CN111440149A - Preparation method of dabigatran etexilate intermediate - Google Patents
Preparation method of dabigatran etexilate intermediate Download PDFInfo
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- CN111440149A CN111440149A CN202010243384.5A CN202010243384A CN111440149A CN 111440149 A CN111440149 A CN 111440149A CN 202010243384 A CN202010243384 A CN 202010243384A CN 111440149 A CN111440149 A CN 111440149A
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- KSGXQBZTULBEEQ-UHFFFAOYSA-N dabigatran etexilate Chemical compound C1=CC(C(N)=NC(=O)OCCCCCC)=CC=C1NCC1=NC2=CC(C(=O)N(CCC(=O)OCC)C=3N=CC=CC=3)=CC=C2N1C KSGXQBZTULBEEQ-UHFFFAOYSA-N 0.000 title claims abstract description 27
- 229960000288 dabigatran etexilate Drugs 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 16
- -1 pyridine-2-yl Chemical group 0.000 claims abstract description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 13
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 9
- 239000003054 catalyst Substances 0.000 claims abstract description 7
- 239000003960 organic solvent Substances 0.000 claims abstract description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 7
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims abstract description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims abstract description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 5
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 5
- 238000006722 reduction reaction Methods 0.000 claims abstract description 5
- 238000007259 addition reaction Methods 0.000 claims abstract description 4
- 239000003513 alkali Substances 0.000 claims abstract description 4
- 230000009471 action Effects 0.000 claims abstract description 3
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 3
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 3
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims abstract 6
- 239000000543 intermediate Substances 0.000 claims description 17
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 6
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 229960003850 dabigatran Drugs 0.000 claims description 4
- YBSJFWOBGCMAKL-UHFFFAOYSA-N dabigatran Chemical compound N=1C2=CC(C(=O)N(CCC(O)=O)C=3N=CC=CC=3)=CC=C2N(C)C=1CNC1=CC=C(C(N)=N)C=C1 YBSJFWOBGCMAKL-UHFFFAOYSA-N 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- 239000007868 Raney catalyst Substances 0.000 claims description 3
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 3
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 3
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 3
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 claims description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 claims description 2
- QKIUAMUSENSFQQ-UHFFFAOYSA-N dimethylazanide Chemical compound C[N-]C QKIUAMUSENSFQQ-UHFFFAOYSA-N 0.000 claims description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 2
- 229940011051 isopropyl acetate Drugs 0.000 claims description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 2
- 239000000758 substrate Substances 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 abstract description 6
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 abstract description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 239000007789 gas Substances 0.000 abstract description 3
- 238000011161 development Methods 0.000 abstract description 2
- CEIPQQODRKXDSB-UHFFFAOYSA-N ethyl 3-(6-hydroxynaphthalen-2-yl)-1H-indazole-5-carboximidate dihydrochloride Chemical compound Cl.Cl.C1=C(O)C=CC2=CC(C3=NNC4=CC=C(C=C43)C(=N)OCC)=CC=C21 CEIPQQODRKXDSB-UHFFFAOYSA-N 0.000 abstract description 2
- 239000000376 reactant Substances 0.000 abstract description 2
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 11
- 239000000047 product Substances 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000001914 filtration Methods 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 4
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 230000002194 synthesizing effect Effects 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000003146 anticoagulant agent Substances 0.000 description 2
- 229940127219 anticoagulant drug Drugs 0.000 description 2
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzenecarbonitrile Natural products N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000007429 general method Methods 0.000 description 2
- KIWBRXCOTCXSSZ-UHFFFAOYSA-N hexyl carbonochloridate Chemical compound CCCCCCOC(Cl)=O KIWBRXCOTCXSSZ-UHFFFAOYSA-N 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 2
- 238000010926 purge Methods 0.000 description 2
- 238000007789 sealing Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 229940123900 Direct thrombin inhibitor Drugs 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 101000712605 Theromyzon tessulatum Theromin Proteins 0.000 description 1
- 206010047249 Venous thrombosis Diseases 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000001099 ammonium carbonate Substances 0.000 description 1
