CN103965171A - Preparation method for Allisartan Isoproxil - Google Patents
Preparation method for Allisartan Isoproxil Download PDFInfo
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- CN103965171A CN103965171A CN201410180568.6A CN201410180568A CN103965171A CN 103965171 A CN103965171 A CN 103965171A CN 201410180568 A CN201410180568 A CN 201410180568A CN 103965171 A CN103965171 A CN 103965171A
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- ITOHRDDXCBTGOI-UHFFFAOYSA-N CCCCc1nc(Cl)c(C(OCO)=O)[n]1Cc(cc1)ccc1-c1ccccc1-c1nnn[nH]1 Chemical compound CCCCc1nc(Cl)c(C(OCO)=O)[n]1Cc(cc1)ccc1-c1ccccc1-c1nnn[nH]1 ITOHRDDXCBTGOI-UHFFFAOYSA-N 0.000 description 1
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
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Abstract
The invention relates to a preparation and refining method for Allisartan Isoproxil. The preparation method comprises the following steps: trityl chloride losartan is oxidized in a polarity organic solvent at the presence of a catalyst to obtain a compound expressed in formula IV; the compound expressed in the formula IV is further oxidized by oxidation reagent hydrogen peroxide/ sodium chlorite, Resorcino/ sodium chlorite, sulfamic acid/ sodium chlorite or 2-methyl-2-butene/sodium chlorite to obtain Allisartan Isoproxil intermediate expressed in formula III; then the Allisartan Isoproxil intermediate is subjected to ester formation and deprotection to obtain an Allisartan Isoproxil crude product; finally, the Allisartan Isoproxil crude product is refined by ethanol/ normal heptane to obtain purified Allisartan Isoproxil. According to the preparation method for Allisartan Isoproxil, the yield and efficiency are high, the by-product is few, the preparation method is environmental-friendly and suitable for industrialized production, the operation is simple and safe and the cost is low.
Description
Technical field
The invention belongs to the synthetic field of medicine, be specifically related to a kind of preparation and process for purification of A Lishatan ester.
Background technology
Hypertension is the major disease that threatens human health, finds antihypertensive drug efficient, low toxicity and contributes to alleviate social pressures and family burden, has good social benefit and economic interests.
Angiotensin II (Ang II) is that the Major Vessels of renin-angiotensin-aldosterone system (RAAS) shrinks hormone, it plays an important role in the pathobiology of multiple chronic disease, particularly it is particularly outstanding to the effect of blood pressure regulation, thereby Ang II acceptor is considered to the development target spot of a good antihypertensive drug.
EP0253310 discloses a series of imdazole derivatives, and the Losartan Potassium of listing is declared and obtained in 1994 in du pont company after deliberation, is the Ang II receptor antagonist antihypertensive drug of first non-peptide class.After this, the smooth class antihypertensive drug of a series of sand that gone on the market: candesartan Cilexetil, valsartan, irbesartan, telmisartan and olmesartan medoxomill etc. (EP0253310, WO2005049587, GB2419592, EP1719766, US5196444).
Losartan Potassium active metabolite EXP3174 in vivo has stronger hypotensive effect than Losartan Potassium, but EXP3174 molecular structure polarity is larger, is difficult to wait Passive intake form permeate through cell membranes by diffusion.US5298915 discloses a series of derivatives that 5 carboxyls of EXP3174 transform as to ester group, study emphatically compound H N-65021, and HN-65021 is disclosed by the hypotensive test effect of oral administration, similar (the British Jouurnal ofClinicalPharmacology of its antihypertensive activity and Losartan Potassium, 40,1995,591).
