CN104774198A - Novel oxazolidinone compound and preparation method thereof - Google Patents

Novel oxazolidinone compound and preparation method thereof Download PDF

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CN104774198A
CN104774198A CN201410018269.2A CN201410018269A CN104774198A CN 104774198 A CN104774198 A CN 104774198A CN 201410018269 A CN201410018269 A CN 201410018269A CN 104774198 A CN104774198 A CN 104774198A
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oxazolidone
methyl
triazole
alkali
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柳惠
孙晋
陈焕明
陈春麟
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Shanghai Medicilon Inc
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Shanghai Medicilon Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

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Abstract

The invention relates to a novel oxazolidinone compound and a preparation method thereof. The novel oxazolidinone compound has a structural formula (V) described in the specification. The preparation method retains an oxazolidinone mother nucleus and a 3-fluoro substituted benzene ring structure, modifies the 4th site of the benzene ring, and realizes synthesis of an unknown oxazolidinone compound by three steps. The novel oxazolidinone compound can be used as an antiseptic. The preparation method has the advantages of simple processes, simple equipment, low production cost and high yield.

Description

A kind of Xin oxazolidinone compounds and preparation method thereof
Technical field
The invention belongs to pharmaceutical intermediate synthesis technical field, be specifically related to a kind of Xin oxazolidinone compounds and synthetic method thereof.
Background technology
Oxazolidinone compounds tool has been widely used, and can be used for medicine, agricultural chemicals, polymer modified, organic synthesis intermediate etc.It can be used as antiseptic-germicide, muscle relaxant, 5-hydroxytryptamine receptor agonist etc.Oxazolidone represents the extremely promising novel complete synthesis antiseptic-germicide of a class, and the mechanism of action of its anti-bacteria early protein synthesis is different from all microbiotic known at present, means that the possibility that cross resistance occurs is less.Within 2000, become first at the Linezolid of U.S.'s listing to get permission to enter clinical application oxazolidone medicine.Linezolid effectively can control the microbial infection of multidrug resistance clinically, for clinical treatment drug-fast bacteria infection disease increases a new highly effective approach.But, it is found that Linezolid has only to narrow spectrum bacterium display anti-microbial activity, the shortcoming that poisonous to human body and therapeutic activity in vivo is poor.And its synthesis is comparatively loaded down with trivial details, yield is lower.
Summary of the invention
The object of the invention is to for the problem in existing synthetic technology, provide a kind of Xin oxazolidinone compounds and brand-new synthetic method.
On the one hand, the invention provides a kind of Xin oxazolidinone compounds, it has following structural formula:
On the other hand, the invention provides the preparation method of Shu oxazolidinone compounds, comprising:
Step a: by (R)-5-((1H-1,2,3-triazole-1-base) methyl)-3-(4-bromine-3-fluorophenyl)-2-oxazolidone (I) is obtained by reacting (R)-5-((1H-1 with connection boric acid pinacol ester under alkali and catalyst, 2,3-triazole-1-base) methyl)-3-(the fluoro-4-(4 of the bromo-3-of 4-, 4,5,5-tetramethyl--1,3,2, dioxy boron-2-bases) phenyl)-2-oxazolidone (II);
Step b: 4-(5-bromopyridine-2-base)-5,6-dihydro-1,2,4-triazines-1 (4H)-formaldehyde (III) piptonychia aldehyde radical in alkali is obtained 4-(5-bromopyridine-2-base)-Isosorbide-5-Nitrae, 5,6-tetrahydrochysene-1,2,4-triazine (IV); And
Step c: the formula IV compound of step b gained and the formula II compound of step a gained instead should be obtained oxazolidone (R)-5-((1H-1 under catalyzer, 2,3-triazole-1-base) methyl)-3-(4-(6-(5.6-dihydro-1,2,4-triazine)-4 (1H)-Ji) pyridine-2-base)-3-fluorophenyl-2-oxazolidone (V);
Preferably, in step a, (R)-5-((1H-1,2,3-triazole-1-base) methyl)-3-(4-bromine-3-fluorophenyl)-2-oxazolidone (I), alkali, connection pinacol borate, 1,1'-two (diphenylphosphine) ferrocene palladium chloride mass ratio be 1:3:1.3:0.03.
