CN102633713B - 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 PDFInfo
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- CN102633713B CN102633713B CN2012100780324A CN201210078032A CN102633713B CN 102633713 B CN102633713 B CN 102633713B CN 2012100780324 A CN2012100780324 A CN 2012100780324A CN 201210078032 A CN201210078032 A CN 201210078032A CN 102633713 B CN102633713 B CN 102633713B
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- 0 CCCCCC(c(cc1nc(CNc(cc2)ccc2C(N)=N)[n](C)c1c1)c1-*1ccccc1)=O Chemical compound CCCCCC(c(cc1nc(CNc(cc2)ccc2C(N)=N)[n](C)c1c1)c1-*1ccccc1)=O 0.000 description 3
- QNEVYUOYQNDIEJ-UHFFFAOYSA-N CCCCCCOC(/N=C(/c(cc1)ccc1N)\N)=O Chemical compound CCCCCCOC(/N=C(/c(cc1)ccc1N)\N)=O QNEVYUOYQNDIEJ-UHFFFAOYSA-N 0.000 description 2
- YRSIJCQDBXQCFK-AWNIVKPZSA-N C/C(/N(C)C(CNc(cc1)ccc1C#N)=C)=C\C=C Chemical compound C/C(/N(C)C(CNc(cc1)ccc1C#N)=C)=C\C=C YRSIJCQDBXQCFK-AWNIVKPZSA-N 0.000 description 1
- KSGXQBZTULBEEQ-UHFFFAOYSA-N CCCCCCOC(/N=C(/c(cc1)ccc1NCc1nc(cc(cc2)C(N(CCC(OCC)=O)c3ncccc3)=O)c2[n]1C)\N)=O Chemical compound CCCCCCOC(/N=C(/c(cc1)ccc1NCc1nc(cc(cc2)C(N(CCC(OCC)=O)c3ncccc3)=O)c2[n]1C)\N)=O KSGXQBZTULBEEQ-UHFFFAOYSA-N 0.000 description 1
- KTAZLKIWZQMDSK-ACCUITESSA-N CCOC(CCN(C(C(/C=C(\C)/N)=C)=O)c1ncccc1)=O Chemical compound CCOC(CCN(C(C(/C=C(\C)/N)=C)=O)c1ncccc1)=O KTAZLKIWZQMDSK-ACCUITESSA-N 0.000 description 1
- VZQNOUAEMFDQAR-UHFFFAOYSA-N CCOC(CCN(C(c(cc1)cc2c1[n](C)c(CBr)n2)=O)c1ccccn1)=O Chemical compound CCOC(CCN(C(c(cc1)cc2c1[n](C)c(CBr)n2)=O)c1ccccn1)=O VZQNOUAEMFDQAR-UHFFFAOYSA-N 0.000 description 1
- UITNIDFEANEWPC-UHFFFAOYSA-O CCOC(CC[NH2+]c1ncccc1)=O Chemical compound CCOC(CC[NH2+]c1ncccc1)=O UITNIDFEANEWPC-UHFFFAOYSA-O 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N Cc1ncccc1 Chemical compound Cc1ncccc1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
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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
Technical field
The present invention relates to a kind of dabigatran etcxilate intermediate and preparation method thereof and adopt this intermediate to prepare the method for dabigatran etcxilate, belong to pharmaceutical chemistry, technology of pharmaceutical engineering field.
Background technology
Dabigatran etcxilate, English name: Dabigatran etexilate, chemical name: the 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:
Be the new oral anticoagulant of German Boethringer Ingelhein company research and development, belong to non-peptide Thrombin-like enzyme inhibitor.
This medicine, in April, 2008 first in Germany and Britain's listing, obtains the U.S. FDA approval in 2010.The advantages such as this medical instrument has oral, potent, monitors without special medication, and drug interaction is few, the future demand can be larger.
At present, the preparation method of dabigatran etcxilate mainly contains following two kinds.
1. the route of the international patent application that is WO9837075 based on publication number.
