CN117886796A - Synthetic method of dabigatran etexilate intermediate process - Google Patents
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- CN117886796A CN117886796A CN202311770802.6A CN202311770802A CN117886796A CN 117886796 A CN117886796 A CN 117886796A CN 202311770802 A CN202311770802 A CN 202311770802A CN 117886796 A CN117886796 A CN 117886796A
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- 238000000034 method Methods 0.000 title claims abstract description 32
- 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 25
- 229960000288 dabigatran etexilate Drugs 0.000 title claims abstract description 24
- 238000010189 synthetic method Methods 0.000 title abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 43
- 150000001875 compounds Chemical class 0.000 claims abstract description 20
- 238000001308 synthesis method Methods 0.000 claims abstract description 16
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims abstract description 9
- 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 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 30
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 22
- 239000003054 catalyst Substances 0.000 claims description 19
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- 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 description 15
- 239000003960 organic solvent Substances 0.000 claims description 13
- 238000003756 stirring Methods 0.000 claims description 12
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- 239000003153 chemical reaction reagent Substances 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 150000007530 organic bases Chemical class 0.000 claims description 2
- 239000000376 reactant Substances 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 238000007363 ring formation reaction Methods 0.000 abstract description 11
- 238000006772 olefination reaction Methods 0.000 abstract description 6
- 125000003368 amide group Chemical group 0.000 abstract description 5
- 150000001556 benzimidazoles Chemical class 0.000 abstract description 4
- 239000006227 byproduct Substances 0.000 abstract description 4
- 230000007547 defect Effects 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 230000009286 beneficial effect Effects 0.000 abstract description 2
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- 238000006467 substitution reaction Methods 0.000 abstract description 2
- 230000001988 toxicity Effects 0.000 abstract description 2
- 231100000419 toxicity Toxicity 0.000 abstract description 2
- 150000001408 amides Chemical class 0.000 abstract 1
- 125000003277 amino group Chemical class 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- 239000000047 product Substances 0.000 description 10
- 239000012074 organic phase Substances 0.000 description 9
- 239000000243 solution Substances 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 238000004821 distillation Methods 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 239000000543 intermediate Substances 0.000 description 7
- 238000001514 detection method Methods 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 239000003513 alkali Substances 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000002156 mixing Methods 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
- 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
- 239000002585 base Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 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
- 239000012535 impurity Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 239000003868 thrombin inhibitor Substances 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
- 241001137307 Cyprinodon variegatus Species 0.000 description 1
- 229940123900 Direct thrombin inhibitor Drugs 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 101000712605 Theromyzon tessulatum Theromin Proteins 0.000 description 1
- 229940122388 Thrombin inhibitor Drugs 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000002598 diffusion tensor imaging Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000011259 mixed solution Substances 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
- 238000002360 preparation method 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
- 230000035484 reaction time Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention discloses a synthetic method of dabigatran etexilate intermediate, which is characterized in that a new cyclization process of benzimidazole derivative is obtained through a reaction method of substitution of amino groups of an amide compound II and halogenated groups of a compound I and double bond transfer of further Shi Tuoke olefination reaction, and then the new cyclization process is reacted with a compound IV to prepare a target intermediate compound V. The beneficial effects of the invention are as follows: the invention provides a new and effective synthesis method of dabigatran etexilate intermediate compound, which is characterized in that a new cyclization process of benzimidazole derivative is obtained by a reaction method of substituting amido and halogenated groups and transferring double bonds through further Shi Tuoke olefination reaction, so that a plurality of defects of the existing cyclization process are effectively avoided; the method has the advantages of easily obtained raw materials, high reaction selectivity, good yield, few byproducts, convenient treatment of the byproducts, simple operation, mild reaction conditions, suitability for industrial large-scale production, avoidance of introducing nitro and reduction of toxicity in the production process.
Description
Technical Field
The invention relates to the technical field related to synthesis of pharmaceutical intermediates, in particular to a process synthesis 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 boildingham, germany, was marketed in germany and uk first at 4 months of 2008, and was approved by the FDA again at 10 month 19 of 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:
in patent WO9837075, the synthetic route of dabigatran etexilate is disclosed for the first time by the company bologna invahn, the synthetic method of which is as follows:
2, bolin, yingrahn, inc. produced the process in 2006
The synthesis method is as follows:
in patent WO2011061080a, a new synthetic route is disclosed by the company boilinginvahn, the synthetic method of which is as follows:
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.
Disclosure of Invention
Aiming at the defects, the invention provides a new and effective synthesis method of a dabigatran etexilate intermediate compound, and a new cyclization process of a benzimidazole derivative is obtained by a reaction method of substitution of amido and halogenated groups and double bond transfer of further Shi Tuoke olefination reaction, so that a plurality of defects of the existing cyclization process are effectively avoided, and the invention adopts the following technical scheme:
a process synthesis method of dabigatran etexilate intermediate comprises the following steps:
firstly, dissolving a compound I in an organic solvent, adding a compound II, adding a catalyst, stirring at room temperature for reaction, and separating a product after the reaction is finished to obtain a compound III;
and secondly, dissolving the compound III obtained in the first step in an organic solvent, adding a compound IV, adding a catalyst, reacting for 10-12 hours at room temperature, and separating a product after the reaction is finished to obtain a target product compound V.