Preferably, in step a, alkali is salt of wormwood, sodium carbonate, sodium-acetate and/or Potassium ethanoate.
Preferably, the temperature of reaction of step a is 25 DEG C ~ reflux temperature, and the reaction times is 4 ~ 12 hours.
Preferably, the post-reaction treatment of described step a comprises: step a1: regulate temperature 0 ~ 25 DEG C after completion of the reaction; Filter, filtrate is concentrated into small volume, adds sherwood oil, is heated to 30 ~ 80 DEG C, stirs 1-5 hour; Step a2: be cooled to room temperature, suction filtration, 60-70 DEG C of drying obtains (R)-5-((1H-1,2,3-triazole-1-base) methyl)-3-(the fluoro-4-(4 of the bromo-3-of 4-, 4,5,5-tetramethyl--1,3,2, dioxy boron-2-bases) phenyl)-2-oxazolidone (II).
Preferably, in described step b, the mol ratio of described 4-(5-bromopyridine-2-base)-5,6-dihydro-1,2,4-triazines-1 (4H)-formaldehyde (III) and alkali is 1:2.
Preferably, described step b comprises: step b1:4-(5-bromopyridine-2-base)-5,6-dihydro-1,2,4-triazines-1 (4H)-formaldehyde (III) mix with alkali, are heated to 80-100 DEG C, insulation reaction 2 ~ 8 hours; Step b2: be cooled to room temperature, adds water, and temperature stirs 0.5-4 hour; Step b3: filter, filter cake is dry at 40-80 DEG C, obtains 4-(5-bromopyridine-2-base)-Isosorbide-5-Nitrae, 5,6-tetrahydrochysene-1,2,4-triazine (IV).
Preferably, the reaction solvent of described step b1 is lower alcohol and/or aprotic polar solvent, preferred lower alcohol; Lower alcohol is selected from C 1~ C 6the saturated alkyl alcohol of straight or branched, more preferably methyl alcohol, ethanol, Virahol, ethylene glycol and/or glycerol.Described alkali is salt of wormwood, sodium carbonate, potassium hydroxide and/or sodium hydroxide.
Preferably, in described step c, described 4-(5-bromopyridine-2-base)-1,4,5,6-tetrahydrochysene-1,2,4-triazine (IV) and described (R)-5-((1H-1,2,3-triazole-1-base) methyl)-3-(the fluoro-4-of the bromo-3-of 4-(4,4,5,5-tetramethyl--1,3,2, dioxy boron-2-base) phenyl)-2-oxazolidone (II), alkali, 1,1'-two (diphenylphosphine) ferrocene palladium chloride, water mol ratio be 1:1:3:0.016:5.Described alkali is selected from salt of wormwood, sodium carbonate, sodium-acetate and/or Potassium ethanoate.
Preferably, described step c comprises: step c1: water, alkali, 1,1'-two (diphenylphosphine) ferrocene palladium chloride, R-5-((1H-1,2,3-triazole-1-base) methyl)-3-(the fluoro-4-of the bromo-3-of 4-(4,4,5,5-tetramethyl--1,3,2, dioxy boron-2-base) phenyl)-2-oxazolidone (II) and 4-(5-bromopyridine-2-base)-1,4,5,6-tetrahydrochysene-1,2,4-triazine (IV) mixes, and is heated to backflow, insulation reaction 1-10 hour; Step c2: suction filtration while hot, filter cake is 40 DEG C ~ 80 DEG C dryings, obtain (R)-5-((1H-1,2,3-triazole-1-base) methyl)-3-(4-(6-(5.6-dihydro-1,2,4-triazine)-4 (1H)-Ji) pyridine-2-base)-3-fluorophenyl-2-oxazolidone (V).