The step of this route is: the chloro-3-nitrobenzene methyl of the 4-of take is raw material, nucleophilic substitution reaction occurs in aqueous methylamine solution, with reduce the nitrated 4-methylamino-3-Methyl anthranilate that makes by 10%Pd/C, again 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) acetic acid, obtain 3-[2-(4-cyano-aniline base) acetamido]-4-methylamino methyl benzoate, obtain benzimidazoles compound under the glacial acetic acid effect, be hydrolyzed into acid through LiOH again, generate acyl chlorides in the sulfur oxychloride reaction, acyl chlorides reacts and obtains cyano compound with 3-(pyridine-2-base amido) ethyl propionate, cyano compound is processed 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 dabigatran etcxilate under the effect of alkali.
Reaction equation is as follows:
2. based on publication number, be WO2009153215, WO2007071743, WO2007071742, the route of the international patent application of WO2006000353.
The step of this route is: first with the 4-aminobenzonitrile, react to obtain successively 4-amino-N with oxammonium hydrochloride and sodium ethylate, N '-hydroxybenzene carbonamidine, react with DMC (being methylcarbonate) and sodium ethylate successively and generate the furodiazole compound; With ethyl bromoacetate, reaction obtains the parahelium compounds again; obtain hydroxy acid through basic hydrolysis; then at CDI, (be N; N '-carbonyl dimidazoles) have lower and 3-[(3-amino-4-methylamino benzoyl) (pyridine-2-yl) amino] the ethyl propionate condensation obtains benzothiazole compound; after the Pd/C catalytic reduction again with the hydrochloric acid salify, react and make dabigatran etcxilate with the positive ethyl ester of chloroformic acid under alkaline condition.
Reaction equation is as follows:
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 expensive being unfavorable for reduces costs; Simultaneously, the intermediate yield that Cheng Huanhou obtains is lower, and uses dewatering agent can introduce a large amount of impurity, causes intermediate purity very low, and finally causes the purity of product dabigatran etcxilate 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 dabigatran etcxilate intermediate that difficulty is lower for preparing is provided, and a kind of all methods of very high this intermediate of preparation of product yield and purity are provided, a kind of method that adopts this intermediate to prepare dabigatran etcxilate is provided in addition.
Technical conceive of the present invention is as follows: the applicant finds after deliberation, causes the not high major cause of prior art products obtained therefrom purity to be that its intermediate prepares difficulty 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 by adopting a kind of new dabigatran etcxilate intermediate.
The technical scheme that the present invention solves its technical problem is as follows:
Dabigatran etcxilate intermediate shown in a kind of formula (2),
Wherein, X is selected from chlorine, bromine, iodine.
A kind of preparation method of above-mentioned dabigatran etcxilate intermediate comprises the following steps:
Formula (1) compound and formula (A) compound carry out acylation reaction and obtain aforementioned dabigatran etcxilate intermediate (being formula (2) compound);
In formula (A), X is selected from chlorine, bromine, iodine, and R is selected from hydroxyl, chlorine ,-O-CH
2cH
3,
A kind of method for preparing dabigatran etcxilate, it is raw material that the method adopts above-mentioned dabigatran etcxilate intermediate.
Preferably, the method comprises the following steps:
The first step, react aforementioned dabigatran etcxilate intermediate (being formula (2) compound) to the formula of obtaining (6) compound with the p-aminophenyl formonitrile HCN;
Second step, formula (6) compound obtains formula (7) compound after hydrogenchloride and volatile salt processing,
Formula (7) compound reacts and obtains dabigatran etcxilate with the just own ester of chloroformic acid.
