A process for the preparation of optically active methyl fluoropyruvate using diethylamine sulfur trifluoride

Abstract

The application designs a method for preparing optically active methyl fluoropropionate by using diethylamine sulfur trifluoride, comprising the following steps: fluorination reaction: under the protection of nitrogen, methyl S-lactate is added to a dry reaction kettle as raw material, the kettle temperature is cooled to a first reaction temperature, diethylamine sulfur trifluoride is added dropwise into the reaction kettle, after dropping, the reaction kettle is heated to a second reaction temperature, after the reaction is completed, the reaction mixture is added dropwise into saturated sodium / potassium bicarbonate aqueous solution to obtain R-2-fluoropropionic acid methyl ester; the molar ratio of diethylamine sulfur trifluoride to methyl S-lactate is 1-1.5:1, the method is high in efficiency, low in three-waste amount, short in reaction path, suitable for industrial production, and has economic value.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of methyl fluoropropanoate chemical industry, and particularly relates to a method for preparing optically active methyl fluoropropanoate by using diethylamine sulfide. BACKGROUND

[0002] The optically active (R)-methyl 2-fluorolactate has a chemical formula of C4H5FO3 and a molecular weight of 118.08 g / mol. It is a colorless transparent liquid with a density of 1.249 g / cm 3 , a melting point of -74 DEG C and a boiling point of 182 DEG C. The compound is an organic fluorine compound with optical activity and chirality, and only one chiral isomer has pharmacological activity. It is widely used as an important organic intermediate in the fields of chemical industry and medicine. For example, it can be used to synthesize various chiral drugs such as amoxicillin and lamotrigine.

[0003] There are various methods for preparing optically active (R)-methyl 2-fluorolactate from S-methyl lactate as a raw material in the prior art, but all have defects.

[0004] For example, a synthesis method of R-2-fluorolactate disclosed in patent CN104774152A, in which S-methyl lactate is fluorinated by sulfuryl fluoride (SO2F2) in the presence of an organic base to obtain R-2-fluorolactate with configuration inversion. Sulfuryl fluoride is a colorless and odorless toxic gas, which will become a strong greenhouse gas after being released into the air. Sulfuryl fluoride and the generated sulfur and fluorine by-products are difficult to handle.

[0005]

[0006] For example, a method for producing optically active alpha-fluorocarboxylic acid ester disclosed in patent CN101578254A, in which S-methyl lactate is used as a raw material, chlorosulfoxide is first reacted to obtain chlorosulfite, and then fluorination treatment is performed by HF to obtain fluorosulfite. R-2-fluorolactate is obtained by catalytic decomposition of pyridine. The reaction route of this scheme is long, and the process is prone to produce sulfite by-products, involves dangerous processes such as HF fluorination, and generates a large amount of three wastes, which are difficult to handle.

[0007]

[0008] For example, the method for preparing enantiomerically enriched 2-fluorocarboxylic acid ester in patent publication CN1800140A uses S-methyl lactate as raw material, first reacts with methyl sulfonyl chloride to obtain (S)-2-methylsulfonyloxy propionic acid methyl ester, and then reacts with KF to obtain R-2-methyl lactate. The methyl sulfonyl chloride used in this scheme is a highly toxic substance and must be handled with care during post-processing. In addition, the potassium fluoride fluorination reaction needs to be purified under high vacuum and reduced pressure while the reaction is ongoing, which is difficult to achieve in industrial production.

[0009]

[0010] For example, the stereoselective one-step fluorination method for preparing 2-fluoropropionic acid ester in patent publication CN101528662A uses S-methyl lactate as raw material, and reacts with tetrafluoroethyl dimethylamine (TFEDMA) for 12 hours to obtain R-2-methyl lactate. According to Zhejiang Chemical Industry 2014, 45(03), the reaction temperature control of TFEDMA is relatively high: at room temperature, primary aliphatic alcohols react with TFEDMA to mainly generate corresponding difluoroacetic ester, and very little fluoroalkane is generated; but at a higher temperature, fluoroalkane and difluoroacetic amide are mainly generated.

[0011]

[0012] In the preparation of optically active (R)-2-fluoromethyl lactate, DAST can be used for fluorination. The scientific name of DAST is diethylaminosulfur trifluoride, which is a commercial liquid fluorination reagent. DAST can convert hydroxyl compounds into monofluorinated compounds, and aldehydes and ketones into difluorinated compounds, while having no effect on the carbonyl group of carboxylic acids and their derived carboxylic acid compounds.

