CN106928195B - A kind of synthetic method of Dabigatran etexilate key intermediate - Google Patents
A kind of synthetic method of Dabigatran etexilate key intermediate Download PDFInfo
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- 238000010189 synthetic method Methods 0.000 title claims abstract description 18
- 229960000288 dabigatran etexilate Drugs 0.000 title claims abstract description 14
- 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 14
- 150000001875 compounds Chemical class 0.000 claims abstract description 47
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims description 41
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 36
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 20
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 20
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- 239000003960 organic solvent Substances 0.000 claims description 14
- 239000003513 alkali Substances 0.000 claims description 11
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 10
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 10
- 229910052794 bromium Inorganic materials 0.000 claims description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical class ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 9
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 9
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 9
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 7
- 239000003153 chemical reaction reagent Substances 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 239000000460 chlorine Substances 0.000 claims description 7
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 6
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-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
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 4
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 3
- 239000005695 Ammonium acetate Substances 0.000 claims description 3
- 235000019257 ammonium acetate Nutrition 0.000 claims description 3
- 229940043376 ammonium acetate Drugs 0.000 claims description 3
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 claims description 3
- 150000004820 halides Chemical class 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 2
- 235000019270 ammonium chloride Nutrition 0.000 claims description 2
- 239000000908 ammonium hydroxide Substances 0.000 claims description 2
- 150000003222 pyridines Chemical class 0.000 claims 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 1
- WJEIYVAPNMUNIU-UHFFFAOYSA-N [Na].OC(O)=O Chemical compound [Na].OC(O)=O WJEIYVAPNMUNIU-UHFFFAOYSA-N 0.000 claims 1
- 229910052799 carbon Inorganic materials 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 9
- 239000002994 raw material Substances 0.000 abstract description 6
- 238000009776 industrial production Methods 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 238000000746 purification Methods 0.000 abstract description 3
- 230000035484 reaction time Effects 0.000 abstract description 3
- 238000011084 recovery Methods 0.000 abstract description 3
- 150000001243 acetic acids Chemical class 0.000 abstract description 2
- 238000007363 ring formation reaction Methods 0.000 abstract description 2
- WRGVPFAJPMIYOX-UHFFFAOYSA-N 2-(chloromethyl)-1-methylbenzimidazole Chemical compound C1=CC=C2N(C)C(CCl)=NC2=C1 WRGVPFAJPMIYOX-UHFFFAOYSA-N 0.000 abstract 1
- 239000007787 solid Substances 0.000 description 18
- 238000003756 stirring Methods 0.000 description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 11
- 238000002360 preparation method Methods 0.000 description 11
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- 239000012044 organic layer Substances 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 8
- 238000001556 precipitation Methods 0.000 description 8
- 229960003850 dabigatran Drugs 0.000 description 7
- 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 description 7
- BAVYZALUXZFZLV-UHFFFAOYSA-N mono-methylamine Natural products NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 239000005711 Benzoic acid Substances 0.000 description 4
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 4
- 235000010233 benzoic acid Nutrition 0.000 description 4
- 230000008878 coupling Effects 0.000 description 4
- 238000010168 coupling process Methods 0.000 description 4
- 238000005859 coupling reaction Methods 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 4
- 235000019345 sodium thiosulphate Nutrition 0.000 description 4
- 208000007536 Thrombosis Diseases 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical class 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- PNVPNXKRAUBJGW-UHFFFAOYSA-N (2-chloroacetyl) 2-chloroacetate Chemical compound ClCC(=O)OC(=O)CCl PNVPNXKRAUBJGW-UHFFFAOYSA-N 0.000 description 2
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 2
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 2
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 235000011054 acetic acid Nutrition 0.000 description 2
- 239000001099 ammonium carbonate Substances 0.000 description 2
- 235000012501 ammonium carbonate Nutrition 0.000 description 2
- 239000003146 anticoagulant agent Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- FDRCDNZGSXJAFP-UHFFFAOYSA-M sodium chloroacetate Chemical group [Na+].[O-]C(=O)CCl FDRCDNZGSXJAFP-UHFFFAOYSA-M 0.000 description 2
- 238000005292 vacuum distillation Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- URFKLQSFBXBOQU-UHFFFAOYSA-N 2-chloro-1,1,1-triethoxyethane Chemical class CCOC(CCl)(OCC)OCC URFKLQSFBXBOQU-UHFFFAOYSA-N 0.000 description 1
- 125000001340 2-chloroethyl group Chemical class [H]C([H])(Cl)C([H])([H])* 0.000 description 1
