CN102633713A - Dabigatran etexilate intermediate, preparation method for same and method for preparing dabigatran etexilate - Google Patents

Dabigatran etexilate intermediate, preparation method for same and method for preparing dabigatran etexilate Download PDF

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CN102633713A
CN102633713A CN2012100780324A CN201210078032A CN102633713A CN 102633713 A CN102633713 A CN 102633713A CN 2012100780324 A CN2012100780324 A CN 2012100780324A CN 201210078032 A CN201210078032 A CN 201210078032A CN 102633713 A CN102633713 A CN 102633713A
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formula
compound
dabigatran ester
ester
reaction
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CN102633713B (en
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徐浩
申国辉
周长岭
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NANJING KANGRUI MEDICAL CHEMICAL CO Ltd
Nanjing Tech University
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NANJING KANGRUI MEDICAL CHEMICAL CO Ltd
Nanjing Tech University
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Abstract

The invention relates to a dabigatran etexilate intermediate, a preparation method for the same and a method for preparing dabigatran etexilate, which belong to the technical field of pharmaceutical chemistry and pharmaceutical engineering. The dabigatran etexilate intermediate is represented as a structural formula (2), so that a preparation process for the dabigatran etexilate is simplified, yield and purity of the dabigatran etexilate are high, reaction temperature is low, expensive dehydrating agent is not needed, and good market prospect is provided.

Description

Dabigatran ester midbody and preparation method thereof and the method for preparing the dabigatran ester
Technical field
The method that the present invention relates to a kind of dabigatran ester midbody and preparation method thereof and adopt this intermediate preparation dabigatran ester belongs to pharmaceutical chemistry, pharmaceutical engineering technical field.
Background technology
The dabigatran ester; English name: Dabigatran etexilate; Chemical name: 3-[[[2-[[[4-[[[(hexyloxy) carbonyl] amino] formamino] phenyl] amino] toluene]-1-methyl isophthalic acid H-benzoglyoxaline-5-yl] carbonyl] (pyridine-2-yl) amino] ethyl propionate, chemical structural formula:
Figure BDA0000146000520000011
Be the new oral anticoagulant of German Boethringer Ingelhein company research and development, belong to non-peptide Thrombin-like enzyme suppressor factor.
This medicine goes on the market in Germany and Britain in April, 2008 first, acquisition drugs approved by FDA in 2010.Advantages such as this medical instrument has oral, and strong the effect need not special medication monitoring, and drug interaction is few estimate that the tomorrow requirement amount can be bigger.
At present, the preparation method of dabigatran ester mainly contains following two kinds.
1. based on publication number the route of the international patent application of WO9837075.
The step of this route is: with 4-chloro-3-nitrobenzoic acid methyl esters is raw material; Nucleophilic substitution reaction takes place in aqueous methylamine solution; With after the nitrated 4-methylamino-3-Methyl anthranilate that makes of 10%Pd/C reduction; With the condensation under EDCI (being 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate) and HOBT (being I-hydroxybenzotriazole) effect of (4-cyano-aniline base) acetate, obtain 3-[2-(4-cyano-aniline base) acetamido]-4-methylamino oil of Niobe again, under the glacial acetic acid effect, obtain benzimidazoles compound; Be hydrolyzed into acid through LiOH again, generate acyl chlorides in the sulfur oxychloride reaction; Acyl chlorides and 3-(pyridine-2-base amido) ethyl propionate reaction obtains cyano compound; Cyano compound is handled with the saturated ethanolic soln of hydrogenchloride and the ethanolic soln of volatile salt in succession, makes amidine compound, and the last and just own ester of chloroformic acid makes the dabigatran ester under the effect of alkali.
Reaction equation is following:
Figure BDA0000146000520000021
2. be WO2009153215 based on publication number, WO2007071743, WO2007071742, the route of the international patent application of WO2006000353.
The step of this route is: earlier with the 4-aminobenzonitrile successively with oxammonium hydrochloride and sodium ethylate react 4-amino-N, N '-hydroxybenzene carbonamidine reacts generation furodiazole compound with DMC (being methylcarbonate) and sodium ethylate successively; Reaction obtains the parahelium compounds with METHYL BROMOACETATE again; Obtain hydroxy acid through basic hydrolysis; (be N at CDI then; N '-carbonyl dimidazoles) exist down and get benzothiazole compound with 3-[(3-amino-4-methylamino benzoyl-) (pyridine-2-yl) amino] ethyl propionate condensation, behind the Pd/C catalytic reduction again with the hydrochloric acid salify, under alkaline condition and the positive ethyl ester of chloroformic acid react and make the dabigatran ester.
