CN102219744A - Preparation method of telmisartan intermediate and intermediate compound - Google Patents
Preparation method of telmisartan intermediate and intermediate compound Download PDFInfo
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Abstract
The invention discloses a preparation method of a telmisartan intermediate compound, and is characterized in that the method comprises the following steps of performing a nitryl reduction reaction and a cyclization reaction of compound 3. The invention also discloses an intermediate for preparing compound 1. The preparation method of the invention has simple operations, has easily purified products, facilitates large-scale production, and achieves high yield.
Description
Technical field
The present invention is specifically related to a kind of preparation method and a kind of midbody compound of midbody compound of telmisartan.
Background technology
The telmisartan intermediate, 2-n-propyl group-4-methyl-6-(the benzoglyoxaline of 1-methyl-benzimidazolyl-2 radicals-yl), English name 2-n-propyl-4-methyl-6-(1-methyl-benzamidazole-2-yl) benzamidazole, CAS is 152628-02-9, its structural formula is as shown in Equation 1.
Compound 1 is sloughed the tertiary butyl at acidic conditions again with the intermediate that 4 '-brooethyl-2-diphenic acid tert-butyl ester process nucleophilic substitution reaction obtains and promptly can be obtained telmisartan (EP502314) as a kind of intermediate of important preparation telmisartan.But as the important intermediate of telmisartan, all there is certain limitation in its synthetic method, and at present, several main synthetic routes of this intermediate are as follows:
1. document J.Med.Chem., 1993,36; to be raw material with 3-methyl-4-Methyl anthranilate obtain through N-acidylate, nitrated, reduction, cyclization, saponification and condensation the synthetic routes of 4040 reports; reactions steps is long, and yield is low, and the telmisartan intermediate that obtains needs column chromatography for separation.
2. the synthetic route of document CN101074213 report is carried out saponification earlier, obtains through condensation again, can be earlier through reduction cyclization again or directly cyclization make, although step shortens, the ring-closure reaction complex operation, yield is lower.
The synthetic route of document WO 2006044754 report carry out earlier condensation again cyclization make the intermediate of telmisartan, the ring-closure reaction complex operation, two step yields have only 12%
All there is certain limitation in above-mentioned three synthetic routes, bring certain difficulty for the suitability for industrialized production of telmisartan, and therefore seeking alternative chemical synthesis is the research topic that current market in urgent need solves.
Summary of the invention
Technical problem to be solved by this invention is for the midbody compound 2-n-propyl group-4-methyl-6-that overcomes the existing preparation telmisartan (defective such as reactions steps length among the preparation method of the benzoglyoxaline of 1-methyl-benzimidazolyl-2 radicals-yl), complex operation, yield are low, and a kind of preparation method and a kind of midbody compound of midbody compound of telmisartan are provided, preparation method of the present invention is easy and simple to handle, the easy purifying of product, amplify easily and produce, can also reach than higher productive rate.
The present invention relates to a kind of preparation method of the telmisartan midbody compound shown in general formula 1, it comprises the following step: compound 3 is carried out the reduction reaction and the ring-closure reaction of nitro, get final product;
Wherein, behind two nitroreductions, two amino that generate can carry out ring-closure reaction with two carbonyls according to the technology of this area routine respectively, can generate compound 1 of the present invention, and these two kinds of reactions are to carry out one pot reaction under the prerequisite of intermediate compound and carry out not isolating.Though the mechanism of two reactions is conventional, the discovery that the inventor is pleasantly surprised utilizes this two kinds of popular responses, the present invention compared with prior art, not only Fan Ying operation is simpler and easy, and productive rate is also very high.
Therefore, the method of described nitro-reduction reaction and ring-closure reaction and condition all can be the ordinary method and the condition of this two classes reaction of this area, preferred especially following method of the present invention and condition: in organic inert solvent, under the effect of nitroreduction agent, compound 3 is carried out nitro-reduction reaction and ring-closure reaction, get final product.
