CN106146559B - A kind of preparation method of Oxazolidinone derivative - Google Patents
A kind of preparation method of Oxazolidinone derivative Download PDFInfo
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Abstract
The present invention provides a kind of preparation methods of Oxazolidinone derivative.Specifically provide a kind of preparation method of 1 compound of formula.The preparation method of 1 compound of formula includes that 2 compound of formula is catalyzed to reduction under N- methyl D-grape amine existence condition, directly generates 1 compound of formula.Preparation provided by the invention simplifies reaction step, shortens reaction route, the yield of final product can be made higher, also, purity is more preferable.
Description
Technical field
The present invention relates to field of medicinal chemistry, and in particular to a kind of preparation method of Oxazolidinone derivative and they
Purposes as drug.
Background technique
Oxazolidone is treating and preventing such as bacterium infection and atherosclerosis as a kind of chemical component discovery
It is widely used in the drug of medical conditions.The various structures of oxazole alkanones derivative are known.Such as US4461773,
The monosubstituted or disubstituted derivatives of 3- phenyl -2- oxazolidone are disclosed in US4476136, US4250318 etc..
Pharmacia&Upjohn develops (WO93/23384, the WO 95/ of oxazole alkanones derivative shown in Formulas I and II
14684 and WO95/07271).Oxazole alkanones derivative shown in the Formulas I of wherein entitled " Zyvox " successfully obtains the U.S.
The license of Food and Drug Administration (Food and Drug Administration, FDA), into market.However, people send out
These existing conventional synthesis oxazole alkanones derivatives have only to narrow spectrum bacterium display antibacterial activity, toxic to human body and in vivo control
The shortcomings that treating poor activity.Since the solubility of Zyvox in water is only about 3 mg/mls, be not suitable for injecting, therefore infuse
It is restricted when penetrating.
;。
WO93/09103 discloses 4 phenyl evils replaced by heterocycle such as thiazole, indoles and quinoline and pyridine of phenyl ring
Oxazolidone.However, since heterocycle has simple substituent group such as alkyl or amino, it is known that these oxazole alkanones derivatives cannot mention
For enough drug effects.WO 01/94342 describes 4 oxazolyl phenyl alkanones replaced by pyridine or phenyl derivatives of phenyl ring
Synthesis of derivatives.The compound of these synthesis has effective inhibitory activity to broad spectrum of bacteria, and is more superior than Zyvox
Antibiotic.However, injection cannot be made in these compounds since dissolubility is less than 30 mcg/mls.
WO2005058886 discloses oxazole alkanones derivative and its pro-drug, and wherein these pro-drugs pass through amino
Acid or phosphate are reacted with the oxazole alkanones derivative with hydroxyl to be made.By using oxazole alkanones derivative pro-drug
Amino amino synthesizes organic acid or inorganic acid and can be light by using a kind of phosphatic hydroxyl in sodium and calcium
It is easily-synthesized the salt of oxazole alkanones derivative pro-drug.And disclose this kind of oxazole alkanones derivative have excellent antibacterial activity and
The dissolubility greatly improved.
Wherein, specially azoles amine phosphate (tedizolid phosphate) has obtained FDA approval for treating golden yellow
Staphylococcus (including methicillin resistant strains, methicillin sensitive strain) and the grams such as various streptococcuses and enterococcus faecalis
Acute bacterial skin caused by positive bacteria and skin structure infection (ABSSSI).Specially azoles amine phosphate ester structure formula such as institute
Show,
,
Chemical name: mono- [(R)-[3- (4- (2- (2- methyl tetrazole -5- base) pyridine -5- base) -3- fluorophenyl) -2- oxygen
Generation -5- oxazolidinyl] methyl] phosphate.
Chinese patent CN102516238A and CN102702184A disclose specially azoles amine and specially azoles amine phosphate chemical combination
Object and preparation method thereof.Specially azoles amine organic phosphate disodium salt is also disclosed in CN1894242B.
Most of identified salt is difficult to be prepared into crystal form or unstable, for example, the disodium salt of free acid usually has
Very hygroscopic is not suitable for preparing tablet；About mono-sodium salt, stable hydrate form is not detected, there is a need in the art for
Accurately it can topple over and weigh when for pharmaceutical preparation, the salt of stability and the good specially azoles amine phosphate of non-hygroscopic.
