CN106146559A - A kind of preparation method of oxazolidinones - Google Patents
A kind of preparation method of oxazolidinones Download PDFInfo
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Abstract
The invention provides the preparation method of a kind of oxazolidinones.Specifically provide the preparation method of a kind of formula 1 compound.The preparation method of described formula 1 compound includes, formula 2 compound is catalyzed under N methyl D Fructus Vitis viniferae amine existence condition reduction, directly generates formula 1 compound.The preparation that the present invention provides simplifies reactions steps, shortens reaction scheme, it is possible to the productivity making end product is higher, and, purity is more preferable.
Description
Technical field
The present invention relates to medicinal chemistry art, be specifically related to the preparation method of a kind of oxazolidinones and they are as the purposes of medicine.
Background technology
Oxazolidone finds to be widely used in the medicine treating and preventing such as antibacterial infection and atherosclerotic medical conditions as a class chemical composition.The various structures of oxazolidinone derivative are known.Such as US4461773, discloses the monosubstituted or disubstituted derivatives of 3-phenyl-2-oxazolidone in US4476136, US4250318 etc..
Pharmacia&Upjohn
Develop oxazolidinone derivative (WO93/23384, the WO shown in Formulas I and II
95/14684 and WO95/07271).The oxazolidinone derivative shown in Formulas I of the most entitled " Zyvox " the most successfully obtains FDA Food and Drug Administration (Food
And Drug Administration, FDA) license, come into the market.It is found, however, that the synthesis oxazolidinone derivative of these routines has only composes, to narrow, the shortcoming that antibacterial shows antibacterial activity, poisonous to human body and therapeutic activity in vivo is poor.Only it is about 3 mg/ml due to Zyvox dissolubility in water, is not suitable for injection, is therefore restricted during injection.
;。
WO93/09103 discloses 4 of phenyl ring by heterocycle such as thiazole, indole and quinoline and the substituted benzyloxazolidinone of pyridine.But, owing to heterocycle has simple substituent group such as alkyl or amino, it is known that these oxazolidinone derivatives are not provided that enough drug effects.WO
01/94342 describes 4 of phenyl ring by the synthesis of derivatives of the substituted benzyloxazolidinone of pyridine or phenyl derivatives.The compound of these synthesis has effective inhibitory activity to broad spectrum of bacteria, and is the antibiotic more excellent than Zyvox.But, owing to dissolubility is less than 30 mcg/ml, these compounds can not make injection.
WO2005058886 discloses oxazolidinone derivative and prodrug thereof, and wherein these prodrug react prepared by aminoacid or phosphate ester with the oxazolidinone derivative with hydroxyl.By using amino amino synthesis organic acid or the mineral acid of oxazolidinone derivative prodrug and the salt of oxazolidinone derivative prodrug can be easily utilized for synthesis by use a kind of phosphatic hydroxyl in sodium and calcium.And the antibacterial activity that this kind of oxazolidinone derivative has excellence and the dissolubility being greatly improved are disclosed.
Wherein, specially azoles amine phosphate ester (tedizolid phosphate) has obtained FDA approval for treating staphylococcus aureus (including methicillin resistant strains, methicillin sensitive strain) and acute bacterial skin that the gram-positive bacterium such as various Streptococcus and enterococcus faecalis causes and skin structure infection (ABSSSI).Specially azoles amine phosphate ester structure formula as indicated,
,
Chemical name: list-[(R)-[3-(4-(2-(2-methyl tetrazole-5-base) pyridine-5-base)-3-fluorophenyl)-2-oxo-5-oxazolidinyl] methyl] phosphate ester.
Chinese patent CN102516238A and CN102702184A discloses specially azoles amine and specially azoles amine phosphate compound and preparation method thereof.CN1894242B is also disclosed specially azoles amine organic phosphate disodium salt.
The salt great majority identified are difficult to be prepared as crystal formation, or unstable, and such as, the disodium salt of free acid is generally of very hygroscopic, is not suitable for preparing tablet；About single sodium salt, it is not detected by stable hydrate forms, there is a need in the art for can accurately toppling over and weighing when pharmaceutical preparation, stability and the salt of the good specially azoles amine phosphate ester of non-hygroscopic.