Reaction equation is following:
Figure BDA0000146000520000031
The subject matter that above-mentioned two kinds of routes exist is: these routes all contain benzoglyoxaline and become the ring step, and this step will adopt dewatering agent usually, and dewatering agent costs an arm and a leg and is unfavorable for reducing cost; Simultaneously, the midbody yield that Cheng Huanhou obtains is lower, and uses dewatering agent can introduce a large amount of impurity, causes midbody purity very low, and finally causes the purity of product dabigatran ester also very low.
Summary of the invention
Technical problem to be solved by this invention is: overcome the problem that prior art exists; A kind of lower dabigatran ester midbody of difficulty for preparing is provided; And the method for all very high this midbody of preparation of a kind of product yield and purity is provided, a kind of method that adopts this intermediate preparation dabigatran ester is provided in addition.
Technical conceive of the present invention is following: the applicant finds that after deliberation causing the not high major cause of prior art products obtained therefrom purity is that its intermediate preparation difficulty is higher, and not only yield is lower and purity is also lower; The applicant is that raw material has solved the problems referred to above smoothly through adopting a kind of new dabigatran ester midbody.
The technical scheme that the present invention solves its technical problem is following:
Dabigatran ester midbody shown in a kind of formula (2),
Figure BDA0000146000520000041
Wherein, X is selected from chlorine, bromine, iodine.
A kind of above-mentioned dabigatran ester intermediates preparation may further comprise the steps:
Formula (1) compound and formula (A) compound carry out acylation reaction and obtain aforementioned dabigatran ester midbody (being formula (2) compound);
Figure BDA0000146000520000042
In the formula (A), X is selected from chlorine, bromine, iodine, and R is selected from hydroxyl, chlorine ,-O-CH 2CH 3,
Figure BDA0000146000520000043
It is raw material that a kind of method for preparing the dabigatran ester, this method adopt above-mentioned dabigatran ester midbody.
Preferably, this method may further comprise the steps:
The first step obtains formula (6) compound with aforementioned dabigatran ester midbody (being formula (2) compound) and the reaction of p-aminophenyl formonitrile HCN;
Figure BDA0000146000520000044
In second step, formula (6) compound obtains formula (7) compound after hydrogenchloride and volatile salt processing,
The just own ester reaction of formula (7) compound and chloroformic acid obtains the dabigatran ester.
Preferably, this method may further comprise the steps: aforementioned dabigatran ester midbody (being formula (2) compound) and the reaction of formula (5) compound are obtained the dabigatran ester,
Figure BDA0000146000520000052
Preferably, this method may further comprise the steps:
The first step, reflux is reacted and is obtained reaction solution in solvent with aforementioned dabigatran ester midbody (being formula (2) compound), then with reaction solution concentrate, cooling, suction filtration, the gained solid is formula (15) compound,
Figure BDA0000146000520000053
Wherein, X is selected from chlorine, bromine, iodine; Said solvent is selected from acetate, ETHYLE ACETATE, THF (THF), methylene dichloride (DCM);
In second step, formula (15) compound and the reaction of p-aminophenyl formonitrile HCN obtain formula (6) compound,
Figure BDA0000146000520000061
In the 3rd step, formula (6) compound obtains formula (7) compound after hydrogenchloride and volatile salt processing,
Figure BDA0000146000520000062
The just own ester reaction of formula (7) compound and chloroformic acid obtains the dabigatran ester.
Preferably, this method may further comprise the steps:
The first step, reflux is reacted and is obtained reaction solution in solvent with aforementioned dabigatran ester midbody (being formula (2) compound), then with reaction solution concentrate, cooling, suction filtration, the gained solid is formula (15) compound,
Figure BDA0000146000520000063
Wherein, X is selected from chlorine, bromine, iodine; Said solvent is selected from acetate, ETHYLE ACETATE, THF (THF), methylene dichloride (DCM);
In second step, formula (15) compound and the reaction of formula (5) compound obtain the dabigatran ester,
Figure BDA0000146000520000064
The present invention has simplified the preparation technology of dabigatran ester through dabigatran ester midbody shown in the employing formula (2), and products obtained therefrom yield and purity are all higher, and temperature of reaction is lower, need not to use expensive dewatering agent, has good market outlook.
