CN101602760A - A kind of preparation method of olmesartan medoxomill - Google Patents

A kind of preparation method of olmesartan medoxomill Download PDF

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CN101602760A
CN101602760A CNA2009101315347A CN200910131534A CN101602760A CN 101602760 A CN101602760 A CN 101602760A CN A2009101315347 A CNA2009101315347 A CN A2009101315347A CN 200910131534 A CN200910131534 A CN 200910131534A CN 101602760 A CN101602760 A CN 101602760A
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沈立新
卞禹卜
刘福双
吴鹏程
姜坤
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WUXI HOWFOND BIOPHARMA Inc
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Abstract

The preparation method who the invention discloses a kind of new olmesartan medoxomill is the preparation method of its key intermediate formula (IV) compound particularly.The present invention is to be raw material with formula (I) compound and formula (II) compound, at alkali Y 1Effect under get formula (III) compound through condensation reaction; formula (III) compound promptly obtains formula (IV) compound through grignard reaction again, and formula (IV) compound can continue to prepare the Olmesartan ester cpds through hydrolysis, esterification, deprotection three-step reaction according to currently known methods further.This method committed step is as follows, wherein R 1, R 2, R 3, R 4, R 5, R 6, X 1, X 2, Y 1The group of representative is seen specification sheets.Prepare the Olmesartan ester cpds by the inventive method, raw material is easy to get, low price, reaction conditions gentleness, easy and simple to handle, and by product is few, end product purity height, total recovery obviously improves, and is environmental protection and the olmesartan medoxomill new synthesis route that is suitable for suitability for industrialized production.

Description

A kind of preparation method of olmesartan medoxomill
Technical field
The present invention relates to the pharmaceutical technology field, specifically, is a kind of preparation method preparation method of its key intermediate particularly of new olmesartan medoxomill.
Background technology
Olmesartan medoxomill (Olmesartan medoxomil) is a kind of novel Angiotensin II 1 receptor (AT1) antagonist, for in various degree hypertension tangible hypotensive effect is arranged all, be a kind of enalapril meleate of easily being accepted safely and efficiently, be considered as the optimal selection of a line depressor by numerous clinicians by the patient.Olmesartan medoxomill synthetic committed step is the preparation of its key intermediate formula (IV) compound, and the method for preparation formula (IV) compound all adopts elder generation that the imidazoles dibasic acid esters of formula (I) compound is carried out grignard reaction, again grignard reaction product and formula (II) compound carried out two steps of condensation at present.The shortcoming of this method is: 1. the imidazoles dibasic acid esters of formula (I) compound carries out the complicated condition, wayward of grignard reaction, usually follows a plurality of side reactions, purification of products difficulty take place; 2. the product tertiary alcohol that obtains of grignard reaction is easily eliminated by highly basic when carrying out next step condensation reaction, has both reduced productive rate, has produced multiple by product once more, has obviously influenced the yield and the purity of follow-up reaction.
Figure A20091013153400041
Summary of the invention
The object of the invention is to provide a kind of new method for preparing the Olmesartan ester cpds, the preparation method of its key intermediate particularly, this method reaction conditions gentleness, easy and simple to handle, by product is few, end product purity height, total recovery height, environmental protection and be suitable for suitability for industrialized production more.
The objective of the invention is to be achieved through the following technical solutions: with formula (I) compound and formula (II) compound is raw material, earlier at alkali Y 1Effect under carry out condensation reaction and obtain formula (III) compound; formula (III) compound promptly obtains key intermediate formula (IV) compound through grignard reaction again, and formula (IV) compound can continue to prepare olmesartan medoxomill through hydrolysis, esterification, deprotection three-step reaction according to currently known methods further.The gordian technique route is as follows:
Figure A20091013153400051
R wherein 1, R 2, R 3All represent hydrogen atom or contain the alkyl of 1～4 carbon atom, R 4Represent carboxylic acid, tetrazolium-5-base, cyano group, protected hydroxyl, protected tetrazolium-5-base, formamyl or alkyl-carbamoyl, R 5, R 6All representative contains the alkyl of 1～6 carbon atom, X 1Represent halogen atom, mesyloxy (OMs) or tolysulfonyl oxygen base (OTs), X 2Represent halogen atom, Y 1Represent alkali metal hydroxide, alkalimetal hydride, alkaline carbonate or alkali metal hydrocarbonate.
