CN110156709A - A kind of preparation method of linezolid intermediate - Google Patents
A kind of preparation method of linezolid intermediate Download PDFInfo
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- CN110156709A CN110156709A CN201910454434.1A CN201910454434A CN110156709A CN 110156709 A CN110156709 A CN 110156709A CN 201910454434 A CN201910454434 A CN 201910454434A CN 110156709 A CN110156709 A CN 110156709A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/18—Oxygen atoms
- C07D263/20—Oxygen atoms attached in position 2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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- C07B2200/07—Optical isomers
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Abstract
The present invention provides a kind of methods of synthesis linezolid intermediate (S)-2- oxo-5- oxazolidinyl acetamide of suitable industrialized production, this method is with N- benzyloxycarbonyl group benzene methanamine and (S)-N(2- acetoxy-3-chloropropane) acetamide recrystallized after cyclization reaction hydrogenate again debenzylation method preparation, synthetic route is short, reaction condition is mild, purification process is simple, it can obtain that yield is higher and the product of 99.9% or more optical purity, be suitble to industrialized production and the Linezolid bulk pharmaceutical chemicals of high quality are further prepared.
Description
Technical field
The present invention relates to pharmaceutical synthesis fields, and in particular to a kind of preparation method of the intermediate of antibacterial drug linezolid.
Background technique
Linezolid was ratified, for controlling as artificial synthesized oxazolidinones antibiotic in acquisition U.S. FDA in 2000
Treat Grain-positive (G+) coccigenic infection, including as caused by MRSA it is doubtful or make a definite diagnosis nosocomial pneumonia (HAP), society
Area's acquired pneumonia (CAP), complexity skin or skin soft-tissue infection (SSTI) and vancomycin-resistant enterococcus (VRE) sense
Dye.Entitled (the S)-N- of Linezolid chemistry [[3- (the fluoro- 4- morpholino phenyl of 3-) 2- oxo -5- oxazolidinyl] methyl] acetyl
Amine, structural formula are as follows:
Have that there are many Linezolid synthetic method reported in the literature, and different synthetic methods is related to different intermediates.
Wherein, the synthetic method of Linezolid disclosed in the embodiment 1 of Chinese patent CN102898394A, reaction equation are as follows:
The synthetic method for the midbody compound 1 that the reaction is related to, document (Northwest University's journal, 2008.Vol.38,
No1,71-74) report the synthetic methods of intermediate similar structures a kind of, reaction route are as follows:
In the route, when R is-C6H5When, product is the precursor compound of linezolid intermediate compound 1, according to the work
Skill prepare compound 1 needs to chemically react by 7 steps, and process route is longer, and it is low to will cause total recovery.Moreover, the processing step
1 reaction can generate isomer impurities, and the technique is not removed isomer impurities, and step 4 requires -15 DEG C~-20
DEG C low-temp reaction, step 6 require 150 DEG C~160 DEG C pyroreactions, and condition is excessively harsh, therefore the process route is not suitable for work
Industry metaplasia produces, and there are more large content of isomer impurities in product, influences the quality of the Linezolid bulk pharmaceutical chemicals of subsequent synthesis.
Summary of the invention
Of the existing technology in order to solve the problems, such as, the present invention provides the synthesis benefits that another is suitble to industrialized production
How the method for azoles amine intermediate, this method synthetic route is short, and reaction condition is mild, and purification process is simple, can obtain optical voidness
The linezolid intermediate of 99.9% or more degree and higher yields.
The preparation method of a kind of linezolid intermediate provided by the invention, which is characterized in that according to following reaction route
Synthesis:
It comprises the steps of:
Step 1): compound 2 is that N- benzyloxycarbonyl group benzene methanamine is (S)-N (2- acetyl oxygen with compound 3 under highly basic effect
Base -3- chloropropane) acetamide cyclization, generate compound 4 (S)-N (benzyl -2- oxo -5- oxazolidinyl) acetamide；
Step 2): compound 4 is subjected to recrystallization purifying and removes isomer impurities；
Step 3): benzyl is taken off in the hydrogenated reaction of compound 4 after purification, obtains linezolid intermediate compound 1
(S) -2- oxo -5- oxazolidinyl acetamide.
Preferably, the selection tert-butyl alcohol lithium of highly basic described in step 1) or sodium tert-butoxide, solvent are selected tetrahydrofuran, are prepared into
Tert-butyl alcohol lithium (sodium)-tetrahydrofuran solution；N- benzyloxycarbonyl group benzene methanamine (compound 2), (S)-N (2- acetoxy-3-chlorine third
Alkane) acetamide (compound 3), alkali molar ratio be 1:1.1~1.5:2.5~5, preferably 1:1.1:3；Reaction temperature selection 10
~25 DEG C, the reaction time 15~for 24 hours.
