CN104262332A - Preparation method of olmesartan medoxomil - Google Patents
Preparation method of olmesartan medoxomil Download PDFInfo
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- CN104262332A CN104262332A CN201410470176.3A CN201410470176A CN104262332A CN 104262332 A CN104262332 A CN 104262332A CN 201410470176 A CN201410470176 A CN 201410470176A CN 104262332 A CN104262332 A CN 104262332A
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
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Abstract
The invention provides a preparation method of olmesartan medoxomil, which comprises the following step: removing triphenylmethyl protecting group from triphenylmethyl olmesartan medoxomil VII in an organic solvent containing an acid ion exchange macroporous resin to obtain the olmesartan medoxomil I. The invention also provides a preparation method of the raw material triphenylmethyl olmesartan medoxomil VII compound. By using the acid ion exchange macroporous resin, the method has the advantages of mild reaction conditions, high reaction selectivity and fewer side reactions; the acid ion exchange macroporous resin can be filtered instead of neutralization or water washing after the reaction finishes, can be recycled, and has the advantages of high stability, high heat resistance, high mechanical strength and long service life; and thus, the method can overcome the defects in the prior art, lowers the reagent cost, is beneficial to environmental protection and suitable for industrial production, and has high application value.
Description
Technical field
The present invention relates to pharmaceutical chemistry, be specifically related to medicine preparation, particularly relate to a kind of preparation method preparing olmesartan medoxomill.
Background technology
Olmesartan medoxomill (Olmesartan Medoxomil) is the orally active non-peptideangiotensinⅱ receptor antagonist of one that Japanese Sankyo company develops.This medicine was approved listing by U.S. FDA in April, 2004, and commodity are called Banicar, was characterized in that the transformation period is longer, within one day, took once, namely in one day, effectively can control blood pressure, therefore easy administration.Olmesartan medoxomill is compared with other Angiotensin Ⅱ receptor antagonist class medicine, and the dosage of this medicine is little, rapid-action, and hypotensive effect is stronger and lastingly, the incidence of untoward reaction is low, has obvious advantage.Therefore develop this antihypertensive drug that is efficient, long-acting, low toxicity of olmesartan medoxomill to have very important significance.
(5 ?first base ?2 ?oxygen are for ?1 for first base miaow azoles ?5 ?carboxylic acid for olmesartan medoxomill chemistry 4 ?(1 ?hydroxyl base ?1 ?methylethyl) ?2 ?third base ?1 ?{ 4 ?[2 ?(four azoles ?5 ?yls) phenyl] phenyl } by name, 3 ?bis-oxygen heterocyclic pentene ?4 ?yls) methyl ester, structural formula is:
Carried out more research to the synthetic method of olmesartan medoxomill both at home and abroad, the committed step in preparation method all needs the skeleton structure be formed by connecting by the phenylbenzene moiety in molecular structure and imidazole fragment.US5616599 discloses the synthetic method of two kinds of olmesartan medoxomills the earliest, first method is: be hydrolyzed after phenylbenzene moiety is connected with imidazole fragment and obtain intermediate salt, this salt again with 4 ?Lv Jia Ji ?5 ?Jia Ji ?1,3 ?bis-oxygen heterocyclic pentene ?2 ?ketone esters obtain trityl olmesartan medoxomil, finally slough trityl and obtain olmesartan medoxomill.Second method is: imidazole fragment first with 4 ?chlorine first base ?5 ?first base ?1,3 ?bis-oxygen heterocyclic pentene ?2 ?ketone esters, then be connected with phenylbenzene moiety and obtain olmesartan medoxomill.What current industrialization investigation and application was maximum is first method, and its reaction equation is as follows.
