CN1204125C - New synthesis route of candixatan ester - Google Patents
New synthesis route of candixatan ester Download PDFInfo
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- CN1204125C CN1204125C CN 00135191 CN00135191A CN1204125C CN 1204125 C CN1204125 C CN 1204125C CN 00135191 CN00135191 CN 00135191 CN 00135191 A CN00135191 A CN 00135191A CN 1204125 C CN1204125 C CN 1204125C
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Abstract
The present invention relates to a preparation method of candesartan cilexetil. A compound IV is prepared from 3-nitro-2-tert-butoxy methyl aminobenzoate as initial raw materials by four-step reaction and hydrolyzed to prepare a compound V; a compound VI is prepared from the V and 1-iodoethyl cyclohexyl carbonate by esterification; then, the cyano group of the VI is converted into tetrazole rings to prepare a target compound VII. Because the nonexistence of the problem of selective protection, the method has no occurrence of unavoidable impurities in the reaction, simplifies operation, improves the yield and the product quality and is suitable for large-scale production.
Description
The present invention relates to a kind of preparation method of active constituents of medicine, a kind of preparation method with compound candesartan Cilexetil of antihypertensive active more specifically says so.
Candesartan Cilexetil is a kind of novel non-peptide class Angiotensin II (ATII) receptor antagonist.
The synthetic route of existing candesartan Cilexetil mainly contains two.Article one, be to be raw material with the 3-nitrophthalic acid, through mono-esterification, repeatedly nitrogenize, amidated and intermediate 3-nitro-2-tert.-butoxy Methyl anthranilate, again through nucleophilic substitution, take off tertbutyloxycarbonyl, reduction, cyclization, tetrazoleization, hydrolysis, N-protected, one-tenth ester, deprotection and final product candesartan Cilexetil (Naka T, Nishikawa K etc., EP 459136,1991; Kubo K, Kohara Y etc., J Med Chem, 1993,36:2182-2196), route is shown in Scheme1.Another route is with 2, and the 3-diamino-methyl benzoate is that raw material also obtains identical intermediate VIII through reactions such as cyclization, nucleophilic substitution, obtains candesartan Cilexetil (Kubo K through same step again, Kohara Y etc., J Med Chem, 1993,36:2343-2349).In these two kinds of preparation methods, all be first synthetic intermediate VIII, hydrolysis obtains IX again.Owing in the structure of IX two active H (tetrazole hydrogen and carboxyl hydrogen) are arranged, all can react, so before the carboxyl of IX becomes ester, need earlier with the active hydrogen on the Triphenyl methane chloride 99 protection tetrazole ring with carbonic acid 1-iodine ethyl cyclohexyl ester.In this step protective reaction, issuable by product aerobic protection thing, oxygen, the two raw material IX that protect thing and have neither part nor lot in reaction of nitrogen.Make the productive rate of X and the raising of purity can not get ensureing.In addition, the deprotection reaction of XI needs to carry out under acidic conditions, under this condition, and the very easy impurity that is decomposed to form of the ester on the carboxyl.And the protecting group of taking off on the nitrogen needs to remove by the post separation.All these problems all make a large amount of preparations of VII become difficulty.
Scheme?1
Reaction conditions:
CH
3CN, K
2CO
3Ii.2M HCl/MeOH; Iii.SnCl
2
iv.C(OC
2H
5)
4；v.(Bu)
3SnCl，NaN
3；vi.NaOH/H
2O；vii.Ph
3CCl/CH
2Cl
2；
Purpose of the present invention: the method that existing document route adopts is first synthetic intermediate VIII, and hydrolysis obtains IX again.And easily participating in later reaction simultaneously, two active H in the structure of IX make product complicated.Adopt methods such as protection, deprotection base that a lot of side reactions are also arranged, the purpose of this invention is to provide a kind of new synthesis method that can overcome the candesartan Cilexetil of above-mentioned shortcoming, and can carry out scale operation.
