CN117946153A - Synthesis method of 3, 3-trifluoro lactic acid - Google Patents

Abstract

The invention relates to the technical field of organic synthesis, in particular to a synthesis method of 3, 3-trifluoro lactic acid. The synthetic route of the 3, 3-trifluoro lactic acid is as follows: . The invention obviously improves the yield and selectivity of the 3, 3-trifluoromethyl-2-trimethylsiloxy-ethyl propionate by optimizing a reaction system, thereby providing a brand new reaction path for 3, 3-trifluoro lactic acid, and the preparation method is simple, efficient, relatively green and environment-friendly and has wide industrial prospect.

Description

Synthesis method of 3, 3-trifluoro lactic acid

Technical Field

The invention relates to the technical field of organic synthesis, in particular to a synthesis method of 3, 3-trifluoro lactic acid.

Background

3, 3-Trifluoro lactic acid is a trifluoromethyl block reagent and plays an important role in the synthesis of organic fluorine chemical industry. The compound has three reaction centers: firstly, hydroxyl groups can be subjected to esterification, halogenation, salification, ether formation and other reactions; second, the carboxyl groups may be esterified, acyl halogenated, amidated, etc.; thirdly, the beta-hydrogen atom is easy to leave due to the influence of trifluoromethyl electroabsorption, and carbanion is formed to carry out nucleophilic reaction. Therefore, it is possible to synthesize complex compounds such as trifluoromethyl heterocyclic compounds; meanwhile, as the chiral structure of the trifluoro lactic acid is introduced, the synthesis of chiral trifluoromethyl chiral compounds plays a significant role. Therefore, the synthesized 3, 3-trifluoro lactic acid is widely applied as a precursor raw material in the fields of new generation medicines, pesticides and the like, and has wide prospect especially for chiral fluorine-containing medicines.

However, in the prior art, when synthesizing 3, 3-trifluoro lactic acid, three specific functional groups (trifluoromethyl, alcoholic hydroxyl and carboxyl) are formed on three carbon atoms in the 3, 3-trifluoro lactic acid structure, and under the condition of selecting different initial raw materials, the synthesis and protection of corresponding functions are difficult to a certain extent; the introduction of trifluoromethyl is more challenging.

At present, the synthesis method of the 3, 3-trifluoro lactic acid mainly comprises the following steps: 1. the derivative with lactic acid structure as main body is prepared through fluoridation, alcoholysis, hydrolysis, acidification and other steps, and adopts fluorine gas direct fluoridation, halogen exchange, carboxylic acid conversion and electrolytic fluoridation in fluoridation step. F ₂, HF and fluoride are needed in the process, and HF and metal fluoride are generated due to different partial reaction substrates, so that high requirements on safety and environmental protection risks and corrosiveness of equipment are provided; meanwhile, the reaction temperature is higher, and the method has very much byproducts and greatly influences the yield, so the industrialization significance is not great. 2. The method adopts a trifluoromethyl reagent (such as trifluoroiodomethane, trifluoromethylpcopper, trifluoromethyl hypofluorite, trifluoromethane and trimethyltrifluoromethyl silane) to carry out nucleophilic addition trifluoromethyl on two carboaldehyde ketones, and prepares the 3, 3-trifluoro lactic acid by the steps of leaving through redundant groups, hydrolysis, acidification and the like, but adopts the trifluoroiodomethane, the trifluoromethylpcopper and the trifluoromethyl hypofluorite as the trifluoromethyl reagent, so that the synthesis cost is high (iodine and copper are relatively expensive, the trifluoromethyl hypofluorite is not easy to synthesize and preserve, and the preparation production cost is high), and meanwhile, the byproducts of iodide ions, copper ions and fluoride ions have large influence on the environment, and are not easy to separate from a reaction system.

Disclosure of Invention

Aiming at the defects existing in the prior art, the invention provides a method for synthesizing 3, 3-trifluoro lactic acid.

In a first aspect, the present invention provides an intermediate compound, ethyl 3, 3-trifluoromethyl-2-trimethylsiloxy-propionate, which is useful for the synthesis of 3, 3-trifluorolactic acid.

Specifically, the intermediate compound has the structure of formula (I):

in a second aspect, the present invention provides a process for the preparation of said intermediate compound comprising:

Ethyl glyoxylate, trifluoromethyl trimethylsilane, aprotic polar solvent and catalyst are mixed and reacted at the temperature of minus 30 ℃ to minus 5 ℃ to prepare the 3, 3-trifluoromethyl-2-trimethylsiloxy-ethyl propionate.

Preferably, in the process of preparing 3, 3-trifluoromethyl-2-trimethylsiloxy-ethyl propionate, the reaction temperature is-20 to-10 ℃; further preferably, the reaction temperature is-25 to-20 ℃.

