CN106397400A - Preparation method for dabigatran etexilate - Google Patents
Preparation method for dabigatran etexilate Download PDFInfo
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- CN106397400A CN106397400A CN201610230951.7A CN201610230951A CN106397400A CN 106397400 A CN106397400 A CN 106397400A CN 201610230951 A CN201610230951 A CN 201610230951A CN 106397400 A CN106397400 A CN 106397400A
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- 238000002360 preparation method Methods 0.000 title claims description 21
- 229960000288 dabigatran etexilate Drugs 0.000 title abstract description 4
- 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 abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 39
- 238000006243 chemical reaction Methods 0.000 claims abstract description 32
- 238000000034 method Methods 0.000 claims abstract description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 8
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims abstract description 7
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims abstract description 7
- 239000002253 acid Substances 0.000 claims abstract description 6
- 239000011230 binding agent Substances 0.000 claims abstract description 5
- 150000003863 ammonium salts Chemical class 0.000 claims abstract description 4
- 230000004913 activation Effects 0.000 claims abstract description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims abstract description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims abstract description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 26
- 229960003850 dabigatran Drugs 0.000 claims description 23
- 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 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 13
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 13
- 239000002904 solvent Substances 0.000 claims description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 4
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- 239000001099 ammonium carbonate Substances 0.000 claims description 4
- 235000012501 ammonium carbonate Nutrition 0.000 claims description 4
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 235000019260 propionic acid Nutrition 0.000 claims description 3
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 235000019270 ammonium chloride Nutrition 0.000 claims description 2
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 claims description 2
- 229910052921 ammonium sulfate Inorganic materials 0.000 claims description 2
- 235000011130 ammonium sulphate Nutrition 0.000 claims description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 239000000460 chlorine Substances 0.000 claims 1
- 229910052801 chlorine Inorganic materials 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 6
- 239000000463 material Substances 0.000 abstract description 2
- 239000012442 inert solvent Substances 0.000 abstract 2
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 30
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- -1 III compound Chemical class 0.000 description 15
- 238000003756 stirring Methods 0.000 description 12
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- QQVIHTHCMHWDBS-UHFFFAOYSA-N perisophthalic acid Natural products OC(=O)C1=CC=CC(C(O)=O)=C1 QQVIHTHCMHWDBS-UHFFFAOYSA-N 0.000 description 7
- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 238000000967 suction filtration Methods 0.000 description 6
- 239000007787 solid Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 239000012043 crude product Substances 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 239000000376 reactant Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 208000007536 Thrombosis Diseases 0.000 description 2
- 150000001556 benzimidazoles Chemical class 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 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 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- HLLSOEKIMZEGFV-UHFFFAOYSA-N 4-(dibutylsulfamoyl)benzoic acid Chemical compound CCCCN(CCCC)S(=O)(=O)C1=CC=C(C(O)=O)C=C1 HLLSOEKIMZEGFV-UHFFFAOYSA-N 0.000 description 1
- 206010003658 Atrial Fibrillation Diseases 0.000 description 1
- 108010027612 Batroxobin Proteins 0.000 description 1
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 1
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- FGDQGIKMWOAFIK-UHFFFAOYSA-N acetonitrile;phosphoric acid Chemical compound CC#N.OP(O)(O)=O FGDQGIKMWOAFIK-UHFFFAOYSA-N 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 229940095054 ammoniac Drugs 0.000 description 1
- 229960002210 batroxobin Drugs 0.000 description 1
- KDPAWGWELVVRCH-UHFFFAOYSA-M bromoacetate Chemical compound [O-]C(=O)CBr KDPAWGWELVVRCH-UHFFFAOYSA-M 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- AOGYCOYQMAVAFD-UHFFFAOYSA-N chlorocarbonic acid Chemical compound OC(Cl)=O AOGYCOYQMAVAFD-UHFFFAOYSA-N 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 229940127066 new oral anticoagluant drug Drugs 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 230000009861 stroke prevention Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention provides a method for preparing dabigatran etexilate. The method comprises the following steps: A) subjecting a compound as shown in a formula I and a compound as shown in a formula II to a reaction in an inert solvent so as to obtain a compound as shown in a formula III, wherein the compound as shown in the formula II comprises an R which is one selected from the group consisting of methyl, ethyl, propyl or isopropyl; B) subjecting the compound as shown in the formula III to activation through a hydrogen chloride solution in an inert solvent, and carrying out a reaction of the activated material and an ammonium salt so as to obtain a product IV; and C) subjecting a compound as shown in a formula IV and a compound as shown in a formula V to a reaction under the action of an acid-binding agent so as to obtain dabigatran etexilate VI. The method provided by the invention has the advantages of low cost, high yield, mild reaction conditions, avoidance of using unstable reagents, etc.
