CN102206186A - Method for preparing candesartan ring compound - Google Patents
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- CN102206186A CN102206186A CN2011100956577A CN201110095657A CN102206186A CN 102206186 A CN102206186 A CN 102206186A CN 2011100956577 A CN2011100956577 A CN 2011100956577A CN 201110095657 A CN201110095657 A CN 201110095657A CN 102206186 A CN102206186 A CN 102206186A
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Abstract
The invention relates to a method for preparing a candesartan ring compound, which comprises the following steps: 1) preparing 3-animo-2-ethyl ethoxy formacyl amino benzoate; 2) preparing 2-ethyoxylbenzimidazole-4-ethyl indole carboxylate; and 3) preparing candesartan ring compound, namely 2-ethyoxyl-1-1[[(2-cyanobiphenyl-4-yl) mthyl] benzimidazole]-7-carboxylate. In the invention, a benzimidazole ring is constructed, tetraethyl orthocarbonate is avoided, and intramolecular dehydration construction is realized; and finally alkylation is accomplished, canobromobiphenyl is introduced; and thus, the minimum consumption of canobromobiphenyl is realized and the cost of the candesartan ring compound is minimized.
Description
Technical field
The present invention relates to have the preparation method of an important intermediate of the depressor candesartan Cilexetil of significant curative effect effect, relate to a kind of preparation method of Candesartan cyclocomplex more specifically.
Background technology
Candesartan Cilexetil is a kind of non-peptide class Angiotensin II (Ang II) receptor antagonist pharmaceuticals, and in this class medicine that has gone on the market, curative effect is best, the safest.Which kind of route no matter synthesizing of this medicine be, all relates to the synthetic preparation of Candesartan cyclocomplex.
The Candesartan cyclocomplex, chemical name: 2-oxyethyl group-1-1[[(2-cyanobiphenyl-4-replaces) methyl] benzoglyoxaline]-7-carboxylicesters (methyl esters or ethyl ester).
Structural formula is as follows:
At present, Candesartan cyclocomplex synthetic, common method can reduce three kinds of A, B, C:
A kind of is to be starting raw material with the 3-nitrophthalic acid, through mono-esterification, chloride, azide, rearrangement esterification (trimethyl carbinol ester), hydrocarbonylation (replacement of cyano group bromo biphenyl), hydrolysis, obtain 2-[[(2-cyanobiphenyl-4-yl earlier) methyl] amino]-3-nitrobenzoyl acid esters (methyl esters or ethyl ester), through reduction, cyclization (tetraethyl orthocarbonate makes up the benzoglyoxaline ring), make Candesartan cyclocomplex (methyl esters or ethyl ester) again.
Operational path A is as follows:
Another kind is to be starting raw material with the 3-nitrophthalic acid, through mono-esterification, chloride, azide, rearrangement, hydrolysis, obtain 2-amino-3-nitro-methyl benzoate earlier, then through reduction, cyclization (tetraethyl orthocarbonate makes up the benzoglyoxaline ring), make 2-oxyethyl group benzo imidazoles-4-carboxylate methyl ester, pass through hydrocarbonylation (replacement of cyano group bromo biphenyl) again, make Candesartan cyclocomplex (methyl esters).
Operational path B is as follows:
Also having a kind of is to be starting raw material with the 3-nitrophthalic acid, through mono-esterification (methyl esters), chloride, azide, rearrangement esterification (ethanol ester), hydrocarbonylation (replacement of cyano group bromo biphenyl), reduction, cyclization (intramolecular dehydration makes up the benzoglyoxaline ring), make Candesartan cyclocomplex (methyl esters).
Operational path C is as follows:
The cost of Candesartan cyclocomplex depends primarily on the consuming cost of cyano group bromo biphenyl and tetraethyl orthocarbonate, above-mentioned three operational paths, owing to used cyano group bromo biphenyl and tetraethyl orthocarbonate prematurely, make that their consumption is higher, cause the final cost of Candesartan cyclocomplex high.
