CN103242296A - Dabigatran etexilate analogue with fluorine-containing group modified pyridine ring as center and synthesis method of analogue - Google Patents
Dabigatran etexilate analogue with fluorine-containing group modified pyridine ring as center and synthesis method of analogue Download PDFInfo
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Abstract
The invention discloses a dabigatran etexilate analogue with fluorine-containing group modified pyridine ring as a center and a synthesis method of the analogue. According to the synthesis method, with a fluorine-containing group aminopyridine compound as a starting material, a series of reactions are carried out to prepare he fluorine-containing group modified dabigatran etexilate analogue. The synthesis method of the analogue has the advantages that the operation is simple, used reagents are low in cost and easily available, synthesis cost is relatively low, rick in the synthetic process is low, yield of each synthesis step is high, and synthesis time is short.
Description
Technical field
The present invention relates to a kind of dabigatran ester analogs and synthetic method thereof centered by the pyridine ring that fluoro-containing group is modified, belong to the field of chemical synthesis.
Background technology
Direct thrombin inhibitors dabigatran ester (dabigatrau etexilate, commodity are called Pradaxa) by the exploitation of German Boehringer Ingelheim company, take the lead in going on the market in Germany and Britain in April, 2008, be a kind of novel, non-peptide class, competitiveness, reversible thrombin inhibitors, it is oral after stomach and intestine absorb, be converted into the dabigatran with direct anticoagulant active in vivo, its structural representation as shown in Figure 1.
The structural representation of dabigatran ester as shown in Figure 2, the dabigatran ester is the new classification oral anticoagulant thing of first listing in 50 years after warfarin, compare with warfarin, characteristics such as the dabigatran ester has can be oral, rapid-action, need not special medication monitoring, drug interaction is few, in the body, in vitro tests and clinical every research shows that all this product has good curative effect and pharmaco-kinetic properties, has good clinical application prospect.
But also there is following defective in the dabigatran ester at present as direct coagulant: dabigatran ester oral administration biaavailability is lower.Similar with other various anticoagulants, the dabigatran ester is used for the anticoagulant therapy process also unavoidably bleeding can occur, and especially when high dosage used, hemorrhage incidence was higher.
Further because fluorine atom has very big electronegativity, be incorporated into fluorine atom in the organic molecule after, tend to make the electronic property of original molecule that very big change takes place.From the level of molecule, the introducing of fluorine atom can cause the lipophilic variation of molecule usually, and the variation of object construction electrostatic interaction reaches the restraining effect to some pathways metabolisms, improves the metabolic stability of medicine; Improve the action time of medicine; Strengthen drug effect; Eliminate activity metabolism intermediate, the covalent attachment of minimizing and albumen etc.From physiological level, fluorine-containing medicine is compared with general floride-free medicine, has better biological penetrance, has better and the selectivity of Target organ effect, and dosage that usually can use reduces greatly.
At present, the dabigatran ester exists bioavailability lower, is used for the anticoagulant therapy process and bleeding can occur, and especially when high dosage used, hemorrhage incidence is the high-technology problem more.And in its preparation process, committed step also will be used HCl volatile and that toxicity is bigger, NH
3Deng gas, so preparation cost is higher, and the danger of preparation process is very big.As CN200610082286.8 at preparation compound 3-({2-[(4-miaow base-benzene imines)-methylene radical]-1-methylene radical-1 hydrogen-benzoglyoxaline-5-carbonyl-[4-fluorobenzene]-2-imines)-process of ethyl propionate in, used HCl volatile and that toxicity is bigger, NH
3Deng gas, increased the danger of preparation process.
Summary of the invention
One of purpose of the present invention is lower in order to solve above-mentioned dabigatran ester biological availability, be used for the bleeding that the anticoagulant therapy process can occur, especially when high dosage uses, hemorrhage incidence is high-technology problem and a kind of high dabigatran ester analogs of bioavailability centered by the pyridine ring that fluoro-containing group is modified is provided more.
Two of purpose of the present invention is in order to use HCl volatile and that toxicity is bigger, NH among the preparation method who solves fluorine-containing dabigatran ester analogs
3Deng gas, and technical problem such as the danger increase of preparation process and a kind of synthetic method of safe and reliable, building-up process simple, synthetic cost is relatively low a kind of dabigatran ester analogs centered by the pyridine ring that fluoro-containing group is modified is provided.
Technical scheme of the present invention
A kind of dabigatran ester analogs centered by the pyridine ring that fluoro-containing group is modified, its structural formula as shown in Figure 3.
Above-mentioned a kind of dabigatran ester analogs centered by the pyridine ring that fluoro-containing group is modified synthetic method, namely the aminopyridine compounds 10 with fluoro-containing group is raw material, synthetic through compound 1 successively, compound 2 is the synthetic of 3-nitro parabromobenzoic acid, compound 3 is the synthetic of 4-amino-3-nitrobenzoic acid, compound 4 is the synthetic of 4-amino-3-nitrobenzoyl chloride, synthesizing of compound 5, synthesizing of compound 6, synthesizing of compound 7,9 steps such as synthetic grade of the synthetic and compound 9 of compound 8 finally obtain a kind of dabigatran ester analogs centered by the pyridine ring that fluoro-containing group is modified.