CN200680000397.8 discloses imidazole-5-carboxylic acid derivative, compound 8 is that A Lishatan ester has good hypotensive activity, its structure is suc as formula I, the following route A of disclosed preparation method in this patent document, Losartan Potassium obtains formula I compound through oxidation, upper protecting group, one-tenth ester, deprotection, and this route the first step oxidation hydroxyl becomes in the process of carboxyl, potassium permanganate can be reduced into fines shape Manganse Dioxide, filter this manganese mud length consuming time, efficiency is low, pollutes larger; Second step transformation efficiency is 70% left and right, and aftertreatment is loaded down with trivial details; And the by product that first two steps produce is more.This makes whole route cost high, is unsuitable for amplifying producing.
CN200710094021.4 discloses the another kind of preparation method of formula I compound, following route B, initial substance through nucleophilic substitution, oxidation, one-tenth ester, become tetrazole ring to obtain formula I compound, the method the first step nucleophilic substitution easily generates the isomer impurities of imidazole ring-3, is difficult for removing; Final step Cheng Huan uses sodium azide, operational hazards.
CN201210020174.5 discloses a series of anti-hypertension compounds and preparation method thereof, following route C, it is prepared the first step temperature and is controlled at 0～5 DEG C, aqueous sodium hypochlorite solution with 5% in the mixing solutions of acetone and water is oxidized, yield 70%, second step is used potassium permanganate, can produce equally Manganse Dioxide, and yield only has 40%, first two steps yield totally 28% is very low, and post-treating method was all that post separates, first two steps all use be organic and inorganic mixed solvent, be unfavorable for reclaim, be not suitable for amplify produce.
Therefore the present invention is directed to the deficiencies in the prior art, provide that a kind of yield is high, efficiency is high, by product is few, the method for environmental friendliness, easy-operating preparation I compound, cost has obtained that significantly price is low, is conducive to suitability for industrialized production.
Summary of the invention
The invention provides a kind of preparation method of A Lishatan ester, its feature comprises the following steps:
(1) under alkaline condition, catalyzer exist, in polar organic solvent under suitable temperature condition with oxidising agent oxidation trityl losartan, filter and obtain the filtrate of containing formula IV compound;
(2) under proper temperature, acidic conditions, above walk filtrate with oxidising agent oxidation and obtain formula III intermediate, described oxidising agent comprises hydrogen peroxide/Textone, Resorcino/Textone, thionamic acid/Textone, 2-methyl-2-butene/Textone;
(3), under alkaline condition, in polar solvent, formula III intermediate and chloromethyl sec.-propyl carbonic ether are reacted and obtain formula II compound under proper temperature;
(4) formula II compound deprotection obtains A Lishatan ester crude product;
(5) A Lishatan ester crude product refining is obtained to the A Lishatan ester of purifying;
In a preferred embodiment, described in step (1), catalyzer is Tempo/KBr, and wherein the mol ratio of Tempo and trityl losartan is 0.05: 1～0.1: 1, and the mol ratio of KBr and trityl losartan is 0.25: 1～1: 1.
In a further preferred embodiment, described in step (1), the mol ratio of catalyzer Tempo and trityl losartan is 0.075: 1～0.1: 1, and the mol ratio of KBr and trityl losartan is 0.25: 1～0.35: 1 and 0.5: 1～1: 1.
In a further preferred embodiment, described in step (1), the mol ratio of catalyzer Tempo and trityl losartan is 0.1: 1, and the mol ratio of KBr and trityl losartan is 0.25: 1.
In a preferred embodiment, described in step (1), suitable temperature of reaction is 10～18 DEG C.
In a further preferred embodiment, described in step (1), suitable temperature of reaction is 13～18 DEG C.
In a preferred embodiment, described in step (1) or step (3), polar solvent comprises DMF, DMA, methylene dichloride, acetonitrile, THF, acetone.
In a further preferred embodiment, described in step (1) or step (3), polar solvent is DMF.
In a preferred embodiment, described in step (1), oxidising agent is the hypochlorite of basic metal or alkaline-earth metal, comprises Ca (ClO)
2, NaClO; Wherein ClO
-with the mol ratio of trityl losartan be 1.4: 1～2: 1.