After above two kinds of methods all need to remove trityl-protecting group; just target product can be obtained; and when using acetic acid deprotection base; more than 10 times equivalents of the consumption of acetic acid normally reaction substrate, need neutralize with alkali during aftertreatment, thus can produce a large amount of waste liquid; and complicated operation; reduce production efficiency, increase production cost and cost of sewage disposal, be unfavorable for energy-saving and emission-reduction and environment protection.Patent WO2010026255A1 ethyl acetate, methyl alcohol and dilute hydrochloric acid mixed solution remove trityl-protecting group, and 1% a large amount of ammoniacal liquor of aftertreatment adjusts pH value, obtains olmesartan medoxomill through extraction and crystallization.The trityl-protecting group that the mixed solution of patent CN1976926A acetone and dilute sulphuric acid removes, aftertreatment adds sodium bicarbonate and adjusts pH value, obtains olmesartan medoxomill after filtration.The method that existing detritylation prepares olmesartan medoxomill all can produce the problem of the above aftertreatment, therefore, needs the preparation method improving olmesartan medoxomill.
The industrial acetic acid catalysis of prior art removes trityl-protecting group and prepares olmesartan medoxomill, and acetic acid consumption is very large, generally needs more than 10 times equivalents of reaction substrate, needs to steam except acetic acid with alkali neutralization during aftertreatment, operates very loaded down with trivial details.Except acetic acid, traditional organic acid or mineral acid, as formic acid, hydrochloric acid, sulfuric acid etc.; may be used to remove trityl-protecting group reaction, but these acid to be finished aftertreatment more loaded down with trivial details, corrosive equipment; need, with alkali neutralization, to produce a large amount of waste liquid, easily pollute environment.And the polymer catalyst that developed recently gets up because it is easy to use, environmental friendliness, increasing concern is caused to zero corrodibility of equipment, wherein, application is obtained in the reaction such as the esterification of strong acidic ion resin in organic synthesis, hydrolysis, polymerization and condensation.Apply more with Amberlyst type and Nafion H type resins synthesis in storng-acid cation exchange resin, Nafion H type resin and more expensive with the resin price of silicon-dioxide compound, be unfavorable for commercial introduction, and Amberlyst type resin price is cheap, is easy to industrial applications.Amberlyst type Zeo-karb has good pore structure, larger surface-area and stability; can use in water and non-aqueous solvent; there is stronger acidity and very high catalytic activity; acid (bonding sulfonic group) comparatively carboxylic acid is strong; therefore, the present invention selects the acid ion of Amberlyst series to exchange macroporous resin to carry out removing trityl-protecting group and prepare olmesartan medoxomill.According to result of study, the preferred Amberlyst of the present invention ?15 type acid ions exchange macroporous resin catalyzed reactions, this reaction preference is high, mild condition, side reaction is few, without the need to neutralization, washing after having reacted, filter, and can reuse, products obtained therefrom can realistic requirement.With traditional sour reagents ratio comparatively, ion-exchange macroporous resin is as a kind of solid acid catalyst, the aftertreatment problem of prior art can be overcome well, not only simplify post-processing operation, can also discharging of waste liquid be reduced, reduce reagent cost, be conducive to environmental protection, be applicable to suitability for industrialized production, have larger using value.
Summary of the invention
Technical problem to be solved by this invention is to overcome above-mentioned weak point, and research and design reaction conditions is gentle, and selectivity is high, simple to operate, and by product is few, and productive rate is high, is conducive to environmental protection, is applicable to the preparation method of the olmesartan medoxomill of suitability for industrialized production.
The invention provides a kind of preparation method of olmesartan medoxomill:
Described method is trityl olmesartan medoxomil VII is removed trityl-protecting group in the organic solvent exchanging macroporous resin containing acid ion obtain olmesartan medoxomill I:
Acid ion exchange macroporous resin described in the inventive method is the high-molecular copolymer by Sulfonated polystyrene and divinylbenzene crosslink, be selected from Amberlyst 15 type, Aberlyst ?16 types or Amberlyst ?the strong acidic ion of 35 types exchange macroporous resin, preferred Amberlyst ?15 type ion exchange resin.Described acid ion exchanges the solid acid catalyst that macroporous resin can be filtered recovery after deprotection reaction.
Described in the inventive method, trityl olmesartan medoxomil VII and acid ion exchange the weight ratio of macroporous resin is 1:0.01 ~ 5.Preferably, the weight ratio that described trityl olmesartan medoxomil VII and acid ion exchange macroporous resin is 1:0.1 ~ 0.5.