- DFXQXFGFOLXAPO-UHFFFAOYSA-N 96-99-1 Chemical compound OC(=O)C1=CC=C(Cl)C([N+]([O-])=O)=C1 DFXQXFGFOLXAPO-UHFFFAOYSA-N 0.000 description 1
- 206010008190 Cerebrovascular accident Diseases 0.000 description 1
- 206010013710 Drug interaction Diseases 0.000 description 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 1
- 102000009123 Fibrin Human genes 0.000 description 1
- 108010073385 Fibrin Proteins 0.000 description 1
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 206010044565 Tremor Diseases 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000002429 anti-coagulating effect Effects 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 230000010100 anticoagulation Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229940049706 benzodiazepine Drugs 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229940125532 enzyme inhibitor Drugs 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 229950003499 fibrin Drugs 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 210000002837 heart atrium Anatomy 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000013011 mating Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000010970 precious metal Substances 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 229960002668 sodium chloride Drugs 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000001291 vacuum drying Methods 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
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 discloses a kind of Dabigatran etexilate key intermediate, the i.e. N- [synthetic methods of [2- (chloromethyl) -1- methyl-1 H- benzimidazole -5- base] carbonyl-N-2- pyridyl group-Beta-alanine ethyl ester (6 compound of formula).Method of the invention prepares key intermediate (6 compound of formula) using 4 compound of formula and halogenated acetic acids and three component of aminating agent, one step cyclization, avoids cumbersome interminable synthesis step.And 4 compound of formula can be prepared by cheap and stable property raw material.Method of the invention compared with prior art, can solve the problems, such as various simultaneously.The prices of raw materials used in the present invention are cheap, property is stablized, reaction time is short, mild condition, purification of intermediate is convenient, total recovery reaches 72% or more, i.e., Dabigatran etexilate key intermediate (6 compound of formula) can be made to low cost and high yield in synthetic method of the invention, has preferable industrial production prospect.
Description
Technical field
The invention belongs to the field of chemical synthesis, and in particular to the chemistry of oral anticoagulant Dabigatran etexilate key intermediate
Synthetic method.
Background technique
Dabigatran etcxilate (Dabigatran etexilate, trade name: Padaxa) is public by German Boehringer Ingelheim
Department's exploitation, the first new oral anticoagulation medicine listed over 50 years after warfarin.Dabigatran etcxilate belongs to non-peptides blood coagulation
Enzyme inhibitor, it blocks the activity of fibrin ferment (sequestered or mating type) to play anticoagulant effect by specificity and selectively
Fruit, has the characteristics that orally available, potent, few without special Medication monitor, drug interaction, is anticoagulant therapy field and latent
A major progress in lethal thrombus prevention field.2008, Europe and Canadian approved dabigatran etcxilate were for preventing
Control Acute Venous thrombus (VTE).U.S. FDA has approved in September, 2010 and is used to reduce non-valvular atrium for dabigatran etcxilate
Tremble the prevention of patient's cerebral apoplexy and whole body thrombus.Dabigatran etcxilate in 2013 obtains what food and medicine Surveillance Authority, China issued
Import drugs registration certificate.
German Boehringer Ingelheim company respectively with 1998 (WO9837075A1) and (J. Med. in 2002
Chem., 2002,45,1757 ~ 1766) synthetic route (referred to as: route 1) for dabigatran etcxilate is reported.Following institute
Show:
The route is existing principal synthetic routes, anti-by 7 steps altogether using 3- nitro -4- chlorobenzoic acid as starting material
Product should be obtained, mild condition is easy to operate, but reaction step is more, synthesizes very complicated, and raw material is not easy, needs to use
To precious metals pd/C, and total recovery is lower, so that the preparation cost of the route is higher.In addition the intermediate of the route needs mostly
Pillar layer separation is not able to satisfy the demand of large-scale industrial production.
German Boehringer Ingelheim company then improves synthetic route in patent WO2011061080, following institute
Show:
The emphasis of the route is the synthesis of key intermediate 6.It is identical with above-mentioned route to be, it need to first be made by the reaction of 4 steps
Obtain intermediate 7.With coupling reagent cyclizative condensation occurs for intermediate 7 again, obtains key intermediate 6.Wherein, used coupling examination
Agent is monoxone, chloracetyl chloride, chloroacetic anhydride or triethoxy chloroethanes.Reaction yield only has 30% when using monoxone；Make
Two acylated by-product impurity are also easy to produce when making coupling reagent with chloracetyl chloride, yield only has 71%；Chloroacetic anhydride price is higher, increases
Production cost is added；Triethoxy chloroethanes is not easy, and needs to make by oneself, and is prepared more complex.Therefore, during which is not suitable for
The industrialized production of mesosome 6 and dabigatran etcxilate.
