CN111253369A - Benzene sulfonate, preparation method thereof and application of benzene sulfonate in preparation of dabigatran etexilate - Google Patents
Benzene sulfonate, preparation method thereof and application of benzene sulfonate in preparation of dabigatran etexilate Download PDFInfo
- Publication number
- CN111253369A CN111253369A CN201811457484.7A CN201811457484A CN111253369A CN 111253369 A CN111253369 A CN 111253369A CN 201811457484 A CN201811457484 A CN 201811457484A CN 111253369 A CN111253369 A CN 111253369A
- Authority
- CN
- China
- Prior art keywords
- compound
- formula
- reaction
- acid
- dabigatran etexilate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The invention relates to benzene sulfonate shown in a formula 7, a preparation method thereof and application thereof in preparing dabigatran etexilate. The invention also discloses a method for preparing dabigatran etexilate, which comprises the following steps: (1) in the presence of a solvent and an acid-attaching agent, carrying out addition reaction on the compound 1 and hydroxylamine hydrochloride to obtain a compound 5; (2) under the action of a reducing agent, carrying out reduction reaction on the compound 5 and hydrogen, and salifying the compound and benzenesulfonic acid to obtain benzenesulfonate shown in a formula 7; (3) and carrying out amidation reaction on the benzene sulfonate shown in the formula 7 and n-hexyl chloroformate to obtain a compound 4, namely dabigatran etexilate. According to the preparation method of dabigatran etexilate, hydrogen chloride polluting the environment and corroding equipment is not used in the process of cyano amidine formation; simultaneously avoids the reduction of iron acetate powder which is about to be eliminated industriallyAnd the dabigatran etexilate with high purity can be obtained.
Description
Technical Field
The invention relates to a benzene sulfonate, a preparation method thereof and application thereof in preparing dabigatran etexilate.
Background
Cardiovascular drugs are always unique directions of drug development companies, and the field of anticoagulation is a hard dish in a cardiovascular large meal, namely warfarin and heparin drugs in textbooks, or blood coagulation factor inhibitors, thrombin inhibitors, PAR-1 antagonists and the like which are developed rapidly in recent years, and the research and development of anticoagulation drugs are absolutely on the way. Among them, dabigatran etexilate, a direct thrombin inhibitor that was approved by the FDA in the united states in 2010, is available. As a novel oral anticoagulant drug approved by FDA for more than 50 years after warfarin, the oral anticoagulant drug becomes a major breakthrough in the field of anticoagulation by virtue of the characteristics of oral administration, strong effect, no need of special medication monitoring, less drug interaction and the like, and has milestone significance.
In the synthesis process of the dabigatran etexilate, the synthesis of 3- {2- [ (4-amidino anilino) methyl ] -1-methyl-benzimidazole-5- [ N- (2-pyridyl) formamido ] } -ethyl propionate is the key point of the whole process. This procedure is currently generally carried out by the Pinner reaction (j.med. chem.2002,45,1757), i.e. the reaction of cyano groups with ethanol under the action of hydrogen chloride to give the hydrochloride of the imidate, and then with ammonium carbonate or ammonia to give the amidino group. In the reaction process, the hydrogen chloride gas amount is reduced, so that the raw materials are not reacted completely; sufficient hydrogen chloride gas causes the increase of impurities, and the waste of materials is caused; the use of a large amount of hydrogen chloride gas can cause corrosion of equipment and environmental pollution, and the production cost is greatly increased. The reaction route is as follows:
patent CN105348262A through the two-step reaction of hydroxylamine addition to cyano-group and reduction of iron powder acetic acid, through salifying with hydrogen chloride and obtained compound 3, not only used hydrogen chloride in above synthetic route, still used the iron acetate powder, can produce a large amount of waste water and waste material in the amplification process, polluted the environment equally. Meanwhile, in the post-treatment process for preparing the compound 3, the mother liquor needs to be concentrated under acidic conditions, which can cause ester hydrolysis in the structure and generate unnecessary impurities 6. The reaction route is as follows:
disclosure of Invention
The technical problem to be solved by the invention is as follows: the problems in the prior art are solved, and hydrogen chloride which pollutes the environment and corrodes equipment is not used in the process of cyanamidine reaction; and simultaneously, iron acetate powder which is about to be eliminated in industry is avoided being used for reduction, and an improved method for preparing dabigatran etexilate is provided.