Additionally, acute bacterial skin and skin structure infection (ABSSSI) are caused by some susceptible bacteria, such as staphylococcus aureus (including methicillin-sensitivity bacterium and methicillin-resistant bacterium) and micrococcus scarlatinae, patient can be produced and have a strong impact on by this kind of infection, and become the most common disease that hospital processes, it is correlated with emergency treatment in recent years and inpatient also dramatically increases.According to statistics, in Some Areas of USA, inpatient, the prevalence of SSTIs is even up to 10%.And in emergency treatment, SSTIs be the third-largest commonly encountered diseases in addition to chest pain, asthma because of, infection site is common with lower limb.Analyzing according to SFDA south medication economics institute, China's dermatosis total prevalence rate is 1.23%, i.e. there are about 0.16 hundred million people and suffers from dermatosis in various degree.
Although having multiple eutherapeutic medicine at present is that clinic provides multiple choices, but there is also problems, the treatment skin such as generally acknowledged and skin structure infection choice drug vancomycin, there is the risk of ototoxicity and nephrotoxicity, drug resistance risk increases；And life-time service Linezolid side effect is obvious, as platelet lack, Flora Disturbance and mortality rate raise, Resistant strain is more.
Due to the gram positive bacteria infection relevant disease continued to bring out and the multiple side effect of the single generation of life-time service, and the generation of antibiotic resistance phenomenon, it is badly in need of the corresponding safely and effectively alternative medicine of exploitation, to meet clinical demand.
Summary of the invention
It is an object of the invention to provide a kind of new oxazolidinones with strong resisting gram-positive bacteria activity and preparation method thereof.
A second aspect of the present invention provides the preparation method of a kind of new oxazolidinones.
First aspect, the invention provides following formula 1 compound:
。
Second aspect, the invention provides the preparation method of formula 1 compound, and described method includes, formula 2 compound is catalyzed under N-methyl D-Fructus Vitis viniferae amine existence condition reduction, directly generates formula 1 compound,
,
Wherein, R is H, C1-4Alkyl, halogen atom, cyano group or nitro；Described C1-4Alkyl includes methyl, ethyl, propyl group, isopropyl, the tert-butyl group, normal-butyl or penta butyl, and wherein R the position of substitution on phenyl ring can be that para-position, ortho position or meta, preferably R are in phenyl ring para-position；Described halogen atom includes F, Cl, Br or I, and the most described halogen atom is Cl or Br.
Include the step of formula 2 compound for catalysis hydro-reduction carrying out catalytic hydrogenation with palladium catalyst, platinum catalyst or ruthenium catalyst.Preferably including carrying out catalytic hydrogenation with palladium catalyst by the step that formula 2 compound for catalysis reduces, described catalyst is selected from: palladium on carbon, the palladium with aluminium oxide as carrier, the palladium with barium sulfate as carrier, the palladium with calcium carbonate as carrier, the palladium with barium sulfate as carrier, the palladium with strontium carbonate as carrier, the palladium dydroxide with silicon dioxide as carrier palladium with carbon as carrier (Pearlman ' s catalyst).It is further preferred that use 10% palladium-carbon catalyst or 5% palladium-carbon catalyst to carry out catalytic hydrogenation.
Solvent for the catalytic hydrogenation of progressive form 2 compound includes C1-4Primary alconol, secondary alcohol and the tert-butyl alcohol and water.The most described solvent includes methanol, ethanol, isopropanol, normal propyl alcohol, n-butyl alcohol, water and mixture thereof.The temperature of described catalytic hydrogenation about 10 ~ 50 DEG C, preferable temperature is 20 ~ 25 DEG C.The catalysis reduction Hydrogen Vapor Pressure of Formula II compound is about 1 ~ 150psi, and preferably pressure is 5 ~ 50psi.Optional, after Formula II compound for catalysis hydro-reduction production 1 compound, contacting to remove catalyst with trialkyl phosphine by the solution of formula 1 compound, described trialkyl phosphine is preferably tri-n-butyl phosphine.
More specifically, formula 2 compound is preferably joined in N-methyl D-Fructus Vitis viniferae amine by described reaction, carries out catalytic reduction reaction in methanol aqueous solution, and described catalyst preferred weight percent is about 10% palladium-carbon catalyst, reaction temperature about 20 ~ 25 DEG C.Wherein, formula 2 compound is 1:2 ~ 3 with the reaction mol ratio of N-methyl D-Fructus Vitis viniferae amine, it is preferable that formula 2 compound is 1:2 with the reaction mol ratio of N-methyl D-Fructus Vitis viniferae amine.
Optional, after reaction terminates, compound 1 is contacted with anti-solvent in methanol solution, to generate formula 1 compound of solid.Described anti-solvent includes the alcohol (such as ethanol, isopropanol, isobutanol or n-butyl alcohol) beyond acetonitrile and methanol, wherein, the volume ratio about 50:50 ~ 75:25 of the alcohol beyond acetonitrile and methanol.