Patent CN 102850325 describes the improvement synthetic method of Dabigatran etexilate key intermediate 6, as follows:
The method is raw material with intermediate 7, selects compound 8 to be used as coupling reagent, mild condition, reaction yield is than above-mentioned
Patent WO2011061080 increases, but 8 price of compound is more expensive, is not easy to obtain, and the method still needs in first obtained
Mesosome 7 does not solve the problem of 7 source of intermediate difficulty, therefore this method does not meet industrial production demand.
Summary of the invention
The invention discloses a kind of Dabigatran etexilate key intermediate 6, i.e. N- [[2- (chloromethyl) -1- methyl-1 H- benzos
Imidazoles -5- base] carbonyl-N-2- pyridyl group-Beta-alanine ethyl ester synthetic method, it is therefore intended that existing technical problem is solved,
This method can prepare Dabigatran etexilate key intermediate 6, raw material used and reagent price at lower cost in high yield
Cheaply, property is stablized, and the reaction time is short, mild condition, and purification of intermediate is convenient, is suitable for industrialized production.
In order to reach the goals above, the technical solution adopted in the present invention is as follows:
(1) p- methylamine yl benzoic acid 1 is mixed in organic solvent with alkali at room temperature, and -20 ~ -10oHalogenation examination is added under C
Agent is reacted 4 ~ 8 hours under nitrogen protection, and saturated aqueous sodium thiosulfate is added, separates organic layer, then use saturated sodium chloride water
Solution is washed, and dries, filters, solvent is removed under reduced pressure, and compound shown in formula 2 is made:
Wherein Hal1(halogen) indicates chlorine or bromine；
(2) compound shown in formula 2 is -20 ~ -10oIt is mixed in organic solvent under C with thionyl chloride, N, N '-diformazan is added
Base formamide makees catalyst, reacts 4 ~ 5 hours under nitrogen protection, is slowly warmed to room temperature naturally, be added 3 compound of formula with it is organic
Alkali stirs 5 ~ 10 hours, and washing separates organic layer, dries, filters, solvent is removed under reduced pressure, obtains 4 compound of formula:
Wherein Hal1(halogen) indicates chlorine or bromine；
(3) compound shown in formula 5 is -20 ~ -10oIt is mixed in organic solvent under C with thionyl chloride, N, N '-diformazan is added
Base formamide makees catalyst, reacts 4 ~ 5 hours under nitrogen protection, and vacuum distillation, residue is dissolved in organic solvent, and formula 4 is added
Compound and alkali stir 4 ~ 10 hours, and aminating agent is then added, and back flow reaction 2 ~ 4 hours, washing separated organic layer, did
It is dry, filter, solvent be removed under reduced pressure, obtain 6 compound of formula:
Wherein Hal2(halogen) indicates chlorine or bromine.
In the reaction step (1) organic solvent be tetrahydrofuran, methylene chloride, 1,2- dichloroethanes, ethyl acetate or
Butyl acetate；In the reaction step (1) alkali be sodium bicarbonate, sodium carbonate, potassium carbonate, pyridine, 4- dimethylaminopyridine or
Triethylamine；
Halide reagent is bromine, N- chlorosuccinimide, N- bromo-succinimide in the reaction step (1)；
Organic solvent is tetrahydrofuran, toluene, methylene chloride, 1,2- dichloroethanes, acetic acid second in the reaction step (2)
Ester or butyl acetate；
Organic base is pyridine, 4- dimethylaminopyridine or triethylamine in the reaction step (2)；
Organic solvent is tetrahydrofuran, toluene, methylene chloride, 1,2- dichloroethanes, acetic acid second in the reaction step (3)
Ester or butyl acetate；
Alkali is sodium bicarbonate, sodium carbonate, potassium carbonate, pyridine, 4- dimethylaminopyridine or three in the reaction step (3)
Ethamine；
Aminating agent is ammonium hydroxide, ammonium carbonate, ammonium formate, ammonium acetate, ammonium chloride in the reaction step (3).
