CN106518758A - Preparation method of Betrixaban intermediate N-(5-chloro-2-pyridyl)-2-(4-cyanobenzeneformamido)-5-metoxybenzamide - Google Patents
Preparation method of Betrixaban intermediate N-(5-chloro-2-pyridyl)-2-(4-cyanobenzeneformamido)-5-metoxybenzamide Download PDFInfo
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- CN106518758A CN106518758A CN201510585204.0A CN201510585204A CN106518758A CN 106518758 A CN106518758 A CN 106518758A CN 201510585204 A CN201510585204 A CN 201510585204A CN 106518758 A CN106518758 A CN 106518758A
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- LXFSCSJMDZZGDN-UHFFFAOYSA-N COc(cc1)cc(C(Nc(cc2)ncc2Cl)=O)c1NC(c(cc1)ccc1C#N)=O Chemical compound COc(cc1)cc(C(Nc(cc2)ncc2Cl)=O)c1NC(c(cc1)ccc1C#N)=O LXFSCSJMDZZGDN-UHFFFAOYSA-N 0.000 description 1
- ZIPODLCWEGXNJS-UHFFFAOYSA-N COc(cc1)cc(C(O)=O)c1NC(c(cc1)ccc1C#N)=O Chemical compound COc(cc1)cc(C(O)=O)c1NC(c(cc1)ccc1C#N)=O ZIPODLCWEGXNJS-UHFFFAOYSA-N 0.000 description 1
- YYDNZTPMFKGSPT-UHFFFAOYSA-N COc(cc1)cc(C(OCc2ccccc2)=O)c1N Chemical compound COc(cc1)cc(C(OCc2ccccc2)=O)c1N YYDNZTPMFKGSPT-UHFFFAOYSA-N 0.000 description 1
- IOHFLQCVTMCKMJ-UHFFFAOYSA-N COc(cc1)cc(C(OCc2ccccc2)=O)c1NC(c(cc1)ccc1C#N)=O Chemical compound COc(cc1)cc(C(OCc2ccccc2)=O)c1NC(c(cc1)ccc1C#N)=O IOHFLQCVTMCKMJ-UHFFFAOYSA-N 0.000 description 1
- USEDMAWWQDFMFY-UHFFFAOYSA-N N#Cc(cc1)ccc1C(Cl)=O Chemical compound N#Cc(cc1)ccc1C(Cl)=O USEDMAWWQDFMFY-UHFFFAOYSA-N 0.000 description 1
- MAXBVGJEFDMHNV-UHFFFAOYSA-N Nc(cc1)ncc1Cl Chemical compound Nc(cc1)ncc1Cl MAXBVGJEFDMHNV-UHFFFAOYSA-N 0.000 description 1
Classifications
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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
Abstract
The invention discloses a preparation method of a Betrixaban intermediate N-(5-chloro-2-pyridyl)-2-(4-cyanobenzeneformamido)-5-metoxybenzamide (a compound II). The synthetic route is as shown in the graphs in the specification. According to the new method, different starting materials, different reaction conditions and different reaction routes are adopted. Thus, the step of reduction of nitro into amino in original patents is avoided. By the adoption of protection of carboxyl group, generation of by-products is greatly reduced. During palladium carbon catalytic hydrogenation, there exist no dechlorination products.
Description
Technical field
The present invention relates to medicinal chemistry art and organic synthesis field, and in particular to the preparation method of betrixaban intermediate N (5- chloro-2-pyridyls) -2- (4- Cyanophenacyl amidos) -5- methoxy benzamides.
Background technology
Cardiovascular and cerebrovascular disease has become one of global pathogenic and fatality rate highest disease, and thrombosiss are the main inducings of cardiovascular and cerebrovascular disease.Traditional anticoagulant is based on heparin and warfarin, but there is bleeding, thrombocytopenic obvious adverse reaction.Researcher finds to suppress Xa factor to have higher anticoagulation than direct enzyme anticoagulant, and the development for anticoagulant provides new direction.Betrixaban is a kind of oral direct Xa factor inhibitor, is also the minimum medicine of currently the only Jing renal excretion, shows good treatment prospect in a series of researchs.(the Expert Opin Pharmacother such as Morganroth J, 2013,14 (1)：5-13) its chemical constitution shown in formula I, chemical entitled N- (5- chloro-2-pyridyls) -2- [[4- [(dimethylamino) iminomethyl] benzoyl] amino] -5- methoxy benzamides.