The invention discovers that when the intermediate compound is prepared, trifluoromethyl trimethylsilane and ethyl glyoxylate undergo nucleophilic addition reaction on aldehyde carbonyl to prepare the 3, 3-trifluoromethyl-2-trimethylsiloxy-ethyl propionate. The above temperature ranges can significantly increase the reaction products and conversion because: because the ethyl glyoxylate has strong H ⁺ ion property by absorbing hydrogen on an aldehyde group by 2 carbonyl groups and is easy to leave, if the temperature is higher in the reaction, electrophilic substitution reaction can be initiated, and CF ₃ ^- and H ⁺ are combined to generate HCF ₃, so that the target product cannot be obtained. Too low a temperature may reduce the activity of the reactants and is detrimental to the reaction.

Meanwhile, the invention discovers that the trifluoroiodomethane, the trifluoromethyl copper, the trifluoromethyl hypofluorite and the trifluoromethane have low boiling points, and the reaction temperature is higher, and the specific solvent can be dissolved, so the pressure requirement on a reaction system is higher. Therefore, the invention comprehensively considers and adopts the trimethyl trifluoromethyl silane as the raw material to prepare the 3, 3-trifluoro lactic acid, and has the advantages that the reaction is carried out at low temperature and normal pressure, and the reaction is mild; 2. the corrosion of raw materials and byproducts is small, the toxicity is low, and the safety and environmental protection risks are low; 3. the byproduct trimethylsilane is very easy to separate from a reaction system, and can be purified and sold as a chemical raw material, so that the synthesis cost is reduced.

Preferably, the aprotic polar solvent includes one or more of THF (tetrahydrofuran), DMF (N, N-dimethylformamide), DMI (1, 3-dimethylimidazolidinone), DMSO (dimethyl sulfoxide), acetonitrile, HMPA (hexamethylphosphoric triamide) and NMP (N-methylpyrrolidone).

More preferably, the aprotic polar solvent is tetrahydrofuran.

Preferably, the catalyst comprises fluoride ion, tertiary butyl oxyanion and lewis base.

More preferably, the catalyst comprises one or more of Bu ₄ NF (tetrabutylammonium fluoride), KF, csF, t-BuOK (potassium tert-butoxide), naBF ₄ and Et ₃ N (triethylamine).

Further preferably, the catalyst is tetrabutylammonium fluoride.

Preferably, the molar ratio of ethyl glyoxylate to trifluoromethyl trimethylsilane is 1:1 to 1.5, more preferably 1:1 to 1.2.

Preferably, the catalyst is used in an amount of 5 to 20mol% based on the molar amount of the trifluoromethyl trimethylsilane; more preferably 5 to 10mol%.

In a third aspect, the present invention provides a method for synthesizing 3, 3-trifluoro lactic acid, which comprises the following synthetic routes:

the synthesis steps comprise:

s1: dropwise adding an acid solution into the intermediate compound (I) at room temperature to obtain 3, 3-trifluoromethyl-2-hydroxy-ethyl propionate;

S2: dropwise adding an alkali solution into 3, 3-trifluoromethyl-2-hydroxy-ethyl propionate to obtain sodium 3, 3-trifluoromethyl-2-hydroxy-propionate;

s3: acidizing 3, 3-trifluoromethyl-2-hydroxy-sodium propionate to obtain 3, 3-trifluoro lactic acid.

Preferably, in the step S1, the acid solution is 5 to 20wt% of a dilute hydrochloric acid and/or a dilute sulfuric acid solution; more preferably, the acid solution concentration is 10 to 15wt%.

In the step S1, an acid solution is slowly dripped into an intermediate compound (I), and a reaction system is stirred in the dripping process, so that the reaction system is continuously overflowed; stopping dripping the acid solution until no bubbles are generated in the reaction solution, and obtaining the 3, 3-trifluoromethyl-2-hydroxy-ethyl propionate after the reaction is completed.

Preferably, in the step S2, the temperature is controlled to be 40 to 80 ℃; more preferably 50 to 60 ℃.

Preferably, in the step S2, the alkali solution is one or more of 5-30wt% sodium hydroxide solution, potassium hydroxide solution and potassium carbonate solution; more preferably, the alkali solution concentration is 10 to 20wt%.

Preferably, the molar ratio of the alkali solution to the ethyl 3, 3-trifluoromethyl-2-hydroxy-propionate is 1 to 1.2 in terms of OH ^-: 1.

In the step 3), the alkali solution is slowly dripped into the 3, 3-trifluoromethyl-2-hydroxy-ethyl propionate according to the proportion, the reaction system is stirred during the dripping process, and after the dripping of the alkali solution is completed, the stirring reaction is carried out for 0.5-2h, thus obtaining the 3, 3-trifluoromethyl-2-hydroxy-sodium propionate.