Further, the solvent used in the first step of reaction is one of dichloromethane and chloroform.
Further, the solvent used in the second step is one of dichloromethane, dimethyl sulfoxide and dimethylformamide.
Furthermore, the catalyst used in the first step is an alkaline reagent, the alkaline reagent is an equimolar mixture of potassium carbonate or calcium carbonate and triethylamine serving as an organic base, the mixed alkali is convenient for controlling acid-base conditions of the reaction, and the two alkaline reagents effectively regulate and control the reaction rate and selectivity of Shi Tuoke olefination reaction of amido, chlorobenzene and amide carbonyl, enhance the catalytic capability and avoid the shortage of the catalytic capability of a single alkaline reagent.
Further, the catalyst used in the second step of reaction is one of potassium carbonate or sodium carbonate.
Further, the catalyst used in the first reaction step is used in an amount of 2.0 to 3.0eq in total molar amount based on the reactant compound I.
Further, the catalyst used in the second reaction step is 1.0 to 1.5eq of the compound III.
Further, the molar ratio of the first-step reaction compound I to the compound II is 1:1.
Further, the molar ratio of the compound III to the compound IV used in the second reaction step is 1:1.0-1.1.
Further, the first step reaction requires adding one tenth of the volume of water of the organic solvent used to the solution.
The beneficial effects of the invention are as follows: 1. the invention provides a new and effective synthesis method of dabigatran etexilate intermediate compound, which is characterized in that a new cyclization process of benzimidazole derivative is obtained by a reaction method of substituting amido and halogenated groups and transferring double bonds through further Shi Tuoke olefination reaction, so that a plurality of defects of the existing cyclization process are effectively avoided; 2. the method has the advantages of easily obtained raw materials, high reaction selectivity, good yield, few byproducts, convenient treatment of the byproducts, simple operation, mild reaction conditions and suitability for industrialized large-scale production; 3. the introduction of nitro is avoided through the reaction route, so that the toxicity in the production process is reduced; 4. the mixed alkali is adopted to control the acid-base condition of the reaction, and the two alkali reagents effectively regulate and control the reaction rate and selectivity of Shi Tuoke olefination reaction of the amido, chlorobenzene and amide carbonyl, thereby enhancing the catalytic capability.
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.
In the first step, 18.0g (0.05 mol) of compound I is dissolved in 200ml of organic solvent dichloromethane, 20ml of water is added, stirring and mixing are carried out, 4.67g (0.05 mol) of compound II is gradually added into the solution, 0.2mol of alkaline catalyst (0.1 mol of potassium carbonate and 0.1mol of triethylamine) is added, stirring and reacting for 6-8 hours at room temperature, HPLC detection is finished, standing and layering are carried out firstly, an organic layer is washed for 2-3 times by saturated saline, an organic phase is separated, the solvent is removed by reduced pressure distillation, and the product is recrystallized by toluene, washed and dried to obtain 18.2g of compound III, the yield is 91.2%, and the purity is 97.3%.
In the second step, 20.0g (0.05 mol) of compound III is dissolved in 200ml of organic solvent dichloromethane, stirred and mixed, 5.9g (0.05 mol) of compound IV is gradually added into the solution, 0.1mol of alkaline catalyst potassium carbonate is added, stirring reaction is carried out at room temperature, HPLC detection reaction is finished, standing and layering are carried out firstly, an organic layer is washed for 2-3 times by saturated saline, an organic phase is separated, the solvent is removed by reduced pressure distillation, a product is recrystallized by toluene, washed and dried, 22.8g of compound V is obtained, and the yield is 94.7% and the purity is 97.6%.
In the first step, 18.0g (0.05 mol) of compound I is dissolved in 200ml of chloroform as an organic solvent, 20ml of water is added, stirring and mixing are carried out, 4.67g (0.05 mol) of compound II is gradually added into the solution, 0.2mol of alkaline catalyst (0.1 mol of potassium carbonate and 0.1mol of triethylamine) is added, stirring and reacting for 6-8 hours at room temperature, HPLC detection is finished, standing and layering are carried out firstly, an organic layer is washed for 2-3 times by saturated saline, an organic phase is separated, the solvent is removed by reduced pressure distillation, and the product is recrystallized by toluene, washed and dried to obtain 18.0g of compound III, the yield is 90.2%, and the purity is 97.2%.
