CN110372582A - A kind of synthesis technology of betrixaban - Google Patents
A kind of synthesis technology of betrixaban Download PDFInfo
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- CN110372582A CN110372582A CN201910745717.1A CN201910745717A CN110372582A CN 110372582 A CN110372582 A CN 110372582A CN 201910745717 A CN201910745717 A CN 201910745717A CN 110372582 A CN110372582 A CN 110372582A
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- betrixaban
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- synthesis technology
- cyanobenzoic acid
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- 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
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- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Abstract
The present invention provides a kind of synthesis technology of betrixaban, more particularly to field of medicine production, S1,1- (3- dimethylaminopropyl) -3- ethylcarbodiimide and n-hydroxysuccinimide (NHS) and paracyanobenzoic acid are passed through in solution, realize cyanobenzoic acid activation, S2, the cyanobenzoic acid after activation is reacted with 2- amino-N- (5- chloro-2-pyridyl) -5- methoxy benzamide, proper amount of methanol cooling crystallization is added into reaction vessel, filters to obtain intermediate I；S3, ensure anhydrous condition, chloroacetic chloride is added dropwise；Intermediate I is added, being evaporated to ensures dry materials；Then reacted with the tetrahydrofuran solution of dimethylamine, and after generate intermediate II under the action of sodium hydroxide；S4, intermediate II and maleic acid reaction are obtained into betrixaban at 60 DEG C~70 DEG C.Not only reaction condition is mild by the present invention, and high income, impurity is few, and can reduce gas preparation and the corrosion to equipment, later period environmental protection treatment cost it is smaller.
Description
Technical field
The invention belongs to field of medicine production, and in particular to a kind of synthesis technology of betrixaban.
Background technique
Betrixaban (Betrixiban) belongs to that directly act on the new of Xa factor, selectivity good, orally active anti-
Solidifying medicine has atrial flutter after the postoperative embolism of potential prevention knee and apoplexy, and betrixaban cannot be by cytochromes because having
The characteristics of P4503A4 (CYP3A4) is metabolized, reduces the risk of drug and drug interaction.
Application No. is the patents of CN201810309075.6, disclose a kind of betrixaban intermediate or the preparation side of its salt
Method, by the way that under the action of catalyst, amide coupling agent is added dropwise in formula SM-III compound and formula SM-I compound or its salt
Condensation reaction forms formula III compound or its salt, this condensation reaction generates in organic solvent；And it further will be in betrixaban
Mesosome or its salt are prepared into betrixaban or its salt；Although the betrixaban or its hydrochloride that the technical solution is prepared are basic
It is upper to be free of dechlorination impurity V and demethyl impurity VI, purity is high, but the preparation process need to use and handle a large amount of highly corrosive
Hydrogen chloride gas requires height to equipment anticorrosion, and later period environmental protection treatment cost is larger.
Summary of the invention
In view of the above deficiencies, a kind of synthesis technology of betrixaban is now needed, not only reaction condition is mild, high income, miscellaneous
Matter is few, and can reduce gas preparation and the corrosion to equipment, later period environmental protection treatment cost it is smaller.
The present invention provides the following technical solutions:
A kind of synthesis technology of betrixaban, the specific steps are as follows:
S1, cyanobenzoic acid is activated: 1- (3- dimethylaminopropyl) -3- ethylcarbodiimide and N- hydroxyl
Succinimide (NHS) and paracyanobenzoic acid are passed through in solution, under 10 DEG C to 15 DEG C proper temperatures, realize cyanobenzoic acid
Activation,
S2, by after activation cyanobenzoic acid and 2- amino-N- (5- chloro-2-pyridyl) -5- methoxy benzamide it is anti-
It answers, at -15 DEG C to 10 DEG C, proper amount of methanol cooling crystallization is added into reaction vessel, filters to obtain intermediate I；
S3, ensure anhydrous condition, chloroacetic chloride is added dropwise；At 2 to 8 DEG C, intermediate I is added, keeps the temperature 30 minutes, is warming up to 40
DEG C, being evaporated to ensures dry materials；Then reacted with the tetrahydrofuran solution of dimethylamine, and after it is raw under the action of sodium hydroxide
At intermediate II；
S4, intermediate II and maleic acid reaction are obtained into betrixaban at 60 DEG C~70 DEG C.
