CN100509799C - Process for synthesizing antithrombin inhibitor of non-asymmetric non-peptide kind - Google Patents
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Abstract
A process for preparing the non-chiral non-peptide antithrombase depressants BIBR-953, BIBR-1048, etc from 3-nitro-4-chlorophenyl formic acid is disclosed. Said depressant contains 1,2,5-trisubstituted benzimdazole as central skeleton or a F atom.
Description
Technical field
The invention belongs to the field of chemical synthesis, relate to a kind of synthetic method that contains the inhibitor of heterogeneous ring compound, especially with 1,2,5-trisubstituted benzene and imidazoles are center framework, or with the synthetic method of the novel anti thrombin inhibitors of a fluorine atom.
Background technology
Thromboembolism is that Western society causes disease and main causes of death.The major reason that causes this symptom is the overexpression of blood clotting.The blood coagulation behavior relates to two crucial step, comprising: 1). and the Prothrombin Complex Concent-activation generates zymoplasm; 2). the former generation insoluble fibre of zymoplasm hydrolysis of fibrin shape coagulum.In addition, zymoplasm also mediates hematoblastic activation, thereby cause thrombosed second-order effect on a large scale, such as vascular smooth muscle cell and fibroblast proliferation, and monocyte chemotaxis and have a liking for the sticking collection of centriole cell.
Present clinical anticoagulation therapy mainly comprises the warfarin (the temparin class is imitated antithrombotics) that uses heparin (a kind of sodium salt of CSSO3) or low molecular weight heparin and be used for oral administration.But these medicines of clinical application have several important disadvantages.Must inject use such as heparin, and warfarin must in use often need carry out the thrombogen monitoring.Secondly, based on their biological action pattern, take that the slow characteristics of back onset and result of treatment and patient's nutritional status is closely related also to make its application be very limited.
In recent years, natural thrombin inhibitors r-hirudin (polypeptide of being made up of 65-66 amino acid) is used to prevent forming of dvt after the great orthopaedic surgery, and it has bigger superiority frequently mutually with heparin and low molecular weight heparin.But because its peptide nature, can only parenteral administration, this just becomes the significant obstacle of subacute and chronic thromboembolism class disease.
Therefore, the research and development synthetic, it is very important to have an oral bioactive direct thrombin inhibitors.In the past in 30 years, research obtains many great progress as anticoagulant active with the thrombin inhibitors of synthetic, especially from the mensuration of eighties of last century the nineties zymoplasm crystalline structure become may after, a large amount of high reactivities and the thrombin inhibitors of highly selective are reported.But, have only minority to have pharmacokinetics and pharmacodynamic properties in the suitable body in them, and this judges that just can they further carry out the important evidence of clinical study.In December, 2003, France has ratified first synthetic and has had oral bioactive thrombin inhibitors-two prodrug Ximelagatran, the clinical generation that is used to prevent great orthopaedic surgery medium sized vein thrombus, it is also in process further to estimate its curative effect and security in thromboembolism class disease.Up to now, the research of thrombin inhibitors remains and competes one of the fiercest research topic in the present pharmaceutical chemistry field.
BIBR-953 and prodrug BIBR-1048 thereof are the s-generation thrombin inhibitorss of German Boehringer Ingelheim Pharma KG company exploitation.It is novel 1,2 to have in the BIBR-953 structure, and the center framework of 5-trisubstituted benzene and imidazoles is nonpolar lipotropism with its binding mode of crystalline structure demonstration after zymoplasm combine.Experiment in vivo and vitro shows that it and zymoplasm have high avidity (Ki=9.3nm), and has good activity in vivo prospect.The two prodrug BIBR-1048 of synthetic have very good oral biological activity on this basis, are carrying out the second stage of clinical experiment now.Nearest report carries out oral biological activity with itself and Ximeiagatran relatively to be found, although Plasma Concentration BIBR-1048 (about 5%) is low than Ximeiagatran (20%) in the body.But the transformation period of BIBR-953 (about 12 hours) improved greatly than the transformation period (3-5 hour) of the active parent drug melagatran of Ximeiagatran.Therefore this compound is considered to most possibly be developed at present the oral thrombin inhibitors of high reactivity of success after Ximeiagatran.
