CN112457236B

CN112457236B - Preparation method of linezolid intermediate

Info

Publication number: CN112457236B
Application number: CN202011321754.9A
Authority: CN
Inventors: 孙炳峰; 孙炳峻; 孔德剑
Original assignee: Taizhou Synhigher Biology Medicine Co ltd
Current assignee: Taizhou Synhigher Biology Medicine Co ltd
Priority date: 2020-11-23
Filing date: 2020-11-23
Publication date: 2022-06-24
Anticipated expiration: 2040-11-23
Also published as: CN112457236A

Abstract

The invention discloses a preparation method of a linezolid intermediate. 3-fluoro-4- (4-morpholinyl) -aniline and 2- ((S) -3-chloro-2-hydroxypropyl) isoindoline-1, 3-diketone are taken as main raw materials and subjected to substitution reaction in an amide dipolar solvent at the temperature of 90-150 ℃ to obtain the N- (3-phthalimido-2- (S) -hydroxypropyl) -3-fluoro-4- (morpholinyl) aniline which is an important intermediate for synthesizing the antibiotic linezolid. The intermediate has simple preparation steps, and the preparation process does not use butyl lithium, sodium azide, chloromethyl acid ester, methanesulfonyl chloride and other dangerous reagents with flammability, explosiveness, high toxicity and the like in the conventional process, so the safety is higher; the main raw materials of 3-fluoro-4- (4-morpholinyl) -aniline and 2- ((S) -3-chloro-2-hydroxypropyl) isoindoline-1, 3-diketone have stable sources and low cost, and the used amide dipolar solvent is easy to recycle and can reduce the pollution to the environment.

Description

Preparation method of linezolid intermediate

Technical Field

The invention relates to the technical field of drug synthesis, in particular to a preparation method of a linezolid intermediate.

Background

Linezolid is the first novel clinical oxazolidinone antibacterial drug, and shows high antibacterial activity on various gram-positive cocci in vitro and in vivo. Linezolid is a bacterial protein synthesis inhibitor that acts on the bacterial 50S ribosomal subunit to terminate bacterial protein synthesis. The linezolid has unique action site and mode, is not easy to generate cross drug resistance with other antibacterial drugs for inhibiting protein synthesis, and is not easy to induce drug resistance in vitro. Mainly used for treating bacteremia caused by vancomycin-resistant enterococcus (VRE), pneumonia and comprehensive skin infection caused by methicillin-resistant staphylococcus aureus (MRSA), and bacteremia (PRSP) caused by penicillin-resistant streptococcus pneumoniae.

Linezolid (formula 1), which has the chemical name of (S) -N- ((3- (3-fluoro-4-morpholinophenyl) -2-oxoxalidin-5-yl) methyl) acetamide, is a novel oxazolidinone antibacterial drug developed by Pharmacia & Upjohn (P & U) in the mid 1990S, approved for marketing in 2000, and included in the world health organization' S basic drug catalog. The medicine has slight side effect and high safety in short-term use, and can be used for people of all ages and people with liver and kidney insufficiency for oral administration. The patent protection period for linezolid compounds has expired.

Unlike many antibiotics, linezolid is not found in nature, nor is it a derivative of a natural product, the drug is completely a synthetic, active screening product, and its manufacturing process is completely chemical. The synthesis methods of linezolid reported in the literature at present include the following methods:

synthetic routes such as shown in formula 2 are reported in patents WO957271 and J.Med.chem.1996,39,673-. The reaction steps of the route are more; reagents such as butyl lithium, sodium azide, chloromethane and methanesulfonyl chloride which have the dangers of flammability, explosiveness, hypertoxicity and the like are required to be used; palladium carbon is an expensive reagent; chiral glycidol butyrate is not easily available; the cyclization reaction needs low temperature of-78 ℃; the hydrogenation reaction needs high pressure, and the requirement on synthesis equipment is high; these factors are not favorable for industrial production.

