阅读说明：本技术 一种噁唑烷酮类化合物的制备方法 (Preparation method of oxazolidinone compound ) 是由 关振睿 邹远林 秦亚东 华阳 黄友元 史丹丹 刘郝敏 吴晓东 于 2021-09-06 设计创作，主要内容包括：本发明属于医药中间体技术领域,具体涉及一种噁唑烷酮类化合物的制备方法,1)酯化：将芳香族氨基酸溶于甲醇中,低温下投入氯化亚砜,升温到50-60℃保温1-2h,2)还原：以乙醇水为溶剂,硼氢化钠完全溶解后加入催化量的锂盐,再将酯化产品完全溶解于乙醇水溶液中,低温下缓慢滴加至硼氢化钠溶液中；3)关环：以甲苯为溶剂,投入还原产物及碳酸二乙脂升温至100℃,滴加甲醇钠溶液,滴加完毕后常压蒸馏至温度再升回100℃保温两小时经后处理及提纯后得到产品；本发明中引入锂盐参与反应,选择乙醇水为溶剂即可使硼氢化钠完全溶解,也可以将锂盐从化合物中游离出来以提高反应活性,使得硼氢化钠的使用量降低至2当量,显著降低了生产成本。(The invention belongs to the technical field of medical intermediates, and particularly relates to a preparation method of oxazolidinone compounds, which comprises the following steps of 1) esterification: dissolving aromatic amino acid in methanol, adding thionyl chloride at low temperature, heating to 50-60 ℃, preserving heat for 1-2h, and 2) reducing: using ethanol water as a solvent, adding a catalytic amount of lithium salt after sodium borohydride is completely dissolved, completely dissolving an esterified product in the ethanol water solution, and slowly dropwise adding the esterified product into the sodium borohydride solution at low temperature; 3) closing the ring: using toluene as a solvent, adding a reduction product and diethyl carbonate, heating to 100 ℃, dropwise adding a sodium methoxide solution, distilling at normal pressure after dropwise adding until the temperature rises to 100 ℃, heating again to 100 ℃, preserving the temperature for two hours, and performing post-treatment and purification to obtain a product; in the invention, lithium salt is introduced to participate in the reaction, and the lithium borohydride can be completely dissolved by selecting ethanol water as a solvent, and the lithium salt can be dissociated from the compound to improve the reaction activity, so that the using amount of the sodium borohydride is reduced to 2 equivalents, and the production cost is obviously reduced.)

1. A preparation method of oxazolidinone compounds is characterized by comprising the following steps: the preparation method comprises the following steps:

1) esterification: dissolving aromatic amino acid in methanol, adding thionyl chloride at low temperature, heating to 50-60 deg.C, keeping the temperature for 1-2h,

2) reduction: using ethanol water as a solvent, adding a catalytic amount of lithium salt after sodium borohydride is completely dissolved, completely dissolving an esterified product in the ethanol water solution, and slowly dropwise adding the esterified product into the sodium borohydride solution at low temperature;

3) closing the ring: and (2) taking toluene as a solvent, adding the reduction product and diethyl carbonate, heating to 100 ℃, dropwise adding a sodium methoxide solution, distilling under normal pressure after dropwise adding, heating to 100 ℃, keeping the temperature for two hours, and performing post-treatment and purification to obtain the product.

2. A method of preparing an oxazolidinone compound as claimed in claim 1, characterised in that: the structural formula of the aromatic amino acid is shown in the specification

Wherein R is Ph, Bn.

3. A method of preparing an oxazolidinone compound as claimed in claim 1, characterised in that: the molar ratio of the aromatic amino acid to the thionyl chloride in the step 1) is 1: 1 to 1.2.

4. A method of preparing an oxazolidinone compound as claimed in claim 1, characterised in that: the mass ratio of the aromatic amino acid to the methanol in the step 1) is 1: 3-7.

5. A method of preparing an oxazolidinone compound as claimed in claim 1, characterised in that: the molar ratio of the esterified product to the sodium borohydride in the step 2) is 1: 1 to 10.

6. A method of preparing oxazolidinones as claimed in claim 5, characterised in that: the molar ratio of the esterified product to the sodium borohydride in the step 2) is 1: 2.

7. a method of preparing an oxazolidinone compound as claimed in claim 1, characterised in that: the mass fraction of the ethanol aqueous solution in the step 2) is 30-70%.

8. A method of preparing an oxazolidinone compound as claimed in claim 1, characterised in that: the lithium salt catalyst in the step 2) is one of lithium chloride, lithium bromide and lithium carbonate, and the molar ratio of the lithium salt catalyst to the esterified product is 1: (0.01-0.1).

9. The novel process for preparing oxazolidinone compounds according to patent claim 1, characterized in that: the low temperature in the step 1) and the step 2) is 0-15 ℃.