Further, said method also includes, is reacted with following formula 3 compound by following formula 4 compound, to generate compound 2:
,
Wherein, L is Br or I；R1For BF3Or BR2R3, wherein R2And R3Independent is selected from, by OH and any substituted C1-6Unitary and the group of dihydroxylic alcohols composition, wherein R2And R3Together can be with cyclization；R is H, C1-4Alkyl, halogen atom or cyano group.
Formula 4 compound reacts with following formula 3 compound, such as, under palladium catalyst catalytic condition, react under alkalescence (such as sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide etc.) environment, solvent is preferably toluene, THF, DMF, DMSO, dioxane, isopropanol or ethanol etc., reaction temperature is about 60 ~ 80 DEG C, and coupling obtains formula 2 compound.
Further, said method also includes, reacts, following formula 5 compound and phosphonylation reagent (formula 6 compound) to generate compound 4 under the effect of hindered base:
,
Wherein, described hindered base is selected from: hexamethyl two silica-based azane sodium, hexamethyl two silica-based azane potassium, hexamethyl two silica-based azane lithium, tert-butyl group potassium, tert-pentyl alcohol potassium, sodium tert-butoxide, amylalcohol potassium, lithium diisopropylamine, tetramethyl piperidine lithium, s-butyl lithium and tert-butyl lithium；Further, the most described hindered base is hexamethyl two silica-based azane sodium, hexamethyl two silica-based azane potassium, hexamethyl two silica-based azane lithium, tert-butyl lithium or lithium diisopropylamine.
Wherein, it is preferable that described phosphonylation reagent (formula 6 compound) is pyrophosphoric acid four benzyl ester (TBPP):
,
Preferably, L is Br or I, R1For BF3、B(OH)2
Or, wherein, dotted line " ... " represents link position.
Formula 5 compound and pyrophosphoric acid four benzyl ester reacts under the effect of hindered base, the reaction of generation compound 4, and wherein, the molar reactive of formula 5 compound and pyrophosphoric acid four benzyl ester ratio is for 1:1 ~ 1:2, it is preferable that 1:1.3.Reaction dissolvent be oxolane, dioxy six alkane, isopropanol or DMF, preferably reaction dissolvent be oxolane.Described reaction temperature is-5 DEG C ~ 5 DEG C, preferably-3 DEG C ~ 0 DEG C.
According to compound shown in prior art formula 5, such as, according to following formula: compound disclosed in Chinese patent CN102516238A and CN102702184A (formula 5 compound, when wherein L is I):
Preparation method prepare.
Described compound 3 can be prepared as follows acquisition:
,
Intermediate 3 ', wherein L is chlorine, bromine or iodine, with the highly basic of 2 equivalents (such as C1~6Lithium alkylide such as n-BuLi or tert-butyl lithium) reaction, it is subsequently adding suitable electrophilic reagent such as B (OR2) 3, concrete, such as C1~6Tri-alkoxy borate (such as triisopropyl borate ester), preferred solvent is THF or toluene, and reaction temperature is about-75 DEG C ~-65 DEG C.When electrophilic reagent is tri-alkoxy borate, gained reactant mixture is post-treated obtains boric acid 3a.The dianion of intermediate 3 ' is reacted with ring borate, then can isolated ring borate 3b.The all right reference of boronic acid compounds IIa " the pyrimidine chloro thing of palladium chtalyst and the Suzuki coupling reaction of pyridine boronic acid ester " (Xiao Wenjing, 2011
-Zhengzhou University: pharmaceutical chemistry, master thesis) disclosed in method prepare.Or diborate (such as diborated two pinacols) being coupled under palladium catalyst effect on halogenated hydrocarbons (3 '), the borate 3b of generation can hydrolyze in sour water becomes boric acid 3a；Trifluoro boronic acid derivatives 3c can pass through 3a Yu KF and/or KHF2Reaction generates；Or trifluoro boronic acid derivatives 3c is reacted (such as n-BuLi) with borate (such as triisopropyl borate ester) in the basic conditions by formula 3 ', solvent is preferably THF, generates boric acid triisopropyl lithium salts, the most again with KHF2Reaction prepares, concrete grammar can be found in " the Suzuki-Miyaura coupling reaction of 2-pyridine three Potassium borofluoride halides miscellaneous with virtue under palladium chtalyst " and (appoints big, 2011-Zhengzhou University: organic chemistry, Master's thesis), the document is incorporated by reference in this patent.Wherein, intermediate ii refers to method disclosed in CN1894242B and prepares.
