CN102702176B - Preparation method for triphenyl candesartan - Google Patents
Preparation method for triphenyl candesartan Download PDFInfo
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- CN102702176B CN102702176B CN201210181215.9A CN201210181215A CN102702176B CN 102702176 B CN102702176 B CN 102702176B CN 201210181215 A CN201210181215 A CN 201210181215A CN 102702176 B CN102702176 B CN 102702176B
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Abstract
The invention discloses a preparation method for novel triphenyl candesartan. According to the method, the interference of an impurity-bistriphenyl candesartan is avoided, so that the reaction rate is improved, an operation process is simplified, the production cost is reduced, and the high purity of final products is ensured. The preparation method comprises the following steps of: 1, in the presence of alkali, compounds in a structural formula 2 are reacted with triphenylchloromethane to obtain compounds in a structural formula 3, wherein R is equal to alkyl between C1 and C4; and 2, the compounds in the structural formula 3 are hydrolyzed to obtain the triphenyl candesartan in a structural formula 1.
Description
Technical field
The invention belongs to organic chemistry filed, be specifically related to a kind of candesartan Cilexetil key intermediate, the preparation method of triphenyl candesartan.
Technical background
Triphenyl candesartan, structural formula as indicated with 1, chemistry is by name: 2-oxyethyl group-1-[[2 '-(1-triphenyltetrazolium-5-base)-(1,1 ' xenyl)-4-base] methyl] benzoglyoxaline-7-formic acid, it is the key intermediate of synthesis candesartan Cilexetil (candesartan cilexetil, structure as figure 5 illustrates).
Candesartan, chemistry is by name: 2-oxyethyl group-1-[[2 '-(1H-TETRAZOLE-5-base)-(1,1 '-xenyl)-4-base] methyl]-1H-benzoglyoxaline-7-formic acid-1-(cyclohexyloxycarbonyloxy) ethyl ester, that a kind of chemical structure is unique, orally active highly selective angiotensinⅡ receptor antagonist, be used for the treatment of hypertension, by Japanese Wu Tian company and A Silate company of Sweden joint development, in November, 1997 first in Sweden's listing, commodity are called Atacand.This product is strong to the avidity of angiotensinⅡ receptor, and better tolerance, long half time, interacting without food/medicine and metabolism, is a kind of antihypertensive drug with good prospect.
The candesartan Cilexetil synthetic route of reported in literature (Kubo K, Kohara Y, etc., J.Med.Chem, 1993,36:2182-2196; Kubo K, Kohara Y, etc.; J.Med.Chem; 1993,36:2343-2349), be all the intermediate of first composite structure formula 2; hydrolysis obtains the intermediate of structural formula 4 again; two active hydrogens are had in intermediate due to structural formula 4---tetrazole base hydrogen and carbonyl hydrogen, can react, therefore before the carbonyl of the intermediate of structural formula 4 becomes ester with 1-iodine ethylcyclohexyl ester; the intermediate triphenyl candesartan of elder generation and triphenyl compound Reactive Synthesis structural formula 1, to protect tetrazole base hydrogen.But in this single step reaction, carbonyl hydrogen also easy and triphenyl compound reacts, and produces the bi triphenyl Candesartan of the structural formula 6 of 5%-8%, and this impurity is difficult to remove, and needs complicated treating process, has a strong impact on quality and the productive rate of the finished product.
Summary of the invention
In order to solve the problems of the technologies described above, the invention provides a kind of preparation method of new triphenyl candesartan, avoiding impurity---the interference of bi triphenyl Candesartan, thus raising reactivity, simplify the operation course, reduce production cost, ensure the high purity of the finished product.
Present invention employs following technical scheme:
A preparation method for the triphenyl candesartan of structural formula 1, comprises the steps,
I. in the presence of an organic base, the compound of structural formula 2 and triphenylmethyl chloride react, and obtain the compound of structural formula 3; Wherein R=C
1-C
4alkyl;
II. the compound of described structural formula 3 is through hydrolysis, obtains the triphenyl candesartan of described structural formula 1.
In described step I, preferably, the mol ratio of the compound of described structural formula 2, triphenylmethyl chloride, organic bases is 1:1:1 ~ 1:2:2; Preferred, the mol ratio of the compound of described structural formula 2, triphenylmethyl chloride, organic bases is 1:1.15:1.