Preferably, the method comprises the following steps: aforementioned dabigatran etcxilate intermediate (being formula (2) compound) is reacted and obtains dabigatran etcxilate with formula (5) compound,
Preferably, the method comprises the following steps:
The first step, by aforementioned dabigatran etcxilate intermediate (being formula (2) compound), in solvent, reflux is reacted and is obtained reaction solution, reaction solution is concentrated, cooling, suction filtration then, the gained solid is formula (15) compound,
Wherein, X is selected from chlorine, bromine, iodine; Described solvent is selected from acetic acid, ethyl acetate, tetrahydrofuran (THF) (THF), methylene dichloride (DCM);
Second step, formula (15) compound reacts the formula of obtaining (6) compound with the p-aminophenyl formonitrile HCN,
The 3rd step, formula (6) compound obtains formula (7) compound after hydrogenchloride and volatile salt processing,
Formula (7) compound reacts and obtains dabigatran etcxilate with the just own ester of chloroformic acid.
Preferably, the method comprises the following steps:
The first step, by aforementioned dabigatran etcxilate intermediate (being formula (2) compound), in solvent, reflux is reacted and is obtained reaction solution, reaction solution is concentrated, cooling, suction filtration then, the gained solid is formula (15) compound,
Wherein, X is selected from chlorine, bromine, iodine; Described solvent is selected from acetic acid, ethyl acetate, tetrahydrofuran (THF) (THF), methylene dichloride (DCM);
Second step, formula (15) compound reacts and obtains dabigatran etcxilate with formula (5) compound,
The present invention has simplified the preparation technology of dabigatran etcxilate by dabigatran etcxilate intermediate shown in employing formula (2), products obtained therefrom yield and purity are all higher, and temperature of reaction is lower, without using expensive dewatering agent, has good market outlook.
The accompanying drawing explanation
Fig. 1 is that the embodiment of the present invention 1 makes formula (2) compound
1h-NMR figure.
Fig. 2 is that the embodiment of the present invention 1 makes formula (2) compound
13c-NMR figure.
Fig. 3 is that the embodiment of the present invention 2,5 makes formula (6) compound
1h-NMR figure.
Fig. 4 is that the embodiment of the present invention 3,6 makes dabigatran etcxilate
1h-NMR figure.
Fig. 5 is that the embodiment of the present invention 4 makes formula (15) compound
1h-NMR figure.
Fig. 6 is that the embodiment of the present 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.
The experiment material related in following content and reagent are commercially available product if not otherwise specified.
The invention provides dabigatran etcxilate intermediate shown in a kind of formula (2),
Wherein, X is selected from chlorine, bromine, iodine.
The present invention also provides a kind of preparation method of above-mentioned dabigatran etcxilate intermediate, comprises the following steps:
Formula (1) compound and formula (A) compound carry out acylation reaction and obtain aforementioned dabigatran etcxilate intermediate (being formula (2) compound);
In formula (A), X is selected from chlorine, bromine, iodine, and R is selected from hydroxyl, chlorine ,-O-CH
2cH
3,
Preferably, formula (1) compound with the detailed process that formula (A) compound reacts is: first will in the tetrahydrofuran solution of ethyl acetate solution dropping type (1) compound of formula (A) compound, obtain reaction solution, again reaction solution is reacted at least 10 hours at the temperature of 25 ℃-50 ℃, then reaction solution is cooling, suction filtration, the gained solid is aforementioned dabigatran etcxilate intermediate (being formula (2) compound).
Formula (1) compound that above-mentioned preparation method adopts is commercially available product, and name is called: 3-[(3-amino-4-methylamino benzoyl) pyridine-2-base amino] ethyl propionate, be for No. CAS: 212322-56-0.
This preparation method's step is simple, and raw material is easily purchased, and adopts lesser temps, obtains intermediate purity high.
The present invention also provides a kind of method for preparing dabigatran etcxilate, and it is raw material that the method adopts above-mentioned dabigatran etcxilate intermediate.
Preferably, the method comprises the following steps:
The first step, aforementioned dabigatran etcxilate intermediate (being formula (2) compound) reacts the formula of obtaining (6) compound with the p-aminophenyl formonitrile HCN;
Second step, formula (6) compound obtains formula (7) compound after hydrogenchloride and volatile salt processing,
Formula (7) compound reacts and obtains dabigatran etcxilate with the just own ester of chloroformic acid.