On the other hand, the preparation method of compound 2 of the present invention, including, following formula 4 ' compound is reacted with following formula 3 ' compound, to generate compound 2:
,
Wherein, L is Br or I；R1For BF3Or BR2R3, wherein R2And R3Independent is selected from, by OH and any substituted C1-6Unitary and the group of dihydroxylic alcohols composition, wherein R2And R3Together can be with cyclization；R is H, C1-4Alkyl, halogen atom, cyano group or nitro.
Formula 4 ' compound reacts with following formula 3 ' compound, to generate compound 2, preferably reacts under palladium catalyst catalytic condition, and solvent is preferably DMF, and reaction temperature is about 60 ~ 80 DEG C, and coupling obtains formula 2 compound.
Further, said method also includes, reacts, following formula 5 ' compound and phosphonylation reagent (formula 6 compound) to generate compound 4 ' under the effect of hindered base:
。
In the method for the invention, preferably R is H, and L is Br or I, R1For BF3、B(OH)2
Or, wherein, dotted line " ... " represents link position；Further preferred, R is H, and L is Br, R1For B (OH)2
Or。
Wherein, described hindered base is selected from: hexamethyl two silica-based azane sodium, hexamethyl two silica-based azane potassium, hexamethyl two silica-based azane lithium, tert-butyl group potassium, tert-pentyl alcohol potassium, sodium tert-butoxide, amylalcohol potassium, lithium diisopropylamine, tetramethyl piperidine lithium, s-butyl lithium and tert-butyl lithium；Further, the most described hindered base is hexamethyl two silica-based azane sodium, hexamethyl two silica-based azane potassium, hexamethyl two silica-based azane lithium, tert-butyl lithium or lithium diisopropylamine.
Formula 5 ' compound and phosphonylation reagent (formula 6 compound) reacts under the effect of hindered base, generate the reaction of compound 4 ', and wherein, the molar reactive of formula 5 ' compound and phosphonylation reagent (formula 6 compound) ratio is for 1:1 ~ 1:2, it is preferable that 1:1.5.Reaction dissolvent be oxolane, Isosorbide-5-Nitrae-dioxane, isopropanol or DMF, preferably reaction dissolvent be oxolane.Described reaction temperature is-5 DEG C ~ 5 DEG C, preferably-3 DEG C ~ 0 DEG C).
Wherein, formula 5 ' compound, can prepare according to formula 3 compound similar approach, concrete reaction equation is as follows:
。
On the other hand, the invention provides following compound:
,,,
Wherein, R is H, C1-4Alkyl, halogen atom, cyano group or nitro, described C1-4Alkyl includes methyl, ethyl, propyl group, isopropyl, the tert-butyl group, normal-butyl or penta butyl, and wherein R the position of substitution on phenyl ring can be that para-position, ortho position or meta, preferably R are in phenyl ring para-position, described halogen atom includes F, Cl, Br or I, the most described halogen atom is Cl or Br；L is Br or I；R1For BF3Or BR2R3, wherein R2And R3Independent is selected from, by OH and any substituted C1-6Unitary and the group of dihydroxylic alcohols composition, wherein R2And R3Together can be with cyclization.
Further, the invention provides the compound of following structure:
,,,, or。
Formula 1 compound structure that the present invention provides is novel, stable in physicochemical property, compared with known specially azoles amine disodic alkaliine, and good stability, it is not easy to the moisture absorption, is more suitable for preparing tablet.When being used for preparing tablet, capsule, without adhesion, it is simple to topple over and accurate weighing.
Inventor studies and finds that formula 1 compound that the present invention provides demonstrates broad spectrum of bacteria, resistance to methicillin BRL-1241 staphylococcus aureus (methicillin-resistant
Staphylococcus aureus, MASA) and vancomycin-resistant enterococcus (vancomycin resistant
Enterococci, VRE) have inhibitory activity with at relative lower concentration or have relative excellent antibacterial activity in vivo.
Further, inventor studies discovery, formula 1 compound that the present invention provides can show including gram positive bacteria such as staphylococcus (Staphylococi), enterococcus (Enterococci) and streptococcus (Streptococi), anaerobe such as bacteroid (Bacteroides) and clostridium body (Clostridia)
And acidproof microorganism such as M tuberculosis bacterium (Mycobacterium tuberculosis), bird branch bacterium (Mycobacterium avium) are at the strong antibacterial activity of interior humans and animals pathogen.
