CN101074213A - Synthesis of 2-n-propyl-4-methyl-6(1-methylbenzimidazole-2-radicle) benzimidazole and its use in synthesis of timishatan and its salts - Google Patents
Synthesis of 2-n-propyl-4-methyl-6(1-methylbenzimidazole-2-radicle) benzimidazole and its use in synthesis of timishatan and its salts Download PDFInfo
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Abstract
Synthesis of 2-n-proply-4-methyl-6(-1-tolimidazole-2-radical)benzimidazole is simple and cheap, it has gentle reactive condition, friendly environment, more yield and better purifying effect. It can be used for large-scale industrial production of 2-n-proply-4-methyl-6(-1-tolimidazole-2-radical)benzimidazole, timistain and its salt.
Description
Technical field
The present invention relates to the synthetic method and the application in telmisartan and salt thereof are synthetic thereof of a kind of 2-n-propyl-4-methyl-6 (1-tolimidazole-2-yl) benzoglyoxaline.
Background technology
Telmisartan (Telmisartan), chemical name be 4 '-{ [2-n-propyl-4-methyl-6 (1-tolimidazole-2-yl) benzoglyoxaline-1-yl] methyl } [1,1 '-xenyl]-2-carboxylic acid (11), its structural formula is as follows:
Telmisartan is a specific specificity angiotensin-ii receptor (ATI type) antagonist.Its mechanism of action is to block combining of the nervous plain II of multiple tissue (as vascular smooth muscle, suprarenal gland) medium vessels and AT acceptor by selectivity, the blocking-up vasoconstriction that causes of Angiotensin II and the secretion of aldosterone, and do not rely on the synthetic path of Angiotensin II.Thereby telmisartan is to the avidity height of acceptor, and do not suppress ACE (Zinc metallopeptidase Zace1), do not influence the reaction of bradykinin, also do not combine or produce blocking effect with other hormone receptors, ionic channel.
Clinical experiment shows: telmisartan can be used for treating hypertension and myocardial function is not strong, ischemic peripheral circulatory diseases etc., for example stenocardia, essential hypertension; Compare with similar other drug, its untoward reaction is for example coughed, is had a headache, incidences such as dizziness and fatigue obviously reduce, and is the medicine that is widely used in treatment hypertension etc. in recent years clinically.
The synthetic route of existing telmisartan (11) mainly contains following several:
J Med Chem; 1993; the disclosed synthetic route of 36:4040-4051 is, and to be raw material with 3-methyl-4-Methyl anthranilate obtain 2-n-propyl-4-methyl-6-(1-tolimidazole-2-yl) benzoglyoxaline (8) through N-acidylate, nitrated, reduction, cyclization, ester hydrolysis, condensation reaction; this compound (8) obtains telmisartan (11) with 4 ｀-bromomethylbiphenyl-resulting product of 2-carboxylic acid tert-butyl ester nucleo philic substitution reaction through hydrolysis, and its synthetic route is as follows:
This method mainly has the following disadvantages:
(1) the synthetic of compound 12 need under high pressure carry out nitroreduction;
(2) compound 12 carries out the long reaction time of ring-closure reaction synthetic compound 13, needs about 20 hours;
(3) product behind the hydrolysis of ester group of compound 13 need be at high temperature (155-160 ℃) synthetic compound 8 that gets off;
(4) adopt the synthetic compound 8 that obtains of this method, be difficult to adopt the method for this area routine to carry out separation and purification, need carry out purifying by means of chromatographic column;
(5) product of compound 8 further substitution reactions needs to be hydrolyzed in the presence of TFA (trifluoroacetic acid), and TFA (trifluoroacetic acid) not only costs an arm and a leg, and this hydrolysis time is normal;
From as can be seen above, this method severe reaction conditions, complicated operation, the total reaction cycle is long, production cost is higher, is unsuitable for big suitability for industrialized production.
CN 01131915.1 discloses with 4 ｀-bromomethylbiphenyl-2-nitrile and has replaced 4 ｀-bromomethylbiphenyl-2-carboxylic acid uncle's ester and 2-n-propyl-4-methyl-6-(1-tolimidazole-2-yl) benzoglyoxaline to carry out nucleophilic substitution reaction, synthetic 4 ｀-[(1 that obtain, 4-dimethyl-2 ｀ [2,6-two-1H-benzoglyoxaline] methyl of-1 ｀-yl)]-[1,1-biphenyl]-the 2-nitrile, again it is hydrolyzed to the method for telmisartan.
Still there is above-mentioned defective in this method.
Summary of the invention
In order to overcome the defective of prior art, the present invention's one purpose provide a kind of reaction conditions gentleness, simple to operate, be convenient to purifying, yield is higher, the method of the Synthetic 2-n-propyl of environmentally friendly type-4-methyl-6 (1-tolimidazole-2-yl) benzoglyoxaline (8), its structural formula is as follows
Comprise following steps:
(1) the positive butyramide of 3-methyl-4--5-nitrobenzoic acid methyl esters (4) reaction that in the presence of alkaline reagents, is hydrolyzed;
(2) the positive butyramide of step (1) the resulting product 3-methyl-4-of reaction-5-nitrobenzoic acid (5) changes compound (7) into;
(3) step (2) reaction resulting product N-methyl-N-(2-aminophenyl)-N-(the positive butyramide of 3-methyl-4--5-nitrophenyl) methane amide (7) changes compound (8) into.
Compound of the present invention (4) can adopt the compound of SILVER REAGENT or technical grade; Also can adopt method of the prior art to synthesize, concrete reaction conditions and operation steps are seen the embodiment of the invention.
Step (1) alkaline reagents that described hydrolysis reaction adopted can be sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide or its mixture.The concentration of described alkaline reagents solution is principle with what do not destroy that reaction be rolled into a ball and be beneficial in other palace can in the reactant.The concentration of the alkaline reagents (sodium hydroxide) that is for example adopted in a preferred embodiment of the present invention is 2N.