Preferred, the detailed process that aforementioned dabigatran etcxilate intermediate (being formula (2) compound) reacts with the p-aminophenyl formonitrile HCN is: in solvent dimethylformamide, add aforementioned dabigatran etcxilate intermediate (being formula (2) compound), p-aminophenyl formonitrile HCN, potassiumiodide, salt of wormwood to obtain reaction solution, the reaction solution heating is reacted, then reaction solution is cooling, aqueous precipitation, suction filtration, the gained solid is formula (6) compound.
Preferably, the method comprises the following steps: aforementioned dabigatran etcxilate intermediate (being formula (2) compound) reacts and obtains dabigatran etcxilate with formula (5) compound,
Preferred, the detailed process that aforementioned dabigatran etcxilate intermediate (being formula (2) compound) reacts with formula (5) compound is: in solvent, add aforementioned dabigatran etcxilate intermediate (being formula (2) compound), formula (5) compound, potassiumiodide, salt of wormwood to obtain reaction solution, reaction solution is heated to 20 ℃-80 ℃ (preferably 30 ℃-40 ℃) to be reacted, then reaction solution is concentrated, aqueous precipitation, suction filtration, the gained solid is dabigatran etcxilate; Described solvent is selected from tetrahydrofuran (THF), acetonitrile, acetone, dimethyl formamide.
Preferably, the method comprises the following steps:
The first step, aforementioned dabigatran etcxilate intermediate (being formula (2) compound) in solvent, react and obtain reaction solution by reflux, reaction solution is concentrated, cooling, suction filtration then, the gained solid is formula (15) compound,
Wherein, X is selected from chlorine, bromine, iodine; Described solvent is selected from acetic acid, ethyl acetate, tetrahydrofuran (THF) (THF), methylene dichloride (DCM);
Second step, formula (15) compound reacts the formula of obtaining (6) compound with the p-aminophenyl formonitrile HCN,
The 3rd step, formula (6) compound obtains formula (7) compound after hydrogenchloride and volatile salt processing,
Formula (7) compound reacts and obtains dabigatran etcxilate with the just own ester of chloroformic acid.
Preferred, the detailed process that formula (15) compound reacts with the p-aminophenyl formonitrile HCN is: in acetonitrile solvent, add formula (15) compound, p-aminophenyl formonitrile HCN, salt of wormwood to obtain reaction solution, the reaction solution heating is reacted, then reaction solution is cooling, aqueous precipitation, suction filtration, the gained solid is formula (6) compound.
Preferably, the method comprises the following steps:
The first step, aforementioned dabigatran etcxilate intermediate (being formula (2) compound) in solvent, react and obtain reaction solution by reflux, reaction solution is concentrated, cooling, suction filtration then, the gained solid is formula (15) compound,
Wherein, X is selected from chlorine, bromine, iodine; Described solvent is selected from acetic acid, ethyl acetate, tetrahydrofuran (THF) (THF), methylene dichloride (DCM);
Second step, formula (15) compound reacts and obtains dabigatran etcxilate with formula (5) compound,
Preferred, formula (15) compound with the detailed process that formula (5) compound reacts is: in acetone solvent, add formula (15) compound, formula (5) compound, potassiumiodide, salt of wormwood to obtain reaction solution, the reaction solution heating is reacted, then by the reaction solution suction filtration, the gained solid is dabigatran etcxilate.