Summary of the invention
Technical problem to be solved by this invention is the above-mentioned shortcoming and defect that overcomes existing synthesis technique, and a kind of preparation method of Candesartan cyclocomplex (ethyl ester) of lower production cost is provided, and it is avoided the tetraethyl orthocarbonate final tache and uses the cyano group bromo biphenyl.
The present invention for the solution that problem adopted of the above-mentioned proposition of solution is: the preparation method of Candesartan cyclocomplex is characterized in that including following steps:
1) preparation of 3-amino-2-ethoxycarbonyl subcutin:
Press 3-nitro-2-ethoxycarbonyl subcutin: methyl alcohol: the weight proportion of glacial acetic acid=1: 6～7: 0.5～0.6, getting above-mentioned three materials mixes, ice bath stirs 0～5 ℃ of cooling down, drip the aqueous solution of sodium borohydride, drip 0～5 ℃ of process control temp, dropwise, insulation reaction 3～5 hours, wherein, the compound method of the aqueous solution of described sodium borohydride is: press 3-nitro-2-ethoxycarbonyl subcutin: sodium borohydride: the weight proportion of water=1: 0.15～0.2: 0.6～0.7, get sodium borohydride and water two materials mix, stirring and dissolving obtains the aqueous solution of sodium borohydride, and ice bath 0～5 ℃ of cooling down is standby; Then,
Press 3-nitro-2-ethoxycarbonyl subcutin: water: the weight proportion of methylene dichloride=1: 4～5: 8～10, add entry and methylene dichloride, extracting and demixing removes methylene dichloride under reduced pressure; Then,
Press 3-nitro-2-ethoxycarbonyl subcutin: the weight proportion of methyl alcohol=1: 2～3, add methyl alcohol, crystallisation by cooling, filtration, washing and drying obtain 3-amino-2-ethoxycarbonyl subcutin;
2) preparation of 2-oxyethyl group benzo imidazoles-4-carboxylic acid, ethyl ester:
Press 3-amino-2-ethoxycarbonyl subcutin: the weight proportion of glacial acetic acid=1: 3～5, get above-mentioned two materials and mix, heat temperature raising, 100～110 ℃ of temperature controls reacted 3～5 hours, removed glacial acetic acid under reduced pressure; Then,
Press 3-amino-2-ethoxycarbonyl subcutin: the weight proportion of methyl alcohol=1: 2～3, add methyl alcohol, crystallisation by cooling, filtration, washing and drying obtain 2-oxyethyl group benzo imidazoles-4-carboxylic acid, ethyl ester;
3) preparation of Candesartan cyclocomplex:
Press 2-oxyethyl group benzo imidazoles-4-carboxylic acid, ethyl ester: acetonitrile: cyano group bromo biphenyl: the weight proportion of salt of wormwood=1: 5～6: 1.1～1.2: 0.6～0.8, getting above-mentioned four materials mixes, 55～75 ℃ of controlled temperature, reacted 8～12 hours, cooling, remove by filter salt of wormwood, remove acetonitrile under reduced pressure; Then,
Press 2-oxyethyl group benzo imidazoles-4-carboxylic acid, ethyl ester: the weight proportion of methyl alcohol=1: 3～4, add methyl alcohol, crystallisation by cooling, filtration, washing and drying get the Candesartan cyclocomplex: 2-oxyethyl group-1-1[[(2-cyanobiphenyl-4-replaces) methyl] benzoglyoxaline]-the 7-carboxylic acid, ethyl ester.