Patent WO2007/116284 and the like propose a more efficient synthetic route. As shown in formula 3, in the presence of ammonia water, (S) -epichlorohydrin reacts with 4-chlorobenzaldehyde to generate optically pure (S) -1-chloro-3- [ (4-chloro-E-benzylidene) -amino ] -propionaldehyde-2-ol, then the optically pure (S) -1-chloro-3- [ (4-chloro-E-benzylidene) -amino ] -propionaldehyde-2-ol reacts with corresponding benzyl ester under the action of tert-butyl lithium alkoxide to generate an oxazolidinone compound, imine is hydrolyzed, and amino is acetylated by acetic anhydride to obtain linezolid. The route needs to prepare optically pure (S) -1-chloro-3- [ (4-chloro-E-benzylidene) -amino ] -propanal-2-ol, which is difficult to purify.

Patent CN 101638392a discloses a synthetic route of linezolid. The reaction route is shown as formula 4, 3-fluoro-4-morpholinyl phenyl isocyanate (obtained by reacting corresponding aniline with phosgene) and (R) -epichlorohydrin are cyclized under the action of Lewis acid such as anhydrous magnesium iodide and the like to generate corresponding oxazolidinone alkyl chloride, the oxazolidone alkyl chloride reacts with sodium azide to introduce azide groups, the azide groups are reduced, and the obtained amino is acetylated to obtain linezolid. This route requires the use of phosgene in the preparation of the isocyanates; and the isocyanate is not easy to store due to instability; sodium azide is extremely toxic and explosive; the optical purity of the isocyanate reacted with the epichlorohydrin in the presence of the lewis acid is also problematic.

Germany bayer s.roehrig et al disclose a high efficiency synthesis method of oxazolidinone in document j.med.chem.2005,48, 5900-. The method is shown in formula 5, and is suitable for synthesizing chiral drugs such as linezolid, rivaroxaban and the like. The method has the advantages of convenient operation and high yield, does not use dangerous reagents, and has low preparation yield of the chiral epoxy fragment used in the method.

Disclosure of Invention

The invention aims to provide a preparation method of a linezolid intermediate to solve the problems in the background technology. In order to solve the technical problems, the invention provides the following technical scheme: a preparation method of a linezolid intermediate is characterized in that 3-fluoro-4- (4-morpholinyl) -aniline (II) and 2- ((S) -3-chloro-2-hydroxypropyl) isoindoline-1, 3-diketone ((III)) are used as starting materials, and substitution reaction is carried out to obtain a linezolid intermediate N- (3-phthalimido-2- (S) -hydroxypropyl) -3-fluoro-4- (morpholinyl) aniline (I); the reaction route is as follows,

further, the preparation method of the linezolid intermediate comprises the following steps;

(1) dissolving (II) in an amide dipolar solvent, adding (III) and a reaction promoter, and reacting to obtain a reaction solution;

(2) cooling the reaction liquid obtained in the step (1), adding dichloromethane, separating liquid, washing with water, drying, concentrating to obtain a crude product, and performing column chromatography on the crude product to obtain an intermediate (I);

(1) dissolving the (II) in an amide dipolar solvent, adding the (III) and a reaction promoter, stirring for 15-25 min, heating to 90-150 ℃, and reacting for 19-22 h to obtain a reaction solution;

(2) cooling the reaction liquid obtained in the step (1) to room temperature; adding dichloromethane and water, stirring, separating, adding water into the organic phase, washing for 3 times, drying the organic phase with anhydrous magnesium sulfate, concentrating to obtain crude product, and performing column chromatography to obtain intermediate (I);

further, the amide dipolar solvent is any one of N, N-dimethylformamide, N-dimethylacetamide and N-methylpyrrolidone.

Further, the (II): (III) the molar ratio is 1-5: 1; more preferably, (II): (III) the molar ratio is 1.5-2.5: 1.

Further, the reaction promoter is one or a mixture of bromide and iodide.

Further, the bromide is any one or more of lithium bromide, sodium bromide, potassium bromide and tetrabutylammonium bromide; further, the iodide is any one or more of lithium iodide, sodium iodide, potassium iodide and tetrabutylammonium iodide.