The synthetic method of above-mentioned a kind of dabigatran ester analogs centered by the pyridine ring that fluoro-containing group is modified, the concrete steps of its building-up process are as follows:
(1), compound 1 is synthetic
The aminopyridine compounds 10 of used fluoro-containing group and 3-ethyl bromide, triethylamine calculate in molar ratio in the above-mentioned reaction, i.e. compound 10:3-ethyl bromide: triethylamine is 1:1～2:1～3;
(2), compound 2 is the synthetic of 3-nitro parabromobenzoic acid
Under the ice bath, the control drop rate is that 3～4mL/min drips 98% vitriol oil in the parabromobenzoic acid, after being warming up to room temperature, the control drop rate is that 2mL/min dropping volume ratio is 98% vitriol oil of 1:1 and the nitration mixture that 65～68% concentrated nitric acids are formed, in 60 ℃ of following stirring reaction 5h, pour in the frozen water reaction solution 2 that obtains into cooling after, suction filtration, the filter cake of gained washes with water to neutrality, and obtaining flaxen compound 2 behind the crude product water recrystallization is 3-nitro parabromobenzoic acid;
Above-mentioned used parabromobenzoic acid, concentration is that 98% the vitriol oil, concentration are that 65～68% concentrated nitric acid and concentration are the amount of the nitration mixture formed of 98% the vitriol oil, and by parabromobenzoic acid: the vitriol oil: concentration is that 65～68% concentrated nitric acid and concentration are that the nitration mixture that 98% the vitriol oil is formed is the ratio calculating of 1mol:500mL:200mL;
(3), compound 3 is the synthetic of 4-amino-3-nitrobenzoic acid
The 3-nitro parabromobenzoic acid of step (2) gained is dissolved in the aqueous solution of methylamine or ethamine, stirring heating back flow reaction 6h, obtaining reaction solution 3 usefulness glacial acetic acids transfers to pH and separated out yellow solid at 4～5 o'clock, suction filtration, obtaining yellow solid compound 3 behind the filtration cakes torrefaction of gained is 4-amino-3-nitrobenzoic acid;
The used compound 2 of above-mentioned reaction is that the amount of 3-nitro parabromobenzoic acid and methylamine or ethamine is calculated in molar ratio, and compound 2 is 3-nitro parabromobenzoic acid: methylamine or ethamine are 1:5～20, are preferably 1:15.2;
(4), compound 4 is the synthetic of 4-amino-3-nitrobenzoyl chloride
Be that 4-amino-3-nitrobenzoic acid is dissolved in the toluene with the compound 3 of step (3) gained, add sulfur oxychloride and N then, dinethylformamide (DMF), the control temperature is 80～85 ℃ of reaction 3h down, the reaction solution 4 that obtains.The control temperature is 60 ~ 65 ℃, and pressure is to carry out behind the concentrating under reduced pressure gained yellow solid under the 0.09-0.1MPa to be compound 4 be 4-amino-3-nitrobenzoyl chloride;
Used compound 3 is the amount of 4-amino-3-nitrobenzoic acid, toluene, sulfur oxychloride and DMF in the above-mentioned reaction process, be 4-amino-3-nitrobenzoic acid in compound 3: toluene: sulfur oxychloride: DMF is that the ratio of 1mol:2～4L:2～5mol:0.01～0.05L is calculated, and is preferably 1mmol:2.08mL:4.65mmol:0.035mL;
(5), compound 5 is synthetic
Compound 1 and triethylamine are dissolved in the methylene dichloride, the dichloromethane solution that with the compound 4 of step (4) gained is 4-amino-3-nitrobenzoyl chloride then splashes into wherein, dripping back control temperature is 20～25 ℃ of following stirring reaction 2-5h, the reaction solution 5 that obtains is used dichloromethane extraction, and the organic layer of gained gets yellow solid compound 5 successively behind saturated common salt water washing, anhydrous sodium sulfate drying, concentrating under reduced pressure, silica gel column chromatography;
Above-mentioned used compound 1, triethylamine, methylene dichloride and compound 4 are the amount of the dichloromethane solution of 4-amino-3-nitrobenzoyl chloride, in compound 1: triethylamine: methylene dichloride: compound 4 is that 4-amino-3-nitrobenzoyl chloride is that the ratio of 1mol:0.5～2mol:2～3L:1mol is calculated, and is preferably 1mol:1.46mol:2.31L:1mol;
(6), compound 6 is synthetic
The compound 5 of step (5) gained is dissolved in the dehydrated alcohol, and then adds 10% Pd/C, feed hydrogen behind the nitrogen replacement, reaction 4h obtains reaction solution 6 under the reflux state.After filtration, namely get oily matter behind concentrating under reduced pressure, the purification by silica gel column chromatography and be compound 6;
Used compound 5, the amount of 10% Pd/C in the above-mentioned reaction process are pressed mass ratio and are calculated, and namely compound 5:Pd/C is that 1:0.3 ~ 0.5 is preferably 1:0.3;
(7), compound 7 is synthetic
Under the ice bath with 2-(4-cyano group phenylamino) acetic acid, 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride, I-hydroxybenzotriazole is dissolved in by tetrahydrofuran (THF) (THF) and N, in the mixed solution that dinethylformamide (DMF) is formed, be warming up to 20～25 ℃ after stirring 30min, tetrahydrofuran solution control drop rate with the compound 6 of step (6) gained of 0.45mol/L is that 2mL/min is added dropwise to wherein then, and dropwising back control temperature is that 20～25 ℃ of row reaction 12h obtain reaction solution 7;
Used 2-(4-cyano group phenylamino in the above-mentioned reaction process) amount of the tetrahydrofuran solution of the mixed solution formed of acetic acid, 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride, I-hydroxybenzotriazole, THF and DMF and compound 6 press 2-(4-cyano group phenylamino) acetic acid: 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride: the mixing solutions that I-hydroxybenzotriazole: THF and DMF form: compound 6 is 1.2mol:1.2mol:1.2mol:4.4L:1.0mol calculating;
In the mixed solution that above-mentioned used THF and DMF form, calculate by volume, namely THF:DMF is preferably 7:1;