The solvent that step (1) reaction is adopted can be the conventional solvent that this area hydrolysis of ester group is adopted, and the selection of reagent is not to destroy other functional group in the reactant and what be beneficial to reaction is principle; Reaction solvent can be selected from methyl alcohol, tetrahydrofuran (THF), 1, the mixture of 4-dioxane, water, methyl alcohol and water, tetrahydrofuran (THF) and water mixture or 1, the mixture of 4-dioxane and water; The volume ratio of organic solvent and water is 1 in the described reaction mixed solvent: 1-5: 1, and preferred volume ratio is 2: 1-4: 1.
The temperature of reaction that step (1) reaction is adopted is 20-80 ℃.In above-mentioned temperature of reaction, not destroy other functional group in the reactant, to be beneficial to the carrying out of reaction and the purifying of reaction product is a principle.Under different reaction conditionss, (comprise different alkaline reagentss, reaction solvent) and select appropriate temperature of reaction, for example in a preferred embodiment of the present invention, the alkaline reagents that reaction is adopted is a sodium hydroxide, and reaction solvent is a methyl alcohol, and the temperature of reaction that this reaction is adopted is 20-30 ℃.
Compound (5) changes compound (7) into and can adopt following two kinds of methods to realize.
First method, step (1) are reacted resulting compound (5) and are converted into compound (7) in the existence of condensing agent and alkaline reagents; Described condensing agent is HBTU (benzotriazole-N, N, N ', N ' ,-tetramethyl-urea phosphofluoric acid ester) and mixture, DCC (dicyclohexyl carbodiimide) or the PyPOP (phosphofluoric acid benzotriazole-1-base-oxygen base tripyrrole alkyl phosphorus) of mixture, HOBT and the EDC of HOBT (I-hydroxybenzotriazole).Described alkaline reagents is selected from DIEA (diisopropylethylamine), triethylamine, Trimethylamine 99 or two cyclohexyl amines.
The solvent of described reaction can be selected from tetrahydrofuran (THF), methylene dichloride, trichloromethane, DMF or 1,4-dioxane.
The temperature of described reaction is 20-60 ℃.Under the different reaction conditions (comprising different condensing agents, alkaline reagents and reaction solvent), the control that is beneficial to react in this temperature range and the purifying of reaction product are principle, select different temperature of reaction to carry out.For example among the present invention one good embodiment, the condensing agent that is adopted is that mixture, the alkaline reagents of HBTU and HOBT is DIEA, and reaction solvent is THF, and the temperature of reaction that is adopted is 25-28 ℃.
Second method, the resulting compound of step (1) (5) changes chloride derivative (14) earlier into, reacts with N-methyl-o-phenylenediamine (6) in the presence of alkaline reagents then and changes compound (7) into, and its reaction is as follows:
Described compound (5) can react with thionyl chloride or oxalyl chloride and change compound (14) into.This reaction can be carried out under the operational condition of this area routine.For example compound (5) changes compound (14) into thionyl chloride in organic solvent, and described organic solvent is methylene dichloride, trichloromethane or methyl alcohol; Described temperature of reaction is 20-60 ℃, in this temperature range, under different reaction conditions (comprising reaction solvent), with the control that helps reacting, the purifying of reaction product is that principle is selected suitable reaction temperature, it for example is solvent with methyl alcohol, compound (5) can be at 20-60 ℃ of scope internal reaction with thionyl chloride, and for control reaction preferably, this reacts preferably at 40-50 ℃ of internal reaction; Compound (5) and oxalyl chloride in methylene dichloride in 0-10 ℃ of internal reaction.
Compound (14) is that the solvent that is adopted in the reaction of compound (7) can be selected from tetrahydrofuran (THF), methylene dichloride, trichloromethane, DMF or 1, the 4-dioxane with N-methyl-o-phenylenediamine (6) condensation.The temperature that reaction is adopted is 30-60 ℃.Described alkaline reagents is DIEA, triethylamine, Trimethylamine 99 or two cyclohexyl amines.
Compound (7) changes compound (8) into can be realized through following reaction.
Compound (7) changes compound (15) into and can adopt following two kinds of methods to realize.
First method: compound (7) carries out reduction reaction and changes compound (15) in the presence of Fe/HCl, Fe/HOAc, Sn/HCl, Sn/HOAc or Zn/HCl.Preferably, compound (7) changes compound (15) in the presence of Fe/HCl.
It is the proportionlity of this area routine that molar ratio between reductive agent that described reduction reaction adopted (Fe, Sn or Zn) and the reaction substrate (7) closes, as 3: 1-5: 1, for example in a preferred embodiment of the present invention, the molar ratio pass of going back between original reagent (Fe) and the reaction substrate (7) is 4: 1.
The choosing of the solvent that described reduction reaction adopted can be selected from methyl alcohol, ethanol or Virahol then with the purifying of the carrying out that help reduction reaction, product with help the principle that rises to of reaction yield.
The temperature of reaction that is adopted is 40-80 ℃.In this temperature range, under different reaction conditions (comprising different reductive agent/acid and different solvents), the temperature that reaction is adopted is beneficial to the carrying out that reacts, the purifying of reaction product is that principle is selected, for example in the present invention's one specific embodiment, the temperature of reaction that is adopted in Fe/HCl/MeOH is 60 ℃.
Second method: compound (7) hydro-reduction under the catalysis of metal catalyst is compound (15), and described metal catalyst is Pd/C or Raney Ni.
It is the conventional proportionlity that adopt this area that mol ratio between described catalyzer and the reaction substrate (7) is closed.The temperature of reaction that is adopted is 25-50 ℃.The absolute pressure that is adopted is 30-50Psi.
In order to promote the carrying out of hydrogenation, in reaction, can add an amount of acid, for example acetic acid or hydrochloric acid.