In a further preferred embodiment, described in step (1), oxidising agent hypochlorite is Losantin, wherein ClO
-with the mol ratio of trityl losartan be 1.6: 1～2: 1.
In a further preferred embodiment, described in step (1), oxidising agent hypochlorite is Losantin, wherein ClO
-with the mol ratio of trityl losartan be 1.6: 1.
In a preferred embodiment, the alkali that described in step (1), alkaline condition uses comprises sodium bicarbonate, saleratus, sodium carbonate, salt of wormwood.
In a further preferred embodiment, the alkali that described in step (1), alkaline condition uses comprises sodium bicarbonate, saleratus.
In a further preferred embodiment, the alkali that described in step (1), alkaline condition uses comprises sodium bicarbonate.
In a preferred embodiment, described in step (2), suitable temperature of reaction is 18～45 DEG C.
In a further preferred embodiment, described in step (2), suitable temperature of reaction is 20～35 DEG C.
In a preferred embodiment, described in step (2), oxidising agent comprises hydrogen peroxide/Textone, Resorcino/Textone, thionamic acid/Textone, 2-methyl-2-butene/Textone.
In a further preferred embodiment, described in step (2), oxidising agent is hydrogen peroxide/Textone, wherein the mol ratio of hydrogen peroxide and trityl losartan is 1.2: 1～2: 1, and the mol ratio of oxidising agent Textone and trityl losartan is 1.2: 1～2: 1.
In a further preferred embodiment, described in step (2), the mol ratio of oxidising agent hydrogen peroxide and trityl losartan is 1.4: 1～2: 1, and the mol ratio of Textone and trityl losartan is 1.2: 1～1.6: 1.
In a further preferred embodiment, described in step (2), the mol ratio of oxidising agent hydrogen peroxide and trityl losartan is 2: 1, and the mol ratio of Textone and trityl losartan is 1.4: 1.
In a preferred embodiment, described in step (2), acidic conditions is to have used buffering salt, comprises SODIUM PHOSPHATE, MONOBASIC or SODIUM PHOSPHATE, MONOBASIC/disodium-hydrogen, and wherein the mol ratio of buffering salt and trityl losartan is 1: 1～2: 1.
In a further preferred embodiment, the buffering salt using in step (2) is SODIUM PHOSPHATE, MONOBASIC, and the mol ratio of preferred SODIUM PHOSPHATE, MONOBASIC and trityl losartan is 1: 1.
In a preferred embodiment, the alkali that described in step (3), alkaline condition uses comprises salt of wormwood, sodium carbonate, triethylamine.
In a further preferred embodiment, be characterised in that, the alkali using at alkaline condition described in step (3) is salt of wormwood.
In a preferred embodiment, described in step (3), suitable temperature of reaction is 43～47 DEG C.
In a further preferred embodiment, described in step (3), suitable temperature of reaction is 44～46 DEG C.
In a preferred embodiment, the method for the described deprotection of step (4) is to reflux in methyl alcohol.
In a preferred embodiment, the described process for purification of step (5) is by dissolvings that reflux in ethanol of A Lishatan ester crude product, adds normal heptane, and stirs the crystallization of lowering the temperature, and filtration obtains purifying A Lishatan ester.
The present invention also provides a kind of method of refining A Lishatan ester, and its feature comprises the dissolving that refluxes in ethanol of A Lishatan ester crude product, adds normal heptane, and stirs cooling crystallization, filters the A Lishatan ester that obtains purifying.
In a preferred embodiment, in step (5) or process for purification, the mass ratio of ethanol used and A Lishatan ester crude product is 0.8: 1～1.4: 1, and the mass ratio of normal heptane used and A Lishatan ester crude product is 1: 1～1.5: 1.
