CN116253715B - Preparation method of dabigatran etexilate intermediate - Google Patents
Preparation method of dabigatran etexilate intermediate Download PDFInfo
- Publication number
- CN116253715B CN116253715B CN202310035825.6A CN202310035825A CN116253715B CN 116253715 B CN116253715 B CN 116253715B CN 202310035825 A CN202310035825 A CN 202310035825A CN 116253715 B CN116253715 B CN 116253715B
- Authority
- CN
- China
- Prior art keywords
- reaction
- compound
- catalyst
- reactant
- added
- 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.)
- Active
Links
- 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 15
- 229960000288 dabigatran etexilate Drugs 0.000 title claims abstract description 14
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 76
- 239000003054 catalyst Substances 0.000 claims abstract description 23
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims abstract description 20
- QSKPIOLLBIHNAC-UHFFFAOYSA-N 2-chloro-acetaldehyde Chemical compound ClCC=O QSKPIOLLBIHNAC-UHFFFAOYSA-N 0.000 claims abstract description 20
- 239000007800 oxidant agent Substances 0.000 claims abstract description 18
- 239000000376 reactant Substances 0.000 claims abstract description 14
- 230000001590 oxidative effect Effects 0.000 claims abstract description 12
- YBAZINRZQSAIAY-UHFFFAOYSA-N 4-aminobenzonitrile Chemical compound NC1=CC=C(C#N)C=C1 YBAZINRZQSAIAY-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000002904 solvent Substances 0.000 claims abstract description 7
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims abstract description 6
- 238000004090 dissolution Methods 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 21
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 claims description 20
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 15
- 239000007864 aqueous solution Substances 0.000 claims description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 9
- 239000011230 binding agent Substances 0.000 claims description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- 239000000377 silicon dioxide Substances 0.000 claims description 5
- 235000012239 silicon dioxide Nutrition 0.000 claims description 3
- JJLJMEJHUUYSSY-UHFFFAOYSA-L Copper hydroxide Chemical compound [OH-].[OH-].[Cu+2] JJLJMEJHUUYSSY-UHFFFAOYSA-L 0.000 claims description 2
- 239000005750 Copper hydroxide Substances 0.000 claims description 2
- 229910001956 copper hydroxide Inorganic materials 0.000 claims description 2
- 239000007787 solid Substances 0.000 claims description 2
- 239000000047 product Substances 0.000 abstract description 18
- 238000000034 method Methods 0.000 abstract description 10
- 239000012535 impurity Substances 0.000 abstract description 7
- 238000009776 industrial production Methods 0.000 abstract description 3
- 230000009286 beneficial effect Effects 0.000 abstract description 2
- 239000007795 chemical reaction product Substances 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- 150000002148 esters Chemical class 0.000 abstract 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- 239000000243 solution Substances 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 238000005406 washing Methods 0.000 description 14
- 239000000203 mixture Substances 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 10
- 239000010949 copper Substances 0.000 description 9
- 238000004821 distillation Methods 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- 238000001914 filtration Methods 0.000 description 8
- 238000007363 ring formation reaction Methods 0.000 description 8
- 238000001035 drying Methods 0.000 description 7
- 239000000543 intermediate Substances 0.000 description 7
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- PNVPNXKRAUBJGW-UHFFFAOYSA-N (2-chloroacetyl) 2-chloroacetate Chemical compound ClCC(=O)OC(=O)CCl PNVPNXKRAUBJGW-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- 206010003658 Atrial Fibrillation Diseases 0.000 description 2
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 2
- 208000005189 Embolism Diseases 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 description 2
- 229940106681 chloroacetic acid Drugs 0.000 description 2
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- -1 imidazole-5-carboxamide propionate Chemical compound 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 239000003868 thrombin inhibitor Substances 0.000 description 2
- HFFLGKNGCAIQMO-UHFFFAOYSA-N trichloroacetaldehyde Chemical compound ClC(Cl)(Cl)C=O HFFLGKNGCAIQMO-UHFFFAOYSA-N 0.000 description 2
- UZNYDSWHWKFYCJ-UHFFFAOYSA-N 1-chloroethane-1,1-diol Chemical compound CC(O)(O)Cl UZNYDSWHWKFYCJ-UHFFFAOYSA-N 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- QZZIBMYRWBVKLM-UHFFFAOYSA-N 3-amino-4-(methylamino)benzoic acid Chemical compound CNC1=CC=C(C(O)=O)C=C1N QZZIBMYRWBVKLM-UHFFFAOYSA-N 0.000 description 1
