CN103275065A - Novel method for producing dabigatran etexilate - Google Patents
Novel method for producing dabigatran etexilate Download PDFInfo
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- CN103275065A CN103275065A CN2013102114445A CN201310211444A CN103275065A CN 103275065 A CN103275065 A CN 103275065A CN 2013102114445 A CN2013102114445 A CN 2013102114445A CN 201310211444 A CN201310211444 A CN 201310211444A CN 103275065 A CN103275065 A CN 103275065A
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Abstract
The invention relates to a novel method for synthesizing dabigatran etexilate. The method comprises the following steps of: 1, performing an esterification reaction by using methylamino-m-nitrobenzoate (D1) as a raw material to obtain an esterification product (D2); 2, reducing the nitryl of the obtained esterification product (D2) into amino to obtain a reducing product (D3); 3, reacting the reducing product (D3) with a compound (D10) to obtain an intermediate (D4); 4, reacting the intermediate (D4) with hydrogen to obtain an intermediate (D5); 5, reacting the intermediate (D5) with chloroformate to obtain an intermediate (D6); 6, removing the R1-O- from the intermediate (D6) to obtain an intermediate (D7); and 7, reacting the intermediate (D7) with a reaction raw material (D8) to obtain the dabigatran etexilate (D9). According to the novel method for synthesizing the dabigatran etexilate, the required raw materials and reagents are cheap and easily available, and the cost is low; reaction at each step is good, the selectivity is high, the synthesis method is simple to operate, and the condition is mild; the total yield can reach 52 percent and the purity is over 99 percent; the method is less in emission of three wastes, environment-friendly and suitable for industrialized mass production; and the dabigatran etexilate has stable quality and accords with the requirement of serving as a medicine intermediate.
Description
Technical field
The present invention relates to a kind of production method of compound, relate in particular to a kind of method of new production dabigatran ester.
Background technology
The dabigatran ester is a kind of new synthetic direct thrombin inhibitors, is the prodrug of dabigatran, belongs to the thrombin inhibitors of non-peptide class.Oral after stomach and intestine absorb, be converted into the dabigatran with direct anticoagulant active in vivo.Dabigatran is incorporated into the scleroproein specific combination site of zymoplasm, stop Fibrinogen to be cracked into scleroproein, thereby final step and the thrombosis of blood coagulation waterfall network have been blocked, dabigatran can dissociate from scleroproein one zymoplasm combination, brings into play reversible anticoagulation.
The dabigatran ester is the direct thrombin inhibitors of of new generation oral anticoagulant (DTIs) of forefront, at the prevention of acute and chronic thrombotic disease and treat the clinical demand that this urgent need satisfies.Direct thrombin inhibitors blocks zymoplasm (free type and mating type) activity by specificity and brings into play powerful anti-freezing curative effect, and zymoplasm is the enzyme with central role in the thrombosis process.Different with the vitamin K antagonist that acts on different thrombin, the dabigatran ester can provide effective, predictable, stable anti-freezing effect, less generation drug interaction simultaneously, no medicine food interacts, and need not routine and carries out coagulation function monitoring or dose titration.
Patent WO9837075 reported first the synthetic method of dabigatran ester, its route is as follows:
In this synthetic method, the method for palladium carbon hydrogenation has been used in the reduction of compound III nitro.But here, the technical requirements of this method is very high, needs high pressure reaction assembly.Even more important a bit is that hydrogenation reduction is difficult to obtain high-quality product I V, reacts the impurity that the oily product that obtains contains 20-40% usually, for its separation and purification has caused great difficulty.Next the reaction yield by compound IV and V synthesizing benzimidazole has only about 50% usually, and the purifying of compound VI needs column chromatography to separate.Above-mentioned these shortcomings make the method for this synthetic dabigatran ester not be suitable for the amplification production of technical grade.Amidineization reaction preference subsequently is also relatively poor, produces strongly acid wastewater.And because the just own ester of chloroformic acid contains more isomer impurities, as final step reaction main raw material, cause the finished product needs repeatedly to be made with extra care and just can make qualified product, the cost height.
Summary of the invention
At the problems referred to above, the invention provides a kind of method of new production dabigatran ester.This production method, desired raw material and reagent are cheap and easy to get, and cost is low; Each step reaction is good, the selectivity height, and production method is simple to operate, mild condition; Total recovery can reach 52%, and purity is more than 99%, and three waste discharge is few, and is environmentally friendly, is fit to industrialized production, and constant product quality, meets the requirement as pharmaceutical intermediate.
The present invention includes following technical scheme:
A kind of method of new production dabigatran ester, wherein, step comprises:
Step 1 is raw material to methylamino--M-NITROBENZOIC ACID (D1), carries out esterification, obtains esterification products (D2);
Wherein, R
1Be alkyl;
Step 2 is amino with the nitroreduction in the esterification products (D2), obtains reduzate (D3);
Step 3 with reduzate (D3) and compound (D10) reaction, obtains intermediate (D4);
Step 4, intermediate (D4) and hydrogen reaction obtain intermediate (D5);
Step 5, intermediate (D5) obtains intermediate (D6) with the chloro-formic ester reaction
Wherein, R is alkyl;
Step 6 removes the R of intermediate (D6)
1-O-obtains intermediate (D7);
Step 7, intermediate (D7) and reaction raw materials (D8) reaction obtain intermediate dabigatran ester (D9);
The method of above-mentioned new production dabigatran ester wherein, in the step 1, is preferably: with N, under dinethylformamide, thionyl chloride, triethylamine exist, react down at 85-100 ℃.
The method of above-mentioned new production dabigatran ester, wherein, more preferably: in the step 1, order of addition(of ingredients) is as follows: add D1 and N earlier, dinethylformamide, add thionyl chloride under 60 ℃ of temperature, 85-100 ℃ of reaction down (reaction times is preferably 0.5-1.5 hour) obtains intermediate product (D1-1); Described intermediate product (D1-1) mixes with ethanol, adds to drip triethylamine, insulation reaction (reaction times is preferably 0.5-1.5 hour) in 60-65 ℃ of scope.
The method of above-mentioned new production dabigatran ester, wherein, more preferably: in the step 1, the material molar ratio of D1, thionyl chloride, triethylamine is preferably 1: (1.7-2.4): (0.8-1.2).
The method of above-mentioned new production dabigatran ester, wherein, more preferably: in the step 1, reaction solvent is preferably toluene.
The method of above-mentioned new production dabigatran ester, wherein, in the step 2, temperature of reaction is preferably 50-65 ℃.
The method of above-mentioned new production dabigatran ester, wherein, in the step 2, reaction solvent is preferably ethyl acetate.
The method of above-mentioned new production dabigatran ester, wherein, in the step 2, catalyzer can be any hydrogenation catalyst, is preferably 10% palladium-carbon catalyst.
The method of above-mentioned new production dabigatran ester, wherein, in the step 3, be preferably: at N, the N'-carbonyl dimidazoles exists down, 45-60 ℃ of reaction (reaction reagent is preferably 0.5-1.5 hour), obtains intermediate product (D2-1), intermediate product (D2-1) is with the glacial acetic acid dissolving, in 85-100 ℃ of reaction (reaction reagent is preferably 1-5 hour).
The method of above-mentioned new production dabigatran ester, wherein, more preferably: in the step 3, the material molar ratio of D10, D3 is 3: (1.8-2.2).
The method of above-mentioned new production dabigatran ester, wherein, more preferably: in the step 3, solvent is tetrahydrofuran (THF).
The method of above-mentioned new production dabigatran ester wherein, in the step 4, is preferably: palladium-carbon catalyst exists down, and D4 and hydrogen are 35-50 ℃ of reaction.
The method of above-mentioned new production dabigatran ester, wherein, more preferably: in the step 4, solvent is N, dinethylformamide.
The method of above-mentioned new production dabigatran ester wherein, in the step 5, is preferably: in the presence of alkaline carbonate, D5 and chloro-formic ester react under≤15 ℃ of conditions.
The method of above-mentioned new production dabigatran ester, wherein, described alkaline carbonate is preferably salt of wormwood.
The method of above-mentioned new production dabigatran ester, wherein, more preferably: in the step 5, the material molar ratio of D5 and the own ester of chloroformic acid is 1: (1-2).
The method of above-mentioned new production dabigatran ester, wherein, more preferably: in the step 5, solvent is tetrahydrofuran (THF).
The method of above-mentioned new production dabigatran ester wherein, in the step 6, is preferably: 80-90 ℃ of reaction, reaction receives the back and carries out acidifying with acid with D6 and alkali.
The method of above-mentioned new production dabigatran ester, wherein, more preferably: in the step 6, the material molar ratio of D6 and alkali is 1: (1.5-2.5).
The method of above-mentioned new production dabigatran ester, wherein, more preferably: in the step 6, D6 and alkali reaction time are 3-3.5 hour.
The method of above-mentioned new production dabigatran ester, wherein, described alkali can be ammoniacal liquor, oxyhydroxide, is preferably potassium hydroxide, sodium hydroxide, most preferably is potassium hydroxide.
The method of above-mentioned new production dabigatran ester, wherein, described acid is preferably sulfuric acid, hydrochloric acid, nitric acid, formic acid, more preferably hydrochloric acid.
Described alkali is preferably with the form of the aqueous solution and D6 reaction.
The method of above-mentioned new production dabigatran ester wherein, in the step 7, is preferably: in the presence of thionyl chloride, D7 and D8 are 40-50 ℃ of reaction.
The method of above-mentioned new production dabigatran ester, wherein, charging process is in the step 7: D7 and D8 join and are warming up to 25-40 ℃ in the reaction solvent, after 25-35 minute, add thionyl chloride.
The method of above-mentioned new production dabigatran ester, wherein, more preferably: in the step 7, D7 and D8 raw material ratio are 1: (0.8-1.3).
The method of above-mentioned new production dabigatran ester, wherein, more preferably: in the step 7, the reaction times is 3-3.5 hour.
The method of above-mentioned new production dabigatran ester, wherein, more preferably: in the step 7, reaction solvent is methylene dichloride.
The method of above-mentioned new production dabigatran ester, wherein, R
1Can be the alkyl of straight chain or branching, and be preferably saturated hydrocarbyl that more preferably the saturated hydrocarbyl of C1-C4 as methyl, ethyl, propyl group, sec.-propyl, butyl, most preferably is ethyl.
The method of above-mentioned new production dabigatran ester, wherein, R can be the alkyl of straight chain or branching, and is preferably saturated hydrocarbyl, the saturated hydrocarbyl of C4-C10 more preferably, and, R
1Different with R.
The method of above-mentioned new production dabigatran ester, wherein, R is preferably butyl, amyl group, hexyl, octyl group, heptyl, nonyl, decyl, most preferably is hexyl.
In the step 1 or 3, be preferably under oxygen free condition and carry out, more preferably under the anhydrous and oxygen-free condition, carry out, and be preferably in inert gas environment and carry out, described rare gas element is preferably nitrogen, argon gas, helium, most preferably is any one or its mixed gas in nitrogen, the argon gas.
The beneficial effect that the technical program produces is:
The method of new production dabigatran ester, desired raw material and reagent are cheap and easy to get, and cost is low; Each step reaction is good, the selectivity height, and production method is simple to operate, mild condition; Total recovery can reach 52%, and purity is more than 99%, and three waste discharge is few, and is environmentally friendly, is fit to industrialized production, and constant product quality, meets the requirement as pharmaceutical intermediate.
Description of drawings
Fig. 1 is the reacting flow chart of producing the dabigatran ester.
Embodiment
The invention provides a kind of method of new production dabigatran ester, as shown in Figure 1, may further comprise the steps a kind of method of new production dabigatran ester, wherein, step comprises:
Step 1 is raw material to methylamino--M-NITROBENZOIC ACID (D1), carries out esterification, obtains esterification products (D2);
Wherein, R
1Be alkyl;
Step 2 is amino with the nitroreduction in the esterification products (D2), obtains reduzate (D3);
Step 3 with reduzate (D3) and compound (D10) reaction, obtains intermediate (D4);
Step 4, intermediate (D4) and hydrogen reaction obtain intermediate (D5);
Step 5, intermediate (D5) obtains intermediate (D6) with the chloro-formic ester reaction
Wherein, R is alkyl;
Step 6 removes the R of intermediate (D6)
1-O-obtains intermediate (D7);
Step 7, intermediate (D7) and reaction raw materials (D8) reaction obtain intermediate dabigatran ester (D9);
Mode below by embodiment further specifies the present invention.
Embodiment 1
Step 1): be reflected in the four-hole reaction flask of 500ml and carry out; be preferably under the protection of inert gas; with 60g(0.306mol) D1(4-methylamino--3-nitro-phenylformic acid; CAS:41263-74-5; or reference: people such as Zhang Weiguang; synthetic 3-(2-pyridine amino) technical study of ethyl propionate; synthetic chemistry; the 69th phase in 2012) with the toluene of 300ml at catalyst n; 90 ℃ of following insulation reaction of dinethylformamide (catalytic amount: 2); wherein; when system temperature is 60 ℃, drip 73g(0.613mol) thionyl chloride, system clarification afterreaction concentrated the back in about 1 hour and adds 300ml ethanol; be warming up to 60-65 ℃ of dropping 32g(0.316mol) triethylamine, insulation reaction 1 hour.Reaction solution is concentrated into dried, methylene dichloride dissolving enriched material is used saturated sodium bicarbonate solution (100ml) and water (100ml) to wash successively, and is dewatered with anhydrous sodium sulfate drying; Described thickening and washing dehydration crystallization is after organic layer is concentrated to certain volume, to cool to 0-5 ℃, and crystallization one hour filters, and filter cake washs 2 times with cold methylene dichloride (25ml), and 60 ℃ of oven dry get yellow crystals D2; Described yellow crystals D2 requires purity〉98.5%, yield 87.5%.
Step 2): described being reflected in the hydrogenation still carried out, with 60g(0.268mol) D2 and the ethyl acetate of 300ml be warming up to 60 ℃, be warmed up to 60 ℃, after the system clarification, drop into 10% palladium carbon (6g); Describedly displace air hydrogenation, follow the tracks of reaction process (developping agent EA) with TLC; After reaction in 2 hours finishes, cool to below 40 ℃, use EA(25ml) wash after, merging filtrate, 50 ℃ of following vacuum concentration go out the ethyl acetate solvent of half, cool to 15 ℃ of following crystallizatioies then 1.5 hours, filter filter cake and use the cold ethyl acetate of 25ml to wash 2 times, 50 ℃ of oven dry get white solid D3; Described white solid D3 requires purity〉98.5%, yield 96.2%.
In the step 3): reaction is to carry out in the four-hole reaction flask of 1L, with 50.05g(0.309mol) N, be warming up to 50 ℃ in N'-carbonyl dimidazoles and the 400ml anhydrous tetrahydro furan, system is molten to add 72.6g(0.309mol after clear slowly) D10(CAS:872728-82-0; Synthetic document: WO2006000353); Described insulation reaction one hour; Disposable adding 40g(0.206mol) D3, TLC follows the tracks of reaction; After treating that D3 disappears, reaction solution is fallen tetrahydrofuran (THF) at 60 ℃ of vacuum concentration; Residuum is dissolved with glacial acetic acid (400ml), and temperature is warming up to 90 ℃, react 2 hours (having red solid to produce in the reaction process gradually), finish the back and add 1L water, and be cooled to room temperature, filtration; Described washing is with filter cake 100ml water washing 3 times, then 70 ℃ of normal pressures oven dry; Described red solid D4 requires purity〉98.5%; Yield 98.8%.
In the step 4): be reflected in the hydrogenation still and carry out, with 80g(0.203mol) D4 and the N of 600ml, N '-dimethyl formamide is warming up to 70 ℃, system molten clear after, drop into 10% palladium carbon (8g); Displaced air hydrogenation is followed the tracks of to react to D4 with TLC and is disappeared; Be cooled to filter cake minor N in 40 ℃ of described filtrations, N '-dimethyl formamide (25ml) washing 2 times, filtrate concentrates out N under 70 ℃ of vacuum, N '-dimethyl formamide; Described after residuum adds the 300ml ethyl acetate, room temperature making beating 30 minutes, filter, filter cake obtains white crystal with ethyl acetate (50ml) washing 2 times, 50 ℃ of oven dry filter cakes; The described white crystal D5 that obtains requires purity〉98.5%, yield 98.2%.
In the step 5): with 70g(0.199mol) D5 and below the water for cooling to 15 of the tetrahydrofuran (THF) of 700ml and 700ml ℃, adding 55.2g(0.4mol) salt of wormwood, drip 49g(0.298mol after 5 minutes) the own ester of chloroformic acid (CAS:6092-54-2), dropwised in 30 minutes, insulation reaction disappears to D5, the water of adding 500ml, stirred 1 hour, filter then, wash 2 times, 50 ℃ of oven dry obtain white solid D6; Described white solid D6 requires purity〉98.5%, yield 90.9%.
In the step 6): with 86.7g(0.181mol) D6 and 72.4ml(0.4525mol) 25% sodium hydroxide be warming up to 85 ℃, reaction 2.5-3.5, reaction solution becomes clarification, it is 4.5 with hydrochloric acid adjusting conditioned reaction objects system pH value that the reaction of TLC tracing display finishes the back, filter, filter cake obtains white solid D7 with twice, 60 ℃ of vacuum-drying of 100ml water washing; Described white solid requires purity〉98.5%, yield 90.9%.
In the step 7): with 74.51g(0.01mol) D7 and 8979g(0.0102mol) D8(3-(pyridine-2-base-amino) ethyl propionate, CAS:103041-38-9) methylene dichloride that adds 50ml in, be warming up to 30 ℃, after 30 minutes, drip 3.59(0.03mol) thionyl chloride, be warming up to 45 ℃ of reactions 3 hours after dropwising in 10 minutes.After reaction finishes.Temperature of reaction system is dropped to 20 ℃ of room temperatures, slowly add 20ml water, stirred 30 minutes, static 10 minutes then, separate obtaining organic layer, the organic layer saturated NaHCO of 10ml
3Solution washing 3 times, with clear water 10ml washing once, 10g anhydrous sodium sulfate drying 2 hours filters, and filtrate concentrating obtains D9 by acetone water recrystallization.
Embodiment 2
Step 1): under the nitrogen protection; with the toluene of the D1 of 0.25mol and 300ml at catalyst n; 88 ℃ of following insulation reaction of dinethylformamide (catalytic amount: 2); wherein; when system temperature is 56 ℃, drip the thionyl chloride of 0.501mol, system clarification afterreaction concentrated the back in about 1 hour and adds 300ml ethanol; be warming up to 60-65 ℃ of dropping 0.253mol triethylamine, insulation reaction 1 hour.Reaction solution is concentrated into dried, methylene dichloride dissolving enriched material is used saturated sodium bicarbonate solution and water washing successively, drying and dehydrating, and crystallization filters, and gets yellow crystals D2; Described yellow crystals D2 requires purity〉98.5%, yield 87.3%.
Step 2): the D2 of 0.25mol and the ethyl acetate of 300ml are warming up to 60 ℃, are warmed up to 60 ℃, after the system clarification, drop into 10% palladium carbon; The described air that displaces carries out hydrogenation, after reaction in 2 hours finishes, cools to below 40 ℃, and crystallization 1.5 hours filters filter cake and uses the cold ethyl acetate of 25ml to wash 2 times, and 50 ℃ of oven dry get white solid D3; Described white solid D3 requires purity〉98.5%, yield 96.2%.
In the step 3): reaction is to carry out in the four-hole reaction flask of 1L, with 0.3mol N, is warming up to 50 ℃ in N'-carbonyl dimidazoles and the 400ml anhydrous tetrahydro furan, and system is molten to add 0.298mol D10 after clear slowly; Described insulation reaction one hour; Disposable adding 0.206mol D3, TLC follows the tracks of reaction; After treating that D3 disappears, reaction solution is fallen tetrahydrofuran (THF) at 60 ℃ of vacuum concentration; Residuum is dissolved with glacial acetic acid (400ml), and temperature is warming up to 90 ℃, reacted 2 hours; Described red solid D4 requires purity〉98.5%; Yield 99.2%.
In the step 4): be reflected in the hydrogenation still and carry out, with the D4 of 0.2mol and the N of 600ml, N '-dimethyl formamide is warming up to 70 ℃, system molten clear after, drop into 10% palladium carbon; Displaced air hydrogenation; Filter, filtrate concentrates out N under 70 ℃ of vacuum, N '-dimethyl formamide; Described after residuum adds the 300ml ethyl acetate, room temperature making beating 30 minutes, filter and obtain white crystal; The described white crystal D5 that obtains requires purity〉98.5%, yield 98.0%.
In the step 5): with below the water for cooling to 15 of the tetrahydrofuran (THF) of the D5 of 0.201mol and 700ml and 700ml ℃, add the salt of wormwood of 0.398mol, drip the own ester of chloroformic acid of 0.3mol after 5 minutes, dropwised in 30 minutes, insulation reaction obtains white solid D6; Described white solid D6 requires purity〉98.5%, yield 92.0%.
In the step 6): the D6 of 0.18mol and the sodium hydroxide of 0.42mol (25wt% solution) are warming up to 85 ℃, and it is 4.5 with hydrochloric acid conditioned reaction objects system pH value that reaction finishes the back, filters and obtains white solid D7; Described white solid requires purity〉98.5%, yield 91.5%.
In the step 7): with adding the methylene dichloride of 100ml among the D8 of the D7 of 0.02mol and 0.02mol, be warming up to 30 ℃, after 30 minutes, drip the 0.032mol thionyl chloride, be warming up to 45 ℃ of reactions 3 hours.React and finish, extraction, washing, dry, filtration, acetone water recrystallization obtains D9.
According to above-described embodiment evidence, use method provided by the invention, can produce the dabigatran ester, desired raw material and reagent are cheap and easy to get, and cost is low; Each step reaction is good, the selectivity height, and production method is simple to operate, mild condition; Total recovery can reach 52%, and purity is more than 99%, and three waste discharge is few, and is environmentally friendly, is fit to industrialized production, and constant product quality, meets the requirement as pharmaceutical intermediate.
More than specific embodiments of the invention are described in detail, but it is just as example, the present invention is not restricted to specific embodiment described above.To those skilled in the art, any equivalent modifications that the present invention is carried out and substituting also all among category of the present invention.Therefore, not breaking away from impartial conversion and the modification of doing under the spirit and scope of the present invention, all should contain within the scope of the invention.
Claims (11)
1. the method for a new synthetic dabigatran ester is characterized in that step comprises:
Step 1 is raw material to methylamino--M-NITROBENZOIC ACID (D1), carries out esterification, obtains esterification products (D2);
Wherein, R
1Be alkyl;
Step 2 is amino with the nitroreduction in the esterification products (D2), obtains reduzate (D3);
Step 3 with reduzate (D3) and compound (D10) reaction, obtains intermediate (D4);
Step 4, intermediate (D4) and hydrogen reaction obtain intermediate (D5);
Step 5, intermediate (D5) obtains intermediate (D6) with the chloro-formic ester reaction
Wherein, R is alkyl;
Step 6 removes the R of intermediate (D6)
1-O-obtains intermediate (D7);
Step 7, intermediate (D7) and reaction raw materials (D8) reaction obtain intermediate dabigatran ester (D9);
2. method according to claim 1 is characterized in that, in the step 1, with N, under dinethylformamide, thionyl chloride, triethylamine exist, reacts down at 85-100 ℃.
3. method according to claim 2 is characterized in that, in the step 1, order of addition(of ingredients) is as follows: add people D1 and N earlier, dinethylformamide adds thionyl chloride under 60 ℃ of temperature, 85-100 ℃ was reacted down 0.5-1.5 hour, and obtained intermediate product (D1-1); Described intermediate product (D1-1) mixes with ethanol, adds to drip triethylamine, insulation reaction 0.5-1.5 hour in 60-65 ℃ of scope.
4. method according to claim 1 is characterized in that, reaction method is in the step 3: at N, the N'-carbonyl dimidazoles exists down, 45-60 ℃ of reaction 0.5-1.5 hour, obtains intermediate product (D2-1), intermediate product (D2-1) is with the glacial acetic acid dissolving, 85-100 ℃ of reaction.
5. method according to claim 1 is characterized in that, reaction described in the step 4 is: palladium-carbon catalyst exists down, and D4 and hydrogen are 35-50 ℃ of reaction.
6. method according to claim 1 is characterized in that, reaction described in the step 5 is: in the presence of alkaline carbonate, D5 and chloro-formic ester react under≤15 ℃ of conditions.
7. method according to claim 1 is characterized in that, step 6 reaction is: 80-90 ℃ of reaction, reaction receives the back and carries out acidifying with acid with D6 and alkali.
8. method according to claim 1 is characterized in that, the described reaction of step 7 is: in the presence of thionyl chloride, D7 and D8 are 40-50 ℃ of reaction.
9. method according to claim 8 is characterized in that, charging process is in the step 7: D7 and D8 join and are warming up to 25-40 ℃ in the reaction solvent, after 25-35 minute, add thionyl chloride.
10. method according to claim 1 is characterized in that, R
1Saturated hydrocarbyl for C1-C4.
11., it is characterized in that R is the saturated hydrocarbyl of C4-C10 according to claim 1 or 10 described methods, and, R
1Different with R.
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Cited By (2)
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| CN105523999A (en) * | 2014-10-21 | 2016-04-27 | 重庆医药工业研究院有限责任公司 | Dabigatran etexilate intermediate synthesis method |
| 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 |
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| CN105523999A (en) * | 2014-10-21 | 2016-04-27 | 重庆医药工业研究院有限责任公司 | Dabigatran etexilate intermediate synthesis method |
| CN105523999B (en) * | 2014-10-21 | 2020-04-24 | 重庆医药工业研究院有限责任公司 | Synthesis method of dabigatran etexilate intermediate |
| 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 |
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