The present invention has found the synthetic route preferably of a preparation candesartan Cilexetil, has solved the problems referred to above effectively.Existing preparation route be earlier with the hydrolysis again of intermediate compound IV elder generation's tetrazoleization, go up protecting group, become ester, deprotection.We find, if earlier IV hydrolysis, one-tenth ester are gone up the tetrazole ring again, then can avoid two active H among the IX to participate in reaction simultaneously, and intermediate V also has only a kind of esterification products with the ester reaction that becomes of carbonic acid 1-iodine ethyl cyclohexyl ester.This route has saved N-protected and the deprotection reaction on the tetrazole ring; the problem that neither has selective protection; also avoided in the protective reaction might by product generation; more there is not the problem that candesartan Cilexetil is decomposed in the deprotection reaction; thereby saved the post lock out operation; also make the corresponding raising of yield and quality product, be suitable for scale operation.
The chemical structure of candesartan Cilexetil is as follows:
The present invention implements by following reactions steps:
Reaction conditions:
DMF, K
2CO
3Ii.2MHCl/EtOAc, 25-35 ℃;
iii.SnCl
2，EtOH；iv.C(OEt)
4，80℃；
V. mineral alkali or organic bases, lower alcohol or DMF, DMS, THF, dioxane, pyrrolidinone compounds;
Organic bases or mineral alkali are catalyzer, and solvent is DMSO, THF, dioxane, pyrrolidinone compounds, hempa acid amide, glycol dimethyl ether, interior ketone, CH
2Cl
2, CHCl
3
The present invention includes the following step:
(1) at K
2CO
3Exist down, with 3-nitro-2-t-butoxycarbonyl amino methyl benzoate is starting raw material, with 4-brooethyl-2 '-the cyanobiphenyl nucleo philic substitution reaction generates 2-[N-(tertbutyloxycarbonyl)-N-[(2 '-cyanobiphenyl-4-yl) amino]-3-nitrobenzoic acid methyl esters (I).
(2) (I) room temperature reaction 2 hours in the saturated ethanol of dry HCl gas is sloughed tertbutyloxycarbonyl, obtains 2-[[2 '-cyanobiphenyl-4-yl] methyl] amino]-3-nitrobenzoic acid methyl esters (II).
(3) nitro of compound (II) is reduced to 2-[[2 '-cyanobiphenyl-4-yl with tin protochloride] methyl] amino]-3-Methyl anthranilate (III).
(4) compound (III) makes 1-[(2 '-cyanobiphenyl-4-yl with tetraethyl orthocarbonate heating cyclization) methyl]-2-oxyethyl group-1H-benzoglyoxaline-7-carboxylate methyl ester (IV).
(5) carboxylate methyl ester (IV) is hydrolyzed to 1-[(2 '-cyanobiphenyl-4-yl under alkaline condition] methyl]-2-oxyethyl group-1H-benzoglyoxaline-7-carboxylic acid (V).More particularly, IV is at mineral alkali (for example NaOH, KOH, CsOH, Ba (OH)
2, Mg (OH)
2, Ca (OH)
2, Sr (OH)
2, KHCO
3, K
2CO
3, Na
2CO
3, Cs
2CO
3) or organic bases (for example sodium alkoxide, triethylamine, tri-n-butylamine, tripropylamine) existence is down, with lower alcohol (for example methyl alcohol, ethanol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol, Pentyl alcohol, primary isoamyl alcohol) or other solvents (for example DMF, DMSO, THF, dioxane, pyrrolidinone compounds) is solvent, temperature range internal reaction 0.5～10 hour (preferred 1～3 hour) 20 ℃～160 ℃ (are good with 60 ℃-100 ℃) is hydrolyzed to carboxylic acid V.
(6) V and carbonic acid 1-iodine ethyl cyclohexyl ester nucleo philic substitution reaction under alkaline condition generates (±)-2-oxyethyl group-1-[(2 '-cyanobiphenyl-4-yl) methyl]-1H-benzoglyoxaline-7-carboxylic acid, 1-[[cyclohexyl oxygen base] carbonyl] the oxygen base] ethyl ester (VI).More particularly, be to adopt organic bases (for example sodium alkoxide, triethylamine, tri-n-butylamine, tripropylamine) or mineral alkali (for example NaOH, KOH, CsOH, Ba (OH)
2, Mg (OH)
2, Ca (OH)
2, Sr (OH)
2, KHCO
3, K
2CO
3, Na
2CO
3, Cs
2CO
3) be catalyzer, (preferred 20～100 ℃) reaction is 8～10 hours in 0～120 ℃ temperature range, generates intermediate (VI).Reaction solvent can be selected DMSO, THF, dioxane, pyrrolidinone compounds, hexamethylphosphoramide, acetone, glycol dimethyl ether, CH for use
2Cl
2, CHCl
3Deng.