- 229940123900 Direct thrombin inhibitor Drugs 0.000 description 1
- 101000712605 Theromyzon tessulatum Theromin Proteins 0.000 description 1
- 229940122388 Thrombin inhibitor Drugs 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 229960000503 bisacodyl Drugs 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000002598 diffusion tensor imaging Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 229940127216 oral anticoagulant drug Drugs 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 229940066336 pradaxa Drugs 0.000 description 1
- 238000011112 process operation Methods 0.000 description 1
- FKRCODPIKNYEAC-UHFFFAOYSA-N propionic acid ethyl ester Natural products CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010992 reflux Methods 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
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of dabigatran etexilate intermediate, which comprises the following steps: and (3) placing 0.05mol of reactant I in a reaction vessel, adding a solvent for dissolution, adding a reactant chloroacetaldehyde, adding an oxidant, adding a catalyst, reacting at room temperature, separating a product after the reaction is finished, recrystallizing and purifying to obtain a high-purity product compound II, and reacting the compound II with p-aminobenzonitrile to obtain the intermediate compound III of the reach bisabolyl ester. The beneficial effects of the invention are as follows: the method has the advantages of simple process, simple and easily obtained reaction raw materials, mild reaction conditions, convenient treatment of reaction products, good reaction selectivity, capability of effectively reducing the generation of reaction impurities, improving the reaction yield, obtaining products with higher purity, increasing the atomic economy of the reaction, and suitability for the requirements of industrial production.
Description
Technical Field
The invention relates to the technical field related to preparation of pharmaceutical intermediates, in particular to a preparation method of dabigatran etexilate intermediates.
Background
Dabigatran etexilate, chemical name 3- [ [ [2- [ [ [4- [ [ [ (hexyloxy) carbonyl ] amino ] iminomethyl ] phenyl ] amino ] methyl ] -1-methyl-1H-benzimidazol-5-yl ] carbonyl ] (pyridin-2-yl) amino ] ethyl propionate, chemical formula C34H41N7O5, is the most clinically leading new generation oral anticoagulant drug Direct Thrombin Inhibitor (DTIs), is thrombin inhibitor dabigatran etexilate capsule (trade name Pradaxa) developed by bologiln, germany, was marketed in germany first in germany and uk in 2008, and FDA approval was obtained again in 10 and 19 days 2010 for preventing stroke and systemic embolism in non-valvular atrial fibrillation patients. The chemical structure is as follows: for preventing stroke and systemic embolism in non-valvular atrial fibrillation patients, the chemical structural formula is as follows:
several synthetic methods have been reported for the preparation of dabigatran etexilate today, as follows:
1. in patent WO9837075, the synthetic route of dabigatran etexilate is disclosed for the first time by the company bringen, the synthetic method of which is as follows:
2. The production process was carried out by Boringer's John in 2006
The synthesis method is as follows:
3. A new synthetic route is disclosed in patent WO2011061080A by Boringer Ghan, which is the following synthetic method:
The above routes all contain imidazole ring-forming steps, the imidazole ring-forming steps are lower in yield by the method of condensation reaction of carboxylic acid and o-diamine in routes 1 and 2, and the step usually needs to use a condensing agent, the condensing agent is expensive and unfavorable for reducing the cost, meanwhile, the reaction temperature is higher, the reaction time is longer, and the intermediate yield after the condensing agent is used for ring-forming is lower, a large amount of impurities are introduced, so that the intermediate purity is low, the purity of dabigatran etexilate is low finally, and the final product yield is not easily influenced by purification. Scheme 3 is an optimization and improvement of schemes 1 and 2, but this scheme requires the use of a cyclization reagent, typically chloroacetic acid, chloroacetyl chloride, chloroacetic anhydride, or chloro-orthoacetate. The reaction yield is only 30% when chloroacetic acid is used; when chloroacetyl chloride is used for cyclization, diacetylated impurities are easy to generate, and the yield is lower by only 71%; the chloroacetic anhydride is expensive, so that the production cost is increased to a great extent; the chlorinated orthoacetate needs to be self-made, so that the whole synthesis process is complex, the process cost is increased, and the time required by the cyclization reaction is long.