Press such scheme, the preparation method of described 3-nitro-2-ethoxycarbonyl subcutin is to include following steps:
1. mono-esterification:
Press the 3-nitrophthalic acid: dehydrated alcohol: the weight proportion of the vitriol oil=1: 4～5: 0.9～1.1, get above-mentioned three materials and mix, 65～80 ℃ of controlled temperature, heating reflux reaction 12～24 hours removes ethanol under reduced pressure; Then
Press the 3-nitrophthalic acid: the weight proportion of chloroform=1: 10～12, add chloroform, stirring, extraction and layering obtain the chloroformic solution of mono-esterification;
2. chloride:
Chloroformic solution with mono-esterification, reflux water-dividing is to complete, then, press 3-nitrophthalic acid: DMF: the weight proportion of sulfur oxychloride=1: 0.04～0.05: 0.5～0.6 adds DMF and sulfur oxychloride, 55～65 ℃ of controlled temperature, reacted 5～8 hours, press the 3-nitrophthalic acid: the weight proportion of chloroform=1: 5～6, steam and remove the part chloroform, obtain the chloroformic solution of acyl chlorides;
3. azide:
Press 3-nitrophthalic acid: DMF: the weight proportion of sodiumazide=1: 0.5～0.6: 0.3～0.4, in the chloroformic solution of acyl chlorides, add DMF and sodiumazide, 25～35 ℃ of controlled temperature reacted 1～3 hour; Then,
Press the 3-nitrophthalic acid: chloroform: the weight proportion of water=1: 5～6: 5～6, add chloroform and water, extracting and demixing obtains the chloroformic solution of acid azide;
4. reset esterification:
Press the 3-nitrophthalic acid: the weight proportion of Sodium sulfate anhydrous.min(99)=1: 2～3, in the chloroformic solution of acid azide, add Sodium sulfate anhydrous.min(99) and carry out drying and dehydrating, filter, obtain filtrate; Then,
Press the 3-nitrophthalic acid: the weight proportion of dehydrated alcohol=1: 3～4, in filtrate, add dehydrated alcohol, heating, 65～75 ℃ of controlled temperature reacted 8～10 hours, steamed and removed chloroform and ethanol; Then,
Press the 3-nitrophthalic acid: the weight proportion of methyl alcohol=1: 2～3, add methyl alcohol, crystallisation by cooling, filtration, washing and drying obtain 3-nitro-2-ethoxycarbonyl subcutin.
The present invention is a starting raw material with the 3-nitrophthalic acid, through mono-esterification (ethyl ester), chloride, azide, rearrangement esterification (ethanol ester), obtains 3-nitro-2-ethoxycarbonyl subcutin earlier; Make 3-amino-2-ethoxycarbonyl subcutin through reduction then; Pass through cyclization (intramolecular dehydration makes up the benzoglyoxaline ring) again, obtain 2-oxyethyl group benzo imidazoles-4-carboxylic acid, ethyl ester; Pass through hydrocarbonylation (replacement of cyano group bromo biphenyl) at last, make Candesartan cyclocomplex (ethyl ester).
Its operational path is as follows:
The present invention makes up the benzoglyoxaline ring, avoids tetraethyl orthocarbonate, realizes that intramolecular dehydration makes up; Final tache is finished alkylation reaction, introduces the cyano group bromo biphenyl, thus realize the consumption of cyano group bromo biphenyl minimize minimumization of Candesartan cyclocomplex cost.
Embodiment
In order to understand the present invention better, further set forth content of the present invention below in conjunction with the test example, but content of the present invention not only is confined to the following examples.