The NorbertH.Hauel of German Boehringer Ingelheim Pharma KG company in 2002 (J.Med.Chem.2002,45,1757-1766) seminar has reported thrombin inhibitors BIBR-953 and BIBR-1048 synthetic route (I):
Utilize this method, with higher raw material 1 beginning of price, used the N of trouble of aftertreatment, dinethylformamide (DMF) is as solvent synthetic compound 2; Compound 4 is synthetic compound 5 under the effect of CDI, and adds (NH after compound 5 acidolysis
4)
2CO
3It is lower that ammonification obtains 6, two step of compound productive rate, makes troubles to production.And the overall yield of this synthetic route lower (11.1%).
Summary of the invention
It is starting raw material with 3-nitro cheap and easy to get-4-chloro-benzoic acid (13) that purpose of the present invention aims to provide a kind of, sets up achirality novel, efficient, high yield, the synthetic method of the antithrombin inhibitor of non-peptide class.
The present invention optimizes the prior art synthetic route and improves, and wherein compound 1 preparation compound 2 adopts solvent C H
2Cl
2Substitute the DMF in the prior art route; Adopt compound 10 or 10 ' by compound 2 synthetic intermediates 3 or 3 ', wherein, compound 10 or 10 ' employing compound 9 or 9 cheap and easy to get ' make; Compound 4 or 4 ' employing condensation effect preferably I-hydroxybenzotriazole (HOBT) and 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride (EDCI) and compound 12 synthetic intermediates 5 or 5 ', wherein, compound 12 adopts compound 11 cheap and easy to get to make; Directly adopt saturated NH after compound 5 or the 5 ' acidolysis
3Dehydrated alcohol carry out ammonification obtain compound 6 or 6 ', the result is more satisfactory, the target compound total recovery is higher, nearly 50%.Simultaneously, the present invention has carried out the synthetic of analogue to it, has obtained result preferably.
Purpose of the present invention is achieved through the following technical solutions:
Concrete synthetic route is as follows, and wherein, A represents H or F, and X represents N or H, and in the statement hereinafter, specific synthetic product is according to the numbering in the structural formula, represents with Arabic numerals.
Compound 10 or 10 ' preparation:
2. the preparation of compound 12:
3. the synthetic route of target compound:
Described compound 10 or 10 ' preparation:
Compound 9 or 9 ' with the reaction of a kind of ester, after filtration, concentrate, obtain behind the silica gel column chromatography compound 10 or 10 '; Perhaps compound 9 or 9 ' in a kind of alcoholic solvent and a kind of ester and the reaction of a kind of organic bases, after filtration, silica gel column chromatography obtain compound 10 or 10 '.Said ester is meant ethyl propenoate especially; Said alcohol is meant ethanol; Said alkali is tertiary amine, particularly triethylamine.
The preparation of described compound 12:
Compound 11 in a kind of common solvent with a kind of acid-respons, after filtration, drip washing, after the drying compound 12.Said common solvent is meant water especially; Said acid is meant a kind of a-halogenated acid, is meant 1-Mono Chloro Acetic Acid or 1-bromoacetic acid especially.
Target compound of the present invention is synthetic by following step:
(1) reactant aqueous solution of compound 13 and a kind of organic amine, through concentrating, acidifying is filtered, and gets compound 1 behind the recrystallization.The said organic amine aqueous solution, particularly nail amine aqueous solution.
(2) compound 1 and a kind of acyl chloride reaction obtain compound 2 through concentrating.Said a kind of acyl chlorides is meant sulfur oxychloride especially.