Description of drawings
Fig. 1 is that the embodiment of the invention 1 makes formula (2) compound 1H-NMR figure.
Fig. 2 is that the embodiment of the invention 1 makes formula (2) compound 13C-NMR figure.
Fig. 3 is that the embodiment of the invention 2,5 makes formula (6) compound 1H-NMR figure.
Fig. 4 is that the embodiment of the invention 3,6 makes the dabigatran ester 1H-NMR figure.
Fig. 5 is that the embodiment of the invention 4 makes formula (15) compound 1H-NMR figure.
Fig. 6 is that the embodiment of the invention 4 makes formula (15) compound 13C-NMR figure.
Embodiment
Below in conjunction with embodiment the present invention is described in further detail.But the invention is not restricted to given example.
Experiment material that relates in the following content and reagent then are commercially available article as not specifying.
The present invention provides dabigatran ester midbody shown in a kind of formula (2),
Figure BDA0000146000520000071
Wherein, X is selected from chlorine, bromine, iodine.
The present invention also provides a kind of above-mentioned dabigatran ester intermediates preparation, may further comprise the steps:
Formula (1) compound and formula (A) compound carry out acylation reaction and obtain aforementioned dabigatran ester midbody (being formula (2) compound);
Figure BDA0000146000520000081
In the formula (A), X is selected from chlorine, bromine, iodine, and R is selected from hydroxyl, chlorine ,-O-CH 2CH 3,
Figure BDA0000146000520000082
Preferably; The detailed process of formula (1) compound and formula (A) compound reaction is: the ethyl acetate solution of formula (A) compound is splashed in the tetrahydrofuran solution of formula (1) compound obtain reaction solution earlier; Again reaction solution was reacted 10 hours under 25 ℃-50 ℃ temperature at least; With reaction solution cooling, suction filtration, the gained solid is aforementioned dabigatran ester midbody (being formula (2) compound) then.
Formula (1) compound that above-mentioned preparation method adopts is commercially available article, and name is called: 3-[(3-amino-4-methylamino benzoyl) pyridine-2-base is amino] ethyl propionate is for CAS number: 212322-56-0.
This preparing method's step is simple, and raw material is purchased easily, and adopts lesser temps, and it is high to obtain midbody purity.
The present invention also provides a kind of method for preparing the dabigatran ester, and it is raw material that this method adopts above-mentioned dabigatran ester midbody.
Preferably, this method may further comprise the steps:
The first step, aforementioned dabigatran ester midbody (being formula (2) compound) obtains formula (6) compound with the reaction of p-aminophenyl formonitrile HCN;
In second step, formula (6) compound obtains formula (7) compound after hydrogenchloride and volatile salt processing,
Figure BDA0000146000520000091
The just own ester reaction of formula (7) compound and chloroformic acid obtains the dabigatran ester.
Preferred; Aforementioned dabigatran ester midbody (being formula (2) compound) with the detailed process of p-aminophenyl formonitrile HCN reaction is: adding aforementioned dabigatran ester midbody (being formula (2) compound), p-aminophenyl formonitrile HCN, potassiumiodide, salt of wormwood obtain reaction solution in solvent dimethylformamide; The reaction solution heating is reacted; With reaction solution cooling, aqueous precipitation, suction filtration, the gained solid is formula (6) compound then.
Preferably, this method may further comprise the steps: aforementioned dabigatran ester midbody (being formula (2) compound) obtains the dabigatran ester with the reaction of formula (5) compound,
Figure BDA0000146000520000092
Preferred; Aforementioned dabigatran ester midbody (being formula (2) compound) with the detailed process of formula (5) compound reaction is: adding aforementioned dabigatran ester midbody (being formula (2) compound), formula (5) compound, potassiumiodide, salt of wormwood obtain reaction solution in solvent; Reaction solution is heated to 20 ℃-80 ℃ (preferred 30 ℃-40 ℃) to react; Then with reaction solution concentrate, aqueous precipitation, suction filtration, the gained solid is the dabigatran ester; Said solvent is selected from THF, acetonitrile, acetone, N.
