CN111763169A - Preparation method of improved edoxaban intermediate - Google Patents
Preparation method of improved edoxaban intermediate Download PDFInfo
- Publication number
- CN111763169A CN111763169A CN202010623583.9A CN202010623583A CN111763169A CN 111763169 A CN111763169 A CN 111763169A CN 202010623583 A CN202010623583 A CN 202010623583A CN 111763169 A CN111763169 A CN 111763169A
- Authority
- CN
- China
- Prior art keywords
- reaction
- alcohol
- compound
- acetonitrile
- preparation
- 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.)
- Granted
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- 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)
- Pyridine Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of an improved edoxaban intermediate. In most of the preparation methods for preparing the compound (1), the system is very easy to be in a solidified state in the reaction process, and the problems of reduction of the yield of the product, deterioration of the quality and the like are caused. For the cure problem in this system, the present invention seeks to provide an improved process for the preparation of edoxaban intermediates. In the process of synthesizing the compound (1), alcohol or a mixture of alcohol and acetonitrile is used as a reaction solvent, so that a reaction system is in a clear state at first, a product is gradually separated out along with the reaction, and the product is uniformly dispersed in the solvent in the whole process from the reaction end point, so that the stirring is easy, and the solidification problem in the reaction process is effectively solved.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of an improved edoxaban intermediate.
Background
Edoxaban (Edoxaban), chemical name N- (5-chloropyridin-2-yl) -N' - [ (1S,2R,4S) -4- (N, N-dimethylcarboxamido) -2- (5-methyl-4, 5,6, 7-tetrahydro [1,3] thiazolo [5,4-c ] pyridine-2-carboxamide) cyclohexyl ] oxamide, the active ingredient of the commercially available drug is p-toluenesulfonate monohydrate of Edoxaban, a small molecule oral anticoagulant developed by the first three co-company of japan, a coagulation factor x (a) inhibitor, marketed in japan 7 months in 2011 and approved by the FDA in 2015 1 month in the us under the trade name Savaysa. The chemical name of the compound (1) is N- (5-chloropiperidin-2-yl) -N' - [ (1S,2R,4S) -4- (N, N-dimethylformamido) -2- (amino tert-butoxycarbonyl) cyclohexyl ] oxamide, which is a key intermediate of edoxaban and plays a key role in the quality of the medicament, so that a method for efficiently preparing the compound (1) is needed.
Patent US8686189B2 discloses a preparation method of edoxaban intermediate compound (1), in the preparation process of compound (1), acetonitrile is used as a solvent, when compound (3) is added into a suspension of compound (2) oxalate and triethylamine, a reaction system is instantly solidified and cannot be stirred, and finally, the yield of the product is reduced and the quality is reduced. Patent US8357808B2 and patent CN105753888B disclose a method for solving the problem of solidification during the preparation of compound (1), which changes the feeding sequence and adds triethylamine in batches, firstly compound (3) is pretreated with part of triethylamine in acetonitrile, then compound (2) oxalate and the other part of triethylamine are added for reaction, the method solves the problem of reaction solidification to a certain extent, but the system is still sticky and is difficult to stir, which is not completely solved, and the process operation becomes complicated.
In most of the preparation methods for preparing the compound (1), the system is very easy to be in a solidified state in the reaction process, and the problems of reduction of the yield of the product, deterioration of the quality and the like are caused. For the cure problem in this system, the present invention seeks to provide an improved process for the preparation of edoxaban intermediates.
Disclosure of Invention
The invention aims to provide an improved preparation method of an edoxaban intermediate, so as to solve the problems in the background technology.
In order to achieve the above object, the present invention provides the following technical solutions.
A method for preparing an improved edoxaban intermediate, comprising the steps of: suspending (1R,2S,5S) -1-amino-4- (dimethylaminocarbonyl) -cyclohexyl-2-carbamic acid tert-butyl ester oxalate (2) in alcohol or a mixed solvent of alcohol and acetonitrile, adding triethylamine at room temperature, adding reaction liquid clear solution, adding 2- [ (5-chloropyridine) amino ] -2-oxoacetic acid ethyl ester hydrochloride (3), heating to 50-70 ℃, adding the reaction liquid clear solution, keeping the temperature and stirring for reaction for 5-8 hours, continuing to react for 4-24 hours at room temperature, adding water into the reaction liquid, cooling to 0-10 ℃, stirring for 0.5-2 hours, filtering, and drying to obtain a compound (1).