Present invention also offers the preparation method of a kind of brand-new formula 1 compound, the method, by using benzyl to protect phosphate, greatly strengthen the stability of each intermediate.Under N-methyl D-Fructus Vitis viniferae amine existence condition, it is catalyzed reduction by formula 2 compound, by single step reaction, directly formula 2 compound is converted into formula 1 compound, simplify reactions steps, shorten reaction scheme, it is possible to the productivity making end product is higher, and, purity is more preferable.By controlling the reaction mol ratio of course of reaction Chinese style 2 compound and N-methyl D-Fructus Vitis viniferae amine, can further improve the quality of reactant, facilitate industrialized production.
Specific embodiment
Below in conjunction with specific embodiment, present invention is further explained, it is to be understood that, following example are merely illustrative purpose, and various modifications or change according to it can be expected by those skilled in the art, and are included in spirit and scope and scope of the following claims.All publications, patents and patent applications cited herein is incorporated by reference for all purposes at this.
Embodiment 1The preparation of pyrophosphoric acid four benzyl ester (TBPP):
Under nitrogen protection; phosphate dibenzyl ester (762g) and isopropyl acetate (3L) is added in 12L round-bottomed flask; this serosity is cooled to 3 ± 3 DEG C; then 1.08M dicyclohexylcarbodiimide (DCC) solution (1.30L) is added by addition funnel; bath temperature is maintained at 3 ± 3 DEG C simultaneously; joining day is usually 25 ~ 35 minutes, reacts about 30 minutes.After reaction terminates, cold serosity is filtered, and dicyclohexylurea waste filter cake isopropyl acetate (3*600ml) is washed (stirring).Merging filtrate and cleaning mixture, being concentrated into final volume is 1.5L.This mixture is transferred in 12L round-bottomed flask, and dilutes with heptane (500ml), and add 1mol% pyrophosphoric acid four benzyl ester crystal seed (8g) to form brilliant bed.Then to 3 ± 3 DEG C, and aging 1 hour.Serosity filters, and filter cake 20% isopropyl acetate/heptanes (3*500ml) is washed, and product cake is dried overnight in room temperature in vacuo under nitrogen protection.Isolate pyrophosphoric acid four benzyl ester (671g, 1.25mol), for white crystalline solid, by its in refrigerator freezing.
When in formula 6 compound structure, R is C1-4When alkyl, halogen atom, cyano group or nitro, its preparation method is similar to the preparation of pyrophosphoric acid four benzyl ester (TBPP).
Embodiment 2: the preparation of formula 4-a compound:
(1), the preparation of N-carbobenzyloxy-3-fluoroaniline (1-7):
100 grams of 3-fluoroanilines are dissolved in 1 liter of oxolane (THF), and by 150 grams of (1.8 moles) bicarbonates
Sodium (NaHCO3) join in this solution, after being cooled to 0 DEG C, it is slowly added in solution react by 154 milliliters of N-carbobenzoxy chlorides (CbzCl).Under agitation by reactant mixture sustained response 2 hours at 0 DEG C, afterwards by 0.5 liter of ethyl acetate extractive reaction system, after separation, organic layer saline washs, and uses anhydrous magnesium sulfate
(MgSO4) be dried and be concentrated in vacuo, residue normal hexane washes twice, and obtains 132 grams of title compounds for white crystal, yield 85%.
(2), the preparation of (R)-3-(3-fluorophenyl)-2-oxo-5-oxazolidinyl methanol (1-9):
132 grams of N-carbobenzyloxy-3-fluoroanilines are dissolved in 1.3 liters of oxolanes, and solution is cooled to-78 DEG C.370 milliliters of n-BuLis (1.6 mol/L, normal hexane) are slowly added in solution in a nitrogen atmosphere, then stirring 10 minutes.By 84 milliliters (R)-(-)-Glycidyl butyrate is slowly added in reactant mixture, stirring 2 hours at that same temperature, the most at room temperature reaction 24 hours.After having reacted, in solution, add ammonium chloride solution, and at room temperature with 0.5 liter of ethyl acetate extraction.Wash separating obtained organic layer with saline, and be dried with anhydrous magnesium sulfate, be concentrated in vacuo.Being dissolved in by gained residue in 100 milliliters of ethyl acetate and wash with normal hexane, obtaining white crystal, this white crystal purification is 80 grams of title compounds, yield 70%.1H-NMR(DMSO-d6) δ 7.85 (t, 1H), 7.58 (dd, 1H), 7.23 (dd, 1H), 4.69 (m, 1H), 4.02 (t, 1H), 3.80 (dd, 1H), 3.60 (br dd, 2H).