Wherein, described organic inert solvent is preferable is selected from water, organic acid, lower alcohol, ester, ketone, lower alcohol and the aromatic hydrocarbon one or more.In organic acid preferable formic acid, acetate and the propionic acid one or more, one or more in lower alcohol particular methanol, ethanol, propyl alcohol, Virahol and the butanols, ester solvent ethyl acetate and/or n-butyl acetate, the preferred acetone of ketone solvent.The volume mass of organic inert solvent and compound 3 than preferable be 1～100mL/g, preferred 5～20mL/g.Described nitroreduction reagent is preferable is in reduced iron powder, zinc powder, V-Brite B, two hydrated stannous chlorides and the sodium borohydride one or more, preferred reduced iron powder.The consumption of described nitroreduction reagent is preferable is 1～infinite times of molar weight of compound 3, The more the better.Described ring-closure reaction and nitro-reduction reaction are same reaction system, what the temperature of two kinds of reactions was preferable is 0 ℃～150 ℃, preferred 60～120 ℃, the time of two kinds of reactions preferable with detection reaction fully till, preferably with TLC detect wherein a kind of reactant consumption intact till.
Among the present invention, described compound 3 can be made by following method: compound 2 and ortho-nitrophenyl methylamine are directly carried out condensation reaction, perhaps compound 2 is become easily and the carboxylic acid derivative of amino condensation, carry out condensation reaction with the ortho-nitrophenyl methylamine then, get final product;
What wherein, described carboxylic acid derivative was preferable is acyl chlorides.
When compound 2 and ortho-nitrophenyl methylamine directly carried out condensation reaction, used method and condition all can be the ordinary method and the condition of this type of reaction of this area.
When compound 2 becomes easily carboxylic acid derivative with amino condensation, when carrying out condensation reaction with the ortho-nitrophenyl methylamine then, used method and condition all can be the ordinary method and the condition of this type of reaction of this area.Preferred especially following method of the present invention and condition: in organic inert solvent or under the condition of no solvent, under the effect of the chloride reagent of carboxylic acid, compound 2 is carried out acyl chloride reaction become the acyl chlorides intermediate, carry out condensation reaction with the ortho-nitrophenyl methylamine again, get final product.
Wherein, described organic inert solvent is preferable is selected from aromatic hydrocarbon, halogenated alkane, N, and one or more in dinethylformamide, N,N-dimethylacetamide and the dimethyl sulfoxide (DMSO) are solvent with the chloride reagent of carboxylic acid directly perhaps.The volume mass of organic inert solvent and compound 2 than preferable be 1～100mL/g, preferred 5～20mL/g; The preferred halogenated alkane of the solvent of acyl chloride reaction, more preferably methylene dichloride, the preferred N of the solvent of condensation reaction, dinethylformamide.Chloride reagent is preferable is selected from sulfur oxychloride, phosphorus trichloride and the phosphorus oxychloride one or more, preferred sulfur oxychloride and/or phosphorus trichloride, more preferably sulfur oxychloride.The consumption of chloride reagent is preferable is 1～infinite times of molar weight of compound 2, The more the better; The consumption of ortho-nitrophenyl methylamine is preferable is 0.1～10 times of molar weight of compound 2, preferred 0.3～1 times.What the temperature of described acyl chloride reaction was preferable is 20 ℃～100 ℃, preferred 30～60 ℃; What the temperature of described condensation reaction was preferable is 10 ℃～60 ℃, preferred 30～50 ℃; The time of two kinds of reactions all preferable with detection reaction fully till, preferably with TLC detect wherein a kind of reactant consumption intact till.
Among the preparation method of the present invention, above-mentioned each optimum condition can promptly get each preferred embodiments of the present invention in arbitrary combination under the prerequisite of this area general knowledge.
The invention still further relates to a kind of midbody compound 3 for preparing compound 1;
Among the present invention, obtain but the method for described compound 2 reference literature CN101074213 is synthetic.