Organic solvent described in the inventive method be methyl alcohol, ethanol, acetone, ethyl acetate, acetonitrile, ether, methyl tertiary butyl ether, tetrahydrofuran (THF), dioxane, methylene dichloride, chloroform, toluene or N, N ?one or more mixed solvent in dimethyl formamide.
Temperature of reaction described in the inventive method is 0 DEG C ~ 100 DEG C.
Preferably, described temperature of reaction is 10 DEG C ~ 70 DEG C.
Another object of the present invention there is provided the preparation method of raw material trityl olmesartan medoxomil VII compound, and the method comprises the following steps:
(1) 1 ?tri-benzene first base ?5 ?(4 ' ?halogenated methyl connection benzene ?2 ?) ?1H ?tetrazolium II and 4 ?(1 ?hydroxyl base ?1 ?methylethyl) ?2 ?propyl group miaow azoles ?5 ?carboxylic acid, ethyl ester III in the presence of a base, prepare 4 ?(1 ?hydroxyl base ?1 ?methylethyl) ?2 ?third base ?1 ?{ 4 ?[2 ?(three phenmethyl four azoles ?5 ?yls) phenyl] phenyl } first base miaow azoles ?5 ?carboxylicesters IV in organic solvent;
(2) formula IV compound prepares 4 ?(1 ?hydroxyl base ?1 ?methylethyl) ?2 ?third base ?1 ?{ 4 ?[2 ?(three phenmethyl four azoles ?5 ?yls) phenyl] phenyl } first base miaow azoles ?5 ?carboxylate salt V through basic hydrolysis, intermediate V crude product is without being further purified, directly obtain trityl olmesartan medoxomil VII with 4 ?halogen for the esterification of first base ?5 ?first base ?1,3 ?bis-oxygen heterocyclic pentene ?2 ?ketone VI;
In above-mentioned reaction formula, R is the alkyl of 1 ~ 5 carbon atom; X is chlorine, bromine or iodine; M is the basic metal of lithium, sodium or potassium.
The described step of above-mentioned reaction (1) concrete operation step: add in reaction vessel 1 ?San Ben Jia Ji ?5 ?(4 ’ ?halogenated methyl Lian Ben ?2 ?) ?1H ?tetrazolium II, 4 ?(1 ?Qiang Ji ?1 ?methylethyl) ?2 ?propyl group Mi Zuo ?5 ?carboxylicesters III, alkali, add organic solvent again, heating reflux reaction 2 ~ 10 hours, filter, filtrate is concentrated into dry, add organic solvent crystallization, filtration drying obtains 4 ?(1 ?hydroxyl base ?1 ?methylethyl) ?2 ?third base ?1 ?{ 4 ?[2 ?(three phenmethyl four azoles ?5 ?yls) phenyl] phenyl } first base miaow azoles ?5 ?carboxylicesters IV.
Described 1 ?San Ben Jia Ji ?5 ?(4 ’ ?halogenated methyl Lian Ben ?2 ?) ?1H ?tetrazolium II and 4 ?(1 ?Qiang Ji ?1 ?methylethyl) ?2 ?propyl group Mi Zuo ?5 ?the mol ratio of carboxylicesters III be 1:0.8 ~ 1.4; Described alkali is the one in sodium carbonate, salt of wormwood or Quilonum Retard, alkali and 1 ?San Ben Jia Ji ?5 ?(4 ’ ?halogenated methyl Lian Ben ?2 ?) ?1H ?the mol ratio of tetrazolium II be 1:3 ~ 5; Described organic solvent be acetonitrile, tetrahydrofuran (THF), dioxane, ethyl acetate, methylene dichloride, toluene, methyl tertiary butyl ether or N, N ?one or more mixed solvents in dimethyl formamide; The described reaction times is 2 ~ 10 hours, preferably 3 ~ 5 hours; Described recrystallisation solvent is one or both mixed solvents in ether, methyl tertiary butyl ether, acetone, ethyl acetate, tetrahydrofuran (THF), methylene dichloride.