Below method of the present invention is further specified:
(1), formula (I) compound and formula (II) compound are at alkali Y 1Existence under in solvent condensation obtain formula (III) compound.
Figure A20091013153400061
R wherein 1, R 2, R 3Represent hydrogen atom or contain the alkyl of 1～4 carbon atom, R 1, R 2Can be the same or different; X 1Represent halogen atom, sulfonyloxy methyl oxygen base (OMs) or tolysulfonyl oxygen base (OTs); R 4Represent carboxylic acid, tetrazolium-5-base, cyano group, protected hydroxyl, protected tetrazolium-5-base, formamyl or alkyl-carbamoyl.
Described alkali Y 1Be alkali metal hydroxide, alkalimetal hydride, alkaline carbonate or alkali metal hydrocarbonate, for example lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride KH, yellow soda ash, sodium bicarbonate, saleratus etc., wherein preferred salt of wormwood.
Described solvent is water, ethers (for example tetrahydrofuran (THF), dioxane) or other non-proton property polar solvents (for example dimethyl sulfoxide (DMSO), acetone, acetonitrile, N, N '-dimethyl formamide, N, N '-N,N-DIMETHYLACETAMIDE, hexamethylphosphoramide), can mix according to any proportioning for above-mentioned two or more.
The temperature of reaction can be in certain width, and precise dose is to reacting unimportant.Usually at-20 ℃～120 ℃, be preferably 0 ℃～100 ℃, the reaction times is as the criterion to react completely, and is generally 30 minutes to 24 hours.
(2), formula (III) compound forms formula (IV) compound through grignard reaction in mixed solvent.
Figure A20091013153400071
R wherein 1, R 2, R 3Represent hydrogen atom or contain the alkyl of 1～4 carbon atom, R 1, R 2Can be the same or different; X 2Represent halogen atom; R 4Represent carboxylic acid, tetrazolium-5-base, cyano group, protected hydroxyl, protected tetrazolium-5-base, formamyl or alkyl-carbamoyl, R 5, R 6Representative contains the alkyl of 1～6 carbon atom.
Grignard reagent (the R that described grignard reaction is selected for use 5) R 6MgX 2Be alkylmagnesium chloride, alkyl magnesium bromide or alkyl magnesium iodide.The solution of Grignard reagent can directly be bought commercially available, also can be according to the ordinary method on-site preparation.
Described mixed solvent is mixed according to any proportioning by any two or more in tetrahydrofuran (THF), ether, toluene, methylene dichloride, the dioxane, wherein is preferably the mixed solvent that tetrahydrofuran (THF) and methylene dichloride are formed.
The temperature of reaction can be in certain width, and precise dose is to reacting unimportant.Usually at-20 ℃～60 ℃, be preferably 0 ℃～60 ℃, the reaction times is as the criterion to react completely, and is generally 30 minutes to 24 hours.
(3), formula (IV) compound is at alkali Y 2Existence under in mixing solutions reaction form the formula V compound.
Figure A20091013153400081
R wherein 2, R 3Represent hydrogen atom or contain the alkyl of 1～4 carbon atom, R 4Represent carboxylic acid, tetrazolium-5-base, cyano group, protected hydroxyl, protected tetrazolium-5-base, formamyl or alkyl-carbamoyl, R 5, R 6All representative contains the alkyl of 1～6 carbon atom, R 7Represent sodium, potassium or hydrogen atom.
Described alkali Y 2Can be alkali metal hydroxide, alkalimetal hydride, alkaline carbonate or alkali metal hydrocarbonate, for example lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride KH, yellow soda ash, salt of wormwood, sodium bicarbonate, saleratus etc., wherein preferred sodium hydroxide and potassium hydroxide.