Reaction solution 7 with above-mentioned gained boils off tetrahydrofuran (THF) then, the gained resistates adds methylene dichloride makes its dissolving back saturated common salt water washing, the anhydrous sodium sulfate drying after-filtration, the filtrate of gained is 40～45 ℃ in temperature, pressure is concentrating under reduced pressure under the 0.09-0.1MPa, the enriched material of gained is incorporated as the glacial acetic acid of 10～15 times of its quality, transferring to pH with strong aqua after heating reflux reaction 2h gets reaction solution 8 and is cooled to 20～25 ℃ is 7～8, stir and use dichloromethane extraction after 30 minutes, the gained dichloromethane layer is used the saturated common salt water washing successively, the anhydrous sodium sulfate drying after-filtration, the filtrate of gained is through concentrating under reduced pressure, purification by silica gel column chromatography namely gets yellow oily compounds 7;
(8), compound 8 is synthetic
The compound 7 of step (7) gained is dissolved in the dehydrated alcohol, adds oxammonium hydrochloride and N, N-diisopropylethylamine, back flow reaction 3h obtain reaction solution 9;
Compound 7, oxammonium hydrochloride and N that above-mentioned reaction process is used, the amount of N-diisopropylethylamine is calculated in molar ratio, and namely compound 7: oxammonium hydrochloride: N, the N-diisopropylethylamine is 1:2～3:2～3, is preferably 1:2.83:2.48;
The reaction solution 9 pressure reducing and steaming ethanol of above-mentioned gained, the resistates acetate dissolution, and then add ammonium formate and Pd/C, under the nitrogen protection, back flow reaction 5h obtains reaction solution 10 after-filtration and removes Pd/C
,The filtrate of gained is 40～45 ℃ in temperature, and pressure is to concentrate under the 0.09-0.1MPa, and the crude product that concentrates gained carries out chromatography purification through silicagel column, namely gets faint yellow solid compound 8;
The ammonium formate that adds in the above-mentioned reaction process and the amount of Pd/C are calculated by its mass ratio with respect to compound 7, and namely compound 7: ammonium formate: Pd/C is 1:0.5～2:0.2～0.8, is preferably 1:0.5:0.5;
(9), compound 9 is synthetic
Under the room temperature compound 8 of step (8) gained is dissolved in that to calculate by volume be tetrahydrofuran (THF): water is in the tetrahydrofuran aqueous solution formed of 5:1, add sodium hydroxide or potassium hydroxide, it is 20～25 ℃ in temperature then, rotating speed is that the control drop rate is that 1mL/min is added dropwise to the just own ester of chloroformic acid wherein under 500～800r/min, dropwising continuation control temperature is 20～25 ℃ of reaction 0.5～1h, the reaction solution 11 that obtains is successively through concentrating under reduced pressure, purification by silica gel column chromatography, namely get the compound 9 of white solid, i.e. a kind of dabigatran ester analogs centered by the pyridine ring that fluoro-containing group is modified;
The amount of compound 8, sodium hydroxide or the potassium hydroxide that above-mentioned reaction process is used and the just own ester of chloroformic acid is calculated in molar ratio, and namely compound 8: sodium hydroxide or potassium hydroxide: the just own ester of chloroformic acid is 1:2～5:1, is preferably 1:5:1.
Beneficial effect of the present invention
A kind of dabigatran ester cpds centered by the pyridine ring that fluoro-containing group is modified of the present invention owing to have the similar structure of dabigatran ester, therefore can effectively be combined with the avtive spot of zymoplasm, is a kind of direct thrombin inhibitors compounds.
Further, a kind of dabigatran ester cpds centered by the pyridine ring that fluoro-containing group is modified of the present invention, because the introducing of fluoro-containing group, make fat-soluble the obtaining of the compound molecule after modifying increase, drug metabolic rate reduces, and it is lower therefore can to solve dabigatran ester biological availability, is used for the anticoagulant therapy process and also unavoidably bleeding can occurs, especially when high dosage uses, the technical problem that hemorrhage incidence is higher.
Further, in the synthetic method of a kind of dabigatran ester cpds centered by the pyridine ring that fluoro-containing group is modified of the present invention, particularly step 8 is wherein compared with the prior art synthetic route, the synthetic middle oxammonium hydrochloride of solid and the N of liquid of using of compound 8 in the step 8, N-diisopropylethylamine or triethylamine have replaced HCl of the prior art, NH
3Gas, thus difficulty and the danger of reacting reduced.Therefore synthetic method of the present invention has simple to operately, and cheap and easy to get, the synthetic cost of agents useful for same is relatively low, the dangerous reduction in the building-up process, and advantage such as each synthesis step productive rate is higher, and generated time is short.
Description of drawings
The structural representation of Fig. 1, dabigatran;
The structural representation of Fig. 2, dabigatran ester;
Fig. 3, a kind of dabigatran ester analogs structural representation centered by the pyridine ring that fluoro-containing group is modified;
The synthetic reaction process synoptic diagram of Fig. 4, a kind of dabigatran ester analogs centered by the pyridine ring that fluoro-containing group is modified.
Embodiment
Also by reference to the accompanying drawings the present invention is further set forth below by specific embodiment, but do not limit the present invention.
Used raw material, the reagent of the present invention is commercially available AR, CP level.
Gained target product of the present invention adopts nuclear magnetic resonance analyser (Avance
500M, Switzerland Bruker company) detect.
Embodiment 1
A kind of dabigatran ester analogs centered by the pyridine ring that fluoro-containing group is modified is with the R among Fig. 3
1For-F, R
2For-C
2H
5Be example, namely with the 3-[[[2-[[[4-[[[(hexyloxy) carbonyl] amino] formamino] phenyl] amino] methyl]-1-ethyl-1H-benzoglyoxaline-5-yl] carbonyl] (5-fluorine pyridine-2-yl) amino] ethyl propionate.