The present invention has the advantages that
Method of the invention is using in 4 compound of formula and halogenated acetic acids and three component of aminating agent, one step cyclization preparation key
Mesosome (6 compound of formula), avoids cumbersome interminable synthesis step.And 4 compound of formula can pass through cheap and stable property original
Material is prepared.Method of the invention improves the synthetic route of Dabigatran etexilate key intermediate 6 from source, with existing skill
Art is compared, and can be solved the problems, such as simultaneously various.The prices of raw materials used in the present invention are cheap, and property is stablized, the reaction time
Short, mild condition, purification of intermediate is convenient, and total recovery reaches 72% or more, i.e., synthetic method of the invention being capable of the high receipts of low cost
Dabigatran etexilate key intermediate (6 compound of formula) is made to rate, there is preferable industrial production prospect.
Specific embodiment:
The present invention will be further described by the following examples, and the description of this part is only exemplary and explanatory, sheet
Invention is not limited only to this.
Embodiment 1
The synthetic method of Dabigatran etexilate key intermediate (6 compound of formula), comprising the following steps:
1. the preparation of 2 compound of formula
P- 30.2 g of methylamine yl benzoic acid (0.2 mol) mixes with 280 ml of methylene chloride at room temperature, and it is small to stir 1
When, it is added 32.2 mL of pyridine (0.4 mol), is cooled to -20oC is slowly added dropwise 10.76 mL of bromine (0.21 mol), keeps low
The reaction was continued 5 hours for temperature, and with 50 mL saturated aqueous sodium thiosulfates, reaction was completed, and 100 mL ethyl acetate are added, have separated
Machine phase, then washed with 300 mL saturated sodium-chloride water solutions, anhydrous sodium sulfate is dry, is concentrated under reduced pressure into about 100 mL, and 50 mL are added
N-hexane has solid precipitation, stirs 2 hours at room temperature, filters, is washed with 50 mL methylene chloride, 50 oC is dried in vacuo 1 hour,
Obtain 43.0 g of white powdery solids, yield: 94%.
2. the preparation of 4 compound of formula
2 compound of formula, 34.4 g (0.15 mol) is mixed with 240 mL of methylene chloride at room temperature, and stirs cooling in 1 hour
To -20oC is added 12.0 mL of thionyl chloride (0.165 mol), then about 0.5 mL of n,N-Dimethylformamide is added dropwise, and continues anti-
It answers 4 hours, is warmed to room temperature naturally, 3 compound of formula, 29.12 g (0.15 mol) and 41.7 mL (0.3 of triethylamine is added
Mol), the reaction was continued at room temperature 6 hours, and 300 mL water are added, and reaction was completed, separates organic layer, then with 200 mL saturated sodium-chlorides
Aqueous solution is washed, and anhydrous sodium sulfate is dry, is concentrated under reduced pressure into about 100 mL of total volume, and 50 mL n-hexanes are added, there is solid precipitation,
It stirs 2.5 hours, filters, 50 at room temperature oC is dried in vacuo 1 hour, obtains 57.7 g of white powdery solids, yield: 95%.
3. the preparation of 6 compound of key intermediate formula
5 compound of formula, 10.34 g (0.11 mol) is mixed with 100 mL of methylene chloride at room temperature, and is stirred 1 hour, cold
But to -20oC is added 8.7 mL of thionyl chloride (0.165 mol), then about 0.5 mL of n,N-Dimethylformamide is added dropwise, and continues
Reaction 4 hours, is warmed to room temperature naturally, is evaporated under reduced pressure, and 200 mL of tetrahydrofuran, 4 compound of formula is added in residue at room temperature
40.5 g (0.1 mol) and 27.9 mL of triethylamine (0.2 mol), the reaction was continued at room temperature 6 hours, and ammonium carbonate 19.22 is added
G (0.2 mol), heating reflux reaction 4 hours, is cooled to room temperature, and 300 mL water are added, and reaction was completed, separates organic layer, then use
200 mL saturated sodium-chloride water solutions are washed, and anhydrous sodium sulfate is dry, are concentrated under reduced pressure into about 100 mL of total volume, and 50 mL are being added just
Hexane has solid precipitation, stirs 2.5 hours at room temperature, filters, 50 oC is dried in vacuo 1 hour, obtains 32.4 g of white solid, is received
Rate: 81%.