Further, the reaction temperature is 90-150 ℃, and the preferable reaction temperature is 110-130 ℃.

Further, the dosage of the reaction promoter is 0.05-3 equivalents of the total amount of the (II), (III) and the amide dipolar solvent; preferably, the reaction promoter is used in an amount of 0.3 to 0.5 equivalent to the total amount of the (II), (III) and the dipolar amide solvent.

Further, the intermediate I reacts with a carbonylation reagent to prepare linezolid intermediate (R) - [3- (3-fluoro-4-morpholinyl) phenyl-2-oxo-5-oxazolidinyl ] methylphthalimide (IV); the carbonylation reagent is any one of carbonyl diimidazole, dimethyl carbonate, diethyl carbonate and triphosgene;

the reaction route is as follows,

compared with the prior art, the invention has the following beneficial effects: the invention uses 3-fluoro-4- (4-morpholinyl) -aniline and 2- ((S) -3-chloro-2-hydroxypropyl) isoindoline-1, 3-diketone to directly react to obtain an important intermediate N- (3-phthalimido-2- (S) -hydroxypropyl) -3-fluoro-4- (morpholinyl) aniline for synthesizing the antibiotic linezolid; the intermediate N- (3-phthalimide-2- (S) -hydroxypropyl) -3-fluoro-4- (morpholinyl) aniline and a carbonylation reagent are subjected to ring-opening reaction to prepare another important intermediate (R) - [3- (3-fluoro-4-morpholinyl) phenyl-2-oxo-5-oxazolidinyl ] methylphthalimide for synthesizing the antibiotic linezolid. The preparation steps are simple, and the product yield is high; in the preparation process, the use of reagents such as butyl lithium, sodium azide, chloromethyl acid ester, methanesulfonyl chloride and the like with the dangers of flammability, explosiveness, hypertoxicity and the like is avoided, and the safety is high; the solvent used in the preparation process is easy to recycle, so that the pollution to the environment is reduced; the raw materials for reaction, namely 3-fluoro-4- (4-morpholinyl) -aniline and 2- ((S) -3-chloro-2-hydroxypropyl) isoindoline-1, 3-diketone, have stable sources and low price, are favorable for reducing the production cost, and are suitable for industrial production.

Detailed Description

The technical solutions in the embodiments of the present invention are clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments obtained by persons of ordinary skill in the art based on the embodiments of the present invention without any creative efforts shall fall within the protection scope of the present invention.

Example 1

The preparation method of the linezolid intermediate N- (3-phthalimido-2- (S) -hydroxypropyl) -3-fluoro-4- (morpholinyl) aniline (I) comprises the following steps:

preparing raw materials: the dipolar amide solvent is N, N-dimethylacetamide, and the reaction accelerator is sodium bromide;

(II): (III) the molar ratio is 2: 1.

(1) Dissolving 4.0g of (II) in 30ml of N, N-dimethylacetamide solvent in a 250 ml reaction bottle, adding 2.4g of (III) and 1.0g of sodium bromide, stirring for 20min, and reacting for 20h under the condition of raising the temperature to 100 ℃ to obtain a reaction solution;

(2) cooling the reaction liquid obtained in the step (1) to room temperature; adding 50ml of dichloromethane and 50ml of water, stirring and separating, adding 50ml of water into an organic phase, washing for 3 times, drying the organic phase by using anhydrous magnesium sulfate, concentrating to obtain a crude product, and performing column chromatography separation on the crude product to obtain 3.0g of an intermediate (I) with the yield of 75%;

example 2

(II): (III) the molar ratio is 1.77: 1.

(1) Dissolving 3.5g of (II) in 30ml of N, N-dimethylacetamide solvent in a 250 ml reaction bottle, adding 2.4g of (III) and 1.5g of sodium bromide, stirring for 20min, and reacting for 20h under the condition of heating to 100 ℃ to obtain reaction liquid;

(2) cooling the reaction liquid obtained in the step (1) to room temperature; adding 50ml of dichloromethane and 50ml of water, stirring and separating, adding 50ml of water into an organic phase, washing for 3 times, drying the organic phase by using anhydrous magnesium sulfate, concentrating to obtain a crude product, and performing column chromatography separation on the crude product to obtain 3.2g of an intermediate (I) with the yield of 80%;

example 3

preparing raw materials: the dipolar amide solvent is N, N-dimethylacetamide, and the reaction accelerator is tetrabutylammonium bromide;

(II): (III) the molar ratio is 1.83: 1.