Preferably, 1- (3- dimethylaminopropyl) -3- ethylcarbodiimide and n-hydroxysuccinimide (NHS)
Molar ratio are as follows: 1.2:1.3~1.5:1.6.
Preferably, in S2 step, at 10 DEG C, proper amount of methanol cooling crystallization is added into reaction vessel, 200 mesh filter,
Obtain intermediate I.
Preferably, in S3 step, at 8 DEG C, intermediate I and Lewis catalyst is added；
Preferably, Lewis catalyst be AlCl3 or BF3 or SbCl5 or FeBr3 or FeCl3 or SnCl4 or TiCl4 or
ZnCl2。
The present invention has the effect that compared with prior art
(1) cyanobenzoic acid is activated: 1- (3- dimethylaminopropyl) -3- ethylcarbodiimide and N- hydroxyl
The synergy of succinimide (NHS), keeps reaction process condition of the invention mild, easily controllable, and the high income of product,
Purity is high is more suitable for scale volume production；
(2) present invention uses chloroacetic chloride and alcohols, it is possible to provide hydrogen chloride required for this technique, different from traditional direct
Logical hydrogen chloride gas, the present invention can reduce the corrosiveness of gas apparatus.
Specific embodiment
Embodiment 1:
S1, cyanobenzoic acid is activated: 1- (3- dimethylaminopropyl) -3- ethylcarbodiimide and N- hydroxyl
Succinimide (NHS) and paracyanobenzoic acid are passed through in solution, under 10 DEG C of proper temperatures, realize cyanobenzoic acid activation；
The molar ratio of 1- (3- dimethylaminopropyl) -3- ethylcarbodiimide and n-hydroxysuccinimide (NHS) are as follows: 1.2:
1.3
S2, by after activation cyanobenzoic acid and 2- amino-N- (5- chloro-2-pyridyl) -5- methoxy benzamide it is anti-
It answers, at -15 DEG C, proper amount of methanol cooling crystallization is added into reaction vessel, 200 mesh filter to obtain intermediate I；
S3, ensure anhydrous condition, chloroacetic chloride is added dropwise；At 2 DEG C, intermediate I and AlCl3 catalysis is added, keeps the temperature 30 minutes,
40 DEG C are warming up to, being evaporated to ensures dry materials；Then reacted with the tetrahydrofuran solution of dimethylamine, and after in sodium hydroxide
Effect is lower to generate intermediate II；
S4, intermediate II and maleic acid reaction are obtained into betrixaban 60.
Embodiment 2:
S1, cyanobenzoic acid is activated: 1- (3- dimethylaminopropyl) -3- ethylcarbodiimide and N- hydroxyl
Succinimide (NHS) and paracyanobenzoic acid are passed through in solution, under 12 DEG C of proper temperatures, realize cyanobenzoic acid activation；
The molar ratio of 1- (3- dimethylaminopropyl) -3- ethylcarbodiimide and n-hydroxysuccinimide (NHS) are as follows: 1.3:
1.5
S2, by after activation cyanobenzoic acid and 2- amino-N- (5- chloro-2-pyridyl) -5- methoxy benzamide it is anti-
It answers, at 6 DEG C, proper amount of methanol cooling crystallization is added into reaction vessel, 200 mesh filter to obtain intermediate I；
S3, ensure anhydrous condition, chloroacetic chloride is added dropwise；At 58 DEG C, intermediate I and TiCl4 catalysis is added, keeps the temperature 30 points
Clock is warming up to 40 DEG C, and being evaporated to ensures dry materials；Then reacted with the tetrahydrofuran solution of dimethylamine, and after in hydroxide
Intermediate II is generated under the action of sodium；
S4, intermediate II and maleic acid reaction are obtained into betrixaban at 65 DEG C.