(7) intermediate VI and alkaline azide (preferred sodiumazide) and tributyltin chloride or other small molecules organic monoacids (for example acetic acid, propionic acid, butyric acid) or Lewis acid (AlCl for example
3, CaCl
2, ZnCl
2, NH
4Cl, (NH
4)
2SO
4Deng) or the triethylamine hydrochloride reaction, cyano group obtains final product (±)-2-oxyethyl group-1-[[2 '-(1H-tetrazole-5-yl) [1 after changing the tetrazole ring into, 1 '-biphenyl]-the 4-yl] methyl]-1H-benzoglyoxaline-7-carboxylic acid, 1-[[cyclohexyl oxygen base] carbonyl] the oxygen base] ethyl ester (VII) is the husky smooth ester of bank sand ground.VII also can be obtained by VI and sodiumazide, triethylamine hydrochloride reaction.This step reaction solvent can be selected the higher solvent of DMF or other boiling points for example toluene, dimethylbenzene, trimethylbenzene, dioxy six alkane, propyl carbinol, Pentyl alcohol, primary isoamyl alcohol etc. for use, and temperature of reaction can be controlled in the scope of 80～170 ℃ (with 100～130 ℃ for good).The purifying of VII can adopt alcohol-water system (for example methanol-water or alcohol-water) recrystallization.
The 5th step of experimental technique and the reaction of the 6th step that the present invention adopts, promptly compound carboxylate methyl ester (IV) is hydrolyzed to 1-[(2 '-cyanobiphenyl-4-yl under alkaline condition) methyl]-2-oxyethyl group-1H-benzoglyoxaline-7-carboxylic acid (V).Compound V and carbonic acid 1-iodine ethyl cyclohexyl ester nucleo philic substitution reaction under alkaline condition generates (±)-2-oxyethyl group-1-[(2 '-cyanobiphenyl-4-yl) methyl]-1H-benzoglyoxaline-7-carboxylic acid, 1-[[cyclohexyl oxygen base] carbonyl] the oxygen base] ethyl ester (VI)
Compound V, VI are the key compound of preparation candesartan Cilexetil.
Advantage of the present invention is as follows:
1, the present invention is a starting raw material with 3-nitro-2-tert.-butoxy Methyl anthranilate, and through the synthetic object of seven steps reaction, compared with prior art, the present invention has saved N-protected and deprotection base two-step reaction, and it is easy that method more becomes, and synthetic route is shorter.
2, owing to saved N-protected and the side reaction of deprotection two-step reaction is few, impurity reduces in the product, is easy to separation and purification, and quality and yield all improve, and is fit to scale operation.
The invention will be further described below in conjunction with embodiment, but do not limit the present invention.
Below starting raw material 3-nitro-2-tert.-butoxy Methyl anthranilate of adopting of reaction, 4-brooethyl-2 '-cyanobiphenyl and carbonic acid 1-iodine ethyl cyclohexyl ester provide by Shanghai specialization company limited.
Embodiment 1 2-[N-(tertbutyloxycarbonyl)-N-[(2 '-cyanobiphenyl-4-yl) amino]-3-nitrobenzoic acid methyl esters (I)
With 3-nitro-2-t-butoxycarbonyl amino methyl benzoate (59.2g, 0.2mol), 4-brooethyl-2 '-(54.4g, 0.2mol), salt of wormwood (56g, 0.4mol, porphyrize) and dry DMF (800ml) mix cyanobiphenyl, 90 ℃ of reactions 6 hours.Put coldly, pour in the frozen water (1000g), stirred 1 hour, extract with ethyl acetate (500ml * 3), organic phase is with washing (500ml * 2), saturated common salt washing (500ml), and dried over sodium sulfate is concentrated into about 400ml, puts coldly, has solid to separate out.Filter, wash with a small amount of cold ethyl acetate.60 ℃ of dryings 1 hour, I (84.9g, 87.2%).Analytic sample is with ethyl acetate-sherwood oil recrystallization.mp152-154℃。Can be without the refining the next step that is directly used in.