Compound (7) also can be at SnCl
2/ HCl changes compound (15) under existing, and the proportionlity between described reagent and the reaction substrate (7) is 3: 1-5: 1; The reaction solvent that is adopted can be and is selected from methyl alcohol, ethanol or Virahol; The temperature of reaction that is adopted is 30-60 ℃, is preferably 30-40 ℃.
Compound (15) changes compound (8) into and can adopt following method to realize.
Compound (15) carries out ring-closure reaction and changes compound (8) in the presence of acetic acid or PPA.Compound (15) temperature of reaction that cyclization is adopted in acetic acid is the reflux temperature of acetic acid; It is 90-100 ℃ that compound in the presence of PPA (15) changes the temperature of reaction that compound (8) adopted into.
Compound (7) directly changes compound (8) into and can adopt following two kinds of methods to realize.
First method: compound (7) can directly change compound (8) in the presence of Fe/HOAc or Sn/HOAc; This reaction is made solvent with acetic acid, changes compound (8) under the acetic acid reflux temperature into.
Second method: compound (7) changes compound (8) in the presence of acetic acid under metal catalyst Pd/C catalysis; Described temperature of reaction is 40-50 ℃; Described reaction pressure is 30-50Psi; The reaction solvent that is adopted can be selected from methyl alcohol, ethanol or methylene dichloride.
The method of synthetic compound of the present invention (8) has the following advantages:
(1) this method reaction conditions gentleness, reaction conditions, reaction times simple to operate, that need not High Temperature High Pressure are reasonable, yield is higher, effective production cost that reduced;
(2) adopt the synthetic compound (8) that obtains of this method to need not to adopt chromatographic column to carry out separation and purification, promptly can reach higher purity;
(3) not only to be suitable for the laboratory synthetic on a small scale for this method, also is suitable for industrialized production compound (8).
Another object of the present invention provide a kind of adopt the synthetic compound (8) that obtains of method of the present invention synthesize 4 '-{ [2-n-propyl-4-methyl-6 (1-tolimidazole-2-yl) benzoglyoxaline-1-yl] methyl } [1,1 '-xenyl]-the 2-carboxylic acid, it is the method for telmisartan (11) and salt thereof, its structural formula is as follows
This method comprises following steps:
(1) compound (8) and 4 '-bromomethylbiphenyl-2-t-butyl formate is in the presence of alkaline reagents, in solvent reaction synthetic 4 '-{ [2-n-propyl-4-methyl-6 (1-methylbenzene imipramine-2-yl) benzimidazole-1-yl] methyl } xenyl-2-carboxylic acid tert-butyl ester (10)
(2) the resulting product of step (1) is hydrolyzed in the presence of acetic acid, synthetic telmisartan (11);
(3) as required, can be with the synthetic corresponding salt of telmisartan (11).
The solvent that reaction is adopted in the step (1) can be DMF, DMSO, THF, dioxane, acetone, CH
2Cl
2, CHCl
3Or ethylene dichloride.
Alkaline reagents described in the step (1) can be selected from saleratus, salt of wormwood or yellow soda ash.
Hydrolysis reaction described in the step (1) carries out under 25-50 ℃.In different solvents, different alkaline reagentss exist down, and the temperature of reaction that is adopted is beneficial to be reflected to be finished in the rational reaction times, and the product of reaction is easy to purifying and reaction, and to have higher yield be that principle is selected in above-mentioned scope.For example in a preferred embodiment of the present invention, the organic solvent that is adopted is DMF, and the alkali that is adopted is K
2CO
3, the temperature of reaction that is adopted is 35-40 ℃.
Compound (10) temperature that hydrolysis reaction adopted in acetic acid is a reflux temperature.
The salt of described telmisartan (11), be telmisartan and basic metal, alkaline-earth metal, pharmaceutically acceptable amine, a kind of formed salt in the amino acid (for example arginine or Methionin), comprise sylvite, sodium salt, magnesium salts, calcium salt, amine salt or amino acid salts, be generally sylvite, sodium salt or tert-butylamine salt.
The synthetic method of compound of the present invention (11) salt can adopt the method for this area routine to carry out, a kind of with in compound (11) and organic bases, mineral alkali, the amino acid (arginine or Methionin), organic solvent and (or) react in the water, generate its salt.
Described organic solvent comprises ethers, alcohols, ketone, halogenated alkane, alkane or aromatic hydrocarbons and composition thereof.Said ethers can be selected from ether, methyl-phenoxide, trimethyl carbinol ether; Described alcohols can be selected from methyl alcohol, ethanol, propyl alcohol or propyl carbinol; Described ketone can be selected from acetone or pimelinketone; Described halogenated alkane can be selected from the saturated alkane of chloro, bromo C1-C3; Described aromatic hydrocarbons can be selected from toluene, dimethylbenzene, chlorotoluene or xylene monochloride.
Described organic bases can be selected from triethylamine, DIEA, diethylamine or TERTIARY BUTYL AMINE; Be preferably TERTIARY BUTYL AMINE.
Described mineral alkali is an alkali metal hydroxide, and the oxyhydroxide of alkaline-earth metal comprises sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, adopts sodium hydroxide or magnesium hydroxide usually.
The synthetic method of compound of the present invention (11) and salt thereof, the hydrolysing agent acetate that hydrolysis reaction adopted described in the step (1), wide material sources not only, low price, and also the reaction times is short, saves the time of reaction greatly, reduces production cost.
This shows, the method of synthetic compound provided by the present invention (8), compound (11) and salt thereof be a kind of reaction conditions gentleness, simple to operate, be convenient to purifying, yield is higher, environment amenable method, this method not only can be synthetic on a small scale in the laboratory, and can be at industrial extensive synthetic compound (8), compound (11) and the salt thereof of carrying out; Also can synthesize intermediate related in this method, for example compound (5), compound (6) and compound (7) etc.