Description
Technical field
The present invention relates to technical field of medicine synthesis is and in particular to a kind of preparation method of dabigatran etcxilate.
Background technology
Dabigatran etcxilate (Dabigatran etexilate), chemical name：3- [[[2- [[[4- [[[(hexyloxy) carbonyl] amino] formamino] phenyl] amino] methyl] -1- methyl isophthalic acid H- benzimidazole -5- base] carbonyl] (pyridine -2- base) amino] ethyl propionate, chemical structural formula：
System, by the new oral anticoagulant of German Boehringer Ingelheim company research and development, belongs to non-peptide batroxobin inhibitor.Take the lead in listing in Germany and Britain in April, 2008, Europe in 2008 and Canada's approval dabigatran etcxilate are used for preventing and treating Acute Venous thrombus.Food and drug administration have approved in September, 2010 and for OA dabigatran etcxilate to be used for patients with atrial fibrillation stroke prevention.Japanese health ministry ratifies this medicine for the prevention of Non-valvular disease heart rate patients with abnormal ishemic stroke and the outbreak of general thrombus within 2011 2 months.
German Boehringer Ingelheim company reports a synthetic route of dabigatran etcxilate in 1998 (WO9837075), as follows：
Above-mentioned route compounds of formula I and Formula II ' compound is in N, N '-carbonyl dimidazoles (CDI) and the lower cyclization of acetic acid effect generate formula III compound, compound III reacts generation formula IV compound under acid effect with ammonium carbonate afterwards, and formula IV compound obtains dabigatran etcxilate end-product with Formula V compound addition again.But the Formula II used in first step reaction ' compound price is higher, and the CDI that uses hygroscopic rotten it is not easy to preserve.There is researcher that it is synthesized later to improve, for example use carboxylic acid halides in CN104003977A, CN102633713A, CN102850325A patent application instead and diamino compounds carry out synthesizing benzimidazole class formation, because chloride compounds are dazzling, toxicity is big, and relatively costly, it is unfavorable for industrialized production.Slightly improve in CN104987323A patent application again, synthesized with two ammoniac compounds with acid anhydrides, but acid anhydrides needs to be prepared with II ' compound with acyl chlorides, therefore still there is the high defect of production cost.
Content of the invention
The invention provides a kind of preparation method of dabigatran etcxilate, compared with known method before this, the method that the present invention provides has low production cost, high income and reaction condition is gentle, it is to avoid the advantages of using unstable reagent.
The present invention is that target is realized in direct cyclization with diamine compounds by providing preparation Formula II compound N-this compound that is easy to get of (4- cyano-phenyl) aminoacetate.
One aspect of the present invention, provides a kind of method preparing dabigatran etcxilate, comprises the steps：
A) in atent solvent, compound shown in Formulas I is reacted with compound shown in Formula II and obtains compound shown in formula III；
Wherein, R is selected from one of methyl, ethyl, propyl group or isopropyl；
B) in atent solvent, compound shown in formula III is reacted with ammonium salt after hydrogen chloride solution activation, obtains product IV；
C) in atent solvent, compound shown in formula IV is reacted under acid binding agent effect with compound shown in Formula V, obtains dabigatran etcxilate VI.
Above-described preparation method, wherein, described atent solvent includes one or more of toluene, dimethylbenzene, acetic acid, propionic acid, DMF, dimethyl sulfoxide (DMSO) or diphenyl ether；Preferably, described atent solvent is DMF.
Above-described preparation method, wherein, in the reaction of step (A), compound shown in Formulas I and the mol ratio of compound shown in Formula II are 1:1～2.