In addition, acute bacterial skin and skin structure infection (ABSSSI) are such as gold as caused by certain susceptible bacterias
Staphylococcus aureus (including methicillin-sensitivity bacterium and methicillin-resistant bacterium) and micrococcus scarlatinae, this kind of infection can to patient
Generation seriously affects, and has become the most common disease of hospital's processing, and related emergency treatment and inpatient also significantly increase in recent years
Add.According to statistics, the illness rate of SSTIs is even up to 10% in Some Areas of USA, inpatient.And in emergency treatment, SSTIs is
The third-largest common disease factor in addition to pectoralgia, asthma, infection site are common with lower limb.According to the south SFDA medication economics research institute point
Analysis, Chinese skin disease total prevalence rate are 1.23%, i.e., there are about 0.16 hundred million people to suffer from different degrees of skin disease.
Although there are many eutherapeutic drugs at present provides multiple choices for clinic, there is also problems, such as
Generally acknowledged treatment skin and skin structure infection choice drug vancomycin, the risk with ototoxicity and renal toxicity, drug resistance
Risk increases；And it is obvious to be used for a long time Linezolid side effect, as blood platelet lacks, Flora Disturbance and the death rate increase, drug resistance
Bacterial strain is more etc..
Due to the gram positive bacteria infection related disease continued to bring out and the single a variety of side effects of generation are used for a long time,
With 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
The object of the present invention is to provide a kind of with the strong active new Oxazolidinone derivative of resisting gram-positive bacteria
And preparation method thereof.
The second aspect of the present invention provides a kind of preparation method of new Oxazolidinone derivative.
In a first aspect, the present invention provides 1 compounds of following formula:
。
Second aspect, the present invention provides the preparation methods of 1 compound of formula, and the method includes by 2 compound of formula in N-
It is catalyzed reduction under methyl D-grape amine existence condition, directly generates 1 compound of formula,
,
Wherein, R is H, C1-4Alkyl, halogen atom, cyano or nitro；The C1-4Alkyl includes methyl, ethyl, propyl, different
Propyl, tert-butyl, normal-butyl or penta butyl, wherein the position of substitution of R on phenyl ring can be contraposition, ortho position or meta position, preferably R
It is aligned in phenyl ring；The halogen atom includes F, Cl, Br or I, and the preferably described halogen atom is Cl or Br.
It include being urged with palladium catalyst, platinum catalyst or ruthenium catalyst by the step of 2 compound for catalysis hydro-reduction of formula
Change hydrogenation.It is preferred that the step of 2 compound for catalysis of formula is restored includes carrying out catalytic hydrogenation, the catalyst choosing with palladium catalyst
From: palladium on carbon is as the palladium of carrier, with barium sulfate as the palladium of carrier, using calcium carbonate as the palladium of carrier, using barium sulfate using aluminium oxide
The palladium of carrier is carrier palladium and using carbon as the palladium dydroxide of carrier as the palladium of carrier, using silica using strontium carbonate
(Pearlman ' s catalyst).It is further preferred that carrying out catalytic hydrogenation using 10% palladium-carbon catalyst or 5% palladium-carbon catalyst.
Solvent for carrying out the catalytic hydrogenation of 2 compound of formula includes C1-4Primary alconol, secondary alcohol and the tert-butyl alcohol and water.It is preferred that institute
Stating solvent includes methanol, ethyl alcohol, isopropanol, normal propyl alcohol, n-butanol, water and its mixture.The temperature of the 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, preferably pressure
For 5 ~ 50psi.Optional, after 1 compound of Formula II compound for catalysis hydro-reduction production, by the solution and three of 1 compound of formula
Alkylphosphines are contacted to remove catalyst, and the trialkyl phosphine is preferably tri-n-butyl phosphine.
More specifically, 2 compound of formula is preferably added in N- methyl D-grape amine by the reaction, in methanol aqueous solution
Middle carry out catalytic reduction reaction, the catalyst preferred weight percent are about 10% palladium-carbon catalyst, reaction temperature about 20 ~ 25
℃.Wherein, it is 1:2 ~ 3 that 2 compound of formula, which reacts molar ratio with N- methyl D-grape amine, it is preferable that 2 compound of formula and N- methyl-
The reaction molar ratio of D- grape amine is 1:2.