First, the present invention provides a benzenesulfonate salt represented by formula 7:
the invention also provides a preparation method of the benzene sulfonate shown in the formula 7:
under the action of a reducing agent, the compound 5 and hydrogen undergo a reduction reaction, and then salified with benzenesulfonic acid to obtain the benzenesulfonate shown in the formula 7.
Preferably, the reducing agent is selected from Pd/C, Pd (OH)2Or raney Ni, more preferably raney Ni;
preferably, the reduction reaction temperature is 50-70 ℃, and more preferably 55-65 ℃; the reduction reaction time is 20-30 hours, and more preferably 22-26 hours;
preferably, the reduction reaction is carried out in the presence of a solvent, which is one or a mixture of both of acetic acid and water.
Further, the compound 5 can be prepared by the following steps:
in the presence of a solvent and an acid-adding agent, the compound 1 and hydroxylamine hydrochloride undergo an addition reaction to obtain a compound 5.
In the above reaction, compound 1, ethyl 3- [ [ [2- [ [ (4-cyanophenyl) amino ] methyl ] -1-methyl-1H-benzimidazol-5-yl ] carbonyl ] pyridin-2-ylamino ] propanoate, is a known compound having CAS number: 211915-84-3.
Preferably, the solvent of the addition reaction is selected from methanol, ethanol and dimethyl sulfoxide, more preferably dimethyl sulfoxide.
Preferably, the acid-attaching agent is selected from sodium methoxide, sodium ethoxide, triethylamine and diisopropylethylamine, more preferably triethylamine or diisopropylethylamine.
Preferably, the molar ratio of the compound 1 to the hydroxylamine hydrochloride is 1: 1 to 1: 4; the molar ratio of compound 1 to base is 1: 1 to 1: 4.
Preferably, the addition reaction temperature is 10-40 ℃, and more preferably 20-30 ℃; the reaction time is 15 to 30 hours, more preferably 20 to 25 hours.
The invention also provides the application of the benzene sulfonate shown in the formula 7 in preparing the compound 4 dabigatran etexilate:
therefore, the invention also provides a method for preparing the compound 4 dabigatran etexilate by using the benzene sulfonate shown in the formula 7, which comprises the following steps:
and carrying out amidation reaction on the benzene sulfonate shown in the formula 7 and n-hexyl chloroformate to obtain a compound 4, namely dabigatran etexilate.
Wherein, the benzene sulfonate shown in the formula 7 can be prepared by the steps.
Preferably, the amidation reaction is carried out in the presence of an acid-adding agent, wherein the acid-adding agent is one of potassium carbonate, sodium carbonate, potassium bicarbonate and sodium bicarbonate.
Accordingly, the present invention also provides a method for preparing dabigatran etexilate, comprising the steps of:
(1) in the presence of a solvent and an acid-attaching agent, carrying out addition reaction on the compound 1 and hydroxylamine hydrochloride to obtain a compound 5;
(2) under the action of a reducing agent, carrying out reduction reaction on the compound 5 and hydrogen, and salifying the compound and benzenesulfonic acid to obtain benzenesulfonate shown in a formula 7;
(3) and carrying out amidation reaction on the benzene sulfonate shown in the formula 7 and n-hexyl chloroformate to obtain a compound 4, namely dabigatran etexilate.
Preferably, the solvent in the addition reaction of step (1) is selected from methanol, ethanol and dimethyl sulfoxide, more preferably dimethyl sulfoxide;
preferably, the acid-attaching agent in the step (1) is selected from sodium methoxide, sodium ethoxide, triethylamine and diisopropylethylamine, preferably triethylamine or diisopropylethylamine.