(3) a kind of halohydrocarbon solution of compound 2 and compound 10 or 10 ' a kind of halohydrocarbon solution and a kind of alkali reaction, through concentrating, obtain after the filtration, silica gel column chromatography compound 3 or 3 '.Said halohydrocarbon is meant C
1～C
4Hydrochloric ether, particularly methylene dichloride or trichloromethane; Said alkali is tertiary amine, particularly triethylamine.
(4) compound 3 or 3 ' be dissolved in a kind of alcohol, with hydrogen reaction, after filtration, concentrate promptly obtain compound 4 or 4 '.Said alcohol is meant ethanol especially.
(5) compound 4 or 4 ' in a kind of organic bases solvent, add a kind of pure and mild a kind of salt, with compound 12 reactions, through extraction, concentrate back and acetic acidreaction, again through extraction, dry, concentrate, silica gel column chromatography obtains compound 5 or 5 '.Said alkali is meant imide, refers in particular to N, dinethylformamide; Said alcohol is meant I-hydroxybenzotriazole especially; Said salt is meant 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride especially.
(6) compound 5 or 5 ' a kind of alcoholic solution in a kind of gas reaction, through after concentrating crude product.A kind of alcoholic solution of this crude product and another kind of gas reaction, warp concentrates, silica gel column chromatography obtains compound 6 or 6 '.Said alcohol is meant ethanol especially; Said a kind of gas is meant hydrogenchloride especially; Said another kind of gas is meant ammonia especially.
(7) compound 6 or 6 ' in a kind of aqueous solution of alcohol and a kind of mineral alkali reaction, after filtration compound 7 or 7 '.Said alcohol is meant ethanol especially; Said mineral alkali is meant sodium hydroxide especially.
Or,
Compound 6 or 6 ' in a kind of ether solvent, add a kind of mineral alkali, with chloroformic acid n-hexyl alcohol ester reaction, through extraction, dry, concentrate, obtain behind the silica gel column chromatography compound 8 or 8 '.Said ether is meant C
2～C
4Alicyclic ether, particularly tetrahydrofuran (THF); Said mineral alkali refers in particular to salt of wormwood.
The present invention is a starting raw material with 3-nitro cheap and easy to get-4-chloro-benzoic acid (13), efficiently, high yield has synthesized antithrombin inhibitor B IBR-953 (7) and BIBR-1048 (8) and analogue thereof (7 ' and 8 '), the operation of the inventive method step separates simple, each step productive rate is higher, used reagent is common agents, cheap and easy to get, route is shorter, and total recovery is higher.
Embodiment
Further specify the present invention with embodiment below.
Embodiment 1
Synthetic 3-(pyridine-2-imines)-ethyl propionate (10)
Under the nitrogen protection, and past compound 9 (A=H, X=N)---2-Fampridine (22.5g; 0.25mol) (27.5g 0.275mol), is being higher than 100 ℃ of following stirring and refluxing 24h to middle adding ethyl propenoate; the elimination precipitate, the remaining back that concentrates gets white solid 10 (38g, 72%) with the silicagel column column purification.
Synthetic 1-(4-cyano group-benzene imines)-acetate (12)
Compound 11 (6.0g, 0.05mol) (10g adds water 150ml reflux till having a large amount of yellow solids to separate out in 0.11mol) with the 1-Mono Chloro Acetic Acid, filter under the room temperature, with water, dehydrated alcohol, anhydrous diethyl ether drip washing, promptly get yellow solid 12 (6.4g, 73%) respectively.
Synthetic 4-amine methyl-3-nitro-phenylformic acid (1)
(25g, 0.124mol) the aqueous methylamine solution 150ml of middle adding 25%～30% make system be higher than 100 ℃ of reaction 5～6h down at compound 13.Add glacial acetic acid behind the concentrating under reduced pressure pH is transferred to 4～5.Standing over night is separated out a large amount of yellow solids, and elimination solution with 95% ethyl alcohol recrystallization at least twice, obtains yellow solid 1 (17.2,76%) with precipitate.
