CN113045509B - Industrial production method of linezolid - Google Patents
Industrial production method of linezolid Download PDFInfo
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- CN113045509B CN113045509B CN202110605924.4A CN202110605924A CN113045509B CN 113045509 B CN113045509 B CN 113045509B CN 202110605924 A CN202110605924 A CN 202110605924A CN 113045509 B CN113045509 B CN 113045509B
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- 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
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- C07D263/20—Oxygen atoms attached in position 2
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Abstract
The invention belongs to the field of pharmaceutical chemistry, and relates to an industrial production method of linezolid. Taking a compound I and a compound II as initial raw materials, and carrying out cyclization and acylation reactions to generate linezolid. The preparation method of linezolid has simple steps, mild reaction conditions, short reaction time, cheap and easily obtained raw materials, safe and economic used reagents, low requirement on equipment, high purity of final products, suitability for industrial production,
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly provides an industrial production method of linezolid.
Background
Linezolid (Linezolid), chemical name: (S) -N- { [3- (3-fluoro-4-morpholinylphenyl) -2-oxo-5-oxazolidinyl ] methyl } acetamide, trade name: swo (Zyvox). Linezolid has the following structural formula:
（Ⅰ）
linezolid, an oxazolidinone antibacterial drug developed by pharmacia & Upjohn, USA (Pfizer), was first marketed in the United states in 4 months of 2000, has a good therapeutic effect on bacteremia caused by vancomycin-resistant enterococcus (VRE) or penicillin-resistant Streptococcus pneumoniae (PRSP), and can be used for treating pneumonia and comprehensive skin infection caused by methicillin-resistant Staphylococcus aureus (MRSA). At present, the medicine is on the market in China and is divided into two dosage forms of injection and tablet.
The document (journal of Chinese medicinal chemistry, 2005,15, 89-93) discloses that 3-fluoro-phenyl isocyanate is used as an initial raw material, and is cyclized with (R) -epichlorohydrin to obtain a chloro-oxazolidinone intermediate, and then subjected to azidation, catalytic hydrogenation and acetylation to obtain a bromobenzene intermediate, and finally subjected to Ullmann reaction with morpholine to obtain linezolid, wherein the preparation route is as follows:
patent US5688792 discloses the synthesis of linezolid from benzyl (3-fluoro-4-morpholinophenyl) carbamate as starting material, which is condensed with benzyl chloroformate, reacted with (R) -glycidylbutyrate, followed by mesylation, azidation, catalytic hydrogenation, and acetylation in sequence, as follows:
the method for synthesizing linezolid has the disadvantages of harsh reaction conditions, complex and tedious operation, more generated impurities and expensive raw materials.
Disclosure of Invention
In order to solve the technical problems in the prior art, the invention provides an industrial production method of linezolid, which has the advantages of mild reaction conditions in each step, simple operation of the synthesis method, high yield and high purity, and is suitable for industrial production.
The technical scheme of the invention is as follows:
an industrial production method of linezolid, comprising the following steps:
(1) dissolving a compound shown in a formula I in an organic solvent, adding an inorganic base and a compound shown in a formula II to react to generate a compound shown in a formula III, wherein the reaction is carried out;
(2) the compound of formula III is acylated with acetamide under the action of inorganic base and catalyst to generate linezolid, which comprises the following steps:
wherein the inorganic base in the steps (1) and (2) is independently selected from sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and cesium carbonate; the catalyst in the step (2) is cuprous iodide.
Preferably, in the industrial production method, the molar ratio of the compound of formula I, the compound of formula II and the inorganic base added in the step (1) is 1: 1-2, and more preferably 1: 1.2-1.5.
Preferably, in the industrial production method, the organic solvent added in step (1) is one or more of toluene, N-dimethylformamide and acetone.
Preferably, in the industrial production method, the reaction temperature in the step (1) is 45-70 ℃, and further preferably 50-60 ℃.
Preferably, in the industrial production method, the molar ratio of the compound of formula III in the step (2) to acetamide is 1: 1-3, and more preferably 1: 1.2-1.5.
Preferably, in the industrial production method, the molar ratio of the compound of formula III in the step (2) to the inorganic base is 1: 2-5, and more preferably 1: 3-4.
Preferably, in the industrial production method, the molar ratio of the compound of formula III in the step (2) to the catalyst is 1: 0.2-1.0, and more preferably 1: 0.5-0.8.
Preferably, the organic solvent added for the acylation reaction in step (2) is toluene.
Further, the industrial production method comprises the steps of extracting and recrystallizing the linezolid obtained in the step (2).
Preferably, the recrystallization solvent is selected from one or two of ethyl acetate, toluene, n-heptane, n-hexane, methylcyclohexane, cyclohexane, more preferably ethyl acetate/n-heptane or toluene/n-heptane.
Preferably, the extraction solvent is selected from ethyl acetate, dichloromethane, chloroform, acetone, more preferably ethyl acetate.