Optional, after reaction terminates, compound 1 is contacted in methanol solution with anti-solvent, to generate the formula 1 of solid
Compound.The anti-solvent includes the alcohol (such as ethyl alcohol, isopropanol, isobutanol or n-butanol) other than acetonitrile and methanol,
In, volume ratio about 50:50 ~ 75:25 of the alcohol other than acetonitrile and methanol.
Further, the above method further includes reacting 4 compound of following formula with 3 compound of following formula, to generate compound 2:
,
Wherein, L is Br or I；R1For BF3Or BR2R3, wherein R2And R3C that is independent to be selected from, by OH and arbitrarily replacing1-6One
The group of member and dihydric alcohol composition, wherein R2And R3It together can cyclization；R is H, C1-4Alkyl, halogen atom or cyano.
4 compound of formula is reacted with 3 compound of following formula, for example, under palladium catalyst catalytic condition, alkaline (such as sodium carbonate, carbon
Sour potassium, sodium hydroxide or potassium hydroxide etc.) it reacts under environment, solvent is preferably toluene, THF, DMF, DMSO, and dioxane is different
Propyl alcohol or ethyl alcohol etc., reaction temperature are about 60 ~ 80 DEG C, and coupling obtains 2 compound of formula.
Further, the above method further includes, by 5 compound of following formula and phosphonylation reagent (6 compound of formula) in steric hindrance
It is reacted under the action of alkali, to generate compound 4:
,
Wherein, the hindered base is selected from: two silicon substrate azane sodium of hexamethyl, two silicon substrate azane potassium of hexamethyl, two silicon of hexamethyl
Base azane lithium, tert-butyl potassium, tert-pentyl alcohol potassium, sodium tert-butoxide, amylalcohol potassium, lithium diisopropylamine, tetramethyl piperidine lithium, sec-butyl
Lithium and tert-butyl lithium；Further, the preferably described hindered base be two silicon substrate azane sodium of hexamethyl, two silicon substrate azane potassium of hexamethyl,
Two silicon substrate azane lithium of hexamethyl, tert-butyl lithium or lithium diisopropylamine.
Wherein, it is preferable that the phosphonylation reagent (6 compound of formula) is four benzyl ester of pyrophosphoric acid (TBPP):
,
It is preferred that L is Br or I, R1For BF3、B(OH)2Or, wherein dotted line " ... " indicates link position.
5 compound of formula reacts under the action of hindered base with four benzyl ester of pyrophosphoric acid, generates the reaction of compound 4, wherein formula
5 compounds and the molar reactive ratio of four benzyl ester of pyrophosphoric acid are 1:1 ~ 1:2, it is preferable that 1:1.3.Reaction dissolvent is tetrahydrofuran, dioxy
Six alkane, isopropanol or DMF, preferably reaction dissolvent are tetrahydrofuran.The reaction temperature is -5 DEG C ~ 5 DEG C, preferably -3 DEG C ~ 0 DEG C.
According to compound shown in prior art preparation formula 5, for example, according to Chinese patent CN102516238A and
Following formula: compound disclosed in CN102702184A (5 compound of formula, when wherein L is I):
Preparation method prepare.
The compound 3 can be prepared as follows acquisition:
,
Intermediate 3 ', wherein L is chlorine, bromine or iodine, highly basic (such as C with 2 equivalents1~6Lithium alkylide such as n-BuLi or tert-butyl
Lithium) reaction, suitable electrophilic reagent such as B (OR is then added2) 3, specifically, such as C1~6(such as boric acid three is different for tri-alkoxy borate
Propyl 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 reaction mixture is post-treated to obtain boric acid 3a.The dianion of intermediate 3 ' is reacted with ring borate, is then
It is separable to obtain ring borate 3b.Boronic acid compounds IIa can also be with reference to " the pyrimidine chloro thing of palladium chtalyst and pyridine boronic acid ester
The preparation of method disclosed in Suzuki coupling reaction " (Xiao Wenjing, 2011-Zhengzhou University: pharmaceutical chemistry, master thesis) obtains
?.Or be coupled to diborate (two pinacols of such as hypoboric acid) on halogenated hydrocarbons (3 ') under palladium catalyst effect, it generates
Borate 3b can be hydrolyzed in sour water and become boric acid 3a；Trifluoro boronic acid derivatives 3c can pass through 3a and KF and/or KHF2
Reaction generates；Or trifluoro boronic acid derivatives 3c passes through formula 3 ' and borate (such as triisopropyl borate ester) under alkaline condition (such as
N-BuLi) reaction, solvent is preferably THF, generate boric acid triisopropyl lithium salts, then again with KHF2Reaction is prepared, tool
Body method can be found in " the Suzuki-Miyaura coupling reaction of three potassium fluoborate of 2- pyridine and the miscellaneous halides of virtue under palladium chtalyst " and (appoint
It is big, 2011- Zhengzhou University: organic chemistry, Master's thesis), the document is incorporated by reference into this patent.Wherein, intermediate
Ii can refer to method disclosed in CN1894242B and prepare.