Among the present invention, but described compound 1 reference literature EP502314, obtain intermediate through carrying out nucleophilic substitution reaction with 4 '-brooethyl-2-diphenic acid tert-butyl ester, slough the tertiary butyl at acidic conditions again and promptly can obtain telmisartan, it is applicable to the treatment of essential hypertension.
Except that specified otherwise, reagent that the present invention relates to and raw material are all commercially available to be got.
Positive progressive effect of the present invention is: preparation method of the present invention can avoid expensive reagent or raw material, working method is simple and convenient, the easy purifying of product, do not need loaded down with trivial details separation means such as column chromatography, the only washing by routine, concentrate, operations such as drying, crystallization can obtain pure product, compared with prior art cost significantly reduces, not only be fit to the laboratory and prepare on a small quantity, also be fit to large-scale industrialization production; It can also reach higher productive rate.
Embodiment
Further specify the present invention with embodiment below, but the present invention is not limited.
Wherein said normal temperature is 20～40 ℃, and normal pressure is 0.8atm～1.2atm.
The preparation of embodiment 1N-methyl-N-(2-nitrophenyl)-N-(the positive butyramide of 3-methyl-4--5-nitrophenyl) methane amide (compound 3)
The positive butyramide of 3-methyl-4--5-nitrobenzoic acid (21.2g, 0.08mol) adding 600mL methylene dichloride and 100mL sulfur oxychloride, temperature rising reflux 20h, concentrating the intermediate that obtains directly is dissolved among the DMF of 100mL without separating, ortho-nitrophenyl methylamine (6.1g, 0.04mmol) add in the reaction flask, stirring at room 2d adds methylene dichloride 500mL, drips the sodium hydroxide solution 200mL of 2N, stirring at room 1h, separatory, water layer be with the 200mL dichloromethane extraction, merges organic layer and with the saturated common salt water washing, dry filter concentrates the crude product that obtains and obtains the flaxen powder of 13.3g, yield 83.1% with ethyl acetate and sherwood oil recrystallization.
H?NMR(300MHz，CDCl
3)δ：8.23(br，1H，NH)，7.76～8.17(m，6H，PhH)，3.31(s，3H，NCH
3)，3.27(s，3H，PhC
H 3)，2.21(m，2H，COCH
2)，1.71(m，2H，C
H 2CH
3)，0.95(t，3H，CH
2C
H 3).
HPLC：93.8％
The preparation of embodiment 2N-methyl-N-(2-nitrophenyl)-N-(the positive butyramide of 3-methyl-4--5-nitrophenyl) methane amide (compound 3)
The positive butyramide of 3-methyl-4--5-nitrobenzoic acid (2.1g, 8mmol) add 100mL methylene dichloride and 10mL sulfur oxychloride, temperature rising reflux 20h, concentrating the intermediate that obtains directly is dissolved among the DMF of 20mL without separating, ortho-nitrophenyl methylamine (1.2g, 8mmmol) add in the reaction flask, stirring at room 2d adds methylene dichloride 50mL, drips the sodium hydroxide solution 40mL of 2N, stirring at room 1h, separatory, water layer be with the 500mL dichloromethane extraction, merges organic layer and with the saturated common salt water washing, dry filter concentrate the crude product obtain with column chromatography separate the flaxen powder of 1.4g, yield 43.6%.
The HPLC:95.1% nuclear magnetic data is with embodiment 1.