Specific embodiment
The present invention is further illustrated below in conjunction with embodiment, understanding purpose of the present invention, feature and effect fully, but the present invention do not done any restriction.
The synthetic embodiment of the positive butyramide of 3-methyl-4--5-nitrobenzoic acid methyl esters is as follows:
The product 3-methyl-4-Methyl anthranilate (30g that in 500mL exsiccant there-necked flask, adds above-mentioned reaction successively; 0.182mol), 300mL methylene dichloride and 51mL TEA; after stirring; be cooled to 0-5 ℃ and keep this temperature; the 50mL dichloromethane solution that slowly adds butyryl chloride (23mL) in the N2 protection down; slowly rise to room temperature after dropwising, continue reaction and finish up to TLC tracking reaction.Reaction mixture is used saturated NaHCO successively
3Solution, 1N HCl solution and saturated aqueous common salt washing reaction mixture, the organic layer anhydrous Na
2SO
4Drying, the resultant faint yellow solid of concentrating under reduced pressure obtains white solid 36.4g with the methylene dichloride recrystallization, and yield is 85.2%.
The HNO of will being fuming
3(97.3g 1.54mol) joins in the reaction flask of exsiccant 500mL, is cooled to-10 ℃, drips dense H then
2SO
4(61.5g, 0.63mol), after stirring, (36.4g, 0.155mol), the reinforced back that finishes tracks to reaction in-10 ℃ of reactions up to TLC and finishes to add the positive butyramide methyl benzoate of 3-methyl-4-down in-10--5 ℃.Reaction mixture is poured into (0 ℃) stirring in the frozen water (having solid to generate).Filter, to neutral, dried filter cake ethyl alcohol recrystallization obtains faint yellow solid 35.8g, productive rate: 82.5% to filter cake with water wash.
Synthesizing of the positive butyramide of 3-methyl-4--5-nitrobenzoic acid
Embodiment 1
With the positive butyramide of the product 3-methyl-4--5-nitrobenzoic acid methyl esters of above-mentioned reaction (2.8g, 0.01mol), 30mL MeOH, 10mL H
2O joins in the reaction flask of 250mL, and after stirring, (0.8g, 0.02mol), stirring reaction is followed the tracks of reaction up to TLC and finished to add NaOH down in 20-25 ℃.The reactant concentrating under reduced pressure, residuum is regulated pH to slightly acidic (6.0-6.8) (having solid to generate) with 1N HCl, leaves standstill after-filtration, and filter cake filtered water drip washing obtains white solid 2.4g after the drying, and productive rate is 90.2%.
Embodiment 2
With the positive acid amides of the product 3-methyl-4--5-nitrobenzoic acid methyl esters of above-mentioned reaction (2.8g, 0.01mol), 30mL 1,4-dioxane, 15mL H
2O joins in the reaction flask of 250mL, and after stirring, (1.12g, 0.02mol), stirring reaction is followed the tracks of reaction up to TLC and finished slowly to add KOH down in 30-40 ℃.Concentrating under reduced pressure, residuum is regulated pH to slightly acidic (6.0-6.8) (having solid to generate) with 1N HCl, leaves standstill after-filtration, and filter cake filtered water drip washing obtains white solid 2.5g after the drying, and productive rate is 94.0%.
Synthesizing of N-methyl-N-(2-aminophenyl)-N-(the positive butyramide of 3-methyl-4--5-nitrophenyl) methane amide
Embodiment 1
The positive butyramide of product 3-methyl-4--5-nitrobenzoic acid (2.4g with 70mL exsiccant THF, above-mentioned reaction, 0.009mol) and the hydrochloride (1.9g of N-methyl-o-phenylenediamine, 0.0097mol) join in the exsiccant 250mL reaction flask, after stirring, add DIEA (5.0g, 0.039mol), (3.4g 0.009mol), adds HOBT (1.2g behind the stirring 0.5h to add HBTU after stirring 0.5h under 25-28 ℃, 0.009mol), stirring reaction is followed the tracks of up to TLC and is reacted completely.Reaction mixture concentrating under reduced pressure, residuum adopt MeOH/DCM=1: 40 (v: mixing solutions recrystallization v) obtains faint yellow solid 2.8g, productive rate: 83.8%.
Embodiment 2
The positive butyramide of product 3-methyl-4--5-nitrobenzoic acid (2.4g with 70mL exsiccant methylene dichloride, above-mentioned reaction, 0.009mol) and the hydrochloride (1.9g of N-methyl-o-phenylenediamine, 0.0097mol) join in the exsiccant 250mL reaction flask, after stirring, (3.63g 0.036mol), adds DCC (1.90g behind the stirring 0.5h down in 30-35 ℃ to add triethylamine, 0.0092mol), the afterreaction that stirs is followed the tracks of up to TLC and is reacted completely.Reaction mixture concentrating under reduced pressure, residuum adopt MeOH/DCM=1: 40 (v: mixing solutions recrystallization v) obtains faint yellow solid 2.75g, productive rate: 82.4%.
Embodiment 3
With 70mL exsiccant 1, the positive butyramide of the product 3-methyl-4--5-nitrobenzoic acid (2.4g of 4-dioxane, above-mentioned reaction, 0.009mol) and the hydrochloride (1.9g of N-methyl-o-phenylenediamine, 0.0097mol) join in the exsiccant 250mL reaction flask, after stirring, add DIEA (2.0g, 0.0097mol), add HBTU (3.4g behind the stirring 0.5h down in 50-60 ℃, 0.009mol), (1.2g, 0.009mol), the afterreaction that stirs is followed the tracks of up to TLC and is reacted completely to add HOBT behind the stirring 0.5h.Reaction mixture concentrating under reduced pressure, residuum adopt MeOH/DCM=1: 40 (v: mixing solutions recrystallization v) obtains yellow solid 2.70g, productive rate: 80.8%.