Inventor carries out investigation discovery to the dosage of alkali, and dosage being affected to reaction of alkali is investigated using not
With the dosage of tert-butyl lithium, when solvent uses the tetrahydrofuran of same amount, reaction solution when reaction stops carrying out is monitored with HPLC
The content of the middle unreacted compound 2 of residue is as a result as follows:
| Compound 2: compound 3: tert-butyl lithium (molar ratio) | The content of the complete compound 2 of unreacted in reaction solution |
| 1:1.1:1.1 | 85% |
| 1:1.1:2 | 54% |
| 1:1.1:2.5 | 12% |
| 1:1.1:3 | 10% |
| 1:1.1:4 | 9% |
| 1:1.1:5 | 9% |
When compound 2: compound 3: when tert-butyl lithium molar ratio is 1:1.1:3, reacting basic and carry out sufficiently, then increase uncle
The dosage of butyl lithium is to the extent of reaction substantially without facilitation.
The purpose of step 2) recrystallization is the optical isomer impurity removed in compound 4, and recrystallization solvent is selected from acetic acid
Ethyl ester, ethyl acetate-light petrol, methylene chloride.Since the isomer impurities contained in compound 3 pass through to its recrystallization purifying
It is difficult to remove, will form the optical isomer impurity of corresponding compound 4 after reacting with compound 2, further reaction also can shape
At the isomer impurities of compound 1, it is very big on the influence of the quality of intermediate and Linezolid bulk pharmaceutical chemicals to remove isomer impurities.Hair
It being found in bright people's research process, selection carries out debenzylation prepare compound 1 after carrying out recrystallization purifying to compound 4 again,
Compared to recrystallizing after direct synthesis compound 1 to it, it can obtain that optical purity is higher, and the higher product of yield is tied again
Brilliant effect is significantly superior.
Applicant studies the recrystallization solvent of compound 4, selects methanol, ethyl alcohol, ethyl acetate, acetic acid second
Ester-petroleum ether, methylene chloride respectively recrystallize 5g compound 4 (optical purity 99.75% before recrystallizing), respective
Under suitable solvent usage and 20 DEG C of crystallization temperatures, the optical purity of products obtained therefrom and the result of yield are as follows:
According to result above it is found that once can using ethyl acetate, ethyl acetate-light petrol, recrystallize with dichloromethane
The product that optical purity reaches 99.9% or more is obtained, and methanol and ethyl alcohol recrystallization purification effect are poor.Further to three kinds
Recrystallization solvent system is investigated, and is equally tied again to 5g compound 4 (optical purity 99.75% before recrystallizing) respectively
Crystalline substance investigates the purification effect of different solvents dosage and crystallization temperature, as a result as follows:
According to result above, in three kinds of recrystallization solvents, ethyl acetate purification effect is optimal.Ethyl acetate is as recrystallization
When solvent, compound 4: ethyl acetate mass volume ratio is 1:10 (g/mL), and at 5~15 DEG C of crystallization temperature, purification effect is optimal,
Optical purity of products, which can reach 99.9% or more while recrystallize yield, reaches 90% or more.
Step 3) hydrogenation catalyst is 10% palladium charcoal, and reaction dissolvent is ethyl acetate or methanol；Reaction pressure 0.1~
0.5MPa；30~50 DEG C of reaction temperature；Palladium charcoal dosage is the 0.25%~5% of 4 weight of compound.
The present invention provides a kind of synthesis linezolid intermediate (S) -2- oxo -5- oxazolidines of suitable industrialized production
The method of yl acetamide, this method is with N- benzyloxycarbonyl group benzene methanamine and (S)-N (2- acetoxy-3-chloropropane) acetamide through ring
The method preparation for hydrogenating debenzylation again is recrystallized after closing reaction, synthetic route is short, and reaction condition is mild, and purification process is simple, energy
It obtains that yield is higher and the product of 99.9% or more optical purity, is suitble to industrialized production that high quality is further simultaneously prepared
Linezolid bulk pharmaceutical chemicals.
The present invention will be further described for embodiment With reference to embodiment.