Patent documentation CN1391555A, CN101595092B, CN102762538A successively disclose the synthetic method of betrixaban and have carried out corresponding protection to which.
The preparation method of main flow is provided with first synthesizing cyano compound II, chemical entitled N- (5- chloro-2-pyridyls) -2- (4- Cyanophenacyl amidos) -5- methoxy benzamides, then convert it into the compound betrixaban containing amidino groups (compound I) this feature.
The content of the invention
The present invention is intended to provide a kind of synthetic method of important intermediate II of betrixaban.
In original patent, initiation material is the benzoic acid containing nitro, is needing nitro is reduced into amino continuation reaction using reducing agent after a step amidation process.Used in this step reaction, Reduction with Stannous Chloride is uneconomical；There are problems that during using iron powder reducing that reaction is incomplete；Improve palladium carbon catalytic hydrogenation used in route, although yield is high, but need to add sodium phosphite to suppress dechlorination in reacting, control improper easy generation dechlorination impurity in products, it is difficult to separate.In sum, the synthetic method of intermediate II is optimized with urgent realistic meaning.
New method employs different initiation materials, different reaction conditions, different reaction schemes, it is to avoid the step of nitro is reduced into amino in original patent；Carboxy protective with the generation for greatly reducing by-product；There is no dechlorination product during palladium carbon catalytic hydrogenation.
In embodiment, the present invention provides a kind of method of synthesis Formula II compound, including：
A) formula G compound is made to contact at reaction conditions to form formula E compound with formula F compound, wherein described formula G compound is：
The formula F compound is：
The formula E compound is：
B) formula E compound is made to contact at reaction conditions to form formula C compound with formula D compound, wherein described formula D compound is：
The formula C compound is：
C) formula C compound is made to expose production B compound at reaction conditions, wherein described formula B compound is：
D) formula A compound is made to be contacted with formula B compound at reaction conditions to form Formula II compound or its salt, wherein described formula A compound is：
The Formula II compound is：
Specific embodiment
The present invention includes the improvement synthetic method of Formula II compound, and wherein described improvement is the improvement relative to the synthetic method of betrixaban intermediate II in existing patent, including different initial compounds, different intermediate, different reaction schemes.
Definition：
As used herein, term " contact " is referred to two or more chemical molecular near so that both or two or more chemical moleculars react.For example be dissolved in one or more dicyandiamide solution by two or more chemical moieties or all, by other generally known to those skilled in the art methods such as the chemical substance in one or more solvent and another kind of or various solid phases or gas chemistry material mixing.
As used herein, term " reaction condition " refers to the concrete condition that chemical reaction is carried out.Including but not limited to one or more following factors：Temperature, solvent, PH, pressure, response time, reactant molar ratio, catalyst etc..Reaction condition can be according to the specified chemical reaction name using these conditions, such as amidatioon, esterification, hydrogenation, reduction etc..
Unless otherwise stated, the abbreviation for being used throughout the specification has following implication：
Compound I=betrixabans
Compound (intermediate) II=N- (5- chloro-2-pyridyls) -2- (4- Cyanophenacyl amidos) -5- methoxy benzamides；
Toluene=toluene；Ts-OH=p-methyl benzenesulfonic acid；CH2Cl2=dichloromethane；THF=tetrahydrofurans；Pd/C=palladium carbons；
H2=hydrogen；CH3OH=methanol；Pyridine=pyridines；Mmol=mM；ML=milliliters；H=hours
Method：
The invention provides a kind of synthetic method of the intermediate II of improvement, the route of synthesis is as follows：
Including
Formula G compound is made to contact at reaction conditions to form formula E compound with the formula F compound of at least 1.5 times of equivalents, wherein described formula G compound is：
The formula F compound is：
The formula E compound is：
The temperature of esterification is between 60 DEG C to 130 DEG C.Carboxy protective reagent is benzylalcohol, and the ester of formation is equal under acid and alkalescence condition to keep stable, be only reduced into acid in catalytic hydrogenation reaction.Catalyst can avoid the coking or other side reactions that concentrated sulphuric acid brings for concentrated sulphuric acid, p-methyl benzenesulfonic acid etc., in a preferred embodiment using p-methyl benzenesulfonic acid.Gained compound E normal hexane: the crystallization of ether mixed solvent system, solvent ratios are between 18: 1 to 25: 1.