(1) Dissolving 3.6g of (II) in 30ml of N, N-dimethylacetamide solvent in a 250 ml reaction bottle, adding 2.4g of (III) and 1.5g of tetrabutylammonium bromide, stirring for 25min, and reacting for 21h under the condition of heating to 120 ℃ to obtain a reaction solution;

(2) cooling the reaction liquid obtained in the step (1) to room temperature; adding 50ml of dichloromethane and 50ml of water, stirring and separating, adding 50ml of water into an organic phase, washing for 3 times, drying the organic phase by using anhydrous magnesium sulfate, concentrating to obtain a crude product, and performing column chromatography separation on the crude product to obtain 2.9g of an intermediate (I) with the yield of 72.5;

example 4

preparing raw materials: the amide dipolar solvent is N-methyl pyrrolidone, and tetrabutylammonium iodide is selected as a reaction promoter;

(II): (III) the molar ratio is 1.73: 1.

(1) Dissolving 3.4g of (II) in 30ml of N-methylpyrrolidone solvent in a 250 ml reaction bottle, adding 2.4g of (III) and 1.8g of tetrabutylammonium iodide, stirring for 18min, heating to 130 ℃, and reacting for 22h to obtain a reaction solution;

(2) cooling the reaction liquid obtained in the step (1) to room temperature; adding 50ml of dichloromethane and 50ml of water, stirring, separating liquid, adding 50ml of water into an organic phase, washing for 3 times, drying the organic phase by using anhydrous magnesium sulfate, concentrating to obtain a crude product, and performing column chromatography separation on the crude product to obtain 3.1g of an intermediate (I) with the yield of 78%;

example 5

preparing raw materials: the amide dipolar solvent is N-methyl pyrrolidone, and the reaction accelerator is potassium iodide;

(II): (III) the molar ratio was 1.73: 1.

(1) Dissolving 3.4g of (II) in 30ml of N-methylpyrrolidone solvent in a 250 ml reaction bottle, adding 2.4g of (III) and 1.4g of potassium iodide, stirring for 20min, heating to 130 ℃, and reacting for 21h to obtain a reaction liquid;

(2) cooling the reaction liquid obtained in the step (1) to room temperature; adding 50ml of dichloromethane and 50ml of water, stirring and separating, adding 50ml of water into the organic phase, washing for 3 times, drying the organic phase by using anhydrous magnesium sulfate, concentrating to obtain a crude product, and performing column chromatography separation on the crude product to obtain 3.0g of an intermediate (I) with the yield of 75%;

example 6

preparing raw materials: the amide dipolar solvent is N, N-dimethylformamide, and sodium iodide is selected as a reaction promoter;

(II): (III) the molar ratio is 2.48: 1.

(1) Dissolving 4.9g of (II) in 30ml of N, N-dimethylformamide solvent in a 250 ml reaction bottle, adding 2.4g of (III) and 1.0g of sodium iodide, stirring for 15min, and reacting for 20h under the condition of raising the temperature to 150 ℃ to obtain a reaction liquid;

example 7

The preparation method of the linezolid intermediate N- (3-phthalimide-2- (S) -hydroxypropyl) -3-fluoro-4- (morpholinyl) aniline (I) comprises the following steps:

(II): (III) the molar ratio was 0.85: 1.