In above each technical scheme, potassiumiodide is catalyzer, and 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 formula (2) compound that X is bromine)
130g formula (1) compound, 4000ml tetrahydrofuran (THF) are dropped in reaction flask, after stirring, in 25 ℃, in bottle, slowly drip the ethyl acetate solution (200ml) that contains 109g bromoacetic acid acid anhydride, then be heated to 50 ℃ of reactions at least 10 hours.Cooling, suction filtration; Tetrahydrofuran (THF) washing (2 * 100ml) for filter cake, obtain N-(3-acetobrom amino-4-methylamino-) benzoyl-N-(2-pyridyl)-3-alanine ethyl ester 166g after drying, yield is that 95.8%, HPLC purity is 98.5%,
1h-NMR schemes as shown in Figure 1,
13c-NMR figure 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:
It is pointed out that above-mentioned bromoacetic acid acid anhydride is also replaceable is: bromoacetic acid, bromoacetyl chloride, ethyl bromoacetate, formula (A) compound that X is bromine.
It should be noted that, 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 preparation process and said process are basic identical, formula (A) compound that formula (A) compound that difference only is to adopt respectively X to be chlorine and X are iodine, yield all is greater than 95%, HPLC purity all is greater than 98%, and therefore concrete preparation process no longer is described in detail in detail.
46.2g N-(3-acetobrom amino-4-methylamino-) benzoyl-N-(2-pyridyl)-3-alanine ethyl ester, 600ml dimethyl formamide (DMF), 17.6g p-aminophenyl formonitrile HCN, 5.2g potassiumiodide, 13.8g salt of wormwood are dropped into to reaction flask, in 40 ℃ of reactions 10 hours, more slowly be heated to 80 ℃ of reactions 2 hours; Be cooled to afterwards room temperature, add the 2500ml water precipitation 0.5 hour (stirring), suction filtration in this process; Filter cake washes (2 * 100ml) with water, after drying from ethyl acetate (960ml) recrystallization, again after drying, obtain 41g formula (6) compound, be the 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 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 formula (7) compound reacts and obtains dabigatran etcxilate with the just own ester of chloroformic acid.This step belongs to prior art route 2, so this paper no longer describes concrete preparation process in detail.
The route that is prepared dabigatran etcxilate by the present embodiment:
It should be noted that, process and said process 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 preparation formula (6) compound are basic identical, and yield all is greater than 85%, optical purity all is greater than 97%, and therefore concrete preparation process no longer is described in detail in detail.
Embodiment 3 directly prepares dabigatran etcxilate 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 tetrahydrofuran (THF) (THF) (also can select acetonitrile, acetone, dimethyl formamide etc.), 21.4g formula (5) compound, 5.2g potassiumiodide, 27.6g salt of wormwood are dropped into to reaction flask, be heated to 30 ℃ of reactions 8 hours, slowly be heated to again 40 ℃ of reactions 1 hour (also can first be heated to 20 ℃ of reaction for some time, more slowly be heated to 80 ℃ of reaction for some time); After finishing, reaction is cooled to room temperature, add the 500ml water precipitation 0.5 hour after the distillation desolventizing (stirring), suction filtration in this process; Filter cake washes (2 * 100ml) with water, then from ethyl acetate (900ml) recrystallization, obtain the 51.5g dabigatran etcxilate after drying, be the 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 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:
It should be noted that, the process and the said process that are directly prepared dabigatran etcxilate 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 all is greater than 82%, optical purity all is greater than 99%, and therefore concrete preparation process no longer is described in detail in detail.
Embodiment 4 prepares Beta-alanine-N-[[-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-brooethyl by N-(3-acetobrom amino-4-methylamino-) benzoyl-N-(2-pyridyl)-3-alanine ethyl ester]-the 5-carbonyl]-N-2-pyridyl-ethyl ester (being formula (15) compound that X is bromine)
4000ml ethyl acetate (also can select acetic acid, tetrahydrofuran (THF) (THF), methylene dichloride (DCM)), 124.5g N-(3-acetobrom amino-4-methylamino-) benzoyl-N-(2-pyridyl)-3-alanine ethyl ester are dropped in reaction flask, reflux is reacted, react after one day, reaction solution is concentrated into to 500ml, be placed in-20 ℃ of Slow coolings and separate out solid, suction filtration; Filter cake vinyl acetic monomer: the mixing solutions washing (2 * 50ml) of sherwood oil=1: 1, obtain Beta-alanine-N-[[-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-brooethyl after drying]-the 5-carbonyl]-N-2-pyridyl-ethyl ester 75g, yield is 62.3%, and optical purity is 97%
1h-NMR schemes as shown in Figure 5,
13c-NMR figure 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:
It should be noted that, Beta-alanine-N-[[-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-chloromethyl]-the 5-carbonyl]-N-2-pyridyl-ethyl ester, Beta-alanine-N-[[-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-iodomethyl]-the 5-carbonyl]-N-2-pyridyl-ethyl ester preparation process and said process basic identical, yield all is greater than 62%, optical purity all is greater than 97%, and therefore concrete preparation process no longer is described in detail in detail.