[0013] The present application uses DAST as a fluorination reagent to fluorinate the hydroxyl group to obtain a structure-inverted fluorinated product. SUMMARY

[0014] In view of the above problems, the present application provides a method for preparing optically active fluorinated propionic acid methyl ester with high efficiency, which is suitable for industrial production and has less waste.

[0015] To achieve the above-mentioned purpose, the present application provides a method for preparing optically active fluorinated propionic acid methyl ester using diethylaminosulfur trifluoride, comprising the following steps,

[0016] Fluorination reaction: under nitrogen protection, S-methyl lactate is added to a dry reaction kettle, the kettle temperature is lowered to a first reaction temperature, diethylaminosulfur trifluoride is added dropwise to the reaction kettle, after the dropwise addition is completed, the reaction kettle is heated to a second reaction temperature;

[0017] After the fluorination reaction is completed, the reaction mixture is added dropwise into the alkaline water to quench, and then an organic solvent is added to extract R-2-fluoromethyl propionate; the molar ratio of diethylamine sulfide to S-methyl lactate is 1-1.5:1.

[0018] Further, the first reaction temperature range is -65℃ to -78℃.

[0019] Further, the second reaction temperature range is 0℃ to 80℃.

[0020] Further, after the reaction kettle is warmed to the second reaction temperature, the reaction time is 0.5-10 hours.

[0021] Further, the main component of the alkaline water is selected from one of sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate.

[0022] Further, the organic solvent used for extraction is selected from ethyl acetate, n-hexane, dichloromethane, or THF.

[0023] Further, in the fluorination reaction, a solvent is also added to the reaction kettle.

[0024] Further, the solvent is dichloromethane or hexane, THF.

[0025] Unlike the prior art, the above preparation method is more efficient, has less waste, has a short reaction path, is suitable for industrial production, and has economic value. DETAILED DESCRIPTION

[0026] To describe the technical content, structural features, purposes and effects of the technical scheme in detail, the following will be described in detail in combination with specific embodiments.

[0027] In this document, the term "embodiment" means that the specific features, structures or characteristics described in combination with the embodiment can be included in at least one embodiment of the present application. The term "embodiment" appearing at various positions in the specification does not necessarily refer to the same embodiment, and does not particularly limit the independence or association between other embodiments. In principle, in this application, as long as there is no technical contradiction or conflict, each technical feature mentioned in each embodiment can be combined in any way to form a corresponding implementable technical scheme.

[0028] Unless otherwise defined, the meaning of the technical terms used herein is the same as that generally understood by those skilled in the art to which the present application belongs; the use of related terms herein is only for the purpose of describing specific embodiments, and is not intended to limit the present application.

[0029] In the description of the present application, the phrase "and / or" is a description of the logical relationship between objects, which means that there can be three relationships, for example, A and / or B, which means that there are three cases: A exists, B exists, and A and B exist at the same time. In addition, the character " / " herein generally represents that the associated objects before and after are a "or" logical relationship.

[0030] In the present application, the terms such as "first" and "second" are only used to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any actual quantity, primary and secondary or order relationship between the entities or operations.

[0031] In the present application, without more limitation, the "includes", "contains", "has" or other similar expressions used in the sentence are intended to cover non-exclusive inclusion, and these expressions do not exclude the presence of other elements in the process, method or product including the described elements, so that the process, method or product including a series of elements can not only include those limited elements, but also include other elements not explicitly listed, or also include the elements inherent to such process, method or product.

[0032] As the same understanding as in the "Guidelines for Examination", in the present application, the expressions such as "greater than", "less than", "exceed" are understood as not including the number; The expressions such as "above", "below", "within" are understood as including the number. In addition, in the description of the embodiments of the present application, the meaning of "multiple" is more than two (including two), and similar expressions related to "multiple" are also understood in this way, for example, "multiple groups", "multiple times" and the like, unless otherwise explicitly limited.