(1) Dissolving 1.7g of (II) in 25ml of N, N-dimethylacetamide solvent in a 250 ml reaction bottle, adding 2.4g of (III) and 1.0g of sodium bromide, stirring for 20min, and reacting for 20h under the condition of heating to 100 ℃ to obtain a reaction solution;

(2) cooling the reaction liquid obtained in the step (1) to room temperature; adding 50ml of dichloromethane and 50ml of water, stirring and separating, adding 50ml of water into an organic phase, washing for 3 times, drying the organic phase by using anhydrous magnesium sulfate, concentrating to obtain a crude product, and performing column chromatography separation on the crude product to obtain 2.5g of an intermediate (I) with the yield of 62.5%;

example 8

(II): (III) the molar ratio was 0.91: 1.

(1) Dissolving 1.8g of (II) in 30ml of N, N-dimethylformamide solvent in a 250 ml reaction bottle, adding 2.4g of (III) and 1.0g of sodium iodide, stirring for 15min, and reacting for 20h under the condition of heating to 97 ℃ to obtain a reaction solution;

(2) cooling the reaction liquid obtained in the step (1) to room temperature; adding 50ml of dichloromethane and 50ml of water, stirring and separating, adding 50ml of water into an organic phase, washing for 3 times, drying the organic phase by using anhydrous magnesium sulfate, concentrating to obtain a crude product, and performing column chromatography separation on the crude product to obtain 2.6g of an intermediate (I) with the yield of 65%;

example 9

(II): (III) the molar ratio was 2.94: 1.

(1) Dissolving 5.8g of (II) in 30ml of N, N-dimethylformamide solvent in a 250 ml reaction bottle, adding 2.4g of (III) and 1.0g of sodium iodide, stirring for 20min, and reacting for 20h under the condition of raising the temperature to 110 ℃ to obtain a reaction liquid;

as described above, in examples 1 to 6 (II): the molar ratio of (III) is 1.5-2.5: 1, and the yield of the prepared intermediate (I) is over 72.5%; examples 7 to 8 (II): the molar ratio of (III) is reduced to 0.85:1 and 0.91:1, and the yield of the intermediate (I) prepared by the method is also reduced to 63 percent and 65 percent; and example 9 (II): (III) at a molar ratio of 2.94:1, which produced an intermediate (I) in 75% yield, the same as in examples 5-6, but using more starting material (II) than in examples 5-6; thus illustrating the invention (II): the molar ratio of (III) is 1.5-2.5: 1, which is the optimal molar ratio, so that the yield can be ensured, and the production cost can be saved.

Finally, it should be noted that: although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that modifications may be made to the embodiments described in the foregoing embodiments, or that equivalents may be substituted for elements thereof. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A preparation method of linezolid intermediate is characterized by comprising the following steps: carrying out substitution reaction on 3-fluoro-4- (4-morpholinyl) -aniline (II) and 2- ((S) -3-chloro-2-hydroxypropyl) isoindoline-1, 3-diketone (III) serving as starting materials to obtain a linezolid intermediate (I); the reaction route is as follows;

the preparation method comprises the following steps;

(2) cooling the reaction liquid obtained in the step (1) to room temperature; adding dichloromethane and water, stirring, separating, adding water into the organic phase, washing for 3 times, drying the organic phase with anhydrous magnesium sulfate, concentrating to obtain a crude product, and performing column chromatography separation on the crude product to obtain an intermediate (I);

the molar ratio of (II) to (III) is 1-5: 1;

the amide dipolar solvent is any one of N, N-dimethylformamide, N-dimethylacetamide and N-methylpyrrolidone;

the reaction promoter is one or a mixture of bromide and iodide;

the bromide is any one or more of lithium bromide, sodium bromide, potassium bromide and tetrabutylammonium bromide;

the iodide is any one or more of lithium iodide, sodium iodide, potassium iodide and tetrabutylammonium iodide;

the dosage of the reaction promoter is 0.05-3 equivalents of the total amount of the (II), (III) and the amide dipolar solvent.

2. A preparation method of linezolid Intermediate (IV) is characterized by comprising the following steps: linezolid intermediate (I) prepared by the process of claim 1, and linezolid Intermediate (IV) prepared by reacting linezolid intermediate (I) with a carbonylation reagent; the carbonylation reagent is any one of carbonyl diimidazole, dimethyl carbonate, diethyl carbonate and triphosgene;

the reaction route is as follows,