The preparation of embodiment 3N-methyl-N-(2-nitrophenyl)-N-(the positive butyramide of 3-methyl-4--5-nitrophenyl) methane amide (compound 3)
The positive butyramide of 3-methyl-4--5-nitrobenzoic acid (21.2g, 0.08mol) adding 600mL methylene dichloride and 60mL phosphorus trichloride, temperature rising reflux 20h, concentrating the intermediate that obtains directly is dissolved among the DMF of 100mL without separating, ortho-nitrophenyl methylamine (6.1g, 0.04mmol) add in the reaction flask, stirring at room 2d adds methylene dichloride 500mL, drips the sodium hydroxide solution 200mL of 2N, stirring at room 1h, separatory, water layer be with the 200mL dichloromethane extraction, merges organic layer and with the saturated common salt water washing, dry filter concentrates the crude product that obtains and obtains the flaxen powder of 10.1g, yield 63.1% with toluene and sherwood oil recrystallization.
The HPLC:92.1% nuclear magnetic data is with embodiment 1.
The preparation of embodiment 4N-methyl-N-(2-nitrophenyl)-N-(the positive butyramide of 3-methyl-4--5-nitrophenyl) methane amide (compound 3)
The positive butyramide of 3-methyl-4--5-nitrobenzoic acid (2.12g, 8mmol) add 100mL methylene dichloride and 10mL phosphorus oxychloride, temperature rising reflux 20h, concentrating the intermediate that obtains directly is dissolved among the DMF of 20mL without separating, ortho-nitrophenyl methylamine (0.61g, 4mmol) add in the reaction flask, stirring at room 2d adds methylene dichloride 50mL, drips the sodium hydroxide solution 50mL of 2N, stirring at room 1h, separatory, water layer be with the 50mL dichloromethane extraction, merges organic layer and with the saturated common salt water washing, dry filter concentrates the crude product that obtains and obtains the flaxen powder of 0.73g, yield 45.6% with toluene and sherwood oil recrystallization.
The HPLC:87.2% nuclear magnetic data is with embodiment 1.
The preparation of embodiment 5N-methyl-N-(2-nitrophenyl)-N-(the positive butyramide of 3-methyl-4--5-nitrophenyl) methane amide (compound 3)
The positive butyramide of 3-methyl-4--5-nitrobenzoic acid (21.2g, 0.08mol) adding 600mL methylene dichloride and 60mL phosphorus trichloride, temperature rising reflux 20h, concentrating the intermediate that obtains directly is dissolved among the DMSO of 100mL without separating, ortho-nitrophenyl methylamine (6.1g, 0.04mmol) add in the reaction flask, stirring at room 2d adds methylene dichloride 500mL, drips the sodium hydroxide solution 200mL of 2N, stirring at room 1h, separatory, water layer be with the 200mL dichloromethane extraction, merges organic layer and with the saturated common salt water washing, dry filter concentrates the crude product that obtains and obtains the flaxen powder of 11.1g, yield 69.4% with ethyl acetate and sherwood oil recrystallization.
The HPLC:90.1% nuclear magnetic data is with embodiment 1.
The embodiment 6 2-n-propyl group-4-methyl-6-(1-methyl-benzimidazolyl-2 radicals-yl) preparation of benzoglyoxaline (compound 1)
N-methyl-N-(2-nitrophenyl)-N-(the positive butyramide of 3-methyl-4--5-nitrophenyl) methane amide (16.0g, 0.04mol) be dissolved in the 200mL acetic acid, add reduced iron powder (18.0g, 0.32mol) be warming up to 90 ℃ the reaction 8h, add 20g diatomite, be cooled to 50 ℃, filter, and with the 200mL washing with alcohol, filtrate concentrating is dissolved in the 500mL methylene dichloride, with the 100mL10% ammonia scrubbing, organic layer is again with the saturated common salt water washing, dry filter concentrates and to obtain crude product 10.6g, obtains the solid of 9.9g white, yield 81.5% with methanol (1/1) recrystallization.
H?NMR(300MHz，d-DMSO)δ：12.4(d，1H，imidazole)，7.23～7.80(m，6H，PhH)，3.90(s，3H，NCH
3)，3.37(s，3H，PhC
H 3)，2.85(m，2H，C
H 2CH
2CH
3)，1.84(m，2H，C
H 2CH
3)，0.97(t，3H，CH
2C
H 3).