Specific embodiment
The preparation of embodiment 1 (S)-N (benzyl -2- oxo -5- oxazolidinyl) acetamide
60ml tetrahydrofuran is added in 250ml clean dried there-necked flask, is added 24g tert-butyl alcohol lithium (0.3mol), and stirring is equal
It is even, it is added 24.1g N- benzyloxycarbonyl group benzene methanamine (0.1mol), nitrogen is replaced 3 times, is stirred at room temperature 30 minutes.It is cooled to 10 ± 5
DEG C, 6.4g anhydrous methanol (0.2mol) is added dropwise in reaction flask, adds rear insulated and stirred 30 minutes, 22.8g (S)-N is added
(2- acetoxy-3-chloropropane) acetamide, after being warming up to 25 ± 5 DEG C, insulated and stirred 15 hours, HPLC monitors reaction end,
It is added dropwise to after completion of the reaction 12g acetic acid (0.2mol), controls temperature of reaction system≤40 DEG C during being added dropwise.Use methylene chloride
50ml × 3 is extracted, and merges organic phase anhydrous magnesium sulfate drying 20 minutes, filtering, filtrate decompression is concentrated, and residue is added
150ml ethyl acetate is cooled to 5 ± 5 DEG C, stirs 3 hours, and filter cake is smashed in filtering to pieces, is dried in vacuo, obtains off-white powder (S)-N
(benzyl -2- oxo -5- oxazolidinyl) acetamide 20.5g, chemical purity 99%, optical purity 99.74%, yield 82.7%.
The recrystallization purifying of embodiment 2 (S)-N (benzyl -2- oxo -5- oxazolidinyl) acetamide
20.5g (S)-N (benzyl -2- oxo -5- oxazolidinyl) acetamide crude product is added in 250ml bottles, and 205ml second is added
Acetoacetic ester dissolves by heating, and slow cooling to 15 DEG C, stirring and crystallizing 3 hours, smash to pieces by filtering, filter cake, is dried in vacuo, obtains white solid
Body, (S)-N (2- acetoxy-3-chloropropane) acetamide 18.5g, yield 90.2%, optical purity 100.0%.
The preparation of embodiment 3 (S) -2- oxo -5- oxazolidinyl acetamide
(S)-N (2- acetoxy-3-chloropropane) acetamide 18.5g (0.0746mol) is added in high-pressure hydrogenation kettle, is added
10% palladium charcoal 0.925g is added in 200ml ethyl acetate, after successively being replaced 3 times with nitrogen, hydrogen, starts to add hydrogen, pressure
0.3MPa, for the control of hydrogenation system temperature at 50 DEG C hereinafter, HPLC monitoring reaction end filters after reaction, filtrate decompression is dense
It is reduced to dry, obtains white solid 11.45g, yield 97.2%, chemical purity 99.9%, optical purity 100%.Total recovery is
72.5%.
The preparation (only intermediate final product is recrystallized) of comparative example (S) -2- oxo -5- oxazolidinyl acetamide
By intermediate (the S)-N being prepared by 1 method of embodiment (benzyl -2- oxo -5- oxazolidinyl) acetamide
20.6g (0.0830mol) is added in high-pressure hydrogenation kettle, and 223ml ethyl acetate is added, and 10% palladium charcoal 1.03g is added, successively uses nitrogen
After gas, hydrogen are replaced 3 times, start plus hydrogen debenzylation, pressure 0.3MPa, temperature of reaction system control at 50 DEG C hereinafter,
HPLC monitors reaction end, and after reaction, filtering, filtrate decompression is concentrated to dryness, and obtains off-white powder 12.8g, yield
97.5%, chemical purity 99.9%, optical purity 99.74%.
12.8g (S) -2- oxo -5- oxazolidinyl acetamide crude product is added in 250ml there-necked flask, and 64ml ethyl alcohol is added, adds
Heat, which is back to, to be completely dissolved, and for slow cooling to 15 DEG C, insulated and stirred crystallization 3h, 15 DEG C of ethanol washing filter cakes are pre-chilled in filtering, 13ml,
It smashs filter cake to pieces, is dried in vacuo 5h or more, obtains off-white color to white solid 11.9g, yield 93.0%, optical purity 99.88%.It will
The above recrystallization operation of obtained solid repetition is primary, obtains 11.1g product, optical purity 99.95%, yield 86.7%.It is total to receive
Rate 65%.
From the above results, it can be seen that, effect only is not recrystallized to the intermediate final product after debenzylation to cyclised products recrystallization
Not as good as the present invention to the technical solution of debenzylation again after cyclised products recrystallization, need that intermediate final product repeatedly tie again
Crystalline substance can be only achieved 99.9% or more optical purity, and yield is caused to reduce.
Claims (8)
1. a kind of preparation method of linezolid intermediate, which is characterized in that synthesized according to following reaction route:
It comprises the steps of:
Step 1): compound 2 is that N- benzyloxycarbonyl group benzene methanamine is (S)-N (2- acetoxyl group-with compound 3 under highly basic effect
3- chloropropane) acetamide cyclization, generate compound 4 (S)-N (benzyl -2- oxo -5- oxazolidinyl) acetamide；
Step 2): compound 4 is subjected to recrystallization purifying and removes isomer impurities；
Step 3): benzyl is taken off in the hydrogenated reaction of compound 4 after purification, obtains linezolid intermediate compound 1 (S) -2-
Oxo -5- oxazolidinyl acetamide.