Synthetic 4-amine methyl-3-nitro-Benzoyl chloride (2)
With compound 1 (11.6g 0.059mol) is dissolved in the 150mol thionyl chloride, backflow 1.5h, concentrating under reduced pressure, remnants add 50～60ml CH
2Cl
2, it is dissolved fully, promptly get the CH of compound 2
2Cl
2Solution.
Synthetic 3-[(4-amine methyl-3-nitro-benzoyl)-pyridine-2-imines]-ethyl propionate (3)
(11.4g 0.05mol) is dissolved in 30ml CH with compound 10
2Cl
2In the 30ml triethylamine, slowly add the CH of compound 2 under the room temperature
2Cl
2Solution.Make mixed system at room temperature react 12h, the elimination precipitate, the remaining back that concentrates gets yellow oily liquid 3 (21.4g, 98%) with the silicagel column column purification.
Synthetic 3-[(3-amino-4-amine methyl-benzoyl)-pyridine-2-imines]-ethyl propionate (4)
(10.0g 0.027mol) is dissolved in the 120ml dehydrated alcohol, adds 1.0g 10%Pd/C, and successive reaction 20h under 30atm. filters, and gets compound 4 (9.0g, 100%) after concentrating with compound 3.
Synthetic 3-(2-[(4-cyano group-benzene imines)-methylene radical]-1-methylene radical-1 hydrogen-benzoglyoxaline-5-carbonyl }-pyridine-2-imines)-ethyl propionate (5)
With compound 12 (2.32g 13.2mmol) is dissolved among the 80mlDMF, add HOBT (1.96g, 14.5mmol), in add below 0 ℃ EDCI (2.77g 14.5mmol) stirs 45min, slowly rises to room temperature, add compound 4 (5.0g, 14.5mmol).Reaction is spent the night under the room temperature, concentrates, and with a large amount of ethyl acetate dilutions, saturated aqueous common salt is given a baby a bath on the third day after its birth inferior, through Na
2SO
4After the drying, concentrate, the thick product 1.5h that refluxes in 60ml acetate after concentrating, adds the alkalization of 1.5N ammoniacal liquor, with ethyl acetate extraction (60mL * 3) three times, organic phase with the saturated common salt washing once, through Na
2SO
4After the drying, concentrate, thick product purification by silica gel column chromatography obtains amorphous solid 5 (5.3g, 83%).
Synthetic 3-(2-[(4-miaow base-benzene imines)-methylene radical]-1-methylene radical-1 hydrogen-benzoglyoxaline-5-carbonyl }-pyridine-2-imines)-ethyl propionate (6)
(11g 23mmol) is dissolved in the 200ml dehydrated alcohol, feeds exsiccant HCl gas until saturated, stirs 12h under the room temperature with compound 5.Concentrating under reduced pressure, remnants add the saturated NH of 200ml
3Dehydrated alcohol, react 5h under the room temperature, concentrate, thick product purification by silica gel column chromatography obtains amorphous solid 6 (10g, 88%).
Synthetic 3-(2-[(4-miaow base-benzene imines)-methylene radical]-1-methylene radical-1 hydrogen-benzoglyoxaline-5-carbonyl }-pyridine-2-imines)-propionic acid (7, BIBR953)
(8.0g 16mmol) is dissolved among the 160ml dehydrated alcohol 80mlH2O, and (1.92g 48mmol), stirs 3h under the room temperature to add sodium hydroxide with compound 6.With 400ml water dilution, add in an amount of acetate and after, leave standstill, have a large amount of white precipitates to separate out, elimination solution, water, dehydrated alcohol, anhydrous diethyl ether drip washing promptly obtains white solid 7 (BIBR953) (6.9g, 91%).