The structure of Bao Liu oxazolidone parent nucleus of the present invention and 3 fluorine substituted benzene rings, carries out structural modification to phenyl ring 4, and three steps have been synthesized new having no and reported oxazolidinone compounds, and the method has the following advantages:
1. the route short (three steps can obtain target compound) of synthesis, yield is high;
2. reaction conditions is gentle, easy handling;
3. atom utilization is high, and purifying products aftertreatment technology is simple;
4. do not use environmentally harmful catalyzer in reaction process, reaction solvent is conventional solvent-recoverable.
Embodiment
Further illustrate the present invention below in conjunction with following embodiment, should be understood that following embodiment is only for illustration of the present invention, and unrestricted the present invention.
In the present invention, the synthetic method of Xin oxazolidone adopts following synthetic route:
With (R)-5-((1H-1,2,3-triazole-1-base) methyl)-3-(4-bromine-3-fluorophenyl)-2-oxazolidone and 4-(5-bromopyridine-2-base)-5,6-dihydro-1,2,4-triazine-1 (4H)-formaldehyde is raw material, obtains product through coupling, piptonychia aldehyde radical, coupling three step.Synthesis step can be described below:
(1) (R)-5-((1H-1,2,3-triazole-1-base) methyl)-3-(4-bromine-3-fluorophenyl)-2-oxazolidone (I) is obtained by reacting (R)-5-((1H-1 with connection boric acid pinacol ester under alkali and catalyst, 2,3-triazole-1-base) methyl)-3-(the fluoro-4-(4 of the bromo-3-of 4-, 4,5,5-tetramethyl--1,3,2, dioxy boron-2-bases) phenyl)-2-oxazolidone (II);
(2) 4-(5-bromopyridine-2-base)-5,6-dihydro-1,2,4-triazines-1 (4H)-formaldehyde (III) piptonychia aldehyde radical in alkali obtains 4-(5-bromopyridine-2-base)-Isosorbide-5-Nitrae, 5,6-tetrahydrochysene-1,2,4-triazine (IV);
(3) 4-(5-bromopyridine-2-base)-1 of gained, 4, 5, 6-tetrahydrochysene-1, 2, 4-triazine (IV) and (R)-5-((1H-1, 2, 3-triazole-1-base) methyl)-3-(the fluoro-4-(4 of the bromo-3-of 4-, 4, 5, 5-tetramethyl--1, 3, 2, dioxy boron-2-base) phenyl)-2-oxazolidone (II) is obtained by reacting Xin oxazolidone (R)-5-((1H-1 under catalyzer, 2, 3-triazole-1-base) methyl)-3-(4-(6-(5.6-dihydro-1, 2, 4-triazine)-4 (1H)-Ji) pyridine-2-base)-3-fluorophenyl-2-oxazolidone (V).
In described step (1), solvent elects dioxane, dimethyl sulfoxide (DMSO), DMF, acetone, acetonitrile as, pyridine, tetrahydrofuran (THF), trichloromethane etc., more preferably DMF and tetrahydrofuran (THF), more preferably tetrahydrofuran (THF); Alkali is selected from salt of wormwood, sodium carbonate, sodium-acetate, Potassium ethanoate, and more preferably Potassium ethanoate or sodium-acetate, most preferably be Potassium ethanoate; React and carry out under catalytic condition in catalysis or not, be preferably catalytic condition, preferred catalyst is two (diphenylphosphine) ferrocene palladium chloride of 1,1'-; Reaction is carried out under 25 DEG C ~ reflux temperature, preferred reflux conditions.
Described step (1) preferably includes following steps:
(a) tetrahydrofuran (THF), Potassium ethanoate, connection pinacol borate, 1, two (diphenylphosphine) ferrocene palladium chloride of 1'-and (R)-5-((1H-1,2,3-triazole-1-base) methyl)-3-(4-bromine-3-fluorophenyl)-2-oxazolidone (I) mixing, be heated to backflow, insulation reaction 4-12 hour, preferably 8 hours; I: Potassium ethanoate: connection pinacol borate: 1,1'-two (diphenylphosphine) ferrocene palladium chloride=1:3:1.3:0.03;
B () after completion of the reaction, adjusts the temperature to room temperature;
C () filters, filtrate is concentrated into small volume.Add sherwood oil, be heated to 30 ~ 80 DEG C, stir 1-5 hour;
D () is cooled to room temperature, suction filtration, 60-70 DEG C of drying obtains (R)-5-((1H-1,2,3-triazole-1-base) methyl)-3-(the fluoro-4-(4 of the bromo-3-of 4-, 4,5,5-tetramethyl--1,3,2, dioxy boron-2-bases) phenyl)-2-oxazolidone (II).