Described step (2) comprises following concrete operations:
(a). in reaction vessel, add 4 ?(1 ?hydroxyl base ?1 ?methylethyl) ?2 ?third base ?1 ?{ 4 ?[2 ?(three phenmethyl four azoles ?5 ?yls) phenyl] phenyl } first base miaow azoles ?5 ?carboxylicesters IV, alkali and solvent, reaction is warming up to 20 DEG C ~ 70 DEG C, stirring reaction 5 ~ 15 is little of reacting completely, and aftertreatment obtains 4 ?(1 ?hydroxyl base ?1 ?methylethyl) ?2 ?third base ?1 ?{ 4 ?[2 ?(three phenmethyl four azoles ?5 ?yls) phenyl] phenyl } first base miaow azoles ?5 ?carboxylate salt V crude product and is directly used in next reaction.
Described alkali is the alkali metal hydroxide of lithium, sodium or potassium; The mol ratio of described alkali and 4 ?(1 ?hydroxyl base ?1 ?methylethyl) ?2 ?third base ?1 ?{ 4 ?[2 ?(three phenmethyl four azoles ?5 ?yls) phenyl] phenyl } first base miaow azoles ?5 ?carboxylate salt V is 1.2 ~ 2:1; Described solvent be N, N ?one or more mixed solvent in dimethyl formamide, dioxane, tetrahydrofuran (THF), acetonitrile, methylene dichloride, toluene, methyl tertiary butyl ether or water;
(b). in reaction vessel, add 4 ?(1 ?hydroxyl base ?1 ?methylethyl) ?2 ?third base ?1 ?{ 4 ?[2 ?(three phenmethyl four azoles ?5 ?yls) phenyl] phenyl } first base miaow azoles ?5 ?carboxylate salt V crude product, alkali and 4 ?halogen for first base ?5 ?first base ?1,3 ?bis-oxygen heterocyclic pentene ?2 ?ketone VI, temperature of reaction is 30 DEG C ~ 100 DEG C, stirring reaction, to completely, obtains trityl olmesartan medoxomil VII through aftertreatment.
Described alkali is alkaline carbonate or the oxyhydroxide of lithium, sodium or potassium; Described 4 ?(1 ?hydroxyl base ?1 ?methylethyl) ?2 ?third base ?1 ?{ 4 ?[2 ?(three phenmethyl four azoles ?5 ?yls) phenyl] phenyl } first base miaow azoles ?5 ?carboxylate salt V, 4 ?halogen is 1:1 ~ 1.5:1 ~ 2 for first base ?5 ?first base ?1,3 ?bis-oxygen heterocyclic pentene ?2 ?ketone VI and the mol ratio of alkali.
Embodiment
Enumerate embodiment below so that the invention will be further described, so that understand the present invention, and concrete material variety, proportioning, processing condition and the result thereof described by embodiment, do not form limiting to the claimed invention.
Embodiment 1
The preparation of 4 ?(1 ?hydroxyl base ?1 ?methylethyl) ?2 ?third base ?1 ?{ 4 ?[2 ?(three phenmethyl four azoles ?5 ?yls) phenyl] phenyl } first base miaow azoles ?5 ?carboxylic acid, ethyl ester
Add in reactor 1 ?San Ben Jia Ji ?5 ?(4 ’ ?bromomethyl Lian Ben ?2 ?) ?1H ?tetrazolium (500g, 0.9mol), 4 ?(1 ?Qiang Ji ?1 ?methylethyl) ?2 ?propyl group Mi Zuo ?5 ?carboxylic acid, ethyl ester (180g, 0.75mol), salt of wormwood (390g), add acetonitrile (7.5L) again, heating reflux reaction 3 ~ 5 hours.After TLC monitoring reacts completely, be cooled to room temperature (25 DEG C), filter, filtrate is concentrated into dry in 40 DEG C of decompressions (-0.09MPa).Add methyl tertiary butyl ether (1L), room temperature (25 DEG C) stirring and crystallizing 2 hours, filtration, 60 DEG C of decompression (-0.09MPa) dryings obtain solid chemical compound 4 ?(1 ?hydroxyl base ?1 ?methylethyl) ?2 ?third base ?1 ?{ 4 ?[2 ?(three phenmethyl four azoles ?5 ?yls) phenyl] phenyl }, and (440 g) for first base miaow azoles ?5 ?carboxylicesters, productive rate 82%, mp:167 ?168 DEG C.