Preferably, this method may further comprise the steps:
The first step, react and obtain reaction solution by reflux in solvent for aforementioned dabigatran ester midbody (being formula (2) compound), then with reaction solution concentrate, cooling, suction filtration, the gained solid is formula (15) compound,
Figure BDA0000146000520000101
Wherein, X is selected from chlorine, bromine, iodine; Said solvent is selected from acetate, ETHYLE ACETATE, THF (THF), methylene dichloride (DCM);
In second step, formula (15) compound and the reaction of p-aminophenyl formonitrile HCN obtain formula (6) compound,
Figure BDA0000146000520000102
In the 3rd step, formula (6) compound obtains formula (7) compound after hydrogenchloride and volatile salt processing,
Figure BDA0000146000520000103
The just own ester reaction of formula (7) compound and chloroformic acid obtains the dabigatran ester.
Preferred; The detailed process of formula (15) compound and the reaction of p-aminophenyl formonitrile HCN is: adding formula (15) compound, p-aminophenyl formonitrile HCN, salt of wormwood obtain reaction solution in acetonitrile solvent; The reaction solution heating is reacted; With reaction solution cooling, aqueous precipitation, suction filtration, the gained solid is formula (6) compound then.
Preferably, this method may further comprise the steps:
The first step, react and obtain reaction solution by reflux in solvent for aforementioned dabigatran ester midbody (being formula (2) compound), then with reaction solution concentrate, cooling, suction filtration, the gained solid is formula (15) compound,
Figure BDA0000146000520000111
Wherein, X is selected from chlorine, bromine, iodine; Said solvent is selected from acetate, ETHYLE ACETATE, THF (THF), methylene dichloride (DCM);
In second step, formula (15) compound and the reaction of formula (5) compound obtain the dabigatran ester,
Preferred; The detailed process of formula (15) compound and the reaction of formula (5) compound is: adding formula (15) compound, formula (5) compound, potassiumiodide, salt of wormwood obtain reaction solution in acetone solvent; The reaction solution heating is reacted; With the reaction solution suction filtration, the gained solid is the dabigatran ester then.
More than in each technical scheme, potassiumiodide is a catalyzer, salt of wormwood is acid binding agent.
Embodiment 1 preparation N-(3-acetobrom amino-4-methylamino-) benzoyl-N-(2-pyridyl)-3-alanine ethyl ester (being that X is formula (2) compound of bromine)
130g formula (1) compound, 4000ml THF are dropped in the reaction flask, after stirring,, be heated to 50 ℃ of reactions at least 10 hours then in 25 ℃ of slow ethyl acetate solutions (200ml) that contain 109g bromoacetic acid acid anhydride that drip in bottle.Cooling, suction filtration; Filter cake with THF washing (2 * 100ml), obtain N-(3-acetobrom amino-4-methylamino-) benzoyl-N-(2-pyridyl)-3-alanine ethyl ester 166g after the drying, yield is 95.8%, HPLC purity is 98.5%, 1H-NMR figure is as shown in Figure 1, 13C-NMR figure is as shown in Figure 2. 1H-NMR(CDCl 3)δ:1.1(t,3H),2.7(t,2H),2.7(s,3H),4.0(m,2H),4.0(s,2H),4.3(t,2H),6.4(m,1H),6.7(m,1H),7.0(m,2H),7.2(m,1H),7.9(m,1H),8.4(m,1H)。 13C-NMR(CDCl 3)δ:14.0,28.6,30.0,33.2,44.5,60.4,109.5,121.0,121.1,122.5,127.3,129.4,137.5,146.1,148,156,165.5(NCO-),170(-COO),171(NCO)。
The present embodiment route:
Figure BDA0000146000520000121
It is pointed out that above-mentioned bromoacetic acid acid anhydride is also replaceable is: bromoacetic acid, bromoacetyl chloride, METHYL BROMOACETATE, promptly X is formula (A) compound of bromine.
Need to prove; N-(3-chloro acetylamino-4-methylamino-) benzoyl-N-(2-pyridyl)-3-alanine ethyl ester, N-(3-iodacetyl amino-4-methylamino-) benzoyl-N-(2-pyridyl)-3-alanine ethyl ester prepares process and said process is basic identical; It is formula (A) compound of chlorine and formula (A) compound that X is iodine that difference only is to adopt respectively X; Yield all greater than 95%, HPLC purity is all greater than 98%, and therefore concrete preparation process no longer is detailed.