Described mixing solutions is mixed according to any proportioning and water by in dimethyl formamide, N,N-DIMETHYLACETAMIDE, dioxane, tetrahydrofuran (THF), the acetone one or more, wherein is preferably the mixing solutions that dioxane and water are formed.
The temperature of reaction can be in certain width, and precise dose is to reacting unimportant.Usually at 0 ℃～100 ℃, be preferably 0 ℃～80 ℃, the reaction times is as the criterion to react completely, and is generally 30 minutes to 24 hours.
(4), with the formula V compound of step (3) gained at alkali Y 3Catalysis under in inert solvent with 4-bromine (or chlorine) methyl-5-methyl-2-oxo-1,3-dioxane reaction forms formula (VI) compound.
Figure A20091013153400091
R wherein 3, R 4, R 5, R 6, R 7Definition the same.
Described alkali Y 3Be preferably alkaline carbonate (for example yellow soda ash, salt of wormwood) or alkali metal hydrocarbonate (for example sodium bicarbonate, saleratus).
Described inert solvent is preferably amides (for example dimethyl formamide, N,N-DIMETHYLACETAMIDE, diethylformamide), ketone (for example acetone) or ethers (for example tetrahydrofuran (THF), ether, dioxane).
The temperature of reaction can be in certain width, and precise dose is to reacting unimportant.Usually at 10 ℃～120 ℃, be preferably 10 ℃～80 ℃, the reaction times is as the criterion to react completely, and is generally 15 minutes to 8 hours.
(5), formula (VI) the compound protecting group of sloughing in solvent under the effect of acid on the tetrazyl forms formula (VII) compound.
Figure A20091013153400092
R wherein 3, R 4, R 5, R 6Definition the same, R 8Represent carboxylic acid, tetrazolium-5-base, cyano group, protected hydroxyl, formamyl or alkyl-carbamoyl.
The character of described acid is unimportant, and the organic acid (for example acetate, formic acid, oxalic acid) or the mineral acid (for example hydrochloric acid, sulfuric acid, phosphoric acid) that have as the proton general function get final product, and are preferably acetate, formic acid, hydrochloric acid, sulfuric acid.
Described solvent does not have special restriction, as long as can dissolve or can dissolve to a certain extent the reagent of participating in reaction and not have side reaction with it, one or more the mixture that water, organic acid (for example acetate, formic acid), ketone (for example acetone, methyl ethyl ketone), ethers (for example tetrahydrofuran (THF), dioxane) are arranged commonly used wherein is preferably the mixture of water, organic acid, alcohol or their any proportionings.
The temperature of reaction can be in certain width, and precise dose is to reacting unimportant.Usually at 10 ℃～80 ℃, be preferably 20 ℃～80 ℃, the reaction times is as the criterion to react completely, and is generally 45 minutes to 15 hours.
Work as R 3Be n-propyl, R 5, R 6Be methyl, R 4During for the tetrazole (N-trityl group-tetrazolium-5 base) of triphenyl protection, the R in formula (VII) compound then 8For tetrazole that is
Figure A20091013153400101
Promptly get target product Olmesartan ester cpds.
Adopt method disclosed by the invention to prepare the Olmesartan ester cpds, reaction conditions gentleness, easy and simple to handle, by product is few, selectivity is high, end product purity height, total recovery height, safety and environmental protection and be suitable for suitability for industrialized production.
Description of drawings
With embodiment the present invention is described in further detail with reference to the accompanying drawings below.