On the other hand, the preparation method of compound 2 of the present invention, including, by 4 ' compound of following formula and 3 ' chemical combination of following formula
Object reaction, to generate compound 2:
,
Wherein, L is Br or I；R1For BF3Or BR2R3, wherein R2And R3C that is independent to be selected from, by OH and arbitrarily replacing1-6One
The group of member and dihydric alcohol composition, wherein R2And R3It together can cyclization；R is H, C1-4Alkyl, halogen atom, cyano or nitro.
4 ' compound of formula is reacted with 3 ' compound of following formula, anti-preferably under palladium catalyst catalytic condition to generate compound 2
It answers, solvent is preferably DMF, and reaction temperature is about 60 ~ 80 DEG C, and coupling obtains 2 compound of formula.
Further, the above method further includes, by 5 ' compound of following formula and phosphonylation reagent (6 compound of formula) in hindered base
Under the action of react, to generate compound 4 ':
。
In the method for the invention, preferably R is H, and L is Br or I, R1For BF3、B(OH)2Or, wherein
Dotted line " ... " indicates link position；Further preferred, R is H, L Br, R1For B (OH)2Or。
Wherein, the hindered base is selected from: two silicon substrate azane sodium of hexamethyl, two silicon substrate azane potassium of hexamethyl, two silicon of hexamethyl
Base azane lithium, tert-butyl potassium, tert-pentyl alcohol potassium, sodium tert-butoxide, amylalcohol potassium, lithium diisopropylamine, tetramethyl piperidine lithium, sec-butyl
Lithium and tert-butyl lithium；Further, the preferably described hindered base be two silicon substrate azane sodium of hexamethyl, two silicon substrate azane potassium of hexamethyl,
Two silicon substrate azane lithium of hexamethyl, tert-butyl lithium or lithium diisopropylamine.
5 ' compound of formula reacts under the action of hindered base with phosphonylation reagent (6 compound of formula), generates compound 4 '
Reaction, wherein the molar reactive ratio of 5 ' compound of formula and phosphonylation reagent (6 compound of formula) is 1:1 ~ 1:2, it is preferable that 1:1.5.
Reaction dissolvent is tetrahydrofuran, Isosorbide-5-Nitrae-dioxane, isopropanol or DMF, and preferably reaction dissolvent is tetrahydrofuran.The reaction temperature
Degree is -5 DEG C ~ 5 DEG C, preferably -3 DEG C ~ 0 DEG C).
Wherein, 5 ' compound of formula can be prepared according to 3 compound similar approach of formula, and specific reaction equation is as follows:
。
On the other hand, the present invention provides following compounds:
,,,
Wherein, R is H, C1-4Alkyl, halogen atom, cyano or nitro, the C1-4Alkyl includes methyl, ethyl, propyl, different
Propyl, tert-butyl, normal-butyl or penta butyl, wherein the position of substitution of R on phenyl ring can be contraposition, ortho position or meta position, preferably R
It is aligned in phenyl ring, the halogen atom includes F, Cl, Br or I, and the preferably described halogen atom is Cl or Br；L is Br or I；R1For BF3Or
BR2R3, wherein R2And R3C that is independent to be selected from, by OH and arbitrarily replacing1-6The group of unitary and dihydric alcohol composition, wherein R2And R3?
It together can cyclization.
Further, the present invention provides the compounds of such as flowering structure:
,,,, or。
1 compound structure of formula provided by the invention is novel, stable in physicochemical property, with known specially azoles amine disodic alkaliine
It compares, stability is good, is not easy to the moisture absorption, is more suitable for preparing tablet.When being used to prepare tablet, capsule, no adhesion, convenient for inclining
And accurate weighing.