Embodiment 2 prepares formula (6) compound by N-(3-acetobrom amino-4-methylamino-) benzoyl-N-(2-pyridyl)-3-alanine ethyl ester
46.2g N-(3-acetobrom amino-4-methylamino-) benzoyl-N-(2-pyridyl)-3-alanine ethyl ester, 600ml N (DMF), 17.6g p-aminophenyl formonitrile HCN, 5.2g potassiumiodide, 13.8g salt of wormwood are dropped into reaction flask; In 40 ℃ of reactions 10 hours, slowly be heated to 80 ℃ of reactions 2 hours again; Be cooled to room temperature afterwards, add 2500ml water precipitation 0.5 hour (in this process, stirring), suction filtration; Filter cake is with water washing (2 * 100ml); Dry back is from ETHYLE ACETATE (960ml) recrystallization; Obtain 41g formula (6) compound behind the after drying, i.e. 3-[[[2-[[(4-cyano-phenyl) amino] methyl]-1-methyl isophthalic acid H-benzoglyoxaline-5-yl] carbonyl] (pyridine-2-yl) amino] ethyl propionate, yield is 85%; Optical purity>=97% 1H-NMR figure is as shown in Figure 3. 1H-NMR(DMSO)δ:1.1(t,3H),2.7(t,2H),3.9(s,3H),3.9(m,2H),4.2(t,2H),4.5(d,2H),6.8(m,3H),7.09-7.52(m,7H),8.3(m,1H)。
Afterwards, formula (6) compound obtains formula (7) compound after hydrogenchloride and volatile salt processing, and the just own ester reaction of formula (7) compound and chloroformic acid obtains the dabigatran ester.This step belongs to prior art route 2, so this paper no longer details concrete preparation process.
The route for preparing the dabigatran ester by present embodiment:
Need to prove; The process and the said process that are prepared formula (6) compound by N-(3-chloro acetylamino-4-methylamino-) benzoyl-N-(2-pyridyl)-3-alanine ethyl ester or N-(3-iodacetyl amino-4-methylamino-) benzoyl-N-(2-pyridyl)-3-alanine ethyl ester are basic identical; And yield is all greater than 85%; Therefore optical purity no longer details concrete preparation process all greater than 97%.
Embodiment 3 directly prepares the dabigatran ester by N-(3-acetobrom amino-4-methylamino-) benzoyl-N-(2-pyridyl)-3-alanine ethyl ester
46.2g N-(3-acetobrom amino-4-methylamino-) benzoyl-N-(2-pyridyl)-3-alanine ethyl ester, 1200ml THF (THF) (also can select acetonitrile, acetone, N etc. for use), 21.4g formula (5) compound, 5.2g potassiumiodide, 27.6g salt of wormwood are dropped into reaction flask; Be heated to 30 ℃ of reactions 8 hours; Slowly be heated to 40 ℃ of reactions 1 hour (also can be heated to 20 ℃ of reaction for some time earlier, slowly be heated to 80 ℃ of reaction for some time again) again; Reaction finishes postcooling to room temperature, adds 500ml water precipitation 0.5 hour (in this process, stirring), suction filtration behind the distillation desolventizing; Filter cake is with water washing (2 * 100ml); Then from ETHYLE ACETATE (900ml) recrystallization; After the drying 51.5g dabigatran ester, i.e. 3-[[[2-[[[4-[[[(hexyloxy) carbonyl] amino] formamino] phenyl] amino] toluene]-1-methyl isophthalic acid H-benzoglyoxaline-5-yl] carbonyl] (pyridine-2-yl) amino] ethyl propionate, yield is 82.1%; Optical purity>=99% 1H-NMR figure is as shown in Figure 4. 1H-NMR(CDCl 3)δ:0.88(t,3H),1.20(t,3H),1.30-1.32(m,6H),1.55-1.59(m,2H),2.8(t,2H),3.73(s,3H),4.0-4.1(m,4H),4.4(t,2H),4.5(d,2H),6.7(d,2H),6.9(d,1H),7.1(t,1H),7.25-7.26(m,1H),7.26(dd,1H),7.31(d,1H),7.33(d,1H),7.71(td,1H),7.77(d,2H),8.4(dq,1H)。
The present embodiment route:
Figure BDA0000146000520000141
Need to prove; The process and the said process that are directly prepared the dabigatran ester by N-(3-chloro acetylamino-4-methylamino-) benzoyl-N-(2-pyridyl)-3-alanine ethyl ester or N-(3-iodacetyl amino-4-methylamino-) benzoyl-N-(2-pyridyl)-3-alanine ethyl ester are basic identical; Yield is all greater than 82%; Therefore optical purity no longer details concrete preparation process all greater than 99%.