HPLC：99.1％
The embodiment 7 2-n-propyl group-4-methyl-6-(1-methyl-benzimidazolyl-2 radicals-yl) preparation of benzoglyoxaline (compound 1)
N-methyl-N-(2-nitrophenyl)-N-(the positive butyramide of 3-methyl-4--5-nitrophenyl) methane amide (3.2g, 8mmol) be dissolved in the 20mL dehydrated alcohol, add reduced iron powder (1.8g, 32mmol), drip the 1mL concentrated hydrochloric acid and be warming up to 90 ℃ of reaction 6h, add 5g diatomite, be cooled to 50 ℃, filter, and with the 50mL washing with alcohol, filtrate concentrating is dissolved in the 100mL methylene dichloride, with the 50mL10% ammonia scrubbing, organic layer is again with the saturated common salt water washing, and dry filter concentrates and obtains crude product and obtain the solid of 1.9g white, yield 78.0% through the methanol recrystallization.
HPLC：98.7％
The embodiment 8 2-n-propyl group-4-methyl-6-(1-methyl-benzimidazolyl-2 radicals-yl) preparation of benzoglyoxaline (compound 1)
N-methyl-N-(2-nitrophenyl)-N-(the positive butyramide of 3-methyl-4--5-nitrophenyl) methane amide (3.2g, 8mmol) be dissolved in the 20mL dehydrated alcohol, add reduced iron powder (2.0g, 32mmol), drip the 1mL concentrated hydrochloric acid and be warming up to 90 ℃ of reaction 6h, add 5g diatomite, be cooled to 50 ℃, filter, and with the 50mL washing with alcohol, filtrate concentrating is dissolved in the 100mL methylene dichloride, with the 50mL10% ammonia scrubbing, organic layer is again with the saturated common salt water washing, and dry filter concentrates and obtains crude product and obtain the solid of 1.7g white, yield 70.0% through the methanol recrystallization.
HPLC：97.5％
The embodiment 9 2-n-propyl group-4-methyl-6-(1-methyl-benzimidazolyl-2 radicals-yl) preparation of benzoglyoxaline (compound 1)
N-methyl-N-(2-nitrophenyl)-N-(the positive butyramide of 3-methyl-4--5-nitrophenyl) methane amide (3.2g, 8mmol) be dissolved in the 20mL ethyl acetate, add zinc powder (32mmol), drip the 1mL concentrated hydrochloric acid and be warming up to 60 ℃ of reaction 6h, add 5g diatomite, be cooled to 50 ℃, filter, and with the 50mL washing with alcohol, filtrate concentrating is dissolved in the 100mL methylene dichloride, and with the 50mL10% ammonia scrubbing, organic layer is again with the saturated common salt water washing, the concentrated crude product that obtains of dry filter obtains white solid, yield 65% through the methanol recrystallization.
HPLC：97.5％
The embodiment 10 2-n-propyl group-4-methyl-6-(1-methyl-benzimidazolyl-2 radicals-yl) preparation of benzoglyoxaline (compound 1)
N-methyl-N-(2-nitrophenyl)-N-(the positive butyramide of 3-methyl-4--5-nitrophenyl) methane amide (3.2g, 8mmol) be dissolved in the 20mL butanols, add V-Brite B (32mmol), drip the 1mL concentrated hydrochloric acid and be warming up to 100 ℃ of reaction 6h, add 5g diatomite, be cooled to 50 ℃, filter, and with the 50mL washing with alcohol, filtrate concentrating is dissolved in the 100mL methylene dichloride, and with the 50mL10% ammonia scrubbing, organic layer is again with the saturated common salt water washing, the concentrated crude product that obtains of dry filter obtains white solid, yield 64% through the methanol recrystallization.