10. A novel process for the preparation of oxazolidinones according to patent claim 1, characterized in that: the dosage of the toluene in the step 3) is 3-7 times of the mass of the reduction product.

Technical Field

The invention belongs to the technical field of medical intermediates, and particularly relates to a preparation method of oxazolidinone compounds.

Background

The oxazolidinone compound has wide application in medicine, organic synthesis and actual production, and is a five-membered ring compound with high application value. Firstly, the oxazolidine compounds also have extremely high application value in inhibiting bacterial protein synthesis. Secondly, 2-oxazolidinone and its derivatives are commonly used chiral aids, with 4-substituted-2-oxazolidinone as a representative having very high induction selectivity. Evans developed it first as a widely used chiral adjuvant, namely Evans reagent. Evans reagent has been effectively applied in many asymmetric reactions, Diels-Alder reaction and Michelal reaction, asymmetric aldol condensation reaction, hydroxylation reaction, etc. Therefore, the oxazolidinone compound has extremely high market value no matter what kind of oxazolidinone compound is used. The low-cost synthesis method is more important.

Early methods for preparing oxazolidinone mostly used aminoalcohol as a raw material, and used phosgene or phosgene analogues for cyclization, which have the defects of high toxicity, complex experimental operation, use of a large amount of solvents, resource waste, environmental pollution and the like. There are also many documents that propose processes similar to this patent, but the cost of aminoalcohol as an important starting material is high, and many documents are either high for the production process or production cost of aromatic aminoalcohol or not suitable for large-scale industrial production;

preparation of oxazolidinones by direct reduction of amino acids to amino alcohols with boranes and cyclization, e.g., by Shengwei Wei, Regina Messer

Hydrogen can be generated in the reaction process in a borane reduction mode, the process temperature changes violently and is dangerous in the actual production process, and the borane is low in concentration in a THF solution, so that the material cost and the production cost are high, and the industrialized production is not suitable.

MaKennon et al found NaBH₄-I₂The system is also capable of direct reduction of amino acids. The alpha-amino acid is reduced into corresponding alpha-amino alcohol, and the yield is 45-94%;

when the reaction is carried out in this system, the reaction is difficult because the product has high water solubility, resulting in a low yield. Such as asparaginic acid and glutamic acid.

Wang X, Li X, Xue J et al explored a method, chemical reaction formula, for reducing esters to alcohols using LiAlH 4. He found that the LiAlH4/BnCl reduction system has a good reduction effect, and the yield can reach 81% -94% when the system is used for reducing a series of esters at room temperature. And the highest yield was obtained when LiAlH4 was 1.5 equivalents (ester: LiAlH 4: BnCl ═ 1: 1.5).

Although the reaction yield is high, lithium aluminum hydrogen is expensive and needs other Lewis acid to be matched, so that the material cost ratio in the actual production process is high. Therefore, the patent provides a new process for preparing oxazolidone compounds.

Disclosure of Invention

The invention aims to: overcomes the defects in the prior art, and provides a preparation method of oxazolidinone compounds, which has mild reaction and low cost and is suitable for industrial production.

In order to achieve the purpose, the invention provides the following technical scheme:

a preparation method of oxazolidinone compounds comprises the following steps:

1) esterification: dissolving aromatic amino acid in methanol, adding thionyl chloride at low temperature, heating to 50-60 deg.C, keeping the temperature for 1-2h,

2) reduction: using ethanol water as a solvent, adding a catalytic amount of lithium salt after sodium borohydride is completely dissolved, completely dissolving an esterified product in the ethanol water solution, and slowly dropwise adding the esterified product into the sodium borohydride solution at low temperature;

3) closing the ring: and (2) taking toluene as a solvent, adding the reduction product and diethyl carbonate, heating to 100 ℃, dropwise adding a sodium methoxide solution, distilling under normal pressure after dropwise adding, heating to 100 ℃, keeping the temperature for two hours, and performing post-treatment and purification to obtain the product.

Further, the structural formula of the aromatic amino acid is shown as

Wherein R is Ph, Bn.

Further, the molar ratio of the aromatic amino acid to the thionyl chloride in the step 1) is 1: 1 to 1.2.

Further, the mass ratio of the aromatic amino acid to the methanol in the step 1) is 1: 3-7.

Further, the molar ratio of the esterification product to the sodium borohydride in the step 2) is 1: 1 to 10.

Further, the molar ratio of the esterification product to the sodium borohydride in the step 2) is 1: 2.

further, the mass fraction of the ethanol aqueous solution in the step 2) is 30-70%.

Further, the lithium salt catalyst in the step 2) is one of lithium chloride, lithium bromide and lithium carbonate, and the molar ratio of the lithium salt catalyst to the esterification product is 1: (0.01-0.1).

Further, the low temperature in the step 1) and the step 2) is 0-15 ℃.