Embodiment 2:
The preparation of 4 ?(1 ?hydroxyl base ?1 ?methylethyl) ?2 ?third base ?1 ?{ 4 ?[2 ?(three phenmethyl four azoles ?5 ?yls) phenyl] phenyl } first base miaow azoles ?5 ?carboxylic acid lithium and trityl olmesartan medoxomil VII
4 ?(1 ?hydroxyl base ?1 ?methylethyl) ?2 ?third base ?1 ?{ 4 ?[2 ?(three phenmethyl four azoles ?5 ?yls) phenyl] phenyl } first base miaow azoles ?5 ?carboxylic acid, ethyl ester (358g is added in reactor, 0.5mol), lithium hydroxide (32g, 0.75mol), dioxane (8L) and water (4L), reaction is warming up to 55 DEG C, stirring reaction 5 ~ 7 hours, after TLC monitoring reacts completely, reaction system is cooled to 25 DEG C, 2L ethyl acetate and 1L saturated aqueous common salt is added, separatory in reaction solution.Aqueous phase is extracted with ethyl acetate three times, each 2L, merge organic phase, after saturated common salt water washing organic phase three times, organic phase anhydrous magnesium sulfate drying, filters, filtrate is concentrated into dry in 40 DEG C of decompressions (-0.09MPa), obtain faint yellow foaming material, being compound V crude product, being directly used in next step without being further purified.Salt of wormwood (97g is added in reactant obtained above, 0.7mol), 4 ?Xiu Jia Ji ?5 ?Jia Ji ?1, 3 ?bis-oxygen heterocyclic pentene ?2 ?ketone (115g, 0.6mol) and N, N ?dimethyl formamide (2.2L), temperature of reaction is 50 DEG C, stirring reaction 2-3 hour, after TLC monitoring reacts completely, reaction system is cooled to 25 DEG C, add 5L ethyl acetate and 5L water, re-extract three times, merge organic phase, organic phase saturated common salt water washing 2 times, anhydrous magnesium sulfate drying, filter, filtrate is concentrated into dry in 40 DEG C of decompressions (-0.09MPa), add after acetone (1.5L) reflux is dissolved and be evaporated to crystal precipitation, stop heating, cooling stirring and crystallizing, after filtration, 60 DEG C of decompression (-0.09MPa) dryings obtain trityl olmesartan medoxomil VII, and (280 g), productive rate 70%, mp:102 ?104 DEG C.
Embodiment 3:
The preparation of 4 ?(1 ?hydroxyl base ?1 ?methylethyl) ?2 ?third base ?1 ?{ 4 ?[2 ?(four azoles ?5 ?yls) phenyl] phenyl } first base miaow azoles ?5 ?carboxylic acid (5 ?first base ?2 ?oxygen for ?1,3 ?bis-oxygen heterocyclic pentene ?4 ?yls) methyl ester (olmesartan medoxomill I)
Trityl olmesartan medoxomil VII (800mg in reaction flask, 1mmol) be dissolved in 4 mL methylene dichloride and 4mL methanol mixed solvent, add 400mg acid ion exchange macroporous resin Amberlyst ?15, stirring at room temperature is reacted, after TLC monitoring reacts completely, filter, use methanol wash resin, TLC monitors washings extremely without organic substance residues, merging filtrate, filtrate is concentrated in 40 DEG C of decompressions (-0.09MPa) and dryly obtains oily matter, add methylene dichloride (3mL) and be heated to 40 DEG C of dissolvings, filter, filtrate is concentrated into dry in 40 DEG C of decompressions (-0.09MPa), add ethyl acetate (3mL) heating for dissolving, be cooled to 4 DEG C of crystallizatioies, filter, 60 DEG C of decompression (-0.09MPa) dryings obtain the white solid (480mg) of olmesartan medoxomill for 8 hours, yield 86%, mp:178 ?180 DEG C, HPLC detection level is 98.7%.
