CN105218519A - A kind of preparation method of dabigatran etexilate intermediate - Google Patents
A kind of preparation method of dabigatran etexilate intermediate Download PDFInfo
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Abstract
The invention provides the preparation method that one prepares Dabigatran etexilate key intermediate formula 3 compound 3-(2-(((4-amidino phenyl) is amino) methyl)-1-methyl-N-(pyridine-2-base)-1H-benzoglyoxaline-5-formamido-) ethyl propionate, belong to pharmaceutical chemistry, technology of pharmaceutical engineering field.Described preparation method comprises step: 1) acyl chlorides and excessive alcohol are reacted, obtain the alcoholic solution containing hydrogenchloride; 2) by formula 1 compound in step 1) obtain containing hydrogenchloride alcoholic solution in alcoholysis, obtain formula 2 compound; 3) by step 2) formula 2 compound that obtains and ammonia react, obtain the compound of formula 3.Present method avoids and directly use hydrogen chloride gas, simplify operation, shorten the reaction times and improve yield, and not needing column chromatography purification, be conducive to the scale operation of dabigatran etcxilate.
Description
Technical field
The present invention relates to a kind of preparation method of Dabigatran etexilate key intermediate, specifically, relate to the preparation method of compound 3-(2-(((4-amidino phenyl) is amino) methyl)-1-methyl-N-(pyridine-2-base)-1H-benzoglyoxaline-5-formamido-) ethyl propionate, belong to pharmaceutical chemistry, technology of pharmaceutical engineering field.
Background technology
Dabigatran etcxilate (Dabigatran) is the novel anticoagulation medicine with various features of German Boehringer Ingelheim company exploitation.In April, 2008, first in Germany and Britain's listing, commodity are called Pradaxa, for preventing and treating Acute Venous thrombus (VTE), are the oral new drugs of anticoagulation of first listing over 50 years after warfarin.
Dabigatran etcxilate is well known in the prior art, and first public in international patent application WO98/37075.The method preparing dabigatran etcxilate also can be known in the article (J.Med.Chem., 2002,45,1757ff) of the people such as international application WO2006/000353 or Hauel.Except international patent application WO98/37075 and WO2006/000353, WO2007/071742Al and WO2007/071743Al also discloses the preparation method of dabigatran etcxilate.
At publication number for the step of synthetic route disclosed in the international patent application of WO98/37075 is:
By N-(4-cyano-phenyl) glycine at N, under the effect of N '-carbonyl dimidazoles (i.e. CDI), with 3-amino-4-Methylamino-benzoic acid-(2-pyridyl) N-(2-ethoxycarbonylethyl group)-amide condensed, obtain 1-methyl-2-[N-(4-cyano-phenyl)-amino methyl]-benzoglyoxaline-5-base-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl group)-acid amides, and then in succession use the saturated ethanolic soln of hydrogenchloride and the ethanolic soln process of volatile salt, obtained 3-(2-(((4-amidino phenyl) is amino) methyl)-1-methyl-N-(pyridine-2-base)-1H-benzoglyoxaline-5-formamido-) ethyl propionate, finally itself and the just own ester of chloroformic acid obtained dabigatran etcxilate under the effect of alkali.
The reaction equation of above-mentioned steps is specific as follows:
Be then disclose following synthetic route in the international application of WO2009/153215, WO2007/071743A1, WO2007/071742A1, WO2006/000353 at publication number:
First react to obtain 4-amino-N with oxammonium hydrochloride and sodium ethylate successively, N'=hydroxybenzene carbonamidine with 4-aminobenzonitrile, react with methylcarbonate (i.e. DMC) and sodium ethylate successively and generate furodiazole compound, parahelium compounds is obtained by reacting again with ethyl bromoacetate, hydroxy acid is obtained through basic hydrolysis, then at N, N'-carbonyl dimidazoles (i.e. CDI) exists lower to 3-(3-amino-4-methylamino benzoyl) (pyridine-2-base) amino) ethyl propionate condensation obtains benzothiazole compound, obtain after Pd/C catalytic reduction and the 3-of hydrochloric acid salify (2-(((4-amidino phenyl) is amino) methyl)-1-methyl-N-(pyridine-2-base)-1H-benzoglyoxaline-5-formamido-) ethyl propionate, finally, just own ester reacts obtained dabigatran etcxilate with chloroformic acid more in the basic conditions.
The reaction equation of above-mentioned steps is specific as follows:
From above-mentioned prior art, compound 3-(2-(((4-amidino phenyl) is amino) methyl)-1-methyl-N-(pyridine-2-base)-1H-benzoglyoxaline-5-formamido-) ethyl propionate is the extremely important midbody product of synthesis dabigatran etcxilate.