- 235000012501 ammonium carbonate Nutrition 0.000 description 1
- MXOQNVMDKHLYCZ-UHFFFAOYSA-N benzamidoxime Chemical compound ON=C(N)C1=CC=CC=C1 MXOQNVMDKHLYCZ-UHFFFAOYSA-N 0.000 description 1
- 150000008359 benzonitriles Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- WCYWZMWISLQXQU-UHFFFAOYSA-N methyl Chemical compound [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- AEXITZJSLGALNH-UHFFFAOYSA-N n'-hydroxyethanimidamide Chemical compound CC(N)=NO AEXITZJSLGALNH-UHFFFAOYSA-N 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229940066336 pradaxa Drugs 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- OVYTZAASVAZITK-UHFFFAOYSA-M sodium;ethanol;hydroxide Chemical compound [OH-].[Na+].CCO OVYTZAASVAZITK-UHFFFAOYSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000003868 thrombin inhibitor Substances 0.000 description 1
- PJVWKTKQMONHTI-UHFFFAOYSA-N warfarin Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 PJVWKTKQMONHTI-UHFFFAOYSA-N 0.000 description 1
- 229960005080 warfarin Drugs 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The invention relates to a preparation method of a dabigatran etexilate intermediate, which comprises the following steps: (1) under the catalysis of an alkali reagent, adding a compound III shown in the following formula and hydroxylamine to obtain a compound II; (2) and (2) putting the compound II obtained in the step (1) into an organic solvent, and carrying out hydrogenation reduction reaction under the action of a catalyst to obtain a compound I shown in the following formula, wherein the compound I is a target product ethyl 3- (2- (((4-formamidinylphenyl) amino) methyl) -1-methyl-N- (pyridine-2-yl) -1H-benzimidazole-5-formamido) propionate. According to the method, the compound III is used as an initial reactant, and the compound II is obtained through an addition reaction, so that the preparation of imidate hydrochloride by using a large amount of hydrogen chloride gas is avoided; the compound I is prepared by hydrogenating and reducing the compound II, the reaction condition is mild, and the safety of the preparation process is improved; meanwhile, the preparation method provided by the invention is simple in process steps, easy to purify the product, capable of large-scale synthesis, and has a relatively high industrial development prospect.
Description
Technical Field
The invention relates to the technical field of preparation of pharmaceutical intermediates, in particular to a preparation method of a dabigatran etexilate intermediate 3- (2- (((4-formamidylphenyl) amino) methyl) -1-methyl-N- (pyridine-2-yl) -1H-benzimidazole-5-formamido) ethyl propionate.
Background
Dabigatran etexilate (english name: Dabigatran etexilate) has a chemical name of ethyl 3- [ [ [2- [ [ [4- [ [ [ (hexyloxy) carbonyl ] amino ] iminomethyl ] phenyl ] amino ] methyl ] -1-methyl-1H-benzimidazol-5-yl ] carbonyl ] (pyridin-2-yl) amino ] propionate, and Dabigatran etexilate (Dabigatran) is a novel anticoagulant drug with various characteristics developed by the company neberger, germany. It is a novel synthetic direct thrombin inhibitor, is a prodrug of dabigatran, and belongs to a non-peptide thrombin inhibitor. In 4 months of 2008, first marketed in germany and uk under the trade name Pradaxa for the prevention and treatment of acute Venous Thrombosis (VTE), marketed in the us in 2010, certified by CFDA import registration in 3 months of 2013, and marketed domestically in 2013. Dabigatran etexilate was the first anticoagulant oral new drug to be marketed 50 years after warfarin.
Dabigatran etexilate is known in the art and is first disclosed in international patent application WO 98/37075. Methods for preparing dabigatran etexilate are also known from international application WO2006/000353 or from the article by Hauel et al (j.med.chem., 2002, 45, 1757 ff). In addition to international patent applications WO98/37075 and WO2006/000353, WO2007/071742Al and WO2007/071743Al also disclose methods for the preparation of dabigatran etexilate.
There are documents in which a nitrile compound and hydroxylamine are added to obtain an amidoxime compound, and then the amidoxime compound is reduced to obtain an imidazole compound, but there is no document in which a dabigatran intermediate can be prepared by this method. There is a literature of using amine formate as a hydrogen source and nitrogen gas protection in the process of reducing amide oxime, but this results in a complicated overall operation process.
The compound ethyl 3- (2- (((4-formamidinophenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzimidazole-5-carboxamido) propionate is an extremely important intermediate for synthesizing dabigatran etexilate, and the synthesis of dabigatran etexilate from the intermediate and N-hexyl chloroformate is the last step of the general method for synthesizing dabigatran etexilate.