Embodiment 2
1. the preparation of 2 compound of formula
P- 30.2 g of methylamine yl benzoic acid (0.2 mol) mixes with 280 ml of tetrahydrofuran at room temperature, and it is small to stir 1
When, it is added 55.7 mL of triethylamine (0.4 mol), is cooled to -20oC is slowly added dropwise 10.76 mL of bromine (0.21 mol), keeps
The reaction was continued 5 hours for low temperature, and with 50 mL saturated aqueous sodium thiosulfates, reaction was completed, and 100 mL ethyl acetate are added, separate
Organic phase, then washed with 300 mL saturated sodium-chloride water solutions, anhydrous sodium sulfate is dry, is concentrated under reduced pressure into about 100 mL, is added 50
ML n-hexane has solid precipitation, stirs 2 hours at room temperature, filters, is washed with 50 mL methylene chloride, 50 oC vacuum drying 1 is small
When, obtain 43.0 g of white powdery solids, yield: 94%.
2. the preparation of 4 compound of formula
2 compound of formula, 34.4 g (0.15 mol) is mixed with 240 mL of tetrahydrofuran at room temperature, and stirs cooling in 1 hour
To -20oC is added 12.0 mL of thionyl chloride (0.165 mol), then about 0.5 mL of n,N-Dimethylformamide is added dropwise, and continues anti-
It answers 4 hours, is warmed to room temperature naturally, 3 compound of formula, 29.12 g (0.15 mol) and 24.1 mL of pyridine (0.3 mol) is added,
The reaction was continued at room temperature 6 hours, and 300 mL water are added, and reaction was completed, separates organic layer, then water-soluble with 200 mL saturated sodium-chlorides
Liquid is washed, and anhydrous sodium sulfate is dry, is concentrated under reduced pressure into about 100 mL of total volume, and 50 mL n-hexanes are added, there is solid precipitation, room temperature
Lower stirring 2.5 hours, filters, 50 oC is dried in vacuo 1 hour, obtains 58.9 g of white powdery solids, yield: 97%.
3. the preparation of 6 compound of key intermediate formula
5 compound of formula, 10.34 g (0.11 mol) is mixed with 1,2- dichloroethanes, 100 mL at room temperature, and it is small to stir 1
When, it is cooled to -20oC is added 8.7 mL of thionyl chloride (0.165 mol), then about 0.5 mL of n,N-Dimethylformamide is added dropwise,
The reaction was continued 4 hours, is warmed to room temperature naturally, and 200 mL of toluene, 4 compound of formula is added in vacuum distillation, residue at room temperature
40.5 g (0.1 mol) and 16.1 mL of pyridine (0.2 mol), the reaction was continued at room temperature 6 hours, and 15.42 g of ammonium acetate is added
(0.2 mol) heating reflux reaction 4 hours, is cooled to room temperature, and 300 mL water are added, and reaction was completed, separates organic layer, then use
200 mL saturated sodium-chloride water solutions are washed, and anhydrous sodium sulfate is dry, are concentrated under reduced pressure into about 100 mL of total volume, and 50 mL are being added just
Hexane has solid precipitation, stirs 2.5 hours at room temperature, filters, 50 oC is dried in vacuo 1 hour, obtains 32.0 g of white solid, is received
Rate: 80%.
Embodiment 3
1. the preparation of 2 compound of formula
P- 30.2 g of methylamine yl benzoic acid (0.2 mol) mixes with 1,2- dichloroethanes, 280 ml at room temperature, and stirs 1
Hour, it is added 33.6 g of sodium bicarbonate (0.4 mol), is cooled to -20oC is slowly added to 37.4 g of N- bromo-succinimide
(0.21 mol), keeping low temperature, the reaction was continued 5 hours, and with 50 mL saturated aqueous sodium thiosulfates, reaction was completed, is added 100
ML ethyl acetate separates organic phase, then is washed with 300 mL saturated sodium-chloride water solutions, and anhydrous sodium sulfate is dry, is concentrated under reduced pressure into
About 100 mL are added 50 mL n-hexanes, there is solid precipitation, stir 2 hours at room temperature, filter, are washed with 50 mL methylene chloride,
50 oC is dried in vacuo 1 hour, obtains 42.1 g of white powdery solids, yield: 92%.
2. the preparation of 4 compound of formula
2 compound of formula, 34.4 g (0.15 mol) is mixed with 240 mL of toluene at room temperature, and stir and be cooled to for 1 hour-
20oC is added 12.0 mL of thionyl chloride (0.165 mol), then about 0.5 mL of n,N-Dimethylformamide is added dropwise, and the reaction was continued 4
Hour, it is warmed to room temperature naturally, 3 compound of formula, 29.12 g (0.15 mol) and 36.6 g of 4- dimethylaminopyridine is added
(0.3 mol), the reaction was continued at room temperature 6 hours, and 300 mL water are added, and reaction was completed, separates organic layer, then be saturated with 200 mL
Sodium-chloride water solution is washed, and anhydrous sodium sulfate is dry, is concentrated under reduced pressure into about 100 mL of total volume, and 50 mL n-hexanes are added, there is solid
It is precipitated, stirs 2.5 hours at room temperature, filter, 50 oC is dried in vacuo 1 hour, obtains 58.3 g of white powdery solids, yield:
96%。
3. the preparation of 6 compound of key intermediate formula
5 compound of formula, 10.34 g (0.11 mol) is mixed with 100 mL of tetrahydrofuran at room temperature, and is stirred 1 hour, cold
But to -20oC is added 8.7 mL of thionyl chloride (0.165 mol), then about 0.5 mL of n,N-Dimethylformamide is added dropwise, and continues
Reaction 4 hours, is warmed to room temperature naturally, is evaporated under reduced pressure, and 1,2- dichloroethanes, 200 mL, 4 chemical combination of formula is added in residue at room temperature
40.5 g of object (0.1 mol) and 27.6 g of potassium carbonate (0.2 mol), the reaction was continued at room temperature 6 hours, and ammonium formate is added
12.62 g (0.2 mol), heating reflux reaction 4 hours, are cooled to room temperature, and 300 mL water are added, and reaction was completed, separate organic
Layer, then washed with 200 mL saturated sodium-chloride water solutions, anhydrous sodium sulfate is dry, is concentrated under reduced pressure into about 100 mL of total volume, is added
50 mL n-hexanes, there is solid precipitation, stir 2.5 hours at room temperature, filter, 50 oC is dried in vacuo 1 hour, obtains white solid
33.2 g, yield: 83%.
The foregoing is merely presently preferred embodiments of the present invention, all equivalent changes done according to scope of the present invention patent with
Modification, is all covered by the present invention.
Claims (9)
1. a kind of synthetic method of dabigatran etexilate intermediate, which comprises the following steps:
(1) 1 compound of formula is mixed in organic solvent with alkali at room temperature, and halide reagent is added, and 2 compound of formula is made after reaction:
、
Wherein Hal1Indicate chlorine or bromine；
(2) 2 compound of formula and thionyl chloride are mixed in organic solvent, and n,N-Dimethylformamide is added and makees catalyst, then
Alkali and 3 compound of formula is added, 4 compound of formula is obtained after reaction:
、
Wherein Hal1Indicate chlorine or bromine；
(3) 5 compound of formula and thionyl chloride are mixed in organic solvent, and n,N-Dimethylformamide is added and makees catalyst, reacts
After be evaporated under reduced pressure, organic solvent is added in residue, alkali and 4 compound of formula are reacted, is eventually adding aminating agent, heats back
Stream reaction, obtains 6 compound of dabigatran etexilate intermediate formula；
、
Wherein Hal1Indicate chlorine or bromine, Hal2Indicate chlorine or bromine.
2. synthetic method as described in claim 1, it is characterised in that: organic solvent described in step (1) be tetrahydrofuran,
Methylene chloride, 1,2- dichloroethanes, ethyl acetate or butyl acetate.
3. synthetic method as described in claim 1, it is characterised in that: alkali described in step (1) is pyridine, 4- dimethylamino
Yl pyridines, triethylamine, sodium bicarbonate, sodium carbonate or potassium carbonate.
4. synthetic method as described in claim 1, it is characterised in that: halide reagent described in step (1) is selected from N- chloro
Succimide, N- bromo-succinimide.
5. synthetic method as described in claim 1, it is characterised in that: organic solvent described in step (2) be tetrahydrofuran,
Toluene, methylene chloride, 1,2- dichloroethanes, ethyl acetate or butyl acetate.
6. synthetic method as described in claim 1, it is characterised in that: alkali described in step (2) is pyridine, 4- dimethylamino
Yl pyridines or triethylamine.
7. synthetic method as described in claim 1, it is characterised in that: organic solvent described in step (3) be tetrahydrofuran,
Toluene, methylene chloride, 1,2- dichloroethanes, ethyl acetate or butyl acetate.
8. synthetic method as described in claim 1, it is characterised in that: alkali described in step (3) is sodium bicarbonate, carbonic acid
Sodium, potassium carbonate, pyridine, 4-dimethylaminopyridine or triethylamine.
9. synthetic method as described in claim 1, it is characterised in that: aminating agent described in step (3) is selected from ammonium hydroxide, carbon
Sour ammonium, ammonium formate, ammonium acetate, ammonium chloride.
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