In the first step, 18.0g (0.05 mol) of compound I is dissolved in 200ml of organic solvent dichloromethane, 20ml of water is added, stirring and mixing are carried out, 4.67g (0.05 mol) of compound II is gradually added into the solution, 0.3mol of alkaline catalyst (0.15 mol of potassium carbonate and 0.15mol of triethylamine) is added, stirring and reacting for 6-8 hours at room temperature, HPLC detection is finished, standing and layering are carried out firstly, an organic layer is washed for 2-3 times by saturated saline, an organic phase is separated, the solvent is removed by reduced pressure distillation, and the product is recrystallized by toluene, washed and dried to obtain 18.3g of compound III, and the yield is 91.7% and the purity is 97.5%.
In the second step, 20.0g (0.05 mol) of compound III is dissolved in 200ml of dimethylformamide as an organic solvent, stirred and mixed, 5.9g (0.05 mol) of compound IV is gradually added into the solution, 0.1mol of alkaline catalyst potassium carbonate is added for stirring reaction at room temperature, 100ml of distilled water is added after the reaction is detected by HPLC, the mixed solution is extracted with methylene chloride for 2 to 3 times, an organic phase is separated, the organic phase is added into saturated saline water for washing for 2 to 3 times, anhydrous magnesium sulfate (MgSO 4) or anhydrous sodium sulfate (Na 2SO 4) is used for drying the organic phase, the solvent is removed by distillation under reduced pressure, and the product is recrystallized by toluene, washed and dried to obtain 22.3g of compound V with the yield of 92.6% and the purity of 97.3%.
In the second step, 20.0g (0.05 mol) of compound III is dissolved in 200ml of organic solvent dichloromethane, stirred and mixed, 5.9g (0.05 mol) of compound IV is gradually added into the solution, 0.15mol of alkaline catalyst potassium carbonate is added, stirring reaction is carried out at room temperature, HPLC detection reaction is finished, standing and layering are carried out firstly, an organic layer is washed for 2-3 times by saturated saline, an organic phase is separated, the solvent is removed by reduced pressure distillation, a product is recrystallized by toluene, washed and dried, 22.5g of compound V is obtained, and the yield is 93.4% and the purity is 97.4%.
In the second step, 20.0g (0.05 mol) of compound III is dissolved in 200ml of organic solvent dichloromethane, stirred and mixed, 5.9g (0.055 mol) of compound IV is gradually added into the solution, 0.10mol of alkaline catalyst potassium carbonate is added, stirring reaction is carried out at room temperature, HPLC detection reaction is finished, standing is carried out firstly for layering, an organic layer is washed for 2-3 times by saturated saline, an organic phase is separated, the solvent is removed by reduced pressure distillation, a product is recrystallized by toluene, washed and dried, 22.6g of compound V is obtained, and the yield is 93.8% and the purity is 97.2%.
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 (10)
1. A process synthesis method of dabigatran etexilate intermediate is characterized by comprising the following steps:
firstly, dissolving a compound I in an organic solvent, adding a compound II, adding a catalyst, stirring at room temperature for reaction for 6-8 hours, and separating a product after the reaction is finished to obtain a compound III;
and secondly, dissolving the compound III obtained in the first step in an organic solvent, adding a compound IV, adding a catalyst, reacting for 10-12 hours at room temperature, and separating a product after the reaction is finished to obtain a target product compound V.
2. The process synthesis method of the dabigatran etexilate intermediate according to claim 1, which is characterized in that: the solvent used in the first step is one of dichloromethane and chloroform.
3. The process synthesis method of the dabigatran etexilate intermediate according to claim 1, which is characterized in that: the solvent used in the second step is one of dichloromethane, dimethyl sulfoxide and dimethylformamide.
4. The process synthesis method of the dabigatran etexilate intermediate according to claim 1, which is characterized in that: the catalyst used in the first step is an alkaline reagent, and the alkaline reagent is an equimolar ratio mixture of potassium carbonate or calcium carbonate and organic base triethylamine.
5. The process synthesis method of the dabigatran etexilate intermediate according to claim 1, which is characterized in that: the catalyst used in the second step is one of potassium carbonate or sodium carbonate.
6. The process synthesis method of the dabigatran etexilate intermediate according to claim 1, which is characterized in that: the total molar quantity of the catalyst used in the first step of reaction is 2.0-3.0 eq of the reactant compound I.
7. The process synthesis method of the dabigatran etexilate intermediate according to claim 1, which is characterized in that: the dosage of the catalyst used in the second step is 1.0-1.5 eq of the compound III.
8. The process synthesis method of the dabigatran etexilate intermediate according to claim 1, which is characterized in that: the molar ratio of the first step reaction compound I to the compound II is 1:1.
9. The process synthesis method of the dabigatran etexilate intermediate according to claim 1, which is characterized in that: the molar ratio of the compound III to the compound IV used in the second reaction step is 1:1.0-1.1.
10. The process synthesis method of the dabigatran etexilate intermediate according to claim 1, which is characterized in that: the first step requires the addition of one tenth of the volume of water of the organic solvent used to the solution.
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