By 1600ml acetonitrile, 44.4g Beta-alanine-N-[[-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-brooethyl]-the 5-carbonyl]-N-2-pyridyl-ethyl ester, 17.6g p-aminophenyl formonitrile HCN, 13.8g salt of wormwood drop in reaction flask, is heated to 30 ℃ of reactions 10 hours; Cool to room temperature after reaction finishes, add the 2500ml water precipitation 0.5 hour (stirring in this process), suction filtration; Filter cake washes (2 * 100ml) with water, after drying from ethyl acetate (1000ml) recrystallization, again after drying, obtain 46.5g formula (6) compound, be the 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 as shown in Figure 3.
Afterwards, formula (6) compound obtains formula (7) compound after hydrogenchloride and volatile salt processing, and formula (7) compound reacts and obtains dabigatran etcxilate with the just own ester of chloroformic acid.This step belongs to prior art route 2, so this paper no longer describes detailed process in detail.
The route that is prepared dabigatran etcxilate by the present embodiment:
It should be noted that, by Beta-alanine-N-[[-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-chloromethyl]-the 5-carbonyl]-N-2-pyridyl-ethyl ester or Beta-alanine-N-[[-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-iodomethyl]-the 5-carbonyl]-process and the said process of N-2-pyridyl-ethyl ester preparation formula (6) compound is basic identical, yield all is greater than 96%, optical purity all is greater than 98%, and therefore concrete preparation process no longer is described in detail in detail.
Embodiment 6 is by Beta-alanine-N-[[-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-brooethyl]-the 5-carbonyl]-N-2-pyridyl-ethyl ester directly prepares dabigatran etcxilate
By 1200ml acetone, 46.2g Beta-alanine-N-[[-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-brooethyl]-the 5-carbonyl]-N-2-pyridyl-ethyl ester, 21.4g formula (5) compound, 5.2g potassiumiodide, 27.6g salt of wormwood drop in reaction flask, is heated to 20 ℃ of reactions 3 hours; Suction filtration after reaction finishes; Filter cake washes (3 * 200ml) with water, then add ethyl acetate (100ml) recrystallization, obtain the 57.2g dabigatran etcxilate after drying, be the 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 as shown in Figure 4.
The present embodiment route:
It should be noted that, by Beta-alanine-N-[[-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-chloromethyl]-the 5-carbonyl]-N-2-pyridyl-ethyl ester or Beta-alanine-N-[[-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-iodomethyl]-the 5-carbonyl]-that N-2-pyridyl-ethyl ester directly prepares process and the said process of dabigatran etcxilate is basic identical, yield all is greater than 91.2%, optical purity all is greater than 99%, and therefore concrete preparation process no longer is described in detail in detail.
Claims (10)
1. dabigatran etcxilate intermediate shown in a formula (2),
Wherein, X is selected from chlorine, bromine, iodine.
2. the preparation method of the described dabigatran etcxilate intermediate of claim 1 comprises the following steps:
Formula (1) compound and formula (A) compound carry out acylation reaction and obtain the described dabigatran etcxilate intermediate of claim 1,
In formula (A), X is selected from chlorine, bromine, iodine, and R is selected from hydroxyl, chlorine ,-O-CH
2cH
3,
3. the described dabigatran etcxilate intermediate of claim 1 is for the preparation of the purposes of dabigatran etcxilate.