The compound ethyl 3- (2- (((4-formamidinylphenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzimidazole-5-carboxamido) propionate was prepared according to the methods disclosed in the prior art by reacting a substituted benzonitrile in a saturated ethanolic hydrogen chloride solution to completion, distilling the solvent, then adding a small amount of ethanol to dissolve, then adding ammonium carbonate to react for 4 hours, desolventizing, and column purifying to give the product in 80% yield. The method needs a large amount of hydrogen chloride gas, is inconvenient to operate in large-scale preparation, is easy to cause serious pollution, has long reaction time, usually needs several days, is incomplete in reaction, is difficult to separate and purify products, needs column chromatography, and has low yield.
Disclosure of Invention
The invention aims to solve the technical problem of the prior art and provides a preparation method of a dabigatran etexilate intermediate, which has the advantages of simple operation steps, short reaction time, environmental friendliness and high yield.
The target product compound dabigatran etexilate intermediate is 3- (2- (((4-formamidinylphenyl) amino) methyl) -1-methyl-N- (pyridine-2-yl) -1H-benzimidazole-5-formamido) ethyl propionate, is an extremely important intermediate for synthesizing dabigatran etexilate, and the synthesis of dabigatran etexilate from the intermediate and N-hexyl chloroformate is the last step of a general method for synthesizing dabigatran etexilate.
The technical scheme adopted by the invention for solving the technical problems is as follows: a preparation method of a dabigatran etexilate intermediate is characterized by comprising the following steps:
(1) under the catalysis of an alkali reagent, a compound III shown in the following formula is added with hydroxylamine to obtain a compound II,
(2) putting the compound II obtained in the step (1) into an organic solvent, carrying out hydrogenation reduction reaction under the action of a catalyst to obtain a compound I with the following formula, wherein the compound I is a target product ethyl 3- (2- (((4-formamidinylphenyl) amino) methyl) -1-methyl-N- (pyridine-2-yl) -1H-benzimidazole-5-formamido) propionate,
in the present invention, the addition reaction process in step (1) is: and (3) placing the compound III in an organic solvent, and reacting for 3-5 h at the temperature of 30-70 ℃.
Preferably, the organic solvent in step (1) and/or step (2) is selected from one or more of C1-8 lower aliphatic alcohol, ethyl acetate, isopropyl acetate, tetrahydrofuran, N-N dimethyl amide, dioxane, ethylene glycol, glycerol, diethanol dimethyl ether, ethylene glycol monomethyl ether, acetonitrile and N-methyl pyrrolidone.
Preferably, the hydroxylamine is used in the step (1) in an amount of 1.0 to 2.0 equivalents.
Preferably, the reaction temperature of the hydrogenation reduction reaction in the step (2) is 20-60 ℃, and the reaction time is 2-20 h.
Preferably, the catalyst in the step (2) is one of raney nickel, palladium carbon and platinum dioxide, and the dosage of the catalyst is 5-50% of the mass of the substrate.
In the present invention, the alkali agent in the step (1) may be an organic base or an inorganic base.
Compared with the prior art, the invention has the advantages that: according to the method, the compound III is used as an initial reactant, and the compound II is obtained through an addition reaction, so that the preparation of imidate hydrochloride by using a large amount of hydrogen chloride gas is avoided; the compound I is prepared by hydrogenating and reducing the compound II, the reaction condition is mild, and the safety of the preparation process is improved; meanwhile, the preparation method provided by the invention is simple in process steps, easy to purify the product, capable of large-scale synthesis, and has a relatively high industrial development prospect.
Drawings
FIG. 1 shows the preparation of compound I of example 1 of the present invention13C NMR chart.
Detailed Description
The invention is described in further detail below with reference to the accompanying examples.
Example 1:
the preparation method of the dabigatran etexilate intermediate comprises the following steps:
(1) adding the compound III to obtain a compound II
Adding 0.1mo L of compound III, namely ethyl 3- [ [ [2- { (4-cyanophenyl) aminomethyl } -1-methyl-1H-benzimidazol-5-yl ] carbonyl) pyridin-2-yl) amino ] propionate and 250m L methanol into a 1000m L four-necked flask equipped with a thermometer and a mechanical stirrer, adding 25m L of triethylamine and 10g of hydroxylamine hydrochloride, reacting at 50-55 ℃ for 3 hours, cooling to room temperature after the TC L detects that the reaction is complete, stirring at room temperature for 2-3 hours, filtering, and drying in vacuum to obtain 49.7g of white-like solid, namely compound II, with the yield of 90%.