(3), the preparation of (R)-3-(4-bromo-3-fluorophenyl)-2-oxo-5-oxazolidinyl methanol (formula 5-a compound):
By 30 grams
(R)-3-(3-fluorophenyl)-2-oxo-5-oxazolidinyl methanol is dissolved in 300 milliliters of acetonitriles, and by 46 grams of trifluoroacetic acid silver salt (CF3COOAg) and 30.5 grams of BrCl join in solution, after being stirred at room temperature 1 day, add water, and be extracted with ethyl acetate in solution, and separating obtained organic layer saline washs and is dehydrated.Then residue is filtered, is concentrated in vacuo and is dried, thus obtain 37.8 grams of title compounds, yield 92%.
(4), the preparation of formula 4-a compound:
Addition formula 5-a compound (11.6g, 40.0mmol) in 250ml there-necked flask, pyrophosphoric acid four benzyl ester (32.3g,
60.0mmol) and THF(200ml), stir molten clearly, cryosel bath chilling temperature to 0 ~ 5 DEG C, be dividedly in some parts sodium tert-butoxide (7.6g, 80.0mmol), in adition process control temperature about-5 ~ 5 DEG C, TLC monitoring reaction terminates.Being poured into by reactant liquor in saturated sodium bicarbonate solution, be subsequently adding 200ml ether, separatory, it is neutrality that organic facies is washed to pH by purified water, is evaporated to do, obtains product 19.2g yield 87.2%, purity 99.7%.
Embodiment 3: the preparation of formula 3-a compound
(1), the preparation of 2-cyano group-5-bromopyridine:
By 100 gram 2,5-dibromo pyridine is dissolved in 1 liter of dimethylformamide, at room temperature 32 grams of copper cyaniders and 17.8 grams of Cyanogran .s is added in solution, solution stirring is reacted for 7 hours at temperature is 150 DEG C.After being cooled to room temperature, reactant mixture adds water, and is extracted with ethyl acetate.Organic layer saline washs and is dehydrated, filters and be concentrated in vacuo, and obtains 54 grams of title compounds, yield 70%.1H-NMR(CDCl3) δ 8.76 (s, 1H), 7.98 (dd, 1H), 7.58 (dd, 1H).
(2), the preparation of 2-(tetrazole-5-base)-5-bromopyridine:
Being dissolved in 100 milliliters of dimethylformamides by 10 grams of 2-cyano group-5-bromopyridines, at room temperature join in solution by 5.33 grams of Hydrazoic acid,sodium salt and 4.4 grams of ammonium chloride, solution stirs 3 hours at temperature is 110 DEG C and reacts.Adding water in reactant mixture, be then extracted with ethyl acetate, separating obtained organic layer saline washs, is dehydrated, filters and is concentrated in vacuo, and thus obtains 10.5 grams of title compounds, yield 85%.
(3), 2-(1-methyl tetrazole-5-base)-5-bromopyridine and the preparation of 2-(2-methyl tetrazole-5-base)-5-bromopyridine
10.5 grams of 2-(tetrazole-5-base)-5-bromopyridine is dissolved in 100 milliliters of dimethylformamides, then 6.5 grams of sodium hydroxide is joined in solution, and at 0 DEG C, 9.3 grams of iodomethanes are slowly added in solution.Solution is stirred at room temperature 6 hours, is subsequently adding water, and is extracted with ethyl acetate.Then gained organic layer saline washs, is dehydrated, filters, is concentrated in vacuo and passes through chromatography over CC, obtains 4 grams of 2-(1-methyl tetrazole-5-base)-5-bromopyridine and 5 grams of 2-(2-methyl tetrazolium-5-base)-5-bromopyridines.
(4), the preparation of compound shown in formula 3-a:
Under nitrogen protection; 240 grams of 2-(2-methyl tetrazole-5-base)-5-bromopyridine is dissolved in 2.4 liters of oxolanes; add 207g triisopropyl borate ester; it is cooled to-75 DEG C in liquid nitrogen/ethanol bath; being slowly added dropwise the n-BuLi tetrahydrofuran solution of 840ml 2.5M, control temperature, below-65 DEG C, reacts 2h in-75 ~-65 DEG C; HPLC detects reaction, until completely.Dropping 1.3L 20% aqueous ammonium chloride solution, control temperature below 0 DEG C, drip finish, stir 0.5h, stratification, organic layer anhydrous sodium sulfate is dried, and draws dry, add 600ml ethyl acetate making beating 2h, filter, be dried, obtain 149.7g target compound, yield is 73%.