Regulate temperature 0 ~ 25 DEG C in described step (b), be preferably 25 DEG C; In described step (c), preferably at 75 DEG C, add sherwood oil, Heating temperature is preferably 60 DEG C, and churning time is preferably 1.5 hours; In described step (d), be cooled to room temperature, be preferably cooled to 25 DEG C, drying temperature preferably 65 DEG C.
In described step (2), described reaction is carried out under having solvent or not having solvent existent condition, preferably carries out in a solvent; Solvent elects lower alcohol, aprotic polar solvent as, preferred lower alcohol; Lower alcohol is selected from C 1~ C 6the saturated alkyl alcohol of straight or branched, more preferably methyl alcohol, ethanol, Virahol, ethylene glycol and glycerol, most preferably be ethanol; Described aprotic polar solvent is acetone, acetonitrile, DMF, dimethyl sulfoxide (DMSO), is preferably acetonitrile.Alkali is selected from salt of wormwood, sodium carbonate, potassium hydroxide, sodium hydroxide, and more preferably potassium hydroxide or sodium hydroxide, most preferably be sodium hydroxide.
Described step (2) preferably includes following steps:
A () 4-(5-bromopyridine-2-base)-5,6-dihydro-1,2,4-triazines-1 (4H)-formaldehyde (III), sodium hydroxide and ethanol mix, equivalence ratio is III: sodium hydroxide=1:2, is heated to 40-100 DEG C; Be preferably 90 DEG C, insulation reaction 2 ~ 8 hours, preferably 3 hours;
B () is cooled to room temperature, add water, stirring at room temperature 0.5-4 hour, preferably 1.5 hours;
C () filters, filter cake is dry at 40-80 DEG C, is preferably 50 DEG C, obtains 4-(5-bromopyridine-2-base)-Isosorbide-5-Nitrae, 5,6-tetrahydrochysene-1,2,4-triazine (IV).
In described step (3), solvent elects dioxane, dimethyl sulfoxide (DMSO), DMF, acetone, acetonitrile as, pyridine, tetrahydrofuran (THF), trichloromethane etc., and more preferably DMF and tetrahydrofuran (THF), most preferably is tetrahydrofuran (THF); Alkali is selected from salt of wormwood, sodium carbonate, sodium-acetate, Potassium ethanoate, and more preferably salt of wormwood or sodium carbonate, most preferably be salt of wormwood; React and carry out under catalytic condition in catalysis or not, be preferably catalytic condition, preferred catalyst is two (diphenylphosphine) ferrocene palladium chloride of 1,1'-; Reaction is carried out under 25 DEG C ~ reflux temperature, preferred reflux conditions.
Described step (3) preferably includes following steps:
(a) tetrahydrofuran (THF), water, salt of wormwood, 1,1'-two (diphenylphosphine) ferrocene palladium chloride, R-5-((1H-1,2,3-triazole-1-base) methyl)-3-(the fluoro-4-of the bromo-3-of 4-(4,4,5,5-tetramethyl--1,3,2, dioxy boron-2-bases) phenyl)-2-oxazolidone (II) and 4-(5-bromopyridine-2-base)-1,4,5,6-tetrahydrochysene-1,2,4-triazine (IV) mixes, be heated to backflow, insulation reaction 1-10 hour, preferably 4 hours; IV: II: salt of wormwood: 1,1'-two (diphenylphosphine) ferrocene palladium chloride: water=1:1:3:0.016:5;
B () be suction filtration while hot, filter cake is 40 DEG C ~ 80 DEG C dryings, preferred drying temperature 60 DEG C, obtain (R)-5-((1H-1,2,3-triazole-1-base) methyl)-3-(4-(6-(5.6-dihydro-1,2,4-triazine)-4 (1H)-Ji) pyridine-2-base)-3-fluorophenyl-2-oxazolidone (V).