Embodiment 4:
The preparation of 4 ?(1 ?hydroxyl base ?1 ?methylethyl) ?2 ?third base ?1 ?{ 4 ?[2 ?(four azoles ?5 ?yls) phenyl] phenyl } first base miaow azoles ?5 ?carboxylic acid (5 ?first base ?2 ?oxygen for ?1,3 ?bis-oxygen heterocyclic pentene ?4 ?yls) methyl ester (olmesartan medoxomill I)
Trityl olmesartan medoxomil VII (800 mg in reaction flask, 1 mmol) be dissolved in 4 mL tetrahydrofuran (THF)s and 4 mL methanol mixed solvent, add 200 mg acid ions exchange macroporous resin Amberlyst ?15, be heated to stirring reaction under 45 DEG C of conditions, after TLC monitoring reacts completely, filter, use methanol wash resin, TLC monitors washings extremely without organic substance residues, merging filtrate, filtrate is concentrated in 40 DEG C of decompressions (-0.09MPa) and dryly obtains oily matter, add methylene dichloride (3mL) and be heated to 40 DEG C of dissolvings, filter, filtrate is concentrated into dry in 40 DEG C of decompressions (-0.09MPa), add ethyl acetate (3mL) heating for dissolving, be cooled to 4 DEG C of crystallizatioies, filter, 60 DEG C of decompression (-0.09MPa) dryings obtain the white solid (450mg) of olmesartan medoxomill for 8 hours, yield 80%, mp:178 ?180 DEG C, HPLC detection level is 99.2%.
Embodiment 5:
The preparation of 4 ?(1 ?hydroxyl base ?1 ?methylethyl) ?2 ?third base ?1 ?{ 4 ?[2 ?(four azoles ?5 ?yls) phenyl] phenyl } first base miaow azoles ?5 ?carboxylic acid (5 ?first base ?2 ?oxygen for ?1,3 ?bis-oxygen heterocyclic pentene ?4 ?yls) methyl ester (olmesartan medoxomill I)
Trityl olmesartan medoxomil VII (80g in reaction flask, 0.1mol) be dissolved in 400mL tetrahydrofuran (THF) and 400mL methanol mixed solvent, add 30g acid ion exchange macroporous resin Amberlyst ?15, room temperature (25 DEG C) stirring reaction, after TLC monitoring reacts completely, filter, use methanol wash resin, TLC monitors washings extremely without organic substance residues, merging filtrate, filtrate is concentrated in 40 DEG C of decompressions (-0.09MPa) and dryly obtains oily matter, add dehydrated alcohol (300mL) reflux to dissolve, 40 DEG C of decompression (-0.09MPa) concentrating steam 150mL ethanol, 4 DEG C of ice bath crystallisation by cooling, filter, filter cake adds ethyl acetate (2.2L) and dissolves, 40 DEG C of decompression (-0.09MPa) concentrating steam 1.5L ethyl acetate, 4 DEG C of ice bath cooling crystallizations, filter, 60 DEG C of decompression (-0.09MPa) dryings obtain the white solid (45.8g) of olmesartan medoxomill for 8 hours, yield 82%, mp:178 ?180 DEG C, HPLC detection level is 99.0%.
Claims (10)
1. a preparation method for olmesartan medoxomill, is characterized in that, the method is that trityl olmesartan medoxomil VII is removed trityl-protecting group in the organic solvent exchanging macroporous resin containing acid ion, obtains olmesartan medoxomill I, represents with following formula:
2. the preparation method of a kind of olmesartan medoxomill according to claim 1, is characterized in that, described acid ion exchange macroporous resin be selected from Amberlyst 15 type, Aberlyst ?16 types or Amberlyst ?the strong acidic ion of 35 types exchange macroporous resin.