The industrial production method of linezolid has the advantages of simple reaction steps, mild reaction conditions, short reaction time, cheap and easily-obtained raw materials, safe and economic used reagents, low requirements on equipment, high purity of final products and suitability for industrial production.
Detailed Description
For better understanding of the present invention, the following description is given with reference to specific examples, but the present invention is not limited to the specific embodiments.
Example 1: preparation of (R) - [3- (3-fluoro-4-morpholinyl) phenyl-2-oxo-5-oxazolidinyl ] methyl chloride (Compound III)
Adding 10.00g of compound I (N-benzyloxycarbonyl-3-fluoro-4-morpholinylaniline) into a 250ml reaction bottle, then adding 100ml of acetone solvent and 5.02g of potassium carbonate, reacting at 55 ℃, continuously stirring for 1 hour, then adding 3.36g of compound II ((R) -epichlorohydrin) into the reaction bottle, and reacting overnight; and (2) carrying out suction filtration, concentrating the filtrate to dryness, adding 150ml of isopropanol solvent, pulping for 2 hours, filtering, and drying a filter cake in vacuum at 40 ℃ to obtain 8.52g of (R) - [3- (3-fluoro-4-morpholinyl) phenyl-2-oxo-5-oxazolidinyl ] methyl chloride with the mass yield of 85.2%.
Example 2: preparation of (R) - [3- (3-fluoro-4-morpholinyl) phenyl-2-oxo-5-oxazolidinyl ] methyl chloride (Compound III)
Adding 10.00g of compound I (N-benzyloxycarbonyl-3-fluoro-4-morpholinylaniline) into a 250ml reaction bottle, then adding 100ml of acetone solvent and 6.27g of potassium carbonate, reacting at 55 ℃, continuously stirring for 1 hour, then adding 3.36g of compound II ((R) -epichlorohydrin) into the reaction bottle, and reacting overnight; and (2) carrying out suction filtration, concentrating the filtrate to dryness, adding 150ml of isopropanol solvent, pulping for 2 hours, filtering, and drying a filter cake in vacuum at 40 ℃ to obtain 8.30g of (R) - [3- (3-fluoro-4-morpholinyl) phenyl-2-oxo-5-oxazolidinyl ] methyl chloride with the mass yield of 83.0%.
Example 3: preparation of (R) - [3- (3-fluoro-4-morpholinyl) phenyl-2-oxo-5-oxazolidinyl ] methyl chloride (Compound III)
Adding 10.00g of compound I (N-benzyloxycarbonyl-3-fluoro-4-morpholinylaniline) into a 250ml reaction bottle, then adding 100ml of acetone solvent and 5.02g of potassium carbonate, reacting at 60 ℃, continuously stirring for 1 hour, then adding 3.36g of compound II ((R) -epichlorohydrin) into the reaction bottle, and reacting overnight; and (2) carrying out suction filtration, concentrating the filtrate to dryness, adding 150ml of isopropanol solvent, pulping for 2 hours, filtering, and drying a filter cake in vacuum at 40 ℃ to obtain 8.15g of (R) - [3- (3-fluoro-4-morpholinyl) phenyl-2-oxo-5-oxazolidinyl ] methyl chloride with the mass yield of 81.5%.
Example 4: preparation of (R) - [3- (3-fluoro-4-morpholinyl) phenyl-2-oxo-5-oxazolidinyl ] methyl chloride (Compound III)
Adding 10.00g of compound I (N-benzyloxycarbonyl-3-fluoro-4-morpholinylaniline) into a 250ml reaction bottle, then adding 100ml of dimethylformamide solvent and 5.02g of potassium carbonate, reacting at 55 ℃, continuously stirring for 1 hour, then adding 3.36g of compound II ((R) -epichlorohydrin) into the reaction bottle, and reacting overnight; and (2) carrying out suction filtration, concentrating the filtrate to dryness, adding 150ml of isopropanol solvent, pulping for 2 hours, filtering, and drying a filter cake in vacuum at 40 ℃ to obtain 8.08g of (R) - [3- (3-fluoro-4-morpholinyl) phenyl-2-oxo-5-oxazolidinyl ] methyl chloride with the mass yield of 80.8%.
Example 5: preparation of (R) - [3- (3-fluoro-4-morpholinyl) phenyl-2-oxo-5-oxazolidinyl ] methyl chloride (Compound III)
Adding 10.00g of compound I (N-benzyloxycarbonyl-3-fluoro-4-morpholinylaniline) into a 250ml reaction bottle, then adding 100ml of acetone solvent and 12.01g of cesium carbonate, reacting at 55 ℃, continuously stirring for 1 hour, then adding 3.36g of compound II ((R) -epichlorohydrin) into the reaction bottle, and reacting overnight; and (2) carrying out suction filtration, concentrating the filtrate to dryness, adding 150ml of isopropanol solvent, pulping for 2 hours, filtering, and drying a filter cake in vacuum at 40 ℃ to obtain 7.05g of (R) - [3- (3-fluoro-4-morpholinyl) phenyl-2-oxo-5-oxazolidinyl ] methyl chloride with the mass yield of 70.5%.