The most preferably preparation method of above-mentioned a kind of A Lishatan ester, comprises the following steps:
(1) under sodium bicarbonate, catalyzer Tempo/KBr exist, in organic solvent DMF, with Losantin oxidation trityl losartan, temperature of reaction is controlled at 13～18 DEG C, and filtration obtains the filtrate of containing formula IV compound;
(2) in upper step filtrate, add SODIUM PHOSPHATE, MONOBASIC, add 50% hydrogen peroxide and sodium chlorite aqueous solution, temperature is controlled at 20～35 DEG C, the oxidized formula III intermediate that obtains of formula IV compound;
(3) under salt of wormwood exists, in solvent DMF, formula III intermediate and chloromethyl sec.-propyl carbonic ether react and obtain formula II compound in 43～47 DEG C;
(4) the formula II compound deprotection that refluxes in methyl alcohol obtains A Lishatan ester crude product;
(5) A Lishatan ester crude product is refluxed in ethanol dissolving, adds normal heptane, and stirs cooling crystallization, filters the A Lishatan ester that obtains purifying;
Its concrete synthetic route is as follows:
Except specified otherwise, all commercially available obtaining of used kit raw material of the present invention.
The effect of actively nourishing of the present invention is: first two steps oxidizing reaction has been avoided use KMnO
4the first step reacted rear direct filtration to filtrate further oxidation obtain intermediate formula III compound, operate very easyly, greatly shortened the reaction times, solvent is that pure polar organic solvent easily reclaims, post-reaction treatment is simple, and by product is few, and first two steps yield can reach 90%-98%, environmental pollution is little, the product purity that final refining obtains is high, and the process costs of whole preparation A Lishatan ester reduces greatly, is suitable for suitability for industrialized production.
According to the description of foregoing, not departing under the prerequisite of basic fundamental thought of the present invention, according to ordinary skill knowledge or customary means, can also there be amendment and the replacement of various ways to the embodiment of foregoing invention.
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment are only for the present invention is described, and be not used in restriction the present invention.The experimental technique of unreceipted actual conditions in the following example, operates according to normal condition conventionally.In below describing, DMF refers to DMF, and TLC refers to thin-layer chromatography, and THF refers to tetrahydrofuran (THF), and Tempo refers to 2,2,6,6-tetramethyl piperidine-1-oxyradical.Unless otherwise described, otherwise umber is considered as parts by weight, and per-cent is considered as weight percent.
Embodiment
The chloro-1-[2`-of embodiment 1 2-butyl-4-(1-trityl-tetrazolium-5-yl)-1,1`-xenyl-methyl]-5-aldehyde radical imidazoles (IV)
Under room temperature, in 10L reactor, add DMF6430mL, start to stir, agitator speed is 300r/min.Add trityl losartan (1170.4g, 1.76mol, 1.00eq), stir 15min, control temperature 10-15 DEG C.Until completely dissolved, in reaction flask, add KBr (52.3g, 0.44mol, 0.25eq), add sodium bicarbonate (295.49g, 3.50mol, 2.00eq), stir 10min.Add Tempo (27.84g, 0.18mol, 0.10eq), reaction solution gradually becomes reddish-brown or orange red.Maintain 13～16 DEG C of temperature of reaction, add Losantin (209.2g, 1.40mol, 0.80eq) in batches.Maintain 13～18 DEG C of temperature of reaction, be incubated 3 hours, after reaction 3h, sample, send HPLC to detect, when adding diatomite after trityl losartan content≤5.0%, continue can stop after stirring 1h.After reaction finishes, stop stirring, suction filtration, and with DMF washing, must more muddy safran formula IV compound reaction solution.Yield 95～99%.