2. preparation method according to claim 1, it is characterised in that highly basic described in step 1) selects tert-butyl alcohol lithium or uncle
Sodium butoxide, reaction dissolvent select tetrahydrofuran.
3. preparation method according to claim 1, it is characterised in that step 1) N- benzyloxycarbonyl group benzene methanamine, (S)-N (2- second
Acyloxy -3- chloropropane) acetamide, alkali molar ratio be 1:1.1~1.5:2.5~5.
4. preparation method according to claim 1, it is characterised in that step 1) N- benzyloxycarbonyl group benzene methanamine, (S)-N (2- second
Acyloxy -3- chloropropane) acetamide, alkali molar ratio be 1:1.1:3.
5. preparation method according to claim 1, it is characterised in that step 1) reaction temperature is 10~25 DEG C, the reaction time
15~for 24 hours.
6. preparation method according to claim 1, it is characterised in that the solvent that the step 2) recrystallization uses is selected from second
Acetoacetic ester, ethyl acetate-light petrol, methylene chloride.
7. preparation method according to claim 1, it is characterised in that the step 2) solvent used that recrystallizes is acetic acid
Ethyl ester, crystallization temperature are 5~15 DEG C, and the mass volume ratio of compound 4 and ethyl acetate is 1:10.
8. preparation method according to claim 1, it is characterised in that step 3) hydrogenation catalyst is 10% palladium charcoal, instead
Answering solvent is ethyl acetate；0.1~0.5MPa of reaction pressure；30~50 DEG C of reaction temperature；Palladium charcoal dosage is 4 weight of compound
0.25%~5%.
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1008590A1 (en) * | 1998-12-07 | 2000-06-14 | Takasago International Corporation | Process for preparing optically active oxazolidinone derivative |
| CN101774978A (en) * | 2009-01-13 | 2010-07-14 | 联化科技股份有限公司 | Preparation method of linezolid and intermediate thereof |
| CN102558085A (en) * | 2011-12-28 | 2012-07-11 | 湖南方盛制药股份有限公司 | Method for preparing inezolid |
| CN102731336A (en) * | 2011-04-12 | 2012-10-17 | 浙江医药股份有限公司新昌制药厂 | Linezolid intermediate and synthetic method of linezolid |
| CN102898394A (en) * | 2012-11-09 | 2013-01-30 | 重庆医科大学 | Method for preparing linezolid |
| CN106749074A (en) * | 2016-11-14 | 2017-05-31 | 沈阳药科大学 | A kind of preparation method of Fang oxazolidinones intermediate |
| US20170217911A1 (en) * | 2015-12-18 | 2017-08-03 | Mankind Research Centre | Process For Preparation Of Linezolid |
-
2019
- 2019-05-29 CN CN201910454434.1A patent/CN110156709A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1008590A1 (en) * | 1998-12-07 | 2000-06-14 | Takasago International Corporation | Process for preparing optically active oxazolidinone derivative |
| CN101774978A (en) * | 2009-01-13 | 2010-07-14 | 联化科技股份有限公司 | Preparation method of linezolid and intermediate thereof |
| CN102731336A (en) * | 2011-04-12 | 2012-10-17 | 浙江医药股份有限公司新昌制药厂 | Linezolid intermediate and synthetic method of linezolid |
| CN102558085A (en) * | 2011-12-28 | 2012-07-11 | 湖南方盛制药股份有限公司 | Method for preparing inezolid |
| CN102898394A (en) * | 2012-11-09 | 2013-01-30 | 重庆医科大学 | Method for preparing linezolid |
| US20170217911A1 (en) * | 2015-12-18 | 2017-08-03 | Mankind Research Centre | Process For Preparation Of Linezolid |
| CN106749074A (en) * | 2016-11-14 | 2017-05-31 | 沈阳药科大学 | A kind of preparation method of Fang oxazolidinones intermediate |
Non-Patent Citations (3)
| Title |
|---|
| MING CHEN等: "Direct Palladium-Catalyzed b-Arylation of Lactams", 《ANGEW. CHEM. INT. ED.》 * |
| 吴煜然等: "利奈唑胺合成新进展", 《淮海工学院学报（自然科学版）》 * |
| 赵宇欣等: "合成利奈唑胺的工艺改进", 《合成化学》 * |
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Application publication date: 20190823 |