Preferably, in the step S3, the acidification treatment is performed by using one or more of hydrochloric acid, sulfuric acid, glacial acetic acid and nitric acid; more preferably, the acidification treatment uses a molar ratio of acid to sodium 3, 3-trifluoromethyl-2-hydroxy-propionate of 1 to 1.2, calculated as H ⁺: 1.

As a preferable technical scheme of the invention, the synthetic route of the 3, 3-trifluoro lactic acid is as follows:

The specific method comprises the following steps:

1) Mixing ethyl glyoxylate, trifluoromethyl trimethylsilane, aprotic polar solvent and catalyst, and reacting at-30 to-5 ℃ to obtain 3, 3-trifluoromethyl-2-trimethylsiloxy-ethyl propionate;

2) Dropwise adding an acid solution into 3, 3-trifluoromethyl-2-trimethylsiloxy-ethyl propionate at room temperature to obtain 3, 3-trifluoromethyl-2-hydroxy-ethyl propionate;

3) Dropwise adding an alkali solution into 3, 3-trifluoromethyl-2-hydroxy-ethyl propionate to obtain sodium 3, 3-trifluoromethyl-2-hydroxy-propionate;

4) Acidizing 3, 3-trifluoromethyl-2-hydroxy-sodium propionate to obtain 3, 3-trifluoro lactic acid.

Based on the technical scheme, the invention has the beneficial effects that:

The invention obviously improves the yield of the 3, 3-trifluoromethyl-2-trimethylsiloxy-ethyl propionate by optimizing a reaction system, thereby providing a brand new reaction path for 3, 3-trifluoro lactic acid, and the preparation method is simple, efficient, relatively green and environment-friendly and has wide industrial prospect.

Drawings

In order to more clearly illustrate the invention or the technical solutions of the prior art, the following description will briefly explain the drawings used in the embodiments or the description of the prior art, and it is obvious that the drawings in the following description are some embodiments of the invention, and other drawings can be obtained according to the drawings without inventive effort for a person skilled in the art.

FIG. 1 is a hydrogen spectrum of an intermediate compound (I) ethyl 3, 3-trifluoromethyl-2-trimethylsiloxy-propionate prepared in example 1 provided by the present invention;

FIG. 2 is a hydrogen spectrum of ethyl 3, 3-trifluoromethyl-2-hydroxy-propionate prepared in example 1 provided by the present invention;

FIG. 3 is a hydrogen spectrum of 3, 3-trifluorolactic acid prepared in example 1 provided herein.

Detailed Description

For the purpose of making the objects, technical solutions and advantages of the present invention more apparent, the technical solutions of the present invention will be clearly and completely described below with reference to the accompanying drawings, and it is apparent that the described embodiments are some embodiments of the present invention, not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.

Unless otherwise indicated, all of the starting materials used in the examples were commercially available conventional starting materials, and the technical means used were conventional means well known to those skilled in the art.

Example 1

This example first provides an intermediate compound (i) prepared by a process comprising the steps of:

Ethyl glyoxylate and trifluoromethyl trimethylsilane are mixed according to the proportion of 1mol:1.2mol, namely 102g of ethyl glyoxylate and 170.4g of trifluoromethyl trimethylsilane are weighed and placed in a 1000ml three-neck flask, and the temperature is reduced to minus 30 ℃ in advance. 62.64g (0.24 mol) of Bu ₄ NF (previously dried in vacuo at 40 ℃ C. For more than 24 hours) were weighed into 450g (6.25 mol) of THF to dissolve, and the solution was cooled and clarified. The THF solution of Bu ₄ NF was slowly added dropwise to the cooled ethyl glyoxylate and trifluoromethyl trimethylsilane, and after the dropwise addition was completed, the reaction was carried out at-20℃with stirring for 10 hours. After the reaction, the reaction mixture was heated to 40 to 60℃and evacuated, THF was distilled off under reduced pressure, bu ₄ NF was precipitated in the reaction mixture, and 233.6g of ethyl 3, 3-trifluoromethyl-2-trimethylsiloxy-propionate as an intermediate compound (I) was obtained by filtration, with a yield of 95.74%.

The intermediate (I) is subjected to nuclear magnetic resonance detection, the hydrogen spectrum of the intermediate is shown in figure 1, and the data is analyzed as follows ：¹¹HNMR(DMSO,300MHz,δ/ppm)：0.06(t,9H),0.82(d,1H),1.07(d,1H),1.21(t,3H),4.21(t,2H),4.38(t,1H).