HPLC：97.5％
The embodiment 11 2-n-propyl group-4-methyl-6-(1-methyl-benzimidazolyl-2 radicals-yl) preparation of benzoglyoxaline (compound 1)
N-methyl-N-(2-nitrophenyl)-N-(the positive butyramide of 3-methyl-4--5-nitrophenyl) methane amide (3.2g, 8mmol) be dissolved in the 20mL acetone, add reduced iron powder (8mmol), drip 0 ℃ of reaction of 1mL concentrated hydrochloric acid 6h, add 5g diatomite, be cooled to 50 ℃, filter, and with the 50mL washing with alcohol, filtrate concentrating is dissolved in the 100mL methylene dichloride, and with the 50mL10% ammonia scrubbing, organic layer is again with the saturated common salt water washing, the concentrated crude product that obtains of dry filter obtains white solid, yield 70% through the methanol recrystallization.
HPLC：97.5％
The embodiment 12 2-n-propyl group-4-methyl-6-(1-methyl-benzimidazolyl-2 radicals-yl) preparation of benzoglyoxaline (compound 1)
N-methyl-N-(2-nitrophenyl)-N-(the positive butyramide of 3-methyl-4--5-nitrophenyl) methane amide (3.2g, 8mmol) be dissolved in the 20mL n-butyl acetate, add sodium borohydride (2.0g, 32mmol), drip 0 ℃ of reaction of 1mL concentrated hydrochloric acid 6h, add 5g diatomite, be cooled to 50 ℃, filter, and with the 50mL washing with alcohol, filtrate concentrating is dissolved in the 100mL methylene dichloride, with the 50mL10% ammonia scrubbing, organic layer is again with the saturated common salt water washing, and the concentrated crude product that obtains of dry filter obtains white solid, yield 65% through the methanol recrystallization.
HPLC：97.5％
The preparation of embodiment 13 N-methyl-N-(2-nitrophenyl)-N-(the positive butyramide of 3-methyl-4--5-nitrophenyl) methane amide (compound 3)
The positive butyramide of 3-methyl-4--5-nitrobenzoic acid (21.2g, 0.08mol) adding 600mL methylene dichloride and sulfur oxychloride (0.08mol), 20 ℃ of reaction 20h, concentrate the intermediate that obtains directly is dissolved in 100mL without separation N, in the N-N,N-DIMETHYLACETAMIDE, ortho-nitrophenyl methylamine (0.08mmol) adds in the reaction flask, 10 ℃ are stirred 2d, add methylene dichloride 500mL, drip the sodium hydroxide solution 200mL of 2N, stirring at room 1h, separatory, water layer be with the 200mL dichloromethane extraction, merges organic layer and with the saturated common salt water washing, dry filter concentrates the crude product that obtains and obtains flaxen powder with ethyl acetate and sherwood oil recrystallization, yield 80%.
H?NMR(300MHz，CDCl
3)δ：8.23(br，1H，NH)，7.76～8.17(m，6H，PhH)，3.31(s，3H，NCH
3)，3.27(s，3H，PhC
H 3)，2.21(m，2H，COCH
2)，1.71(m，2H，C
H 2CH
3)，0.95(t，3H，CH
2C
H 3).
HPLC：93％
The preparation of embodiment 14 N-methyl-N-(2-nitrophenyl)-N-(the positive butyramide of 3-methyl-4--5-nitrophenyl) methane amide (compound 3)
The positive butyramide of 3-methyl-4--5-nitrobenzoic acid (21.2g, 0.08mol) adding 600mL dimethyl sulfoxide (DMSO) and sulfur oxychloride (0.08mol), 100 ℃ of reaction 20h, directly be dissolved in the dimethyl sulfoxide (DMSO) of 100mL without separating, ortho-nitrophenyl methylamine (0.8mol) adds in the reaction flask, 60 ℃ are stirred 2d, add methylene dichloride 500mL, drip the sodium hydroxide solution 200mL of 2N, stirring at room 1h, separatory, water layer is with the 200mL dichloromethane extraction, merge organic layer and with the saturated common salt water washing, dry filter concentrates the crude product that obtains and obtains flaxen powder with ethyl acetate and sherwood oil recrystallization, yield 81%.