(2) Hydrogenating and reducing the compound II to obtain a target product compound I
To a 500m L autoclave was added 26g of N- [ [2- [ [ [4- (methylamidoxime) phenyl ] N- [ [2- [ [ (benzamide-oxime)]Amino group]Methyl radical]-1-methyl-1H-benzimidazol-5-yl]Carbonyl radical]-N- (2-pyridyl) - β -alanine ethyl ester hydrochloride (compound II), adding 300m L of methanol, stirring for dissolving, adding 5g of washed raney nickel, introducing hydrogen gas to the mixture at 1.5MPa (firstly purging and then sealing), reacting for 4 hours at 50 ℃, filtering the mixture after monitoring the reaction completion by TC L, concentrating the filtrate under reduced pressure, adding 100m L of isopropanol for crystallization, stirring for 2-3 hours at room temperature, filtering, drying in vacuum to obtain 22.7g of white-like solid, wherein the white-like solid is compound I, the yield is 89.7%,13c NMR indicated correct structure, as shown in FIG. 1:13C NMR(101MHz,CD3OD), the abscissa indicates chemical shift (unit ppm), the ordinate indicates absorption peak intensity, and the groups represented by the respective absorption peaks are as follows, (ppm) ═ 171.83(-C ═ O), (ppm) ═ 171.71 (COOC)2H5),(ppm)＝165.65(-CNHNH2),(ppm)＝155.79(Py-C),(ppm)＝153.67(Ar-C),(ppm)＝153.22(Imidazole-C),(ppm)＝148.57(Py-C),(ppm)＝140.28(Imidazole-C),(ppm)＝138.08(Imidazole-C),(ppm)＝137.28(Pr-C),(ppm)＝129.81(Ar-C),(ppm)＝129.31(Ar-C),(ppm)＝123.45(Ar-C),(ppm)＝122.98(Py-C),(ppm)＝121.76(Py-C),(ppm)＝119.25(Ar-C),(ppm)＝114.10(Ar-C),(ppm)＝111.99(Ar-C),(ppm)＝109.41(Ar-C),(ppm)＝60.38(-CH2-),(ppm)＝44.74(-CH2-),(ppm)＝39.70(-CH2-),(ppm)＝32.72(-CH2-),(ppm)＝29.35(-CH3),(ppm)＝13.05(-CH3)。
Example 2:
the preparation method of the dabigatran etexilate intermediate comprises the following steps:
(1) adding the compound III to obtain a compound II
Adding 0.1mo L of compound III and 300M L of ethanol into a 500M L high-pressure kettle, adding 10g of hydroxylamine hydrochloride, heating to 60-65 ℃, dropwise adding 0.01M sodium hydroxide ethanol solution, detecting by TC L, and cooling to room temperature after complete reaction to obtain an ethanol solution of compound II.
(2) Hydrogenating and reducing the compound II to obtain a target product compound I
Adding 7g (dried) of 10% palladium carbon into the solution, introducing 2.5MPa hydrogen (firstly purging and then sealing), reacting for 3h at 60 ℃, filtering the mixture after the reaction is finished, concentrating the dried filtrate under reduced pressure at 40 ℃, adding 150m L acetonitrile for crystallization, cooling to 10-20 ℃, stirring for 2-3 h, filtering, and drying in vacuum to obtain 35.8g of white-like solid, wherein the white-like solid is a compound I.
Claims (6)
1. A preparation method of a dabigatran etexilate intermediate is characterized by comprising the following steps:
(1) under the catalysis of an alkali reagent, a compound III shown in the following formula is added with hydroxylamine to obtain a compound II,
(2) putting the compound II obtained in the step (1) into an organic solvent, carrying out hydrogenation reduction reaction under the action of a catalyst to obtain a compound I with the following formula, wherein the compound I is a target product ethyl 3- (2- (((4-formamidinylphenyl) amino) methyl) -1-methyl-N- (pyridine-2-yl) -1H-benzimidazole-5-formamido) propionate,
2. the preparation method of the dabigatran etexilate intermediate as claimed in claim 1, characterized in that: the addition reaction process in the step (1) is as follows: and (3) placing the compound III in an organic solvent, and reacting for 3-5 h at the temperature of 30-70 ℃.
3. The preparation method of the dabigatran etexilate intermediate as claimed in claim 2, characterized in that: the organic solvent in the step (1) and/or the step (2) is selected from C1-8One or more of lower aliphatic alcohol, ethyl acetate, isopropyl acetate, tetrahydrofuran, N-N dimethyl amide, dioxane, ethylene glycol, glycerol, diethanol dimethyl ether, ethylene glycol monomethyl ether, acetonitrile and N-methyl pyrrolidone.