Fig. 1 is the mass spectrometry results of embodiment 1, m/z:M ++ 1=731 (m/e);
Fig. 2 is the mass spectrometry results of embodiment 3, m/z:M ++ 1=711 (m/e);
Fig. 3 is the mass spectrometry results of embodiment 4, m/z:M ++ 1=801.6 (m/e);
Fig. 4 is the mass spectrometry results of embodiment 5, m/z:M ++ 1=559.3 (m/e);
Fig. 5 be embodiment 2 nucleus magnetic resonance ( 1H NMR) analytical results, 1H NMR (300MHz, CDCl 3): δ=0.86-1.06 (t, J=7.6Hz, 3H), 1.05-1.10 (m, 3H), 1.65 (m, 7H), 2.44-2.65 (m, 2H), 4.09-4.16 (m, 2H), 5.35 (s, 2H), 5.79 (s, 1H), 6.70-7.88 (m, 23H);
Fig. 6 be embodiment 5 nucleus magnetic resonance ( 1H NMR) analytical results, 1H NMR (300MHz, CDCl 3): δ=0.88-0.93 (t, J=7.2H z, 3H), 1.57-1.70 (m, 6H), 2.17 (s, 3H), 2.50-2.55 (m, 2H), 4.95 (s, 2H), 5.40 (s, 2H), 6.76-6.78 (d, J=8.0Hz, 2H), 7.06-7.09 (d, J=8.0Hz, 2H), 7.43-7.81 (m, 4H);
Fig. 7 is the high-efficient liquid phase analysis result of embodiment 5, HPLC:99.7%.
Embodiment
Following examples are preferred implementations of the present invention, but are not in order to limit the present invention.
Embodiment 1:
1-[[[2 '-(trityl)-2H-tetrazole-5-yl] biphenyl-4-yl] methyl]-2-propyl group-4, the preparation of 5-imidazole-2-carboxylic acid ethyl ester
In the single port bottle that magnetic agitation and oil bath heating is housed, with 2-propyl group-4,5-imidazole-2-carboxylic acid ethyl ester 35.4mg (139.3mmol) is dissolved in 100ml acetone, add N successively, N '-dimethyl formamide 32ml, N-trityl-5-(4 '-bromomethylbiphenyl-2-yl) tetrazolium 81.5mg (146mmol) and salt of wormwood 38.5mg (278mmol), reflux 7～8 hours, pressure reducing and steaming acetone, cool to room temperature adds entry 200ml and separates out white solid, filter, vacuum-drying is 3～4 hours under 70～80 ℃ of conditions, gets product 100g, yield 99%; Mp:167-169 ℃; HPLC:97.0%; M/z (see figure 1): M ++ 1=731 (m/e).
Embodiment 2:
1-[[[2 '-(trityl)-2H-tetrazole-5-yl] biphenyl-4-yl] methyl]-preparation of 2-propyl group-4-(1-hydroxyl-1-methylethyl) imidazole-5-carboxylic acid methyl esters
In the there-necked flask of magnetic agitation is housed, magnesium chips 4g (100mmol) is added to the 100ml anhydrous tetrahydro furan, promptly make Grignard reagent to wherein dripping the 200ml anhydrous toluene solution that is dissolved with 35g (246mmol) methyl iodide until the magnesium chips completely dissolve, the there-necked flask that Grignard reagent is housed placed 0～10 ℃ ice-water bath, get 1-[[[2 '-(the trityl)-2H-tetrazole-5-yl that makes among the embodiment 1] biphenyl-4-yl] methyl]-2-propyl group-4,5-imidazolyl carboxylic acid diethyl ester 36.5g (50mmol) is dissolved in the 30ml dichloromethane solution, drop in the above-mentioned Grignard reagent, and temperature of reaction risen to 40～45 ℃, keep 2h.Hydrochloric acid 70ml cancellation reaction with 2N adds the 100ml ethyl acetate, tells organic layer, and again with the saturated nacl aqueous solution washing, anhydrous magnesium sulfate drying gets white solid after concentrating, and gets product 32.9g through recrystallization, yield 90%. 1H NMR (300MHz, CDCl 3) (see figure 5): δ=0.86-1.06 (t, J=7.6Hz, 3H), 1.05-1.10 (m, 3H), 1.65 (m, 7H), 2.44-2.65 (m, 2H), 4.09-4.16 (m, 2H), 5.35 (s, 2H), 5.79 (s, 1H), 6.70-7.88 (m, 23H); HPLC:95.0%; M/z:M ++ 1=690.3 (m/e).