Above-described preparation method, wherein it is preferred to, in the reaction of step (A), compound shown in Formulas I and the mol ratio of compound shown in Formula II are 1:1.1.
Preparation method described in any of the above, wherein, the temperature of the reaction of step (A) is preferably 60 DEG C～200 DEG C, and the reaction time is preferably 2～20 hours.
Above-described preparation method, wherein it is preferred to, the temperature of described reaction is 100～150 DEG C.
Above-described preparation method, wherein, hydrogen chloride solution described in step (B) is dissolved in acquisition in reaction dissolvent for hydrogen chloride, and described reaction dissolvent is one or more of methyl alcohol, ethanol or isopropanol.
Above-described preparation method, wherein, ammonium salt described in step (B) is one of ammonium chloride, ammonium carbonate or ammonium sulfate.
Above-described preparation method, wherein, the acid binding agent that step (C) is used is one or more of sodium carbonate, potassium carbonate, sodium acid carbonate, saleratus, triethylamine or pyridine.
Present invention firstly provides benzimidazole class compound III is prepared with N- (4- cyano-phenyl) amion acetic acid esters compound and diamine compounds condensation, decrease the use of CDI class reagent, make the preservation of reagent needed for reaction easier；Due to the present invention use compound shown in Formula II than Formula II used in prior art ' shown in compound easily prepared, so compound low price shown in Formula II, therefore can substantially reduce production cost, simplify production operation；Reaction condition is gentle, easy control of reaction；And the reagent that the present invention uses will not produce dazzling or sharp aroma, toxicity is low, safer to people；It is demonstrated experimentally that the yield of the dabigatran etcxilate of the present invention is higher, 78% can be reached it was demonstrated that being suitably applied industrialized production.
Figure of description
Fig. 1 is purity detecting HPLC collection of illustrative plates after dabigatran etcxilate crystallization once of the present invention, and as can be seen from the figure dabigatran etcxilate (11.60min) first product purity reaches 99.73%, single miscellaneous 0.26%.
Fig. 2 is the HPLC collection of illustrative plates after dabigatran etcxilate crystallization twice of the present invention, and as can be seen from the figure dabigatran etcxilate (11.60min) purity is 99.70%, single miscellaneous respectively less than 0.1%.
Specific embodiment
With reference to embodiments, the specific embodiment of the present invention is described in more details, so as to the advantage more fully understanding the solution of the present invention and its various aspects.However, specific embodiments described below and embodiment are only descriptive purposes, rather than limitation of the present invention.
Experimental technique used in following embodiments if no special instructions, is conventional method.
Material used, reagent etc. in following embodiments, if no special instructions, all commercially obtain.
Room temperature described in following embodiments refers both to 20～30 DEG C of temperature.
Embodiment 1 prepares N- (4- cyano-phenyl) ethyl aminoacetate (II)
Under room temperature, p-aminophenyl nitrile (11.8g, 0.1mol) and potassium carbonate (10.0g, 0.1mol) add in acetonitrile (100ml), stirring is lower to drip bromoacetate (16.7g, 0.1mol), it is warming up to backflow, after reaction 16h, be cooled to room temperature, filter, concentrate and remove solvent, residue adds water stirring, filter, twice of washing, then obtain II (17.9g, 88%) through re crystallization from toluene.
Embodiment 2 prepares the method () of 3- [[[2- [[(4- cyano-phenyl) amino] methyl] -1- methyl isophthalic acid H- benzimidazole -5- base] carbonyl] (pyridine -2- base) amino] ethyl propionate (III)
In 500mL reaction bulb; add 3- [N- (4- methylamino -3- amino benzoyl)-N- (pyridine -2- base) amino] ethyl propionate (I) (16.4g; 0.048mol), N- (4- cyano-phenyl) ethyl aminoacetate (II) (11.2g; 0.055mol) with 300mL DMF (N; dinethylformamide); stirring 1h, is warmed up to 120 DEG C of stirring reactions 10h.After being down to room temperature, reactant liquor pours precipitation solid, suction filtration in 1000ml frozen water into, and filter cake washes 3 times with water and obtains crude product III, is obtaining sterling (18.3g, 79%) with re-crystallizing in ethyl acetate.