Preferably, the molar ratio of the compound 1 to the hydroxylamine hydrochloride is 1: 1 to 1: 4; the molar ratio of compound 1 to base is 1: 1 to 1: 4.
Preferably, the addition reaction temperature is 10-40 ℃, and more preferably 20-30 ℃; the reaction time is 15 to 30 hours, more preferably 20 to 25 hours.
Preferably, the catalyst for the hydrogenation reaction in step (2) is selected from Pd/C, Pd (OH)2Raney Ni is preferred. Preferably, the adding amount of the catalyst is 5-10% of the mass of the compound 5; when the catalyst is Raney nickel (Raney Ni), the amount of the catalyst is not less than 5% of the mass of the compound 5.
Preferably, the hydrogenation reaction temperature in the step (2) is 50-70 ℃, and more preferably 55-65 ℃; the hydrogenation reaction time is 20 to 30 hours, and more preferably 22 to 26 hours.
Preferably, the amidation reaction in step (3) is performed in the presence of an acid-adding agent, wherein the acid-adding agent is one of potassium carbonate, sodium carbonate, potassium bicarbonate and sodium bicarbonate.
Preferably, the temperature of the amidation reaction in the step (3) is 5-40 ℃, more preferably 10-20 ℃, and the time of the amidation reaction is 0.5-2 hours, more preferably 1-2 hours.
As a more preferred method of preparation, there is provided,
the step (1) may specifically be: dissolving the compound 1 in dimethyl sulfoxide, adding hydroxylamine hydrochloride, dropwise adding an acid attaching agent (such as triethylamine or diisopropylethylamine), controlling the temperature to be 20-30 ℃, reacting for 20-25 hours, adding a proper amount of purified water, and filtering to obtain a compound 5; wherein the molar ratio of the compound 1 to the hydroxylamine hydrochloride is 1: 1-1: 4; the molar ratio of compound 1 to base is 1: 1 to 1: 4.
The step (2) may specifically be: dissolving the compound 5 in an acetic acid aqueous solution, adding a catalyst (such as Raney Ni), hydrogenating under a hydrogen atmosphere, controlling the reaction temperature to be 55-65 ℃, reacting for 22-26 hours, filtering, sequentially adding benzenesulfonic acid and ammonia water into the filtrate, and filtering to obtain the benzenesulfonate shown in the formula 7. Wherein the molar ratio of the compound 5 to the benzenesulfonic acid is 1: 1-1: 4; the molar ratio of the compound 5 to ammonia water is 1: 1-1: 4.
The step (3) may specifically be: the benzene sulfonate shown in the formula 7 and n-hexyl chloroformate are subjected to amidation reaction under the action of an acid-attaching agent (such as potassium carbonate, sodium carbonate, potassium bicarbonate or sodium bicarbonate) to obtain a compound 4 (namely dabigatran etexilate), wherein the temperature of the amidation reaction is 5-40 ℃, and the time is 0.5-2 hours.
By adopting the technical scheme, the dabigatran etexilate with higher purity can be prepared.
Detailed Description
The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention.
All the starting materials referred to in the following examples are known substances and are commercially available.
EXAMPLE 1
Preparation of compound 5:
adding 180mL of dimethyl sulfoxide into a reaction bottle, adding 36.2g of the compound 1 while stirring, adding 20.7g of hydroxylamine hydrochloride after dissolution, slowly dropwise adding 30g of triethylamine, keeping the temperature of 20-30 ℃ after dropwise adding, reacting for 24 hours, slowly dropwise adding 720mL of purified water, filtering, washing a filter cake with 30mL of purified water, and drying to obtain 27g of a compound 5, wherein the yield is as follows: 70 percent.
1H NMR(400MHz,DMSO)δ9.25(s,1H),8.40(dd,J＝4.8,1.2Hz,1H),7.61–7.52(m,1H),7.48(t,J＝5.0Hz,1H),7.40(dd,J＝8.4,6.9Hz,3H),7.24–7.05(m,2H),6.90(d,J＝8.1Hz,1H),6.73(t,J＝11.3Hz,2H),6.44(t,J＝5.5Hz,1H),5.55(s,2H),4.53(d,J＝5.5Hz,2H),4.24(t,J＝7.1Hz,2H),3.98(q,J＝7.1Hz,2H),3.77(s,3H),2.77–2.62(m,2H),1.20–1.08(m,3H).