Aiming at the defects that the yield of a product is lower, the reaction selectivity is lower, acylated impurities are easy to generate, and the process flow is complicated because part of the cyclization reagents are required to be self-made in the preparation process of the original cyclization reagent in the route 3, the invention provides the preparation method of the dabigatran etexilate intermediate, which is characterized in that the original process route of the route 3 is improved, the appropriate cyclization reagent chloroacetaldehyde is selected, the reaction selectivity is increased, the generation of reaction impurities is reduced, the reaction yield is improved, the product with higher purity is obtained, the atomic economy of the reaction is increased, the reaction time is short, the process operation is simple, and the synthesis route of the key intermediate is as follows:
Disclosure of Invention
Aiming at the defects of higher reaction temperature, longer reaction time by using the original cyclization reagent, lower reaction yield, lower reaction selectivity, easiness in generating acylated impurities, complicated process flow caused by self-making and the like in the prior art, the invention adopts the following technical scheme:
A preparation method of dabigatran etexilate intermediate comprises the following steps:
firstly, placing 0.05mol of reactant I in a reaction vessel, adding a solvent for dissolution, adding a reactant chloroacetaldehyde, adding an oxidant, adding a catalyst, reacting at room temperature, separating a product after the reaction is finished, and recrystallizing and purifying to obtain a high-purity product compound II;
And secondly, reacting the compound II obtained in the previous step with p-aminobenzonitrile in the presence of a catalyst and an acid binding agent to obtain a compound III.
Further, the solvent selected in the first step is one of TFE, HFIP, toluene and dioxane, and the solvent used in the second step is Dimethylformamide (DMF).
Further, the molar ratio of the chloroacetaldehyde used in the reaction to the compound I is 1:1.5 to 2.5, preferably 1:2.
Further, the reaction condition required by the first step of reaction is that the reaction is carried out for 4 to 6 hours at room temperature, and the reaction condition of the second step of reaction is that the reaction is carried out for 6 hours at 60 ℃.
Furthermore, the oxidant used in the first step is nitrobenzene or dimethyl sulfoxide, and the molar ratio of the oxidant used in the first step to the reactant I is 1:1.
Further, the chloroacetaldehyde as the reactant in the first step is an aqueous solution with the mass fraction of 40%.
Further, the first-step reaction oxidant is impregnated and supported on the silicon dioxide to participate in the reaction.
Further, the catalyst of the first step reaction is copper hydroxide solid, and the dosage of the catalyst is 5-15% of the molar quantity of the reactant I, preferably 10%.
Further, the catalyst used in the second step of reaction is potassium iodide, and the reaction acid binding agent is potassium carbonate.
Further, the molar ratio of the reactant compound II, the acid binding agent and the catalyst in the second step is 1:1: 1-2: 0.4, preferably 1:1:1.5:0.4.
The beneficial effects of the invention are as follows: the method has the advantages of simple process, simple and easily obtained reaction raw materials, mild reaction conditions, convenient reaction product treatment and good reaction selectivity, can effectively reduce the generation of reaction impurities, improve the reaction yield, obtain a product with higher purity, increase the atomic economy of the reaction, and is suitable for the requirement of industrial production.
Drawings
FIG. 1 is a schematic diagram of the structure of dabigatran etexilate;
FIG. 2 is a schematic illustration of the reaction scheme of scheme 1;
FIG. 3 is a schematic illustration of the reaction scheme of scheme 2;
FIG. 4 is a schematic illustration of the reaction scheme of scheme 3;
FIG. 5 is a schematic illustration of the reaction scheme of the present invention.
Detailed Description
The following description of the embodiments of the present invention will be made clearly and completely with reference to the embodiments of the present invention and the accompanying drawings, and it is apparent that the described embodiments are only some embodiments of the present invention, not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1
In the first step, 17.1g (0.05 mol) of compound I is taken, 200mlTFE mol of compound I is added to dissolve the compound I, 7.85g of chloroacetaldehyde (40% w/w aqueous solution) is added to the solution, 0.05mol of nitrobenzene supported on silica is added as an oxidant, 2.4g of catalyst Cu (OH) 2 is added to react for 4 hours at room temperature, filtration is carried out after the reaction is completed, saturated saline and water are used for washing residues for 2 to 3 times, washing liquid is combined into the filtrate, an organic phase is separated, and the product is recrystallized after reduced pressure distillation to obtain 18.5g of compound II, and the yield is 95.7% and the purity is 99.0%.