Prepare the method (two) of 3- [[[2- [[(4- cyano-phenyl) amino] methyl] -1- methyl isophthalic acid H- benzimidazole -5- base] carbonyl] (pyridine -2- base) amino] ethyl propionate (III)
In 500mL reaction bulb; add 3- [N- (4- methylamino -3- amino benzoyl)-N- (pyridine -2- base) amino] ethyl propionate (I) (16.4g; 0.048mol), N- (4- cyano-phenyl) ethyl aminoacetate (II) (14.7g; 0.072mol) with 300mL dimethylbenzene; stirring 1h, is warmed up to 100 DEG C of stirring reactions 20h.After being down to room temperature, reactant liquor separates out solid, suction filtration, and filter cake washes 3 times with water and obtains crude product III, is obtaining sterling (13.5g, 58%) with re-crystallizing in ethyl acetate.
Prepare the method (three) of 3- [[[2- [[(4- cyano-phenyl) amino] methyl] -1- methyl isophthalic acid H- benzimidazole -5- base] carbonyl] (pyridine -2- base) amino] ethyl propionate (III)
In 500mL reaction bulb; add 3- [N- (4- methylamino -3- amino benzoyl)-N- (pyridine -2- base) amino] ethyl propionate (I) (16.4g; 0.048mol), N- (4- cyano-phenyl) ethyl aminoacetate (II) (14.7g; 0.072mol) with 300mL DMSO (dimethyl sulfoxide); stirring 1h, is warmed up to 140 DEG C of stirring reactions 20h.After being down to room temperature, reactant liquor pours precipitation solid, suction filtration in 1000ml frozen water into, and filter cake washes 3 times with water and obtains crude product III, is obtaining sterling (17.8g, 77%) with re-crystallizing in ethyl acetate.
Prepare the method (four) of 3- [[[2- [[(4- cyano-phenyl) amino] methyl] -1- methyl isophthalic acid H- benzimidazole -5- base] carbonyl] (pyridine -2- base) amino] ethyl propionate (III)
In 500mL reaction bulb; add 3- [N- (4- methylamino -3- amino benzoyl)-N- (pyridine -2- base) amino] ethyl propionate (I) (16.4g; 0.048mol), N- (4- cyano-phenyl) ethyl aminoacetate (II) (11.8g; 0.058mol) with 300mL propionic acid; stirring 1h, is warmed up to 130 DEG C of stirring reactions 12h.After being down to room temperature, reactant liquor is poured in (10%) in 1000ml sodium carbonate liquor and is separated out solid, suction filtration, and filter cake washes 3 times with water and obtains crude product III, is obtaining sterling (18.8g, 81%) with re-crystallizing in ethyl acetate.
Embodiment 3 prepares 3- [[[2- [[(4- carbamimido-phenyl) amino] methyl] -1- methyl isophthalic acid H- benzimidazole -5- base] carbonyl] (pyridine -2- base) amino] ethyl propionate (IV)
3- [[[2- [[(4- cyano-phenyl) amino] methyl] -1- methyl isophthalic acid H- benzimidazole -5- base] carbonyl] (pyridine -2- base) amino] ethyl propionate (III) (10.0g, 0.021mol) add the ethanol solution (50ml) of the hydrogen chloride of 6M, an evening is stirred at room temperature.Boil off excessive solvent, residue is dissolved in 40ml ethanol solution, add ammonium carbonate (19.2g, 0.2mol), be stirred overnight under room temperature.Filter, remove insoluble matter, filtrate reduced in volume is extremely dry.Residue is dissolved in 60ml ethyl acetate and the mixed solution (5: 1) of ethanol, reaction 2h is stirred at room temperature.Suction filtration, is dried, obtains the hydrochloride (10.2g, 92%) of compound IV.