4. a method for preparing dabigatran etcxilate, it is characterized in that, adopting the described dabigatran etcxilate intermediate of claim 1 is raw material, said method comprising the steps of: the first step, the described dabigatran etcxilate intermediate of claim 1 is reacted to the formula of obtaining (6) compound with the p-aminophenyl formonitrile HCN;
Second step, formula (6) compound obtains formula (7) compound after hydrogenchloride and volatile salt processing,
Formula (7) compound reacts and obtains dabigatran etcxilate with the just own ester of chloroformic acid.
5. prepare according to claim 4 the method for dabigatran etcxilate, it is characterized in that, the detailed process that the described dabigatran etcxilate intermediate of claim 1 is reacted with the p-aminophenyl formonitrile HCN is: in solvent dimethylformamide, add the described dabigatran etcxilate intermediate of claim 1, p-aminophenyl formonitrile HCN, potassiumiodide, salt of wormwood to obtain reaction solution, the reaction solution heating is reacted, then reaction solution is cooling, aqueous precipitation, suction filtration, the gained solid is formula (6) compound.
6. a method for preparing dabigatran etcxilate, it is characterized in that, adopting the described dabigatran etcxilate intermediate of claim 1 is raw material, said method comprising the steps of: the described dabigatran etcxilate intermediate of claim 1 is reacted and obtains dabigatran etcxilate with formula (5) compound
7. prepare according to claim 6 the method for dabigatran etcxilate, it is characterized in that, by the described dabigatran etcxilate intermediate of claim 1, with the detailed process that formula (5) compound reacts, be: in solvent, add the described dabigatran etcxilate intermediate of claim 1, formula (5) compound, potassiumiodide, salt of wormwood to obtain reaction solution, reaction solution is heated to 20 ℃-80 ℃ to be reacted, then reaction solution is concentrated, aqueous precipitation, suction filtration, the gained solid is dabigatran etcxilate; Described solvent is selected from tetrahydrofuran (THF), acetonitrile, acetone, dimethyl formamide.
8. a method for preparing dabigatran etcxilate, is characterized in that, adopting the described dabigatran etcxilate intermediate of claim 1 is raw material, said method comprising the steps of:
The first step, react the described dabigatran etcxilate intermediate of claim 1 reflux in solvent to obtain reaction solution, reaction solution is concentrated, cooling, suction filtration then, and the gained solid is formula (15) compound,
Wherein, X is selected from chlorine, bromine, iodine; Described solvent is selected from acetic acid, ethyl acetate, tetrahydrofuran (THF), methylene dichloride;
Second step, formula (15) compound reacts the formula of obtaining (6) compound with the p-aminophenyl formonitrile HCN,
The 3rd step, formula (6) compound obtains formula (7) compound after hydrogenchloride and volatile salt processing,
Formula (7) compound reacts and obtains dabigatran etcxilate with the just own ester of chloroformic acid.
9. prepare according to claim 8 the method for dabigatran etcxilate, it is characterized in that, the detailed process that formula (15) compound reacts with the p-aminophenyl formonitrile HCN is: in acetonitrile solvent, add formula (15) compound, p-aminophenyl formonitrile HCN, salt of wormwood to obtain reaction solution, the reaction solution heating is reacted, then reaction solution is cooling, aqueous precipitation, suction filtration, the gained solid is formula (6) compound.