H?NMR(300MHz，CDCl
3)δ：8.23(br，1H，NH)，7.76～8.17(m，6H，PhH)，3.31(s，3H，NCH
3)，3.27(s，3H，PhC
H 3)，2.21(m，2H，COCH
2)，1.71(m，2H，C
H 2CH
3)，0.95(t，3H，CH
2C
H 3).
HPLC：93％
The preparation of embodiment 14 N-methyl-N-(2-nitrophenyl)-N-(the positive butyramide of 3-methyl-4--5-nitrophenyl) methane amide (compound 3)
The positive butyramide of 3-methyl-4--5-nitrobenzoic acid (21.2g, 0.08mol) adding 600mL toluene and sulfur oxychloride (0.08mol), 100 ℃ of reaction 20h, directly be dissolved in the dimethyl sulfoxide (DMSO) of 100mL without separating, ortho-nitrophenyl methylamine (0.4mol) adds in the reaction flask, 60 ℃ are stirred 2d, add methylene dichloride 500mL, drip the sodium hydroxide solution 200mL of 2N, stirring at room 1h, separatory, water layer is with the 200mL dichloromethane extraction, merge organic layer and with the saturated common salt water washing, dry filter concentrates the crude product that obtains and obtains flaxen powder with ethyl acetate and sherwood oil recrystallization, yield 80%.
H?NMR(300MHz，CDCl
3)δ：8.23(br，1H，NH)，7.76～8.17(m，6H，PhH)，3.31(s，3H，NCH
3)，3.27(s，3H，PhC
H 3)，2.21(m，2H，COCH
2)，1.71(m，2H，C
H 2CH
3)，0.95(t，3H，CH
2C
H 3).
HPLC：93％
The embodiment 15 2-n-propyl group-4-methyl-6-(1-methyl-benzimidazolyl-2 radicals-yl) preparation of benzoglyoxaline (compound 1)
N-methyl-N-(2-nitrophenyl)-N-(the positive butyramide of 3-methyl-4--5-nitrophenyl) methane amide (3.2g, 8mmol) be dissolved in the 20mL dimethylbenzene, add reduced iron powder (8mmol), drip the 1mL concentrated hydrochloric acid and be warming up to 150 ℃ of reaction 6h, add 5g diatomite, be cooled to 50 ℃, filter, and with the 50mL washing with alcohol, filtrate concentrating is dissolved in the 100mL methylene dichloride, and with the 50mL10% ammonia scrubbing, organic layer is again with the saturated common salt water washing, the concentrated crude product that obtains of dry filter obtains white solid, yield 70% through the methanol recrystallization.
HPLC：97.5％
Claims (10)
1. the preparation method of a telmisartan midbody compound as shown in Equation 1 is characterized in that comprising the following step: compound 3 is carried out the reduction reaction and the ring-closure reaction of nitro, get final product;
2. preparation method as claimed in claim 1 is characterized in that: described preparation method comprises the following step: in organic inert solvent, under the effect of nitroreduction agent, compound 3 is carried out nitro-reduction reaction and ring-closure reaction, get final product; Wherein, described nitroreduction agent is one or more in reduced iron powder, zinc powder, V-Brite B, two hydrated stannous chlorides and the sodium borohydride.
3. preparation method as claimed in claim 2 is characterized in that: described organic inert solvent is selected from one or more in water, organic acid, lower alcohol, ester, ketone and the aromatic hydrocarbon; The consumption of described nitroreduction agent is 1～infinite times of molar weight of compound 3.
4. preparation method as claimed in claim 3 is characterized in that: described organic acid is one or more in formic acid, acetate and the propionic acid; Described lower alcohol is one or more in methyl alcohol, ethanol, propyl alcohol, Virahol and the butanols; Described ester solvent is ethyl acetate and/or n-butyl acetate; Described ketone solvent is an acetone.
