CN105566297A - Preparation method of dabigatran etexilate mesylate - Google Patents
Preparation method of dabigatran etexilate mesylate Download PDFInfo
- Publication number
- CN105566297A CN105566297A CN201511030125.XA CN201511030125A CN105566297A CN 105566297 A CN105566297 A CN 105566297A CN 201511030125 A CN201511030125 A CN 201511030125A CN 105566297 A CN105566297 A CN 105566297A
- Authority
- CN
- China
- Prior art keywords
- crude product
- reaction
- amino
- stirring
- thf
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 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 3
- 229960004951 dabigatran etexilate mesylate Drugs 0.000 title abstract 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims abstract description 61
- 238000006243 chemical reaction Methods 0.000 claims abstract description 61
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 claims abstract description 53
- -1 3-amino-4-methylaminobenzoyl Chemical group 0.000 claims abstract description 30
- 235000011114 ammonium hydroxide Nutrition 0.000 claims abstract description 15
- 239000002994 raw material Substances 0.000 claims abstract description 13
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 140
- 238000003756 stirring Methods 0.000 claims description 108
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 70
- 239000012043 crude product Substances 0.000 claims description 61
- 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 55
- 229960003850 dabigatran Drugs 0.000 claims description 55
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 52
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 41
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 40
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 40
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 39
- 238000001291 vacuum drying Methods 0.000 claims description 34
- 238000010792 warming Methods 0.000 claims description 33
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- 239000008213 purified water Substances 0.000 claims description 29
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 27
- 238000000034 method Methods 0.000 claims description 25
- 239000012046 mixed solvent Substances 0.000 claims description 25
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 24
- 230000000694 effects Effects 0.000 claims description 24
- 229960000583 acetic acid Drugs 0.000 claims description 20
- 238000010583 slow cooling Methods 0.000 claims description 20
- 239000012362 glacial acetic acid Substances 0.000 claims description 19
- 239000003795 chemical substances by application Substances 0.000 claims description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 16
- 239000007810 chemical reaction solvent Substances 0.000 claims description 16
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 16
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 16
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 15
- 238000007670 refining Methods 0.000 claims description 14
- AOGYCOYQMAVAFD-UHFFFAOYSA-N chlorocarbonic acid Chemical compound OC(Cl)=O AOGYCOYQMAVAFD-UHFFFAOYSA-N 0.000 claims description 8
- 150000002148 esters Chemical class 0.000 claims description 8
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 7
- 238000001914 filtration Methods 0.000 claims description 7
- 238000002156 mixing Methods 0.000 claims description 6
- 238000001953 recrystallisation Methods 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- GJRQTCIYDGXPES-UHFFFAOYSA-N iso-butyl acetate Natural products CC(C)COC(C)=O GJRQTCIYDGXPES-UHFFFAOYSA-N 0.000 claims description 4
- FGKJLKRYENPLQH-UHFFFAOYSA-M isocaproate Chemical compound CC(C)CCC([O-])=O FGKJLKRYENPLQH-UHFFFAOYSA-M 0.000 claims description 4
- OQAGVSWESNCJJT-UHFFFAOYSA-N isovaleric acid methyl ester Natural products COC(=O)CC(C)C OQAGVSWESNCJJT-UHFFFAOYSA-N 0.000 claims description 4
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- 230000008901 benefit Effects 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 3
- 238000004176 ammonification Methods 0.000 abstract description 2
- KJRQMXRCZULRHF-UHFFFAOYSA-N 2-(4-cyanoanilino)acetic acid Chemical compound OC(=O)CNC1=CC=C(C#N)C=C1 KJRQMXRCZULRHF-UHFFFAOYSA-N 0.000 abstract 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 abstract 1
- 239000002253 acid Substances 0.000 abstract 1
- 239000003814 drug Substances 0.000 abstract 1
- DZGCGKFAPXFTNM-UHFFFAOYSA-N ethanol;hydron;chloride Chemical compound Cl.CCO DZGCGKFAPXFTNM-UHFFFAOYSA-N 0.000 abstract 1
- KIWBRXCOTCXSSZ-UHFFFAOYSA-N hexyl carbonochloridate Chemical compound CCCCCCOC(Cl)=O KIWBRXCOTCXSSZ-UHFFFAOYSA-N 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- 239000000047 product Substances 0.000 description 15
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 12
- 238000004821 distillation Methods 0.000 description 11
- 239000012535 impurity Substances 0.000 description 11
- 239000000706 filtrate Substances 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 235000015320 potassium carbonate Nutrition 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 description 6
- 229910017053 inorganic salt Inorganic materials 0.000 description 5
- 238000009833 condensation Methods 0.000 description 3
- 230000005494 condensation Effects 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 239000000126 substance 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
- 208000007536 Thrombosis Diseases 0.000 description 2
- 239000003146 anticoagulant agent Substances 0.000 description 2
- 230000010100 anticoagulation Effects 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- QQVIHTHCMHWDBS-UHFFFAOYSA-N perisophthalic acid Natural products OC(=O)C1=CC=CC(C(O)=O)=C1 QQVIHTHCMHWDBS-UHFFFAOYSA-N 0.000 description 2
- 238000004064 recycling Methods 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 description 1
- 0 CCCCCCOC(*=C(*)C1C=CC(NCc2nc(cc(cc3)C(N(CCC(OCC)=*)C4=CC=CCN4)=O)c3[n]2C)=CC1)=O Chemical compound CCCCCCOC(*=C(*)C1C=CC(NCc2nc(cc(cc3)C(N(CCC(OCC)=*)C4=CC=CCN4)=O)c3[n]2C)=CC1)=O 0.000 description 1
- LNINMNIZDFTMTJ-UHFFFAOYSA-N CCCCCCOC(/N=C(\c(cc1)ccc1NCc1nc2cc(C(N(CCC(OCC)=O)C3=CC=CCN3)O)ccc2[n]1C)/N)=[O-] Chemical compound CCCCCCOC(/N=C(\c(cc1)ccc1NCc1nc2cc(C(N(CCC(OCC)=O)C3=CC=CCN3)O)ccc2[n]1C)/N)=[O-] LNINMNIZDFTMTJ-UHFFFAOYSA-N 0.000 description 1
- 108010049003 Fibrinogen Proteins 0.000 description 1
- 102000008946 Fibrinogen Human genes 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 101000712605 Theromyzon tessulatum Theromin Proteins 0.000 description 1
- 229940122388 Thrombin inhibitor Drugs 0.000 description 1
- ODFJOVXVLFUVNQ-UHFFFAOYSA-N acetarsol Chemical compound CC(=O)NC1=CC([As](O)(O)=O)=CC=C1O ODFJOVXVLFUVNQ-UHFFFAOYSA-N 0.000 description 1
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229940012952 fibrinogen Drugs 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 231100000225 lethality Toxicity 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 235000007715 potassium iodide Nutrition 0.000 description 1
- 229960004839 potassium iodide 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
- YYFIGOPUHPDIBO-UHFFFAOYSA-N propanoic acid;hydrochloride Chemical compound Cl.CCC(O)=O YYFIGOPUHPDIBO-UHFFFAOYSA-N 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000003868 thrombin inhibitor Substances 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
Abstract
The invention discloses a preparation method of dabigatran etexilate mesylate, and belongs to the technical field of medicine. The preparation method comprises the following steps: taking 3-[(3-amino-4-methylaminobenzoyl)pyridine-2-ylamino]ethyl propanoate and N-(4-cyanphenyl)amino acetic acid as the raw materials to synthesize an intermediate (S3); making the intermediate (S3) carry out ring-closure reactions to generate an intermediate (S4); subjecting the intermediate (S4) to acid splitting in the presence of a hydrogen chloride-ethanol solution at first, then carrying out ammonification in the presence of ammonia water to generate an intermediate (S5); carrying out reactions between the intermediate (S5) and n-hexyl chloroformate under an alkaline condition to generate an intermediate (S6); dissolving the intermediate (S6), and finally carrying out reactions between the intermediate (S6) and methylsulfonic acid to obtain dabigatran etexilate mesylate. The preparation method has the advantages of simpleness, controllable and mild conditions, high yield, high product purity, stable product property, and suitability for industrial production.