[0033] The present application provides a method for preparing optically active methyl fluoropropanoate with diethylamine sulfur trifluoride, comprising the following steps,

[0034] Fluorination reaction: under nitrogen protection, S-methyl lactate is added to a dry reaction kettle as raw material, the kettle temperature is cooled to the first reaction temperature, diethylamine sulfur trifluoride is added dropwise into the reaction kettle, after dropping, the reaction kettle is heated to the second reaction temperature;

[0035] After the completion of the fluorination reaction, the reaction mixture is added dropwise into saturated sodium / potassium bicarbonate aqueous solution to obtain R-2-fluoromethyl propionate; The molar ratio of diethylamine sulfur trifluoride to S-methyl lactate is 1-1.5:1.

[0036] Further, the first reaction temperature range is -65℃ to -78℃.

[0037] Further, the second reaction temperature range is 0℃-80℃.

[0038] Further, the reaction kettle is warmed to the second reaction temperature, and the reaction time is 0.5-10 hours.

[0039] Further, the main component of the alkali water is selected from one of sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate.

[0040] Further, the organic solvent used for extraction is selected from ethyl acetate, n-hexane, dichloromethane or THF.

[0041] Further, in the fluorination reaction, a solvent is also added into the reaction kettle.

[0042] Further, the solvent is dichloromethane or hexane, THF.

[0043] Specifically, the technical scheme of the present application is as follows:

[0044]

[0045] Under the protection of nitrogen, S-methyl lactate (104.1g, 1mol, optical purity 99%) is added into a dry reaction kettle, the kettle is cooled to -65℃ to -78℃, diethylamine sulfur trifluoride (DAST, 161.2g, 1mol) is added into the reaction kettle as a fluorination reagent, and the reaction is exothermic in the initial stage. After the dropping is completed, the reaction kettle is warmed to (0-80℃), and the reaction (0.5h-10h) is carried out. The sample is taken for control of the raw material, and the reaction is complete. The reaction mixture is slowly added dropwise into alkali water (for example, saturated sodium / potassium bicarbonate aqueous solution). The dropping process is exothermic, and the temperature needs to be controlled (below 30℃). After the dropping is completed, CO2 gas does not come out, and the reaction mixture is extracted with an organic solvent (for example, ethyl acetate). After the organic layer is dried and concentrated, simple distillation purification is carried out, and R-methyl 2-fluoropropionate is obtained.

[0046] Wherein:

[0047] (1) The amount of DAST diethylamine sulfur trifluoride added is (1-1.5 molar ratio, based on S-methyl lactate as standard 1)

[0048] (2) The calculation method of optical purity (calculated in terms of enantiomeric excess percentage)

[0049]

[0050] ee(R) is the optical purity of the R enantiomer; ee(S) is the optical purity of the S enantiomer;

[0051] (3) The reaction can be carried out in the absence of a solvent or in the presence of a solvent, and the solvent can be selected from dichloromethane, hexane, THF and the like.

[0052]

[0053] Preparation of R-methyl 2-fluoropropanoate (yield 90.7%, optical purity 98.72%)

[0054] Under nitrogen protection, S-methyl lactate (104.1 g, optical purity 99%) was added to a dry reaction kettle, the kettle temperature was lowered to -65°C, diethylamine sulfur trifluoride (DAST, 161.2 g, 1 mole ratio) was added dropwise to the reaction kettle, and the reaction was exothermic in the early stage. After the dropwise addition was completed, the reaction kettle was slowly warmed to 70-80°C for 1.5 h, and the sample was taken for control of the complete reaction of the raw material. The reaction mixture was slowly added dropwise to saturated sodium bicarbonate aqueous solution. After the dropwise addition was completed, (3 x 104 g) ethyl acetate was used for extraction, the organic layer was dried with anhydrous sodium sulfate, filtered, concentrated, and then simply distilled and purified to obtain R-methyl 2-fluoropropanoate.

[0055] Preparation of R-methyl 2-fluoropropanoate (yield 93.7%, optical purity 98.81%)

[0056] Under nitrogen protection, S-methyl lactate (104.1 g, optical purity 99%) was added to a dry reaction kettle, the kettle temperature was lowered to -65°C, diethylamine sulfur trifluoride (DAST, 161.2 g, 1 mole ratio) was added dropwise to the reaction kettle, and the reaction was exothermic in the early stage. After the dropwise addition was completed, the reaction kettle was slowly warmed to 70-80°C for 1.5 h, and the sample was taken for control of the complete reaction of the raw material. The reaction mixture was slowly added dropwise to saturated sodium bicarbonate aqueous solution. After the dropwise addition was completed, (3 x 104 g) ethyl acetate was used for extraction, the organic layer was dried with anhydrous sodium sulfate, filtered, concentrated, and then simply distilled and purified to obtain R-methyl 2-fluoropropanoate.