Embodiment 4
The positive butyramide of the product 3-methyl-4--5-nitrobenzoic acid (2.4g of above-mentioned reaction, 0.009mol) join in the 70mL exsiccant methyl alcohol, after being cooled to 0 ℃, drip the thionyl chloride (3.21g of 30mL methylene dichloride, 0.027mol) solution, after dropwising, slowly be raised to 40-45 ℃ of reaction and react completely up to the TLC tracking.Residuum after concentrating is dissolved in the tetrahydrofuran (THF) of 50mL, and (1.9g, 0.0097mol), after stirring, (5.0g 0.024mol), follows the tracks of to react completely up to TLC in 35-40 ℃ of reaction to add DIEA to add the hydrochloride of N-methyl-o-phenylenediamine then.Reaction mixture concentrating under reduced pressure, residuum adopt MeOH/DCM=1: 35 (v: mixing solutions recrystallization v) obtains yellow solid 2.63g, productive rate: 78.7%.
Embodiment 5
The positive butyramide of the product 3-methyl-4--5-nitrobenzoic acid (2.4g of above-mentioned reaction, 0.009mol) join in the 70mL exsiccant methylene dichloride, after being cooled to 0 ℃, drip the thionyl chloride (3.21g of 30mL methylene dichloride, 0.027mol) solution, after dropwising, slowly be raised to the room temperature afterreaction and react completely up to the TLC tracking.The residuum of reaction mixture after concentration is dissolved in the methylene dichloride of 60mL, add then the N-methyl-o-phenylenediamine hydrochloride (1.9g, 0.0097mol), after stirring, (4.54g 0.045mol), reacts completely up to the TLC tracking in 40-50 ℃ of reaction to add triethylamine.Reaction mixture concentrating under reduced pressure, residuum adopt MeOH/DCM=1: 35 (v: mixing solutions recrystallization v) obtains yellow solid 2.68g, productive rate: 80.3%.
Synthesizing of 2-n-propyl-4-methyl-6 (1-tolimidazole-2-yl) benzoglyoxaline
Embodiment 1
Product N-methyl-N-(2-aminophenyl)-N-(the positive butyramide of 3-methyl-4--5-nitrophenyl) methane amide (2.8g with 5mL 36.5%HCl, 100mL methyl alcohol and above-mentioned reaction, 0.0075mol) join in the reaction flask, after stirring, be heated to 60 ℃, every 10 minutes, add reductibility Fe powder 0.5g afterwards at every turn, amount to (2.0g, 0.036mol), reaction is followed the tracks of up to TLC and is reacted completely.Leave standstill the HCl that concentrating under reduced pressure methyl alcohol and unreacted are intact behind the cool to room temperature.Add 50mL acetic acid in the residuum after concentrating, be heated to the reflux temperature reaction once more and finish up to TLC tracking reaction.Concentrating under reduced pressure acetic acid, residuum is with 10% NaHCO
3Solution is regulated pH to 5.5-6.5.With methylene dichloride (150mL * 3) extraction, the anhydrous MgSO of organic layer
4Dry, concentrated, residuum adopts methyl alcohol: (v: mixing solutions recrystallization v) obtains ashen solid 1.8g to methylene dichloride=1: 20, and yield is 78.3%.mp：142～144℃。
1H-NMR(CDCl
3)6(ppm)：7.26-7.44(m，6H，aromaties)；3.85(s，3H，N-CH
3)；2.74(t，2H，CH
2C
2H
5)；2.48(s，3H，phenyl-CH
3)；1.72(m，2H，CH
2CH
3)；0.88(t，3H，CH
2CH
3)
Embodiment 2
(2.8g 0.0075mol) joins in the reaction flask, after stirring, slowly adds SnCl with product N-methyl-N-(2-aminophenyl)-N-(the positive butyramide of 3-methyl-4--5-nitrophenyl) methane amide of 5mL 36.5%HCl, 100mL methyl alcohol and above-mentioned reaction
2(6.5g 0.034mol), after stirring, reacts completely up to the TLC tracking in 30-35 ℃ of reaction.Post reaction mixture is with 10% NaHCO
3Solution is regulated pH to 5.5-6.5, with ethyl acetate (250mL * 3) extraction, adds acetic acid in the residuum after concentrated, reacts and processing obtains ashen solid 1.5g according to the method among the embodiment 1, and yield is 65.2%.
Embodiment 3
Product N-methyl-N-(2-aminophenyl)-N-(the positive butyramide of 3-methyl-4--5-nitrophenyl) methane amide (2.8g with 5mL HOAc, 100mL methyl alcohol and above-mentioned reaction, 0.0075mol) join in the reaction flask, after stirring, slowly add Sn (4.0g, 0.034mol), after stirring, react completely up to the TLC tracking in 40-50 ℃ of reaction.Post reaction mixture is with 10% NaHCO
3Solution is regulated pH to 5.5-6.5, with ethyl acetate (250mL * 3) extraction, the anhydrous MgSO of organic layer
4Add acetic acid in dry, the residuum after concentrating, react and processing obtains khaki color solid 1.67g according to the method among the embodiment 1, yield is 72.6%.
Embodiment 4
Product N-methyl-N-(2-aminophenyl)-N-(the positive butyramide of 3-methyl-4--5-nitrophenyl) methane amide (2.8g with 5mL 36.5%HCl, 100mL ethanol and above-mentioned reaction, 0.0075mol) join in the reaction flask, after stirring, slowly add Zn (2.0g, 0.031mol), after stirring, behind 60-70 ℃ of reaction 3h, be warmed up to 60-70 ℃ of reaction afterwards and react completely up to the TLC tracking.Post reaction mixture is with 10% NaHCO
3Solution is regulated pH to 5.5-6.5, with ethyl acetate (250mL * 3) extraction, adds acetic acid in the residuum after concentrated, reacts and processing obtains ashen solid 1.45g according to the method among the embodiment 1, and yield is 63.0%.