Description
Technical field
The present invention relates to a kind of preparation method of dabigatran etcxilate mesylate, belong to medical art.
Background technology
Dabigatran etcxilate is the prodrug of dabigatran, it is the oral thrombin inhibitor developed by German Boehringer Ingelheim drugmaker, in March, 2008 is granted in Europe, this is the five first new classification oral anticoagulant things gone on the market during the last ten years after warfarin, be a major progress in anticoagulation therapy field and potential lethality thrombus prevention field, there is milestone significance.
Dabigatran etcxilate is converted into the dabigatran with direct anticoagulant active in vivo, dabigatran is incorporated into the scleroproein specific binding site of zymoplasm, Fibrinogen is stoped to be cracked into scleroproein, thus blocked final step and the thrombosis of blood coagulation network, dabigatran can dissociate from scleroproein-zymoplasm combination, plays reversible anticoagulation.
The synthetic route of dabigatran etcxilate of patent EP0966454 report is as follows: with 3-[(3-amino-4-methylamino benzoyl) pyridine-2-base is amino] ethyl propionate and N-(4-cyano-phenyl)-Padil for starting raw material, obtain dabigatran etcxilate through condensation, acidolysis ammonification, substitution reaction.This route is workable, and starting material used is easy to get, but yield is lower, and each intermediate is difficult to carry out refining purification, have impact on the quality of the finished product.
Patent WO2007071742 reports another synthetic route: with 3-[(3-amino-4-methylamino benzoyl) pyridine-2-base is amino] ethyl propionate and 2-[4-(1,2,4-oxazolidinyl-5-oxygen-3-base) phenyl amino] acetic acid is starting raw material, obtains dabigatran etcxilate through condensation, hydro-reduction, replacement.This route needs to use palladium carbon and hydrogen to carry out reduction reaction, and cost is higher, have hidden danger, and palladium carbon not easily reclaims, and is not suitable for industrialization in security simultaneously.
Patent US2011275824 for starting raw material, is obtained by reacting dabigatran etcxilate through a few steps such as replacement, cyclization, condensations with 3-[(3-amino-4-methylamino benzoyl) pyridine-2-base amino] ethyl propionate and sym-dichloroacetic anhydride.
This route synthetic route used is shorter, and yield is also more satisfactory, but employs sym-dichloroacetic anhydride, and corrodibility and toxicity are comparatively large, and used potassiumiodide, tetrabutylammonium iodide, cost is higher simultaneously, is not suitable for industrial production and uses.
Summary of the invention
The present invention is directed to the deficiency that existing dabigatran etcxilate synthesis technique carries out, a kind of preparation method of dabigatran etcxilate is provided.This technique has easy and simple to handle, the advantage such as productive rate is higher, cost is low, product purity is high, good stability, is suitable for large-scale industrial production.
The object of the present invention is to provide a kind of preparation method of dabigatran etcxilate mesylate, the method comprises the steps:
(1) with 3-[(3-amino-4-methylamino benzoyl) pyridine-2-base amino] ethyl propionate (S1) and N-(4-cyano-phenyl) Padil (S2) for starting raw material raw material, react under the effect of condensing agent, obtain intermediate S3, react as follows:
(2) intermediate S3 is dissolved in reaction solvent, under the effect of Glacial acetic acid, obtain S4 crude product through ring-closure reaction, then to its carry out refining after obtain intermediate S4, react as follows:
(3) intermediate S4 carries out acidolysis in ethanol solution of hydrogen chloride, then under the effect of ammoniacal liquor, generates S5 crude product through aminating reaction, then obtains intermediate S5 through recrystallization, react as follows:
(4) intermediate S5 is dissolved in reaction solvent, and just own ester is obtained by reacting S6 crude product with chloroformic acid in the basic conditions, then to its carry out refining after obtain intermediate S6;
(5) intermediate S6 carries out reaction with methylsulfonic acid in acetone and generates dabigatran etcxilate mesylate.
Preferably, described method, comprises the steps:
1) be that starting raw material reacts under the effect of condensing agent with 3-[(3-amino-4-methylamino benzoyl) pyridine-2-base amino] ethyl propionate and N-(4-cyano-phenyl) Padil, obtain intermediate S3;
2) intermediate S3 is dissolved in reaction solvent, under the effect of Glacial acetic acid, obtains S4 crude product through ring-closure reaction, then obtain intermediate S4 through refining;
3) intermediate S4 carries out acidolysis in ethanol solution of hydrogen chloride, then under the effect of ammoniacal liquor, generates intermediate S5 crude product through aminating reaction, then obtains intermediate S5 through recrystallization;
4) intermediate S5 is dissolved in reaction solvent, just own ester is obtained by reacting intermediate S6 crude product with chloroformic acid in the basic conditions, tetrahydrofuran (THF) is added in intermediate S6 crude product, be warming up to 40 ~ 45 DEG C of stirring and dissolving, drip 38 DEG C ~ 40 DEG C purified water extremely wherein, be cooled to 0 DEG C ~ 5 DEG C stirring and crystallizing subsequently, after filtration, obtain intermediate S6;
5) intermediate S6 carries out reaction with methylsulfonic acid in acetone and generates dabigatran etcxilate mesylate.
Preferably, step 1) mol ratio of described 3-[(3-amino-4-methylamino benzoyl) pyridine-2-base amino] ethyl propionate, N-(4-cyano-phenyl) Padil and condensing agent is S1:S2: condensing agent=1:1.1:1.3.
Preferably, described method, comprises the steps:
1) be that starting raw material reacts under the effect of condensing agent with 3-[(3-amino-4-methylamino benzoyl) pyridine-2-base amino] ethyl propionate and N-(4-cyano-phenyl) Padil, obtain intermediate S3; The mol ratio of described 3-[(3-amino-4-methylamino benzoyl) pyridine-2-base is amino] ethyl propionate, N-(4-cyano-phenyl) Padil and condensing agent is 1:1.1:1.3;
2) intermediate S3 is dissolved in reaction solvent, under the effect of Glacial acetic acid, obtains S4 crude product through ring-closure reaction, then obtain intermediate S4 through refining;
3) intermediate S4 carries out acidolysis in ethanol solution of hydrogen chloride, then under the effect of ammoniacal liquor, intermediate S5 crude product is generated through aminating reaction, solvent is added in intermediate S5 crude product, be heated to 70 ~ 75 DEG C, be stirred to whole dissolving, be cooled to 0 DEG C ~ 5 DEG C stirring and crystallizing subsequently gradually, filter and obtain intermediate S5;
4) intermediate S5 is dissolved in reaction solvent, just own ester is obtained by reacting intermediate S6 crude product with chloroformic acid in the basic conditions, tetrahydrofuran (THF) is added in intermediate S6 crude product, be warming up to 40 ~ 45 DEG C of stirring and dissolving, drip 38 DEG C ~ 40 DEG C purified water extremely wherein, be cooled to 0 DEG C ~ 5 DEG C stirring and crystallizing subsequently, after filtration, obtain intermediate S6;
5) intermediate S6 carries out reaction with methylsulfonic acid in acetone and generates dabigatran etcxilate mesylate.
Preferably, step 1) described condensing agent, be selected from the one in dicyclohexylcarbodiimide and N, N-carbonyl dimidazoles.
Preferably, step 2) described reaction solvent is selected from one in ethyl acetate, n-butyl acetate, isobutyl acetate, is more preferably n-butyl acetate.
Preferably, step 2) described refining, one or more the mixture in the solvent selected from methanol of employing, ethanol, Virahol, be more preferably ethanol and methanol mixed solvent that volume ratio is 5:1, time refining, recrystallization temperature is 0 DEG C ~ 10 DEG C.
Preferably, step 3) described ethanol solution of hydrogen chloride concentration is 32% ~ 37%; Be more preferably 35% ~ 37%.
Preferably, step 3) described solvent, be one or more mixed solvents in water, acetonitrile and tetrahydrofuran (THF), be more preferably water, acetonitrile, tetrahydrofuran (THF) mixed solvent that volume ratio is 2:1:1.
Preferably, step 4) described reaction solvent is selected from the mixture of any one and equal-volume water in tetrahydrofuran (THF), acetone, acetonitrile; Be more preferably tetrahydrofuran (THF), water mixed solvent that volume ratio is 1:1; Step 4) described crystallization, the time is 2h.