The chloro-1-[2`-of embodiment 2 2-butyl-4-(1-trityl-tetrazolium-5-yl)-1,1`-xenyl-methyl]-5-aldehyde radical imidazoles (IV)
Under room temperature, in 1L reaction flask, add THF350mL, start to stir, agitator speed is 300r/min.Add trityl losartan (66.5g, 0.1mol, 1.00eq), stir 15min, control temperature 10-15 DEG C.Until completely dissolved, in reaction flask, add KBr (4.1g, 0.035mol, 0.35eq), add sodium bicarbonate (16.8g, 0.2mol, 2.00eq), stir 10min.Add Tempo (1.1g, 7.5mmol, 0.075eq), reaction solution gradually becomes reddish-brown or orange red.Maintain 13～16 DEG C of temperature of reaction, add Losantin (14.8g, 0.1mol, 1.0eq) in batches.Maintain 13～18 DEG C of temperature of reaction, be incubated 3 hours, after reaction 3h, sample, send HPLC to detect, when adding diatomite after trityl losartan content≤5.0%, continue can stop after stirring 1h.After reaction finishes, stop stirring, suction filtration, must more muddy safran formula IV compound reaction solution.Yield 65～85%.
The chloro-1-[2`-of embodiment 3 2-butyl-4-(1-trityl-tetrazolium-5-yl)-1,1`-xenyl-methyl]-5-aldehyde radical imidazoles (IV)
Under room temperature, in 10L reactor, add DMF6900mL, start to stir, agitator speed is 300r/min.Add trityl losartan (1064g, 1.6mol, 1.00eq), stir 15min, control temperature 10-15 DEG C.Until completely dissolved, in reaction flask, add KBr (95.2g, 0.8mol, 0.50eq), add sodium bicarbonate (268.8g, 3.2mol, 2.00eq), stir 10min.Add Tempo (12.16g, 0.08mol, 0.05eq), reaction solution gradually becomes reddish-brown or orange red.Maintain 13～16 DEG C of temperature of reaction, add Losantin (213.9g, 1.44mol, 0.90eq) in batches.Maintain 13～18 DEG C of temperature of reaction, be incubated 3 hours, after reaction 3h, sample, send HPLC to detect, when adding diatomite after trityl losartan content≤5.0%, continue can stop after stirring 1h.After reaction finishes, stop stirring, suction filtration, and with DMF washing, must more muddy safran formula IV compound reaction solution.Yield 95～99%.
The chloro-1-[2`-of embodiment 4 2-butyl-4-(1-trityl-tetrazolium-5-yl)-1,1`-xenyl-methyl]-5-carboxyl imidazoles (III)
IV compound filtrate (about 7000mL, 1.7mol) is transferred to 10L reactor, 13～18 DEG C of holding temperatures, start to stir, add AMSP (409.72g, 3.4mol, 2.00eq), stir 20-25min and keep 13～18 DEG C of the interior temperature of reaction flask.Configure at normal temperatures sodium chlorite solution with pure water, 480ml pure water is added in 1L beaker, under stirring, add Textone (280.3g, 2.48mol, 1.60eq) to make it to dissolve completely.In reactor, slowly drip 50% hydrogen peroxide (168.6g, 2.48mol, 1.60eq) and sodium chlorite aqueous solution, about 2h dropwises simultaneously.Control 20～35 DEG C of reacting liquid temperatures, and send HPLC to detect, when after IV compounds content≤1.00%, reaction can stop.After reaction finishes, stop stirring, reaction mixture is transferred in 50L reactor, slowly add in filtrate with the water of 20L, about 2h adds, and dropwises rear continuation stirring 3h, and white solid is separated out completely.Filtration under diminished pressure, washes filter cake with water, press dry rear suction filtration 1h, and 12h is dried in 60 DEG C of air blast.Obtain white formula III intermediate, productive rate 95～99%.