Embodiment 3:
1-[[[2 '-(trityl)-2H-tetrazole-5-yl] biphenyl-4-yl] methyl]-preparation of 2-propyl group-4-(1-hydroxyl-1-methylethyl) imidazole-5-carboxylic acid sodium
In the single port bottle of magnetic agitation is housed, get 1-[[[2 '-(the trityl)-2H-tetrazole-5-yl that makes among the embodiment 2] biphenyl-4-yl] methyl]-2-propyl group-4-(1-hydroxyl-1-methylethyl) imidazole-5-carboxylic acid ethyl ester 3.05g (4.27mmol) is dissolved in the mixing solutions of 100ml tetrahydrofuran (THF) and 100ml water, add sodium hydroxide 3.10g (78mmol) again, said mixture reacts 1h under 75～85 ℃ condition; After reaction finishes,, repeats 3 times, merge organic layer,, use anhydrous magnesium sulfate drying again, get white plates solid product 5.5g, crude product yield 99% after concentrating with the saturated sodium-chloride water solution washing with 100ml ethyl acetate extraction reaction solution.Mp:169-171 ℃; HPLC:90%; M/z (see figure 2): M ++ 1=711 (m/e).
Embodiment 4:
1-[[[2 '-(trityl)-2H-tetrazole-5-yl] biphenyl-4-yl] methyl]-preparation of 2-propyl group-4-(1-hydroxyl-1-methylethyl) imidazole-5-carboxylic acid (5-methyl-2-oxo-1,3 dioxy cyclopentenes-4-yl) methyl esters
In the single port bottle of magnetic agitation is housed, get 1-[[[2 '-(the trityl)-2H-tetrazole-5-yl that makes among the embodiment 3] biphenyl-4-yl] methyl]-2-propyl group-4-(1-hydroxyl-1-methylethyl) imidazole-5-carboxylic acid sodium 4.1g (14mmol) is dissolved in the 50ml acetone; Add salt of wormwood 2.3g (16.7mmol); Drip 3.8g (33mmol) 4-brooethyl-5-methyl isophthalic acid while stirring in the single port bottle, 3-dioxy cyclopentenes-2-ketone is dissolved in the mixed solution of 5ml acetone gained; React 1h under the room temperature; Elevated temperature to 50 ℃ reacts 2h again; After reaction finishes,, repeat 3 times with 50ml ethyl acetate extraction reaction solution; Merge organic layer, use anhydrous magnesium sulfate drying, concentrating under reduced pressure leaves standstill, filter white powder solid product 10.1g, yield 90%; Mp:101-103 ℃; 1H NMR (300MHz, CDCl 3): δ=0.85 (t, J=7.2Hz, 3H), 1.41-1.60 (m, 2H), 1.56 (s, 6H), 2.0 (s, 3H), 2.30-2.60 (m, 2H), 5.02 (s, 2H), 5.22 (s, 1H), 5.31 (s, 2H), 6.75 (d, J=8.2Hz, 2H), 6.82 (d, J=8.2Hz, 4H), 6.98 (d, J=8.2Hz, 2H), 7.23-7.82 (m, 15H); HPLC:99%; M/z (see figure 3): M ++ 1=801.6 (m/e).