EXAMPLE 2
Preparation of compound 5:
adding 125mL of methanol into a reaction bottle, adding 36.2g of the compound 1 while stirring, adding 5.2g of hydroxylamine hydrochloride after dissolution, heating to 58 ℃, slowly dropwise adding 19.3g of 21% sodium methoxide methanol solution, keeping the temperature of 55 ℃ after dropwise adding for reaction for 23 hours, cooling to 0-5 ℃, stirring for 1 hour, filtering, washing a filter cake with 15mL of methanol, and drying to obtain 21.9g of the compound 5, wherein the yield is as follows: 56.7 percent.
EXAMPLE 3
Preparation of compound 5:
adding 125mL of ethanol into a reaction bottle, adding 36.2g of the compound 1 while stirring, adding 7.8g of hydroxylamine hydrochloride after dissolution, heating to 58 ℃, slowly dropwise adding 36.5g of 21% sodium ethoxide ethanol solution, keeping the temperature of 58 ℃ after the dropwise adding for reaction for 23 hours, cooling to 0-5 ℃, stirring for 1 hour, filtering, washing a filter cake with 15mL of ethanol, and drying to obtain 26.2g of the compound 5, wherein the yield is as follows: 67.8 percent.
EXAMPLE 4
Preparation of a benzenesulfonate salt represented by formula 7:
adding 20g of the compound 5 into a reaction flask, adding 400mL of purified water and 20mL of glacial acetic acid, adding 1.0g of Raney Ni under stirring, controlling the temperature to be 55-65 ℃, reacting for 24 hours under hydrogen atmosphere (1-2 atmospheric pressures), filtering, sequentially adding 20g of benzenesulfonic acid and 20mL of ammonia water into the filtrate, continuing stirring for 1 hour, filtering, and washing the filter cake with 40mL of water to obtain 23.6g of benzenesulfonate shown in formula 7, wherein the yield is as follows: 92.7 percent.
1H NMR(400MHz,DMSO)δ8.85(s,2H),8.43(d,J＝25.7Hz,3H),7.66(d,J＝5.5Hz,4H),7.53(d,J＝20.7Hz,2H),7.45–7.23(m,5H),7.22–7.07(m,2H),6.90(t,J＝8.7Hz,3H),4.65(d,J＝5.1Hz,2H),4.23(t,J＝6.9Hz,2H),3.98(q,J＝7.1Hz,2H),3.77(s,3H),2.69(t,J＝6.9Hz,2H),1.13(t,J＝7.1Hz,3H).
EXAMPLE 5
Preparation of a benzenesulfonate salt represented by formula 7:
adding 20g of compound 5 into a reaction flask, adding 400mL of purified water and 20mL of glacial acetic acid, adding 1.0g of Pd/C under stirring, controlling the temperature to be 55-65 ℃, reacting for 24 hours under hydrogen atmosphere (1-2 atmospheric pressures), filtering, sequentially adding 20g of benzenesulfonic acid and 20mL of ammonia water into the filtrate, continuing stirring for 1 hour, filtering, and washing the filter cake with 40mL of water to obtain 13.2g of benzenesulfonate shown in formula 7, wherein the yield is as follows: 51.6 percent.
EXAMPLE 6
Preparation of a benzenesulfonate salt represented by formula 7:
20g of Compound 5 was charged into a reaction flask, 400mL of purified water and 20mL of glacial acetic acid were added, and 1.0g of Pd (OH) was added under stirring2Controlling the temperature to be 55-65 ℃, reacting for 24 hours under hydrogen atmosphere (1-2 atmospheric pressures), filtering, sequentially adding 20g of benzenesulfonic acid and 20mL of ammonia water into the filtrate, continuously stirring for 1 hour, filtering, washing the filter cake with 40mL of water to obtain 12.4g of benzenesulfonate shown in formula 7, wherein the yield is as follows: 48.7 percent.