The alcohol is methanol, ethanol, isopropanol, preferably ethanol.
The volume ratio of alcohol to acetonitrile in the alcohol and acetonitrile mixture solvent is as follows: acetonitrile ═ (0.4-2): 1, preferably alcohol: acetonitrile 1: 1.
preferably, the reaction temperature after the temperature rise is 50 to 60 ℃.
Preferably, the reaction time of the heat preservation stirring reaction is 5-6 hours.
Compared with the prior art, the invention has the beneficial effects that:
1. in the process of synthesizing the compound (1), alcohol or a mixture of alcohol and acetonitrile is used as a reaction solvent, so that a reaction system is in a clear state at first, a product is gradually separated out along with the reaction, and the product is uniformly dispersed in the solvent in the whole process from the end point of the reaction and is easy to stir, thereby effectively solving the solidification problem in the reaction process;
2. the method not only thoroughly solves the problems that the reaction is not thorough due to easy solidification and difficult stirring in the reaction process, raw materials and impurities are easily brought into the product, and the product quality, the purification cost and the like of the compound (1) and edoxaban are seriously influenced, but also simplifies the operation process, and is more controllable and convenient compared with other methods.
Drawings
FIG. 1 is a liquid phase detection spectrum of a product of Compound (1) in reference example 1;
FIG. 2 is a liquid phase detection spectrum of the product of Compound (1) in reference example 2;
FIG. 3 is a liquid phase detection spectrum of the product of Compound (1) in reference example 3;
FIG. 4 is a liquid phase detection spectrum of the product of the compound (1) in example 1;
FIG. 5 is a liquid phase detection spectrum of the product of Compound (1) in example 2.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings and tables in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Reference example 1
Compound (1) was prepared with reference to patent US8686189B 2: to an acetonitrile suspension (550ml) of (1R,2S,5S) -1-amino-4- (dimethylaminocarbonyl) -cyclohexyl-2-carbamic acid tert-butyl ester oxalate (100.1g) was added triethylamine (169ml) at 60 ℃. At this temperature, ethyl 2- [ (5-chloropyridine) amino ] -2-oxoacetate hydrochloride (84.2g) was added, and after stirring for 6 hours, the mixture was stirred at room temperature for 16 hours. After adding water to the reaction mixture and stirring at 10 ℃ for 1 hour and 30 minutes, crystals were collected by filtration and dried to obtain compound (1) (106.6 g).
Reference example 2
Compound (1) was prepared with reference to patent US8357808B 2: ethyl 2- [ (5-chloropyridine) amino ] -2-oxoacetate hydrochloride (8.48g) was suspended in acetonitrile (50ml), and triethylamine (3.17g) was added to the suspension at 10 ℃ followed by addition of tert-butyl (1R,2S,5S) -1-amino-4- (dimethylaminocarbonyl) -cyclohexyl-2-carbamate oxalate (10.0 g). Triethylamine (10.9g) was added thereto at 60 ℃ and the mixture was stirred at 70 ℃ for 7 hours. The reaction solution was cooled, and water (90ml) was added thereto. The crystals were collected by filtration at 10 ℃ and washed with water (50ml), followed by drying under reduced pressure to obtain compound (1) (11.6 g).
Reference example 3
Compound (1) was prepared with reference to patent CN 105753888B: suspending ethyl 2- [ (5-chloropyridine) amino ] -2-oxoacetate hydrochloride (25.5g) in acetonitrile (300ml), adding dropwise a first amount of triethylamine (9.6g) at 10 ℃. + -. 2 ℃, then adding dropwise a second amount of triethylamine (39g), heating to 60 ℃. + -. 5 ℃, stirring at 60 ℃. + -. 5 ℃ for 6-8 hours, then cooling to room temperature, adding a first amount of water (300ml) and quenching the reaction; after stirring at 10 ℃. + -. 2 ℃ for 1-1.5 hours, a second amount of water (600ml) was added, filtration was carried out, and the resulting solid was washed with water and dried to give compound (1) (34.8 g).