Further, the amount of the toluene used in the step 3) is 3-7 times of the mass of the reduction product.

The technical scheme adopted by the invention has the beneficial effects that:

the inventor finds that lithium salt can effectively reduce the influence caused by steric hindrance in the reduction process of sodium borohydride in the research and development process, so the lithium salt is introduced to participate in the reaction, but when the lithium salt can not be dissociated in a system to form free ions, the optimization effect of the lithium salt on the reaction can not be obviously reflected, so that the sodium borohydride can be completely dissolved by selecting ethanol water as a solvent, and the lithium salt can be dissociated from a compound to improve the reaction activity. So that the amount of sodium borohydride used is reduced to 2 equivalents. Compared with other systems of sodium borohydride, the common dosage of the sodium borohydride is 3-10 equivalents and even higher, so that the production cost can be obviously reduced.

Taking (S) -4-phenyl-2-oxazolidinone as an example, the annual market demand of only India is about 50T, and when only 3 equivalents of sodium borohydride is reduced to 2 equivalents, the annual production cost can be reduced by about 1000W yuan. Therefore, the method has obvious advantage in reducing the production cost.

Detailed Description

The following will clearly and completely describe the technical solutions in the embodiments of the present invention, 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, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

The experimental procedures used in the following examples are all conventional procedures unless otherwise specified.

Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.

A preparation method of oxazolidinone compounds comprises the following steps:

1) esterification: dissolving aromatic amino acid in methanol, adding thionyl chloride at low temperature, heating to 50-60 deg.C, keeping the temperature for 1-2h,

2) reduction: using ethanol water as a solvent, adding a catalytic amount of lithium salt after sodium borohydride is completely dissolved, completely dissolving an esterified product in the ethanol water solution, and slowly dropwise adding the esterified product into the sodium borohydride solution at low temperature;

3) closing the ring: and (2) taking toluene as a solvent, adding the reduction product and diethyl carbonate, heating to 100 ℃, dropwise adding a sodium methoxide solution, distilling under normal pressure after dropwise adding, heating to 100 ℃, keeping the temperature for two hours, and performing post-treatment and purification to obtain the product.

Wherein R is Ph, Bn

Research finds that lithium salt can effectively reduce the influence caused by steric hindrance in the reduction process of sodium borohydride, so that the lithium salt is introduced to participate in the reaction, but when the lithium salt cannot be dissociated in a system to form free ions, the optimization effect of the lithium salt on the reaction cannot be obviously reflected, so that the lithium salt can be completely dissolved by selecting ethanol water as a solvent, and the lithium salt can be dissociated from a compound to improve the reaction activity. So that the amount of sodium borohydride used is reduced to 2 equivalents. Compared with other systems of sodium borohydride, the common dosage of the sodium borohydride is 3-10 equivalents and even higher, so that the production cost can be obviously reduced.

Taking (S) -4-phenyl-2-oxazolidinone as an example, the annual market demand of only India is about 50T, and when only 3 equivalents of sodium borohydride is reduced to 2 equivalents, the annual production cost can be reduced by about 1000W yuan. Therefore, the method has obvious advantage in reducing the production cost.

In the actual production process, we prefer the following reaction examples for reference, based on the economic principle.

Example 1: ((S) -4-benzyl-2-oxazolidinone)

1) Esterification: adding 250g of L-phenylalanine and 625g of methanol into a 2L three-neck flask with magnetons, stirring, cooling to 0-10 ℃, starting to slowly dropwise add 197.6g of thionyl chloride, controlling the process temperature to be not more than 15 ℃, after dropwise addition, heating to 50-60 ℃, and carrying out aftertreatment by using HPLC (high performance liquid chromatography) to detect that the content of raw materials is not more than 0.5%.

After-treatment, cooling to room temperature, distilling under reduced pressure until no solvent is evaporated, adding 500g of methyl tert-ether, heating to 50-55 ℃, stirring for 0.5h, cooling to 0-5 ℃, crystallizing for 2h, filtering 50g of methyl tert-ether, leaching twice, and drying to obtain 323.4g of white-like solid;

2) reduction: 1000g of 50% ethanol is put into a 2L three-neck flask with mechanical stirring, the temperature is reduced to 0-5 ℃, 87.7g of sodium borohydride and 2.4g of lithium chloride are added, and stirring is started to completely dissolve the solid. And then 250g of esterified product is completely dissolved and transferred into a dropping funnel with 500g of 50% ethanol solution, the temperature is controlled not to exceed 15 ℃ in the process of slow dropping, and the raw material is subjected to aftertreatment with the content of less than or equal to 0.5% by HPLC detection.