Above-mentioned a kind of dabigatran ester analogs centered by the pyridine ring that fluoro-containing group is modified is the 3-[[[2-[[[4-[[[(hexyloxy) carbonyl] amino] formamino] phenyl] amino] methyl]-1-ethyl-1H-benzoglyoxaline-5-yl] carbonyl] (5-fluorine pyridine-2-yl) amino] synthetic method of ethyl propionate, be raw material with 5-fluorine pyridine-2-base amino namely, obtain the dabigatran ester analogs that final product is fluorine-containing modification through 9 step reactions are synthetic, be the 3-[[[2-[[[4-[[[(hexyloxy) carbonyl] amino] formamino] phenyl] amino] methyl]-1-ethyl-1H-benzoglyoxaline-5-yl] carbonyl] (5-fluorine pyridine-2-yl) amino] ethyl propionate, per step building-up reactions is specific as follows:
(1), compound 1 is the synthetic of 3-(5-fluorine pyridine-2-base is amino) ethyl propionate
In round-bottomed flask, add 5-fluorine pyridine-2-base amino (5.57g, 50.0mmol), the 3-ethyl bromide (16.45g, 90.0mmol) and triethylamine (21.0mL), toluene is made solvent, 100 ℃ are reacted 12h down and obtain reaction solution 1;
5-fluorine pyridine-2-base amino and 3-ethyl bromide used in the above-mentioned reaction calculate in molar ratio, and namely 5-fluorine pyridine-2-base is amino: the 3-ethyl bromide is 1:1.8;
The reaction solution 1 of gained is 50～60 ℃ in temperature, pressure is to concentrate under 0.09～0.1MPa condition, the enriched material that concentrates the back gained carries out chromatography purification through silicagel column, use ethyl acetate in the purge process: sherwood oil is that 1:5～1:3 carries out wash-out as eluent, collect the outflow product of 1:4, be spin-dried for and obtain the sorrel solid and be 3-(4-fluorophenyl amino) ethyl propionate (8.2g, 78%);
(2), compound 2 is the synthetic of 3-nitro parabromobenzoic acid
Under the ice bath, the control drop rate is that 3～4mL/min is to parabromobenzoic acid (6.0 g, 0.03mol) in slowly to drip concentration be 98% the vitriol oil (15.0mL), be warming up to 20 ℃, controlling drop rate then and be 2mL/min is that 65～68% concentrated nitric acid (3.0 mL) and concentration are the nitration mixture that 98% the vitriol oil (3.0 mL) is formed to wherein dripping by concentration, dropwises the back temperature control and obtains reaction solution 2 in 60 ℃ of stirring reaction 5h;
Used parabromobenzoic acid, concentration is that 98% the vitriol oil, concentration are that 65～68% concentrated nitric acid and concentration are the amount of the nitration mixture formed of 98% the vitriol oil in the above-mentioned reaction process, and by parabromobenzoic acid: the vitriol oil: concentration is that 65～68% concentrated nitric acid and concentration are that the nitration mixture that 98% the vitriol oil is formed is 1mol:500mL:200mL calculating;
The reaction solution 2 of gained is poured in the 100mL frozen water, suction filtration, the filter cake of gained washes with water to neutrality, and suction filtration gets crude product water recrystallization, gets faint yellow needle-like crystal compound 2 and is 3-nitro parabromobenzoic acid (5.54g, 76%);
(3), compound 3 is the synthetic of 4-ethylamino-3-nitrobenzoic acid
With compound 2 be 3-nitro parabromobenzoic acid (5.73g, 0.023mol) be dissolved in mass percent concentration be 70% ethylamine solution (28mL, 0.35mol) in, stirring heating back flow reaction 6h gets reaction solution 3;
The used compound 2 of above-mentioned reaction is that the amount of the ethylamine solution of 3-nitro parabromobenzoic acid, concentration 70% is calculated in molar ratio, i.e. 3-nitro parabromobenzoic acid: ethamine is 1:15.2;
It is 4～5 that the reaction solution 3 usefulness glacial acetic acids of above-mentioned gained are transferred to pH, separates out yellow solid, suction filtration, and the filter cake control temperature of gained is that to obtain yellow solid compound 3 after 80～85 ℃ of dryings be 4-ethylamino-3-nitrobenzoic acid (3.32g, 68%);
(4), compound 4 is the synthetic of 4-ethylamino-3-nitrobenzoyl chloride
With compound 3 be 4-ethylamino-3-nitrobenzoic acid (3.0g 14.4mmol) is dissolved in the toluene (30.0mL), add then sulfur oxychloride (12.0mL, 67mmol) and the catalyzer DMF of 0.5mL, 85 ℃ of reactions of control temperature 3h obtains reaction solution 4;
Be 60～65 ℃ with the reaction solution 4 of above-mentioned gained in temperature, pressure be under 0.09～0.1MPa concentrating under reduced pressure to get yellow solid compound 4 be 4-ethylamino-3-nitrobenzoyl chloride (2.63g, 80%);
(5), compound 5 is 3-[(4-ethylamino-3-nitro benzoyl)-(5-fluorine pyridine-2-yl) amino] ethyl propionate synthetic
With 3-(5-fluorine pyridine-2-base is amino) ethyl propionate (2.82g, 0.013mol) and triethylamine (1.5mL, 0.019mol) be dissolved in the methylene dichloride (30.0mL), the control drop rate is that 3mL/min is 4-ethylamino--3-nitrobenzoyl chloride (3.0g with compound 4,0.013mol) dichloromethane solution be added dropwise to wherein, dripping the back is 20～25 ℃ in the control temperature, and rotating speed is that 500～800r/min reacts 5h and obtains reaction solution 5;
Used 3-in the above-mentioned reaction process (5-fluorine pyridine-2-base is amino) ethyl propionate, triethylamine, methylene dichloride and compound 4 are 4-ethylamino--3-nitrobenzoyl chloride amount, and by 3-(5-fluorine pyridine-2-base is amino) ethyl propionate: triethylamine: methylene dichloride: compound 4 is that 4-ethylamino--3-nitrobenzoyl chloride is 1mol:1.46mol:2.31L:1mol calculating;
The reaction solution 5 of above-mentioned gained is used dichloromethane extraction, organic layer saturated common salt water washing, anhydrous sodium sulfate drying after-filtration, filtrate is 40～45 ℃ in temperature, pressure is to concentrate under 0.09～0.1MPa, concentrate the crude product of back gained through purification by silica gel column chromatography, use ethyl acetate in the purge process: sherwood oil is that 1:4～1:2 carries out wash-out as eluent, collecting eluent is the outflow product of 1:2, be spin-dried for to such an extent that yellow solid compound 5 is 3-[(4 ethylamino-3-nitro benzoyl)-(5-fluorine pyridine-2-yl) amino] ethyl propionate (3.9g, 75%);
(6), compound 6 is 3-[(3-amino-4-ethylamino benzoyl) (5-fluorine pyridine-2-yl) amino] ethyl propionate synthetic
Be 3-[(4-ethylamino-3-nitro benzoyl with compound 5)-(5-fluorine pyridine-2-yl) amino] ethyl propionate (5.0g, 0.012mol) be dissolved in the 50mL dehydrated alcohol, add 10%Pd/C then, feed hydrogen under the nitrogen replacement, the about 4h of reaction obtains reaction solution 6 under the reflux state;
The reaction solution 6 of above-mentioned gained is filtered, filtrate is 40～45 ℃ in temperature, pressure is to carry out concentrating under reduced pressure under 0.09～0.1MPa, the crude product that concentrates gained carries out chromatography purification through silicagel column, use ethyl acetate in the purge process: sherwood oil is that 1:2～1:1 carries out wash-out as eluent, collecting eluent is the outflow product of 1:1, and being spin-dried for gained oily matter compound 6 is 3-[(3-amino-4-ethylamino benzoyl) (5-fluorine pyridine-2-yl) amino] ethyl propionate (3.6g, 80%);
(7), compound 7 is the 3-[[[2-[[(4-cyano-phenyl) amino] methyl]-1-ethyl-1H-benzoglyoxaline-5-yl] carbonyl] (5-fluorine pyridine-2-yl) amino] ethyl propionate synthetic
Under the ice bath with 2-(4-cyano group phenylamino) acetic acid (1.76g, 0.01mol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (1.9g, 0.01mol), I-hydroxybenzotriazole (1.35g, 0.01mol) be dissolved in by tetrahydrofuran (THF) (THF) (35.0mL) and N, in the THF that dinethylformamide (DMF) (5.0mL) is formed and the mixed solution of DMF, stir 30min, be warming up to 25 ℃ then, the control drop rate is that 20mL is dissolved with compound 6 is 3-[(3-amino-4-ethylamino benzoyl to 2mL/min) (5-fluorine pyridine-2-yl) amino] ethyl propionate (3.24g, 0.009mol,) tetrahydrofuran solution slowly be added dropwise to wherein, dropwise back control temperature and be 25 ℃ down reaction 12h obtain reaction solution 7;
Used 2-(4-cyano group phenylamino in the above-mentioned reaction process) acetic acid, 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride, I-hydroxybenzotriazole, tetrahydrofuran (THF) and N, mixed solution and compound 6 that dinethylformamide is formed are 3-[(3-amino-4-ethylamino benzoyl) (5-fluorine pyridine-2-yl) amino] amount of tetrahydrofuran solution of ethyl propionate, press 2-(4-cyano group phenylamino) acetic acid: 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride: I-hydroxybenzotriazole: the mixed solution that tetrahydrofuran (THF) and N, dinethylformamide form: compound 6 is 3-[(3-amino-4-ethylamino benzoyl) (5-fluorine pyridine-2-yl) amino] ethyl propionate is that 1.1mol:1.1mol:1.1mol:4.4L:1.0mol calculates;
Reaction solution 7 with above-mentioned gained boils off tetrahydrofuran (THF) then, the gained resistates adds methylene dichloride makes its dissolving, and with saturated common salt water washing, anhydrous sodium sulfate drying after-filtration, filtrate is concentrated into dried, add the 20mL glacial acetic acid in the enriched material of gained, heating reflux reaction 2h gets reaction solution 8;
It is that to transfer to pH value of solution be 7～8 for 25～28% strong aqua that the reaction solution 8 of above-mentioned gained is cooled to after 25 ℃ with concentration, and stirring 30min, the solution dichloromethane extraction of gained, the saturated common salt water washing, the anhydrous sodium sulfate drying after-filtration, the filtrate of gained is 40～45 ℃ in temperature, pressure be evaporated under 0.09～0.1MPa dried, the enriched material of gained carries out chromatography purification through silicagel column, use methylene dichloride in the purge process: methyl alcohol is that 30:1～20:1 carries out wash-out as eluent, collect the outflow product of 25:1, getting yellow oily compounds 7 after being spin-dried for is the 3-[[[2-[[(4-cyano-phenyl) amino] methyl]-1-ethyl-1H-benzoglyoxaline-5-yl] carbonyl] (5-fluorine pyridine-2-yl)-amino] ethyl propionate (2.9g, 65%);
(8), compound 8 is 3-[[[2-[[(4-amidino groups phenyl) amino] methyl]-1-ethyl-1H-benzoglyoxaline-5-yl] carbonyl] (5-fluorine pyridine-2-yl) amino] ethyl propionate synthetic
Be the 3-[[[2-[[(4-cyano-phenyl with compound 7) amino] methyl]-1-ethyl-1H-benzoglyoxaline-5-yl] carbonyl] (5-fluorine pyridine-2-yl) amino] ethyl propionate (1.20 g, 2.3mmol) be dissolved in the 30.0mL dehydrated alcohol, add oxammonium hydrochloride (0.42g, 6.5mmol) and N, N-diisopropylethylamine (1.0mL, 5.7mmol), the about 3h of back flow reaction obtains reaction solution 9;
The used compound 7 of above-mentioned reaction process is the 3-[[[2-[[(4-cyano-phenyl) amino] methyl]-1-ethyl-1H-benzoglyoxaline-5-yl] carbonyl] (5-fluorine pyridine-2-yl) amino] ethyl propionate, oxammonium hydrochloride and N, the amount of N-diisopropylethylamine, be the 3-[[[2-[[(4-cyano-phenyl by compound 7) amino] methyl]-1-ethyl-1H-benzoglyoxaline-5-yl] carbonyl] (5-fluorine pyridine-2-yl) amino] ethyl propionate: oxammonium hydrochloride: N, N-diisopropylethylamine are that 1mol:2.83mol:2.48mol calculates;
The reaction solution 9 pressure reducing and steaming ethanol of above-mentioned gained, resistates 20.0mL acetate dissolution, and then add ammonium formate (0.6g) and Pd/C(0.6 g), under the nitrogen protection, the about 5h of back flow reaction obtains reaction solution 10;
The ammonium formate that adds in the above-mentioned reaction process and Pd/C's is the 3-[[[2-[[(4-cyano-phenyl by itself and compound 7) amino] methyl]-1-ethyl-1H-benzoglyoxaline-5-yl] carbonyl] (5-fluorine pyridine-2-yl) amino] mass ratio of ethyl propionate calculates, namely compound 7 is the 3-[[[2-[[(4-cyano-phenyl) amino] methyl]-1-ethyl-1H-benzoglyoxaline-5-yl] carbonyl] (5-fluorine pyridine-2-yl) amino] ethyl propionate: ammonium formate: Pd/C is 1.0:0.5:0.5;
The reaction solution 10 of above-mentioned gained filters out Pd/C
,Filtrate is 60～65 ℃ in temperature, pressure be advance under 0.09～0.1MPa concentrated, the crude product that concentrates gained carries out chromatography purification through silicagel column, use methylene dichloride in the purge process: methyl alcohol is that 20:1～10:1 carries out wash-out as eluent, collect the outflow product of 10:1, be spin-dried for to such an extent that faint yellow solid compound 8 is 3-[[[2-[[(4-amidino groups phenyl) amino] methyl]-1-ethyl-1H-benzoglyoxaline-5-yl] carbonyl] (5-fluorine pyridine-2-yl)-amino] ethyl propionate (0.87g, 70%);
(9), compound 9 is the 3-[[[2-[[[4-[[[(hexyloxy) carbonyl] amino] formamino] phenyl] amino] methyl]-1-methyl isophthalic acid H-benzoglyoxaline-5-yl] carbonyl] (5-fluorine pyridine-2-yl) amino] ethyl propionate synthetic
Be 3-[[[2-[[(4-amidino groups phenyl with compound 8) amino] methyl]-1-ethyl-1H-benzoglyoxaline-5-yl] carbonyl] (5-fluorine pyridine-2-yl) amino] ethyl propionate (0.20g, 0.38mmol) be dissolved in by tetrahydrofuran (THF) (5mL) and water (1mL) and in the tetrahydrofuran aqueous solution that forms, add sodium hydroxide (0.05g, 1.9mmol), it is 20～25 ℃ in temperature then, under rotating speed 500～800r/min, the control drop rate is that 1.0 mL/min are with just own ester (62.0 mg of chloroformic acid, 0.38mmol) add wherein, dropwising continuation control temperature is that 20～25 ℃ of about 1h of reaction obtain reaction solution 11;
The used compound 8 of above-mentioned reaction process is 3-[[[2-[[(4-amidino groups phenyl) amino] methyl]-1-ethyl-1H-benzoglyoxaline-5-yl] carbonyl] (5-fluorine pyridine-2-yl) amino] amount of ethyl propionate, potassium hydroxide and the just own ester of chloroformic acid, calculate in molar ratio, namely compound 8 is 3-[[[2-[[(4-amidino groups phenyl) amino] methyl]-1-ethyl-1H-benzoglyoxaline-5-yl] carbonyl] (5-fluorine pyridine-2-yl) amino] ethyl propionate: sodium hydroxide: the just own ester of chloroformic acid is 1.0:5.0:1.0.
Be 40～45 ℃ with the reaction solution 11 of above-mentioned gained in temperature, pressure is to concentrate under 0.09～0.1MPa condition, the crude product of gained carries out chromatography purification through silicagel column, use methylene dichloride in the purge process: methyl alcohol is that 40:1～20:1 carries out wash-out as eluent, collect the outflow product of 25:1, be spin-dried for and namely get white solid compound 9 (0.15g, 60%).
The white solid compound 9 of above-mentioned gained detects through nuclear magnetic resonance analyser, and the result is as follows:
1H NMR（DMSO-
d 6, 500MHz）δ：0.88（t,3H）,1.12(t,3H),1.27-1.33(m,6H),
1.55-1.59(m,5H),2.68(t,2H),3.77(m,2H),3.95-3.99(m,4H),4.22(t,2H),4.59(d, 2H),6.76(d,2H),6.88(d,1H), 7.10-7.13(m,1H),7.15(dd,1H),7.40(d, 1H),7.47(d,1H),7.54(td,1H),7.80(d,2H),8.39(dq,1H),8.90(brs,2H)。
Above-mentioned detected result shows, in the white solid compound 9 and the structural formula among Fig. 3 of above-mentioned gained, namely works as R
1For-F, R
2For-C
2H
5The time, represented a kind of dabigatran ester analogs centered by the pyridine ring that fluoro-containing group is modified, i.e. 3-[[[2-[[[4-[[[(hexyloxy) carbonyl] amino] formamino] phenyl] amino] methyl]-1-ethyl-1H-benzoglyoxaline-5-yl] carbonyl] (5-fluorine pyridine-2-yl) amino] ethyl propionate is consistent.
Foregoing only is the basic explanation of the present invention under conceiving, and according to any equivalent transformation that technical scheme of the present invention is done, all should belong to protection scope of the present invention.
Claims (5)
1. dabigatran ester analogs centered by the pyridine ring that fluoro-containing group is modified is characterized in that its structural formula is as follows:
R wherein
1Be CF
3-, CF
3CH
2-, CF
3CH
2O-, CF
3O-, F-or CF
3CH
2OOC-;
R
2Be C
1-C
20Alkyl or contain fluoroalkyl.
2. a kind of dabigatran ester analogs centered by the pyridine ring that fluoro-containing group is modified as claimed in claim 1 is characterized in that wherein R
1For-F, R
2For-C
2H
5
3. the synthetic method of a kind of dabigatran ester analogs centered by the pyridine ring that fluoro-containing group is modified as claimed in claim 1 or 2 is characterized in that specifically comprising the steps:
(1), compound 1 is synthetic
The aminopyridine compounds 10 of adding fluoro-containing group and 3-ethyl bromide, triethylamine in container, toluene is made solvent, and the control temperature is that reaction 12 ~ 24h obtains reaction solution 1 concentrating under reduced pressure, purification by silica gel column chromatography successively under 100 ℃, obtains compound 1;
The aminopyridine compounds 10 of used fluoro-containing group and 3-ethyl bromide, triethylamine calculate in molar ratio in the above-mentioned reaction process, i.e. the aminopyridine compounds 10:3-ethyl bromide of fluoro-containing group: triethylamine is 1:1～2:1～3;
(2), compound 2 is the synthetic of 3-nitro parabromobenzoic acid
Under the ice bath, the control drop rate is that to drip concentration be to be warming up to 20 ℃ behind 98% the vitriol oil to 3～4mL/min in the parabromobenzoic acid, control drop rate again and be that 2mL/min drips by concentration is that 65～68% concentrated nitric acid and concentration are that 98% the vitriol oil is calculated as the nitration mixture that 1:1 forms by volume, drip the back temperature control in 60 ℃ of stirring reaction 4～6h, the reaction solution 2 that obtains is poured in the frozen water, suction filtration, the filter cake of gained washes with water to neutrality, suction filtration gets crude product water recrystallization, and getting faint yellow needle-like crystal is that compound 2 is 3-nitro parabromobenzoic acid;
Used parabromobenzoic acid, concentration is that 98% the vitriol oil, concentration are that 65～68% concentrated nitric acid and concentration are the amount of the nitration mixture formed of 98% the vitriol oil in the above-mentioned reaction process, and by parabromobenzoic acid: the vitriol oil: concentration is that 65～68% concentrated nitric acid and concentration are that the nitration mixture that 98% the vitriol oil is formed is the ratio calculating of 1mol:500mL:200mL;
(3), compound 3 is the synthetic of 4-ethylamino-3-nitrobenzoic acid
Be that 3-nitro parabromobenzoic acid is dissolved in the aqueous solution of methylamine or ethamine with the compound 2 of step (2) gained, stirring heating back flow reaction 5～8h obtains reaction solution 3 usefulness glacial acetic acids and transfers to pH and separated out yellow solid at 4～5 o'clock, suction filtration, obtaining yellow solid compound 3 behind the filtration cakes torrefaction of gained is 4-ethylamino-3-nitrobenzoic acid;
The used compound 2 of above-mentioned reaction is that the amount of 3-nitro parabromobenzoic acid and methylamine or ethamine is calculated in molar ratio, and namely compound 2 is 3-nitro parabromobenzoic acid: methylamine or ethamine are 1:5～20;
(4), compound 4 is the synthetic of 4-amino-3-nitrobenzoyl chloride
Be that 4-ethylamino-3-nitrobenzoic acid is dissolved in the toluene with the compound 3 of step (3) gained, add sulfur oxychloride and N then, dinethylformamide, the control temperature be 80～85 ℃ down reaction 3～8h obtain reaction solution 4 through concentrating under reduced pressure, getting yellow solid, to be compound 4 be 4-amino-3-nitrobenzoyl chloride;
Used compound 3 is 4-amino-3-nitrobenzoic acid, toluene, sulfur oxychloride and N in the above-mentioned reaction process, the amount of dinethylformamide, be 4-amino-3-nitrobenzoic acid by compound 3: toluene: sulfur oxychloride: N, dinethylformamide are that the ratio of 1mol:2～4L:2～5mol:0.01～0.05L is calculated;
(5), compound 5 is synthetic
Compound 1 and the triethylamine of step (1) gained are dissolved in the methylene dichloride, the dichloromethane solution that with the compound 4 of step (4) gained is 4-amino-3-nitrobenzoyl chloride then is added dropwise to wherein, dripping back control temperature is that the reaction solution 5 that 20～25 ℃ of stirring reaction 1～5h obtain is used dichloromethane extraction, and the organic layer of gained gets yellow solid compound 5 successively behind saturated common salt water washing, anhydrous sodium sulfate drying, concentrating under reduced pressure, purification by silica gel column chromatography;
Used compound 1, triethylamine, methylene dichloride and compound 4 is the amount of 4-ethylamino--3-nitrobenzoyl chloride in the above-mentioned reaction process, and in compound 1: triethylamine: methylene dichloride: compound 4 is that 4-ethylamino--3-nitrobenzoyl chloride is that the ratio of 1mol:0.5～2mol:2～3L:1mol is calculated;
(6), compound 6 is synthetic
The compound 5 of step (5) gained is dissolved in the dehydrated alcohol, and then add 10%Pd/C, and feed hydrogen behind the nitrogen replacement, react 3～6h under the reflux state, the reaction solution 6 that obtains is filtered, and filtrate gets oily matter through concentrating under reduced pressure, purification by silica gel column chromatography and is compound 6;
Used compound 5, Pd/C presses mass ratio calculating in the above-mentioned reaction process, and namely compound 5:Pd/C is 1:0.3～0.5;
(7), compound 7 is synthetic
Under the ice bath with 2-(4-cyano group phenylamino) acetic acid, 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride, I-hydroxybenzotriazole is dissolved in by tetrahydrofuran (THF) and N, in the mixed solution that dinethylformamide is formed, be warming up to 20～25 ℃ after stirring 30min, the tetrahydrofuran solution control drop rate that with concentration is the compound 6 of 0.45mol/L then is that 2mL/min is added dropwise to wherein, dropwising back control temperature and be 20～25 ℃ reacts 12～24h and obtains reaction solution 7 and boil off tetrahydrofuran (THF), the gained resistates adds methylene dichloride makes its dissolving back saturated common salt water washing, the anhydrous sodium sulfate drying after-filtration, the filtrate of gained is 40～45 ℃ in temperature and carries out concentrating under reduced pressure, the enriched material of gained is incorporated as the glacial acetic acid of 10～15 times of its quality, after the reaction solution 8 that heating reflux reaction 2～3h obtains is cooled to 20～25 ℃ with strong aqua transfer to pH be 7～8 and stir 30min after use dichloromethane extraction, the gained dichloromethane layer is successively through the saturated common salt water washing, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure, purification by silica gel column chromatography namely gets yellow oily compounds 7;
Used 2-(4-cyano group phenylamino in the above-mentioned reaction process) acetic acid, 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride, I-hydroxybenzotriazole, tetrahydrofuran (THF) and N, the amount of the mixed solution that dinethylformamide is formed and the tetrahydrofuran solution of compound 6, press 2-(4-cyano group phenylamino) acetic acid: 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride: I-hydroxybenzotriazole: tetrahydrofuran (THF) and N, the mixed solution that dinethylformamide is formed: compound 6 is that the ratio of 1.23mol:1.23mol:1.23mol:4.9L:1.0mol is calculated;
(8), compound 8 is synthetic
The compound 7 of step (7) gained is dissolved in the dehydrated alcohol; add oxammonium hydrochloride and N; N-diisopropylethylamine or triethylamine; the reaction solution 9 pressure reducing and steaming ethanol that back flow reaction 3～5h obtains; gained resistates acetate dissolution; and then adding ammonium formate and Pd/C, under the nitrogen protection, back flow reaction 4～8h obtains reaction solution 10 after-filtration and removes Pd/C
,The filtrate of gained is to carry out concentrating under reduced pressure under 60～65 ℃ in temperature, and the crude product that concentrates gained gets faint yellow solid compound 8 through purification by silica gel column chromatography;
Compound 7, oxammonium hydrochloride and N that above-mentioned reaction process is used, the amount of N-diisopropylethylamine or triethylamine is calculated in molar ratio, and namely compound 7: oxammonium hydrochloride: N, N-diisopropylethylamine or triethylamine are 1:2～3:2～3;
Used ammonium formate and the amount of Pd/C are by itself and the calculating of the mass ratio of compound 7, and namely compound 7: ammonium formate: Pd/C is 1:0.5～2:0.2～0.8;
(9), compound 9 is synthetic
Under the room temperature compound 8 of step (8) gained is dissolved in and calculates tetrahydrofuran (THF) by volume: water is in the mixing solutions of the tetrahydrofuran (THF) formed of 5:1 and water, add potassium hydroxide or sodium hydroxide, it is 20～25 ℃ in temperature then, rotating speed is that the control drop rate is that 1mL/min is added dropwise to the just own ester of chloroformic acid wherein under 500～800r/min, dropwising continuation control temperature is 20～25 ℃ of reaction 1～3h, the reaction solution 11 that obtains is through concentrating under reduced pressure, purification by silica gel column chromatography gets the compound 9 of white solid, i.e. dabigatran ester analogs centered by the pyridine ring that fluoro-containing group is modified;
The amount of compound 8, sodium hydroxide or the potassium hydroxide that above-mentioned reaction process is used and the just own ester of chloroformic acid is calculated in molar ratio, and namely compound 8: sodium hydroxide or potassium hydroxide: the just own ester of chloroformic acid is 1:2～5:1.
4. the synthetic method of a kind of dabigatran ester analogs centered by the pyridine ring that fluoro-containing group is modified as claimed in claim 3 is characterized in that:
Used compound 10 and the 3-ethyl bromide of reaction calculates in molar ratio in the step (1), and namely compound 10:3-ethyl bromide is 1:1.8;
The amount of the 3-nitro parabromobenzoic acid that step (3) is used and methylamine, ethamine is calculated in molar ratio, i.e. 3-nitro parabromobenzoic acid: methylamine or ethamine are 1:15.2;
Used compound 3 is 4-amino-3-nitrobenzoic acid, toluene, sulfur oxychloride and N in step (4) reaction process, the amount of dinethylformamide, be 4-amino-3-nitrobenzoic acid by compound 3: toluene: sulfur oxychloride: N, dinethylformamide are that the ratio of 1mol:2.08L:4.65 mol:0.035L is calculated;
Used compound 1, triethylamine, methylene dichloride and compound 4 is the amount of the dichloromethane solution of 4-ethylamino--3-nitrobenzoyl chloride in step (5) reaction process, and in compound 1: triethylamine: methylene dichloride: compound 4 is that 4-ethylamino--3-nitrobenzoyl chloride is that the ratio of 1mol:1.46mol:2.31L:1mol is calculated;
Used compound 5, the amount of 10% Pd/C in step (6) reaction process are pressed mass ratio and are calculated, and namely compound 5:10% Pd/C is 1:0.3 ~ 0.5;
Used compound 7, oxammonium hydrochloride and the N of reaction process in the step (8), the amount of N-diisopropylethylamine or triethylamine is calculated in molar ratio, and namely compound 7: oxammonium hydrochloride: N, N-diisopropylethylamine or triethylamine are 1:2.83:2.48;
The ammonium formate that adds in step (8) reaction process and the amount of 10%Pd/C are calculated by the mass ratio of itself and compound 7, and namely compound 7: ammonium formate: Pd/C is 1:0.5:0.5;
The amount of compound 8, sodium hydroxide or the potassium hydroxide that step (9) reaction process is used and the just own ester of chloroformic acid is calculated in molar ratio, and namely compound 8: sodium hydroxide or potassium hydroxide: the just own ester of chloroformic acid is 1:5:1.
5. the synthetic method of a kind of dabigatran ester analogs centered by the pyridine ring that fluoro-containing group is modified as claimed in claim 4 is characterized in that:
The mixed solution that tetrahydrofuran (THF) and N that step (7) is used, dinethylformamide form calculates by volume, i.e. tetrahydrofuran (THF): N, and dinethylformamide is 7:1.
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| TWI678365B (en) * | 2015-04-27 | 2019-12-01 | 大陸商四川海思科製藥有限公司 | Fluorodabigatran etexilate derivative, preparation method and pharmaceutical use thereof |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104003933A (en) * | 2014-05-14 | 2014-08-27 | 上海应用技术学院 | Preparation method of fluorine group-containing 3-(pyridyl-2-imine)ethyl propionate analogue |
| WO2016019847A1 (en) * | 2014-08-06 | 2016-02-11 | 四川海思科制药有限公司 | Fluorine substituted dabigatran ester derivative, preparation method therefor, and pharmaceutical use thereof |
| CN106536504A (en) * | 2014-08-06 | 2017-03-22 | 四川海思科制药有限公司 | Fluorine substituted dabigatran ester derivative, preparation method therefor, and pharmaceutical use thereof |
| TWI678365B (en) * | 2015-04-27 | 2019-12-01 | 大陸商四川海思科製藥有限公司 | Fluorodabigatran etexilate derivative, preparation method and pharmaceutical use 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 |
| CN105348262B (en) * | 2015-11-25 | 2018-09-04 | 蚌埠丰原医药科技发展有限公司 | A kind of improved method preparing dabigatran etcxilate |
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