Preferably, step 5) mol ratio of described intermediate S6 and methylsulfonic acid is 1:0.95-1:0.98, is more preferably 1:0.96.
Preferably, step 5) described reaction, temperature is 30 DEG C ~ 35 DEG C.
More preferably, described method, comprises the steps:
1) be that starting raw material is at dicyclohexylcarbodiimide or N with 3-[(3-amino-4-methylamino benzoyl) pyridine-2-base amino] ethyl propionate and N-(4-cyano-phenyl) Padil, react under the effect of N-carbonyl dimidazoles, obtain intermediate S3; Described 3-[(3-amino-4-methylamino benzoyl) pyridine-2-base is amino] ethyl propionate, N-(4-cyano-phenyl) Padil and condensing agent mol ratio are followed successively by 1:1.1:1.3;
2) intermediate S3 is dissolved in n-butyl acetate, S4 crude product is obtained through ring-closure reaction under the effect of Glacial acetic acid, the ethanol that volume ratio is 5:1 and methanol mixed solvent is added in S4 crude product, slow cooling to 0 DEG C after heated and stirred ~ 10 DEG C of stirring and crystallizing, filter, vacuum-drying obtain intermediate S4;
3) in 36% ethanol solution of hydrogen chloride, add intermediate S4 and carry out acidolysis, then under the effect of ammoniacal liquor, S5 crude product is generated through aminating reaction, the mixed solvent of purified water that volume ratio is 2:1:1, acetonitrile, tetrahydrofuran (THF) is added in S5 crude product, be heated to 70 ~ 75 DEG C, be stirred to whole dissolving, be cooled to 0 ~ 5 DEG C of stirring subsequently, filter, vacuum-drying obtains intermediate S5;
4) intermediate S5 is dissolved in the mixing solutions of isopyknic tetrahydrofuran (THF) and purified water, just own ester is obtained by reacting intermediate S6 crude product with chloroformic acid in the basic conditions, tetrahydrofuran (THF) is added in intermediate S6 crude product, be warming up to 40 ~ 45 DEG C of stirring and dissolving, drip 38 DEG C ~ 40 DEG C purified water extremely wherein, be cooled to 0 DEG C ~ 5 DEG C stirring and crystallizing subsequently, after filtration, obtain intermediate S6;
5) intermediate S6 is dissolved, be then that 1:0.96 drips methylsulfonic acid according to the mol ratio of intermediate S6 and methylsulfonic acid at 30 ~ 35 DEG C, keep thermotonus, obtain dabigatran etcxilate mesylate.
Most preferably, described method, concrete steps are as follows:
1) condensing agent is dissolved, add N-(4-cyano-phenyl)-Padil, add 3-[(3-amino-4-methylamino benzoyl) pyridine-2-base is amino] ethyl propionate after stirring, through concentrating under reduced pressure and vacuum-drying after reaction, obtain intermediate S3; Described condensing agent is dicyclohexylcarbodiimide or N, N-carbonyl dimidazoles; Described 3-[(3-amino-4-methylamino benzoyl) pyridine-2-base is amino] ethyl propionate, N-(4-cyano-phenyl) Padil and condensing agent mol ratio are followed successively by 1:1.1:1.3;
2) in intermediate S3, n-butyl acetate and Glacial acetic acid is added, underpressure distillation after temperature reaction, be down to room temperature and add methylene dichloride, and then add sodium carbonate solution, separate dichloromethane layer, wash, be evaporated to thickness, then add ethanol, the methanol mixed solvent that volume ratio is 5:1, slow cooling to 0 DEG C after heated and stirred ~ 10 DEG C of stirring and crystallizing, filter, vacuum-drying obtain intermediate S4;
3) in 36% ethanol solution of hydrogen chloride, add intermediate S4, reacted rear cooling, drip ammoniacal liquor and be warming up to 15 ~ 20 DEG C, stirring reaction 3 ~ 4 hours, filter in backward filtrate and add ethyl acetate, slow cooling stirs, and filters to obtain intermediate S5 crude product, the mixed solvent of purified water that volume ratio is 2:1:1, acetonitrile, tetrahydrofuran (THF) is added in crude product, be heated to 70 ~ 75 DEG C, be stirred to whole dissolving, be cooled to 0 ~ 5 DEG C subsequently and stir 2 hours, filter, vacuum-drying obtains intermediate S5;
4) intermediate S5 is added in the mixing solutions of isopyknic tetrahydrofuran (THF) and purified water, be cooled to 0 ~ 5 DEG C and add salt of wormwood, after stirring, just own for chloroformic acid ester is dropped in reaction solution, keep 0 DEG C ~ 5 DEG C to react 1 ~ 2 hour, filter to obtain intermediate S6 crude product, then crude product is added in tetrahydrofuran (THF), be warming up to 40 ~ 45 DEG C of stirring and dissolving and drip 38 DEG C ~ 40 DEG C purified water in reaction solution, slow cooling to 0 ~ 5 DEG C subsequently, stirring and crystallizing, filtration, vacuum-drying obtain intermediate S6;
5) dissolved by intermediate S6, be then that 1:0.96 drips methylsulfonic acid according to the mol ratio of intermediate S6 and methylsulfonic acid at 30 ~ 35 DEG C, keep thermotonus 2 hours, filter, vacuum-drying obtains dabigatran etcxilate mesylate.The above either method is preparing the application in dabigatran etcxilate mesylate.
In this patent, intermediate S3 is 3 [3-[2-(4-cyano-phenyl) kharophen]-4-(methylamino)-N-(pyridine-2-base) benzoyl] ethyl propionate, and structural formula is such as formula (1):
Intermediate S4 is 3-[[[2-[[(4-cyano-phenyl) is amino] methyl]-1-methyl isophthalic acid H-benzoglyoxaline-5-base] carbonyl] (pyridine-2-base) is amino] ethyl propionate, and structural formula is such as formula (2):
Intermediate S5 is 3-[[[2-[[[4-(amino formamino) phenyl] is amino] methyl]-1-methyl isophthalic acid H-benzoglyoxaline-5-base] carbonyl] (pyridine-2-base) is amino] propionate hydrochloride, and structural formula is such as formula (3):
Intermediate S6 is dabigatran etcxilate, and structural formula is such as formula (4):
Dabigatran etcxilate mesylate structural formula structural formula is such as formula (5):
Beneficial effect of the present invention:
The present invention passes through technical optimization, provide a kind of easy and simple to handle, reaction conditions is gentle, selectivity is high, cost is low, be suitable for the preparation method of the dabigatran etcxilate mesylate of suitability for industrialized production, its advantage is mainly reflected in: the purification process 1) in the present invention, 0.1% can be not more than by the list effectively controlled in product content of mixing, total mixing is not more than 0.5%, the dabigatran etcxilate Mesylate Form obtained is single-minded, improves quality and the security of product, can meet pharmacy demand; 2) total molar yield of the present invention can reach more than 45%, and the organic solvent used in technique all can recycling use, greatly reduces production cost.
Embodiment
Below in conjunction with specific embodiment, the present invention will be further described, but the present invention is not by the restriction of embodiment.
Embodiment 1:
Present embodiments provide a kind of preparation method of dabigatran etcxilate mesylate, be prepared in accordance with the following steps:
1, intermediate S3 is prepared
Get N, N'-carbonyl dimidazoles 0.38kg (2.3mol) is added in 4.5L tetrahydrofuran (THF), stirred at ambient temperature adds N-(4-cyano-phenyl)-Padil 0.36kg (2mol), stir 30 minutes, add 3-[(3-amino-4-methylamino benzoyl) pyridine-2-base is amino] ethyl propionate 0.62kg (1.8mol) again, and keep room temperature reaction 10 ~ 12 hours.Add 0.05kg purified water, stir 10 minutes, concentrating under reduced pressure at 30 ~ 60 DEG C, vacuum-drying obtains intermediate (S3) 0.85kg, productive rate 93.8%.