Embodiment 5
Product N-methyl-N-(2-aminophenyl)-N-(the positive butyramide of 3-methyl-4--5-nitrophenyl) methane amide (2.8g with 100mL methyl alcohol, 10%Pd/C (0.028g), 5mL acetic acid and above-mentioned reaction, 0.0075mol) join in the hydrogenation still, under absolute pressure 30-35Psi, at 20-25 ℃ of logical hydrogen 3h.Post reaction mixture is directly used in next step reaction after concentrating.
Above-mentioned resulting product and 40mL acetic acid 40-45 ℃ of reaction, are followed the tracks of to react completely up to TLC, reaction mixture is regulated pH to 6.5-7.5 with 2N sodium hydroxide, adds 100mL water afterwards, adopts methylene dichloride (150mL * 3) to extract the organic layer anhydrous Na
2SO
4Drying, concentrating under reduced pressure obtain white crystal 1.65g, and yield is 71.7%.
Embodiment 6
Product N-methyl-N-(2-aminophenyl)-N-(the positive butyramide of 3-methyl-4--5-nitrophenyl) methane amide (2.8g with 100mL ethanol, Raney Ni (0.5g), 5mL acetic acid and above-mentioned reaction, 0.0075mol) join in the hydrogenation still, under absolute pressure 45-50Psi, at 40-45 ℃ of logical hydrogen 3.5h.Post reaction mixture is directly used in next step reaction after concentrating.
Above-mentioned resulting product and 40mL acetic acid 40-45 ℃ of reaction, are followed the tracks of to react completely up to TLC, reaction mixture is regulated pH to 6.5-7.5 with 2N sodium hydroxide, adds 100mL water afterwards, adopts methylene dichloride (150mL * 3) to extract the organic layer anhydrous Na
2SO
4Drying, concentrating under reduced pressure obtain white crystal 1.5g, and yield is 65.2%.
Embodiment 7
Product N-methyl-N-(2-aminophenyl)-N-(the positive butyramide of 3-methyl-4--5-nitrophenyl) methane amide (2.8g with 100mL methyl alcohol, 10%Pd/C (0.028g) and above-mentioned reaction, 0.0075mol) join in the hydrogenation still, under absolute pressure 35-40Psi, at 30-35 ℃ of logical hydrogen 2.5h.The product that post reaction mixture is filtered, filtrate obtains after concentrating directly enters next step reaction.
Above-mentioned resulting product and 40mL acetic acid 40-45 ℃ of reaction, are followed the tracks of to react completely up to TLC, reaction mixture is regulated pH to 6.5-7.5 with 2N sodium hydroxide, adds 100mL water afterwards, adopts methylene dichloride (150mL * 3) to extract the organic layer anhydrous Na
2SO
4Drying, concentrating under reduced pressure obtain white crystal 1.6g, and yield is 69.5%.
Embodiment 8
Product N-methyl-N-(2-aminophenyl)-N-(the positive butyramide of 3-methyl-4--5-nitrophenyl) methane amide (2.8g with 100mL methyl alcohol, 10%Pd/C (0.028g), 40mL acetic acid and above-mentioned reaction, 0.0075mol) join in the hydrogenation still, under absolute pressure 40Psi, at 40-45 ℃ of logical hydrogen 3h.Post reaction mixture is filtered, filtrate is used methyl alcohol drip washing, and filtrate obtains faint yellow solid 1.7g after concentrating, and yield is 73.9%.
Embodiment 9
Change the temperature of reaction among the embodiment 8 into 45-50 ℃, the absolute pressure of reaction is 30-35Psi, and all the other and embodiment 8 do not have substantive difference, obtains khaki color solid 1.65g, and yield is 71.7%.
Embodiment 10
Change the temperature of reaction among the embodiment 8 into 40-45 ℃, the absolute pressure of reaction is 45-50Psi, and all the other and embodiment 8 do not have substantive difference, obtains khaki color solid 1.45g, and yield is 63.04%.
Embodiment 11
Product N-methyl-N-(2-aminophenyl)-N-(the positive butyramide of 3-methyl-4--5-nitrophenyl) methane amide (2.8g with 40mL HOAc and above-mentioned reaction, 0.0075mol) join in the reaction flask, after stirring, be heated to 60 ℃, (2.0g 0.036mol), is heated to reflux temperature afterwards and reacts to add reductibility Fe powder, directly TLC follows the tracks of and reacts completely, and post reaction mixture is with 10% NaHCO
3Solution is regulated pH to 5.5-6.5, with methylene dichloride (150mL * 3) extraction, the anhydrous MgSO of organic layer
4Dry, concentrated, residuum adopts methyl alcohol: (v: mixing solutions recrystallization v) obtains ashen solid 1.8g to methylene dichloride=1: 20, and yield is 78.3%.
Embodiment 12
Change the temperature of reaction among the embodiment 11 into 40-45 ℃, the solvent of reaction should be methylene dichloride.Obtain khaki color solid 1.6g, yield is 69.6%.
Embodiment 13
Change the temperature of reaction among the embodiment 12 into 50-55 ℃, be reflected among the HOAc of 40mL and react.Obtain khaki color solid 1.7g, yield is 73.9%.
4 '-the synthetic embodiment of { [2-n-propyl-4-methyl-6 (1-methylbenzene imipramine-2-yl) benzimidazole-1-yl] methyl } xenyl-2-carboxylic acid tert-butyl ester is as follows:
With product 2-n-propyl-4-methyl-6 (1-tolimidazole-2-yl) benzoglyoxaline of above-mentioned reaction (0.2g, 0.66mmol), 4 '-bromomethylbiphenyl-2-t-butyl formate (0.24g, 0.69mmol), K
2CO
3(1.0g 0.007mol) joins in the reaction flask with 20mL DMF, and post-heating to the 40 ℃ reaction that stirs tracks to reaction up to TLC and finishes.Concentrating under reduced pressure, residuum adds 50mL water, after stirring, adopts ethyl acetate (150mL * 3) extraction, the organic layer anhydrous Na
2SO
4Dry, concentrating under reduced pressure, residuum MeOH/DCM=1: 20 (v: mixing solutions v) comes recrystallization, obtains white crystal 0.29g, and yield is 86.9%.