Embodiment 3:
S1, cyanobenzoic acid is activated: 1- (3- dimethylaminopropyl) -3- ethylcarbodiimide and N- hydroxyl
Succinimide (NHS) and paracyanobenzoic acid are passed through in solution, under 15 DEG C of proper temperatures, realize cyanobenzoic acid activation；
The molar ratio of 1- (3- dimethylaminopropyl) -3- ethylcarbodiimide and n-hydroxysuccinimide (NHS) are as follows: 1.5:
1.6
S2, by after activation cyanobenzoic acid and 2- amino-N- (5- chloro-2-pyridyl) -5- methoxy benzamide it is anti-
It answers, at 10 DEG C, proper amount of methanol cooling crystallization is added into reaction vessel, 200 mesh filter to obtain intermediate I；
S3, ensure anhydrous condition, chloroacetic chloride is added dropwise；At 8 DEG C, intermediate I and AlCl3 catalysis is added, keeps the temperature 30 minutes,
40 DEG C are warming up to, being evaporated to ensures dry materials；Then reacted with the tetrahydrofuran solution of dimethylamine, and after in sodium hydroxide
Effect is lower to generate intermediate II；
S4, intermediate II and maleic acid reaction are obtained into betrixaban at 70 DEG C.
Embodiment 4: existing technique production
2- chlorine-4,6-dimethoxy-1,3,5-triazine 79.0g (0.45mol, 2.5eq) is taken to be dissolved in 100.0g dimethyl methyl
It is spare in amide；I compound 50.0g (0.18mol, 1.0eq) of formula SM-, III compound 29.1g of SM- are added in round-bottomed flask
(0.20mol, 1.1eq), 4-dimethylaminopyridine 4.4g (0.036mol, 0.2eq), dimethylformamide 400.0g；It is stirring
Under, the dimethyl formamide solution control temperature of 2- chlorine-4,6-dimethoxy-1,3,5-triazine is added dropwise at 0~10 DEG C；It drips
Finish and be warming up to 25~30 DEG C of insulation reactions 2 hours, reaction is detected by HPLC and is completed；With vigorous stirring, 500.0g water is added；
Filtering；Filter cake obtains III compound 64.0g of formula using ethanol washing；
Analysis of experimental data:
Embodiment 1 random inspection, 4 samples, are respectively labeled as A1, A2, A3, A4；
Embodiment 2 random inspection, 4 samples, are respectively labeled as B1, B2, B3, B4；
Embodiment 3 random inspection, 4 samples, are respectively labeled as C1, C2, C3, C4；
4 samples as a control group of embodiment 4, are respectively labeled as D1, D2, D3, D4；
Detect its purity and yield；Specific data are as follows:
| Label | A1 | A2 | A3 | A4 |
| Purity/yield | 96.1/87.4 | 95.8/86.6 | 96.1/84.9 | 94.9/86.2 |
| Label | B1 | B2 | B3 | B4 |
| Purity/yield | 98.1/89.2 | 97.1/88.3 | 96.8/87.9 | 98.3/87.2 |
| Label | C1 | C2 | C3 | C4 |
| Purity/yield | 93.7/85.2 | 95.3/85.6 | 95.1/84.6 | 95.3/87.1 |
| Label | D1 | D2 | D3 | D4 |
| Purity/yield | 95.7/84.2 | 94.1/83.7 | 93.2/85.6 | 91.2/82.2 |
By yield purity and yield of the invention known to above-mentioned data, hence it is evident that be better than control group, the present invention is by cyano benzene first
Acid is activated: 1- (3- dimethylaminopropyl) -3- ethylcarbodiimide is combined with n-hydroxysuccinimide (NHS's)
Effect, keeps reaction process condition of the invention mild, easily controllable, and the high income of product, and purity is high is more suitable for scale amount
It produces；Using chloroacetic chloride and alcohols, it is possible to provide hydrogen chloride required for this technique directly leads to hydrogen chloride gas different from traditional,
The present invention can reduce the corrosiveness of gas apparatus.
These are only the preferred embodiment of the present invention, is not intended to restrict the invention, although with reference to the foregoing embodiments
Invention is explained in detail, for those skilled in the art, still can be to foregoing embodiments institute
The technical solution of record is modified or equivalent replacement of some of the technical features.It is all in spirit of the invention and
Within principle, any modification, equivalent replacement, improvement and so on be should all be included in the protection scope of the present invention.