Synthetic 3-[(2-{[4-(amino-normal hexane oxygen base imide-methylene radical)-benzene imines]-methylene radical }-1-methylene radical-1 hydrogen-benzoglyoxaline-5-carbonyl)-pyridine-2-imines]-ethyl propionate (8, BIBR1048)
(5.0g 10mmol) is dissolved in 250mlTHF and 50mlH with compound 6
2Among the O, (2.1g, 15mmol), (1.81g 11mmol) continues to stir 2h to stir the positive caproyl chloride of the slow adding of 15min. under the room temperature to add potassium hydroxide.Concentrate, ethyl acetate extraction (20 * 3) three times is through Na
2SO
4After the drying, concentrate, thick product purification by silica gel column chromatography obtains white solid 8 (BIBR1048) (4.75g, 76%).
Embodiment 2
Synthetic 3-(4-fluorophenyl-1-imines)-ethyl propionate (10 ')
Under the nitrogen protection; toward compound 9 ' (A=F; X=H)---4-fluoroaniline (23.5g; 0.25mol) (27.5g 0.275mol), adds 10ml dehydrated alcohol and 10ml triethylamine to middle adding ethyl propenoate; be higher than 100 ℃ of following stirring and refluxing 24h; the elimination precipitate, the remaining back that concentrates gets light red solid 10 ' (43g, 77%) with the silicagel column column purification.
Synthetic 3-[(4-amine methyl-3-nitro-benzoyl)-(4-fluorobenzene)-2-imines]-ethyl propionate (3 ')
With compound 10 ' (10.5g 0.05mol) is dissolved in 30ml CH
2Cl
2In the 30ml triethylamine, slowly add the CH of compound 2 under the room temperature
2Cl
2Solution.Make mixed system at room temperature react 12h, the elimination precipitate, the remaining back that concentrates gets yellow oily liquid 3 ' (19.0g, 98%) with the silicagel column column purification.
Synthetic 3-[(3-amino-4-amine methyl-benzoyl)-(4-fluorobenzene)-2-imines]-ethyl propionate (4 ')
With compound 3 ' (10.0g 0.026mol) is dissolved in the 120ml dehydrated alcohol, adds 1.0g10%Pd/C, and successive reaction 20h under 30atm. filters, and gets compound 4 ' (9.2g, 100%) after concentrating.
Synthetic 3-(2-[(4-cyano group-benzene imines)-methylene radical]-1-methylene radical-1 hydrogen-benzoglyoxaline-5-carbonyl }-(4-fluorobenzene)-2-imines)-ethyl propionate (5 ')
With compound 12 (2.32g 13.2mmol) is dissolved among the 80mlDMF, add HOBT (1.96g, 14.5mmol), in-20 ℃ add down EDCI (2.77g 14.5mmol) stirs 45min, slowly rises to room temperature, add compound 4 ' (5.2g, 14.5mmol).Reaction is spent the night under the room temperature, concentrates, and with a large amount of ethyl acetate dilutions, saturated aqueous common salt is given a baby a bath on the third day after its birth inferior, through Na
2SO
4After the drying, concentrate, the thick product 1.5h that refluxes in 60ml acetate after concentrating, adds the alkalization of 1.5N ammoniacal liquor, with ethyl acetate extraction (60mL * 3) three times, organic phase with the saturated common salt washing once, through Na
2SO
4After the drying, concentrate, thick product purification by silica gel column chromatography obtains amorphous solid 5 ' (5.5g, 83%).
Synthetic 3-(2-[(4-miaow base-benzene imines)-methylene radical]-1-methylene radical-1 hydrogen-benzoglyoxaline-5-carbonyl }-[4-fluorobenzene]-2-imines)-ethyl propionate (6 ')
With compound 5 ' (10g 20mmol) is dissolved in the 200ml dehydrated alcohol, feeds exsiccant HCl gas until saturated, stirs 12h under the room temperature.Concentrating under reduced pressure, remnants add the saturated NH of 200ml
3Dehydrated alcohol, react 5h under the room temperature, concentrate, thick product purification by silica gel column chromatography obtains amorphous solid 6 ' (9.1g, 88%).