Example 1
The technical scheme adopted by the invention is used for preparing the compound (1): suspending (1R,2S,5S) -1-amino-4- (dimethylaminocarbonyl) -cyclohexyl-2-carbamic acid tert-butyl ester oxalate (70g) in absolute ethyl alcohol (350ml), adding triethylamine (86.8g) at room temperature, adding ethyl 2- [ (5-chloropyridine) amino ] -2-oxoacetate hydrochloride (58.8g) into a reaction solution, heating to 50-60 ℃, adding the reaction solution into the reaction solution, keeping the temperature, stirring, reacting for 6 hours, continuing to react for 16 hours at room temperature, adding water (700ml) into the reaction solution, cooling to 0-10 ℃, stirring for 1 hour, filtering, and drying to obtain a compound (1) (78.4 g).
Example 2
The technical scheme adopted by the invention is used for preparing the compound (1): suspending (1R,2S,5S) -1-amino-4- (dimethylaminocarbonyl) -cyclohexyl-2-carbamic acid tert-butyl ester oxalate (70g) in acetonitrile (350ml) and absolute ethyl alcohol (350ml), adding triethylamine (86.8g) at room temperature, adding ethyl 2- [ (5-chloropyridine) amino ] -2-oxoacetate hydrochloride (58.8g), heating to 50-60 ℃, reacting the reaction solution with the solution clear, keeping the temperature and stirring for reaction for 6 hours, continuing to react for 16 hours at room temperature, adding water (700ml) into the reaction solution, cooling to 0-10 ℃, stirring for 1 hour, filtering, and drying to obtain a compound (1) (80.5 g).
Example 3
The technical scheme adopted by the invention is used for preparing the compound (1): suspending (1R,2S,5S) -1-amino-4- (dimethylaminocarbonyl) -cyclohexyl-2-carbamic acid tert-butyl ester oxalate (70g) in methanol (350ml), adding triethylamine (86.8g) at room temperature, adding ethyl 2- [ (5-chloropyridine) amino ] -2-oxoacetate hydrochloride (58.8g) into a reaction solution, heating to 50-60 ℃, adding the reaction solution into the reaction solution, keeping the temperature, stirring for reaction for 6 hours, continuing to react at room temperature for 16 hours, adding water (700ml) into the reaction solution, cooling to 0-10 ℃, stirring for 1 hour, filtering, and drying to obtain a compound (1) (77.8 g).
Example 4
The technical scheme adopted by the invention is used for preparing the compound (1): suspending (1R,2S,5S) -1-amino-4- (dimethylaminocarbonyl) -cyclohexyl-2-carbamic acid tert-butyl ester oxalate (70g) in isopropanol (350ml), adding triethylamine (86.8g) at room temperature, adding ethyl 2- [ (5-chloropyridine) amino ] -2-oxoacetate hydrochloride (58.8g) into a reaction solution, heating to 50-60 ℃, adding the reaction solution into the reaction solution, keeping the temperature, stirring, reacting for 6 hours, continuing to react for 16 hours at room temperature, adding water (700ml) into the reaction solution, cooling to 0-10 ℃, stirring for 1 hour, filtering, and drying to obtain a compound (1) (78.4 g).
Example 5
The technical scheme adopted by the invention is used for preparing the compound (1): suspending (1R,2S,5S) -1-amino-4- (dimethylaminocarbonyl) -cyclohexyl-2-carbamic acid tert-butyl ester oxalate (70g) in acetonitrile (350ml) and absolute ethyl alcohol (150ml), adding triethylamine (86.8g) at room temperature, adding ethyl 2- [ (5-chloropyridine) amino ] -2-oxoacetate hydrochloride (58.8g), heating to 50-60 ℃, reacting the reaction solution with the solution clear, keeping the temperature and stirring for reaction for 6 hours, continuing to react for 16 hours at room temperature, adding water (700ml) into the reaction solution, cooling to 0-10 ℃, stirring for 1 hour, filtering, and drying to obtain a compound (1) (79.5 g).
Example 6
The technical scheme adopted by the invention is used for preparing the compound (1): suspending (1R,2S,5S) -1-amino-4- (dimethylaminocarbonyl) -cyclohexyl-2-carbamic acid tert-butyl ester oxalate (70g) in acetonitrile (350ml) and absolute ethyl alcohol (525ml), adding triethylamine (86.8g) at room temperature, adding ethyl 2- [ (5-chloropyridine) amino ] -2-oxoacetate hydrochloride (58.8g), heating to 50-60 ℃, reacting the reaction solution with the solution clear, keeping the temperature and stirring for reaction for 6 hours, continuing to react for 16 hours at room temperature, adding water (700ml) into the reaction solution, cooling to 0-10 ℃, stirring for 1 hour, filtering, and drying to obtain a compound (1) (78.7 g).