Inventor, which studies, finds that 1 compound of formula provided by the invention is shown to broad spectrum of bacteria, resistance to methicillin BRL-1241
Staphylococcus aureus (methicillin-resistant Staphylococcus aureus, MASA) and resistance to mould through the ages
Plain enterococcus (vancomycin resistant Enterococci, VRE) have inhibitory activity and relative lower concentration or
There is relatively excellent antibacterial activity in vivo.
Further, inventor is the study found that 1 compound of formula provided by the invention can be shown to including Gram-positive
Bacterium such as staphylococcus (Staphylococi), enterococcus (Enterococci) and streptococcus (Streptococi), anaerobism is micro-
Biology such as bacteroid (Bacteroides) and clostridium body (Clostridia) and acidproof microorganism such as M tuberculosis bacterium
Humans and animals cause of disease including (Mycobacterium tuberculosis), bird branch bacterium (Mycobacterium avium)
The strong antibacterial activity of body.
The present invention also provides a kind of preparation methods of completely new 1 compound of formula, and this method is by using benzyl to phosphoric acid
Base is protected, and the stability of each intermediate is greatly strengthened.By 2 compound of formula under N- methyl D-grape amine existence condition
Catalysis reduction, by single step reaction, directly converts 1 compound of formula for 2 compound of formula, simplifies reaction step, shortens reaction
Route can make the yield of final product higher, also, purity is more preferable.Pass through control 2 compound of reaction process Chinese style and N- first
The reaction molar ratio of base-D- grape amine, can further improve the quality of reactant, facilitate industrialized production.
Specific embodiment
The content of present invention is further explained below in conjunction with specific embodiment, it should be understood that, following embodiment is only
For illustration purposes, can be expected by those skilled in the art according to its various modifications or alterations, and including the application's
In spirit and scope and scope of the appended claims.All publications, patents and patent applications cited herein are herein
It is incorporated by reference for all purposes.
The preparation of 1 pyrophosphoric acid of embodiment, four benzyl ester (TBPP):
Under nitrogen protection, phosphate dibenzyl ester (762g) and isopropyl acetate (3L) are added into 12L round-bottomed flask, by the slurry
Liquid is cooled to 3 ± 3 DEG C, 1.08M dicyclohexylcarbodiimide (DCC) solution (1.30L) then is added by addition funnel, simultaneously
Bath temperature is maintained at 3 ± 3 DEG C, it is usually 25 ~ 35 minutes that the time, which is added, is reacted about 30 minutes.After reaction, by cold slurry
Liquid filtering, and dicyclohexylurea waste filter cake is washed into (stirring) with isopropyl acetate (3*600ml).Merging filtrate and washing
Liquid, being concentrated into final volume is 1.5L.The mixture is transferred in 12L round-bottomed flask, and is diluted with heptane (500ml), and is added
Enter four benzyl ester crystal seed (8g) of 1mol% pyrophosphoric acid to form brilliant bed.Then to 3 ± 3 DEG C, and aging 1 hour.Slurries filtering, filter cake
It is washed with 20% isopropyl acetate/heptanes (3*500ml), product cake is dried overnight in room temperature in vacuo under nitrogen protection.Separation
Four benzyl ester of pyrophosphoric acid (671g, 1.25mol) out is white crystalline solid, it is freezed in refrigerator.
When R is C in 6 compound structure of formula1-4When alkyl, halogen atom, cyano or nitro, preparation method is similar to pyrophosphoric acid
The preparation of four benzyl esters (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 tetrahydrofuran (THF), and by 150 grams of (1.8 moles) bicarbonates
Sodium (NaHCO3) be added in the solution, after being cooled to 0 DEG C, by 154 milliliters of N- carbobenzoxy chlorides (CbzCl)
It is slowly added to be reacted in solution.Under agitation by reaction mixture at 0 DEG C sustained response 2 hours, later with 0.5
It rises ethyl acetate and extracts reaction system, after separation, organic layer is washed with brine, with anhydrous magnesium sulfate (MgSO4) dry and vacuum
Concentration, residue are washed twice with n-hexane, obtain 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 tetrahydrofurans, and solution is cooled to -78
℃.370 milliliters of n-BuLis (1.6 mol/Ls, n-hexane) are slowly added in solution in a nitrogen atmosphere, are then stirred
10 minutes.84 milliliters of (R)-(-)-Glycidyl butyrates are slowly added in reaction mixture, are stirred at that same temperature
It mixes 2 hours, then reacts 24 hours at room temperature.After the reaction was completed, ammonium chloride solution is added into solution, and uses at room temperature
0.5 liter of ethyl acetate extraction.It is washed with brine separating obtained organic layer, and, vacuum concentration dry with anhydrous magnesium sulfate.By institute
It obtains residue to be dissolved in 100 milliliters of ethyl acetate and washed with n-hexane, obtains white crystal, white crystal purifying is 80 grams
Title compound, 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):
30 grams of (R) -3- (3- fluorophenyl) -2- oxo -5- oxazolidinyl methanol are dissolved in 300 milliliters of acetonitriles, and will
46 grams of trifluoroacetic acid silver salt (CF3COOAg it) is added in solution with 30.5 grams of BrCl, after being stirred at room temperature 1 day, toward solution
Middle addition water, and be extracted with ethyl acetate, separating obtained organic layer is washed with brine and is dehydrated.Then residue is filtered,
It is concentrated in vacuo and dries, thus obtain 37.8 grams of title compounds, yield 92%.