Formula E compound is made to contact at reaction conditions to form formula C compound with the formula D compound of 1.3 to 2 times of equivalents, wherein described formula D compound is：
The formula C compound is：
Amidation process can adopt dichloromethane, chloroform, tetrahydrofuran equal solvent.Acid binding agent can be triethylamine, pyridine, sodium carbonate, sodium bicarbonate etc..
Formula C compound is made to be exposed to production B compound under the conditions of hydrogenation, wherein described formula B compound is：
Hydrogenation is used for releasing the protection to carboxyl.Make catalyst using palladium carbon, platinum carbon etc., reaction is typically carried out at 25 DEG C to 30 DEG C, pressure is normal pressure between 0.3MPa, in a preferred embodiment from 5% palladium carbon as catalyst.
The formula A compound of 1.5 to 2 times of equivalents is made to be contacted with formula B compound at reaction conditions to form Formula II compound or its salt, wherein described formula A compound is：
The Formula II compound is：
When using pyridine as acid binding agent, 3 to 5 times equivalents of its consumption for compound B, reaction condition include non-protonic solvent, and in a preferred embodiment, non-protonic solvent is tetrahydrofuran.
Embodiment one：(preferred embodiment)
The first step：Formula G compound and formula F compound of formula E compounds
It is furnished with magnetic stirring bar at one, the compound G of 3.34g (20mmol) is added in the 300mL single necked round bottom flask of water knockout drum and condensation reflux unit, the p-methyl benzenesulfonic acid and 40mL toluene of the benzylalcohol F of 3.25g (30mmol), 47.5mg (0.25mmol).Above-mentioned mixed system can collect the water of 0.31mL during this period in theory in 130 DEG C of condensing reflux 13h.After the completion of reaction, question response system is cooled to room temperature, adds ether dilution, pours in the saturated sodium bicarbonate aqueous solution of 50mL, take organic faciess, and remaining water is extracted twice with the ether of 20mL.Merge organic faciess, anhydrous sodium sulfate drying, rotary evaporation remove solvent.Product grinds, with normal hexane: ether=20: 1 mixed system crystallization, the crystal of compound E is filtrated to get, after surplus solution concentration, continues crystallization.
Second step：Formula E compound and formula D compound of formula C compounds
The anhydrous pyridine of the compound E and 40mmol of 10mmol is added in being furnished with magnetic stirring bar, and the 300mL single necked round bottom flask of condensation reflux unit at one.The compound D of 20mmol is dissolved in anhydrous methylene chloride, is slowly added dropwise into above-mentioned system, under room temperature, is reacted 2h.Reactant liquor uses 10%HCl and 10%NaHCO respectively3Aqueous solution is washed one time, anhydrous MgSO4It is dried, rotary evaporation, removes solvent.Products therefrom ethyl alcohol recrystallization obtains pure compound C.
3rd step：Formula C compound of formula B compounds
The absolute methanol of the compound C and 50mL of 10mmol is added in the 150mL for connecting biexhaust pipe has arm eggplant shaped reaction bottle, weigh 5% palladium carbon, drenched with methanol and be transferred in eggplant-shape bottle, stoppered with rubber stopper, open pumping vacuum, with nitrogen displacement air 3 times, take out 2min after bubble-free in system again and change hydrogen balloon reaction.Reaction system is slowly heated to into 28 DEG C, not more than 30 DEG C, HPLC monitoring raw material point reactions are complete, are filtered to remove palladium carbon and obtain compound B.
4th step：Formula B compound and formula A compound of formula II compounds
The anhydrous pyridine of the compound B and 30mmol of 10mmol is added in being furnished with magnetic stirring bar, and the 300mL single necked round bottom flask of condensation reflux unit at one.The compound A of 20mmol is dissolved in 100mL anhydrous tetrahydro furans, is slowly added dropwise into above-mentioned system, under room temperature, is reacted 2h.Reactant liquor uses 10%HCl and 10%NaHCO respectively3Aqueous solution is washed one time, anhydrous MgSO4It is dried, rotary evaporation, removes solvent.Products therefrom ethyl alcohol recrystallization obtains pure compound II.