Embodiment 5:
4-(1-hydroxyl-1-methylethyl)-2-propyl group-1-{4-[2-(tetrazole-5-yl) phenyl] phenyl } preparation of Methylimidazole-5-carboxylic acid (5-methyl-2-oxo-1,3-dioxa cyclopentenyl-4-yl) methyl ester (olmesartan medoxomill)
In the single port bottle of magnetic agitation is housed, with 1-[[[2 '-(the trityl)-2H-tetrazole-5-yl that makes among the embodiment 4] biphenyl-4-yl] methyl]-to be dissolved in the 0.75ml massfraction be in 75% the acetum to 2-propyl group-4-(1-hydroxyl-1-methylethyl) imidazole-5-carboxylic acid (5-methyl-2-oxo-1,3 dioxy cyclopentenes-4-yl) methyl esters 25mg (31.25mmol); Stirred after being heated to 75 ℃ 4～6 hours; With the dilution of 0.5ml water, separate out white solid, filter; With ethyl acetate 5ml extraction filtrate, repeat 3 times; Merge organic layer, dry back concentrate yellow thick solid, treat behind the ethyl alcohol recrystallization white solid product 23.8g, yield 85%; Mp:180-182 ℃; 1H NMR (300MHz, CDCl 3) (see figure 6): δ=0.88-0.93 (t, J=7.2Hz, 3H), 1.57-1.70 (m, 6H), 2.17 (s, 3H), 2.50-2.55 (m, 2H), 4.95 (s, 2H), 5.40 (s, 2H), 6.76-6.78 (d, J=8.0Hz, 2H), 7.06-7.09 (d, J=8.0Hz, 2H), and 7.43-7.81 (m, 4H); HPLC (see figure 7): 99.7%; M/z (see figure 4): M ++ 1=559.3 (m/e).

Claims (2)

1, a kind of method for preparing olmesartan medoxomill; prepare key intermediate formula (IV) compound earlier; prepare Olmesartan ester cpds according to currently known methods through hydrolysis, esterification, deprotection three-step reaction by formula (IV) compound again, it is characterized in that the method for preparing key intermediate formula (IV) compound comprises the steps:
Figure A2009101315340002C1
(1) with formula (I) compound and formula (II) compound at alkali Y 1Effect under condensation obtain formula (III) compound;
Figure A2009101315340002C2
(2) formula (III) compound is obtained formula (IV) compound through grignard reaction;
Figure A2009101315340002C3
Wherein,
R 1Representative: hydrogen atom or contain the alkyl of 1～4 carbon atom;
R 2Representative: hydrogen atom or contain the alkyl of 1～4 carbon atom;
R 3Representative: hydrogen atom or contain the alkyl of 1～4 carbon atom;
R 4Representative: carboxylic acid, tetrazolium-5-base, cyano group, protected hydroxyl, protected tetrazolium-5-base, formamyl or alkyl-carbamoyl;
R 5Representative: the alkyl that contains 1～6 carbon atom;
R 6Representative: the alkyl that contains 1～6 carbon atom;
X 1Representative: halogen atom, mesyloxy (OMs) or tolysulfonyl oxygen base (OTs);
X 2Representative: halogen atom;
Y 1Representative: alkali metal hydroxide, alkalimetal hydride, alkaline carbonate or alkali metal hydrocarbonate.
2, the method for preparing olmesartan medoxomill according to claim 1 is characterized in that described R 1, R 2Represent methylidene or ethyl, the two can be the same or different, described R 3Represent n-propyl, described R 4Represent N-trityl group-tetrazolium-5 base, described halogen atom is chlorine atom, bromine atoms or iodine atom.
CNA2009101315347A 2009-04-07 2009-04-07 A kind of preparation method of olmesartan medoxomill Pending CN101602760A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102850333A (en) * 2011-06-30 2013-01-02 北京万生药业有限责任公司 Olmesartan medoxomil crystal and preparation method thereof
CN103304550A (en) * 2012-03-16 2013-09-18 湖南欧亚生物有限公司 Preparation method of Olmesartan Medoxomil

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102850333A (en) * 2011-06-30 2013-01-02 北京万生药业有限责任公司 Olmesartan medoxomil crystal and preparation method thereof
CN103304550A (en) * 2012-03-16 2013-09-18 湖南欧亚生物有限公司 Preparation method of Olmesartan Medoxomil
CN103304550B (en) * 2012-03-16 2016-01-27 湖南欧亚生物有限公司 A kind of preparation method of olmesartan medoxomill

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Open date: 20091216