In the second step, 19.3g (0.05 mol) of compound II is dissolved in 300ml of Dimethylformamide (DMF), 8.9g (0.075 mol) of p-aminobenzonitrile is added, 2.6g (0.02 mol) of potassium iodide is added as a catalyst, 6.9g (0.05 mol) of potassium carbonate as an acid-binding agent is added, the mixture is reacted at 60 ℃ for 6 hours, 1000ml of water is added to the mixture for cooling to room temperature, the mixture is mixed and stirred, the mixture is precipitated for 30 minutes, suction filtration is carried out, 100ml of water is used for washing a filter cake for 2 to 3 times, anhydrous sodium sulfate is used for drying, and after the drying, 200 ethyl acetate is used for recrystallization, the compound III is obtained by drying again, and the yield is 86.7 percent and the purity is 98.5 percent.
Example 2
17.1G (0.05 mol) of compound I was taken, 200mlHFIP g of dissolved compound I was added, 7.85g of chloroacetaldehyde (40% w/w aqueous solution) was added to the solution, 0.05mol of silica-supported nitrobenzene was added as an oxidizing agent, 2.4g of Cu (OH) 2 as a catalyst was added, the reaction was carried out at room temperature for 4 hours, after completion of the reaction, filtration was carried out, saturated brine and water were washed for 2 to 3 times, the washing solution was combined with the filtrate, the organic phase was separated, and the product was recrystallized after distillation under reduced pressure to give 18.3g of compound II in 94.7% yield with a purity of 98.3%.
Example 3
17.1G (0.05 mol) of compound I was taken, 200ml of toluene was added to dissolve the compound I, 7.85g of chloroacetaldehyde (40% w/w aqueous solution) was added to the solution, 0.05mol of silica-supported nitrobenzene was added as an oxidizing agent, 2.4g of Cu (OH) 2 as a catalyst was added to react at room temperature for 4 hours, after completion of the reaction, filtration was carried out, saturated brine and water were washed for 2 to 3 times, the washing solution was combined with the filtrate, the organic phase was separated, and the product was recrystallized after distillation under reduced pressure to give 17.8g of compound II in 92.1% yield with a purity of 98.0%.
Example 4
17.1G (0.05 mol) of compound I was taken, 200ml of dioxane was added to dissolve the compound I, 7.85g of chloroacetaldehyde (40% w/w aqueous solution) was added to the solution, 0.05mol of silica-supported nitrobenzene was added as an oxidizing agent, 2.4g of Cu (OH) 2 was added as a catalyst, the reaction was carried out at room temperature for 4 hours, after the completion of the reaction, the residue was filtered, saturated brine and water were washed 2 to 3 times, the washing solution was combined with the filtrate, the organic phase was separated, and the product was recrystallized after distillation under reduced pressure to give 18.0g of compound II, yield 93.2%, purity 98.0%.
Example 5
17.1G (0.05 mol) of compound I is taken, 200mlTFE g (0.1 mol) of chloroacetaldehyde (40% w/w aqueous solution) is added to dissolve the compound I, 5.89g (0.1 mol) of chloroacetaldehyde is added to the solution, 0.05mol of nitrobenzene supported on silica is added as an oxidant, 2.4g of Cu (OH) 2 is added to react for 4 hours at room temperature, after the reaction is completed, filtration is carried out, saturated saline water and water are used for washing residues for 2 to 3 times, washing liquid is combined into the filtrate, an organic phase is separated, and the product is recrystallized after reduced pressure distillation, thus 17.3g of compound II is obtained, the yield is 89.5%, and the purity is 98.5%.