He Cheng oxazolidinone compounds of the present invention, has simple process, equipment used is simple, production cost is low, yield advantages of higher.
The present invention is further illustrated with the preparation of particular compound below in conjunction with embodiment.Should be understood that following examples are only used to further illustrate the present invention equally, can not limiting the scope of the invention be interpreted as.
Embodiment 1
In 250ml there-necked flask, add 10g (R)-5-((1H-1 successively, 2,3-triazole-1-base) methyl)-3-(4-bromine-3-fluorophenyl)-2-oxazolidone (I), 8.6g Potassium ethanoate, 9.5g join pinacol borate, 0.64g1, the tetrahydrofuran (THF) of two (diphenylphosphine) the ferrocene palladium chloride of 1'-and 100ml, be warming up to backflow, interior temperature 80 DEG C, back flow reaction 8 hours, reaction system is cooled to 25 DEG C, filters, concentrated, add ethyl acetate: in the solution of sherwood oil=1:1, be stirred to intensification 75 DEG C, insulated and stirred 1.5 hours, be cooled to room temperature, suction filtration, brown solid (R)-5-((1H-1 is obtained 65 DEG C of dryings, 2, 3-triazole-1-base) methyl)-3-(the fluoro-4-(4 of the bromo-3-of 4-, 4, 5, 5-tetramethyl--1, 3, 2, dioxy boron-2-base) phenyl)-2-oxazolidone (II), yield: 96.2%, 1H NMR [400MHz, DMSO-d6/TMS, δ (ppm)]: 1.07-1.29 (s, 12H), 3.90-3.94 (q, J=6.0Hz, 1H), 4.23 (m, J=6.0Hz, 1H), 4.84 (d, J=4.8Hz, 2H), 5.15 (m, 1H), 7.28 (d, J=8.0Hz, 1H), 7.38 (d, J=12Hz, 1H), 7.63 (t, J=8.0Hz, 1H), 7.76 (s, 1H), 8.17 (s, 1H),
At 250ml there-necked flask, add 10g (R)-5-((1H-1,2 successively, 3-triazole-1-base) methyl)-3-(the fluoro-4-of the bromo-3-of 4-(4,4,5,5-tetramethyl--1,3,2, dioxy boron-2-base) phenyl)-2-oxazolidone (II), 6N NaOH (12.3ml) and ethanol 120ml, be heated to 90 DEG C, insulation reaction 3 hours, be down to room temperature, add water (60ml) and stir 1.5 hours, filter, filter cake is 50 DEG C of dryings.Obtain faint yellow solid, 4-(5-bromopyridine-2-base)-Isosorbide-5-Nitrae, 5,6-tetrahydrochysene-1,2,4-triazine (IV), yield: 94.6%, fusing point is 240.3-240.7 DEG C; Be soluble in ethanol, the organic solvents such as methyl alcohol.1H NMR[400MHz,DMSO-d 6/TMS,δ(ppm)]:3.10-3.13(t,J=4.8Hz,2H),3.71-3.74(t,J=4.8Hz,2H),6.26(s,1H),7.02(d,J=8.8Hz,1H),7.81(s,1H),7.88(q,J=2.4Hz,1H),8.31(q,J=2.7Hz,1H)；