Method disclosed in prior art, the benzonitrile of replacement reacts to completely in saturated ethanol solution of hydrogen chloride, and solvent distillation, then adds a small amount of dissolve with ethanol, then adds volatile salt and react 4 hours, precipitation, and column purification obtains product, yield 80%.This method needs to use a large amount of hydrogen chloride gas, and during extensive preparation, operation is very inconvenient, and easily cause severe contamination, the long reaction time of aforesaid method, needs a couple of days usually in addition, and reaction is not thorough, and product separation purification difficult, yield is low.
Summary of the invention
For shortcoming of the prior art, the invention provides one and synthesize dabigatran etcxilate on a large scale with mode of ameliorating, and the method for above-mentioned shortcoming can be avoided, present method avoids and directly use hydrogen chloride gas, simplify operation, shorten the reaction times and improve yield, and not needing column chromatography purification.
The invention provides a kind of preparation method as shown in the formula Dabigatran etexilate key intermediate 3-(2-(((4-amidino phenyl) is amino) methyl)-1-methyl-N-(pyridine-2-the base)-1H-benzoglyoxaline-5-formamido-) ethyl propionate shown in 3, its reaction equation is as follows:
Wherein, comprise the steps:
1) reacted by the alcohol of acyl chlorides and excessive formula R-OH, obtain the alcoholic solution containing hydrogenchloride, wherein R represents C
1-C
4alkyl; Preferably, described acyl chlorides is added drop-wise in described alcohol, more preferably, with the speed of 1 ~ 2 second/, described acyl chlorides is added drop-wise in described alcohol;
2) by formula 1 compound in step 1) obtain containing hydrogenchloride alcoholic solution in alcoholysis, obtain formula 2 compound;
3) by step 2) formula 2 compound that obtains and ammonia react, obtain the compound of formula 3.
Preferably, the inventive method step 1) in acyl chlorides used be selected from one in Acetyl Chloride 98Min., propionyl chloride, butyryl chloride, Benzoyl chloride, methylsulfonyl chloride, Tosyl chloride, 4-Nitrobenzenesulfonyl chloride, more preferably Acetyl Chloride 98Min.; Alcohol is selected from the one in methyl alcohol, ethanol, Virahol, is preferably methyl alcohol or ethanol; Wherein, the mol ratio of acyl chlorides and alcohol is 0.95 ~ 0.2:1, is preferably 0.6:1.
In one embodiment of the invention, step 2) in formula 1 compound and the mol ratio of acyl chlorides be 1:20 ~ 160, more preferably 1:40 ~ 120, be especially preferably 1:80 ~ 100.
In one embodiment of the invention, step 2) and/or step 3) can also comprise and add Lewis acid, described Lewis acid is selected from the one in aluminum chloride, iron(ic) chloride, zinc chloride, boron trifluoride, tin chloride, is preferably zinc chloride.
In one embodiment of the invention, step 2) can also comprise: the completely rear concentrated solvent of alcoholysis reaction, obtain the strong solution of formula 2 compound, the volume of the strong solution of described formula 2 compound is 1/5 ~ 1/8 of concentrated front solvent volume, and the volume being preferably the strong solution of formula 2 compound is 1/8 of concentrated front solvent volume; Preferably, heat concentrated solvent by rotary evaporation, Heating temperature is 40-55 DEG C, more preferably 45-50 DEG C.
In another embodiment of the invention, step 3) also comprise:
3-a) strong solution of formula 2 compound is dissolved in ethanol, the alcoholic solution of formula 2 compound; Wherein, in described step 2) often use 1 gram of described formula 1 compound, need 13mL ethanol accordingly when dissolving described formula 2 compound strong solution;
3-b) by step 3-a) described in the alcoholic solution of formula 2 compound and the aqueous solution (NH of ammonia or ammonia
4oH) react, be preferably and contain the aqueous solution that weight ratio is the ammonia of 20-25%; Preferably, under the condition of the ice-water bath of 0-10 DEG C, pass into gaseous ammonia to the alcoholic solution of described formula 2 compound or drip the aqueous solution of ammonia, formula 1 compound described in 1mol adds 2-20mol ammonia, is preferably 6-16mol ammonia, is more preferably 6-13mol ammonia.