(4), the preparation of formula 4-a compound:
Formula 5-a compound (11.6g, 40.0mmol) is added into 250ml there-necked flask, four benzyl ester of pyrophosphoric acid (32.3g,
60.0mmol) and THF(200ml), stir dissolved clarification, ice salt bath cooling temperature to 0 ~ 5 DEG C, be added portionwise sodium tert-butoxide (7.6g,
80.0mmol), about -5 ~ 5 DEG C of temperature are controlled in adition process, TLC monitoring reaction terminates.Reaction solution is poured into saturated sodium bicarbonate
In solution, 200ml ether, liquid separation is then added, organic phase is in neutrality to pH with purifying water washing, is concentrated to dryness, 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 -5- bromopyridine:
100 grams of 2,5- dibromo pyridines are dissolved in 1 liter of dimethylformamide, at room temperature by 32 grams of copper cyaniders and
17.8 grams of Cymags are added in solution, stir solution 7 hours at being 150 DEG C in temperature and react.After being cooled to room temperature, instead
It answers and water is added in mixture, and be extracted with ethyl acetate.Organic layer is washed with brine and is dehydrated, filters and is 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:
10 grams of 2- cyano -5- bromopyridines are dissolved in 100 milliliters of dimethylformamides, at room temperature by 5.33 grams of Azides
Sodium and 4.4 grams of ammonium chlorides are added in solution, and solution stirs 3 hours at being 110 DEG C in temperature to be reacted.In reaction mixture
Water is added, is then extracted with ethyl acetate, separating obtained organic layer is washed with brine, is dehydrated, is filtered and concentrated in vacuo, thus
Obtain 10.5 grams of title compounds, yield 85%.
(3), 2- (1- methyl tetrazole -5- base) -5- bromopyridine and 2- (2- methyl tetrazole -5- base) -5- bromopyridine
Preparation
10.5 grams of 2- (tetrazole -5- base) -5- bromopyridine is dissolved in 100 milliliters of dimethylformamides, then by 6.5 grams
Sodium hydroxide is added in solution, and 9.3 grams of iodomethanes are slowly added in solution at 0 DEG C.Solution stirs at room temperature
It mixes 6 hours, water is then added, and be extracted with ethyl acetate.Then organic layer obtained by is washed with brine, is dehydrated, filtering, vacuum is dense
It contracts and is purified by column chromatography, obtain 4 grams of 2- (1- methyl tetrazole -5- base) -5- bromopyridine and 5 grams of 2- (2- methyl tetrazolium -5-
Base) -5- bromopyridine.
(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 tetrahydrofurans,
207g triisopropyl borate ester is added, is cooled to -75 DEG C in liquid nitrogen/ethanol bath, the normal-butyl of 840ml 2.5M is slowly added dropwise
Lithium tetrahydrofuran solution controls temperature at -65 DEG C hereinafter, in -75 ~ -65 DEG C of reaction 2h, HPLC detection reactions, until completely.Drop
Add 20% aqueous ammonium chloride solution of 1.3L, control temperature at 0 DEG C hereinafter, drop finishes, stir 0.5h, stratification, organic layer is with anhydrous
Sodium sulphate is dry, draws and does, and 600ml ethyl acetate is added and is beaten 2h, filters, dry, obtains 149.7g target compound, yield
It is 73%.