10g IV is added successively in 250ml there-necked flask, 0.5g1, two (diphenylphosphine) ferrocene palladium chloride of 1'-, 17g salt of wormwood, 16g II, water (17mL) and tetrahydrofuran (THF) (40mL), be heated to 80 DEG C, insulation reaction 4 hours, suction filtration while hot, filter cake was 60 DEG C of dryings 12 hours, obtain brown solid (R)-5-((1H-1, 2, 3-triazole-1-base) methyl)-3-(4-(6-(5.6-dihydro-1, 2, 4-triazine)-4 (1H)-Ji) pyridine-2-base)-3-fluorophenyl-2-oxazolidone (V), purity is greater than 95%, yield 92%, be soluble in methyl-sulphoxide, the organic solvents such as ethanol. 1H NMR[400MHz,DMSO-d 6/TMS,δ(ppm)]:3.14-3.16(t,J=4.8Hz,2H),3.79-3.82(t,J=4.8Hz,2H),3.93-3.97(m,1H),4.27-4.31(t,J=9.2Hz,1H),4.86(d,J=4.8Hz,1H),5.15-5.21(m,1H),6.26(s,1H),7.13(d,J=8.8Hz,1H),7.35(d,J=8.8Hz,1H),7.37(d,J=2.0Hz,1H),7.56-7.62(d,J=2.0Hz,2H),7.78(s,1H),7.88-7.93(d,J=2.0Hz,2H),8.19(s,1H),8.42(s,1H)。
Embodiment 2
In 250ml there-necked flask, add 10g (R)-5-((1H-1 successively, 2,3-triazole-1-base) methyl)-3-(4-bromine-3-fluorophenyl)-2-oxazolidone (I), 8.6g Potassium ethanoate, 9.5g join pinacol borate, 0.64g1, two (diphenylphosphine) the ferrocene palladium chloride of 1'-and 100ml tetrahydrofuran (THF), be warming up to backflow, interior temperature 80 DEG C, back flow reaction, 10 hours; Reaction system is cooled to 25 DEG C, filters, concentrated, add ethyl acetate: in the solution of sherwood oil=1:1, be stirred to intensification 45 DEG C, insulated and stirred 2 hours; Be cooled to room temperature, suction filtration, obtains brown solid (R)-5-((1H-1,2 65 DEG C of dryings, 3-triazole-1-base) methyl)-3-(the fluoro-4-(4 of the bromo-3-of 4-, 4,5,5-tetramethyl--1,3,2, dioxy boron-2-bases) phenyl)-2-oxazolidone (II), yield: 90.2%;
At 250ml there-necked flask, add 10g (R)-5-((1H-1,2 successively, 3-triazole-1-base) methyl)-3-(the fluoro-4-of the bromo-3-of 4-(4,4,5,5-tetramethyl--1,3,2, dioxy boron-2-base) phenyl)-2-oxazolidone (II), 6N NaOH (12.3ml) and Virahol 120ml, be heated to 100 DEG C, insulation reaction 2 hours, be down to room temperature, add water (60ml) and stir 1 hour, filter, filter cake is 60 DEG C of dryings.Obtain light yellow solid 4-(5-bromopyridine-2-base)-Isosorbide-5-Nitrae, 5,6-tetrahydrochysene-1,2,4-triazine (IV); Yield: 85.6%;
10g IV is added successively in 250ml there-necked flask, 0.5g1, two (diphenylphosphine) ferrocene palladium chloride of 1'-, 17g salt of wormwood, 16g II, water (17mL) and tetrahydrofuran (THF) (40mL), be heated to 80 DEG C, insulation reaction 8 hours, suction filtration while hot, filter cake was 40 DEG C of dryings 12 hours, obtain brown solid (R)-5-((1H-1, 2, 3-triazole-1-base) methyl)-3-(4-(6-(5.6-dihydro-1, 2, 4-triazine)-4 (1H)-Ji) pyridine-2-base)-3-fluorophenyl-2-oxazolidone (V), purity is greater than 90%, yield 89%.