EXAMPLE 7
Preparation of compound 4:
adding 20g of benzenesulfonate shown in formula 7 into a reaction bottle, adding 150mL of acetone, 90mL of purified water and 9.5g of potassium carbonate into the reaction bottle, dropwise adding 5.6g of chloroformic acid n-hexyl ester at the temperature of 10-20 ℃, and stirring for 1-2 hours at the temperature of 10-20 ℃. Filtered, drained, then rinsed with 5/3 parts by volume acetone/purified water, and drained. And (3) pulping the filter cake with water, recrystallizing acetone and water, and mixing and refining ethyl acetate and tetrahydrofuran to obtain 14g of finished dabigatran etexilate free base 4 with the following yield: 73.7 percent.
1H NMR(400MHz,DMSO)δ9.15(s,1H),8.64(s,1H),8.46–8.29(m,1H),7.79(d,J＝8.9Hz,2H),7.56–7.49(m,1H),7.46(d,J＝1.1Hz,1H),7.38(d,J＝8.4Hz,1H),7.15(dd,J＝8.4,1.5Hz,1H),7.10(ddd,J＝7.4,4.9,0.8Hz,1H),6.95(d,J＝5.6Hz,1H),6.87(d,J＝8.1Hz,1H),6.75(d,J＝8.9Hz,2H),4.58(d,J＝5.5Hz,2H),4.21(t,J＝7.1Hz,2H),4.00–3.90(m,4H),3.75(s,3H),2.67(t,J＝7.1Hz,2H),1.61–1.50(m,2H),1.37–1.19(m,6H),1.10(t,J＝7.1Hz,3H),0.85(t,J＝6.8Hz,3H).
Claims (16)
1. A benzenesulfonate salt of formula 7:
2. the process for preparing a benzenesulfonate salt according to claim 1:
under the action of a reducing agent, the compound 5 and hydrogen undergo a reduction reaction, and then salified with benzenesulfonic acid to obtain the benzenesulfonate shown in the formula 7.
3. The method of claim 2, wherein: the reducing agent is selected from Pd/C, Pd (OH)2Or raney Ni, preferably raney Ni.
4. The method of claim 2, wherein: the reduction reaction temperature is 50-70 ℃, and preferably 55-65 ℃; the reduction reaction time is 20-30 hours, preferably 22-26 hours.
5. The method of claim 2, wherein: the reduction reaction is carried out in the presence of a solvent, wherein the solvent is one or a mixture of acetic acid and water.
6. The method according to any one of claims 2 to 5, wherein: the compound 5 is prepared by the following steps:
in the presence of a solvent and an acid-adding agent, the compound 1 and hydroxylamine hydrochloride undergo an addition reaction to obtain a compound 5.
7. The method of claim 6, wherein: the solvent for the addition reaction is selected from methanol, ethanol and dimethyl sulfoxide, and is preferably dimethyl sulfoxide.
8. The method of claim 6, wherein: the acid-attaching agent is selected from sodium methoxide, sodium ethoxide, triethylamine and diisopropylethylamine, and is preferably triethylamine or diisopropylethylamine.
9. The method of claim 6, wherein: the molar ratio of the compound 1 to the hydroxylamine hydrochloride is 1: 1-1: 4; the molar ratio of compound 1 to base is 1: 1 to 1: 4.
10. The method of claim 6, wherein: the addition reaction temperature is 10-40 ℃, and preferably 20-30 ℃; the reaction time is 15 to 30 hours, preferably 20 to 25 hours.
11. Use of the benzenesulfonate salt represented by formula 7 according to claim 1, in the preparation of compound 4 dabigatran etexilate:
12. a preparation method of dabigatran etexilate is characterized by comprising the following steps:
carrying out amidation reaction on benzene sulfonate shown in a formula 7 and n-hexyl chloroformate to obtain a compound 4, namely dabigatran etexilate.