Example 7
The technical scheme adopted by the invention is used for preparing the compound (1): suspending (1R,2S,5S) -1-amino-4- (dimethylaminocarbonyl) -cyclohexyl-2-carbamic acid tert-butyl ester oxalate (70g) in acetonitrile (350ml) and absolute ethyl alcohol (700ml), adding triethylamine (86.8g) at room temperature, adding ethyl 2- [ (5-chloropyridine) amino ] -2-oxoacetate hydrochloride (58.8g), heating to 50-60 ℃, reacting the reaction solution with the solution clear, keeping the temperature and stirring for reaction for 6 hours, continuing to react for 16 hours at room temperature, adding water (700ml) into the reaction solution, cooling to 0-10 ℃, stirring for 1 hour, filtering, and drying to obtain a compound (1) (79.1 g).
Example 8
The technical scheme adopted by the invention is used for preparing the compound (1): suspending (1R,2S,5S) -1-amino-4- (dimethylaminocarbonyl) -cyclohexyl-2-carbamic acid tert-butyl ester oxalate (70g) in acetonitrile (350ml) and absolute ethyl alcohol (350ml), adding triethylamine (86.8g) at room temperature, adding ethyl 2- [ (5-chloropyridine) amino ] -2-oxoacetate hydrochloride (58.8g), heating to 60-70 ℃, reacting the reaction solution with the solution clear, keeping the temperature and stirring for reaction for 6 hours, continuing to react for 16 hours at room temperature, adding water (700ml) into the reaction solution, cooling to 0-10 ℃, stirring for 1 hour, filtering, and drying to obtain a compound (1) (81.0 g).
Example 9
The technical scheme adopted by the invention is used for preparing the compound (1): suspending (1R,2S,5S) -1-amino-4- (dimethylaminocarbonyl) -cyclohexyl-2-carbamic acid tert-butyl ester oxalate (70g) in acetonitrile (350ml) and absolute ethyl alcohol (350ml), adding triethylamine (86.8g) at room temperature, adding ethyl 2- [ (5-chloropyridine) amino ] -2-oxoacetate hydrochloride (58.8g), heating to 60-70 ℃, reacting the reaction solution with the solution clear, keeping the temperature and stirring for reaction for 5 hours, continuing to react for 16 hours at room temperature, adding water (700ml) into the reaction solution, cooling to 0-10 ℃, stirring for 1 hour, filtering, and drying to obtain a compound (1) (80.0 g).
Example 10
The technical scheme adopted by the invention is used for preparing the compound (1): suspending (1R,2S,5S) -1-amino-4- (dimethylaminocarbonyl) -cyclohexyl-2-carbamic acid tert-butyl ester oxalate (70g) in acetonitrile (350ml) and absolute ethyl alcohol (350ml), adding triethylamine (86.8g) at room temperature, adding ethyl 2- [ (5-chloropyridine) amino ] -2-oxoacetate hydrochloride (58.8g), heating to 60-70 ℃, reacting the reaction solution with the solution, keeping the temperature, stirring for reaction for 7 hours, continuing to react for 16 hours at room temperature, adding water (700ml) into the reaction solution, cooling to 0-10 ℃, stirring for 1 hour, filtering, and drying to obtain a compound (1) (80.2 g).
Example 11
The technical scheme adopted by the invention is used for preparing the compound (1): suspending (1R,2S,5S) -1-amino-4- (dimethylaminocarbonyl) -cyclohexyl-2-carbamic acid tert-butyl ester oxalate (70g) in acetonitrile (350ml) and absolute ethyl alcohol (350ml), adding triethylamine (86.8g) at room temperature, adding ethyl 2- [ (5-chloropyridine) amino ] -2-oxoacetate hydrochloride (58.8g), heating to 60-70 ℃, reacting the reaction solution with the solution clear, keeping the temperature and stirring for reaction for 8 hours, continuing to react for 16 hours at room temperature, adding water (700ml) into the reaction solution, cooling to 0-10 ℃, stirring for 1 hour, filtering, and drying to obtain a compound (1) (79.1 g).