3. the preparation method of a kind of olmesartan medoxomill according to claim 1, is characterized in that, described acid ion exchange macroporous resin be Amberlyst ?15 type ion-exchange macroporous resins.
4. the preparation method of a kind of olmesartan medoxomill according to claim 1, is characterized in that, the weight ratio that described trityl olmesartan medoxomil VII and acid ion exchange macroporous resin is 1:0.01 ~ 5.
5. the preparation method of a kind of olmesartan medoxomill according to claim 4, is characterized in that, the weight ratio that described trityl olmesartan medoxomil VII and acid ion exchange macroporous resin is 1:0.1 ~ 0.5.
6. the preparation method of a kind of olmesartan medoxomill according to claim 1, it is characterized in that, described organic solvent be methyl alcohol, ethanol, acetone, ethyl acetate, acetonitrile, ether, methyl tertiary butyl ether, tetrahydrofuran (THF), dioxane, methylene dichloride, chloroform, toluene or N, N ?one or more mixed solvent in dimethyl formamide; Temperature of reaction is 0 DEG C ~ 100 DEG C.
7. the preparation method of a kind of olmesartan medoxomill according to claim 6, it is characterized in that, described temperature of reaction is 10 DEG C ~ 70 DEG C.
8. the preparation method of a kind of olmesartan medoxomill according to claim 1, it is characterized in that, described trityl olmesartan medoxomil VII compound is prepared by following method, comprises the following steps:
(1) 1 ?tri-benzene first base ?5 ?(4 ' ?halogenated methyl connection benzene ?2 ?) ?1H ?tetrazolium II and 4 ?(1 ?hydroxyl base ?1 ?methylethyl) ?2 ?propyl group miaow azoles ?5 ?carboxylic acid, ethyl ester III in the presence of a base, prepare 4 ?(1 ?hydroxyl base ?1 ?methylethyl) ?2 ?third base ?1 ?{ 4 ?[2 ?(three phenmethyl four azoles ?5 ?yls) phenyl] phenyl } first base miaow azoles ?5 ?carboxylicesters IV in organic solvent;
(2) formula IV compound prepares 4 ?(1 ?hydroxyl base ?1 ?methylethyl) ?2 ?third base ?1 ?{ 4 ?[2 ?(three phenmethyl four azoles ?5 ?yls) phenyl] phenyl } first base miaow azoles ?5 ?carboxylate salt V through basic hydrolysis, intermediate V crude product is without being further purified, directly obtain trityl olmesartan medoxomil VII with 4 ?halogen for the esterification of first base ?5 ?first base ?1,3 ?bis-oxygen heterocyclic pentene ?2 ?ketone VI;
In above-mentioned reaction formula, R is the alkyl of 1 ~ 5 carbon atom; X is chlorine, bromine or iodine; M is the basic metal of lithium, sodium or potassium.
9. the preparation method of a kind of olmesartan medoxomill according to claim 8, it is characterized in that, the preparation process (1) of described trityl olmesartan medoxomil VII is: add in reaction vessel 1 ?San Ben Jia Ji ?5 ?(4 ’ ?halogenated methyl Lian Ben ?2 ?) ?1H ?tetrazolium II, 4 ?(1 ?Qiang Ji ?1 ?methylethyl) ?2 ?propyl group Mi Zuo ?5 ?carboxylicesters III, alkali, add organic solvent again, heating reflux reaction 2 ~ 10 hours, filter, filtrate is concentrated into dry, add organic solvent crystallization, filtration drying obtains 4 ?(1 ?hydroxyl base ?1 ?methylethyl) ?2 ?third base ?1 ?{ 4 ?[2 ?(three phenmethyl four azoles ?5 ?yls) phenyl] phenyl } first base miaow azoles ?5 ?carboxylicesters IV, described 1 ?San Ben Jia Ji ?5 ?(4 ’ ?halogenated methyl Lian Ben ?2 ?) ?1H ?tetrazolium II and 4 ?(1 ?Qiang Ji ?1 ?methylethyl) ?2 ?propyl group Mi Zuo ?5 ?the mol ratio of carboxylicesters III be 1:0.8 ~ 1.4, described alkali is the one in sodium carbonate, salt of wormwood or Quilonum Retard, alkali and 1 ?San Ben Jia Ji ?5 ?(4 ’ ?halogenated methyl Lian Ben ?2 ?) ?1H ?the mol ratio of tetrazolium II be 1:3 ~ 5, described organic solvent be acetonitrile, tetrahydrofuran (THF), dioxane, ethyl acetate, methylene dichloride, toluene, methyl tertiary butyl ether or N, N ?one or more mixed solvents in dimethyl formamide, the described reaction times is 2 ~ 10 hours, preferably 3 ~ 5 hours, described recrystallisation solvent is one or both mixed solvents in ether, methyl tertiary butyl ether, acetone, ethyl acetate, tetrahydrofuran (THF), methylene dichloride.