Example 6
17.1G (0.05 mol) of compound I was taken, 200mlTFE g (0.1 mol) of chloroacetaldehyde (40% w/w aqueous solution) was added to dissolve the compound I, 9.81g (0.1 mol) of chloroacetaldehyde was added to the solution, 0.05mol of silica-supported nitrobenzene was added as an oxidizing agent, 2.4g of Cu (OH) 2 as a catalyst was added, the reaction was carried out at room temperature for 4 hours, after the completion of the reaction, filtration was carried out, saturated brine and water were used to wash the residue 2 to 3 times, the washing solution was combined with the filtrate, the organic phase was separated, and the product was recrystallized after distillation under reduced pressure to give 18.4g of compound II, yield 95.2% and purity 98.6%.
Example 7
17.1G (0.05 mol) of compound I is taken, 200mlTFE g (0.1 mol) of chloral (40% w/w aqueous solution) is added to dissolve the compound I, 7.85g (0.1 mol) of chloral is added to the solution, 0.05mol of dimethyl sulfoxide loaded with silicon dioxide is added as an oxidant, 2.4g of catalyst Cu (OH) 2 is added to react for 4 hours at room temperature, after the reaction is finished, filtration is carried out, saturated saline water and water are used for washing residues for 2 to 3 times, washing liquid is combined into filtrate, an organic phase is separated, the product is recrystallized after reduced pressure distillation, 17.9g of compound II is obtained, the yield is 92.6%, and the purity is 98.8%.
Example 8
17.1G (0.05 mol) of compound I was taken, 200mlTFE g (0.1 mol) of chloroacetaldehyde (40% w/w aqueous solution) was added to dissolve the compound I, 7.85g (0.1 mol) of chloroacetaldehyde was added to the solution, 0.05mol of silica-supported nitrobenzene was added as an oxidizing agent, 2.4g of Cu (OH) 2 was added, the reaction was carried out at room temperature for 5 hours, after the completion of the reaction, filtration was carried out, saturated brine and water were used to wash the residue 2 to 3 times, the washing solution was combined with the filtrate, the organic phase was separated, and the product was recrystallized after distillation under reduced pressure to give 18.5g of compound II, yield 95.7% and purity 98.9%.
Example 9
17.1G (0.05 mol) of compound I was taken, 200mlTFE g (0.1 mol) of chloroacetaldehyde (40% w/w aqueous solution) was added to dissolve the compound I, 7.85g (0.1 mol) of chloroacetaldehyde was added to the solution, 0.05mol of silica-supported nitrobenzene was added as an oxidizing agent, 2.4g of Cu (OH) 2 as a catalyst was added, the reaction was carried out at room temperature for 6 hours, after the completion of the reaction, filtration was carried out, saturated brine and water were used to wash the residue 2 to 3 times, the washing solution was combined with the filtrate, the organic phase was separated, and the product was recrystallized after distillation under reduced pressure to obtain 18.6g of compound II, yield 96.2% and purity 98.6%.
Example 10
In the second step, 19.3g (0.05 mol) of Compound II was dissolved in 300ml of Dimethylformamide (DMF), 5.9g (0.05 mol) of p-aminobenzonitrile was added, 2.6g (0.02 mol) of potassium iodide was added as a catalyst, 6.9g (0.05 mol) of potassium carbonate as an acid-binding agent was added, the mixture was reacted at 60℃for 6 hours, 1000ml of water was added to cool to room temperature, the mixture was stirred, and the mixture was precipitated for 30 minutes, suction filtration, washing the cake with 100ml of water 2 to 3 times, drying over anhydrous sodium sulfate, recrystallization with 200 ethyl acetate, and re-drying to give 20.2g of Compound III in 83.5% yield and 98.7% purity.
Example 11
In the second step, 19.3g (0.05 mol) of Compound II was dissolved in 300ml of Dimethylformamide (DMF), 11.8g (0.1 mol) of p-aminobenzonitrile was added, 2.6g (0.02 mol) of potassium iodide was added as a catalyst, 6.9g (0.05 mol) of potassium carbonate as an acid-binding agent was added, the mixture was reacted at 60℃for 6 hours, 1000ml of water was added to the mixture to room temperature, the mixture was stirred and precipitated for 30 minutes, suction filtration was performed, the cake was washed with 100ml of water for 2 to 3 times, dried over anhydrous sodium sulfate, recrystallized with 200 ethyl acetate after drying, and dried again to give 21.1g of Compound III in a yield of 87.3% and a purity of 98.8%.