10. a method for preparing dabigatran etcxilate, is characterized in that, adopting the described dabigatran etcxilate intermediate of claim 1 is raw material, and described method method comprises the following steps:
The first step, react the described dabigatran etcxilate intermediate of claim 1 reflux in solvent to obtain reaction solution, reaction solution is concentrated, cooling, suction filtration then, and the gained solid is formula (15) compound,
Wherein, X is selected from chlorine, bromine, iodine; Described solvent is selected from acetic acid, ethyl acetate, tetrahydrofuran (THF), methylene dichloride;
Second step, formula (15) compound reacts and obtains dabigatran etcxilate with formula (5) compound,
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| CN103664882A (en) * | 2012-09-20 | 2014-03-26 | 天津药物研究院 | Dabigatran etexilate in crystal modification form, and preparation method and use of dabigatran etexilate |
| CN103664881A (en) * | 2012-09-20 | 2014-03-26 | 天津药物研究院 | Dabigatran etexilate of crystallized variant form B as well as preparation method thereof and application |
| CN103922999B (en) * | 2013-01-16 | 2016-05-04 | 上海医药工业研究院 | A kind of preparation method of dabigatran etcxilate intermediate and midbody compound |
| CN104030977B (en) * | 2013-03-07 | 2016-05-04 | 上海医药工业研究院 | A kind of preparation method of dabigatran etcxilate intermediate |
| ES2791187T3 (en) * | 2013-03-25 | 2020-11-03 | Usv Private Ltd | Dabigatran synthesis |
| CN104177337B (en) * | 2013-05-28 | 2019-04-23 | 海思科医药集团股份有限公司 | A kind of intermediate of dabigatran etcxilate and preparation method thereof |
| CN104418839B (en) * | 2013-08-26 | 2019-02-01 | 深圳翰宇药业股份有限公司 | The synthetic method of dabigatran etcxilate |
| CN104418805B (en) * | 2013-09-11 | 2017-02-22 | 浙江海正药业股份有限公司 | Dabigatran etexilate intermediate as well as preparation method and application thereof |
| CN104003977B (en) * | 2014-06-05 | 2016-04-13 | 雅本化学股份有限公司 | The preparation method of N-(2-chloromethyl-1-methyl isophthalic acid H-benzoglyoxaline-5-acyl group)-N-(pyridine-2-base)-3-alanine ethyl ester |
| EP3165521B1 (en) | 2014-07-03 | 2019-01-16 | Shanghai Institute Of Pharmaceutical Industry | Method of preparing dabigatran etexilate intermediate and intermediate compound |
| CN105523999B (en) * | 2014-10-21 | 2020-04-24 | 重庆医药工业研究院有限责任公司 | Synthesis method of dabigatran etexilate intermediate |
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| CN106032374A (en) * | 2015-03-17 | 2016-10-19 | 天津药物研究院有限公司 | Dabigatran etexilate of crystal variant form D, preparation method and uses thereof |
| CN106032372A (en) * | 2015-03-17 | 2016-10-19 | 天津药物研究院有限公司 | Dabigatran etexilate of crystal variant form E, preparation method and uses thereof |
| CN106032376A (en) * | 2015-03-17 | 2016-10-19 | 天津药物研究院有限公司 | Dabigatran etexilate of crystal variant form C, preparation method and uses thereof |
| CN106032375A (en) * | 2015-03-17 | 2016-10-19 | 天津药物研究院有限公司 | Dabigatran etexilate of crystal variant form F, preparation method and uses thereof |
| CN106032373A (en) * | 2015-03-17 | 2016-10-19 | 天津药物研究院有限公司 | Dabigatran etexilate of crystal variant form G, preparation method and uses thereof |
| CN105348148B (en) * | 2015-11-30 | 2017-12-26 | 山东新华制药股份有限公司 | The method for preparing the oxalates of the impurity of dabigatran etexilate intermediate condensation product |
| CN106928195B (en) * | 2017-03-29 | 2019-04-19 | 福建省微生物研究所 | A kind of synthetic method of Dabigatran etexilate key intermediate |
| 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 |
| CN114380797A (en) * | 2021-12-27 | 2022-04-22 | 山东诚汇双达药业有限公司 | Synthesis method of dabigatran etexilate |
| CN116003384A (en) * | 2023-01-31 | 2023-04-25 | 宿迁盛基医药科技有限公司 | Synthesis method of dabigatran etexilate important intermediate |
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