4 '-the synthetic embodiment of { [2-n-propyl-4-methyl-6 (1-tolimidazole-2-yl) benzoglyoxaline-1-yl] methyl } [1,1 '-xenyl]-2-carboxylic acid is as follows:
With the product 4 of above-mentioned reaction '-{ [2-n-propyl-4-methyl-6 (1-methylbenzene imipramine-2-yl) benzimidazole-1-yl] methyl } xenyl-2-carboxylic acid tert-butyl ester (0.29g, 0.5mmol), 10mL HOAc joins in the reaction flask, the post-heating that stirs refluxes, and follows the tracks of reacting completely up to TLC.Concentrating under reduced pressure, residuum 10%NaHCO
3Solution is regulated pH behind 5.5-6.5.With methylene dichloride (150mL * 3) extraction, organic layer anhydrous Na
2SO
4Drying, concentrating under reduced pressure obtain white crystal 0.22g, and yield is 84.6%.mp：267～269℃。
4 '-the synthetic embodiment of { [2-n-propyl-4-methyl-6 (1-tolimidazole-2-yl) benzoglyoxaline-1-yl] methyl } [1,1 '-xenyl]-2-carboxylate salt is as follows:
With the product 4 of above-mentioned reaction '-{ [2-n-propyl-4-methyl-6 (1-tolimidazole-2-yl) benzoglyoxaline-1-yl] methyl } [1,1 '-xenyl]-2-carboxylic acid (0.29g, 0.56mmol), 20mL methyl alcohol and NaOH (0.03g, 0.75mmol) join in the reaction flask, stir 1h in 20-25 ℃.Filtration, elimination insolubles, concentrating under reduced pressure adds 5mL ethanol in the residuum, concentrate back adding 2mL normal hexane and concentrate in the residuum to reacting, and concentrates and obtains the sodium salt of telmisartan 0.29g, and yield is 95.9%.
The described just preferable specific embodiment of the present invention of this specification sheets.In every case those skilled in the art of the present technique conceive change or the modification of being made according to the present invention, all should drop within the protection domain of claim of the present invention.
Claims (16)
1. the synthetic method of 2-n-propyl-4-methyl-6 (1-tolimidazole-2-yl) benzoglyoxaline (8),
Comprise following steps:
(1) the positive butyramide of 3-methyl-4--5-nitrobenzoic acid methyl esters (4) reaction that in the presence of alkaline reagents, is hydrolyzed;
(2) the positive butyramide of step (1) the resulting product 3-methyl-4-of reaction-5-nitrobenzoic acid (5) changes compound (7) into;
(3) step (2) reaction resulting product N-methyl-N-(2-aminophenyl)-N-(the positive butyramide of 3-methyl-4--5-nitrophenyl) methane amide (7) changes compound (8) into.
2. a kind of synthetic method as claimed in claim 1, wherein the described alkaline reagents of step (1) is sodium hydroxide, potassium hydroxide, lithium hydroxide or cesium hydroxide; The solvent that described hydrolysis reaction adopted is methyl alcohol, tetrahydrofuran (THF), 1, the mixture of the mixture of 4-dioxane, water, methyl alcohol and water, tetrahydrofuran (THF) and water or 1, the mixture of 4-dioxane and water.
3. a kind of synthetic method as claimed in claim 1, wherein the described compound of step (2) (5) is to leave with the reaction of N-methyl-o-phenylenediamine at condensing agent and alkaline reagents to be converted into compound (7); Described condensing agent is mixture or the DCC of mixture, HOBT and the EDC (1, the 2-ethylene dichloride) of HBTU and HOBT; Described alkaline reagents is selected from DIEA, triethylamine, Trimethylamine 99 or two cyclohexyl amines; The temperature that reaction is adopted is 20-60 ℃.
4. a kind of synthetic method as claimed in claim 1, wherein the described compound of step (2) (5) is converted into chloride derivative (14) earlier, reacts with N-methyl-o-phenylenediamine (6) in the presence of alkaline reagents then, and its reaction is as follows:
Described alkaline reagents is DIEA, triethylamine, Trimethylamine 99 or two cyclohexyl amines.
5. a kind of synthetic method as claimed in claim 1, the wherein described compound of step (3) (7)
Change compound (8) into through as above reacting.
6. a kind of synthetic method as claimed in claim 5, wherein compound (7) is to carry out reduction reaction to change compound (15) in the presence of Fe/HCl, Fe/HOAc, Sn/HCl, Sn/HOAc or Zn/HCl.
7. a kind of synthetic method as claimed in claim 6, wherein compound (7) is to carry out reduction reaction to change compound (15) in the presence of Fe/HCl.
8. as claim 6 or 7 described a kind of synthetic methods, the solvent that wherein said reduction reaction adopted is selected from methyl alcohol, ethanol or Virahol; The temperature that reaction is adopted is 40-80 ℃.
9. a kind of synthetic method as claimed in claim 5, wherein compound (7) is under the catalytic hydrogenation of metal catalyst, changes compound (15) into through reduction reaction, described metal catalyst is Pd/C or Raney Ni.
10. a kind of synthetic method as claimed in claim 9, the absolute pressure that wherein said reduction reaction adopted is 30-50Psi.
11. a kind of synthetic method as claimed in claim 5, wherein compound (15) is to carry out ring-closure reaction to change compound (8) in the presence of acetic acid.
12. a kind of synthetic method as claimed in claim 1, wherein compound (7) is directly to change compound (8) in the presence of Fe/HOAc or Sn/HOAc into.