Embodiment 4: the preparation of 2 compound of formula
,
In the there-necked flask configured with reflux condensing tube and the 500ml of thermometer, it is added 1.57g Pd (OAc)2, 3.7g
PPh3150 ml DMF are dissolved in, nitrogen is replaced as, 33.75 ml triethylamines are then added, stirring at 70 DEG C is until solution becomes red
77.0g formula 4-a compound and 34.4g formula 3-a compound is added in black, is dissolved in 100ml DMF solution, under nitrogen protection,
90 DEG C are stirred to react 2h, and TLC monitoring reaction is filtered through diatomite while hot.It is concentrated into 50ml at 70 DEG C, 500ml purifying is added
Water stirs 1.0h, filtering, and filter cake is washed with 50% methanol aqueous solution of 50ml (volumetric concentration), 50 DEG C of dry 8h.In obtained solid
Middle 50% methanol aqueous solution (volumetric concentration) of addition 430ml, is heated to 70 DEG C of mashing 2h, is cooled to room temperature, filtering, 30ml first
Alcohol rinse is dried to obtain 2 compound 76.8g of formula, yield 87% in 50 DEG C.
Embodiment 5: the preparation of formula 4-b compound
In the there-necked flask configured with reflux condensing tube and the 500ml of thermometer, addition 14.5g formula 5-a compound,
13.97g (1.1eq.) pinacol diborate, 1.83g(0.05eq.) PdCl2(dppf)2, 110ml DMF, under nitrogen protection,
It is stirred to react at 70 DEG C, HPLC monitoring reaction is filtered through diatomite while hot.It is concentrated into 50ml at 70 DEG C, 400ml purifying is added
Water is extracted with methylene chloride (400ml*2), and anhydrous sodium sulfate dries, filters, and is concentrated to get formula 5-b compound 12.74g, is received
Rate 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).
Formula 5-a compound (10.1g, 30.0mmol) is added into 250ml there-necked flask, four benzyl ester of pyrophosphoric acid (24.2g,
45.0mmol) and THF(150ml), stir dissolved clarification, two silicon substrate azane of hexamethyl is added portionwise to 0 ~ 5 DEG C in ice salt bath cooling temperature
Sodium (11.1g, 60.4mmol) controls about -5 ~ 5 DEG C of temperature in adition process, and TLC monitoring reaction terminates.Reaction solution is poured into full
In sodium bicarbonate solution, 150ml ether, liquid separation is then added, organic phase is in neutrality with purifying water washing to pH, is concentrated under reduced pressure
To doing, product (formula 4-b compound) 16.0g yield 89.3% is obtained.
Embodiment 6: the preparation of 2 compound of formula
In the there-necked flask configured with reflux condensing tube and the 500ml of thermometer, 1.83g Pd is added2(dba)3, 1.12g
PCy3It is dissolved in 400ml DMF, is replaced as nitrogen, stirs 0.5h at room temperature, 60.6g triethylamine is then added, 119.5g formula is added
4-b compound and 57.6g formula 3-b compound under nitrogen protection, are stirred to react at 70 DEG C, HPLC monitoring reaction, while hot through silicon
Diatomaceous earth filtering.It is concentrated into 50ml at 70 DEG C, 500ml purified water is added, is extracted with methylene chloride 400ml*2, anhydrous sodium sulfate is dry
Dry, filtering is concentrated to get solid, and 50% methanol aqueous solution of 500ml (volumetric concentration) is added in obtained solid, is heated to 70
DEG C mashing 2h, is cooled to room temperature, filters, 40ml methanol rinses are dried to obtain 2 compound 112.1g of formula in 50 DEG C, and yield is
88.9%。
Embodiment 7: the preparation of 1 compound of formula
2 compound of formula (315.3g, 0.5mol) and N- methyl-D-glucosamine (195.21,1.0mol) are mixed, and molten
It solves in methanol (2.0L) and water (120ml).By 5%Pd/C (16.0g) pulp in 360ml methanol, then by the catalyst
After room temperature and 40pasi are concentrated again, it is added in above-mentioned 2 compound of formula and N- methyl-D-glucosamine slurries, by the system
Hydrogenated over night.After reaction, it by hydrogenation slurries filtering, and is washed, then filter vacuum is concentrated, room temperature with methanol (2*2L)
Being maintained at and being concentrated into ultimate density not higher than 18 DEG C is 200g/L, is precipitated.