[0057] Preparation of R-methyl 2-fluoropropanoate (yield 93.4%, optical purity 98.87%)

[0058] Under nitrogen protection, S-methyl lactate (104.1 g, optical purity 99%) was added to a dry reaction kettle, the kettle temperature was lowered to -65°C, diethylamine sulfur trifluoride (DAST, 161.2 g, 1 mole ratio) was added dropwise to the reaction kettle, and the reaction was exothermic in the early stage. After the dropwise addition was completed, the reaction kettle was slowly warmed to 70-80°C for 1.5 h, and the sample was taken for control of the complete reaction of the raw material. The reaction mixture was slowly added dropwise to saturated sodium bicarbonate aqueous solution. After the dropwise addition was completed, (3 x 104 g) ethyl acetate was used for extraction, the organic layer was dried with anhydrous sodium sulfate, filtered, concentrated, and then simply distilled and purified to obtain R-methyl 2-fluoropropanoate.

[0059] Preparation of R-methyl 2-fluoropropanoate (yield 93.4%, optical purity 98.87%)

[0060] Under nitrogen protection, S-methyl lactate (104.1 g, 99% optical purity) was used as raw material, dichloromethane (104.1 g, 1 m / m) was added into a dry reaction kettle, the kettle temperature was lowered to -78 °C, diethylamine sulfur trifluoride (DAST, 209.6 g, 1.3 molar ratio) solution in dichloromethane (104.1 g, 1 m / m) was added dropwise into the reaction kettle, and the reaction was exothermic at the beginning. After the dropwise addition was completed, the reaction kettle was returned to room temperature (20-35 °C) and reacted for 8 h. The sample was taken for control of the complete reaction of the raw material. The reaction mixture was slowly added dropwise into saturated sodium carbonate aqueous solution. After the addition was completed, the liquid was separated, the aqueous phase was extracted with (2 x 104 g) dichloromethane, the organic layer was dried with anhydrous sodium sulfate, filtered, concentrated and then simply distilled to obtain R-methyl 2-fluoropropionate.

[0061] Example 5 Preparation of R-methyl 2-fluoropropionate (yield 92.1%, optical purity 98.89%)

[0062] Under nitrogen protection, S-methyl lactate (104.1 g, 99% optical purity) was used as raw material, dichloromethane (104.1 g, 1 m / m) was added into a dry reaction kettle, the kettle temperature was lowered to -78 °C, diethylamine sulfur trifluoride (DAST, 209.6 g, 1.3 molar ratio) solution in dichloromethane (104.1 g, 1 m / m) was added dropwise into the reaction kettle, and the reaction was exothermic at the beginning. After the dropwise addition was completed, the reaction kettle was returned to room temperature (20-35 °C) and reacted for 8 h. The sample was taken for control of the complete reaction of the raw material. The reaction mixture was slowly added dropwise into saturated sodium carbonate aqueous solution. After the addition was completed, the liquid was separated, the aqueous phase was extracted with (2 x 104 g) dichloromethane, the organic layer was dried with anhydrous sodium sulfate, filtered, concentrated and then simply distilled to obtain R-methyl 2-fluoropropionate.

[0063] Example 6 Preparation of R-methyl 2-fluoropropionate (yield 91.3%, optical purity 98.96%)

[0064] Under nitrogen protection, S-methyl lactate (104.1 g, 99% optical purity) was used as raw material, dichloromethane (104.1 g, 1 m / m) was added into a dry reaction kettle, the kettle temperature was lowered to -78 °C, diethylamine sulfur trifluoride (DAST, 209.6 g, 1.3 molar ratio) solution in dichloromethane (104.1 g, 1 m / m) was added dropwise into the reaction kettle, and the reaction was exothermic at the beginning. After the dropwise addition was completed, the reaction kettle was returned to room temperature (20-35 °C) and reacted for 8 h. The sample was taken for control of the complete reaction of the raw material. The reaction mixture was slowly added dropwise into saturated sodium carbonate aqueous solution. After the addition was completed, the liquid was separated, the aqueous phase was extracted with (2 x 104 g) dichloromethane, the organic layer was dried with anhydrous sodium sulfate, filtered, concentrated and then simply distilled to obtain R-methyl 2-fluoropropionate.