Table 1: reaction phenomena and results of Synthesis of Compound (1) in reference examples 1 to 3 and example 1-
Instrumentation and materials used in the detection of compound (1) species:
the instrument comprises the following steps: liquid chromatograph, electronic balance (one hundred thousand)
A chromatographic column: waters Xbridge C184.6mm. times.250 mm (5um) or equivalent chromatography columns.
Buffer solution: 0.002g/ml ammonium dihydrogen phosphate solution with pH 2.0.
Mobile phase A: a buffer solution;
mobile phase B: buffer-acetonitrile (20:80)
Gradient elution procedure:
flow rate: 1.5 ml/min; column temperature: 35 ℃; and (3) detection: UV210 nm; sample introduction: 5 ul.
Experimental results prove that when alcohol or a mixture of the alcohol and acetonitrile is used as a solvent in the process of preparing the compound (1), the problem of solidification in the reaction can be completely eradicated, and meanwhile, the product quality is improved.
Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (7)
1. A method for preparing an improved edoxaban intermediate, comprising the steps of: suspending (1R,2S,5S) -1-amino-4- (dimethylaminocarbonyl) -cyclohexyl-2-carbamic acid tert-butyl ester oxalate (2) in alcohol or a mixed solvent of alcohol and acetonitrile, adding triethylamine at room temperature, adding reaction liquid clear solution, adding 2- [ (5-chloropyridine) amino ] -2-oxoacetic acid ethyl ester hydrochloride (3), heating to 50-70 ℃, adding the reaction liquid clear solution, keeping the temperature and stirring for reaction for 5-8 hours, continuing to react for 4-24 hours at room temperature, adding water into the reaction liquid, cooling to 0-10 ℃, stirring for 0.5-2 hours, filtering, and drying to obtain a compound (1).
2. The process of claim 1 for the preparation of an improved edoxaban intermediate, wherein: the alcohol is methanol, ethanol, or isopropanol.
3. The process of claim 2 for the preparation of an improved edoxaban intermediate, wherein: the alcohol is ethanol.
4. The process of claim 1 for the preparation of an improved edoxaban intermediate, wherein: the volume ratio of alcohol to acetonitrile in the alcohol and acetonitrile mixture solvent is as follows: acetonitrile = (0.4-2): 1.
5. the process of claim 4 for the preparation of an improved edoxaban intermediate wherein: the volume ratio of alcohol to acetonitrile in the alcohol and acetonitrile mixture solvent is as follows: acetonitrile = 1: 1.
6. the process of claim 1 for the preparation of an improved edoxaban intermediate, wherein: and the reaction temperature is 50-60 ℃ after the temperature is raised.
7. The process of claim 1 for the preparation of an improved edoxaban intermediate, wherein: the reaction time is 5-6 hours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010623583.9A CN111763169B (en) | 2020-06-30 | 2020-06-30 | Improved preparation method of idexaban intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010623583.9A CN111763169B (en) | 2020-06-30 | 2020-06-30 | Improved preparation method of idexaban intermediate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111763169A true CN111763169A (en) | 2020-10-13 |
| CN111763169B CN111763169B (en) | 2023-06-27 |
Family
ID=72723235
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010623583.9A Active CN111763169B (en) | 2020-06-30 | 2020-06-30 | Improved preparation method of idexaban intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111763169B (en) |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20120041206A1 (en) * | 2009-03-10 | 2012-02-16 | Daiichi Sankyo Company, Limited | Process for producing diamine derivative |
| US8686189B2 (en) * | 2005-09-16 | 2014-04-01 | Daiichi Sankyo Company, Limited | Optically active diamine derivative and process for producing the same |
| CN104761571A (en) * | 2015-03-10 | 2015-07-08 | 山东科兴生物制品有限公司 | Synthesis method of edoxaban |
| CN105753888A (en) * | 2016-04-05 | 2016-07-13 | 乐普药业股份有限公司 | Preparation method for free-state edoxaban |