Comparative document (CN 104418805B) example
Example 1: preparation of 2- (chloromethyl) -1-methyl-1H-benzo [ d ] imidazole-5-carboxylic acid
6 G of 3-amino-4-methylaminobenzoic acid, 6.3 g of chloroacetic anhydride were introduced into a reaction flask, and 60 ml of ethyl acetate were added. 2 drops of concentrated hydrochloric acid are added dropwise, and reflux reaction is carried out for 2 hours at 80 ℃. After the completion of the reaction, the reaction mixture was cooled to 0℃and filtered. 5.1 g of 2- (chloromethyl) -1-methyl-1H-benzo [ d ] imidazole-5-carboxylic acid are obtained in 62.9% yield
Example 2: synthesis of dabigatran etexilate
1.2 G of ethyl 3- (2-chloromethyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [ d ] imidazole-5-carboxamide propionate was dissolved in 12 ml of 1, 4-dioxane, 1.9 g of sodium hydrogencarbonate, 0.7 g of sodium iodide was added and the mixture was reacted for 30 minutes. Then, 20 ml of a 1, 4-dioxane solution in which 1.2 g of 4-aminobenzamidine-N-hexyl carbamate was dissolved was added and reacted at 60℃for 6 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, 120 ml of ethyl acetate was added, the mixture was washed with water, and the organic phase was collected by separation, dried over anhydrous sodium sulfate, concentrated under reduced pressure and dried by spin-drying to obtain 1.7 g of bisacodyl ester. The yield thereof was found to be 90.4%.
In summary, the cyclization reaction and the reaction of substituting the halogen atom with the amino group in the examples of the comparison document show that the same type of reaction can be realized, compared with the technical scheme of the prior art described in the comparison document, the technical scheme provided by the invention has higher yield, good atom economy, good reaction selectivity, fewer reaction byproducts and convenient treatment of the product, and is more suitable for the requirement of industrial production.
It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative embodiments, and that the present invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein. Any reference sign in a claim should not be construed as limiting the claim concerned.
Furthermore, it should be understood that although the present disclosure describes embodiments, not every embodiment is provided with a separate embodiment, and that this description is provided for clarity only, and that the disclosure is not limited to the embodiments described in detail below, and that the embodiments described in the examples may be combined as appropriate to form other embodiments that will be apparent to those skilled in the art.
Claims (1)
1. The preparation method of the dabigatran etexilate intermediate is characterized by comprising the following steps:
Firstly, placing 0.05mol of reactant I in a reaction vessel, adding a solvent for dissolution, adding reactant chloroacetaldehyde, adding an oxidant, adding a catalyst, reacting at room temperature, separating a product after the reaction is finished, and recrystallizing and purifying to obtain a product compound II;
Secondly, reacting the compound II obtained in the previous step with p-aminobenzonitrile in the presence of a catalyst and an acid binding agent to obtain a compound III; the solvent selected in the first step is one of TFE, HFIP, toluene and dioxane, and the solvent used in the second step is DMF;
The molar ratio of the chloroacetaldehyde used in the reaction to the compound I is 1:1.5 to 2.5; the reaction condition required by the first step of reaction is that the reaction is carried out for 4 to 6 hours at room temperature, and the reaction condition of the second step of reaction is that the reaction is carried out for 6 hours at 60 ℃; the oxidant used in the first step is nitrobenzene or dimethyl sulfoxide, and the molar ratio of the oxidant used in the first step to the reactant I is 1:1; the chloroacetaldehyde as the reactant in the first step is 40% of aqueous solution in mass fraction; the oxidant is impregnated and loaded on the silicon dioxide to participate in the reaction in the first step; the catalyst of the first step is copper hydroxide solid, and the dosage of the catalyst is 5-15% of the molar quantity of the reactant I; the catalyst used in the second step of reaction is potassium iodide, and the reaction acid-binding agent is potassium carbonate; the molar ratio of the reactant compound II, the acid binding agent, the p-aminobenzonitrile and the catalyst in the second step is 1:1:1.5:0.4.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310035825.6A CN116253715B (en) | 2023-01-10 | 2023-01-10 | Preparation method of dabigatran etexilate intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310035825.6A CN116253715B (en) | 2023-01-10 | 2023-01-10 | Preparation method of dabigatran etexilate intermediate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN116253715A CN116253715A (en) | 2023-06-13 |