The chloro-1-[2`-of embodiment 5 2-butyl-4-(1-trityl-tetrazolium-5-yl)-1,1`-xenyl-methyl]-5-carboxyl imidazoles (III)
IV compound filtrate (about 450mL, 78mmol) is transferred to 1L reactor, 13～18 DEG C of holding temperatures, start to stir, add AMSP (9.5g, 78mmol, 1.00eq), stir 20-25min and keep 13～18 DEG C of the interior temperature of reaction flask.Configure at normal temperatures sodium chlorite solution with pure water, 17mL pure water is added in beaker, under stirring, add Textone (10.6g, 93.6mmol, 1.20eq) to make it to dissolve completely.In reactor, slowly drip 50% hydrogen peroxide (7.4g, 109.2mmol, 1.4eq) and sodium chlorite aqueous solution, about .1h dropwises simultaneously.Control 20～35 DEG C of reacting liquid temperatures, and send HPLC to detect, when after IV compounds content≤1.00%, reaction can stop.After reaction finishes, stop stirring, reaction mixture is transferred in 5L reactor, slowly add in filtrate with the water of 1.5L, about 2h adds, and dropwises rear continuation stirring 3h, and white solid is separated out completely.Filtration under diminished pressure, washes filter cake with water, press dry rear suction filtration 1h, and 12h is dried in 60 DEG C of air blast.Obtain white formula III intermediate, productive rate 95～99%.
The chloro-1-[2`-of embodiment 6 butyl-4-(1-trityl-tetrazolium-5-yl)-1,1`-xenyl-methyl]-5-carboxyl imidazoles (III)
IV compound filtrate (about 3700mL, 0.768mol) is transferred to 5L reactor, 13～18 DEG C of holding temperatures, start to stir, add AMSP (92.16g, 0.768mol, 1.00eq), stir 20-25min and keep 13～18 DEG C of the interior temperature of reaction flask.Configure at normal temperatures sodium chlorite solution with pure water, 200ml pure water is added in beaker, under stirring, add Textone (121.5g, 1.07mol, 1.40eq) to make it to dissolve completely.In reactor, slowly drip 50% hydrogen peroxide (104.4g, 1.53mol, 2.00eq) and sodium chlorite aqueous solution, about 2h dropwises simultaneously.Control 20～35 DEG C of reacting liquid temperatures, and send HPLC to detect, when after IV compounds content≤1.00%, reaction can stop.After reaction finishes, stop stirring, reaction mixture is transferred in 3L reactor, slowly add in filtrate with the water of 11L, about 2h adds, and dropwises rear continuation stirring 3h, and white solid is separated out completely.Filtration under diminished pressure, washes filter cake with water, press dry rear suction filtration 1h, and 12h is dried in 60 DEG C of air blast.Obtain white formula III intermediate, productive rate 95～99%.
The chloro-1-[2 ' of embodiment 7 2-butyl-4--(1-trityl-tetrazolium-5-yl)-1,1`-xenyl-methyl] imidazole-5-carboxylic acid, 1-[(isopropoxy) carbonyl acyl group] methoxyl group ester (II)
Formula III intermediate (1018.5g, 1.50mol, 1.00eq) is added in the reactor of 5L, add 2600ml DMF to make it to dissolve completely, under room temperature, add salt of wormwood (258.8g, 1.87mol, 1.25eq) g, stir 30min, add chloromethyl sec.-propyl carbonic ether (285g, 1.87mol, 1.25eq), stir 15min, be warming up to 43～47 DEG C, insulation reaction 3h.Send HPLC to detect, when after formula III intermediate content≤1.00%, reaction can stop.After reaction finishes, stop stirring, filter, obtain the faint yellow filtrate of clear, filtrate is transferred in 20L reactor, slowly add 10L water, about 1.5h dropwises, and finishes, and continues to stir 1h, obtains oyster white fine granularity suspension.Suction filtration, uses deionized water wash.Suction filtration 1h again after pressing dry, obtains white solid.Gained filter cake is dry 12h in the convection oven of 60 DEG C, obtains white formula II solid chemical compound (1225.3g, productive rate 96.36%).