10. the preparation method of a kind of olmesartan medoxomill according to claim 8, it is characterized in that, the preparation process (2) of described trityl olmesartan medoxomil VII is:
(a). in reaction vessel, add 4 ?(1 ?hydroxyl base ?1 ?methylethyl) ?2 ?third base ?1 ?{ 4 ?[2 ?(three phenmethyl four azoles ?5 ?yls) phenyl] phenyl } first base miaow azoles ?5 ?carboxylicesters IV, alkali and solvent, reaction is warming up to 20 DEG C ~ 70 DEG C, stirring reaction 5 ~ 15 is little of reacting completely, and aftertreatment obtains 4 ?(1 ?hydroxyl base ?1 ?methylethyl) ?2 ?third base ?1 ?{ 4 ?[2 ?(three phenmethyl four azoles ?5 ?yls) phenyl] phenyl } first base miaow azoles ?5 ?carboxylate salt V crude product and is directly used in next reaction; Described alkali is the alkali metal hydroxide of lithium, sodium or potassium; The mol ratio of described alkali and 4 ?(1 ?hydroxyl base ?1 ?methylethyl) ?2 ?third base ?1 ?{ 4 ?[2 ?(three phenmethyl four azoles ?5 ?yls) phenyl] phenyl } first base miaow azoles ?5 ?carboxylate salt V is 1.2 ~ 2:1; Described solvent be N, N ?one or more mixed solvent in dimethyl formamide, dioxane, tetrahydrofuran (THF), acetonitrile, methylene dichloride, toluene, methyl tertiary butyl ether or water;
(b). in reaction vessel, add 4 ?(1 ?hydroxyl base ?1 ?methylethyl) ?2 ?third base ?1 ?{ 4 ?[2 ?(three phenmethyl four azoles ?5 ?yls) phenyl] phenyl } first base miaow azoles ?5 ?carboxylate salt V crude product, alkali and 4 ?halogen for first base ?5 ?first base ?1,3 ?bis-oxygen heterocyclic pentene ?2 ?ketone VI, temperature of reaction is 30 DEG C ~ 100 DEG C, stirring reaction, to completely, obtains trityl olmesartan medoxomil VII through aftertreatment; Described alkali is alkaline carbonate or the oxyhydroxide of lithium, sodium or potassium; Described 4 ?(1 ?hydroxyl base ?1 ?methylethyl) ?2 ?third base ?1 ?{ 4 ?[2 ?(three phenmethyl four azoles ?5 ?yls) phenyl] phenyl } first base miaow azoles ?5 ?carboxylate salt V, 4 ?halogen is 1:1 ~ 1.5:1 ~ 2 for first base ?5 ?first base ?1,3 ?bis-oxygen heterocyclic pentene ?2 ?ketone VI and the mol ratio of alkali.
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CN107474042A (en) * | 2017-09-07 | 2017-12-15 | 浙江华海致诚药业有限公司 | A kind of crystal formation H of trityl olmesartan medoxomil |
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CN107474042A (en) * | 2017-09-07 | 2017-12-15 | 浙江华海致诚药业有限公司 | A kind of crystal formation H of trityl olmesartan medoxomil |
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