Embodiment 1:
The preparation of step 1) 3-nitro-2-ethoxycarbonyl subcutin: 1. mono-esterification: get dehydrated alcohol 400g, 3-nitrophthalic acid 90g and vitriol oil 90g mix, 70 ℃ of controlled temperature, heating reflux reaction 12 hours, remove ethanol under reduced pressure, add chloroform 1000g, stirring, extraction and layering obtain the chloroformic solution of mono-esterification; 2. chloride: with the chloroformic solution of mono-esterification, reflux water-dividing adds 4g DMF and 45g sulfur oxychloride then to fully, 60 ℃ of controlled temperature, and back flow reaction 5 hours is steamed and is removed chloroform 500g, obtains the chloroformic solution of acyl chlorides; 3. azide: in the chloroformic solution of acyl chlorides, add the DMF of 50g, the sodiumazide of 30g, 25 ℃ of reactions of normal temperature 3 hours add the chloroform of 500g, the water of 500g, extracting and demixing obtains the chloroformic solution of acid azide; 4. reset esterification: the Sodium sulfate anhydrous.min(99) that adds 200g in the chloroformic solution of acid azide carries out drying and dehydrating, filter, filtrate adds the 300g dehydrated alcohol, slowly is heated to backflow, 70 ℃ of controlled temperature, back flow reaction 8 hours, steam and remove chloroform and ethanol, add the methyl alcohol of 250g, crystallisation by cooling, filtration, washing and drying, obtain 3-nitro-2-ethoxycarbonyl subcutin product 81.2g, purity is more than 98%;
Step 2) preparation of 3-amino-2-ethoxycarbonyl subcutin: 3-nitro-2-ethoxycarbonyl subcutin 50g, methyl alcohol 320g, glacial acetic acid 25g, ice bath stirs 0～5 ℃ of cooling down, dropping 8g sodium borohydride mixes the solution of stirring and dissolving gained with 30g water, drip 0～5 ℃ of process control temp, dropwise insulation reaction 5 hours, add entry 200g, methylene dichloride 400g, extracting and demixing removes methylene dichloride under reduced pressure, add methyl alcohol 120g, crystallisation by cooling, filter, washing and dry obtains 3-amino-2-ethoxycarbonyl subcutin 38.6g product, and purity is more than 98%;
The preparation of step 3) 2-oxyethyl group benzo imidazoles-4-carboxylic acid, ethyl ester: get 3-amino-2-ethoxycarbonyl subcutin 50g and glacial acetic acid 200g and mix, heat temperature raising, 105 ℃ of temperature controls, back flow reaction 3 hours, remove glacial acetic acid under reduced pressure, add methyl alcohol 120g, crystallisation by cooling, filtration, washing and drying, get 2-oxyethyl group benzo imidazoles-4-carboxylic acid, ethyl ester product 40.3g, purity is more than 98%.
The preparation of step 4) Candesartan cyclocomplex (ethyl ester): get 2-oxyethyl group benzo imidazoles-4-carboxylic acid, ethyl ester 45g, acetonitrile 240g, cyano group bromo biphenyl 52g, salt of wormwood 30g mixes, 60 ℃ of controlled temperature, back flow reaction 8 hours, cooling removes by filter salt of wormwood, remove acetonitrile under reduced pressure, add methyl alcohol 150g, crystallisation by cooling filters, washing, drying gets Candesartan cyclocomplex (ethyl ester) product 73.8g (2-oxyethyl group-1-1[[(2-cyanobiphenyl-4-replaces) methyl] benzoglyoxaline]-the 7-carboxylic acid, ethyl ester), purity is more than 98%.
Embodiment 2:
The preparation of step 1) 3-nitro-2-ethoxycarbonyl subcutin: 1. mono-esterification: get dehydrated alcohol 1800g, 3-nitrophthalic acid 450g and vitriol oil 485g mix, 70 ℃ of controlled temperature, heating reflux reaction 17 hours, remove ethanol under reduced pressure, add chloroform 4500g, stirring, extraction and layering obtain the chloroformic solution of mono-esterification; 2. chloride: with the chloroformic solution of mono-esterification, reflux water-dividing adds 20g DMF and 250g sulfur oxychloride then to fully, 60 ℃ of controlled temperature, and back flow reaction 5 hours is steamed and is removed chloroform 2600g, obtains the chloroformic solution of acyl chlorides; 3. azide: in the chloroformic solution of acyl chlorides, add the DMF of 260g, the sodiumazide of 150g, 25 ℃ of reactions of normal temperature 3 hours add the chloroform of 2500g, the water of 2600g, extracting and demixing obtains the chloroformic solution of acid azide; 4. reset esterification: the Sodium sulfate anhydrous.min(99) that adds 1000g in the chloroformic solution of acid azide carries out drying and dehydrating, filter, filtrate adds the 1500g dehydrated alcohol, slowly is heated to backflow, 70 ℃ of controlled temperature, back flow reaction 8 hours, steam and remove chloroform and ethanol, add the methyl alcohol of 1000g, crystallisation by cooling, filtration, washing and drying, obtain 3-nitro-2-ethoxycarbonyl subcutin product 405g, purity is more than 98%;