The chloro-1-[2 ' of embodiment 8 2-butyl-4--(1-tetrazolium-5-yl)-1,1`-xenyl-methyl] imidazole-5-carboxylic acid, 1-[(isopropoxy) carbonyl acyl group] methoxyl group ester (A Lishatan ester crude product)
Add 9800ml methyl alcohol to 20L reactor, start to stir, rotating speed adds 1225.3g formula II solid chemical compound while being 200r/min, be heated to reflux.Reaction send after 8-10h HPLC to detect, and formula II compound is residual≤1.0% be considered as reaction end.After reaching reaction end, stop heating, continue to stir, rotating speed is 180r/min.About 3-4h is down to 20-25 DEG C, has water white transparency needle-like solid to separate out.Reaction solution is continued to be cooled to 15-20 DEG C, maintain 15-20 DEG C and stir 3h, by reacting liquid filtering, obtain faint yellow clear filtrate.This filtrate moves to concentrating under reduced pressure in 20L bottle, and vacuum tightness is 0.075MPa, distills out methyl alcohol at 40-45 DEG C, until without distillate.Add 800ml dehydrated alcohol, vacuum tightness is 0.075MPa, and distillation at 40-45 DEG C, until without distillate.
Add 900ml dehydrated alcohol, be warming up to backflow.Slowly add normal heptane 1100ml, backflow 15min, is cooled to 15 ± 2 DEG C with-10 DEG C/h speed, insulated and stirred 3h.Filtration under diminished pressure, with the mixed solution washing leaching cake of ethanol/normal heptane=1/3, press dry rear decompress filter 1h, get A Lishatan ester crude product (800.1g, productive rate 93.8%).Be directly used in without dry that next step is refining.
The chloro-1-[2 ' of embodiment 9 2-butyl-4--(1-tetrazolium-5-yl)-1,1`-xenyl-methyl] imidazole-5-carboxylic acid, 1-[(isopropoxy) carbonyl acyl group] methoxyl group ester (A Lishatan ester)
In 3L reactor, add 850ml dehydrated alcohol, add A Lishatan ester crude product (800.1g, 1.45mol), be warming up to backflow.Until completely molten clear after, slowly add normal heptane 1300ml, backflow 15min, is cooled to 10 ± 2 DEG C with-10 DEG C/h speed, insulated and stirred 3h.Filtration under diminished pressure, with the mixed solution washing leaching cake of ethanol/normal heptane=1/3, press dry rear decompress filter, obtains the A Lishatan ester (780.9g, yield 97.6%) of purifying.
The chloro-1-[2 ' of embodiment 10 2-butyl-4--(1-tetrazolium-5-yl)-1,1`-xenyl-methyl] imidazole-5-carboxylic acid, 1-[(isopropoxy) carbonyl acyl group] methoxyl group ester (A Lishatan ester)
In 5L reactor, add 950ml dehydrated alcohol, add A Lishatan ester crude product (549.9g, 1.72mol), be warming up to backflow.Until completely molten clear after, slowly add normal heptane 1200ml, backflow 15min, is cooled to 10 ± 2 DEG C with-10 DEG C/h speed, insulated and stirred 3h.Filtration under diminished pressure, with the mixed solution washing leaching cake of ethanol/normal heptane=1/3, press dry rear decompress filter, obtains the A Lishatan ester (540.0g, yield 98.2%) of purifying.
Claims (17)
1. the preparation method of Yi Zhong A Lishatan ester, its feature comprises the following steps:
(1) under alkaline condition, catalyzer exist, in polar organic solvent under suitable temperature condition with oxidising agent oxidation trityl losartan, filter and obtain the filtrate of containing formula IV compound;
(2) under proper temperature, acidic conditions, above walk filtrate with oxidising agent oxidation and obtain formula III intermediate, described oxidising agent comprises hydrogen peroxide/Textone, Resorcino/Textone, thionamic acid/Textone, 2-methyl-2-butene/Textone;
(3), under alkaline condition, in polar solvent, formula III intermediate and chloromethyl sec.-propyl carbonic ether are reacted and obtain formula II compound under proper temperature;
(4) formula II compound deprotection obtains A Lishatan ester crude product;
(5) A Lishatan ester crude product refining is obtained to the A Lishatan ester of purifying;
2. preparation method according to claim 1, is characterized in that, in step (1), described catalyzer is Tempo/KBr; Wherein the mol ratio of Tempo and trityl losartan is 0.05: 1～0.1: 1, and the mol ratio of KBr and trityl losartan is 0.25: 1～1: 1.