Embodiment 4 prepares Beta-alanine-N-[[1-methyl isophthalic acid H-benzimidazolyl-2 radicals-brooethyl]-5-carbonyl]-N-2-pyridyl-ethyl ester (being that X is formula (15) compound of bromine) by N-(3-acetobrom amino-4-methylamino-) benzoyl-N-(2-pyridyl)-3-alanine ethyl ester
4000ml ETHYLE ACETATE (also can select acetate, THF (THF), methylene dichloride (DCM) for use), 124.5g N-(3-acetobrom amino-4-methylamino-) benzoyl-N-(2-pyridyl)-3-alanine ethyl ester are dropped in the reaction flask; Reflux is reacted; React after one day; Reaction solution is concentrated into 500ml, places-20 ℃ slowly to cool off and separate out solid, suction filtration; Filter cake is used vinyl acetic monomer: the mixing solutions washing of sherwood oil=1: 1 (2 * 50ml), after the drying Beta-alanine-N-[[1-methyl isophthalic acid H-benzimidazolyl-2 radicals-brooethyl]-5-carbonyl]-N-2-pyridyl-ethyl ester 75g, yield is 62.3%, optical purity is 97%, 1H-NMR figure is as shown in Figure 5, 13C-NMR figure is as shown in Figure 6. 1H-NMR(CDCl 3)δ:1.2(t,3H),2.2(t,2H),3.3(s,3H),4.08(m,2H),4.4(m,2H),4.6(s,2H),6.7(m,1H),7.16-7.36(m,4H),7.7(m,1H),8.4(m,1H)。 13C-NMR(CDCl 3)δ:14.1,21.0,30.4,33.2,44.6,60.4,109.0,120.9,121.3,122.3,124.6,130.4,137.3,141.2,148.9,150.4(NCN),156.1,170.6(COO),171.6(NCO)。
The present embodiment route:
Need to prove; [[1-methyl isophthalic acid H-benzimidazolyl-2 radicals-iodomethyl]-5-carbonyl]-N-2-pyridyl-ethyl ester prepares process and said process is basic identical for Beta-alanine-N-[[1-methyl isophthalic acid H-benzimidazolyl-2 radicals-chloromethyl]-5-carbonyl]-N-2-pyridyl-ethyl ester, Beta-alanine-N-; Yield all greater than 62%, optical purity is all greater than 97%, and therefore concrete preparation process no longer is detailed.
Embodiment 5 prepares formula (6) compound by Beta-alanine-N-[[1-methyl isophthalic acid H-benzimidazolyl-2 radicals-brooethyl]-5-carbonyl]-N-2-pyridyl-ethyl ester
1600ml acetonitrile, 44.4g Beta-alanine-N-[[1-methyl isophthalic acid H-benzimidazolyl-2 radicals-brooethyl]-5-carbonyl]-N-2-pyridyl-ethyl ester, 17.6g p-aminophenyl formonitrile HCN, 13.8g salt of wormwood are dropped in the reaction flask, be heated to 30 ℃ of reactions 10 hours; Reaction finishes postcooling to room temperature, adds 2500ml water precipitation 0.5 hour (in this process, stirring), suction filtration; Filter cake is with water washing (2 * 100ml); Dry back is from ETHYLE ACETATE (1000ml) recrystallization; Behind the after drying 46.5g formula (6) compound, i.e. 3-[[[2-[[(4-cyano-phenyl) amino] methyl]-1-methyl isophthalic acid H-benzoglyoxaline-5-yl] carbonyl] (pyridine-2-yl) amino] ethyl propionate, yield is 96.5%; Optical purity>=98.5% 1H-NMR figure is as shown in Figure 3.