In described step I, preferably, described organic alkaline agent is selected from one or more in triethylamine, pyridine, diethylamine, thanomin or morpholine; Preferred, described organic bases is triethylamine.
In described step I, preferably, reaction solvent is selected from toluene, benzene, dimethylbenzene, trimethylbenzene, dioxy six alkane, propyl carbinol, Pentyl alcohol, Virahol, cyclohexane, normal hexane, methyl cyclohexanol, tetrahydrofuran (THF), one or more in DMF; Preferred, described reaction solvent is toluene.
In described step I, temperature of reaction is 0-100 DEG C; Preferred, temperature of reaction is 30-50 DEG C.
In described Step II, the compound of described structural formula 3 is first hydrolyzed in the basic conditions, then adjusts pH to 5-6.
Described hydrolyzed under basic conditions, preferably adopts NaOH, KOH, CaOH, KHCO
3, Na
2cO
3or K
2cO
3in one or more.
Then, one or more adjustments pH to 5-6 in hydrochloric acid, sulfuric acid, phosphoric acid, glacial acetic acid, formic acid, propionic acid, butyric acid, oxalic acid or tartrate is preferably adopted.
In described Step II, temperature of reaction is 0-100 DEG C, is preferably 40-60 DEG C.
Preparation method of the present invention, the compound of described structural formula 2, preferred R=methyl or ethyl, purity is greater than 98%.
The intermediate of the present invention to existing structural formula 2 is first hydrolyzed, then the synthetic route that N-protected obtains triphenyl candesartan ester has carried out bold improvement, directly carries out N-protected, is then hydrolyzed, obtain triphenyl candesartan ester to the intermediate of structural formula 2.Utilize preparation method of the present invention, the content of impurity bi triphenyl candesartan Cilexetil is by 5-8%(HPLC integrating peak areas method), be reduced to HPLC and detect below limitation, thus decrease refining for what remove that bi triphenyl candesartan Cilexetil and having to carries out, simplify operation, improve efficiency accordingly, reduce cost, ensure that the Quality and yield of final product candesartan Cilexetil.
Accompanying drawing explanation
Fig. 1 is the HPLC collection of illustrative plates of triphenyl candesartan prepared by embodiment 1, and wherein 1 is triphenyl candesartan peak.
Fig. 2 be comparative example 1 prepare the HPLC collection of illustrative plates of triphenyl candesartan, wherein 1 is triphenyl candesartan peak, and 2 is bi triphenyl Candesartan peak.
Embodiment
Below by embodiment and comparative example, the present invention will be further described.Should be appreciated that, these embodiments only for illustration of the present invention, and are not used in and limit the scope of the invention.The experimental technique of the unreceipted actual conditions of the following example, usually conveniently condition, or the condition providing according to manufacturer or advise.Unless otherwise indicated, all specialties used herein and scientific terminology and those skilled in the art the same meaning be familiar with.
Embodiment 1
The preparation of I, triphenyl candesartan methyl esters (shown in structural formula 8)
In 1000ml reaction flask, add the Candesartan methyl esters (45.4g of structural formula 7, 0.1mol), triethylamine (10g, 0.1mol), toluene (100ml) stirring and dissolving, temperature control 35-40 DEG C, slow dropping triphenylmethyl chloride (32g, 0.115mol) and the mixed solution of toluene (200ml), drip rear insulation reaction 1 hour, be chilled to 25-30 DEG C, add water washing 2 times, merge organic layer, underpressure distillation is about 200-250ml to residual solution, be chilled to 0 DEG C, filter, decompression drying, obtain the described target compound 60.5g of light yellow crystals, yield 87%, HPLC detects, purity 99.3%.
The preparation of II, triphenyl candesartan
In 1000ml reaction flask, add the triphenyl candesartan methyl esters (60.5g, 0.087mol) of preparation in step 1,5%NaOH(is equivalent to NaOH0.2535mol), stirring is warming up to 50-55 DEG C, and question response liquid slowly becomes clearly, is chilled to 10-15 DEG C, instill 35% hydrochloric acid, adjust PH=5-6, after white solid is no longer separated out, be chilled to 0 DEG C, filter, filter cake decompression drying, obtains 56.3g white crystals, i.e. triphenyl candesartan, yield 95%; HPLC detects, purity 99.0%.