13. a kind of synthetic method as claimed in claim 1, wherein compound (7) is under metal catalyst Pd/C catalysis, changes compound (8) in the presence of acetic acid into; The temperature that reaction is adopted is 40-50 ℃; The absolute pressure that reaction is adopted is 30-50Psi.
14. the method with 2-n-propyl-4-methyl-6 (1-tolimidazole-2-yl) benzoglyoxaline (8) synthetic treatment antihypertensive medicine telmisartan (11) and salt thereof, described salt is sylvite, sodium salt or tert-butylamine salt,
This method comprises following steps:
(1) compound (8) and 4 '-bromomethylbiphenyl-2-t-butyl formate is in the presence of alkaline reagents, in solvent reaction synthetic 4 '-{ [2-n-propyl-4-methyl-6 (1-methylbenzene imipramine-2-yl) benzimidazole-1-yl] methyl } xenyl-2-carboxylic acid tert-butyl ester (10), described alkaline reagents is Na
2CO
3Or K
2CO
3, the structure of compound (10) is as follows:
(2) the resulting compound of step (1) (10) is hydrolyzed in the presence of acetic acid, synthetic telmisartan (11);
(3) as required, the product (11) of step (2) reaction is converted into corresponding salt.
15. a kind of method as claimed in claim 14, wherein the temperature of the described hydrolysis reaction of step (2) is a reflux temperature.
16. the method for claim 1 synthetic compound
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| CN 200610026698 CN101074213A (en) | 2006-05-18 | 2006-05-18 | Synthesis of 2-n-propyl-4-methyl-6(1-methylbenzimidazole-2-radicle) benzimidazole and its use in synthesis of timishatan and its salts |
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| CN 200610026698 CN101074213A (en) | 2006-05-18 | 2006-05-18 | Synthesis of 2-n-propyl-4-methyl-6(1-methylbenzimidazole-2-radicle) benzimidazole and its use in synthesis of timishatan and its salts |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102212034A (en) * | 2011-04-14 | 2011-10-12 | 威海迪素制药有限公司 | Method for preparing telmisartan impurity B |
| CN102219744A (en) * | 2010-04-13 | 2011-10-19 | 上海联化生物医药技术有限公司 | Preparation method of telmisartan intermediate and intermediate compound |
| CN102219746A (en) * | 2011-04-07 | 2011-10-19 | 威海迪素制药有限公司 | Preparation method of telmisartan impurity B |
| CN102659686A (en) * | 2012-04-11 | 2012-09-12 | 宁波九胜创新医药科技有限公司 | Preparation method of 2-n-propyl-4-methyl-6-(1'-methylbenzimidazolyl-2-yl)benzimidazole |
| CN109020896A (en) * | 2018-09-13 | 2018-12-18 | 湖北舒邦药业有限公司 | The sodium salt of telmisartan with and preparation method thereof |
| CN111041516A (en) * | 2019-12-19 | 2020-04-21 | 湖南大学 | New preparation method of telmisartan intermediate of antihypertensive drug |
| CN111689903A (en) * | 2020-07-17 | 2020-09-22 | 浙江金立源药业有限公司 | Synthesis method of 2-n-propyl-4-methyl-6- (1-methylbenzimidazole-2-yl) benzimidazole |
| WO2021037127A1 (en) * | 2019-08-29 | 2021-03-04 | 上海特化医药科技有限公司 | Benzimidazole substitution-based phenyl n-butyramide compound and preparation method therefor |
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| CN102219744A (en) * | 2010-04-13 | 2011-10-19 | 上海联化生物医药技术有限公司 | Preparation method of telmisartan intermediate and intermediate compound |
| CN102219744B (en) * | 2010-04-13 | 2013-01-16 | 上海联化生物医药技术有限公司 | Preparation method of telmisartan intermediate and intermediate compound |
| CN102219746A (en) * | 2011-04-07 | 2011-10-19 | 威海迪素制药有限公司 | Preparation method of telmisartan impurity B |
| CN102219746B (en) * | 2011-04-07 | 2014-02-26 | 威海迪素制药有限公司 | Preparation method of telmisartan impurity B |
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| CN102659686B (en) * | 2012-04-11 | 2014-11-26 | 宁波九胜创新医药科技有限公司 | Preparation method of 2-n-propyl-4-methyl-6-(1'-methylbenzimidazolyl-2-yl)benzimidazole |
| CN109020896A (en) * | 2018-09-13 | 2018-12-18 | 湖北舒邦药业有限公司 | The sodium salt of telmisartan with and preparation method thereof |
| WO2021037127A1 (en) * | 2019-08-29 | 2021-03-04 | 上海特化医药科技有限公司 | Benzimidazole substitution-based phenyl n-butyramide compound and preparation method therefor |
| CN112441984A (en) * | 2019-08-29 | 2021-03-05 | 上海特化医药科技有限公司 | Benzimidazole substituted phenyl n-butylamide-based compound and preparation method thereof |
| JP2022546126A (en) * | 2019-08-29 | 2022-11-02 | トップハーマン シャンハイ カンパニー リミティド | Benzimidazole-substituted phenyl-n-butanamide compound and method for producing same |
| CN112441984B (en) * | 2019-08-29 | 2024-04-19 | 上海特化医药科技有限公司 | Benzimidazole-substituted phenyl n-butyramide-based compound and preparation method thereof |
| CN111041516A (en) * | 2019-12-19 | 2020-04-21 | 湖南大学 | New preparation method of telmisartan intermediate of antihypertensive drug |
| CN111689903A (en) * | 2020-07-17 | 2020-09-22 | 浙江金立源药业有限公司 | Synthesis method of 2-n-propyl-4-methyl-6- (1-methylbenzimidazole-2-yl) benzimidazole |
| CN113045501A (en) * | 2021-03-28 | 2021-06-29 | 石家庄学院 | Preparation method of telmisartan intermediate |
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