Example 6: preparation of linezolid
Adding 8.20g of compound III, 1.85g of acetamide, 10.80g of potassium carbonate, 2.48g of cuprous iodide and 40ml of toluene solvent into a 250ml reaction bottle, and heating and refluxing for reaction for 5 hours; and cooling the reaction liquid to room temperature, carrying out suction filtration, adding 50ml of ethyl acetate solvent and 50ml of purified water into the filtrate for extraction, standing, separating liquid, drying, filtering and concentrating the separated organic phase to dryness, adding 20ml of ethyl acetate, adding 60ml of n-heptane, stirring, crystallizing, drying the filter cake at the temperature of 45 ℃ in vacuum for 4 hours, and obtaining 7.38g of finished linezolid, wherein the mass yield is 90%, and the HPLC purity is 99.7%.
Example 7: preparation of linezolid
Adding 8.20g of compound III, 1.85g of acetamide, 10.80g of potassium carbonate, 3.97g of cuprous iodide and 40ml of toluene solvent into a 250ml reaction bottle, and heating and refluxing for 5 hours; cooling the reaction liquid to room temperature, carrying out suction filtration, adding 50ml of ethyl acetate solvent and 50ml of purified water into the filtrate for extraction, standing, separating liquid, drying, filtering and concentrating the separated organic phase to dryness, adding 20ml of ethyl acetate, adding 60ml of n-heptane, stirring and crystallizing; the filter cake is dried for 4h under vacuum at 45 ℃ to obtain 7.22g of finished linezolid with the mass yield of 88% and the HPLC purity of 99.8%.
Example 8: preparation of linezolid
Adding 8.20g of compound III, 1.85g of acetamide, 14.40g of potassium carbonate and 2.48g of cuprous iodide into a 250ml reaction bottle, adding 40ml of toluene solvent, and heating and refluxing for reaction for 5 hours; cooling the reaction liquid to room temperature, carrying out suction filtration, adding 50ml of ethyl acetate solvent and 50ml of purified water into the filtrate for extraction, standing, separating liquid, drying, filtering and concentrating the separated organic phase to dryness, adding 20ml of toluene, adding 60ml of n-heptane, stirring and crystallizing; the filter cake is dried for 4h under vacuum at 45 ℃ to obtain 7.13g of finished linezolid with the mass yield of 87% and the HPLC purity of 99.6%.
Example 9: preparation of linezolid
Adding 8.20g of compound III, 1.85g of acetamide, 10.80g of potassium carbonate, 2.48g of cuprous iodide and 40ml of toluene solvent into a 250ml reaction bottle, and heating and refluxing for reaction for 5 hours; and cooling the reaction liquid to room temperature, carrying out suction filtration, adding 50ml of ethyl acetate solvent and 50ml of purified water into the filtrate for extraction, standing, separating liquid, drying, filtering and concentrating the separated organic phase to dryness, adding 20ml of toluene, adding 60ml of n-heptane, stirring, crystallizing, drying the filter cake at the temperature of 45 ℃ in vacuum for 4 hours to obtain 7.79g of finished linezolid, wherein the mass yield is 95%, and the HPLC purity is 99.8%.
Claims (9)
1. An industrial production method of linezolid is characterized by comprising the following steps:
(1) dissolving a compound shown in a formula I in an organic solvent, adding an inorganic base and a compound shown in a formula II to react to generate a compound shown in a formula III, wherein the reaction is as follows:
(2) the compound of formula III is acylated with acetamide under the action of inorganic base and catalyst to generate linezolid, which comprises the following steps:
the inorganic base in the steps (1) and (2) is independently selected from potassium carbonate and cesium carbonate, and the molar ratio of the compound of the formula I, the compound of the formula II and the inorganic base added in the step (1) is 1: 1-2; the catalyst in the step (2) is cuprous iodide.
2. The industrial production method of linezolid according to claim 1, wherein the organic solvent added in step (1) is one or more of toluene, N-dimethylformamide and acetone.
3. The industrial production method of linezolid according to claim 1, wherein the reaction temperature in step (1) is 45 ℃ to 70 ℃.
4. The industrial production method of linezolid according to claim 3, wherein the reaction temperature in step (1) is 50 ℃ to 60 ℃.
5. The industrial production method of linezolid according to claim 1, wherein the molar ratio of the compound of formula iii to the catalyst in step (2) is 1:0.2 to 1.0.
6. The industrial production method of linezolid according to claim 5, wherein the molar ratio of the compound of formula III to the catalyst in step (2) is 1:0.5 to 0.8.
7. The industrial production method of linezolid according to claim 1, wherein the molar ratio of the compound of formula iii to acetamide in step (2) is 1:1 to 3.
8. The industrial production method of linezolid according to claim 1, wherein the molar ratio of the compound of formula iii to the inorganic base in step (2) is 1:2 to 5.
9. The industrial production method of linezolid according to claim 1, further comprising recrystallizing linezolid obtained in step (2) in a solvent selected from ethyl acetate/n-heptane or toluene/n-heptane.
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