| CN116253715B true CN116253715B (en) | 2024-09-27 |
Family
ID=86685591
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310035825.6A Active CN116253715B (en) | 2023-01-10 | 2023-01-10 | Preparation method of dabigatran etexilate intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116253715B (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108864047A (en) * | 2018-07-02 | 2018-11-23 | 河南师范大学 | A kind of preparation method of non-peptide batroxobin inhibitor dabigatran etcxilate |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105753840A (en) * | 2015-12-30 | 2016-07-13 | 江西胜富化工有限公司 | Method for synthesizing dabigatran etexilate intermediate |
| CN106928195B (en) * | 2017-03-29 | 2019-04-19 | 福建省微生物研究所 | A kind of synthetic method of Dabigatran etexilate key intermediate |
-
2023
- 2023-01-10 CN CN202310035825.6A patent/CN116253715B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108864047A (en) * | 2018-07-02 | 2018-11-23 | 河南师范大学 | A kind of preparation method of non-peptide batroxobin inhibitor dabigatran etcxilate |
Also Published As
| Publication number | Publication date |
|---|---|
| CN116253715A (en) | 2023-06-13 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| WO1997022603A1 (en) | Method for the synthesis of a benzimidazole compound | |
| CN107365275B (en) | High purity celecoxib | |
| KR101502322B1 (en) | Process for the preparation of pure anastrozole | |
| CN116253715B (en) | Preparation method of dabigatran etexilate intermediate | |
| JP2008266172A (en) | Method for producing 3-o-alkyl-5,6-o-(1-methylethylidene)-l-ascorbic acid and method for producing 5,6-o-(1-methylethylidene)-l-ascorbic acid | |
| AU2021297767A1 (en) | Preparation method for aromatic ether compound | |
| JPS6046104B2 (en) | Method for producing butene derivatives | |
| RU2539298C2 (en) | Method for producing flupirtine | |
| TW202210486A (en) | Method for preparing glp-1 receptor agonist | |
| JP5637710B2 (en) | {2-Amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidin-3-yl) ester 5-isopropyl ester } Manufacturing method | |
| CN116283798B (en) | Novel preparation method of urapidil | |
| CN115697970B (en) | Preparation method of aromatic ether compound | |
| CN117886796A (en) | Synthetic method of dabigatran etexilate intermediate process | |
| KR100448642B1 (en) | Method for producing phenyl propionic acid derivatives from 2-phenylpropionic acid by simple processing steps with high yield and purity | |
| CN116003384A (en) | Synthesis method of dabigatran etexilate important intermediate | |
| CN115785019A (en) | Synthesis method of ethyl-1-oxo-4-azaspiro [5.5] undecane-9-carboxylate | |
| KR100448640B1 (en) | Method for producing phenyl propionic acid derivatives with high yield and purity | |
| JP4673313B2 (en) | Process for producing 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one or a salt thereof | |
| CN116354952A (en) | Synthesis process of dabigatran etexilate key intermediate | |
| CN117510469A (en) | Efficient synthesis process of dabigatran etexilate intermediate | |
| CN107365299B (en) | Preparation method of dabigatran etexilate and intermediate thereof | |
| CN117964583A (en) | Preparation method of Engliclazide chiral intermediate | |
| CN117447448A (en) | Synthesis method of dabigatran etexilate intermediate | |
| KR900002053B1 (en) | Process for preparing alpha-aryl-4-substituted piperidine alkanol derivatives | |
| CN115093399A (en) | Preparation method of anti-gout drug topiroxostat |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| CB02 | Change of applicant information | ||
| CB02 | Change of applicant information |
Country or region after: China Address after: No. 58, Yangzi Road, Ecological Chemical Technology Industrial Park, Suqian City, Jiangsu Province, 223800 Applicant after: Jiangsu Alpha Group Shengji Pharmaceutical (Suqian) Co.,Ltd. Address before: No. 58, Yangzi Road, Ecological Chemical Technology Industrial Park, Suqian City, Jiangsu Province, 223800 Applicant before: Suqian Shengji Pharmaceutical Technology Co.,Ltd. Country or region before: China |
|
| GR01 | Patent grant | ||
| GR01 | Patent grant |