And (3) post-treatment, namely filtering the reaction solution, rinsing a filter cake twice by 125mL of absolute ethyl alcohol, spin-drying the filtrate, adding 250g of water, and extracting for four times by using DCM (DCM) sequentially by using 1L, 0.5L and 0.5L. The organic phases are combined, washed once with brine water (187.5g water +62.5g sodium chloride +4.6g sodium hydroxide), separated, dried to give a colorless liquid, and then added with 500g methyl tert-ether to precipitate a large amount of white solid which is cooled to 0-5 ℃ for crystallization for 2 h. Filtering 50g of methyl tert-ether, leaching twice and drying to obtain 155.4g of white solid

3) Cyclization: 650mL of toluene, 130g of reduction product and 121.9g of dimethyl carbonate are put into a mechanically-stirred three-neck flask with 1L, the temperature is raised to 100 ℃, 46.4g of 30% sodium methoxide solution is slowly dripped, after the dripping is finished, the mixture is distilled under normal pressure until the system temperature returns to 100 ℃, a reflux device is removed, the temperature is kept for 2h, and the raw material is subjected to aftertreatment when the HPLC detection is less than or equal to 0.5%.

And (3) post-treatment, namely cooling to 60 ℃, adding 260g of water, dissolving the solid, separating the liquid, extracting the water phase once by using 130mL of toluene, combining the organic phases, adding 260g of 20% sodium chloride solution, heating to 50-55 ℃, separating the liquid, cooling the organic phase, evaporating the solvent under reduced pressure to separate out a large amount of solid, adding 260g of methyl tert-ether, and crystallizing for 2 hours at 0-5 ℃. 30g of methyl tert-ether is filtered, rinsed twice and dried to obtain 145.3g of white solid.

Example 2: ((S) -4-phenyl-2-oxazolidinone)

1) Esterification: adding 250g of L-phenylglycine and 625g of methanol into a 2L three-neck flask with magnetons, stirring, cooling to 0-10 ℃, starting to slowly dropwise add 216.8g of thionyl chloride, controlling the process temperature to be not more than 15 ℃, after dropwise addition, heating to 50-60 ℃, and carrying out aftertreatment by using HPLC (high performance liquid chromatography) to detect that the content of raw materials is not more than 0.5%.

After-treatment, cooling to room temperature, distilling under reduced pressure until no solvent is evaporated, adding 500g of methyl tert-ether, heating to 50-55 ℃, stirring for 0.5h, cooling to 0-5 ℃, crystallizing for 2h, filtering 50g of methyl tert-ether, leaching twice, and drying to obtain 316.5g of white-like solid;

2) reduction: 1000g of 50% ethanol is put into a 2L three-neck flask with mechanical stirring, the temperature is reduced to 0-5 ℃, 94g of sodium borohydride and 2.7g of lithium chloride are added, and stirring is started to completely dissolve the solid. And then 250g of esterified product is completely dissolved and transferred into a dropping funnel with 500g of 50% ethanol solution, the temperature is controlled not to exceed 15 ℃ in the process of slow dropping, and the raw material is subjected to aftertreatment with the content of less than or equal to 0.5% by HPLC detection.

And (3) post-treatment, namely filtering the reaction solution, rinsing a filter cake twice by 125mL of absolute ethyl alcohol, spin-drying the filtrate, adding 250g of water, and extracting for four times by using DCM (DCM) sequentially by using 1L, 0.5L and 0.5L. The organic phases are combined, washed once with brine water (187.5g water +62.5g sodium chloride +5.3g sodium hydroxide) and separated, the organic phase is dried to form a colorless liquid, and then 500g methyl tertiary ether is added to separate out a large amount of white solid which is cooled to 0-5 ℃ for crystallization for 2 hours. Filtering 50g of methyl tert-ether, leaching twice and drying to obtain 162.4g of white solid

3) Cyclization: in a mechanically stirred 1L three-neck flask, 750mL of toluene, 150g of reduction product and 159.4g of dimethyl carbonate are added, the temperature is raised to 100 ℃, 50g of 30% sodium methoxide solution is slowly dripped, after the dripping is finished, the mixture is distilled under normal pressure until the system temperature returns to 100 ℃, a reflux device is removed, the temperature is kept for 2h, and the HPLC detection raw material is less than or equal to 0.5% for post-treatment.

And (3) post-treatment, namely cooling to 60 ℃, adding 300g of water, dissolving the solid, separating liquid, extracting the water phase once by using 150mL of toluene, combining the organic phases, adding 300g of 20% sodium chloride solution, heating to 50-55 ℃, separating liquid, cooling the organic phase, evaporating the solvent under reduced pressure to separate out a large amount of solid, adding 300g of methyl tert-ether, and crystallizing for 2 hours at 0-5 ℃. 50g of methyl tert-ether is filtered, rinsed twice and dried to obtain 165.6g of white solid.

Although the present invention has been described with reference to a preferred embodiment, it should be understood that various changes, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.