Synthetic 3-(2-[(4-miaow base-benzene imines)-methylene radical]-1-methylene radical-1 hydrogen-benzoglyoxaline-5-carbonyl }-[4-fluorobenzene]-2-imines)-propionic acid (7 ')
With compound 6 ' (8.2g 16mmol) is dissolved among the 160ml dehydrated alcohol 80mlH2O, and (1.92g 48mmol), stirs 3h under the room temperature to add sodium hydroxide.With 400ml water dilution, add in an amount of acetate and after, leave standstill, have a large amount of white precipitates to separate out, elimination solution, water, dehydrated alcohol, anhydrous diethyl ether drip washing promptly obtains white solid 7 ' (7.1g, 91%).
Synthetic 3-[(2-{[4-(amino-normal hexane oxygen base imide-methylene radical)-benzene imines]-methylene radical }-1-methylene radical-1 hydrogen-benzoglyoxaline-5-carbonyl)-[4-fluorobenzene]-2-imines]-ethyl propionate (8 ')
With compound 6 ' (5.2g 10mmol) is dissolved in 250mlTHF and 50mlH
2Among the O, (2.1g, 15mmol), (1.8g 11mmol) continues to stir 2h to stir the positive caproyl chloride of the slow adding of 15min. under the room temperature to add potassium hydroxide.Concentrate, ethyl acetate extraction (20 * 3) three times is through Na
2SO
4After the drying, concentrate, thick product purification by silica gel column chromatography obtains white solid 8 ' (4.89g, 76%).
Claims (15)
1, a kind of synthetic achirality, the method for the antithrombin inhibitor of non-peptide class is characterized in that having following synthetic route:
Starting raw material is a compound 13, at first be prepared into compound 1 by compound 13, compound 1 prepares compound 2 in the presence of methylene dichloride, compound 2 and compound 10 or 10 ' prepared in reaction obtain compound 3 or 3 ' after, further prepare compound 4 or 4 ', compound 4 or 4 ' with condensing agent I-hydroxybenzotriazole and 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride and compound 12 prepare compound 5 or 5 ', directly adopt saturated NH after compound 5 or the 5 ' acidolysis
3Dehydrated alcohol carry out ammonification prepare compound 6 or 6 ', last, by compound 6 or 6 ' through hydrolysis reaction prepare target compound 7 or 7 '; Or compound 6 or 6 ' through acylation reaction prepare target compound 8 or 8 ';
Described compound 10 or 10 ' by compound 9 or 9 ' make by following formula:
Described compound 12 is made by following formula by compound 11:
2, by the described method of claim 1, it is characterized in that described compound 10 or 10 ' be by compound 9 or 9 ' with a kind of ester reaction, concentrate after filtration,, make behind the silica gel column chromatography, or by compound 9 or 9 ' in a kind of alcoholic solvent and a kind of ester and the reaction of a kind of organic bases, after filtration, silica gel column chromatography makes.
3, by the described method of claim 2, wherein said ester is an ethyl propenoate; Said alcohol is ethanol; Said alkali is tertiary amine.
4, by the described method of claim 2, wherein said alkali is triethylamine.
5, by the described method of claim 1, it is characterized in that, described compound 13 and aqueous methylamine solution reaction, through concentrating, acidifying is filtered, and gets compound 1 behind the recrystallization.
By the described method of claim 1, it is characterized in that 6, described compound 1 direct and sulfur oxychloride reaction obtains compound 2 through concentrating.
7, by the described method of claim 1, it is characterized in that, a kind of halohydrocarbon solution of described compound 2 and compound 10 or 10 ' a kind of halohydrocarbon solution and a kind of alkali reaction, through obtain behind concentrated, filtration, the silica gel column chromatography compound 3 or 3 '.
8, by the described method of claim 7, wherein said halohydrocarbon is C
1～C
4Hydrochloric ether, said alkali is tertiary amine.