2, intermediate S4 is prepared
Intermediate (S3) 0.80kg (1.6mol) step 1 obtained adds 2.5kg n-butyl acetate and 0.3kg Glacial acetic acid, is warming up to 85 ~ 90 DEG C of reactions 3 ~ 4 hours.Underpressure distillation removing n-butyl acetate and Glacial acetic acid at 60 ~ 80 DEG C subsequently.Be down to room temperature after distillation, add 30L methylene dichloride, after stirring and dissolving, add 5% aqueous sodium carbonate 10kg, stir 10 minutes, separate dichloromethane layer, and wash twice with 5L.Be evaporated to thickness at 20 ~ 50 DEG C, add ethanol, methanol mixed solvent that 2L volume ratio is 5:1, be heated to 40 ~ 45 DEG C, stir 30 minutes, then 2 hours crystallizatioies are stirred in slow cooling to 0 ~ 10 DEG C, filter, vacuum-drying obtains intermediate (S4) 0.70kg, productive rate 90.8%.
3, intermediate S5 is prepared
By 2kg concentration be 36% ethanol solution of hydrogen chloride stir be cooled to 10 ~ 15 DEG C, add 0.67kg (1.4mol) intermediate S4, be stirred to whole dissolving.Be warming up to 20 ~ 25 DEG C of reactions 16 ~ 20 hours.Be cooled to 0 ~ 10 DEG C subsequently, drip 1.6kg ammoniacal liquor.Dropwise and be warming up to 15 ~ 20 DEG C, stirring reaction 3 ~ 4 hours.Cross and filter inorganic salt, add 10L ethyl acetate in filtrate, slow cooling to 0 ~ 5 DEG C, stir 2 ~ 3h.Filter, obtain intermediate S5 crude product.Crude product is added in the mixed solvent of purified water that 4L volume ratio is 2:1:1, acetonitrile, tetrahydrofuran (THF), is warming up to 70 ~ 75 DEG C, stir and product is all dissolved, naturally be down to room temperature, be cooled to 0 ~ 5 DEG C of stirring 2 hours subsequently.Filter, vacuum-drying obtains intermediate (S5) 0.61kg, productive rate 81.9%.
4, intermediate S6 is prepared
Intermediate (S5) 0.27kg (0.5mol) being added to 4L volume ratio is that in the water of 1:1 and the mixed solvent of tetrahydrofuran (THF), stirring and dissolving, is cooled to 0 ~ 5 DEG C, adds 0.21kg (1.5mol) salt of wormwood, stirs 0.5 hour.Subsequently just own for chloroformic acid ester 0.10kg (0.6mol) is dropped in reaction solution, keep 0 ~ 5 DEG C to react 1 ~ 2 hour.Filter, obtain intermediate S6 crude product.Crude product is added in 1.5L tetrahydrofuran (THF), be warming up to 40 ~ 45 DEG C, stirring and dissolving.3L is preheated to the purified water of 38 ~ 40 DEG C, drops in reaction solution, stir, slow cooling to 0 ~ 5 DEG C subsequently, stirring and crystallizing 2 hours.Filter, vacuum-drying obtains intermediate (S6) 0.22kg, productive rate 69.6%, maximum single impurity 0.08%, purity 99.73%.
5, dabigatran etcxilate mesylate is prepared
Be added in 2.5L acetone by intermediate (S6) 0.19kg (0.3mol) obtained for above-mentioned steps 4, stirred at ambient temperature dissolves.Methylsulfonic acid 27.8g (0.29mol) is added in 0.3L acetone, stirring and dissolving, drops in reaction solution at 30 ~ 35 DEG C.After dropwising, keep thermotonus 2 hours.Filter, vacuum-drying obtains dabigatran etcxilate mesylate 0.20kg, productive rate 91.3%, maximum single impurity 0.08%, purity 99.79%.
Embodiment 2
Present embodiments provide a kind of preparation method of dabigatran etcxilate mesylate, be prepared in accordance with the following steps:
1, intermediate S3 is prepared
Get N, N'-carbonyl dimidazoles 0.38kg (2.3mol) is added in 4.5L tetrahydrofuran (THF), stirred at ambient temperature adds N-(4-cyano-phenyl)-Padil 0.36kg (2mol), stir 30 minutes, add 3-[(3-amino-4-methylamino benzoyl) pyridine-2-base is amino] ethyl propionate 0.62kg (1.8mol) again, and keep room temperature reaction 10 ~ 12 hours.Add 0.05kg purified water, stir 10 minutes, concentrating under reduced pressure at 30 ~ 60 DEG C, vacuum-drying obtains intermediate (S3) 0.83kg, productive rate 91.6%.
2, intermediate S4 is prepared
Intermediate (S3) 0.80kg (1.6mol) step 1 obtained adds 2.5kg n-butyl acetate and 0.3kg Glacial acetic acid, is warming up to 85 ~ 90 DEG C of reactions 3 ~ 4 hours.Underpressure distillation removing n-butyl acetate and Glacial acetic acid at 60 ~ 80 DEG C subsequently.Be down to room temperature after distillation, add 30L methylene dichloride, after stirring and dissolving, add 5% aqueous sodium carbonate 10kg, stir 10 minutes, separate dichloromethane layer, and wash twice with 5L.Be evaporated to thickness at 20 ~ 50 DEG C, add ethanol, methanol mixed solvent that 2L volume ratio is 5:1, be heated to 40 ~ 45 DEG C, stir 30 minutes, then 2 hours crystallizatioies are stirred in slow cooling to 0 ~ 10 DEG C, filter, vacuum-drying obtains intermediate (S4) 0.70kg, productive rate 90.8%.
3, intermediate S5 is prepared
By 2kg concentration be 36% ethanol solution of hydrogen chloride stir be cooled to 10 ~ 15 DEG C, add 0.67kg (1.4mol) intermediate S4, be stirred to whole dissolving.Be warming up to 20 ~ 25 DEG C of reactions 16 ~ 20 hours.Be cooled to 0 ~ 10 DEG C subsequently, drip 1.6kg ammoniacal liquor.Dropwise and be warming up to 15 ~ 20 DEG C, stirring reaction 3 ~ 4 hours.Cross and filter inorganic salt, add 10L ethyl acetate in filtrate, slow cooling to 0 ~ 5 DEG C, stir 2 ~ 3h.Filter, obtain intermediate S5 crude product.Crude product is added in the mixed solvent of purified water that 4L volume ratio is 1:1, acetonitrile, is warming up to 70 ~ 75 DEG C, stir and product is all dissolved, naturally be down to room temperature, be cooled to 0 ~ 5 DEG C of stirring 2 hours subsequently.Filter, vacuum-drying obtains intermediate (S5) 0.59kg, productive rate 79.3%.
4, intermediate S6 is prepared
Intermediate (S5) 0.27kg (0.5mol) is added to 4L volume ratio be in the water of 1:1 and the mixed solvent of tetrahydrofuran (THF) in, stirring and dissolving, be cooled to 0 ~ 5 DEG C, add 0.21kg (1.5mol) salt of wormwood, stir 0.5 hour.Subsequently just own for chloroformic acid ester 0.10kg (0.6mol) is dropped in reaction solution, keep 0 ~ 5 DEG C to react 1 ~ 2 hour.Filter, obtain intermediate S6 crude product.Crude product is added in 1.5L tetrahydrofuran (THF), be warming up to 40 ~ 45 DEG C, stirring and dissolving.4.5L is preheated to the purified water of 38 ~ 40 DEG C, drops in reaction solution, stir, slow cooling to 0 ~ 5 DEG C subsequently, stirring and crystallizing 2 hours.Filter, vacuum-drying obtains intermediate (S6) 0.23kg, productive rate 72.7%, maximum single impurity 0.10%, purity 99.70%.
5, dabigatran etcxilate mesylate is prepared
Be added in 2.5L acetone by intermediate (S6) 0.19kg (0.3mol) obtained for above-mentioned steps 4, stirred at ambient temperature dissolves.Methylsulfonic acid 27.8g (0.29mol) is added in 0.3L acetone, stirring and dissolving, drops in reaction solution at 30 ~ 35 DEG C.After dropwising, keep thermotonus 2 hours.Filter, vacuum-drying obtains dabigatran etcxilate mesylate 0.20kg, productive rate 91.3%, maximum single impurity 0.10%, purity 99.74%.