In yet another embodiment of the present invention, method of the present invention also comprises step 4 further):
4-a) described step 3) react completely after, concentrated solvent, obtains the strong solution of formula 3 compound;
4-b) with the mixed solution of ethyl acetate and glycol dimethyl ether, or the mixed solution mixing of ethyl acetate and ethanol, abundant dispersed with stirring solid, filters, dries, obtain the solid product of formula 3 compound;
Wherein, preferably, the volume of the strong solution of described formula 3 compound is 1/5 ~ 1/8 of concentrated front solvent volume, and the volume concentration being preferably the strong solution of extremely described formula 3 compound is 1/8 of solvent volume before concentrating; Preferably by rotary evaporation heating concentrated solvent, Heating temperature is 40-55 DEG C, is preferably 45-50 DEG C;
Preferably, in step 2) often use 1 gram of described formula 1 compound, the strong solution of described formula 3 compound needs 5 ~ 20mL ethyl acetate accordingly, is preferably 10-15mL ethyl acetate; In step 2) often use 1 gram of described formula 1 compound, the strong solution of described formula 3 compound needs 1-10mL glycol dimethyl ether or 1-10mL ethanol accordingly, is preferably 2-5mL glycol dimethyl ether or 2-5mL ethanol;
Preferably, stirring at room temperature was filtered after 3 hours.
In yet another embodiment of the present invention, described step 2) further comprising the steps:
2-a) strong solution of described formula 2 compound mixed with ethyl acetate and stir, stirring after 3 hours, filtering, obtain solid crude product, wherein, preferably, often use 1 gram of described formula 1 compound, namely need 10-25mL ethyl acetate accordingly, be preferably 15-20mL;
2-b) by step 2-a) described in solid crude product be dispersed in normal hexane, stir 3 hours, filter, obtain formula 2 compound solid product, wherein, described step 2) often use 1 gram of described formula 1 compound, namely need 5-15mL normal hexane accordingly, be preferably 5-10mL.
In one embodiment of the invention, step 3) further comprising the steps:
3'-a) described formula 2 compound solid product is dissolved in alcohol, obtains the alcoholic solution of formula 2 compound; Wherein, every 1 gram of described formula 2 compound solid product needs 13mL alcohol accordingly;
3'-b) under the condition of the ice-water bath of 0-10 DEG C, step 3'-a) described in the alcoholic solution of formula 2 compound and the reactant aqueous solution of ammonia or ammonia, it is the aqueous solution of the ammonia of 20 ~ 25% that the alcoholic solution be preferably to described formula 2 compound drips containing weight ratio; Described in every 1mol, formula 2 compound solid product needs 2-20mol ammonia accordingly, is preferably 6-16mol ammonia, is more preferably 6-13mol ammonia.
Also step 4' is comprised further in another embodiment of the present invention):
4'-a) described step 3) react completely after, concentrated solvent, obtains the strong solution of formula 3 compound;
4'-b) add ethyl acetate and glycol dimethyl ether mixed solution, or ethyl acetate and alcohol mixeding liquid, abundant dispersed with stirring solid, filters, dries, obtain the solid product of formula 3 compound;
Wherein, preferably, concentrated solvent is 1/5 ~ 1/8 of concentrated front solvent volume to the volume concentration of the strong solution of described formula 3 compound, and the volume concentration being preferably the strong solution of described formula 3 compound is 1/8 of solvent volume before concentrating; Preferably, heat concentrated solvent by rotary evaporation, Heating temperature is 40-55 DEG C, is preferably 45-50 DEG C;
Preferably, at described step 3'-a) often use 1 gram of described formula 2 compound solid product, the strong solution of described formula 3 compound needs ethyl acetate 5-20mL, more preferably 10-15mL accordingly; At described step 3'-a) often use 1 gram of described formula 2 compound solid product, the strong solution of described formula 3 compound needs 1-10mL glycol dimethyl ether or 1-10mL ethanol accordingly, is preferably 2-5mL glycol dimethyl ether or 2-5mL ethanol;
Preferably, stirring at room temperature was filtered after 3 hours.
In the present invention, first acyl chlorides and excessive alcohol are reacted, obtain the alcoholic solution containing hydrogenchloride.Wherein, alcohol can be selected from the one in methyl alcohol, ethanol, Virahol, is preferably methyl alcohol and ethanol.Acyl chlorides can be selected from the one in Acetyl Chloride 98Min., propionyl chloride, butyryl chloride, Benzoyl chloride, methylsulfonyl chloride, benzene sulfonyl chloride, Tosyl chloride, 4-Nitrobenzenesulfonyl chloride, is preferably Acetyl Chloride 98Min..
The acyl chlorides used and the mol ratio of alcohol are 0.2 ~ 0.95:1, are preferably 0.6 ~ 1.
Formula 1 compound adds in the above-mentioned alcoholic solution containing hydrogenchloride and carries out alcoholysis reaction, and the consumption of formula 1 compound and the mol ratio of acyl chlorides are 1:20 ~ 160, preferably 1:40 ~ 120, more preferably 1:80 ~ 100.