Claims (9)
1. a kind of synthetic method for preparing Formula II compound
Including：
Formula A compound is made to be contacted with formula B compound at reaction conditions to form Formula II compound or its salt,
Its compound of formula A is：
The formula B compound is：
2. method according to claim 1, wherein described acid binding agent are anhydrous pyridine, pyridine and formula B
The ratio of the amount of the material of compound is 3: 1.
3. method according to claim 1, formula B compound is by formula C compound is exposed to instead
To be formed under the conditions of answering, the wherein described formula B compound of protection is during synthesis betrixaban and its intermediate
Application.
4. method according to claim 3, wherein described reaction condition include the temperature between 19 DEG C -28 DEG C
Degree, catalyst are the palladium carbon of the 5% of activation.
5. method according to claim 3, wherein described formula C compound is by reaction conditions
Make formula D compound：
Contact with formula E compound：
Prepared with forming the formula C compound.
6. method according to claim 5, should make solvent comprising dichloromethane, wherein described acid binding agent
For anhydrous pyridine, pyridine is 4: 1 with the ratio of the amount of the material of formula E compound.
7. method according to claim 5, wherein described formula E compound is by reaction conditions
Make formula G compound：
Contact with formula F compound：
Prepared with forming the formula E compound.
8. method according to claim 7, the amount of the material of wherein described compound F and compound G
Ratio be 3: 2, should comprising p-methyl benzenesulfonic acid as catalyst for esterification reaction.
9. method according to claim 7, should include normal hexane: ether=20: 1 mixed system crystallization
Obtain compound E.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510585204.0A CN106518758A (en) | 2015-09-11 | 2015-09-11 | Preparation method of Betrixaban intermediate N-(5-chloro-2-pyridyl)-2-(4-cyanobenzeneformamido)-5-metoxybenzamide |
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| CN201510585204.0A CN106518758A (en) | 2015-09-11 | 2015-09-11 | Preparation method of Betrixaban intermediate N-(5-chloro-2-pyridyl)-2-(4-cyanobenzeneformamido)-5-metoxybenzamide |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107868039A (en) * | 2017-11-27 | 2018-04-03 | 中国药科大学 | A kind of shellfish Qu Shaban intermediate Ns（5- chloro-2-pyridyls）- 2-（4- cyanobenzoyls）Amino ］ -5- methoxy benzamides preparation method |
| CN109180573A (en) * | 2018-09-17 | 2019-01-11 | 珠海润都制药股份有限公司 | A kind of preparation method of betrixaban intermediate |
| CN111349016A (en) * | 2018-12-20 | 2020-06-30 | 北京万全德众医药生物技术有限公司 | Synthetic method of betrixaban intermediate |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1391555A (en) * | 1999-09-17 | 2003-01-15 | 千禧药品公司 | Benzamides and related inhibitors of factor Xa |
| CN104693114A (en) * | 2013-12-10 | 2015-06-10 | 四川海思科制药有限公司 | Improved method for preparing betrixaban |
-
2015
- 2015-09-11 CN CN201510585204.0A patent/CN106518758A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1391555A (en) * | 1999-09-17 | 2003-01-15 | 千禧药品公司 | Benzamides and related inhibitors of factor Xa |
| CN104693114A (en) * | 2013-12-10 | 2015-06-10 | 四川海思科制药有限公司 | Improved method for preparing betrixaban |
Non-Patent Citations (5)
| Title |
|---|
| JIANYE LI等: "A facile method for the synthesis of Betrixaban", 《JOURNAL OF CHEMICAL RESEARCH》 * |
| PENGLIE ZHANG等: "Anthranilamide-based N,N-dialkylbenzamidines as potent and orally bioavailable factor Xa inhibitors:P4 SAR", 《BIOORGANIC & MEDINICINAL CHEMISTRY LETTERS》 * |
| 刘军，等: "《有机化学》", 31 August 2014 * |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107868039A (en) * | 2017-11-27 | 2018-04-03 | 中国药科大学 | A kind of shellfish Qu Shaban intermediate Ns（5- chloro-2-pyridyls）- 2-（4- cyanobenzoyls）Amino ］ -5- methoxy benzamides preparation method |
| CN109180573A (en) * | 2018-09-17 | 2019-01-11 | 珠海润都制药股份有限公司 | A kind of preparation method of betrixaban intermediate |
| CN111349016A (en) * | 2018-12-20 | 2020-06-30 | 北京万全德众医药生物技术有限公司 | Synthetic method of betrixaban intermediate |
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Application publication date: 20170322 |