Embodiment 3
Present embodiments provide a kind of preparation method of dabigatran etcxilate mesylate, be prepared in accordance with the following steps:
1, intermediate S3 is prepared
Getting dicyclohexylcarbodiimide 0.47kg (2.3mol) is added in 4.5L tetrahydrofuran (THF), stirred at ambient temperature adds N-(4-cyano-phenyl)-Padil 0.36kg (2mol), stir 30 minutes, add 3-[(3-amino-4-methylamino benzoyl) pyridine-2-base is amino] ethyl propionate 0.62kg (1.8mol) again, and keep room temperature reaction 10 ~ 12 hours.Add 0.05kg purified water, stir 10 minutes, concentrating under reduced pressure at 30 ~ 60 DEG C, vacuum-drying obtains intermediate (S3) 0.81kg, productive rate 89.4%.
2, intermediate S4 is prepared
Intermediate (S3) 0.75kg (1.5mol) step 1 obtained adds 2.5kg ethyl acetate and 0.3kg Glacial acetic acid, is warming up to back flow reaction 5 ~ 6 hours.Subsequently at underpressure distillation removing ethyl acetate and Glacial acetic acid.Be down to room temperature after distillation, add 30L methylene dichloride, after stirring and dissolving, add 5% aqueous sodium carbonate 10kg, stir 10 minutes, separate dichloromethane layer, and wash twice with 5L.Be evaporated to thickness at 20 ~ 50 DEG C, add 2L ethanol, be heated to 40 ~ 45 DEG C, stir 30 minutes, then 2 hours crystallizatioies are stirred in slow cooling to 0 ~ 10 DEG C, and filter, vacuum-drying obtains intermediate (S4) 0.63kg, productive rate 87.1%.
3, intermediate S5 is prepared
By 2kg concentration be 32% ethanol solution of hydrogen chloride stir be cooled to 10 ~ 15 DEG C, add 0.59kg (1.2mol) intermediate S4, be stirred to whole dissolving.Be warming up to 20 ~ 25 DEG C of reactions 16 ~ 20 hours.Be cooled to 0 ~ 10 DEG C subsequently, drip 1.5kg ammoniacal liquor.Dropwise and be warming up to 15 ~ 20 DEG C, stirring reaction 3 ~ 4 hours.Cross and filter inorganic salt, add 10L ethyl acetate in filtrate, slow cooling to 0 ~ 5 DEG C, stir 2 ~ 3h.Filter, obtain intermediate S5 crude product.Crude product is added in the mixed solvent of purified water that 4L volume ratio is 1:1, tetrahydrofuran (THF), is warming up to 70 ~ 75 DEG C, stir and product is all dissolved, naturally be down to room temperature, be cooled to 0 ~ 5 DEG C of stirring 2 hours subsequently.Filter, vacuum-drying obtains intermediate (S5) 0.51kg, productive rate 77.8%.
4, intermediate S6 is prepared
Intermediate (S5) 0.27kg (0.5mol) being added to 4L volume ratio is that in the water of 1:1 and the mixed solvent of acetone, stirring and dissolving, is cooled to 0 ~ 5 DEG C, adds 0.21kg (1.5mol) salt of wormwood, stirs 0.5 hour.Subsequently just own for chloroformic acid ester 0.10kg (0.6mol) is dropped in reaction solution, keep 0 ~ 5 DEG C to react 1 ~ 2 hour.Filter, obtain intermediate S6 crude product.Crude product is added in 1.5L tetrahydrofuran (THF), be warming up to 40 ~ 45 DEG C, stirring and dissolving.3L is preheated to the purified water of 38 ~ 40 DEG C, drops in reaction solution, stir, slow cooling to 0 ~ 5 DEG C subsequently, stirring and crystallizing 2 hours.Filter, vacuum-drying obtains intermediate (S6) 0.21kg, productive rate 66.5%, maximum single impurity 0.08%, purity 99.65%.
5, dabigatran etcxilate mesylate is prepared
Be added in 2.5L acetone by intermediate (S6) 0.19kg (0.3mol) obtained for above-mentioned steps 4, stirred at ambient temperature dissolves.Methylsulfonic acid 27.3g (0.28mol) is added in 0.3L acetone, stirring and dissolving, drops in reaction solution at 30 ~ 35 DEG C.After dropwising, keep thermotonus 2 hours.Filter, vacuum-drying obtains dabigatran etcxilate mesylate 0.20kg, productive rate 91.3%, maximum single impurity 0.07%, purity 99.69%.
Embodiment 4
Present embodiments provide a kind of preparation method of dabigatran etcxilate mesylate, be prepared in accordance with the following steps:
1, intermediate S3 is prepared
Get N, N-carbonyl dimidazoles 0.38kg (2.3mol) is added in 4.5L tetrahydrofuran (THF), stirred at ambient temperature adds N-(4-cyano-phenyl)-Padil 0.36kg (2mol), stir 30 minutes, add 3-[(3-amino-4-methylamino benzoyl) pyridine-2-base is amino] ethyl propionate 0.62kg (1.8mol) again, and keep room temperature reaction 10 ~ 12 hours.Add 0.05kg purified water, stir 10 minutes, concentrating under reduced pressure at 30 ~ 60 DEG C, vacuum-drying obtains intermediate (S3) 0.83kg, productive rate 91.6%.
2, intermediate S4 is prepared
Intermediate (S3) 0.80kg (1.6mol) step 1 obtained adds 2.5kg isobutyl acetate and 0.3kg Glacial acetic acid, is warming up to 85 ~ 90 DEG C of reactions 3 ~ 4 hours.Underpressure distillation removing isobutyl acetate and Glacial acetic acid at 60 ~ 80 DEG C subsequently.Be down to room temperature after distillation, add 30L methylene dichloride, after stirring and dissolving, add 5% aqueous sodium carbonate 10kg, stir 10 minutes, separate dichloromethane layer, and wash twice with 5L.Thickness is evaporated at 20 ~ 50 DEG C, add methyl alcohol, isopropyl alcohol mixed solvent that 2L volume ratio is 8:1, be heated to 40 ~ 45 DEG C, stir 30 minutes, then 2 hours crystallizatioies are stirred in slow cooling to 0 ~ 10 DEG C, filter, vacuum-drying obtains intermediate (S4) 91.6kg, productive rate 88.2%.
3, intermediate S5 is prepared
By 2kg concentration be 37% ethanol solution of hydrogen chloride stir be cooled to 10 ~ 15 DEG C, add 0.59kg (1.2mol) intermediate S4, be stirred to whole dissolving.Be warming up to 20 ~ 25 DEG C of reactions 16 ~ 20 hours.Be cooled to 0 ~ 10 DEG C subsequently, drip 1.5kg ammoniacal liquor.Dropwise and be warming up to 15 ~ 20 DEG C, stirring reaction 3 ~ 4 hours.Cross and filter inorganic salt, add 10L ethyl acetate in filtrate, slow cooling to 0 ~ 5 DEG C, stir 2 ~ 3h.Filter, obtain intermediate S5 crude product.Crude product is added in the mixed solvent of purified water that 4L volume ratio is 1:1:1, acetonitrile, tetrahydrofuran (THF), is warming up to 70 ~ 75 DEG C, stir and product is all dissolved, naturally be down to room temperature, be cooled to 0 ~ 5 DEG C of stirring 2 hours subsequently.Filter, vacuum-drying obtains intermediate (S5) 0.53kg, productive rate 80.9%.
4, intermediate S6 is prepared
Intermediate (S5) 0.27kg (0.5mol) being added to 4L volume ratio is that in the water of 1:1 and the mixed solvent of acetonitrile, stirring and dissolving, is cooled to 0 ~ 5 DEG C, adds 0.21kg (1.5mol) salt of wormwood, stirs 0.5 hour.Subsequently just own for chloroformic acid ester 0.10kg (0.6mol) is dropped in reaction solution, keep 0 ~ 5 DEG C to react 1 ~ 2 hour.Filter, obtain intermediate S6 crude product.Crude product is added in 1.5L tetrahydrofuran (THF), be warming up to 40 ~ 45 DEG C, stirring and dissolving.3L is preheated to the purified water of 38 ~ 40 DEG C, drops in reaction solution, stir, slow cooling to 0 ~ 5 DEG C subsequently, stirring and crystallizing 2 hours.Filter, vacuum-drying obtains intermediate (S6) 0.21kg, productive rate 66.5%, maximum single impurity 0.08%, purity 99.60%.
5, dabigatran etcxilate mesylate is prepared
Be added in 2.5L acetone by intermediate (S6) 0.19kg (0.3mol) obtained for above-mentioned steps 4, stirred at ambient temperature dissolves.Methylsulfonic acid 28.5g (0.29mol) is added in 0.3L acetone, stirring and dissolving, drops in reaction solution at 30 ~ 35 DEG C.After dropwising, keep thermotonus 2 hours.Filter, vacuum-drying obtains dabigatran etcxilate mesylate 0.19kg, productive rate 86.8%, maximum single impurity 0.08%, purity 99.62%.
Embodiment 5
Present embodiments provide a kind of preparation method of dabigatran etcxilate mesylate, be prepared in accordance with the following steps:
1, intermediate S3 is prepared
Getting dicyclohexylcarbodiimide 0.47kg (2.3mol) is added in 4.5L tetrahydrofuran (THF), stirred at ambient temperature adds N-(4-cyano-phenyl)-Padil 0.36kg (2mol), stir 30 minutes, add 3-[(3-amino-4-methylamino benzoyl) pyridine-2-base is amino] ethyl propionate 0.62kg (1.8mol) again, and keep room temperature reaction 10 ~ 12 hours.Add 0.05kg purified water, stir 10 minutes, concentrating under reduced pressure at 30 ~ 60 DEG C, vacuum-drying obtains intermediate (S3) 0.80kg, productive rate 88.3%.
2, intermediate S4 is prepared
Intermediate (S3) 0.75kg (1.5mol) step 1 obtained adds 2.5kg n-butyl acetate and 0.3kg Glacial acetic acid, is warming up to 85 ~ 90 DEG C of reactions 3 ~ 4 hours.Underpressure distillation removing n-butyl acetate and Glacial acetic acid at 60 ~ 80 DEG C subsequently.Be down to room temperature after distillation, add 30L methylene dichloride, after stirring and dissolving, add 5% aqueous sodium carbonate 10kg, stir 10 minutes, separate dichloromethane layer, and wash twice with 5L.Be evaporated to thickness at 20 ~ 50 DEG C, add ethanol, methanol mixed solvent that 2L volume ratio is 2:1, be heated to 40 ~ 45 DEG C, stir 30 minutes, then 2 hours crystallizatioies are stirred in slow cooling to 0 ~ 10 DEG C, filter, vacuum-drying obtains intermediate (S4) 0.65kg, productive rate 89.9%.
3, intermediate S5 is prepared
By 2kg concentration be 35% ethanol solution of hydrogen chloride stir be cooled to 10 ~ 15 DEG C, add 0.59kg (1.2mol) intermediate S4, be stirred to whole dissolving.Be warming up to 20 ~ 25 DEG C of reactions 16 ~ 20 hours.Be cooled to 0 ~ 10 DEG C subsequently, drip 1.5kg ammoniacal liquor.Dropwise and be warming up to 15 ~ 20 DEG C, stirring reaction 3 ~ 4 hours.Cross and filter inorganic salt, add 10L ethyl acetate in filtrate, slow cooling to 0 ~ 5 DEG C, stir 2 ~ 3h.Filter, obtain intermediate S5 crude product.Crude product is added in the mixed solvent of acetonitrile that 4L volume ratio is 2:1, purified water, is warming up to 70 ~ 75 DEG C, stir and product is all dissolved, naturally be down to room temperature, be cooled to 0 ~ 5 DEG C of stirring 2 hours subsequently.Filter, vacuum-drying obtains intermediate (S5) 0.52kg, productive rate 79.4%.
4, intermediate S6 is prepared
Intermediate (S5) 0.27kg (0.5mol) being added to 4L volume ratio is that in the water of 1:1 and the mixed solvent of acetone, stirring and dissolving, is cooled to 0 ~ 5 DEG C, adds 0.21kg (1.5mol) salt of wormwood, stirs 0.5 hour.Subsequently just own for chloroformic acid ester 0.10kg (0.6mol) is dropped in reaction solution, keep 0 ~ 5 DEG C to react 1 ~ 2 hour.Filter, obtain intermediate S6 crude product.Crude product is added in 1.5L tetrahydrofuran (THF), be warming up to 40 ~ 45 DEG C, stirring and dissolving.3L is preheated to the purified water of 38 ~ 40 DEG C, drops in reaction solution, stir, slow cooling to 0 ~ 5 DEG C subsequently, stirring and crystallizing 2 hours.Filter, vacuum-drying obtains intermediate (S6) 0.22kg, productive rate 69.6%, maximum single impurity 0.07%, purity 99.71%.
5, dabigatran etcxilate mesylate is prepared
Be added in 2.5L acetone by intermediate (S6) 0.19kg (0.3mol) obtained for above-mentioned steps 4, stirred at ambient temperature dissolves.Methylsulfonic acid 28.0g (0.29mol) is added in 0.3L acetone, stirring and dissolving, drops in reaction solution at 30 ~ 35 DEG C.After dropwising, keep thermotonus 2 hours.Filter, vacuum-drying obtains dabigatran etcxilate mesylate 0.20kg, productive rate 91.3%, maximum single impurity 0.06%, purity 99.72%.
Embodiment 6
In the building-up process of dabigatran etcxilate mesylate, the quality of intermediate S6 (dabigatran etcxilate) is very crucial, this is because intermediate S6 synthesizes dabigatran etcxilate mesylate only relate to a salt-forming reaction, very large impact can not be caused, so need to carry out strict control to the purification process of intermediate S6 and quality to foreign matter content wherein.
Through experiment sieving, determine the process for purification of intermediate S6, details are as follows: add in appropriate tetrahydrofuran (THF) by intermediate S6 crude product, be heated to 40 ~ 45 DEG C of stirring and dissolving, drip 38 ~ 40 DEG C of purified water to wherein, be cooled to 0 ~ 5 DEG C of stirring and crystallizing 2 hours subsequently, filter.Aforesaid operations step can be repeated, to ensure intermediate satisfactory quality according to defects inspecting result.Shaker test result is as shown in the table:
To the present invention and prior art carry out refining after product carry out HPLC analysis, purity and foreign matter content as follows:
| The method of prior art | The embodiment of the present invention | |
| Purity | 99.1％ | 99.7％ |
| Maximum list is mixed | 0.35％ | 0.10％ |
| Total assorted | 0.79％ | 0.25％ |
Compared with prior art, major advantage of the present invention is: pass through process for purification, effective control is carried out to the related substance of product (comprise maximum list assorted, always mix), the quality of product is improved greatly, thus reduced because impurity causes the hidden danger of untoward reaction.
Dabigatran etcxilate mesylate prepared by the inventive method and the dabigatran etcxilate mesylate that patent EP2522662 obtains compare, and the results are shown in following table:
The dabigatran etcxilate mesylate purity that as can be seen here prepared by the inventive method can up to 99.8%, and maximum simple substance amount is minimum reaches 0.06%, total assorted minimumly reaches 0.21%., the quality product of the dabigatran etcxilate mesylate that the present invention obtains is more excellent, is embodied in that purity is high, its related substances is low.
The purification process that the present invention adopts, can be not more than 0.1% by the list effectively controlled in product content of mixing, and is always assortedly not more than 0.5%, and the dabigatran etcxilate Mesylate Form obtained is single-minded, improves quality and the security of product, can meet pharmacy demand.
Total molar yield of the present invention can reach more than 45%, and the organic solvent used in technique all can recycling use, greatly reduces production cost.
Although the present invention with preferred embodiment openly as above; but it is also not used to limit the present invention, any person skilled in the art, without departing from the spirit and scope of the present invention; can do various change and modification, what therefore protection scope of the present invention should define with claims is as the criterion.
Claims (10)
1. a preparation method for dabigatran etcxilate mesylate, is characterized in that, comprises the steps:
1) be that starting raw material reacts under the effect of condensing agent with 3-[(3-amino-4-methylamino benzoyl) pyridine-2-base amino] ethyl propionate and N-(4-cyano-phenyl) Padil, obtain intermediate S3; Described intermediate S3 has structure shown in formula (1):
2) intermediate S3 is dissolved in reaction solvent, under the effect of Glacial acetic acid, obtains S4 crude product through ring-closure reaction, then obtain intermediate S4 through refining; Described intermediate S4 has structure shown in formula (2):
3) intermediate S4 carries out acidolysis in ethanol solution of hydrogen chloride, then under the effect of ammoniacal liquor, generates intermediate S5 crude product through aminating reaction, then obtains intermediate S5 through recrystallization; Described intermediate S5 has structure shown in formula (3):
4) intermediate S5 is dissolved in reaction solvent, and just own ester is obtained by reacting intermediate S6 crude product with chloroformic acid in the basic conditions, then to its carry out refining after obtain intermediate S6; Described intermediate S6 has structure shown in formula (4):
5) intermediate S6 carries out reaction with methylsulfonic acid in acetone and generates dabigatran etcxilate mesylate; Described dabigatran etcxilate mesylate has structure shown in formula (5):
2. method according to claim 1, is characterized in that, comprises the steps:
1) be that starting raw material reacts under the effect of condensing agent with 3-[(3-amino-4-methylamino benzoyl) pyridine-2-base amino] ethyl propionate and N-(4-cyano-phenyl) Padil, obtain intermediate S3;
2) intermediate S3 is dissolved in reaction solvent, under the effect of Glacial acetic acid, obtains S4 crude product through ring-closure reaction, then obtain intermediate S4 through refining;
3) intermediate S4 carries out acidolysis in ethanol solution of hydrogen chloride, then under the effect of ammoniacal liquor, generates intermediate S5 crude product through aminating reaction, then obtains intermediate S5 through recrystallization;
4) intermediate S5 is dissolved in reaction solvent, just own ester is obtained by reacting intermediate S6 crude product with chloroformic acid in the basic conditions, tetrahydrofuran (THF) is added in intermediate S6 crude product, be warming up to 40 ~ 45 DEG C of stirring and dissolving, drip 38 DEG C ~ 40 DEG C purified water extremely wherein, be cooled to 0 DEG C ~ 5 DEG C stirring and crystallizing subsequently, after filtration, obtain intermediate S6;
5) intermediate S6 carries out reaction with methylsulfonic acid in acetone and generates dabigatran etcxilate mesylate.
3. method according to claim 2, is characterized in that, comprises the steps:
1) be that starting raw material reacts under the effect of condensing agent with 3-[(3-amino-4-methylamino benzoyl) pyridine-2-base amino] ethyl propionate and N-(4-cyano-phenyl) Padil, obtain intermediate S3; The mol ratio of described 3-[(3-amino-4-methylamino benzoyl) pyridine-2-base is amino] ethyl propionate, N-(4-cyano-phenyl) Padil and condensing agent is 1:1.1:1.3;
2) intermediate S3 is dissolved in reaction solvent, under the effect of Glacial acetic acid, obtains S4 crude product through ring-closure reaction, then obtain intermediate S4 through refining;
3) intermediate S4 carries out acidolysis in ethanol solution of hydrogen chloride, then under the effect of ammoniacal liquor, intermediate S5 crude product is generated through aminating reaction, solvent is added in intermediate S5 crude product, be heated to 70 ~ 75 DEG C, be stirred to whole dissolving, be cooled to 0 DEG C ~ 5 DEG C stirring and crystallizing subsequently gradually, filter and obtain intermediate S5;
4) intermediate S5 is dissolved in reaction solvent, just own ester is obtained by reacting intermediate S6 crude product with chloroformic acid in the basic conditions, tetrahydrofuran (THF) is added in intermediate S6 crude product, be warming up to 40 ~ 45 DEG C of stirring and dissolving, drip 38 DEG C ~ 40 DEG C purified water extremely wherein, be cooled to 0 DEG C ~ 5 DEG C stirring and crystallizing subsequently, after filtration, obtain intermediate S6;
5) intermediate S6 carries out reaction with methylsulfonic acid in acetone and generates dabigatran etcxilate mesylate.
4. method according to claim 3, is characterized in that, step 1) described condensing agent, be selected from the one in dicyclohexylcarbodiimide and N, N-carbonyl dimidazoles.
5. method according to claim 3, is characterized in that, step 2) described reaction solvent is selected from one in ethyl acetate, n-butyl acetate, isobutyl acetate; Step 2) described refining, one or more the mixture in the solvent selected from methanol of employing, ethanol, Virahol, time refining, recrystallization temperature is 0 DEG C ~ 10 DEG C.
6. method according to claim 3, is characterized in that, step 3) described ethanol solution of hydrogen chloride concentration is 32% ~ 37%; Step 3) described solvent is one or more mixed solvents in water, acetonitrile and tetrahydrofuran (THF).
7. method according to claim 3, is characterized in that, step 4) described reaction solvent is selected from the mixture of any one and equal-volume water in tetrahydrofuran (THF), acetone, acetonitrile; Step 4) described crystallization, the time is 2h.
8. method according to claim 3, is characterized in that, step 5) mol ratio of described intermediate S6 and methylsulfonic acid is 1:0.95-1:0.98; Step 5) described reaction, temperature is 30 DEG C ~ 35 DEG C.
9. method according to claim 3, is characterized in that, comprises the steps:
1) be that starting raw material is at dicyclohexylcarbodiimide or N with 3-[(3-amino-4-methylamino benzoyl) pyridine-2-base amino] ethyl propionate and N-(4-cyano-phenyl) Padil, react under the effect of N-carbonyl dimidazoles, obtain intermediate S3; Described 3-[(3-amino-4-methylamino benzoyl) pyridine-2-base is amino] ethyl propionate, N-(4-cyano-phenyl) Padil and condensing agent mol ratio are followed successively by 1:1.1:1.3;
2) intermediate S3 is dissolved in n-butyl acetate, S4 crude product is obtained through ring-closure reaction under the effect of Glacial acetic acid, the ethanol that volume ratio is 5:1 and methanol mixed solvent is added in S4 crude product, slow cooling to 0 DEG C after heated and stirred ~ 10 DEG C of stirring and crystallizing, filter, vacuum-drying obtain intermediate S4;
3) in 36% ethanol solution of hydrogen chloride, add intermediate S4 and carry out acidolysis, then under the effect of ammoniacal liquor, S5 crude product is generated through aminating reaction, the mixed solvent of purified water that volume ratio is 2:1:1, acetonitrile, tetrahydrofuran (THF) is added in S5 crude product, be heated to 70 ~ 75 DEG C, be stirred to whole dissolving, be cooled to 0 ~ 5 DEG C of stirring subsequently, filter, vacuum-drying obtains intermediate S5;
4) intermediate S5 is dissolved in the mixing solutions of isopyknic tetrahydrofuran (THF) and purified water, just own ester is obtained by reacting intermediate S6 crude product with chloroformic acid in the basic conditions, tetrahydrofuran (THF) is added in intermediate S6 crude product, be warming up to 40 ~ 45 DEG C of stirring and dissolving, drip 38 DEG C ~ 40 DEG C purified water extremely wherein, be cooled to 0 DEG C ~ 5 DEG C stirring and crystallizing subsequently, after filtration, obtain intermediate S6;
5) intermediate S6 is dissolved, be then that 1:0.96 drips methylsulfonic acid according to the mol ratio of intermediate S6 and methylsulfonic acid at 30 ~ 35 DEG C, keep thermotonus, obtain dabigatran etcxilate mesylate.
10. either method described in claim 1-9 is preparing the application in dabigatran etcxilate mesylate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201511030125.XA CN105566297A (en) | 2015-12-31 | 2015-12-31 | Preparation method of dabigatran etexilate mesylate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201511030125.XA CN105566297A (en) | 2015-12-31 | 2015-12-31 | Preparation method of dabigatran etexilate mesylate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN105566297A true CN105566297A (en) | 2016-05-11 |
Family
ID=55876989
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201511030125.XA Pending CN105566297A (en) | 2015-12-31 | 2015-12-31 | Preparation method of dabigatran etexilate mesylate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105566297A (en) |
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106349221A (en) * | 2016-08-29 | 2017-01-25 | 常州市阳光药业有限公司 | Preparation method of high-purity dabigatran etexilate |
| CN106397403A (en) * | 2016-08-30 | 2017-02-15 | 苏州天马精细化学品股份有限公司 | Method for purifying dabigatran etexilate mesylate intermediate |
| CN106543144A (en) * | 2016-09-29 | 2017-03-29 | 成都丽凯手性技术有限公司 | A kind of industrialized process for preparing of dabigatran etcxilate |
| CN110128407A (en) * | 2018-02-02 | 2019-08-16 | 连云港恒运药业有限公司 | A kind of preparation method of Dabigatran etexilate key intermediate |
| 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 |
| CN113968840A (en) * | 2020-07-22 | 2022-01-25 | 北京四环制药有限公司 | High-purity dabigatran etexilate, preparation method and application thereof |
| CN114716411A (en) * | 2022-04-29 | 2022-07-08 | 天方药业有限公司 | Method for recovering and preparing dabigatran etexilate mesylate from production mother liquor |
| WO2022198361A1 (en) * | 2021-03-22 | 2022-09-29 | 天津睿创康泰生物技术有限公司 | Novel crystal form of dabigatran etexilate ethyl ester hydrochloride, preparation method therefor and use thereof |
| CN115417854A (en) * | 2022-09-21 | 2022-12-02 | 安徽美诺华药物化学有限公司 | Preparation method of key intermediate of anticoagulant drug |
| CN115417855A (en) * | 2022-09-22 | 2022-12-02 | 安徽美诺华药物化学有限公司 | Synthesis process of dabigatran etexilate mesylate |
| CN116003384A (en) * | 2023-01-31 | 2023-04-25 | 宿迁盛基医药科技有限公司 | A kind of synthetic method of dabigatran etexilate important intermediate |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1248251A (en) * | 1997-02-18 | 2000-03-22 | 贝林格尔英格海姆法玛公司 | Disubstituted bicyclic heterocycles, their production and use as medicaments |
| WO2012152855A1 (en) * | 2011-05-11 | 2012-11-15 | Medichem S.A. | Dabigatran etexilate and related substances, processes and compositions, and use of the substances as reference standards and markers |
| CN103804354A (en) * | 2012-11-08 | 2014-05-21 | 天津药物研究院 | Dabigatran preparation method |
-
2015
- 2015-12-31 CN CN201511030125.XA patent/CN105566297A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1248251A (en) * | 1997-02-18 | 2000-03-22 | 贝林格尔英格海姆法玛公司 | Disubstituted bicyclic heterocycles, their production and use as medicaments |
| WO2012152855A1 (en) * | 2011-05-11 | 2012-11-15 | Medichem S.A. | Dabigatran etexilate and related substances, processes and compositions, and use of the substances as reference standards and markers |
| CN103804354A (en) * | 2012-11-08 | 2014-05-21 | 天津药物研究院 | Dabigatran preparation method |
Cited By (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106349221A (en) * | 2016-08-29 | 2017-01-25 | 常州市阳光药业有限公司 | Preparation method of high-purity dabigatran etexilate |
| CN106397403A (en) * | 2016-08-30 | 2017-02-15 | 苏州天马精细化学品股份有限公司 | Method for purifying dabigatran etexilate mesylate intermediate |
| CN106543144A (en) * | 2016-09-29 | 2017-03-29 | 成都丽凯手性技术有限公司 | A kind of industrialized process for preparing of dabigatran etcxilate |
| CN106543144B (en) * | 2016-09-29 | 2019-05-17 | 成都丽凯手性技术有限公司 | A kind of industrialized process for preparing of dabigatran etcxilate |
| CN110128407A (en) * | 2018-02-02 | 2019-08-16 | 连云港恒运药业有限公司 | A kind of preparation method of Dabigatran etexilate key intermediate |
| CN110128407B (en) * | 2018-02-02 | 2022-04-01 | 连云港恒运药业有限公司 | Preparation method of dabigatran etexilate key intermediate |
| 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 |
| CN113968840A (en) * | 2020-07-22 | 2022-01-25 | 北京四环制药有限公司 | High-purity dabigatran etexilate, preparation method and application thereof |
| CN113968840B (en) * | 2020-07-22 | 2025-03-25 | 北京四环制药有限公司 | A kind of high-purity dabigatran etexilate and its preparation method and application |
| CN117043150A (en) * | 2021-03-22 | 2023-11-10 | 天津睿创康泰生物技术有限公司 | New crystal form of dabigatran etexilate ethyl ester hydrochloride as well as preparation method and application thereof |
| WO2022198361A1 (en) * | 2021-03-22 | 2022-09-29 | 天津睿创康泰生物技术有限公司 | Novel crystal form of dabigatran etexilate ethyl ester hydrochloride, preparation method therefor and use thereof |
| CN114716411A (en) * | 2022-04-29 | 2022-07-08 | 天方药业有限公司 | Method for recovering and preparing dabigatran etexilate mesylate from production mother liquor |
| CN114716411B (en) * | 2022-04-29 | 2024-03-15 | 天方药业有限公司 | Method for recovering and preparing dabigatran etexilate mesylate from production mother liquor |
| CN115417854A (en) * | 2022-09-21 | 2022-12-02 | 安徽美诺华药物化学有限公司 | Preparation method of key intermediate of anticoagulant drug |
| CN115417855A (en) * | 2022-09-22 | 2022-12-02 | 安徽美诺华药物化学有限公司 | Synthesis process of dabigatran etexilate mesylate |
| CN116003384A (en) * | 2023-01-31 | 2023-04-25 | 宿迁盛基医药科技有限公司 | A kind of synthetic method of dabigatran etexilate important intermediate |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105566297A (en) | Preparation method of dabigatran etexilate mesylate | |
| Dunn et al. | Stereoselective synthesis of 2, 3-diamino acids. 2, 3-Diamino-4-phenylbutanoic acid | |
| CN102985416B (en) | Process of preparing a thrombin specific inhibitor | |
| CN103974949B (en) | A kind of I type crystallization of 2-maleate of tyrosine kinase inhibitor and preparation method | |
| CN113717176B (en) | Method for preparing remazolam | |
| CN102281920A (en) | Quinazolinone derivatives useful as vanilloid antagonists | |
| WO2019019795A1 (en) | Method for preparing sacubitril intermediate | |
| CN112062767B (en) | Preparation method and intermediate of rumepilone | |
| CN101277948B (en) | Chemical process | |
| CN103025715A (en) | Intermediates and process for preparing a thrombin specific inhibitor | |
| CN114573500A (en) | Preparation method of lefenacin intermediate | |
| EP2066626B1 (en) | Azetidine derivatives as muscarinic receptor antagonists | |
| CN103450201B (en) | Preparation method of chiral 8-(3-aminopiperidine-1-yl)-xanthine | |
| CN105523999A (en) | Dabigatran etexilate intermediate synthesis method | |
| CN102977077A (en) | Method for preparing dabigatran etexilate intermediate | |
| CN110078718A (en) | A kind of preparation method of Afatinib degradation cyclisation impurity | |
| CN105153118A (en) | Central control method of midbody in dabigatran etexilate mesylate preparation process | |
| TW202330535A (en) | Preparation method of DPP-IV inhibitor and key intermediate thereof | |
| WO2007010235A1 (en) | Ethanolamine salt of n- (3-methoxy-5-methylpyrazin-2yl) -2- (4- [1 , 3 , 4-0xadiaz0le-2-yl] phenyl) pyridine-3- sulphonamide | |
| CN108658961A (en) | A kind of preparation method of Azilsartan | |
| JP2002540108A (en) | [S- (R *, S *)]-β-[[[1- [1-oxo-3- (4-piperidinyl) propyl] -3-piperidinyl] carbonyl] amino] -3-pyridinepropanoic acid and derivatives How to manufacture | |
| CN115594613B (en) | Edoxaban intermediate and preparation method thereof | |
| CN103755624B (en) | A kind of synthetic method of piperidine derivative | |
| CN110981858A (en) | Preparation method of anticoagulant drug dabigatran etexilate and analogue thereof | |
| CN110143947B (en) | A kind of preparation method of ceritinib analog |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20160511 |
|
| WD01 | Invention patent application deemed withdrawn after publication |