The alcoholysis reaction of formula 1 compound can use lewis acid as catalyzer, and the Lewis acid of use is preferably the one in aluminum chloride, iron(ic) chloride, zinc chloride, boron trifluoride, tin chloride, more preferably zinc chloride.
After the alcoholysis reaction of formula 1 compound, concentrated solvent, can by heating the mode concentrated solvent of concentrated or concentrating under reduced pressure, and more preferably, heat concentrated solvent by rotary evaporation, Heating temperature is 40-55 DEG C, is preferably 45-50 DEG C; Concentrated volume to 1/5 ~ 1/8, preferably 1/8, obtain the strong solution of formula 2 compound, the strong solution of this formula 2 compound can be directly used in next step and ammonia react preparation formula 3 compound without process further.
The strong solution of formula 2 compound also first can process the solid of the formula of obtaining 2 compound further, and then carry out next step reaction, the operation steps of process is as follows: the strong solution of formula 2 compound mixed with ethyl acetate, dispersed with stirring solid, preferably, calculate with every gram of formula 1 compound used, add the ethyl acetate of 10-25mL, be more preferably 15-20mL.Stir 3 hours, filter, obtain solid product; Solid is dispersed in normal hexane again, calculates with every gram of formula 1 compound used, preferably add 5-15mL normal hexane, be more preferably 5-10mL, stir 3 hours, filter, obtain the solid product of formula 2 compound.
Then the strong solution of formula 2 compound or solid product are dissolved in ethanol, if use the strong solution of formula 2 compound, then calculate, by 13mL dissolve with ethanol formula 2 strong solution by every gram of formula 1 compound used; If use the solid product of formula 2 compound, then every gram of formula 2 solid is dissolved in 13mL ethanol.Ammonia can react with formula 2 compound with ammonia form or as an aqueous solution, is preferably the ammonia of aqueous solution form, is more preferably the aqueous solution (NH containing 20%-25% (w/w) ammonia
4oH).At the initial stage of formula 2 compound and ammonia react, preferably carry out under the ice-water bath condition of 0-10 DEG C.If use the strong solution of formula 2 compound, then every mole of formula 1 compound used herein, is preferably and adds 2-20mol ammonia, more preferably add 6-16mol ammonia, especially preferably add the ammonia of 6-13mol; If use the solid product of formula 2 compound, then every mole of formula 2 compound used herein, preferably needs 2-20mol ammonia, more preferably needs 6-16mol ammonia, especially preferably need 6-13mol ammonia.
React completely, heat concentrated solvent by rotary evaporation, Heating temperature is preferably 40-55 DEG C, is more preferably 45-50 DEG C; Concentrated volume to 1/5 ~ 1/8 of solvent volume before concentrated, preferably 1/8.Then add ethyl acetate and glycol dimethyl ether or ethanol dispersed with stirring solid, if use the strong solution of formula 2 compound, then every gram of formula 1 compound used, the ethyl acetate added is preferably 5-20mL, is more preferably 10-15mL; Glycol dimethyl ether or ethanol are preferably 1-10mL, are more preferably 2-5mL; If use the solid product of formula 2 compound, then calculate by the solid product of every gram of formula 2 compound, the ethyl acetate added is preferably 5-20mL, is more preferably 10-15mL; Glycol dimethyl ether or ethanol are preferably 1-10mL, are more preferably 2-5mL; Stir 3 hours, filter, dry, namely obtain the solid product of formula 3 compound.
Beneficial effect of the present invention is as follows: the preparation method of Dabigatran etexilate key intermediate 3-provided by the invention (2-(((4-amidino phenyl) is amino) methyl)-1-methyl-N-(pyridine-2-base)-1H-benzoglyoxaline-5-formamido-) ethyl propionate avoids and directly uses hydrogen chloride gas, and do not need column chromatography purification, simplify operation, and shorten the reaction times, improve yield, be conducive to the large-scale production of Dabigatran etexilate key intermediate 3-(2-(((4-amidino phenyl) is amino) methyl)-1-methyl-N-(pyridine-2-base)-1H-benzoglyoxaline-5-formamido-) ethyl propionate.
Accompanying drawing explanation
Fig. 1 is the HPLC figure of the purity detecting the dabigatran etexilate intermediate prepared according to an embodiment of the preparation method of Dabigatran etexilate key intermediate of the present invention.
Fig. 2 is the HPLC figure of the purity detecting the dabigatran etexilate intermediate prepared according to another embodiment of the preparation method of Dabigatran etexilate key intermediate of the present invention.
Fig. 3 is the purity HPLC figure detecting the dabigatran etexilate intermediate prepared according to another embodiment of the preparation method of Dabigatran etexilate key intermediate of the present invention.
Fig. 4 is the purity HPLC figure detecting the dabigatran etexilate intermediate prepared according to another embodiment of the preparation method of Dabigatran etexilate key intermediate of the present invention.
Fig. 5 is the purity HPLC figure detecting the dabigatran etexilate intermediate prepared according to another embodiment of the preparation method of Dabigatran etexilate key intermediate of the present invention.
Fig. 6 is the HPLC figure of the purity detecting the dabigatran etexilate intermediate prepared according to another embodiment of the preparation method of Dabigatran etexilate key intermediate of the present invention.
Embodiment
The present invention is further illustrated below in conjunction with embodiment.Below in an example, formula 1 compound in reaction raw materials is provided by Shanghai Hong Bang Pharmaceutical Technology Co., Ltd.Explanation synthetic method exemplary by way of example below, it only as the embodiment with possibility step, instead of limits content of the present invention.
embodiment 1
The mol ratio of acyl chlorides and alcohol is the mol ratio of the consumption of 0.6:1, Lewis acid and the consumption of formula 1 compound is 0.4:1, and uses the strong solution of formula 2 compound
In 1.95L (34.5mol) ethanol, 1.47L (20.7mol) Acetyl Chloride 98Min. is slowly dripped under stirring at room temperature, drip Bi Jixu and stir 3h, then formula 1 compound 100g (0.207mol) is added, be stirred to solid to dissolve completely, add 11.3g (0.083mol) zinc chloride again, react and separate out white solid in 3 hours, thin-layer chromatography is followed the tracks of, and reacts completely after 10 hours.Rotary evaporation heating concentrated solvent, Heating temperature 45-50 DEG C, the strong solution volume being concentrated into formula 2 compound is about 400ml, add 1300mL ethanol, stir, under 0-10 DEG C of ice-water bath, slowly pass into excess of ammonia gas, drip and finish, stirring at room temperature 8 hours, after reacting completely, concentrated solvent, when the strong solution volume to remaining formula 3 compound is about 200mL, under agitation add 1500mL ethyl acetate and 500mL glycol dimethyl ether, stirring at room temperature 3 hours.Filter, obtain the solid product 100.3g of white formula 3 compound.
Yield: 96.9%.It is 99.72% that HPLC detects purity.Fig. 1 and table 1 is collection of illustrative plates and the peak result of the purity detecting the dabigatran etexilate intermediate that embodiment 1 obtains respectively.
Table 1 peak result
embodiment 2
The mol ratio of acyl chlorides and alcohol is the mol ratio of the consumption of 0.95:1, Lewis acid and the consumption of formula 1 compound is 0.2:1, uses the strong solution of formula 2 compound
In 0.762L (18.8mol) methyl alcohol, 1.26L (17.8mol) Acetyl Chloride 98Min. is slowly dripped under stirring at room temperature, drip Bi Jixu and stir 3h, then formula 1 compound 100g (0.207mol) is added, be stirred to solid to dissolve completely, add 5.65g (0.041mol) zinc chloride again, react and separate out white solid in 3 hours, thin-layer chromatography is followed the tracks of, and reacts completely after 10 hours.Rotary evaporation heating concentrated solvent, Heating temperature 45-50 DEG C, is concentrated into about 400ml, add 1300mL ethanol, stir, slowly drip under 0-10 DEG C of ice-water bath and contain the ammoniacal liquor 192mL that weight ratio is the ammonia of 25%, drip and finish, stirring at room temperature 8 hours, after reacting completely, concentrated solvent, when the strong solution volume to remaining formula 3 compound is about 300mL, under agitation add 1500mL ethyl acetate and 300mL ethanol, stirring at room temperature 3 hours.Filter, obtain the solid product 98.8g of formula 3 compound of white.
It is 99.55% that yield: 95.4%, HPLC detects purity.Fig. 2 and table 2 is collection of illustrative plates and the peak result of the purity detecting the dabigatran etexilate intermediate that embodiment 1 obtains respectively.
Table 2 peak result
embodiment 3
The mol ratio of acyl chlorides and alcohol is the consumption of 0.2:1, Lewis acid and the mol ratio of formula 1 compound is 1.5:1, uses the strong solution of formula 2 compound
In 5.37L (95.3mol) ethanol, 1.35L (19.1mol) Acetyl Chloride 98Min. is slowly dripped under stirring at room temperature, drip Bi Jixu and stir 3h, then formula 1 compound 100g (0.207mol) is added, be stirred to solid to dissolve completely, add 42.4g (0.31mol) zinc chloride again, react and separate out white solid in 3 hours, thin-layer chromatography is followed the tracks of, and reacts completely after 10 hours.By the mode concentrated solvent of concentrating under reduced pressure, the strong solution volume being concentrated into formula 2 compound is about 900ml, adds 1300mL ethanol, stirs, slowly drip under 0-10 DEG C of ice-water bath and contain the ammoniacal liquor 383mL that weight ratio is the ammonia of 20%, drip and finish, stirring at room temperature 8 hours, after reacting completely, concentrated solvent, when strong solution volume to remaining formula 3 compound is about 320mL, under agitation add 1400mL ethyl acetate and 200mL glycol dimethyl ether, stirring at room temperature 3 hours.Filter, obtain the solid product 97.4g of white formula 3 compound.
Yield: 94.1%.It is 99.49% that HPLC detects purity.Fig. 3 and table 3 is collection of illustrative plates and the peak result of the purity detecting the dabigatran etexilate intermediate that embodiment 1 obtains respectively.
Table 3 peak result
embodiment 4
The mol ratio of acyl chlorides and alcohol is the consumption of 0.6:1, Lewis acid and the mol ratio of formula 1 compound is 0.4:1, uses the solid product of formula 2 compound
In 1.40L (34.5mol) methyl alcohol, 1.47L (20.7mol) Acetyl Chloride 98Min. is slowly dripped under stirring at room temperature, drip Bi Jixu and stir 3h, then formula 1 compound 100g (0.207mol) is added, be stirred to solid to dissolve completely, add 11.3g (0.083mol) zinc chloride again, react and separate out white solid in 3 hours, thin-layer chromatography is followed the tracks of, and reacts completely after 10 hours.Heating concentrated solvent, Heating temperature 45-50 DEG C, is concentrated into about 400ml, adds 1800mL ethyl acetate, stir 3 hours, filter, obtain solid crude product, in solid crude product, add 500mL normal hexane, stir 3 hours, filter, obtain the solid product of 117.1 grams of formula 2 compounds.
By the solid product 1520mL dissolve with ethanol of above-mentioned formula 2 compound, stir, slowly drip under ice-water bath and contain the ammoniacal liquor 350mL that weight ratio is the ammonia of 25%, drip and finish, stirring at room temperature 8 hours, after reacting completely, heating concentrated solvent, when strong solution volume to remaining formula 3 compound is about 250mL, under agitation add 1300mL ethyl acetate and 350mL glycol dimethyl ether, stirring at room temperature 3 hours.Filter, obtain the solid product 96.1 grams of white formula 3 compound.
Yield: 92.8%.It is 99.36% that HPLC detects purity.Fig. 4 and table 4 is collection of illustrative plates and the peak result of the purity detecting the dabigatran etexilate intermediate that embodiment 1 obtains respectively.
Table 4 peak result
embodiment 5
The mol ratio of acyl chlorides and alcohol is 0.6:1, does not use Lewis acid, uses the strong solution of formula 2 compound
In 1.95L (34.5mol) ethanol, 1.47L (20.7mol) Acetyl Chloride 98Min. is slowly dripped under stirring at room temperature, drip Bi Jixu and stir 3h, then formula 1 compound 100g (0.207mol) is added, be stirred to solid to dissolve completely, react and separate out white solid in 6 hours, thin-layer chromatography is followed the tracks of, and reacts completely after 18 hours.Rotary evaporation heating concentrated solvent, Heating temperature 45-50 DEG C, the strong solution volume being concentrated into formula 2 compound is about 400ml, 1300mL ethanol is added in formula 2 compound strong solution, stir, slowly drip under 0-10 DEG C of ice-water bath and contain the ammoniacal liquor 415mL that weight ratio is the ammonia of 20%, drip and finish, stirring at room temperature 8 hours, after reacting completely, concentrated solvent, when the strong solution volume to remaining formula 3 compound is about 300mL, under agitation add 1400mL ethyl acetate and 400mL glycol dimethyl ether, stirring at room temperature 3 hours.Filter, obtain the solid product 99.1 grams of formula 3 compound of white.
Yield: 95.7%.It is 99.18% that HPLC detects purity.Fig. 5 and table 5 is collection of illustrative plates and the peak result of the purity detecting the dabigatran etexilate intermediate that embodiment 1 obtains respectively.