Embodiment 4 prepares dabigatran etcxilate (VI)
By IV (10.0g, 18.6mmol) dissolve in THF (oxolane) (75ml) and water (15ml), add potassium carbonate (9.4g, 65.0mmol), 0.5h is stirred at room temperature, is cooled to less than 10 DEG C, add the just own ester (4.30g of chloro-carbonic acid, 26.1mmol), stir 2h.Concentrated solvent, adds ethanol 100ml, stirs 1h, suction filtration, reduced pressure concentration.Residue with ethyl acetate recrystallizes twice, obtains 8.62g solid dabigatran etcxilate, yield 78%, mp:127～128 DEG C.HPLC detection, testing equipment are carried out respectively to the dabigatran etcxilate crystallizing acquisition twice：Agilent 1200 high performance liquid chromatograph, VWD detector；Chromatographic column：Octadecylsilane chemically bonded silica is the chromatographic column (150 × 4.6mm, 5 μm) of filler；Column temperature：30 DEG C, (mobile phase)：0.2%H3PO4Phosphoric acid-acetonitrile (3:2), flow velocity：1.0ml/min, Detection wavelength：254nm, sample size 10 μ L, from testing result as can be seen that dabigatran etcxilate crystallization purity twice is all higher than 99%, specifically the peak area situation of each testing result is shown in Tables 1 and 2, can also intuitively impurity removal peak area very little (being specifically shown in Fig. 1 and Fig. 2) from collection of illustrative plates.
Table 1 is the peak area situation of the detection collection of illustrative plates of the dabigatran etcxilate first time crystallized product of Fig. 1 of the present invention
Table 2 is the peak area situation of the detection collection of illustrative plates after second crystallization of dabigatran etcxilate of Fig. 2 of the present invention
Finally it should be noted that：Obviously, above-described embodiment is only intended to clearly illustrate example of the present invention, and the not restriction to embodiment.For those of ordinary skill in the field, can also make other changes in different forms on the basis of the above description.There is no need to be exhaustive to all of embodiment.And the obvious change thus amplified out or change still in protection scope of the present invention among.
Claims (9)
1. a kind of method preparing dabigatran etcxilate is it is characterised in that comprise the steps：
A) in atent solvent, compound shown in Formulas I is reacted with compound shown in Formula II and obtains formula III
Shown compound；
Wherein, R is selected from one of methyl, ethyl, propyl group or isopropyl；
B) in atent solvent, compound shown in formula III is reacted with ammonium salt after hydrogen chloride solution activation,
Obtain product IV；
C) in atent solvent, compound shown in formula IV is acted in acid binding agent with compound shown in Formula V
Lower reaction, obtains dabigatran etcxilate VI.
2. preparation method as claimed in claim it is characterised in that described atent solvent include toluene,
One of dimethylbenzene, acetic acid, propionic acid, N,N-dimethylformamide, dimethyl sulfoxide (DMSO) or diphenyl ether
Or it is multiple.
3. preparation method as claimed in claim 1 is it is characterised in that in the reaction of step (A)
Compound shown in Formulas I is 1 with the mol ratio of compound shown in Formula II:1～2.
4. preparation method as claimed in claim 3 is it is characterised in that in the reaction of step (A)
Compound shown in Formulas I is 1 with the mol ratio of compound shown in Formula II:1.1.
5. as described preparation method arbitrary in Claims 1-4 it is characterised in that step (A)
Reaction temperature be 60 DEG C～200 DEG C.
6. preparation method as claimed in claim 5 it is characterised in that described reaction temperature be 100～
150℃.
7. preparation method as claimed in claim 1 is it is characterised in that chlorine described in step (B)
Change hydrogen solution be hydrogen chloride be dissolved in reaction dissolvent obtain, described reaction dissolvent be methyl alcohol, ethanol or
One or more of isopropanol.
8. preparation method as claimed in claim 1 is it is characterised in that ammonium described in step (B)
Salt is one of ammonium chloride, ammonium carbonate or ammonium sulfate.
9. preparation method as claimed in claim 1 is it is characterised in that what step (C) was used
Acid binding agent is one of sodium carbonate, potassium carbonate, sodium acid carbonate, saleratus, triethylamine or pyridine
Or it is multiple.
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| CN110981858A (en) * | 2019-12-16 | 2020-04-10 | 南通常佑药业科技有限公司 | Preparation method of anticoagulant drug dabigatran etexilate and analogue thereof |
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| CN110981858A (en) * | 2019-12-16 | 2020-04-10 | 南通常佑药业科技有限公司 | Preparation method of anticoagulant drug dabigatran etexilate and analogue thereof |
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