Embodiment 4: the preparation of formula 2 compound
,
In being configured with the there-necked flask of 500ml of reflux condensing tube and thermometer, add 1.57g Pd (OAc)2, 3.7g
PPh3It is dissolved in 150 ml DMF; it is replaced as nitrogen; it is subsequently adding 33.75 ml triethylamines; stirring at 70 DEG C, until solution becomes reddish black, adds 77.0g formula 4-a compound and 34.4g formula 3-a compound, is dissolved in 100ml DMF solution; under nitrogen protection; monitor reaction at 90 DEG C of stirrings reaction 2h, TLC, filter through kieselguhr while hot.Being concentrated into 50ml at 70 DEG C, add 500ml purified water, stir 1.0h, filter, filter cake 50ml 50% methanol aqueous solution (volumetric concentration) washs, 50 DEG C of dry 8h.Adding 430ml 50% methanol aqueous solution (volumetric concentration) in gained solid, be heated to 70 DEG C of making beating 2h, be cooled to room temperature, filter, 30ml methanol rinses, be dried to obtain formula 2 compound 76.8g in 50 DEG C, yield is 87%.
Embodiment
5:
Formula
4-b
The preparation of compound
In being configured with the there-necked flask of 500ml of reflux condensing tube and thermometer, add 14.5g formula 5-a compound, 13.97g (1.1eq.) pinacol diborate, 1.83g(0.05eq.) PdCl2(dppf)2, 110ml DMF, under nitrogen protection, 70 DEG C of stirring reactions, HPLC monitor reaction, while hot through kieselguhr filtration.Being concentrated into 50ml at 70 DEG C, add 400ml purified water, extract with dichloromethane (400ml*2), anhydrous sodium sulfate is dried, and filters, is concentrated to give formula 5-b compound 12.74g, and yield is 74%；1H-NMR (DMSO-D6): 1.32 (s, 12H), 4.45 (s, 3H), 8.13 (d, 1H), 8.18 (d, 1H), 8.90 (s, 1H).
Addition formula 5-a compound (10.1g, 30.0mmol) in 250ml there-necked flask, pyrophosphoric acid four benzyl ester (24.2g,
45.0mmol) and THF(150ml), stir molten clearly, cryosel bath chilling temperature to 0 ~ 5 DEG C, be dividedly in some parts hexamethyl two silica-based azane sodium (11.1g, 60.4mmol), in adition process control temperature about-5 ~ 5 DEG C, TLC monitoring reaction terminates.Being poured into by reactant liquor in saturated sodium bicarbonate solution, be subsequently adding 150ml ether, separatory, it is neutrality that organic facies is washed to pH by purified water, is evaporated to do, obtains product (formula 4-b compound) 16.0g yield 89.3%.
Embodiment 6: the preparation of formula 2 compound
In being configured with the there-necked flask of 500ml of reflux condensing tube and thermometer, add 1.83g Pd2(dba)3, 1.12g PCy3It is dissolved in 400ml
DMF, is replaced as nitrogen, stirs 0.5h, be subsequently adding 60.6g triethylamine under room temperature, adds 119.5g formula 4-b compound and 57.6g formula 3-b compound, and under nitrogen protection, 70 DEG C of stirring reactions, HPLC monitors reaction, filters through kieselguhr while hot.Being concentrated into 50ml at 70 DEG C, add 500ml purified water, extract with dichloromethane 400ml*2, anhydrous sodium sulfate is dried, and filters, is concentrated to give solid, adds 500ml in gained solid
50% methanol aqueous solution (volumetric concentration), is heated to 70 DEG C of making beating 2h, is cooled to room temperature, filters, 40ml methanol rinses, be dried to obtain formula 2 compound 112.1g in 50 DEG C, and yield is 88.9%.
Embodiment 7: the preparation of formula 1 compound
Formula 2 compound (315.3g, 0.5mol) and N-methyl-D-glucosamine (195.21,1.0mol) are mixed, and is dissolved in methanol (2.0L) and water (120ml).By 5%Pd/C (16.0g) pulp in 360ml methanol, then by this catalyst after room temperature and 40pasi concentrate again, join in above-mentioned formula 2 compound and N-methyl-D-glucosamine serosity, by this system hydrogenated over night.After reaction terminates, being filtered by hydrogenation serosity, and wash with methanol (2*2L), then filter vacuum is concentrated, room temperature is maintained at not higher than 18 DEG C and is concentrated into ultimate density is 200g/L, precipitates.
In the compound of formula I (294g) solution in methanol, add tri-n-butyl phosphine (TBP) (1.8ml), and be stirred overnight (adding TBP for removing the Pd of excess) at 20 DEG C.Then at 20 DEG C, this solution is slowly added in the mixture of 8.5L acetonitrile and 8.5L ethanol, within about 1 hour, adds.Then acetonitrile (17L) is slowly added in this mixture, within about 120 minutes, adds.This serosity settles about 30 minutes, is decanted off 70% supernatant, and transfers in filter, residue serosity is suspended again, and filters under stress, and filter cake acetonitrile (3.5L) washs, and collects product, vacuum drying, yield about 94%, purity more than 99.3%.