。
Embodiment 2
The preparation of I, triphenyl candesartan ethyl ester (shown in structural formula 10)
In 1000ml reaction flask, add the ethyl ester of candesartan (54.5g of structural formula 9, 0.116mol), pyridine (19g, 0.24mol), stirring and dissolving, temperature control 45-50 DEG C, slow dropping triphenylmethyl chloride (66g, 0.237mol) and the mixed solution of dimethylbenzene (300ml), drip rear insulation reaction 1 hour, be chilled to 25-30 DEG C, add water washing 2 times, merge organic layer, underpressure distillation is about 200-250ml to residual solution, be chilled to 0 DEG C, filter, decompression drying, obtain the described target compound 71.4g of light yellow crystals, yield 86.4%, HPLC detects, purity 99.1%.
The preparation of II, triphenyl candesartan
The triphenyl candesartan ethyl ester (71g, 0.1mol) of preparation in step 1 is added, 35% KHCO in 1000ml reaction flask
3(be equivalent to KHCO
30.3mol), stir and be warming up to 50-55 DEG C, question response liquid slowly becomes clearly, is chilled to 10-15 DEG C, instillation Glacial acetic acid, adjust PH=5-6, after white solid is no longer separated out, be chilled to 0 DEG C, filter, filter cake decompression drying, obtains 64.5 g white crystals, i.e. triphenyl candesartan, yield 94.6%; HPLC detects, purity 99.2%.
。
Embodiment 3
The preparation of I, triphenyl candesartan propyl ester (shown in structural formula 12)
In 1000ml reaction flask, add the Candesartan propyl ester (54.5g0.113mol) of structural formula 11, thanomin (9g, 0.15mol), stirring and dissolving, temperature control 60-65 DEG C, slow dropping triphenylmethyl chloride (345g, 0.124mol) and the mixed solution of dioxane (250ml), drip rear insulation reaction 1 hour, be chilled to 20-25 DEG C, add water washing 2 times, merge organic layer, underpressure distillation is about 200-250ml to residual solution, be chilled to 0 DEG C, filter, decompression drying, obtain the described target compound 70.6g of light yellow crystals, yield 86.2%, HPLC detects, purity 99.4%.
The preparation of II, triphenyl candesartan
The triphenyl candesartan propyl ester (65g, 0.09mol) of preparation in step 1 is added, 30% Na in 1000ml reaction flask
2cO
3the aqueous solution (is equivalent to Na
2cO
30.2mol), stir and be warming up to 50-55 DEG C, question response liquid slowly becomes clearly, is chilled to 10-15 DEG C, instillation sulfuric acid, adjust PH=5-6, after white solid is no longer separated out, be chilled to 0 DEG C, filter, filter cake decompression drying, obtains 57.7 g white crystals, i.e. triphenyl candesartan, yield 94.2%; HPLC detects, purity 99.1%.
。
Embodiment 4
The preparation of I, triphenyl candesartan isobutyl ester (shown in structural formula 14)
In 1000ml reaction flask, add the Candesartan isobutyl ester (61.g of structural formula 13, 0.123mol), diethylamine (6.3g, 0.062mol), morpholine (5.4g, 0.062mol) stirring and dissolving, temperature control 25-30 DEG C, slow dropping triphenylmethyl chloride (49.5g, 0.178mol) and the mixed solution of hexanaphthene (300ml), drip rear insulation reaction 3 hours, be chilled to 20-25 DEG C, add water washing 2 times, merge organic layer, underpressure distillation is about 200-250ml to residual solution, be chilled to 0 DEG C, filter, decompression drying, obtain the described target compound 77.8g of light yellow crystals, yield 85.7%, HPLC detects, purity 99.2%.
The preparation of II, triphenyl candesartan
In 1000ml reaction flask, add the triphenyl candesartan isobutyl ester (73.8g, 0.1mol) of preparation in step 1,10% KOH(is equivalent to KOH0.15mol), stirring is warming up to 45-50 DEG C, and question response liquid slowly becomes clearly, is chilled to 10-15 DEG C, instillation formic acid, adjusts PH=5-6, after white solid is no longer separated out, be chilled to 0 DEG C, filter, filter cake decompression drying, obtains 64.4g white crystals, i.e. triphenyl candesartan, yield 94.5%; HPLC detects, purity 99.3%.