3. preparation method according to claim 2, it is characterized in that, in step (1), the mol ratio of described catalyzer Tempo and trityl losartan is 0.075: 1～0.1: 1, and the mol ratio of KBr and trityl losartan is 0.25: 1～0.35: 1.
4. preparation method according to claim 1, is characterized in that, in step (1), described suitable temperature of reaction is 10～18 DEG C.
5. preparation method according to claim 1, is characterized in that, described polar solvent comprises DMF, DMA, methylene dichloride, acetonitrile, THF, acetone.
6. preparation method according to claim 5, is characterized in that, described polar solvent is DMF.
7. preparation method according to claim 1, is characterized in that, in step (1), described oxidising agent is the hypochlorite of basic metal or alkaline-earth metal, comprises Ca (ClO)
2, NaClO; Wherein ClO
-with the mol ratio of trityl losartan be 1.4: 1～2: 1.
8. preparation method according to claim 7, is characterized in that, in step (1), described oxidising agent is Losantin, wherein ClO
-with the mol ratio of trityl losartan be 1.6: 1～2: 1.
9. preparation method according to claim 1, is characterized in that, in step (1), the alkali that described alkaline condition uses comprises sodium bicarbonate, saleratus, sodium carbonate, salt of wormwood.
10. preparation method according to claim 1, is characterized in that, in step (2), described suitable temperature of reaction is 18～45 DEG C.
11. preparation methods according to claim 1, it is characterized in that, in step (2), described oxidising agent is hydrogen peroxide/Textone, wherein the mol ratio of hydrogen peroxide and trityl losartan is 1.2: 1～2: 1, and the mol ratio of Textone and trityl losartan is 1.2: 1～2: 1.
12. preparation methods according to claim 11, is characterized in that, the mol ratio of described hydrogen peroxide and trityl losartan is 1.4: 1～2: 1, and the mol ratio of Textone and trityl losartan is 1.2: 1～1.6: 1.
13. according to preparation method claimed in claim 1, it is characterized in that, in step (2), described acidic conditions is to have used buffering salt, comprise SODIUM PHOSPHATE, MONOBASIC or SODIUM PHOSPHATE, MONOBASIC/disodium-hydrogen, wherein the mol ratio of buffering salt and trityl losartan is 1: 1～2: 1.
14. preparation methods according to claim 1, is characterized in that, in step (3), the alkali that described alkaline condition uses comprises salt of wormwood, sodium carbonate, triethylamine, and described proper temperature is 43～47 DEG C; Described in step (4), the method for deprotection is to reflux in methyl alcohol.
15. preparation methods according to claim 1, is characterized in that, the described process for purification of step (5) is by dissolvings that reflux in ethanol of A Lishatan ester crude product, adds normal heptane, and stirs the crystallization of lowering the temperature, and filtration obtains purifying A Lishatan ester.
The method of 16. 1 kinds of refining A Lishatan esters, its feature comprises the dissolving that refluxes in ethanol of A Lishatan ester crude product, adds normal heptane, and stirs cooling crystallization, filters the A Lishatan ester that obtains purifying.
17. according to the method described in claim 15 or 16, it is characterized in that, the mass ratio of ethanol used and A Lishatan ester crude product is 0.8: 1～1.4: 1, and the mass ratio of normal heptane used and A Lishatan ester crude product is 1: 1～1.5: 1.
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