4. The method for preparing dabigatran according to claim 1, 2 or 3, characterized in that: the dosage of the hydroxylamine in the step (1) is 1.0-2.0 equivalent.
5. The process for the preparation of dabigatran etexilate intermediates according to claim 1, 2 or 3, characterized in that: the reaction temperature of the hydrogenation reduction reaction in the step (2) is 20-60 ℃, and the reaction time is 2-20 h.
6. The process for the preparation of dabigatran etexilate intermediates according to claim 1, 2 or 3, characterized in that: in the step (2), the catalyst is one of raney nickel, palladium carbon and platinum dioxide, and the dosage of the catalyst is 5-50% of the mass of the substrate.
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|---|---|---|---|---|
| CN116102463A (en) * | 2023-02-28 | 2023-05-12 | 江苏阿尔法药业股份有限公司 | Synthesis process of dabigatran etexilate amidine intermediate |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996017827A1 (en) * | 1994-12-05 | 1996-06-13 | G.D. Searle & Co. | PROCESS FOR THE PREPARATION OF AMIDINO PHENYL PYRROLIDINE β-ALANINE UREA ANALOGS |
| CN1675193A (en) * | 2002-08-02 | 2005-09-28 | 贝林格尔英格海姆法玛两合公司 | Prodrugs of 1-methyl-2-(4-amidinophenylaminomethyl)-benzimidazol-5-yl-carboxylic acid-(n-2-pyridyl-n-2-hydroxycarbonylethyl)-amide |
| CN105348262A (en) * | 2015-11-25 | 2016-02-24 | 蚌埠丰原医药科技发展有限公司 | Improved method for preparing Dabigatran etexilate |
| CN106565540A (en) * | 2016-11-05 | 2017-04-19 | 柳东虹 | Synthesis method for benzamidine derivatives |
| CN106565542A (en) * | 2016-11-05 | 2017-04-19 | 李景丕 | Synthesis method of benjia amidine derivative |
| CN106565539A (en) * | 2016-11-05 | 2017-04-19 | 王密治 | Method for synthesizing benzamidine derivative |
| CN106565541A (en) * | 2016-11-05 | 2017-04-19 | 林文练 | Synthesis method for benzamidine derivatives |
| CN111253369A (en) * | 2018-11-30 | 2020-06-09 | 上海医药集团股份有限公司 | Benzene sulfonate, preparation method thereof and application of benzene sulfonate in preparation of dabigatran etexilate |
-
2020
- 2020-03-31 CN CN202010243384.5A patent/CN111440149A/en active Pending
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996017827A1 (en) * | 1994-12-05 | 1996-06-13 | G.D. Searle & Co. | PROCESS FOR THE PREPARATION OF AMIDINO PHENYL PYRROLIDINE β-ALANINE UREA ANALOGS |
| CN1675193A (en) * | 2002-08-02 | 2005-09-28 | 贝林格尔英格海姆法玛两合公司 | Prodrugs of 1-methyl-2-(4-amidinophenylaminomethyl)-benzimidazol-5-yl-carboxylic acid-(n-2-pyridyl-n-2-hydroxycarbonylethyl)-amide |
| CN105348262A (en) * | 2015-11-25 | 2016-02-24 | 蚌埠丰原医药科技发展有限公司 | Improved method for preparing Dabigatran etexilate |
| CN106565540A (en) * | 2016-11-05 | 2017-04-19 | 柳东虹 | Synthesis method for benzamidine derivatives |
| CN106565542A (en) * | 2016-11-05 | 2017-04-19 | 李景丕 | Synthesis method of benjia amidine derivative |
| CN106565539A (en) * | 2016-11-05 | 2017-04-19 | 王密治 | Method for synthesizing benzamidine derivative |
| CN106565541A (en) * | 2016-11-05 | 2017-04-19 | 林文练 | Synthesis method for benzamidine derivatives |
| CN111253369A (en) * | 2018-11-30 | 2020-06-09 | 上海医药集团股份有限公司 | Benzene sulfonate, preparation method thereof and application of benzene sulfonate in preparation of dabigatran etexilate |
Non-Patent Citations (1)
| Title |
|---|
| 朱津津等: "达比加群酯的合成工艺改进", 《中国药物化学杂志》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116102463A (en) * | 2023-02-28 | 2023-05-12 | 江苏阿尔法药业股份有限公司 | Synthesis process of dabigatran etexilate amidine intermediate |
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