Step 2) preparation of 3-amino-2-ethoxycarbonyl subcutin: 3-nitro-2-ethoxycarbonyl subcutin 250g, methyl alcohol 1650g, glacial acetic acid 140g, ice bath stirs 0～5 ℃ of cooling down, dropping 40g sodium borohydride mixes the solution of stirring and dissolving gained with 160g water, insulation reaction 5 hours adds entry 1200g, methylene dichloride 2200g, extracting and demixing removes methylene dichloride under reduced pressure, adds methyl alcohol 600g, crystallisation by cooling, filter washing, drying, get 3-amino-2-ethoxycarbonyl subcutin 193.6g product, purity is more than 98%;
The preparation of step 3) 2-oxyethyl group benzo imidazoles-4-carboxylic acid, ethyl ester: get 3-amino-2-ethoxycarbonyl subcutin 250g and glacial acetic acid 1000g and mix, heat temperature raising, 105 ℃ of temperature controls, back flow reaction 3 hours, remove glacial acetic acid under reduced pressure, add methyl alcohol 700g, crystallisation by cooling, filtration, washing and drying, get 2-oxyethyl group benzo imidazoles-4-carboxylic acid, ethyl ester product 202g, purity is more than 98%;
The preparation of step 4) Candesartan cyclocomplex (ethyl ester): 2-oxyethyl group benzo imidazoles-4-carboxylic acid, ethyl ester 225g, acetonitrile 1300g, cyano group bromo biphenyl 260g, salt of wormwood 160g mixes, 60 ℃ of controlled temperature, back flow reaction 8 hours, cooling removes by filter salt of wormwood, removes acetonitrile under reduced pressure, add methyl alcohol 700g, crystallisation by cooling filters, washing, drying gets Candesartan cyclocomplex (ethyl ester) product 370g, and purity is more than 98%.
Embodiment 3:
The preparation of step 1) 3-nitro-2-ethoxycarbonyl subcutin: 1. mono-esterification: dehydrated alcohol 40Kg, 3-nitrophthalic acid 9Kg, vitriol oil 9Kg, heating reflux reaction 18 hours, remove ethanol under reduced pressure, add chloroform 100Kg, stirring, extraction, layering obtain the chloroformic solution of mono-esterification; 2. chloride: the chloroformic solution of mono-esterification, reflux water-dividing adds the DMF of 0.3kg to fully, the sulfur oxychloride of 4.5Kg, back flow reaction 5 hours is steamed and is removed chloroform 50Kg, obtains the chloroformic solution of acyl chlorides; 3. azide: the chloroformic solution of acyl chlorides, add the DMF of 5.4Kg, the sodiumazide of 3Kg, normal-temperature reaction 3 hours adds the chloroform of 50Kg, the water of 50Kg, extracting and demixing obtains the chloroformic solution of acid azide; 4. reset esterification: the chloroformic solution of acid azide, the Sodium sulfate anhydrous.min(99) that adds 20Kg carries out drying and dehydrating, filters; the 30Kg dehydrated alcohol that filtrate adds slowly is heated to backflow, back flow reaction 8 hours; steam and remove chloroform and ethanol; the methyl alcohol that adds 25Kg, crystallisation by cooling filters; washing; drying gets 3-nitro-2-ethoxycarbonyl subcutin product 8.1Kg, and purity is more than 98%.
Step 2) preparation of 3-amino-2-ethoxycarbonyl subcutin: 3-nitro-2-ethoxycarbonyl subcutin 5Kg, methyl alcohol 32Kg, glacial acetic acid 2.5Kg, ice bath stirs down, the solution that the sodium borohydride of dropping 0.8Kg and the water of 3Kg are joined, insulation reaction 5 hours adds entry 20Kg, methylene dichloride 40Kg, extracting and demixing removes methylene dichloride under reduced pressure, adds methyl alcohol 12Kg, crystallisation by cooling, filter washing, drying, get 3-amino-2-ethoxycarbonyl subcutin 3.7Kg product, purity is more than 98%.