5. preparation method as claimed in claim 3 is characterized in that: the temperature of described ring-closure reaction and nitro-reduction reaction is 0 ℃～150 ℃.
6. preparation method as claimed in claim 5 is characterized in that: the temperature of described ring-closure reaction and nitro-reduction reaction is 60～120 ℃.
7. preparation method as claimed in claim 3 is characterized in that: the time of described ring-closure reaction and nitro-reduction reaction with detection reaction fully till.
8. preparation method as claimed in claim 1, it is characterized in that: described compound 3 is made by following method: compound 2 and ortho-nitrophenyl methylamine are directly carried out condensation reaction, perhaps compound 2 is become carboxylic acid derivative easy and amino condensation, carry out condensation reaction with the ortho-nitrophenyl methylamine then, get final product;
9. preparation method as claimed in claim 8 is characterized in that: described carboxylic acid derivative is an acyl chlorides; When compound 2 becomes easily and the carboxylic acid derivative of amino condensation, when carrying out condensation reaction with the ortho-nitrophenyl methylamine then, used method and condition are as follows: in organic inert solvent or under the condition of no solvent, under the effect of the chloride reagent of carboxylic acid, compound 2 is carried out acyl chloride reaction become the acyl chlorides intermediate, carry out condensation reaction with the ortho-nitrophenyl methylamine again, get final product; Wherein, described organic inert solvent is selected from aromatic hydrocarbon, halogenated alkane, N, one or more in dinethylformamide, N,N-dimethylacetamide and the dimethyl sulfoxide (DMSO), and described condition of no solvent is a solvent for the chloride reagent with carboxylic acid; Described chloride reagent is selected from one or more in sulfur oxychloride, phosphorus trichloride and the phosphorus oxychloride; The consumption of chloride reagent is 1～infinite times of molar weight of compound 2; The consumption of ortho-nitrophenyl methylamine is 0.1～10 times of molar weight of compound 2; The temperature of described acyl chloride reaction is 20 ℃～100 ℃; The temperature of described condensation reaction is 10 ℃～60 ℃; The time of two kinds of reactions all with detection reaction fully till.
10. midbody compound 3 for preparing compound 1;
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| CN111041516A (en) * | 2019-12-19 | 2020-04-21 | 湖南大学 | New preparation method of telmisartan intermediate of antihypertensive drug |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2006044754A2 (en) * | 2004-10-18 | 2006-04-27 | Dr. Reddy's Laboratories Ltd. | Process for preparing telmisartan |
| CN101074213A (en) * | 2006-05-18 | 2007-11-21 | 上海科胜药物研发有限公司 | Synthesis of 2-n-propyl-4-methyl-6(1-methylbenzimidazole-2-radicle) benzimidazole and its use in synthesis of timishatan and its salts |
| WO2009004064A1 (en) * | 2007-07-03 | 2009-01-08 | Krka, Tovarna Zdravil, D.D., Novo Mesto | Process for preparing telmisartan |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2006044754A2 (en) * | 2004-10-18 | 2006-04-27 | Dr. Reddy's Laboratories Ltd. | Process for preparing telmisartan |
| CN101074213A (en) * | 2006-05-18 | 2007-11-21 | 上海科胜药物研发有限公司 | Synthesis of 2-n-propyl-4-methyl-6(1-methylbenzimidazole-2-radicle) benzimidazole and its use in synthesis of timishatan and its salts |
| WO2009004064A1 (en) * | 2007-07-03 | 2009-01-08 | Krka, Tovarna Zdravil, D.D., Novo Mesto | Process for preparing telmisartan |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111041516A (en) * | 2019-12-19 | 2020-04-21 | 湖南大学 | New preparation method of telmisartan intermediate of antihypertensive drug |
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