Table 5 peak result
embodiment 6
The mol ratio of acyl chlorides and alcohol is 0.6:1, does not use Lewis acid, uses the solid product of formula 2 compound
In 1.40L (34.5mol) methyl alcohol, 1.47L (20.7mol) Acetyl Chloride 98Min. is dripped with the speed of 1 ~ 2 second/under stirring at room temperature, drip Bi Jixu and stir 3h, then formula 1 compound 100g (0.207mol) is added, be stirred to solid to dissolve completely, react and separate out white solid in 6 hours, thin-layer chromatography is followed the tracks of, and reacts completely after 18 hours.By the mode concentrated solvent of concentrating under reduced pressure, when the strong solution volume being concentrated into formula 2 compound is about 400ml, add 1600mL ethyl acetate, stir 3 hours, filter, obtain solid crude product, 600mL normal hexane is added in solid crude product, continue stirring 3 hours, filter, obtain the solid product of 116.7g formula 2 compound.
By the solid product 1517mL dissolve with ethanol of above-mentioned formula 2 compound, stir, slowly drip under 0-10 DEG C of ice-water bath and contain the ammoniacal liquor 318mL that weight ratio is the ammonia of 25%, drip and finish, stirring at room temperature 8 hours, after reacting completely, by the mode concentrated solvent of concentrating under reduced pressure, when strong solution volume to remaining formula 3 compound is about 230mL solvent, under agitation add 1650mL ethyl acetate and 450mL glycol dimethyl ether, stirring at room temperature 3 hours.Filter, obtain the solid product 94.8g of formula 3 compound of white.
Yield: 91.6%.It is 99.21% that HPLC detects purity.Fig. 6 and table 6 is collection of illustrative plates and the peak result of the purity detecting the dabigatran etexilate intermediate that embodiment 1 obtains respectively.
Table 6 peak result
Claims (10)
1. be prepared as follows a method for dabigatran etexilate intermediate 3-(2-(((4-amidino phenyl) is amino) methyl)-1-methyl-N-(pyridine-2-the base)-1H-benzoglyoxaline-5-formamido-) ethyl propionate shown in formula 3, its reaction equation is as follows:
Described method comprises the steps:
1) reacted by the alcohol of acyl chlorides and excessive formula R-OH, obtain the alcoholic solution containing hydrogenchloride, wherein R represents C
1-C
4alkyl; Preferably, described acyl chlorides is added drop-wise in described alcohol, more preferably, with the speed of 1 ~ 2 second/, described acyl chlorides is added drop-wise in described alcohol;
2) by formula 1 compound in step 1) obtain containing hydrogenchloride alcoholic solution in alcoholysis, obtain formula 2 compound;
3) by step 2) formula 2 compound that obtains and ammonia react, obtain the compound of formula 3.
2. the method for claim 1, is characterized in that, in described step 1) in:
The mol ratio of acyl chlorides and alcohol is 0.2 ~ 0.95:1, is preferably 0.6:1;
Wherein, described acyl chlorides is selected from the one in Acetyl Chloride 98Min., propionyl chloride, butyryl chloride, Benzoyl chloride, methylsulfonyl chloride, Tosyl chloride, 4-Nitrobenzenesulfonyl chloride, is preferably Acetyl Chloride 98Min.;
Described alcohol is selected from the one in methyl alcohol, ethanol, Virahol, is preferably methyl alcohol or ethanol.
3. method as claimed in claim 1 or 2, is characterized in that, in described step 2) in:
The mol ratio of described formula 1 compound and acyl chlorides is 1:20 ~ 160, is preferably 1:40 ~ 120, is more preferably 1:80 ~ 100.
4. the method according to any one of claim 1-3, it is characterized in that, the method is also included in described step 2) and/or step 3) in add the step of Lewis acid, described Lewis acid is selected from the one in aluminum chloride, iron(ic) chloride, zinc chloride, boron trifluoride, tin chloride, is preferably zinc chloride.
5. the method according to any one of claim 1-4, is characterized in that, described step 2) be that method by comprising the steps is carried out:
The completely rear concentrated solvent of alcoholysis reaction, the strong solution of formula 2 compound obtained, the volume of the strong solution of described formula 2 compound is 1/5 ~ 1/8 of concentrated front solvent volume, is preferably 1/8; Preferably, heat concentrated solvent by rotary evaporation, Heating temperature is 40-55 DEG C, more preferably 45-50 DEG C.