Embodiment 2 2-[[2 '-cyanobiphenyl-4-yl] methyl] amino]-3-nitrobenzoic acid methyl esters (II)
(48.7g 0.1mol) is dissolved in ethyl acetate (500ml), adds with the saturated ethanol (200ml) of dry HCl gas, and 25-35 ℃ was stirred 2 hours to get I.Concentrate the recovery part ethyl acetate.Precipitate is leached, be washed to neutrality, 60-70 ℃ of drying gets II (36.1g, 93.4%).Analytic sample is with ethyl alcohol recrystallization, mp141-143 ℃.Can be without the refining the next step that is directly used in.
Embodiment 3 2-[[2 '-cyanobiphenyl-4-yl] methyl] amino]-3-Methyl anthranilate (III)
(100g 0.26mol) mixes with ethanol (800ml), and gradation adds SnCl to get II
22H
2O (280g, 12.4mol), reflux 4 hours, decompression recycling ethanol, (4M 2000ml), stirred 1 hour, told organic phase, and water uses ethyl acetate (500ml) to extract once again to add ethyl acetate (1000ml) and NaOH solution in the excess.Merge organic phase, with saturated common salt washing, dried over sodium sulfate.Leach Na
2SO
4, organic phase is concentrated into dried, gets III (78.2g, 84.3%).Analytic sample is with ethyl acetate-sherwood oil recrystallization, mp107-110 ℃.Can be without the refining the next step that is directly used in.
Embodiment 4 1-[(2 '-cyanobiphenyl-4-yl) methyl]-2-oxyethyl group-1H-benzoglyoxaline-7-carboxylate methyl ester (IV)
(100g 0.28mol) mixes with tetraethyl orthocarbonate (700ml), adds acetic acid (20ml), and 80～90 ℃ were reacted 3 hours to get III.Filter, filtering layer is washed with a small amount of sherwood oil.60-70 ℃ of drying gets IV (93.4g, 81.2%).Analytic sample is with re-crystallizing in ethyl acetate, mp168-170 ℃.
Embodiment 5 1-[(2 '-cyanobiphenyl 4-yl) methyl]-2-oxyethyl group-1H-benzoglyoxaline-7-carboxylic acid (V)
Get IV (82.2g 0.2mol), adds ethanol (or other lower alcohols) as previously mentioned (300ml), the NaOH aqueous solution (or other mineral alkalis) as previously mentioned (4M, 100ml), 80 ℃ of reactions 1 hour.Decompression recycling ethanol drips concentrated hydrochloric acid to PH=4-3 to the long-pending 200ml that is about of remaining liquid.Filter, filtering layer is with washing.60-70 ℃ of drying gets crude product V.With this crude product ethyl alcohol recrystallization, get V (59.1g, 74.4%).Mp199-202 ℃, Rf=0.66 (ethyl acetate/methanol=9.5/0.5,33 ℃).
MS (EI) m/z:379 (M
+), 351,322,249,192 (base peaks), 165,152,90,66
IR(cm
-1)：3408，2982，2222，1693，1614，1552，1479，1431，1389，1309，1240，1136，1036，764，741，729
1HNMR(CDCl
3+DMSO-d
6)：1.38(3H，t，OCH
2CH
3)，4.55(2H，q，OCH
2CH
3)，5.71(2H，s，ArCH
2)，7.10(3H，t，ArH)，7.35(4H，t，ArH)，7.53(2H，t，ArH)，7.62(2H，q，ArH)
Embodiment 6 1-[(2 '-cyanobiphenyl-4-yl) methyl]-2-oxyethyl group-1H-benzoglyoxaline-7-carboxylic acid (V)
Get IV (82.2g 0.2mol), adds THF (or other solvent) as previously mentioned (400ml), triethylamine (or other organic bases) as previously mentioned (0.8mol), back flow reaction 3 hours.Aftertreatment is with embodiment 5.
Embodiment 7 1-[(2 '-cyanobiphenyl-4-yl) methyl]-2-oxyethyl group-1H-benzoglyoxaline-7-carboxylic acid (V)
Get IV (82.2g 0.2mol), adds ethanol (or other lower alcohol) as previously mentioned (300ml), sodium ethylate (or other organic bases) as previously mentioned (0.5mol), room temperature (20～30 ℃) reaction 10 hours.Aftertreatment is with embodiment 5.