The preparation of step 3) 2-oxyethyl group benzo imidazoles-4-carboxylic acid, ethyl ester: 3-amino-2-ethoxycarbonyl subcutin 5Kg, glacial acetic acid 20kg, heat temperature raising, 105 ℃ of temperature controls, back flow reaction 3 hours removes glacial acetic acid under reduced pressure, adds methyl alcohol 12Kg, crystallisation by cooling, filter washing, drying, get 2-oxyethyl group benzo imidazoles-4-carboxylic acid, ethyl ester product 4Kg, purity is more than 98%.
The preparation of step 4) Candesartan cyclocomplex (ethyl ester): 2-oxyethyl group benzo imidazoles-4-carboxylic acid, ethyl ester 4.5Kg, acetonitrile 24Kg, cyano group bromo biphenyl 5.2Kg, salt of wormwood 3Kg, temperature rising reflux reaction 8 hours, cooling, remove by filter salt of wormwood, remove acetonitrile under reduced pressure, add methyl alcohol 15Kg, crystallisation by cooling, filter washing, drying, get Candesartan cyclocomplex (ethyl ester) product 7.5Kg, purity is more than 98%.
Claims (2)
1. the preparation method of Candesartan cyclocomplex is characterized in that including following steps:
1) preparation of 3-amino-2-ethoxycarbonyl subcutin:
Press 3-nitro-2-ethoxycarbonyl subcutin: methyl alcohol: the weight proportion of glacial acetic acid=1: 6～7: 0.5～0.6, getting above-mentioned three materials mixes, ice bath stirs 0～5 ℃ of cooling down, drip the aqueous solution of sodium borohydride, drip 0～5 ℃ of process control temp, dropwise, insulation reaction 3～5 hours, wherein, the compound method of the aqueous solution of described sodium borohydride is: press 3-nitro-2-ethoxycarbonyl subcutin: sodium borohydride: the weight proportion of water=1: 0.15～0.2: 0.6～0.7, get sodium borohydride and water two materials mix, stirring and dissolving obtains the aqueous solution of sodium borohydride, and ice bath 0～5 ℃ of cooling down is standby; Then,
Press 3-nitro-2-ethoxycarbonyl subcutin: water: the weight proportion of methylene dichloride=1: 4～5: 8～10, add entry and methylene dichloride, extracting and demixing removes methylene dichloride under reduced pressure; Then,
Press 3-nitro-2-ethoxycarbonyl subcutin: the weight proportion of methyl alcohol=1: 2～3, add methyl alcohol, crystallisation by cooling, filtration, washing and drying obtain 3-amino-2-ethoxycarbonyl subcutin;
2) preparation of 2-oxyethyl group benzo imidazoles-4-carboxylic acid, ethyl ester:
Press 3-amino-2-ethoxycarbonyl subcutin: the weight proportion of glacial acetic acid=1: 3～5, get above-mentioned two materials and mix, heat temperature raising, 100～110 ℃ of temperature controls reacted 3～5 hours, removed glacial acetic acid under reduced pressure; Then,
Press 3-amino-2-ethoxycarbonyl subcutin: the weight proportion of methyl alcohol=1: 2～3, add methyl alcohol, crystallisation by cooling, filtration, washing and drying obtain 2-oxyethyl group benzo imidazoles-4-carboxylic acid, ethyl ester;
3) preparation of Candesartan cyclocomplex:
Press 2-oxyethyl group benzo imidazoles-4-carboxylic acid, ethyl ester: acetonitrile: cyano group bromo biphenyl: the weight proportion of salt of wormwood=1: 5～6: 1.1～1.2: 0.6～0.8, getting above-mentioned four materials mixes, 55～75 ℃ of controlled temperature, reacted 8～12 hours, cooling, remove by filter salt of wormwood, remove acetonitrile under reduced pressure; Then,
Press 2-oxyethyl group benzo imidazoles-4-carboxylic acid, ethyl ester: the weight proportion of methyl alcohol=1: 3～4, add methyl alcohol, crystallisation by cooling, filtration, washing and drying get the Candesartan cyclocomplex: 2-oxyethyl group-1-1[[(2-cyanobiphenyl-4-replaces) methyl] benzoglyoxaline]-the 7-carboxylic acid, ethyl ester.