Afterwards, formula (6) compound obtains formula (7) compound after hydrogenchloride and volatile salt processing, and the just own ester reaction of formula (7) compound and chloroformic acid obtains the dabigatran ester.This step belongs to prior art route 2, so this paper no longer details detailed process.
The route for preparing the dabigatran ester by present embodiment:
Figure BDA0000146000520000171
Need to prove; The process and the said process that are prepared formula (6) compound by Beta-alanine-N-[[1-methyl isophthalic acid H-benzimidazolyl-2 radicals-chloromethyl]-5-carbonyl]-N-2-pyridyl-ethyl ester or Beta-alanine-N-[[1-methyl isophthalic acid H-benzimidazolyl-2 radicals-iodomethyl]-5-carbonyl]-N-2-pyridyl-ethyl ester are basic identical; Yield is all greater than 96%; Therefore optical purity no longer details concrete preparation process all greater than 98%.
Embodiment 6 directly prepares the dabigatran ester by Beta-alanine-N-[[1-methyl isophthalic acid H-benzimidazolyl-2 radicals-brooethyl]-5-carbonyl]-N-2-pyridyl-ethyl ester
1200ml acetone, 46.2g Beta-alanine-N-[[1-methyl isophthalic acid H-benzimidazolyl-2 radicals-brooethyl]-5-carbonyl]-N-2-pyridyl-ethyl ester, 21.4g formula (5) compound, 5.2g potassiumiodide, 27.6g salt of wormwood are dropped in the reaction flask, be heated to 20 ℃ of reactions 3 hours; Reaction finishes the back suction filtration; Filter cake is with water washing (3 * 200ml); Add ETHYLE ACETATE (100ml) recrystallization then; After the drying 57.2g dabigatran ester, i.e. 3-[[[2-[[[4-[[[(hexyloxy) carbonyl] amino] formamino] phenyl] amino] toluene]-1-methyl isophthalic acid H-benzoglyoxaline-5-yl] carbonyl] (pyridine-2-yl) amino] ethyl propionate, yield is 91.2%; Optical purity>=99.2% 1H-NMR figure is as shown in Figure 4.
The present embodiment route:
Figure BDA0000146000520000181
Need to prove; The process and the said process that are directly prepared the dabigatran ester by Beta-alanine-N-[[1-methyl isophthalic acid H-benzimidazolyl-2 radicals-chloromethyl]-5-carbonyl]-N-2-pyridyl-ethyl ester or Beta-alanine-N-[[1-methyl isophthalic acid H-benzimidazolyl-2 radicals-iodomethyl]-5-carbonyl]-N-2-pyridyl-ethyl ester are basic identical; Yield is all greater than 91.2%; Therefore optical purity no longer details concrete preparation process all greater than 99%.

Claims (10)

1. dabigatran ester midbody shown in the formula (2),
Wherein, X is selected from chlorine, bromine, iodine.
2. the said dabigatran ester of claim 1 intermediates preparation may further comprise the steps:
Formula (1) compound and formula (A) compound carry out acylation reaction and obtain the said dabigatran ester of claim 1 midbody,
In the formula (A), X is selected from chlorine, bromine, iodine, and R is selected from hydroxyl, chlorine ,-O-CH 2CH 3,
Figure FDA0000146000510000013
3. a method for preparing the dabigatran ester is characterized in that, it is raw material that said method adopts the said dabigatran ester of claim 1 midbody.
4. according to the said method for preparing the dabigatran ester of claim 3, it is characterized in that, said method comprising the steps of: the first step obtains formula (6) compound with claim 1 said dabigatran ester midbody and the reaction of p-aminophenyl formonitrile HCN;
Second step; Formula (6) compound obtains formula (7) compound,
Figure FDA0000146000510000022
after hydrogenchloride and volatile salt processing
The just own ester reaction of formula (7) compound and chloroformic acid obtains the dabigatran ester.
5. according to the said method for preparing the dabigatran ester of claim 4; It is characterized in that; With the detailed process of claim 1 said dabigatran ester midbody and the reaction of p-aminophenyl formonitrile HCN be: the said dabigatran ester of adding claim 1 midbody, p-aminophenyl formonitrile HCN, potassiumiodide, salt of wormwood obtain reaction solution in solvent dimethylformamide; The reaction solution heating is reacted, and then with reaction solution cooling, aqueous precipitation, suction filtration, the gained solid is formula (6) compound.