Embodiment 8 (±)-2-oxyethyl group-1-[(2 '-cyanobiphenyl-4-yl) methyl]-1H-benzoglyoxaline-7-carboxylic acid, 1-[[cyclohexyl oxygen base] carbonyl] the oxygen base] ethyl ester (VI)
Get V (100g, 0.25mol) with carbonic acid 1-iodine ethyl cyclohexyl ester (75.1g, 0.25mol), K
2CO
3(or other mineral alkali) as previously mentioned (0.50mol), dry DMF (or other solvent) as previously mentioned (800ml) mixes, 60 ℃ of reactions 8 hours.Reactant is poured in the frozen water (1000ml), with ethyl acetate extraction (600ml * 2,300ml * 1).Merge organic phase, with washing (500ml * 2), saturated common salt washing (500ml), anhydrous sodium sulfate drying.After organic phase concentrated thickness arborescens VI (127.8g, 90.2%).Rf=0.50 (petrol ether/ethyl acetate=5/3,33 ℃).
MS (EI) m/z:567 (M+), 479,396,379 (base peaks), 351,322,192,161,91,82,55
IR(cm-1)：3429，2939，2224，1755，1724，1618，1552，1479，1427，1352，1279，1242，1078，1038，987，910，754
1HNMR(CDCl
3)：1.15～1.30(3H，m，cyclohexyl-CH
2)，1.40～1.49(6H，m，2×CH3)，1.67(4H，br，cyclo?hexyl-CH
2)，1.89(3H，br，cyclohexyl-CH
2)，4.58～4.68(3H，m，OCH
2CH
3，COOCH(CH
2)
5)，5.64-5.76(2H，q，ArCH
2)，6.90(1H，q，CHCH
3)，7.10～7.16(3H，m，ArH)，7.37(4H，m，ArH)，7.56(2H，t，ArH)，7.73(2H，t，ArH)
Embodiment 9 (±)-2-oxyethyl group-1-[(2 '-cyanobiphenyl-4-yl) methyl]-1H-benzoglyoxaline-7-carboxylic acid, 1-[[cyclohexyl oxygen base] carbonyl] the oxygen base] ethyl ester (VI)
Get V (100g, 0.25mol) with carbonic acid 1-iodine ethyl cyclohexyl ester (75.1g, 0.25mol), triethylamine (or other organic bases) as previously mentioned (0.50mol), DMSO (or other solvent) as previously mentioned (700ml) mixes back flow reaction 8 hours.Aftertreatment is with embodiment 8.
Embodiment 10 (±)-2-oxyethyl group-1-[(2 '-cyanobiphenyl-4-yl) methyl]-1H-benzoglyoxaline-7-carboxylic acid, 1-[[cyclohexyl oxygen base] carbonyl] the oxygen base] ethyl ester (VI)
Get V (100g, 0.25mol) and carbonic acid 1-iodine ethyl cyclohexyl ester (75.1g, 0.25mol), NaOH (or other mineral alkali) as previously mentioned (0.50mol), THF (or other solvent) as previously mentioned (700ml) mixes room temperature (20～30 ℃) reaction 10 hours.Aftertreatment is with embodiment 8.