Embodiment 3
In 250ml there-necked flask, add 10g (R)-5-((1H-1 successively, 2,3-triazole-1-base) methyl)-3-(4-bromine-3-fluorophenyl)-2-oxazolidone (I), 8.6g Potassium ethanoate, 9.5g join pinacol borate, 0.64g1, two (diphenylphosphine) the ferrocene palladium chloride of 1'-and 100ml DMF, be warming up to backflow, interior temperature 60 DEG C, back flow reaction 10 hours; Reaction system is cooled to 25 DEG C, filters, concentrated, add ethyl acetate: in the solution of sherwood oil=1:1, be stirred to intensification 60 DEG C, insulated and stirred 4 hours; Be cooled to room temperature, suction filtration, obtains brown solid (R)-5-((1H-1,2 65 DEG C of dryings, 3-triazole-1-base) methyl)-3-(the fluoro-4-(4 of the bromo-3-of 4-, 4,5,5-tetramethyl--1,3,2, dioxy boron-2-bases) phenyl)-2-oxazolidone (II), yield 81.2%;
At 250ml there-necked flask, add 10g (R)-5-((1H-1,2 successively, 3-triazole-1-base) methyl)-3-(the fluoro-4-of the bromo-3-of 4-(4,4,5,5-tetramethyl--1,3,2, dioxy boron-2-base) phenyl)-2-oxazolidone (II), 6N NaOH (12.3ml) and ethanol 120ml, be heated to 80 DEG C, insulation reaction 6 hours, be down to room temperature, add water (60ml) and stir 4 hours, filter, filter cake is 50 DEG C of dryings.Obtain faint yellow solid 4-(5-bromopyridine-2-base)-Isosorbide-5-Nitrae, 5,6-tetrahydrochysene-1,2,4-triazine (IV), productive rate: 74.5%;
10g IV is added successively in 250ml there-necked flask, 0.5g1, two (diphenylphosphine) ferrocene palladium chloride of 1'-, 17g salt of wormwood, 16g II, water (17mL) and N, dinethylformamide (40mL), be heated to 80 DEG C, insulation reaction 8 hours, suction filtration while hot, filter cake was 60 DEG C of dryings 12 hours, obtain brown solid (R)-5-((1H-1, 2, 3-triazole-1-base) methyl)-3-(4-(6-(5.6-dihydro-1, 2, 4-triazine)-4 (1H)-Ji) pyridine-2-base)-3-fluorophenyl-2-oxazolidone (V), purity is greater than 90%, yield 80.3%.
Oxazolidinone compounds of the present invention can be used as antiseptic-germicide.He Cheng oxazolidinone compounds of the present invention, has simple process, equipment used is simple, production cost is low, yield advantages of higher, can be applicable to the synthesis of similar Jie Gou oxazolidinone compounds.

Claims (11)

1. Yi Zhong oxazolidinone compounds, is characterized in that, has following structural formula:
2. the preparation method of oxazolidinone compounds that states of claim 1, is characterized in that, comprising:
Step a: by (R)-5-((1H-1,2,3-triazole-1-base) methyl)-3-(4-bromine-3-fluorophenyl)-2-oxazolidone (I) is obtained by reacting (R)-5-((1H-1 with connection boric acid pinacol ester under alkali and catalyst, 2,3-triazole-1-base) methyl)-3-(the fluoro-4-(4 of the bromo-3-of 4-, 4,5,5-tetramethyl--1,3,2, dioxy boron-2-bases) phenyl)-2-oxazolidone (II);
Step b: 4-(5-bromopyridine-2-base)-5,6-dihydro-1,2,4-triazines-1 (4H)-formaldehyde (III) piptonychia aldehyde radical in alkali is obtained 4-(5-bromopyridine-2-base)-Isosorbide-5-Nitrae, 5,6-tetrahydrochysene-1,2,4-triazine (IV); And
Step c: the formula IV compound of step b gained and the formula II compound of step a gained instead should be obtained oxazolidone (R)-5-((1H-1 under catalyzer, 2,3-triazole-1-base) methyl)-3-(4-(6-(5.6-dihydro-1,2,4-triazine)-4 (1H)-Ji) pyridine-2-base)-3-fluorophenyl-2-oxazolidone (V);
3. preparation method according to claim 2, it is characterized in that, in step a, (R)-5-((1H-1,2,3-triazole-1-base) methyl)-3-(4-bromine-3-fluorophenyl)-2-oxazolidone (I), alkali, connection pinacol borate, 1,1'-two (diphenylphosphine) ferrocene palladium chloride mass ratio be 1:3:1.3:0.03.
4. the synthetic method according to Claims 2 or 3, is characterized in that, in step a, alkali is salt of wormwood, sodium carbonate, sodium-acetate and/or Potassium ethanoate.
5. the preparation method according to any one of claim 2 ~ 4, is characterized in that, the temperature of reaction of step a is 25 DEG C ~ reflux temperature, and the reaction times is 4 ~ 12 hours.