2. by the preparation method of the described Candesartan cyclocomplex of claim 1, it is characterized in that the preparation method of described 3-nitro-2-ethoxycarbonyl subcutin is to include following steps:
1. mono-esterification:
Press the 3-nitrophthalic acid: dehydrated alcohol: the weight proportion of the vitriol oil=1: 4～5: 0.9～1.1, get above-mentioned three materials and mix, 65～80 ℃ of controlled temperature, heating reflux reaction 12～24 hours removes ethanol under reduced pressure; Then
Press the 3-nitrophthalic acid: the weight proportion of chloroform=1: 10～12, add chloroform, stirring, extraction and layering obtain the chloroformic solution of mono-esterification;
2. chloride:
Chloroformic solution with mono-esterification, reflux water-dividing is to complete, then, press 3-nitrophthalic acid: DMF: the weight proportion of sulfur oxychloride=1: 0.04～0.05: 0.5～0.6 adds DMF and sulfur oxychloride, 55～65 ℃ of controlled temperature, reacted 5～8 hours, press the 3-nitrophthalic acid: the weight proportion of chloroform=1: 5～6, steam and remove the part chloroform, obtain the chloroformic solution of acyl chlorides;
3. azide:
Press 3-nitrophthalic acid: DMF: the weight proportion of sodiumazide=1: 0.5～0.6: 0.3～0.4, in the chloroformic solution of acyl chlorides, add DMF and sodiumazide, 25～35 ℃ of controlled temperature reacted 1～3 hour; Then,
Press the 3-nitrophthalic acid: chloroform: the weight proportion of water=1: 5～6: 5～6, add chloroform and water, extracting and demixing obtains the chloroformic solution of acid azide;
4. reset esterification:
Press the 3-nitrophthalic acid: the weight proportion of Sodium sulfate anhydrous.min(99)=1: 2～3, in the chloroformic solution of acid azide, add Sodium sulfate anhydrous.min(99) and carry out drying and dehydrating, filter, obtain filtrate; Then,
Press the 3-nitrophthalic acid: the weight proportion of dehydrated alcohol=1: 3～4, in filtrate, add dehydrated alcohol, heating, 65～75 ℃ of controlled temperature reacted 8～10 hours, steamed and removed chloroform and ethanol; Then,
Press the 3-nitrophthalic acid: the weight proportion of methyl alcohol=1: 2～3, add methyl alcohol, crystallisation by cooling, filtration, washing and drying obtain 3-nitro-2-ethoxycarbonyl subcutin.
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| CN102391254A (en) * | 2011-12-16 | 2012-03-28 | 珠海润都制药股份有限公司 | Preparation method of Candesartan |
| CN103922948A (en) * | 2014-05-04 | 2014-07-16 | 青岛雪洁助剂有限公司 | Preparation method of 2-amino-3-nitrobenzoic acid |
| CN105294568A (en) * | 2015-12-05 | 2016-02-03 | 山东汇海医药化工有限公司 | Novel preparation method of benzimidazolone |
| CN107089972A (en) * | 2017-06-23 | 2017-08-25 | 浙江华海药业股份有限公司 | A kind of preparation method of candesartan Cilexetil |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102391254A (en) * | 2011-12-16 | 2012-03-28 | 珠海润都制药股份有限公司 | Preparation method of Candesartan |
| CN103922948A (en) * | 2014-05-04 | 2014-07-16 | 青岛雪洁助剂有限公司 | Preparation method of 2-amino-3-nitrobenzoic acid |
| CN105294568A (en) * | 2015-12-05 | 2016-02-03 | 山东汇海医药化工有限公司 | Novel preparation method of benzimidazolone |
| CN107089972A (en) * | 2017-06-23 | 2017-08-25 | 浙江华海药业股份有限公司 | A kind of preparation method of candesartan Cilexetil |
| CN107089972B (en) * | 2017-06-23 | 2021-05-18 | 浙江华海药业股份有限公司 | Preparation method of candesartan cilexetil |
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Application publication date: 20111005 |