。
Comparative example 1
The preparation of I, Candesartan
In 1000ml four-hole bottle, add dimethylbenzene (200ml), water 120ml, sodium azide 17.5g, feeds intake complete, is ice-cooling to 3-6 DEG C, control to drip 63.5g tributyltin chloride and 125ml xylene solution at this temperature, drip and finish in 3-6 DEG C of insulation 5h, reaction is finished, layering, obtain tributyl azide tin xylene solution, reaction solution is proceeded in reaction flask, temperature rising reflux dehydration 7h, for subsequent use.
In 1000ml there-necked flask, throw in above-mentioned reserve liquid, 40g (0.088mol) Candesartan methyl esters is warming up to backflow, reaction 72h, after reaction terminates, is cooled to 35-40 DEG C, add 400g5%NaOH, 35-40 DEG C of insulation reaction 4h, layering, organic layer xylene extraction, extraction liquid 30%HCl slowly adjusts PH=2-3, adjusts and finishes, obtain Candesartan 32.7g, yield 84%, purity 90%.
The preparation of II, triphenyl candesartan
In 500ml there-necked flask, throw in above-mentioned Candesartan 25g(0.057mol), 1.5g potassiumiodide, 200ml methylene dichloride, 6.3g triethylamine, 35-40 DEG C of stirring, drip triphenylmethyl chloride 20g(0.072mol) with the mixed liquid of 200ml methylene dichloride, insulation reaction finishes to reaction, cooling 25-30 DEG C, add water extraction, layering, organic layer filters, filtrate less than 35 DEG C, reclaim under reduced pressure methylene dichloride, the 200ml methyl alcohol that residue adds, stir, be refrigerated to 0 ± 2 DEG C, insulation 8h, filter, obtain triphenyl candesartan 32.9g, yield 85%, HPLC detects purity 87%, separately there is bi triphenyl Candesartan 8%.
Test example 1
The purity of triphenyl candesartan prepared by HPLC method detection embodiment 1 and comparative example
Chromatographic condition:
Chromatographic column: Agilent ZORBAX Eclipse XDB-C18,4.6mm × 150mm × 5 μm
Column temperature: 30 DEG C
Moving phase: mobile phase A: water: acetic acid=100: 1(volume ratio)
Mobile phase B: acetonitrile: acetic acid=500: 1(volume ratio)
Gradient elution, eluent gradient is as shown in the table
Flow velocity: 1.0ml/min
Sample size: 20 μ l
Determined wavelength: 254nm
Test sample concentration 0.4mg/ml(solvent: DMF: acetonitrile=5: 95)
Attached Fig. 1 and 2 is shown in by the HPLC collection of illustrative plates of triphenyl candesartan prepared by embodiment 1 and comparative example, adopts integrating peak areas method, calculates the content of triphenyl candesartan and bi triphenyl Candesartan.
Result: adopt the inventive method, triphenyl candesartan prepared by embodiment 1, purity is 99.0%, and bi triphenyl Candesartan is below detectability; Triphenyl candesartan prepared by comparative example, purity is only 87%, and bi triphenyl Candesartan content is 8%.The inventive method, relative to prior art, serves impurity such as avoiding bi triphenyl Candesartan really, improves the effect of product purity and quality.
Claims (3)
1. a preparation method for the triphenyl candesartan of structural formula 1,
It is characterized in that, comprise the steps,
I. in the presence of an organic base, the compound of structural formula 2 and triphenylmethyl chloride react, and obtain the compound of structural formula 3; Wherein R=methyl or ethyl, organic bases is triethylamine, and the mol ratio of the compound of described structural formula 2, triphenylmethyl chloride, triethylamine is 1:1.15:1, and reaction solvent is toluene, and temperature of reaction is 30-50 DEG C;
II. the compound of described structural formula 3 is first hydrolyzed in the basic conditions, and temperature of reaction is 40-60 DEG C, then adjusts pH to 5-6, obtains the triphenyl candesartan of described structural formula 1.