[0065] Example 7 Preparation of R-methyl 2-fluoropropionate (yield 92.5%, optical purity 98.84%)

[0066] Under nitrogen protection, S-methyl lactate (104.1 g, 99% optical purity) was used as raw material, THF (104.1 g, 1 m / m) was added into a dry reaction kettle, the kettle was cooled to -78°C, diethylamine sulfur trifluoride (DAST, 209.6 g, 1.3 molar ratio) was added dropwise into the reaction kettle, and the reaction was exothermic at the beginning. After the dropwise addition was completed, the reaction kettle was warmed to 30-40°C, and the reaction was carried out for 6.5 h. The sample was taken for control of the complete reaction of the raw material. The reaction mixture was slowly added dropwise into saturated sodium bicarbonate aqueous solution. After the addition was completed, the liquid was separated, the aqueous phase was extracted with THF (2 x 104 g), the organic layer was dried with anhydrous sodium sulfate, filtered, concentrated, and then simply distilled and purified to obtain R-methyl 2-fluoropropionate.

[0067] Example 8 Preparation of R-methyl 2-fluoropropionate (yield 92.5%, 98.84% optical purity)

[0068] Under nitrogen protection, S-methyl lactate (104.1 g, 99% optical purity) was used as raw material, THF (104.1 g, 1 m / m) was added into a dry reaction kettle, the kettle was cooled to -78°C, diethylamine sulfur trifluoride (DAST, 209.6 g, 1.3 molar ratio) was added dropwise into the reaction kettle, and the reaction was exothermic at the beginning. After the dropwise addition was completed, the reaction kettle was warmed to 30-40°C, and the reaction was carried out for 6.5 h. The sample was taken for control of the complete reaction of the raw material. The reaction mixture was slowly added dropwise into saturated sodium bicarbonate aqueous solution. After the addition was completed, the liquid was separated, the aqueous phase was extracted with THF (2 x 104 g), the organic layer was dried with anhydrous sodium sulfate, filtered, concentrated, and then simply distilled and purified to obtain R-methyl 2-fluoropropionate.

[0069] It should be noted that although the above embodiments have been described in this paper, the patent protection scope of the present application is not limited thereby. Therefore, based on the innovative idea of the present application, changes and modifications of the embodiments described in this paper, or equivalent structure or equivalent process transformation made by using the present application specification, direct or indirect application of the above technical solutions to other related technical fields, are all included in the patent protection scope of the present application.

Claims

1. A process for the preparation of optically active methyl fluoropropanoate from diethylamine sulfur trifluoride, characterized in that, The method comprises the following steps, The fluorination reaction is carried out as follows: under the protection of nitrogen, S-methyl lactate is added into a dry reaction kettle, the kettle temperature is lowered to a first reaction temperature, diethylamine sulfide trifluoride is added dropwise into the reaction kettle, after the dropping is completed, the reaction kettle is heated to a second reaction temperature; After the fluorination reaction is completed, the reaction mixture is added dropwise into alkaline water for quenching, and then an organic solvent is added for extraction to obtain R-2-fluoropropionic acid methyl ester; the molar ratio of diethylamine sulfide trifluoride to S-methyl lactate is 1-1.5:

1.

2. A process for the preparation of optically active methyl fluoropropanoate from diethylamine sulfur trifluoride according to claim 1, characterized in that, The first reaction temperature ranges from-65°C to-78°C.

3. A process for the preparation of optically active methyl fluoropropanoate from diethylamine sulfur trifluoride according to claim 2, characterized in that, The second reaction temperature ranges from 0°C to 80°C.

4. A process for the preparation of optically active methyl fluoropropanoate from diethylamine sulfur trifluoride according to claim 3, characterized in that, After the reaction kettle is heated to the second reaction temperature, the reaction time is 0.5-10 hours.

5. The process for preparing optically active methyl fluoropropanoate with diethylamine sulfur trifluoride according to claim 1, characterized in that, After the extraction is completed, the organic layer is dried and concentrated, and then distilled and purified.

6. The process for preparing optically active methyl fluoropropanoate with diethylamine sulfur trifluoride according to claim 1, characterized in that, In the fluorination reaction, a solvent is further added into the reaction kettle.

7. A process for the preparation of optically active methyl fluoropropanoate from diethylamine sulfur trifluoride according to claim 6, characterized in that, The solvent is dichloromethane, hexane or THF.

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