benzoglyoxaline-7-carboxylic acid;
H) 2-oxyethyl group-1-[[2 '-(1-trityl-tetrazole-5-yl) biphenyl-4-yl] methyl] benzoglyoxaline-7-carboxylate methyl ester;
I) 2-oxyethyl group-1-[[2 '-(1-trityl-tetrazole-5-yl) biphenyl-4-yl] methyl] benzoglyoxaline-7-carboxylic acid, ethyl ester;
G) 2-oxyethyl group-1-[[2 '-(1-trityl-tetrazole-5-yl) biphenyl-4-yl] methyl] benzoglyoxaline-7-carboxylic acid 1-(hexamethylene oxygen methanoyl) ethyl ester.
CN03112622A 2003-01-07 2003-01-07 Process for preparing 2-alkoxybenzimidazole compound Pending CN1425654A (en)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008129077A2 (en) * 2007-04-24 2008-10-30 Krka, D.D. Novo Mesto Crystalline 1-(cyclohexyloxycarbonyloxy) ethyl 1-((2'-cyanobiphenyl-4-yl)methyl)-2-ethoxy-1h-benzo[d]imidazole-7-carboxylate and a process for its preparation
CN102206186A (en) * 2011-04-18 2011-10-05 张家港市信谊化工有限公司 Method for preparing candesartan ring compound
CN102382108A (en) * 2011-08-29 2012-03-21 南开大学 Tetrazole compounds containing 1,2,3-bismuththiol methylene, preparation methods for same and application thereof
CN101648918B (en) * 2008-08-15 2013-01-09 联化科技股份有限公司 Intermediate compound of candesartan cilexetil and synthesis method thereof
CN102887890A (en) * 2012-11-06 2013-01-23 峨眉山天梁星制药有限公司 Synthesis method of candesartan cilexetil
CN107709313A (en) * 2015-06-05 2018-02-16 浙江华海药业股份有限公司 A kind of 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

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008129077A2 (en) * 2007-04-24 2008-10-30 Krka, D.D. Novo Mesto Crystalline 1-(cyclohexyloxycarbonyloxy) ethyl 1-((2'-cyanobiphenyl-4-yl)methyl)-2-ethoxy-1h-benzo[d]imidazole-7-carboxylate and a process for its preparation
WO2008129077A3 (en) * 2007-04-24 2009-01-29 Krka D D Novo Mesto Crystalline 1-(cyclohexyloxycarbonyloxy) ethyl 1-((2'-cyanobiphenyl-4-yl)methyl)-2-ethoxy-1h-benzo[d]imidazole-7-carboxylate and a process for its preparation
CN101648918B (en) * 2008-08-15 2013-01-09 联化科技股份有限公司 Intermediate compound of candesartan cilexetil and synthesis method thereof
CN102206186A (en) * 2011-04-18 2011-10-05 张家港市信谊化工有限公司 Method for preparing candesartan ring compound
CN102382108A (en) * 2011-08-29 2012-03-21 南开大学 Tetrazole compounds containing 1,2,3-bismuththiol methylene, preparation methods for same and application thereof
CN102382108B (en) * 2011-08-29 2014-11-19 南开大学 Tetrazole compounds containing 1,2,3-bismuththiol methylene, preparation methods for same and application thereof
CN102887890B (en) * 2012-11-06 2014-09-03 峨眉山天梁星制药有限公司 Synthesis method of candesartan cilexetil
CN102887890A (en) * 2012-11-06 2013-01-23 峨眉山天梁星制药有限公司 Synthesis method of candesartan cilexetil
CN107709313A (en) * 2015-06-05 2018-02-16 浙江华海药业股份有限公司 A kind of method for preparing trityl candesartan
CN107709313B (en) * 2015-06-05 2020-10-23 浙江华海药业股份有限公司 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
CN113544113A (en) * 2019-01-02 2021-10-22 临海市华南化工有限公司 Synthesis method of candesartan cilexetil intermediate
CN113544113B (en) * 2019-01-02 2023-12-26 临海市华南化工有限公司 Synthesis method of candesartan cilexetil intermediate

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