2. a preparation method for the triphenyl candesartan of structural formula 1,
It is characterized in that, comprise the steps,
I. the preparation of the triphenyl candesartan methyl esters of structural formula 8
In 1000ml reaction flask, add the Candesartan methyl esters 0.1mol of structural formula 7, triethylamine 0.1mol, toluene 100ml stirring and dissolving, temperature control 35-40 DEG C, slowly drips the mixed solution of triphenylmethyl chloride 0.115mol and toluene 200ml, drip rear insulation reaction 1 hour, be chilled to 25-30 DEG C, add water washing 2 times, merge organic layer, underpressure distillation is to residual solution 200-250ml, be chilled to 0 DEG C, filter, decompression drying, obtain light yellow crystalline described target compound 60.5g, yield 87%, HPLC detects, purity 99.3%;
II. the preparation of triphenyl candesartan
In 1000ml reaction flask, add the triphenyl candesartan methyl esters 0.087mol prepared in step I, be equivalent to the 5%NaOH of NaOH 0.2532mol, stir and be warming up to 50-55 DEG C, question response liquid slowly becomes clearly, is chilled to 10-15 DEG C, instills 35% hydrochloric acid, adjust pH=5-6, after white solid is no longer separated out, be chilled to 0 DEG C, filter, filter cake decompression drying, obtains 56.3g white crystals, i.e. triphenyl candesartan, yield 95%, HPLC detects, purity 99.0%;
3. a preparation method for the triphenyl candesartan of structural formula 1,
It is characterized in that, comprise the steps,
I. the preparation of the triphenyl candesartan ethyl ester of structural formula 10
In 1000ml reaction flask, add the ethyl ester of candesartan 0.116mol of structural formula 9, pyridine 0.24mol, stirring and dissolving, temperature control 45-50 DEG C, slowly drips the mixed solution of triphenylmethyl chloride 0.237mol and dimethylbenzene 300ml, drip rear insulation reaction 1 hour, be chilled to 25-30 DEG C, add water washing 2 times, merge organic layer, underpressure distillation is to residual solution 200-250ml, be chilled to 0 DEG C, filter, decompression drying, obtain light yellow crystalline described target compound 71.4g, yield 86.4%, HPLC detects, purity 99.1%;
II. the preparation of triphenyl candesartan
In 1000ml reaction flask, add the triphenyl candesartan ethyl ester 0.1mol prepared in step I, be equivalent to KHCO
3the 35%KHCO of 0.3mol
3, stir and be warming up to 50-55 DEG C, question response liquid slowly becomes clearly, be chilled to 10-15 DEG C, instillation Glacial acetic acid, adjusts pH=5-6, after white solid is no longer separated out, be chilled to 0 DEG C, filter, filter cake decompression drying, obtain 64.5g white crystals, i.e. triphenyl candesartan, yield 94.6%, HPLC detects, purity 99.2%;
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Citations (4)
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|---|---|---|---|---|
| CN1800179A (en) * | 2005-12-22 | 2006-07-12 | 浙江天宇药业有限公司 | Method for preparing candestartan |
| WO2006076215A2 (en) * | 2005-01-11 | 2006-07-20 | Glasstech, Inc. | Apparatus and method for glass sheet quenching |
| CN101323610A (en) * | 2007-06-15 | 2008-12-17 | 横店集团成都分子实验室有限公司 | Novel preparation of trityl group candesartan cilexetil intermediate |
| CN101641918A (en) * | 2007-03-23 | 2010-02-03 | 高通股份有限公司 | Backhaul communication for interference management |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006076215A2 (en) * | 2005-01-11 | 2006-07-20 | Glasstech, Inc. | Apparatus and method for glass sheet quenching |
| CN1800179A (en) * | 2005-12-22 | 2006-07-12 | 浙江天宇药业有限公司 | Method for preparing candestartan |
| CN101641918A (en) * | 2007-03-23 | 2010-02-03 | 高通股份有限公司 | Backhaul communication for interference management |
| CN101323610A (en) * | 2007-06-15 | 2008-12-17 | 横店集团成都分子实验室有限公司 | Novel preparation of trityl group candesartan cilexetil intermediate |
Non-Patent Citations (2)
| Title |
|---|
| Medicinal Chemistry》.2009,第17卷7971-7977. * |
| Tayebeh Hadizad et al.Novel O-[11C]methylated derivatives of candesartan as angiotensin II AT1 receptor imaging ligands:Radiosynthesis and ex vivo evaluation in rats.《Bioorganic & * |
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