6. according to the said method for preparing the dabigatran ester of claim 3, it is characterized in that, said method comprising the steps of: claim 1 said dabigatran ester midbody and the reaction of formula (5) compound are obtained the dabigatran ester,
Figure FDA0000146000510000023
7. according to the said method for preparing the dabigatran ester of claim 6; It is characterized in that; With the detailed process of claim 1 said dabigatran ester midbody and the reaction of formula (5) compound be: the said dabigatran ester of adding claim 1 midbody, formula (5) compound, potassiumiodide, salt of wormwood obtain reaction solution in solvent; Reaction solution is heated to 20 ℃-80 ℃ reacts, then with reaction solution concentrate, aqueous precipitation, suction filtration, the gained solid is the dabigatran ester; Said solvent is selected from THF, acetonitrile, acetone, N.
8. according to the said method for preparing the dabigatran ester of claim 3, it is characterized in that, said method comprising the steps of:
The first step is reacted the said dabigatran ester of claim 1 midbody reflux in solvent and is obtained reaction solution, then with reaction solution concentrate, cooling, suction filtration, the gained solid is formula (15) compound,
Figure FDA0000146000510000031
Wherein, X is selected from chlorine, bromine, iodine; Said solvent is selected from acetate, ETHYLE ACETATE, THF, methylene dichloride;
In second step, formula (15) compound and the reaction of p-aminophenyl formonitrile HCN obtain formula (6) compound,
Figure FDA0000146000510000032
The 3rd step; Formula (6) compound obtains formula (7) compound,
Figure FDA0000146000510000033
after hydrogenchloride and volatile salt processing
The just own ester reaction of formula (7) compound and chloroformic acid obtains the dabigatran ester.
9. the said according to Claim 8 method for preparing the dabigatran ester; It is characterized in that; The detailed process of formula (15) compound and the reaction of p-aminophenyl formonitrile HCN is: adding formula (15) compound, p-aminophenyl formonitrile HCN, salt of wormwood obtain reaction solution in acetonitrile solvent; The reaction solution heating is reacted, and then with reaction solution cooling, aqueous precipitation, suction filtration, the gained solid is formula (6) compound.
10. according to the said method for preparing the dabigatran ester of claim 3, it is characterized in that said method method may further comprise the steps:
The first step is reacted the said dabigatran ester of claim 1 midbody reflux in solvent and is obtained reaction solution, then with reaction solution concentrate, cooling, suction filtration, the gained solid is formula (15) compound,
Wherein, X is selected from chlorine, bromine, iodine; Said solvent is selected from acetate, ETHYLE ACETATE, THF, methylene dichloride;
In second step, formula (15) compound and the reaction of formula (5) compound obtain the dabigatran ester,
Figure FDA0000146000510000042
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1338499A (en) * 2001-08-20 2002-03-06 清华大学 Bispirocyclo derivative and its application in electroluminescent material
CN101600709A (en) * 2007-02-06 2009-12-09 贝林格尔·英格海姆国际有限公司 The method for preparing benzimidizole derivatives
WO2010045900A1 (en) * 2008-10-24 2010-04-29 Zentiva, K.S. A method for the preparation of dabigatran and its intermediates
CN102050814A (en) * 2009-11-06 2011-05-11 北京美倍他药物研究有限公司 Ester derivatives of dabigatran
CN102066355A (en) * 2008-06-16 2011-05-18 贝林格尔.英格海姆国际有限公司 Method for producing an intermediate product of dabigatran etexilate

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1338499A (en) * 2001-08-20 2002-03-06 清华大学 Bispirocyclo derivative and its application in electroluminescent material
CN101600709A (en) * 2007-02-06 2009-12-09 贝林格尔·英格海姆国际有限公司 The method for preparing benzimidizole derivatives
CN102066355A (en) * 2008-06-16 2011-05-18 贝林格尔.英格海姆国际有限公司 Method for producing an intermediate product of dabigatran etexilate
WO2010045900A1 (en) * 2008-10-24 2010-04-29 Zentiva, K.S. A method for the preparation of dabigatran and its intermediates
CN102050814A (en) * 2009-11-06 2011-05-11 北京美倍他药物研究有限公司 Ester derivatives of dabigatran

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US9688657B2 (en) * 2013-03-25 2017-06-27 Usv Private Limited Synthesis of dabigatran
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