6. method as claimed in claim 5, is characterized in that, described step 3) be that method by comprising the steps is carried out:
3-a) strong solution of formula 2 compound is dissolved in ethanol, obtains the alcoholic solution of formula 2 compound; Wherein, in described step 2) often use 1 gram of described formula 1 compound, need ethanol 13mL accordingly when dissolving described formula 2 compound strong solution;
3-b) by step 3-a) described in the alcoholic solution of formula 2 compound and the aqueous solution (NH of ammonia or ammonia
4oH) react, be preferably and contain the aqueous solution that weight ratio is the ammonia of 20-25%; Preferably, under the condition of the ice-water bath of 0-10 DEG C, pass into gaseous ammonia to the alcoholic solution of described formula 2 compound or drip the aqueous solution of ammonia, described in 1mol, formula 1 compound needs 2-20mol ammonia accordingly, preferably needs 6-16mol ammonia, is more preferably and needs 6-13mol ammonia.
7. the method according to any one of claim 1-6, is characterized in that, the method also comprises the steps 4):
4-a) described step 3) react completely after, concentrated solvent, obtains the strong solution of formula 3 compound;
4-b) with the mixed solution of ethyl acetate and glycol dimethyl ether, or the mixed solution mixing of ethyl acetate and ethanol, abundant dispersed with stirring solid, filters, dries, obtain the solid product of formula 3 compound;
Wherein, preferably, concentrated solvent to the volume concentration of strong solution of described formula 3 compound be concentrated before solvent volume 1/5 ~ 1/8, the volume concentration be more preferably to the strong solution of described formula 3 compound be concentrated before solvent volume 1/8;
Preferably, heat concentrated solvent by rotary evaporation, Heating temperature is 40-55 DEG C, is preferably 45-50 DEG C;
Preferably, in step 2) often use 1 gram of described formula 1 compound, the strong solution of described formula 3 compound needs 5-20mL ethyl acetate accordingly, more preferably needs 10-15mL ethyl acetate; In step 2) often use 1 gram of described formula 1 compound, the strong solution of described formula 3 compound needs 1-10mL glycol dimethyl ether or 1-10mL ethanol accordingly, is more preferably 2-5mL glycol dimethyl ether or 2-5mL ethanol;
Preferably, stirring at room temperature was filtered after 3 hours.
8. method as claimed in claim 5, is characterized in that, described step 2) further comprising the steps of:
2-a) strong solution of described formula 2 compound mixed with ethyl acetate and stir, stirring after 3 hours, filtering, obtain solid crude product, wherein preferably, often use 1 gram of described formula 1 compound, need 10-25mL ethyl acetate accordingly, more preferably need 15-20mL ethyl acetate;
2-b) by step 2-a) described solid crude product is dispersed in normal hexane, stirs 3 hours, filter, obtain formula 2 compound solid product, wherein, in step 2) often use 1 gram of described formula 1 compound, need 5-15mL normal hexane accordingly, preferably need 5-10mL normal hexane.
9. method as claimed in claim 8, is characterized in that, described step 3) further comprising the steps of:
3'-a) described formula 2 compound solid product is dissolved in alcohol, obtains the alcoholic solution of formula 2 compound; Wherein, every 1 gram of described formula 2 compound solid product needs 13mL alcohol accordingly;
3'-b) under the condition of the ice-water bath of 0-10 DEG C, by step 3'-a) described in the alcoholic solution of formula 2 compound and the reactant aqueous solution of gaseous ammonia or ammonia, being preferably containing weight ratio is the aqueous solution of the ammonia of 20-25%; Described in every 1mol, formula 2 compound solid product needs 2-20mol ammonia accordingly, is preferably 6-16mol ammonia, is more preferably 6-13mol ammonia.
10. method as claimed in claim 9, it is characterized in that, the method also comprises the steps 4'):
4'-a) described step 3) react completely after, concentrated solvent, obtains the strong solution of formula 3 compound;
4'-b) add ethyl acetate and glycol dimethyl ether, or ethyl acetate and ethanol, abundant dispersed with stirring solid, filters, dries, obtain the solid product of formula 3 compound;
Wherein, preferably, concentrated solvent is 1/5 ~ 1/8 of concentrated front solvent volume to the volume concentration of the strong solution of described formula 3 compound, and more preferably extremely the volume concentration of the strong solution of described formula 3 compound is 1/8 of solvent volume before concentrating;
Preferably, heat concentrated solvent by rotary evaporation, Heating temperature is 40-55 DEG C, more preferably 45-50 DEG C;
Preferably, at described step 3'-a) often use 1 gram of described formula 2 compound solid product, the strong solution of described formula 3 compound needs 5-20mL ethyl acetate accordingly, more preferably 10-15mL ethyl acetate; At described step 3'-a) often use 1 gram of described formula 2 compound solid product, the strong solution of described formula 3 compound needs 1-10mL glycol dimethyl ether or 1-10mL ethanol accordingly, more preferably 2-5mL glycol dimethyl ether or 2-5mL ethanol;
Preferably, stirring at room temperature was filtered after 3 hours.
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