9, by the described method of claim 7, wherein said halohydrocarbon is methylene dichloride or trichloromethane; Said alkali is triethylamine.
10, by the described method of claim 1, it is characterized in that, described compound 3 or 3 ' be dissolved in the ethanol, with hydrogen reaction, after filtration, concentrate make compound 4 or 4 '.
11, by the described method of claim 1, it is characterized in that, described compound 4 or 4 ' in a kind of organic bases solvent, add I-hydroxybenzotriazole and 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride, with 1-(4-cyano group-benzene imines)-acetic acidreaction, through extraction, concentrate back and acetic acidreaction, again through extraction, dry, concentrate, silica gel column chromatography obtains compound 5 or 5 '.
12, by the described method of claim 11, wherein said alkali is imide.
13, by the described method of claim 11, wherein said alkali is N, dinethylformamide.
14, by the described method of claim 1, it is characterized in that, described compound 5 or 5 ' ethanolic soln and hydrogen chloride gas precursor reactant, after concentrating crude product, the ethanolic soln of this crude product and ammonia gas react, warp concentrates, silica gel column chromatography obtains compound 6 or 6 '.
15, by the described method of claim 1, it is characterized in that, described compound 6 or 6 ' aqueous ethanolic solution and the reaction of a kind of sodium hydroxide, after filtration compound 7 and 7 '; Or compound 6 or 6 ' in tetrahydrofuran solution adds salt of wormwood, with the reaction of chloroformic acid n-hexyl alcohol ester, through extraction, dry, concentrate, obtain behind the silica gel column chromatography compound 8 and 8 '.
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Families Citing this family (26)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
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| EP1956018A1 (en) * | 2007-02-06 | 2008-08-13 | Boehringer Ingelheim Pharma GmbH & Co. KG | Method of preparing a derivative of benzimidazole |
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| CN103626740B (en) * | 2013-12-05 | 2015-02-04 | 南京欧信医药技术有限公司 | Synthetic method of compound |
| CN104974086A (en) * | 2014-04-04 | 2015-10-14 | 华东师范大学 | Synthetic method of 3-(pyridine-2-yl-amino) ethyl propionate |
| CN103896919A (en) * | 2014-04-21 | 2014-07-02 | 南京靖龙药物研发有限公司 | Preparation method of deuterium-substituted dabigatran etexilate |
| CN104045597A (en) * | 2014-04-29 | 2014-09-17 | 南通常佑药业科技有限公司 | Preparation method of pradaxa |
| CN104003933A (en) * | 2014-05-14 | 2014-08-27 | 上海应用技术学院 | Preparation method of fluorine group-containing 3-(pyridyl-2-imine)ethyl propionate analogue |
| CN104230888A (en) * | 2014-06-03 | 2014-12-24 | 长春工业大学 | Preparation method of benzimidazole compound |
| CN103992241B (en) * | 2014-06-05 | 2016-08-24 | 雅本化学股份有限公司 | The preparation method of N-substituted-phenyl glycine |
| JP6403865B2 (en) | 2014-07-03 | 2018-10-10 | シャンハイ インスティテュート オブ ファーマシューティカル インダストリー | Method for producing dabigatran etexilate intermediate and intermediate compound |
| CN104628733A (en) * | 2015-03-02 | 2015-05-20 | 中国药科大学 | Tetrahydrobenzo[4,5] imidazo[1,2-a] pyrazine thrombin inhibitors |
| CN104910047B (en) * | 2015-05-11 | 2017-06-06 | 常州市阳光药业有限公司 | The preparation method of dabigatran etexilate intermediate |
| CN108516941B (en) * | 2018-03-26 | 2021-05-18 | 济南大学 | Preparation method of 3- (phenylamino) ethyl propionate compound |
| CN110981858A (en) * | 2019-12-16 | 2020-04-10 | 南通常佑药业科技有限公司 | Preparation method of anticoagulant drug dabigatran etexilate and analogue thereof |
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