| CN106459087A (en) * | 2014-02-18 | 2017-02-22 | 第三共株式会社 | Method for producing inhibitor of activated blood coagulation factor x (FXa) |
| WO2018038426A1 (en) * | 2016-08-23 | 2018-03-01 | 동화약품주식회사 | Acid addition salt of diamine derivative and preparation method therefor |
| WO2019004114A1 (en) * | 2017-06-26 | 2019-01-03 | 第一三共株式会社 | Production method for diamine derivative by flow synthesis |
-
2020
- 2020-06-30 CN CN202010623583.9A patent/CN111763169B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8686189B2 (en) * | 2005-09-16 | 2014-04-01 | Daiichi Sankyo Company, Limited | Optically active diamine derivative and process for producing the same |
| US20120041206A1 (en) * | 2009-03-10 | 2012-02-16 | Daiichi Sankyo Company, Limited | Process for producing diamine derivative |
| CN106459087A (en) * | 2014-02-18 | 2017-02-22 | 第三共株式会社 | Method for producing inhibitor of activated blood coagulation factor x (FXa) |
| CN104761571A (en) * | 2015-03-10 | 2015-07-08 | 山东科兴生物制品有限公司 | Synthesis method of edoxaban |
| CN105753888A (en) * | 2016-04-05 | 2016-07-13 | 乐普药业股份有限公司 | Preparation method for free-state edoxaban |
| WO2018038426A1 (en) * | 2016-08-23 | 2018-03-01 | 동화약품주식회사 | Acid addition salt of diamine derivative and preparation method therefor |
| WO2019004114A1 (en) * | 2017-06-26 | 2019-01-03 | 第一三共株式会社 | Production method for diamine derivative by flow synthesis |
Also Published As
| Publication number | Publication date |
|---|---|
| CN111763169B (en) | 2023-06-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP2023113730A (en) | Compositions and methods for phosphoramidite and oligonucleotide synthesis | |
| EP3068757B1 (en) | Lysine salt of 15-hydroxy-8(z),11(z),13(e)-eicosatrienoic acid | |
| CN106046254B (en) | It is enriched with the hydrophilic molecular engram polymer and preparation method and application of geniposide | |
| CN104829673B (en) | A kind of preparation method of rope fluorine cloth Wei crystal formation 6 | |
| CN101914098A (en) | Preparation method of Meropenem trihydrate crystals | |
| CN111763169A (en) | Preparation method of improved edoxaban intermediate | |
| US7709644B2 (en) | Process for the enantiomeric enrichment of cis-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane | |
| Ge et al. | Enantioseparation of racemic bupivacaine via ultrasonic-assisted diastereomeric crystallization using 12, 14-dinitrodehydroabietic acid | |
| JP7320628B2 (en) | Method for synthesizing furoimidazopyridine compound, crystalline form of furoimidazopyridine compound and crystalline form of salt thereof | |
| EP4574825A1 (en) | Crystal form of pyrazolopyrimidine ester compound and preparation method therefor | |
| CN102358721B (en) | More stable aceglutamide compound and medicinal composition thereof | |
| WO2012142983A1 (en) | Optically active salts of (3ar,4s,6r,6as)-6-amino-2,2-dimethyltetrahydro-3ah- cyclopenta-[d] [1,3]dioxol-4-ol and a method of their preparation | |
| CN111606927B (en) | Preparation method of high-purity ixaban | |
| CN106478636B (en) | Ticagrelor crystal form and preparation method | |
| CN110128500B (en) | Ugi mixed solvent process for preparing alpha-amido amides | |
| CN110124049B (en) | PEGylated fenretinide prodrugs and their uses | |
| CN101195618A (en) | Method for producing beta crystal system anhydrous aztreonam | |
| CN113979896A (en) | Sitagliptin impurity I and preparation method thereof | |
| CN112250591A (en) | Preparation method of lysine-amino-profen | |
| CN112679370B (en) | Preparation method of medicinal arginine glutamic acid | |
| JPS62242692A (en) | Production of moranoline derivative | |
| EP4431515A1 (en) | Novel crystal forms of peptide boric acid compound and preparation methods therefor | |
| CN117658833B (en) | A mixed solvent for purifying L-adrenaline and its salts, and a method for purifying L-adrenaline and its salts | |
| CN111606815B (en) | Preparation method of phenylephrine hydrochloride impurity standard | |
| CN115232022B (en) | Preparation method of acetaminophen dimer derivative |
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 | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |