CN103224469A - Pradaxa analogue with fluorine-containing group modified benzene ring as center and synthesis method thereof - Google Patents
Pradaxa analogue with fluorine-containing group modified benzene ring as center and synthesis method thereof Download PDFInfo
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Abstract
The invention discloses a pradaxa analogue with a fluorine-containing group modified benzene ring as a center and a synthesis method thereof. The pradaxa analogue centering on a fluorine-containing group modified benzene ring disclosed by the invention is finally synthesized through a series of reactions of a fluorine-containing group aniline compound serving as a starting material. The synthesis method of the pradaxa analogue has the advantages that operation is simple, used reagents are cheap and easily available, synthesis cost is relatively low, risks in the process of synthesis are reduced, the yield of each synthesis step is high, and synthesis time is hort.
Description
Technical field
The present invention relates to a kind of phenyl ring of modifying with fluoro-containing group is the dabigatran ester analogs and the synthetic method thereof at center, belongs 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, minimizing and proteic covalent attachment 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, dabigatran exists bioavailability lower, and be used for the anticoagulant therapy process and bleeding often occurs, especially when high dosage uses, the technical problem that hemorrhage incidence is more high.And in its preparation process, committed step is generally used HCl volatile and that toxicity is bigger, NH
3Deng gas, therefore 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 occurs, especially when high dosage uses, the technical problem that hemorrhage incidence is more high and a kind of bioavailability phenyl ring that high fluoro-containing group is modified is provided is the dabigatran ester analogs at center.
Two of purpose of the present invention is in order to use HCl volatile and that toxicity is bigger, NH in the preparation process that solves dabigatran ester analogs fluorine-containing in the prior art
3Thereby increased the preparation cost of dabigatran ester analogs, and technical problem such as the danger increase of preparation process and a kind of a kind of phenyl ring of modifying with fluoro-containing group safe and reliable, that building-up process simple, synthetic cost is relatively low is provided is the synthetic method of the dabigatran ester analogs at center Deng gas.
Technical scheme of the present invention
A kind of phenyl ring of modifying with fluoro-containing group is the dabigatran ester analogs at center, its structural formula as shown in Figure 3, 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.
Above-mentioned a kind of phenyl ring of modifying with fluoro-containing group is the synthetic method of the dabigatran ester analogs at center, promptly the amino benzenes compounds 10 with fluoro-containing group is a 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 obtaining a kind of phenyl ring of modifying with fluoro-containing group is the dabigatran ester analogs at center.
Above-mentioned a kind of phenyl ring of modifying with fluoro-containing group is the synthetic method of the dabigatran ester analogs at center, and its building-up process specifically comprises the steps:
(1), compound 1 is synthetic
The amino benzenes compounds 10 and the ethyl propenoate of fluoro-containing group are dissolved in the toluene, and controlled temperature is that reaction 6 ~ 24h obtains reaction solution 1 through concentrating under reduced pressure, purification by silica gel column chromatography under 100 ℃, promptly obtains the compound 1 of sorrel solid state;
The amino benzenes compounds 10 and the ethyl propenoate of used fluoro-containing group calculates in molar ratio in the above-mentioned reaction, i.e. the aminocompound 10 of fluoro-containing group: ethyl propenoate is that 1:1～2 are preferably 1:1.8;
(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 earlier in parabromobenzoic acid, after being warming up to room temperature, controlling drop rate again 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, then in 60 ℃ of following stirring reaction 4-6h, reaction solution 2 is poured in the ice cube after the cooling suction filtration into, the filter cake of gained is washed 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
With the compound 2 of step (2) gained is that 3-nitro parabromobenzoic acid is dissolved in the aqueous solution of methylamine or ethamine, stirring heating back flow reaction 5-8h, 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 promptly compound 2 is a 3-nitro parabromobenzoic acid: methylamine or ethamine are 1:5～20, are preferably to be 1:15.2;
(4), compound 4 is the synthetic of 4-amino-3-nitrobenzoyl chloride
With the compound 3 of step (3) gained is that 4-amino-3-nitrobenzoic acid is dissolved in the toluene, add sulfur oxychloride and N then, dinethylformamide (DMF), controlled temperature be 80～85 ℃ down reaction 3-8h obtain reaction solution 4 again controlled temperature be 60～65 ℃, 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 that the amount of 4-amino-3-nitrobenzoic acid, toluene, sulfur oxychloride and DMF is 4-amino-3-nitrobenzoic acid in compound 3 in the above-mentioned reaction process: toluene: sulfur oxychloride: DMF is that the ratio of 1mol:2～4L:2～5mol:0.01～0.05L is calculated, and is preferably 1mol:2.1L:4.69mol:0.035L;
(5), compound 5 is synthetic
The 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 splashes into wherein, dripping the back controlled temperature is 20～25 ℃ of following stirring reaction 1～5h, the reaction solution 5 that obtains is used dichloromethane extraction, the organic layer of gained is successively through saturated common salt water washing, anhydrous sodium sulfate drying, filtration, the filtrate of gained is 40～45 ℃ in temperature, and pressure is to get yellow solid compound 5 under the 0.09-0.1MPa behind concentrating under reduced pressure, the 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, adds 10%Pd/C then, feed hydrogen behind the nitrogen replacement, react 3～6h down in reflux state and obtain reaction solution 6.Filter, filtrate is 40～45 ℃ in temperature, and pressure is that concentrating under reduced pressure, residuum promptly get oily matter and be compound 6 under the 0.09-0.1MPa behind purification by silica gel column chromatography;
Used compound 5,10%Pd/C presses mass ratio calculating in the above-mentioned reaction process, and promptly compound 5:10%Pd/C is 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) acetate, 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 slowly is added dropwise to wherein then, dropwising the back controlled temperature is 20～25 ℃ of row reaction 12h, obtains 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 acetate, 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride, I-hydroxybenzotriazole, THF and DMF and compound 6 is in 2-(4-cyano group phenylamino) acetate: 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride: the mixing solutions that I-hydroxybenzotriazole: THF and DMF form: compound 6 is the ratio calculating of 1.23mol:1.23mol:1.23mol:4.9L:1.0mol;
In the mixed solution that THF that above-mentioned reaction process is used and DMF form, calculate by volume, promptly THF:DMF is preferably 7:1;
The reaction solution 7 of above-mentioned gained is boiled 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, 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, heating reflux reaction 2～3h, transferring to pH with strong aqua after the reaction solution 8 that obtains is cooled to 20～25 ℃ is 7～8, use dichloromethane extraction after stirring 30min, 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 40～45 ℃ in temperature, pressure is concentrating under reduced pressure under the 0.09-0.1MPa, purification by silica gel column chromatography promptly 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, the N-diisopropylethylamine, back flow reaction 3～5h obtains 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 promptly compound 7: oxammonium hydrochloride: N, the N-diisopropylethylamine is 1:2～3:2～3, is preferably 1:2:2;
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, and under the nitrogen protection, back flow reaction 4～8h, the reaction solution 10 that obtains is crossed and is filtered out Pd/C
,The filtrate of gained is 40～45 ℃ in temperature, and pressure is to carry out concentrating under reduced pressure under the 0.09-0.1MPa, and the crude product that concentrates gained carries out chromatography purification through silicagel column, promptly gets faint yellow solid compound 8;
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 promptly compound 7: ammonium formate: Pd/C is 1:0.4～2:0.2～0.8, is preferably 1:0.4:0.2;
(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 mixed solution of the tetrahydrofuran (THF) formed of the ratio of 5:1 and water, add sodium hydroxide or potassium hydroxide, it is 20～25 ℃ in temperature then, rotating speed is that the control drop rate is that 1.0 mL/min slowly are added dropwise to the just own ester of chloroformic acid wherein under 500～800r/min, dropwising the continuation controlled temperature is 20～25 ℃ of reaction 1～3h, the reaction solution 11 that obtains is successively through concentrating under reduced pressure, purification by silica gel column chromatography, promptly get the compound 9 of white solid, promptly the phenyl ring of modifying with fluoro-containing group is the dabigatran ester analogs at center;
The amount of compound 8, sodium hydroxide or potassium hydroxide that above-mentioned reaction process is used and the just own ester of chloroformic acid is calculated in molar ratio, and promptly compound 8: sodium hydroxide or potassium hydroxide: the just own ester of chloroformic acid is 1:2～5:1.2, is preferably 1:2:1.2.
Beneficial effect of the present invention
A kind of phenyl ring of modifying with fluoro-containing group of the present invention is the dabigatran ester cpds at center, owing to have and the similar structure of dabigatran ester, therefore can effectively combine with the avtive spot of zymoplasm, and be a kind of direct thrombin inhibitors compounds.
Further, a kind of phenyl ring of modifying with fluoro-containing group of the present invention is the dabigatran ester cpds at center, because the adding 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 unavoidably bleeding can occurs, especially when high dosage uses, the technical problem that hemorrhage incidence is higher.
Further, in the synthetic method of the dabigatran ester cpds that a kind of phenyl ring of modifying with fluoro-containing group of the present invention is the center, the synthetic N that has used solid oxammonium hydrochloride and liquid of the compound 8 in the step 8 wherein particularly, N-diisopropylethylamine or triethylamine etc. have replaced HCl of the prior art, NH
3Gas, thus the 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 phenyl ring of modifying with fluoro-containing group are the dabigatran ester analogs structural representation at center;
Fig. 4, a kind of phenyl ring of modifying with fluoro-containing group are the synthetic reaction process synoptic diagram of the dabigatran ester analogs at center.
Embodiment
Also in conjunction with 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 phenyl ring of modifying with fluoro-containing group is the dabigatran ester analogs at center, with the R among Fig. 3
1For-F; R
2For-C
2H
5Be example, i.e. the 3-[[[2-[[[4-[[[(hexyloxy) carbonyl] amino] formamino] phenyl] amino] methyl]-1-ethyl-1H-benzoglyoxaline-5-yl] carbonyl] (4-fluorophenyl) amino] ethyl propionate.
Above-mentioned a kind of phenyl ring of modifying with fluoro-containing group is the dabigatran ester analogs at center, be the 3-[[[2-[[[4-[[[(hexyloxy) carbonyl] amino] formamino] phenyl] amino] methyl]-1-ethyl-1H-benzoglyoxaline-5-yl] carbonyl] (4-fluorophenyl) amino] synthetic method of ethyl propionate, be raw material promptly with the 4-fluoroaniline, through the synthetic 3-[[[2-[[[4-[[[(hexyloxy that obtains of 9 steps reaction) carbonyl] amino] formamino] phenyl] amino] methyl]-1-ethyl-1H-benzoglyoxaline-5-yl] carbonyl] (4-fluorophenyl) amino] ethyl propionate, per step building-up reactions is specific as follows:
(1), compound 1 is the synthetic of 3-(4-fluorophenyl amino) ethyl propionate
The amino benzenes compounds 10 that in round-bottomed flask, adds fluoro-containing group be the 4-fluoroaniline (5.56g, 50.0mmol), ethyl propenoate (9.0g, 90.0mmol), toluene is solvent (100.0 mL), 100 ℃ down reaction 24h obtain reaction solution 1;
4-fluoroaniline and ethyl propenoate used in the above-mentioned reaction calculate in molar ratio, i.e. the 4-fluoroaniline: ethyl propenoate 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 crude product 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 sorrel solid chemical compound 1 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, suction filtration gets crude product water recrystallization, faint yellow needle-like crystal to be compound 2 be 3-nitro parabromobenzoic acid (5.54g, 75%);
(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 3-nitro parabromobenzoic acid, mass percent concentration are that the amount of 70% ethylamine solution is calculated in molar ratio, and promptly compound 2 is a 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, and suction filtration, the filter cake controlled temperature of gained are to obtain yellow solid compound 3 after 80～85 ℃ of dryings to 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 14.3mmol) is dissolved in the toluene (30.0mL), add then sulfur oxychloride (12.0mL, 67mmol) and the DMF of 0.5mL, 80 ℃ of reactions of controlled temperature 3h obtains reaction solution 4;
4-ethylamino-3-nitrobenzoic acid, toluene, sulfur oxychloride and DMF used in the above-mentioned reaction process calculate in molar ratio, i.e. 4-ethylamino-3-nitrobenzoic acid: toluene: sulfur oxychloride: DMF is 1mmol:2.1mL:4.69mmol:0.035mL;
Is 60～65 ℃ with the reaction solution 4 of above-mentioned gained in temperature, and pressure is that concentrating under reduced pressure gets yellow solid compound 4 and is 4-ethylamino-3-nitrobenzoyl chloride (2.63g, 81%) under 0.09～0.1MPa;
(5), compound 5 is 3-[(4-ethylamino-3-nitro benzoyl)-(4-fluorophenyl) amino] ethyl propionate synthetic
With the compound 1 of step (1) gained is 3-(4-fluorophenyl 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 3mL/min with the compound 4 of step (4) gained is 4-ethylamino--3-nitrobenzoyl chloride (3.0g, 0.013mol) dichloromethane solution be added dropwise to wherein, dripping the back is 20～25 ℃ in controlled temperature, and rotating speed is that 500～800r/min reacts 2h and obtains reaction solution 5;
Used compound 1 is that 3-(4-fluorophenyl amino) ethyl propionate, triethylamine, methylene dichloride and compound 4 are the amount of 4-ethylamino--3-nitrobenzoyl chloride in the above-mentioned reaction process, is 3-(4-fluorophenyl amino) ethyl propionate by compound 1: triethylamine: methylene dichloride: compound 4 is that 4-ethylamino--3-nitrobenzoyl chloride is that 1mol:1.46mol:2.31L:1mol calculates;
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 that 0.09～0.1MPa concentrates down, the crude product that concentrates the back gained is 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 yellow solid compound 5 and be 3-[(4-ethylamino-3-nitro benzoyl)-(4-fluorophenyl) amino] ethyl propionate (3.9g, 74%);
(6), compound 6 is 3-[(3-amino-4-ethylamino benzoyl) (4-fluorophenyl) amino] ethyl propionate synthetic
With compound 5 is 3-[(4-ethylamino-3-nitro benzoyl)-(4-fluorophenyl) amino] ethyl propionate (7.3g, 0.018mol) be dissolved in the 50mL dehydrated alcohol, and then adding 10%Pd/C (2.2g), feed hydrogen behind the nitrogen replacement, the reflux state about 4h of reaction down obtains reaction solution 6;
Used compound 5 is 3-[(4-ethylamino-3-nitro benzoyl in the above-mentioned reaction process)-(4-fluorophenyl) amino] amount of ethyl propionate, 10%Pd/C, be 3-[(4-ethylamino-3-nitro benzoyl by compound 5)-(4-fluorophenyl) amino] ethyl propionate: 10%Pd/C is that 1.0g:0.3g calculates;
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, is spin-dried for gained oily matter compound 6 and is 3-[(3-amino-4-ethylamino benzoyl) (4-fluorophenyl) amino] ethyl propionate (5.0g, 74%);
(7), compound 7 is the 3-[[[2-[[(4-cyano-phenyl) amino] methyl]-1-ethyl-1H-benzoglyoxaline-5-yl] carbonyl] (4-fluorophenyl) amino] ethyl propionate synthetic
Under the ice bath with 2-(4-cyano group phenylamino) acetate (2.8g, 0.016mol), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (3.07g, 0.016mol), I-hydroxybenzotriazole (2.16g, 0.016mol) be dissolved in by tetrahydrofuran (THF) (THF) (56.0mL) and N, in THF that dinethylformamide (DMF) (8.0mL) 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) (4-fluorophenyl) amino] ethyl propionate (5.0g, 0.013mol) tetrahydrofuran solution slowly be added dropwise to wherein, dropwise the back controlled temperature and be 25 ℃ down reaction 12h obtain reaction solution 7;
Used 2-(4-cyano group phenylamino in the above-mentioned reaction process) acetate, 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate, I-hydroxybenzotriazole, tetrahydrofuran (THF) and N, mixed solution and compound 6 that dinethylformamide is formed are 3-[(3-amino-4-ethylamino benzoyl) (4-fluorophenyl) amino] amount of tetrahydrofuran solution of ethyl propionate, press 2-(4-cyano group phenylamino) acetate: 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) (4-fluorophenyl) amino] ethyl propionate is that the ratio of 1.23mol:1.23mol:1.23mol:4.9L:1.0mol is calculated;
Reaction solution 7 with above-mentioned gained boils off tetrahydrofuran (THF) then, the gained resistates adds methylene dichloride makes its dissolving, and with the saturated brine washing, through the anhydrous sodium sulfate drying after-filtration, filtrate is concentrated into dried, add the 50mL glacial acetic acid in the enriched material of gained, heating reflux reaction 2h obtains 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 mass percent concentration, and stirring 30min, the solution dichloromethane extraction of gained, the saturated brine washing, the anhydrous sodium sulfate drying after-filtration, filtrate is 40～45 ℃ in temperature, pressure be concentrated 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 compound 7 after being spin-dried for is the 3-[[[2-[[(4-cyano-phenyl) amino] methyl]-1-ethyl-1H-benzoglyoxaline-5-yl] carbonyl] (4-fluorophenyl) amino] ethyl propionate (5.5g, 80%);
(8), compound 8 is a 3-[[[2-[[(4-amidino groups phenyl) amino] methyl]-1-ethyl-1H-benzoglyoxaline-5-yl] carbonyl] (4-fluorophenyl) amino] ethyl propionate synthetic
With compound 7 is the 3-[[[2-[[(4-cyano-phenyl) amino] methyl]-1-ethyl-1H-benzoglyoxaline-5-yl] carbonyl] (4-fluorophenyl) amino] ethyl propionate (5.5 g, 0.011mol) be dissolved in the 40.0mL dehydrated alcohol, add oxammonium hydrochloride (1.53g, 0.022mol) and triethylamine (3.0mL, 0.022mol), 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] (4-fluorophenyl) amino] amount of ethyl propionate, oxammonium hydrochloride and triethylamine, be the 3-[[[2-[[(4-cyano-phenyl by compound 7) amino] methyl]-1-ethyl-1H-benzoglyoxaline-5-yl] carbonyl] (4-fluorophenyl) amino] ethyl propionate: oxammonium hydrochloride: triethylamine is 1:2:2;
The reaction solution 9 pressure reducing and steaming ethanol of above-mentioned gained, resistates 20.0mL acetate dissolution, and then add ammonium formate (2.2g) and Pd/C(1.1 g), under the nitrogen protection, the about 5h of back flow reaction obtains reaction solution 10;
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] (4-fluorophenyl) amino] mass ratio of ethyl propionate calculates, promptly compound 7 is the 3-[[[2-[[(4-cyano-phenyl) amino] methyl]-1-ethyl-1H-benzoglyoxaline-5-yl] carbonyl] (4-fluorophenyl) amino] ethyl propionate: ammonium formate: Pd/C is 1.0:0.4:0.2;
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 a 3-[[[2-[[(4-amidino groups phenyl) amino] methyl]-1-ethyl-1H-benzoglyoxaline-5-yl] carbonyl] (4-fluorophenyl) amino] ethyl propionate (3.5g, 60%);
(9), compound 9 is the 3-[[[2-[[[4-[[[(hexyloxy) carbonyl] amino] formamino] phenyl] amino] methyl]-1-methyl isophthalic acid H-benzoglyoxaline-5-yl] carbonyl] (4-fluorophenyl)-amino] ethyl propionate synthetic
With compound 8 is 3-[[[2-[[(4-amidino groups phenyl) amino] methyl]-1-ethyl-1H-benzoglyoxaline-5-yl] carbonyl] (4-fluorophenyl) amino] ethyl propionate (250mg, 0.47mmol) be dissolved in by tetrahydrofuran (THF) (5.0 mL) and water (1.0 mL) and in the mixed solution of tetrahydrofuran (THF) of forming and water, add sodium hydroxide (37.6mg, 0.94mmol), 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 (92.8 mg of chloroformic acid, 0.56mmol) add wherein, dropwising the continuation controlled temperature is that 20～25 ℃ of about 1h of reaction obtain reaction solution 11;
The used compound 8 of above-mentioned reaction process is a 3-[[[2-[[(4-amidino groups phenyl) amino] methyl]-1-ethyl-1H-benzoglyoxaline-5-yl] carbonyl] (4-fluorophenyl) amino] amount of ethyl propionate, sodium hydroxide and the just own ester of chloroformic acid, calculate in molar ratio, promptly compound 8 is a 3-[[[2-[[(4-amidino groups phenyl) amino] methyl]-1-ethyl-1H-benzoglyoxaline-5-yl] carbonyl] (4-fluorophenyl) amino] ethyl propionate: sodium hydroxide: the just own ester of chloroformic acid is 1.0mol:2.0mol:1.2mol;
Is 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 promptly get white solid compound 9 (195.2mg, 63%).
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：0.85（t, 6H）,1.15(t, 3H), 1.27-
1.29(m,10H), 3.95-3.98(m, 4H), 4.06(t, 2H), 4.25(d, 2H), 4.59(d, 2H), 6.76(d, 2H), 6.97(t, 1H),7.08-7.10(m, 2H), 7.12(d,1H), 7.23-7.25(m, 2H), 7.41(d, 1H),7.49(d,1H), 7.80(d,2H),8.60(brs,1H), 9.08(brs,1H)。
Above-mentioned detected result shows, in the white solid compound 9 and the structural formula among Fig. 3 of above-mentioned gained, promptly works as R
1For-F; R
2Be C
2H
5The time, represented a kind of phenyl ring of modifying with fluoro-containing group is the dabigatran ester analogs at center, i.e. 3-[[[2-[[[4-[[[(hexyloxy) carbonyl] amino] formamino] phenyl] amino] methyl]-1-ethyl-1H-benzoglyoxaline-5-yl] carbonyl] (4-fluorophenyl) 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. a phenyl ring of modifying with fluoro-containing group is the dabigatran ester analogs at center, it 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 etc.
2. a kind of phenyl ring of modifying with fluoro-containing group as claimed in claim 1 is the dabigatran ester analogs at center, it is characterized in that described R
1For-F; R
2For-C
2H
5
3. a kind of phenyl ring of modifying with fluoro-containing group as claimed in claim 1 or 2 is the synthetic method of the dabigatran ester analogs at center, it is characterized in that specifically comprising the steps:
(1), compound 1 is synthetic
Add the amino benzenes compounds 10 and the ethyl propenoate of fluoro-containing group in container, toluene is made solvent, controlled temperature be 100 ℃ down the reaction solution 1 that obtains of reaction 24h obtain compound 1 successively through concentrating under reduced pressure, purification by silica gel column chromatography;
The amino benzenes compounds 10 and the ethyl propenoate of the fluoro-containing group that above-mentioned reaction is used, calculate in molar ratio, i.e. the aminocompound 10 of fluoro-containing group: ethyl propenoate is 1:1～2;
(2), compound 2 is the synthetic of 3-nitro parabromobenzoic acid
Under the ice bath, earlier 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 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, then 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 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-amino-3-nitrobenzoic acid
With the compound 2 of step (2) gained is that 3-nitro parabromobenzoic acid is dissolved in the aqueous solution of methylamine or ethamine, the reaction solution 3 usefulness glacial acetic acids that stirring heating back flow reaction 5～8h obtains transfer 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 promptly compound 2 is a 3-nitro parabromobenzoic acid: methylamine or ethamine are 1:5～20;
(4), compound 4 is the synthetic of 4-ethylamino--3-nitrobenzoyl chloride
With the compound 3 of step (3) gained is that 4-amino-3-nitrobenzoic acid is dissolved in the toluene, add sulfur oxychloride and N then, dinethylformamide, controlled temperature be 80～85 ℃ down the reaction solution 4 that obtains of reaction 3～8h through concentrating under reduced pressure, yellow solid to be compound 4 be 4-ethylamino--3-nitrobenzoyl chloride;
Above-mentioned used compound 3 is 4-amino-3-nitrobenzoic acid, toluene, sulfur oxychloride and N, the amount of dinethylformamide is 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
The 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-ethylamino--3-nitrobenzoyl chloride then is added dropwise to wherein, dripping the back controlled temperature is 20～25 ℃ of stirring reaction 1～5h, 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, 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 feeds hydrogen after adding the 10%Pd/C nitrogen replacement, reflux state is reaction 3～6h down, the reaction solution 6 that obtains;
Filter, filtrate is concentrated into dried, and residuum gets oily matter through purification by silica gel column chromatography and is compound 6;
Used compound 5,10%Pd/C in the above-mentioned reaction process presses mass ratio and calculates, and promptly compound 5:10% Pd/C is 1:0.3～0.5;
(7), compound 7 is synthetic
Under the ice bath with 2-(4-cyano group phenylamino) acetate, 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 the back controlled temperature is 20～25 ℃ and reacts 12～24h, the reaction solution 7 that obtains boils 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, gained filtrate is carried out concentrating under reduced pressure, the enriched material of gained is incorporated as the glacial acetic acid of 10～15 times of its quality, heating reflux reaction 2～3h, after the reaction solution 8 that 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 promptly gets yellow oily compounds 7;
Used 2-(4-cyano group phenylamino in the above-mentioned reaction process) acetate, 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) acetate: 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride: I-hydroxybenzotriazole: tetrahydrofuran (THF) and N, the mixed solution that dinethylformamide is formed: compound 6 calculates for the 1.23mol:1.23mol:1.23mol:4.9L:1.0mol ratio;
(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; the resistates acetate dissolution, and then add ammonium formate and Pd/C, under the nitrogen protection; back flow reaction 4～8h, the reaction solution 10 that obtains is crossed and is filtered out Pd/C
,The filtrate of gained is carried out concentrating under reduced pressure, purification by silica gel column chromatography gets faint yellow solid compound 8;
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 promptly 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 promptly compound 7: ammonium formate: Pd/C is 1:0.4:0.2;
(9), compound 9 is synthetic
Compound 8 with step (8) gained under the room temperature is dissolved in calculating by volume, be tetrahydrofuran (THF): water is in the mixed solution of the tetrahydrofuran (THF) that forms of the ratio 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 1.0 mL/min are added dropwise to the just own ester of chloroformic acid wherein under 500～800r/min, dropwising the continuation controlled 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 obtains white solid compound 9, and promptly the phenyl ring of modifying with fluoro-containing group is the dabigatran ester analogs at center;
The amount of compound 8, sodium hydroxide or potassium hydroxide that above-mentioned reaction process is used and the just own ester of chloroformic acid is calculated in molar ratio, and promptly compound 8: sodium hydroxide or potassium hydroxide: the just own ester of chloroformic acid is 1:2～5:1.2.
4. a kind of phenyl ring of modifying with fluoro-containing group as claimed in claim 3 is the synthetic method of the dabigatran ester analogs at center, it is characterized in that:
The amino benzenes compounds 10 and the ethyl propenoate of the fluoro-containing group that the middle reaction of step (1) is used calculate in molar ratio, i.e. the aminocompound 10 of fluoro-containing group: ethyl propenoate is 1:1.8;
The used compound 2 of step (3) reaction is that the amount of 3-nitro parabromobenzoic acid and methylamine or ethamine is calculated in molar ratio, and promptly compound 2 is a 3-nitro parabromobenzoic acid: methylamine or ethamine are 1:15.2;
The used compound 3 of step (4) is the amount of 4-amino-3-nitrobenzoic acid, toluene, sulfur oxychloride and DMF, is 4-amino-3-nitrobenzoic acid in compound 3: toluene: sulfur oxychloride: DMF is that the ratio of 1mol:2.1L:4.69mol: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 promptly compound 5: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 promptly compound 7: oxammonium hydrochloride: N, N-diisopropylethylamine or triethylamine are 1:2:2;
Ammonium formate that adds in step (8) reaction process and the amount of Pd/C are calculated by the mass ratio of itself and compound 7, and promptly compound 7: ammonium formate: Pd/C is 1:0.4:0.2;
The amount of compound 8, sodium hydroxide or potassium hydroxide that step (9) reaction process is used and the just own ester of chloroformic acid is calculated in molar ratio, and promptly compound 8: sodium hydroxide or potassium hydroxide: the just own ester of chloroformic acid is 1:2:1.2.
5. a kind of phenyl ring of modifying with fluoro-containing group as claimed in claim 4 is the synthetic method of the dabigatran ester analogs at center, it is characterized in that: tetrahydrofuran (THF) and N that step (7) is used, the mixed solution that dinethylformamide is formed, calculate by volume, be tetrahydrofuran (THF): N, dinethylformamide are 7:1.
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| CN103694224A (en) * | 2013-12-17 | 2014-04-02 | 上海应用技术学院 | Dabigatran etexilate analog centered by fluorine-containing-group-modified benzene ring and synthesis method thereof |
| 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 |
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