Embodiment 11 (±)-2-oxyethyl group-1-[[2 '-(1H-tetrazole-5-yl) [1,1 '-biphenyl]-the 4-yl) methyl]-1H-benzoglyoxaline-7-carboxylic acid, 1-[[cyclohexyl oxygen base] carbonyl] the oxygen base] ethyl ester (VII)
Get VI (56.7g, 0.1mol) and NaN
3(26.0g, 0.4mol), tributyltin chloride (or other organic monoacid) as previously mentioned (0.4mol), DMF (or the higher solvent of other boiling point) as previously mentioned (600ml) mixes, 120-130 ℃ of reaction 40 hours.Decompression is desolvated, and excess is with ethanol (200ml) dissolving, and (6M 100ml), stirred 1 hour to add hydrochloric acid.Add ethyl acetate (300ml) and water (200ml) again, stir, leave standstill, tell ethyl acetate layer, water layer extracts once with ethyl acetate (300ml) again, merges organic phase, (300ml) washes once with saturated aqueous common salt, and anhydrous sodium sulfate drying is concentrated into organic phase dried, be dissolved in again in the ethanol (150ml), add distilled water (50ml), 20-30 ℃ left standstill 7 hours, filtered, filtering layer is washed with ethanol, and 40 ℃ of drying under reduced pressure get crude product VII.With ethanol/water=4/1 recrystallization, 40 ℃ of drying under reduced pressure get VII (40.9g, 67.1%).mp157-160℃。
Embodiment 12 (±)-2-oxyethyl group-1-[[2 '-(1H-tetrazole-5-yl) [1,1 '-biphenyl]-the 4-yl) methyl]-1H-benzoglyoxaline-7-carboxylic acid, 1-[[cyclohexyl oxygen base] carbonyl] the oxygen base] ethyl ester (VII)
Get VI (56.7g, 0.1mol), with NaN
3(26.0g, 0.4mol), triethylamine hydrochloride (0.4mol), toluene (or the higher solvent of other boiling point) as previously mentioned (600ml) mixes, back flow reaction 45 hours.Removal of solvent under reduced pressure, excess are with ethanol (200ml) dissolving, and (6M 100ml), stirred 1 hour to add hydrochloric acid.Add ethyl acetate (300ml) and water (200ml) again, stir, leave standstill, tell ethyl acetate layer, water layer extracts once with ethyl acetate (300ml) again, merges organic phase, (300ml) washes once with saturated aqueous common salt, and anhydrous sodium sulfate drying is concentrated into organic phase dried, be dissolved in again in the ethanol (150ml), add distilled water (50ml), 20-30 ℃ left standstill 7 hours, filtered, filtering layer is washed with ethanol, and 40 ℃ of drying under reduced pressure get crude product VII.With ethanol/water=4/1 recrystallization, 40 ℃ of drying under reduced pressure get VII (43.3g, 71.0%).
Embodiment 13 (±)-2-oxyethyl group-1-[[2 '-(1H-tetrazole-5-yl) [1,1 '-biphenyl]-the 4-yl) methyl]-1H-benzoglyoxaline-7-carboxylic acid, 1-[[cyclohexyl oxygen base] carbonyl] the oxygen base] ethyl ester (VII)
Get VI (56.7g, 0.1mol), with NaN
3(19.5g, 0.3mol), NH
4Cl (or other Lewis acid as previously mentioned) (0.6mol), dioxy six alkane (or the higher solvent of other boiling point) as previously mentioned (600ml) mix, back flow reaction 40 hours.Removal of solvent under reduced pressure, excess dissolves with ethanol (200ml), (6M 100ml), adds ethyl acetate (300ml) and water (200ml) again to add hydrochloric acid, stir, leave standstill, tell ethyl acetate layer, water layer extracts once with ethyl acetate (300ml) again, merge organic phase, (300ml) washes once with saturated aqueous common salt, and anhydrous sodium sulfate drying is concentrated into organic phase dried, be dissolved in again in the ethanol (150ml), add distilled water (50ml), 20-30 ℃ left standstill 7 hours, filtered, filtering layer is washed with ethanol, and 40 ℃ of drying under reduced pressure get crude product VII.With methanol=4/1 recrystallization, 40 ℃ of drying under reduced pressure get VII (40.1g, 65.7%).
Claims (14)
1, a kind of method for preparing candesartan Cilexetil, form by the following step:
(1) by 3-nitro-2-t-butoxycarbonyl amino methyl benzoate at K
2CO
3Exist down with 4-brooethyl-2 '-cyanobiphenyl nucleo philic substitution reaction generation 2-[N-(tertbutyloxycarbonyl)-N-[(2 '-cyanobiphenyl-4-yl) amino]-3-nitrobenzoic acid methyl esters (I);
(2) compound (I) room temperature reaction in the saturated ethanol of dry HCl gas is sloughed tertbutyloxycarbonyl, 2-[[2 '-cyanobiphenyl-4-yl] methyl] amino]-3-nitrobenzoic acid methyl esters (II);
(3) nitro of compound (II) with tin protochloride reduce 2-[[2 '-cyanobiphenyl-4-yl] methyl] amino]-3-Methyl anthranilate (III);
(4) compound (III) gets 1-[(2 '-cyanobiphenyl-4-yl with tetraethyl orthocarbonate heating cyclization) methyl]-2-oxyethyl group-1H-benzoglyoxaline-7-carboxylate methyl ester (IV);
(5) compound (IV) is hydrolyzed to 1-[(2 '-cyanobiphenyl-4-yl under alkaline condition) methyl]-2-oxyethyl group-1H-benzoglyoxaline-7-carboxylic acid (V);
(6) compound V and carbonic acid 1-iodine ethyl cyclohexyl ester nucleo philic substitution reaction under alkaline condition generates (±)-2-oxyethyl group-1-[(2 '-cyanobiphenyl-4-yl) methyl]-1H-benzoglyoxaline-7-carboxylic acid, 1-[[cyclohexyl oxygen base] carbonyl] the oxygen base] ethyl ester (VI);
(7) compound (VI) and alkaline azide and tributyltin chloride or other organic monoacids or Lewis acid or triethylamine hydrochloride reaction, cyano group obtains final product (±)-2-oxyethyl group-1-[[2 '-(1H-tetrazole-5-yl) [1 after changing the tetrazole ring into, 1 '-biphenyl]-the 4-yl] methyl]-1H-benzoglyoxaline-7-carboxylic acid, 1-[[cyclohexyl oxygen base] carbonyl] the oxygen base] ethyl ester (VII).
2, according to the preparation method of the described candesartan Cilexetil of claim 1, it is characterized in that step (5) hydrolysis under alkaline condition, be to be selected from NaOH, KOH, CsOH, Ba (OH)
2, Mg (OH)
2, Ca (OH)
2, Sr (OH)
2, KHCO
3, K
2CO
3, Na
2CO
3Or Cs
2CO
3Mineral alkali exist and to carry out down.
3, according to the preparation method of the described candesartan Cilexetil of claim 1, it is characterized in that step (5) hydrolysis under alkaline condition, be in the presence of the organic bases that is selected from sodium alkoxide, triethylamine, tri-n-butylamine or tripropylamine, to carry out.
4, according to the preparation method of the described candesartan Cilexetil of claim 1, it is characterized in that step (5) hydrolysis under alkaline condition, its solvent is DMF, DMSO, THF, dioxane or pyrrolidinone compounds.
5, the preparation method of candesartan Cilexetil according to claim 1 is characterized in that step (5) hydrolysis under alkaline condition, and temperature of reaction is 20 ℃～160 ℃.
6, according to the preparation method of the described candesartan Cilexetil of claim 1, it is characterized in that step (5) carries out nucleophilic substitution reaction under alkaline condition, adopting organic bases sodium alkoxide, triethylamine, tri-n-butylamine, tripropylamine is catalyzer.
7, according to the preparation method of the described candesartan Cilexetil of claim 1, it is characterized in that step (5) carries out nucleophilic substitution reaction under alkaline condition, mineral alkali NaOH, KOH, CsOH, Ba (OH) are adopted in reaction
2, Mg (OH)
2, Ca (OH)
2, Sr (OH)
2, KHCO
3, K
2CO
3, Na
2CO
3, Cs
2CO
3Be catalyzer.
8,, it is characterized in that step (5) reaction solvent is DMSO, THF, dioxy six alkane, pyrrolidinone compounds, hexamethylphosphoramide, acetone, glycol dimethyl ether, methylene dichloride, chloroform according to the preparation method of the described candesartan Cilexetil of claim 1.
9, the preparation method of candesartan Cilexetil according to claim 1 is characterized in that step (5) carries out nucleophilic substitution reaction under alkaline condition, and temperature of reaction is 0 ℃～120 ℃.
10, according to the preparation method of the described candesartan Cilexetil of claim 1, it is characterized in that in the step (6), compound VI and alkaline azide and tributyltin oxide or other small molecules organic monoacids or Lewis acid-respons, small molecular organic acid is acetic acid, propionic acid, butyric acid, Lewis acid is AlCl
3, CaCl
2, ZnCl
2, NH
4Cl, (NH
4)
2SO
4
11,, it is characterized in that compound VI and sodiumazide, triethylamine hydrochloride reaction obtain the husky smooth ester of final product bank sand ground according to the preparation method of the described candesartan Cilexetil of claim 1.
12, according to the preparation method of the described candesartan Cilexetil of claim 1, it is characterized in that in the step (7), compound VI and the reaction of alkaline triazo-compound, reaction solvent is DMF, toluene, dimethylbenzene, trimethylbenzene, dioxy six alkane, propyl carbinol, Pentyl alcohol or primary isoamyl alcohol.
13, the preparation method of candesartan Cilexetil according to claim 1 is characterized in that in the step (7), compound VI and the reaction of alkaline triazo-compound, and its temperature of reaction is 80 ℃～170 ℃.
14, according to the preparation method of the described candesartan Cilexetil of claim 1, it is characterized in that reacting by following formula two compound key intermediates, its structure is:
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| CN 00135191 CN1204125C (en) | 2000-12-27 | 2000-12-27 | New synthesis route of candixatan ester |
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| CN 00135191 CN1204125C (en) | 2000-12-27 | 2000-12-27 | New synthesis route of candixatan ester |
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| CN1361101A CN1361101A (en) | 2002-07-31 |
| CN1204125C true CN1204125C (en) | 2005-06-01 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101200464B (en) * | 2007-12-04 | 2011-02-16 | 王俊华 | Method for preparing sartan drug candesartan treating hypertension |
| CN101323610B (en) * | 2007-06-15 | 2013-10-30 | 横店集团成都分子实验室有限公司 | Preparation of trityl group candesartan cilexetil intermediate |
Families Citing this family (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2005206603A (en) * | 2004-01-21 | 2005-08-04 | Teva Pharmaceutical Industries Ltd | Preparation of candesartan cilexetil |
| US7692023B2 (en) | 2004-02-11 | 2010-04-06 | Teva Pharmaceutical Industries Ltd. | Candesartan cilexetil polymorphs |
| CN1953973A (en) * | 2004-05-05 | 2007-04-25 | 特瓦制药工业有限公司 | Preparation of candesartan cilexetil in high purity |
| JP2009185060A (en) * | 2004-05-19 | 2009-08-20 | Teva Pharmaceutical Industries Ltd | Candesartan cilexetil polymorph |
| JP2005330277A (en) * | 2004-05-19 | 2005-12-02 | Teva Pharmaceutical Industries Ltd | Candesartan cilexetil polymorph |
| TW200716615A (en) * | 2005-05-10 | 2007-05-01 | Teva Pharma | Stable micronized candesartan cilexetil and methods for preparing thereof |
| SI22488A (en) * | 2007-04-24 | 2008-10-31 | Krka, Tovarna Zdravil, D.D., Novo Mesto | Crystal 1-(cyclohexyloxycarbonyloxy)ethyl 1-((2'-cyanobiphenyl-4-yl)methyl)-ethoxy-1h-benz(d)imidazol-7-carboxyn |
| CN101646659B (en) * | 2007-04-26 | 2012-05-30 | 上海特化医药科技有限公司 | The method for making candixatan ester and intermediates thereof |
| WO2010067912A1 (en) * | 2008-12-12 | 2010-06-17 | Pharmacostech Co., Ltd. | Methods for preparing biphenyl benzoic acid derivatives |
| CN101781286B (en) * | 2010-01-28 | 2013-07-10 | 青岛黄海制药有限责任公司 | Method for preparing candesartan cilexetil |
| CN101880241B (en) * | 2010-07-14 | 2013-04-17 | 浙江美诺华药物化学有限公司 | Method for preparing 2-(substituted phenyl) methylamino-3-nitrobenzene methyl formate by one-pot method |
| CN102952040A (en) * | 2012-11-20 | 2013-03-06 | 峨眉山天梁星制药有限公司 | Method for reducing nitro group of candesartan cilexetil intermediate into amino group |
| CN103073537A (en) * | 2013-02-01 | 2013-05-01 | 武汉工程大学 | Synthesis process 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 |
-
2000
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101323610B (en) * | 2007-06-15 | 2013-10-30 | 横店集团成都分子实验室有限公司 | Preparation of trityl group candesartan cilexetil intermediate |
| CN101200464B (en) * | 2007-12-04 | 2011-02-16 | 王俊华 | Method for preparing sartan drug candesartan treating hypertension |
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| Publication number | Publication date |
|---|---|
| CN1361101A (en) | 2002-07-31 |
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Assignee: Lvye Chemical Co., Ltd., Yancheng Assignor: Shanghai Institute of Materia Medica, Chinese Academy of Sciences Contract fulfillment period: 2007.3.11 to 2017.3.10 contract change Contract record no.: 2008320000329 Denomination of invention: New synthesis route of candixatan ester Granted publication date: 20050601 License type: Exclusive license Record date: 2008.9.24 |
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