Claims (6)
1. a kind of synthesis technology of betrixaban, which is characterized in that specific step is as follows:
S1, cyanobenzoic acid is activated: 1- (3- dimethylaminopropyl) -3- ethylcarbodiimide and N- hydroxysuccinimidyl
Acid imide (NHS) and paracyanobenzoic acid are passed through in solution, under 10 DEG C to 15 DEG C proper temperatures, realize that cyanobenzoic acid is living
Change；
S2, the cyanobenzoic acid after activation is reacted with 2- amino-N- (5- chloro-2-pyridyl) -5- methoxy benzamide,
At -15 DEG C to 10 DEG C, proper amount of methanol cooling crystallization is added into reaction vessel, filters to obtain intermediate I；
S3, ensure anhydrous condition, chloroacetic chloride is added dropwise；At 2 to 8 DEG C, intermediate I is added, keeps the temperature 30 minutes, is warming up to 40 DEG C,
Being evaporated to ensures dry materials；Then reacted with the tetrahydrofuran solution of dimethylamine, and after generated under the action of sodium hydroxide
Intermediate II；
S4, intermediate II and maleic acid reaction are obtained into betrixaban at 60 DEG C~70 DEG C.
2. a kind of synthesis technology of betrixaban according to claim 1, it is characterised in that: 1- (3- dimethylamino third
Base) -3- ethylcarbodiimide and n-hydroxysuccinimide (NHS) molar ratio are as follows: 1.2:1.3~1.5:1.6.
3. a kind of synthesis technology of betrixaban according to claim 1, it is characterised in that: in S1 step, by cyano benzene
Formic acid is activated: 1- (3- dimethylaminopropyl) -3- ethylcarbodiimide and n-hydroxysuccinimide (NHS) and right
Cyanobenzoic acid is passed through in solution, under 12 DEG C of proper temperatures, realizes cyanobenzoic acid activation.
4. a kind of synthesis technology of betrixaban according to claim 1, it is characterised in that: in S2 step, at 10 DEG C,
Proper amount of methanol cooling crystallization is added into reaction vessel, the filtering of 200 mesh obtains intermediate I.
5. a kind of synthesis technology of betrixaban according to claim 1, it is characterised in that: in S3 step, at 8 DEG C,
Intermediate I and Lewis catalyst is added.
6. a kind of synthesis technology of betrixaban according to claim 1, it is characterised in that: Lewis catalyst is AlCl3
Or BF3 or SbCl5 or FeBr3 or FeCl3 or SnCl4 or TiCl4 or ZnCl2.
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| CN201910745717.1A CN110372582A (en) | 2019-08-13 | 2019-08-13 | A kind of synthesis technology of betrixaban |
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| CN201910745717.1A CN110372582A (en) | 2019-08-13 | 2019-08-13 | A kind of synthesis technology of betrixaban |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114057607A (en) * | 2020-07-29 | 2022-02-18 | 鲁南制药集团股份有限公司 | Preparation method of betrixaban intermediate compound |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105732490A (en) * | 2016-03-25 | 2016-07-06 | 重庆医科大学 | Preparation method of betrixaban |
| CN106831553A (en) * | 2015-09-11 | 2017-06-13 | 天津科伦药物研究有限公司 | The preparation method of betrixaban or its analog |
| CN107778224A (en) * | 2016-08-31 | 2018-03-09 | 鲁南制药集团股份有限公司 | A kind of preparation method of betrixaban intermediate |
| CN107778223A (en) * | 2016-08-31 | 2018-03-09 | 鲁南制药集团股份有限公司 | A kind of preparation method of maleic acid betrixaban |
| CN108530349A (en) * | 2018-04-09 | 2018-09-14 | 重庆三圣实业股份有限公司 | The preparation method and products thereof of betrixaban intermediate and betrixaban |
-
2019
- 2019-08-13 CN CN201910745717.1A patent/CN110372582A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106831553A (en) * | 2015-09-11 | 2017-06-13 | 天津科伦药物研究有限公司 | The preparation method of betrixaban or its analog |
| CN105732490A (en) * | 2016-03-25 | 2016-07-06 | 重庆医科大学 | Preparation method of betrixaban |
| CN107778224A (en) * | 2016-08-31 | 2018-03-09 | 鲁南制药集团股份有限公司 | A kind of preparation method of betrixaban intermediate |
| CN107778223A (en) * | 2016-08-31 | 2018-03-09 | 鲁南制药集团股份有限公司 | A kind of preparation method of maleic acid betrixaban |
| CN108530349A (en) * | 2018-04-09 | 2018-09-14 | 重庆三圣实业股份有限公司 | The preparation method and products thereof of betrixaban intermediate and betrixaban |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114057607A (en) * | 2020-07-29 | 2022-02-18 | 鲁南制药集团股份有限公司 | Preparation method of betrixaban intermediate compound |
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