13. The method for preparing dabigatran etexilate as claimed in claim 12, further comprising the steps of: the benzenesulfonate salt represented by formula 7 is produced according to the method for producing a benzenesulfonate salt as claimed in any one of claims 2 to 10.
14. The method for preparing dabigatran according to claim 12 or claim 13, wherein the amidation reaction is performed in the presence of an acid-adding agent, and the acid-adding agent is one of potassium carbonate, sodium carbonate, potassium bicarbonate and sodium bicarbonate.
15. A method for preparing dabigatran etexilate, which is characterized by comprising the following steps:
(1) in the presence of a solvent and an acid-attaching agent, carrying out addition reaction on the compound 1 and hydroxylamine hydrochloride to obtain a compound 5;
(2) under the action of a reducing agent, carrying out reduction reaction on the compound 5 and hydrogen, and salifying the compound and benzenesulfonic acid to obtain benzenesulfonate shown in a formula 7;
(3) and carrying out amidation reaction on the benzene sulfonate shown in the formula 7 and n-hexyl chloroformate to obtain a compound 4, namely dabigatran etexilate.
16. The method for preparing dabigatran etexilate as claimed in claim 15, characterized in that:
the step (1) is as follows: dissolving the compound 1 in dimethyl sulfoxide, adding hydroxylamine hydrochloride, dropwise adding an acid-attaching agent, controlling the temperature to be 20-30 ℃, reacting for 20-25 hours, adding a proper amount of purified water, and filtering to obtain a compound 5; wherein the molar ratio of the compound 1 to the hydroxylamine hydrochloride is 1: 1-1: 4; the molar ratio of the compound 1 to the base is 1: 1-1: 4;
the step (2) is as follows: dissolving a compound 5 in an acetic acid aqueous solution, adding a reducing agent, hydrogenating under a hydrogen atmosphere, controlling the reaction temperature to be 55-65 ℃, reacting for 22-26 hours, filtering, sequentially adding benzenesulfonic acid and ammonia water into the filtrate, and filtering to obtain benzenesulfonate shown in a formula 7; wherein the molar ratio of the compound 5 to the benzenesulfonic acid is 1: 1-1: 4; the molar ratio of the compound 5 to ammonia water is 1: 1-1: 4;
the step (3) is as follows: and carrying out amidation reaction on the benzene sulfonate shown in the formula 7 and n-hexyl chloroformate under the action of an acid-attaching agent to obtain a compound 4, wherein the temperature of the amidation reaction is 5-40 ℃, and the time is 0.5-2 hours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811457484.7A CN111253369A (en) | 2018-11-30 | 2018-11-30 | Benzene sulfonate, preparation method thereof and application of benzene sulfonate in preparation of dabigatran etexilate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811457484.7A CN111253369A (en) | 2018-11-30 | 2018-11-30 | Benzene sulfonate, preparation method thereof and application of benzene sulfonate in preparation of dabigatran etexilate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN111253369A true CN111253369A (en) | 2020-06-09 |
Family
ID=70943867
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811457484.7A Pending CN111253369A (en) | 2018-11-30 | 2018-11-30 | Benzene sulfonate, preparation method thereof and application of benzene sulfonate in preparation of dabigatran etexilate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111253369A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111440149A (en) * | 2020-03-31 | 2020-07-24 | 浙江美诺华药物化学有限公司 | Preparation method of dabigatran etexilate intermediate |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101346360A (en) * | 2005-12-21 | 2009-01-14 | 贝林格尔.英格海姆国际有限公司 | Improved process for the preparation of 4-(benzimidazolylmethylamino)-benzamides and the salts thereof |
| CN102557982A (en) * | 2004-05-06 | 2012-07-11 | 赛特凯恩蒂克公司 | Certain chemical entities, compositions, and methods |
| CN104230887A (en) * | 2013-06-19 | 2014-12-24 | 上海医药工业研究院 | New Dabigatran etexilate intermediate and preparation method thereof |
| CN105348262A (en) * | 2015-11-25 | 2016-02-24 | 蚌埠丰原医药科技发展有限公司 | Improved method for preparing Dabigatran etexilate |
| US20160060248A1 (en) * | 2013-03-25 | 2016-03-03 | Usv Limited | Synthesis of dabigatran |
| CN105566297A (en) * | 2015-12-31 | 2016-05-11 | 哈药集团技术中心 | Preparation method of dabigatran etexilate mesylate |
-
2018
- 2018-11-30 CN CN201811457484.7A patent/CN111253369A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102557982A (en) * | 2004-05-06 | 2012-07-11 | 赛特凯恩蒂克公司 | Certain chemical entities, compositions, and methods |
| CN101346360A (en) * | 2005-12-21 | 2009-01-14 | 贝林格尔.英格海姆国际有限公司 | Improved process for the preparation of 4-(benzimidazolylmethylamino)-benzamides and the salts thereof |
| US20160060248A1 (en) * | 2013-03-25 | 2016-03-03 | Usv Limited | Synthesis of dabigatran |
| CN104230887A (en) * | 2013-06-19 | 2014-12-24 | 上海医药工业研究院 | New Dabigatran etexilate intermediate and preparation method thereof |
| CN105348262A (en) * | 2015-11-25 | 2016-02-24 | 蚌埠丰原医药科技发展有限公司 | Improved method for preparing Dabigatran etexilate |
| CN105566297A (en) * | 2015-12-31 | 2016-05-11 | 哈药集团技术中心 | Preparation method of dabigatran etexilate mesylate |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111440149A (en) * | 2020-03-31 | 2020-07-24 | 浙江美诺华药物化学有限公司 | Preparation method of dabigatran etexilate intermediate |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP7097467B2 (en) | Bribalacetam intermediate, its manufacturing method and bribalacetam manufacturing method | |
| EA018227B1 (en) | A method for the preparation of dabigatran and its intermediates | |
| KR20110033276A (en) | A process for preparing r-beta-amino phenylbutyric acid derivatives | |
| JP2009531313A5 (en) | ||
| CN110590635A (en) | Preparation method of levetiracetam and intermediate thereof | |
| CN102746288B (en) | Preparation methods of anticoagulant and key intermediate of anticoagulant | |
| CN111253369A (en) | Benzene sulfonate, preparation method thereof and application of benzene sulfonate in preparation of dabigatran etexilate | |
| CN106957299B (en) | Preparation method of lenalidomide | |
| CA2894826A1 (en) | Asymmetric synthesis of a substituted pyrrolidine-2-carboxamide | |
| CN116751136A (en) | Novel preparation method of oxo-pyridine compound and key intermediate | |
| MX2014009309A (en) | Method for preparing compound by novel michael addition reaction using water or various acids as additive. | |
| CN110078636A (en) | A method of preparing Iopromide intermediate | |
| JP6239751B2 (en) | Method for producing lacosamide | |
| JP2018525376A (en) | Novel process for producing chromanol derivatives | |
| CN112341413A (en) | Intermediate for synthesizing brivaracetam and preparation method thereof | |
| CN115246781B (en) | Preparation method of sand-fenamide | |
| JP5279449B2 (en) | Process for producing 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} -2,4-thiazolidinedione hydrochloride | |
| EP1760075A1 (en) | Method for producing acetamidopyrrolidine derivative and intermediate compound thereof | |
| CN116410128A (en) | Method for preparing tosylate Ai Duosha class intermediate by one-pot method | |
| JP2002371060A (en) | Method for producing optically active aminopiperidine derivative | |
| CN117623957A (en) | Synthesis method of milbelin benzenesulfonate diastereoisomer [ (1R, 5S, 6R) -6- (aminomethyl) -3-ethylbicyclo [3.2.0] hept-3-en-6-yl ] acetic acid benzenesulfonate | |
| JP2013221025A (en) | Method of manufacturing biphenyl acetamide derivative and intermediate of the same | |
| EP1380578A1 (en) | Process for producing nitrile compound | |
| US9908858B2 (en) | Method for the synthesis of a hydrazine that can be used in the treatment of the papilloma virus | |
| CA3207714A1 (en) | Pyrrolopyridine derivative preparation method |
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 |