6. the preparation method according to any one of claim 2 ~ 5, is characterized in that, the post-reaction treatment of described step a comprises: step a1: regulate temperature 0 ~ 25 DEG C after completion of the reaction; Filter, filtrate is concentrated into small volume, adds sherwood oil, is heated to 30 ~ 80 DEG C, stirs 1-5 hour; Step a2: be cooled to room temperature, suction filtration, 60-70 DEG C of drying obtains (R)-5-((1H-1,2,3-triazole-1-base) methyl)-3-(the fluoro-4-(4 of the bromo-3-of 4-, 4,5,5-tetramethyl--1,3,2, dioxy boron-2-bases) phenyl)-2-oxazolidone (II).
7. the preparation method according to any one of claim 2 ~ 6, is characterized in that, in described step b, described 4-(5-bromopyridine-2-base)-5, the mol ratio of 6-dihydro-1,2,4-triazine-1 (4H)-formaldehyde (III) and alkali is 1:2.
8. the preparation method according to any one of claim 2 ~ 7, it is characterized in that, described step b comprises: step b1:4-(5-bromopyridine-2-base)-5,6-dihydro-1,2,4-triazine-1 (4H)-formaldehyde (III) mixes with alkali, is heated to 80-100 DEG C, insulation reaction 2 ~ 8 hours; Step b2: be cooled to room temperature, adds water, and temperature stirs 0.5-4 hour; Step b3: filter, filter cake is dry at 40-80 DEG C, obtains 4-(5-bromopyridine-2-base)-Isosorbide-5-Nitrae, 5,6-tetrahydrochysene-1,2,4-triazine (IV).
9. preparation method according to claim 8, is characterized in that, the reaction solvent of described step b1 is lower alcohol and/or aprotic polar solvent, preferred lower alcohol; Lower alcohol is selected from C 1~ C 6the saturated alkyl alcohol of straight or branched, more preferably methyl alcohol, ethanol, Virahol, ethylene glycol and/or glycerol, described alkali is salt of wormwood, sodium carbonate, potassium hydroxide and/or sodium hydroxide.
10. the preparation method according to any one of claim 2 ~ 10, it is characterized in that, in described step c, described 4-(5-bromopyridine-2-base)-Isosorbide-5-Nitrae, 5,6-tetrahydrochysene-1,2,4-triazine (IV) and described (R)-5-((1H-1,2,3-triazole-1-base) methyl)-3-(the fluoro-4-(4 of the bromo-3-of 4-, 4,5,5-tetramethyl--1,3,2, dioxy boron-2-bases) phenyl)-2-oxazolidone (II), alkali, 1,1'-two (diphenylphosphine) ferrocene palladium chloride, water mol ratio be 1:1:3:0.016:5; Described alkali is selected from salt of wormwood, sodium carbonate, sodium-acetate and/or Potassium ethanoate.
11. preparation methods according to any one of claim 2 ~ 10, it is characterized in that, described step c comprises: step c1: water, alkali, 1,1'-two (diphenylphosphine) ferrocene palladium chloride, R-5-((1H-1,2,3-triazole-1-base) methyl)-3-(the fluoro-4-(4 of the bromo-3-of 4-, 4,5,5-tetramethyl--1,3,2, dioxy boron-2-bases) phenyl)-2-oxazolidone (II) and 4-(5-bromopyridine-2-base)-Isosorbide-5-Nitrae, 5,6-tetrahydrochysene-1,2,4-triazine (IV) mixes, be heated to backflow, insulation reaction 1-10 hour; Step c2: suction filtration while hot, filter cake is 40 DEG C ~ 80 DEG C dryings, obtain (R)-5-((1H-1,2,3-triazole-1-base) methyl)-3-(4-(6-(5.6-dihydro-1,2,4-triazine)-4 (1H)-Ji) pyridine-2-base)-3-fluorophenyl-2-oxazolidone (V).
CN201410018269.2A 2014-01-15 2014-01-15 Novel oxazolidinone compound and preparation method thereof Pending CN104774198A (en)

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