Above example be only used for illustrate the present invention, when in formula 2 compound structure benzyl (Bn) by C1-4When alkyl, halogen atom, cyano group or nitro replace, its preparation method, and it is for the method for formula 1 compound, those of ordinary skill in the art can be according to present disclosure, such as method disclosed in the embodiment of the present invention 2 ~ 7 operates.
Claims (13)
1. the preparation such as method of following formula 1 compound,
,
Described method includes, formula 2 compound is catalyzed under N-methyl D-Fructus Vitis viniferae amine existence condition reduction, directly generates formula 1 compound,
,
Wherein, R is H, C1-4Alkyl, halogen atom, cyano group or nitro.
The most according to claim 1, method, it is characterised in that described method also includes, react following formula 4 compound with following formula 3 compound, to generate compound 2:
Wherein, L is Br or I；R1For BF3Or BR2R3, wherein R2And R3Independent is selected from, by OH and any substituted C1-6Unitary and the group of dihydroxylic alcohols composition, wherein R2And R3Together can be with cyclization；R is H, C1-4Alkyl, halogen atom, cyano group or nitro.
The most according to claim 2, method, it is characterised in that described method also includes, react following formula 5 compound and phosphonylation reagent (formula 6 compound), to generate compound 4 under the effect of hindered base:
。
The most according to claim 1, method, it is characterised in that described method also includes, react following formula 4 ' compound with following formula 3 ' compound, to generate compound 2:
,
Wherein, L is Br or I；R1For BF3Or BR2R3, wherein R2And R3Independent is selected from, by OH and any substituted C1-6Unitary and the group of dihydroxylic alcohols composition, wherein R2And R3Together can be with cyclization；R is H, C1-4Alkyl, halogen atom, cyano group or nitro.
The most according to claim 4, method, it is characterised in that described method also includes, react following formula 5 ' compound and phosphonylation reagent (formula 6 compound), to generate compound 4 ' under the effect of hindered base:
。
6. according to the arbitrary described method of claim 2 ~ 5, it is characterised in that R be H, L be Br or I, R1For BF3、B(OH)2Or, wherein, dotted line " ... " represents link position.
Method the most according to claim 6, it is characterised in that R be H, L be Br, R1For B (OH)2Or。
8. according to method described in claim 3 or 5, it is characterized in that, described hindered base is selected from: hexamethyl two silica-based azane sodium, hexamethyl two silica-based azane potassium, hexamethyl two silica-based azane lithium, tert-butyl group potassium, sodium tert-butoxide, tert-pentyl alcohol potassium, amylalcohol potassium, lithium diisopropylamine, tetramethyl piperidine lithium, s-butyl lithium and tert-butyl lithium.
Method the most according to claim 8, it is characterised in that described hindered base is selected from: hexamethyl two silica-based azane sodium, hexamethyl two silica-based azane potassium, hexamethyl two silica-based azane lithium, tert-butyl lithium and lithium diisopropylamine.
Method the most according to claim 1, it is characterised in that described catalysis reduction is to complete with palladium-carbon catalyst.
11. according to the arbitrary described method of claim 7 ~ 10, also includes contacting formula 1 compound with trialkyl phosphine.
12. following formula: compounds:
,,,
Wherein, R is H, C1-4Alkyl, halogen atom, cyano group or nitro；L is Br or I；R1For BF3Or BR2R3, wherein R2And R3Independent is selected from, by OH and any substituted C1-6Unitary and the group of dihydroxylic alcohols composition, wherein R2And R3Together can be with cyclization.
13. according to compound described in claim 12, and it is:
,,,, or。
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| CN1894242A (en) * | 2003-12-18 | 2007-01-10 | 东亚制药株式会社 | Novel oxazolidinone derivatives |
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| CN104496979A (en) * | 2014-09-17 | 2015-04-08 | 博瑞生物医药技术(苏州)有限公司 | Method for preparing oxazolidinone compound and intermediate thereof |
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| CN101720325A (en) * | 2007-08-06 | 2010-06-02 | 盟科医药技术公司 | Antimicrobial ortho-fluorophenyl oxazolidinones for treatment of bacterial infections |
| CN104496979A (en) * | 2014-09-17 | 2015-04-08 | 博瑞生物医药技术(苏州)有限公司 | Method for preparing oxazolidinone compound and intermediate thereof |
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