Tri-n-butyl phosphine (TBP) (1.8ml) is added in the solution in methanol to compound of formula I (294g), and 20
It DEG C is stirred overnight and (TBP is added for removing excessive Pd).Then the solution is slowly added to 8.5L acetonitrile and 8.5L at 20 DEG C
In the mixture of ethyl alcohol, add within about 1 hour.Then acetonitrile (17L) is slowly added in the mixture, is added within about 120 minutes.It should
Slurries settle about 30 minutes, are decanted off 70% supernatant, and be transferred in filter, residue slurries are suspended again, and under stress
Filtering, filter cake are washed with acetonitrile (3.5L), collect product, vacuum drying, yield about 94%, 99.3% or more purity.
Above embodiments are only used for illustrating the present invention, when in 2 compound structure of formula benzyl (Bn) by C1-4Alkyl, halogen
When atom, cyano or nitro replace, preparation method and its method for being used to prepare 1 compound of formula, ordinary skill
Personnel can according to the present disclosure, such as method disclosed in the embodiment of the present invention 2 ~ 7 is operated.
Claims (10)
1. the method for preparation such as 1 compound of following formula,
The method includes,
(1) 4 compound of following formula is reacted with 3 compound of following formula, to generate compound 2:
(2) 2 compound of formula is catalyzed to reduction under N- methyl D-grape amine existence condition, directly generates 1 compound of formula,
Wherein, R is H, C1-4Alkyl, halogen atom, cyano or nitro, L are Br or I；R1For BF3Or BR2R3, wherein R2And R3It is independent
Be selected from, the C by OH and arbitrarily replaced1-6The group of unitary and dihydric alcohol composition, wherein R2And R3It together can cyclization；
Wherein, step (2) the catalysis reduction is completed with palladium-carbon catalyst.
2. method according to claim 1, which is characterized in that the method also includes by 5 compound of following formula and phosphonylation examination
Agent (6 compound of formula) is reacted under the action of hindered base, to generate compound 4:
3. method according to claim 1, which is characterized in that the method also includes by 4 ' compound of following formula and following formula 3 '
Compound reaction, to generate compound 2:
Wherein, L is Br or I；R1For BF3Or BR2R3, wherein R2And R3C that is independent to be selected from, by OH and arbitrarily replacing1-6Unitary and
The group of dihydric alcohol composition, wherein R2And R3It together can cyclization；R is H, C1-4Alkyl, halogen atom, cyano or nitro.
4. method according to claim 3, which is characterized in that the method also includes, by 5 ' compound of following formula with it is phosphonylation
Reagent (6 compound of formula) reacts under the action of hindered base, to generate compound 4 ':
5. according to any one of claim 2~4 the method, which is characterized in that R H, L are Br or I, R1For BF3、B(OH)2OrWherein, dotted line " ... " indicates link position.
6. method according to claim 5, which is characterized in that R H, L Br, R1For B (OH)2Or
7. according to claim 2 or 4 the methods, which is characterized in that the hindered base is selected from: two silicon substrate azane sodium of hexamethyl,
It is two silicon substrate azane potassium of hexamethyl, two silicon substrate azane lithium of hexamethyl, tert-butyl potassium, sodium tert-butoxide, tert-pentyl alcohol potassium, amylalcohol potassium, two different
Propylcarbamic lithium, tetramethyl piperidine lithium, s-butyl lithium and tert-butyl lithium.
8. method according to claim 7, which is characterized in that the hindered base is selected from: two silicon substrate azane sodium of hexamethyl, pregnancy
Two silicon substrate azane potassium of base, two silicon substrate azane lithium of hexamethyl, tert-butyl lithium and lithium diisopropylamine.
9. method according to claim 7 further includes contacting 1 compound of formula with trialkyl phosphine.
10. method according to claim 8 further includes contacting 1 compound of formula with trialkyl phosphine.
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| CN1894242A (en) * | 2003-12-18 | 2007-01-10 | 东亚制药株式会社 | Novel oxazolidinone derivatives |
| 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 |
| CN104327119A (en) * | 2014-10-17 | 2015-02-04 | 苏州明锐医药科技有限公司 | Preparation method of tedizolid phosphate |
| 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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| CN1894242A (en) * | 2003-12-18 | 2007-01-10 | 东亚制药株式会社 | Novel oxazolidinone derivatives |
| 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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