The embodiment further provides a synthesis method of 3, 3-trifluoro lactic acid, the synthesis route is as follows:

S1: 122g (0.5 mol) of ethyl 3, 3-trifluoromethyl-2-trimethylsiloxy-propionate is weighed and placed in a 500ml three-neck flask, 15% (w/w) hydrochloric acid solution is slowly dripped at room temperature (25+/-5 ℃) and is stirred during the dripping process until no bubbles emerge in the reaction liquid, and the stirring reaction is continued for 1.0h after the dripping is completed. 77.5g of ethyl 3, 3-trifluoromethyl-2-hydroxy-propionate product was obtained in a yield of 90.11%. The nuclear magnetism detection is carried out on the product, the hydrogen spectrogram is shown in figure 2, and the data analysis is as follows: ¹ H NMR (DMSO, 300MHz, delta/ppm): 1.21 (t, 3H), 4.21 (t, 2H), 6.53 (s, 1H), 7.22 to 7.18 (s, 1H).

S2: 86g (0.5 mol) of ethyl 3, 3-trifluoromethyl-2-hydroxy-propionate was weighed and placed in a 250ml three-neck flask, the temperature was raised to 50 ℃, 120g of 20% aqueous sodium hydroxide solution was slowly added dropwise, the dripping process was accompanied by stirring, and after the dripping was completed, the stirring reaction was continued for 2.0h. 113.5g (wet product) of 3, 3-trifluoromethyl-2-hydroxy-propionic acid sodium salt is obtained. The mixture was dried at 90℃for 12 hours to give 76.2g of dried sodium 3, 3-trifluoromethyl-2-hydroxy-propionate in a yield of 91.80%.

S3: 83g (0.5 mol) of sodium 3, 3-trifluoromethyl-2-hydroxy-propionate was weighed, 110g of a 20% (w/w) hydrochloric acid solution was added at room temperature (25.+ -. 5 ℃ C.) and the reaction was stirred for 0.5h to obtain 62.3g of 3, 3-trifluoro lactic acid as a product with a yield of 86.53%. The products were subjected to nuclear magnetic resonance detection, the hydrogen spectrum of which is shown in FIG. 3, and the data were analyzed as follows by ¹ H NMR (DMSO, 300MHz, delta/ppm): 6.57 (s, 1H), 7.23-7.18 (s, 1H), 12.91-12.86 (s, 1H).

Example 2

This example provides an intermediate compound (i) prepared by a process comprising the steps of:

Ethyl glyoxylate and trifluoromethyl trimethylsilane are mixed according to the proportion of 1mol:1.2mol, namely 102g of ethyl glyoxylate and 170.4g of trifluoromethyl trimethylsilane are weighed and placed in a 1000ml three-neck flask, and the temperature is reduced to-25 ℃ in advance. 26.88gt-BuOK (0.24 mol) was weighed into 401.5gDMF (5.0 mol) and dissolved, and the solution was allowed to cool and clear. Slowly dropwise adding the t-BuOK DMF solution into the cooled ethyl glyoxylate and trifluoromethyl trimethylsilane, and maintaining the temperature of minus 15 ℃ to stir and react for 10 hours after the dropwise adding is completed. The reaction mixture was heated to 60 to 80℃and evacuated, and then distilled under reduced pressure to give 210.3g of ethyl 3, 3-trifluoromethyl-2-trimethylsiloxy-propionate, the yield being 86.12%.

Example 3

This example provides an intermediate compound (i) which is prepared in substantially the same manner as in example 1, except that: the reaction temperature is-30 ℃, and the yield of the 3, 3-trifluoromethyl-2-trimethylsiloxy-ethyl propionate is 87.56 percent.

Comparative example 1

This example provides an intermediate compound (i) which is prepared in substantially the same manner as in example 1, except that: the reaction temperature was 0℃and the yield of ethyl 3, 3-trifluoromethyl-2-trimethylsiloxy-propionate was 57.85%.

Finally, it should be noted that: the above embodiments are only for illustrating the technical solution of the present invention, and are not limiting; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims (10)

1. An intermediate compound characterized by having the structure of formula (i):

2. A process for the preparation of an intermediate compound as claimed in claim 1, comprising:

Ethyl glyoxylate, trifluoromethyl trimethylsilane, aprotic polar solvent and catalyst are mixed and reacted at the temperature of minus 30 ℃ to minus 5 ℃ to prepare the 3, 3-trifluoromethyl-2-trimethylsiloxy-ethyl propionate.

3. The process for producing an intermediate compound according to claim 2, wherein the reaction temperature is-20 to-10 ℃ during the production of ethyl 3, 3-trifluoromethyl-2-trimethylsiloxy-propionate.

4. A process for the preparation of an intermediate compound according to claim 2 or 3, wherein the aprotic polar solvent comprises one or more of tetrahydrofuran, N-dimethylformamide, 1, 3-dimethylimidazolidinone, dimethylsulfoxide, acetonitrile, hexamethylphosphoric triamide and N-methylpyrrolidone;

And/or the catalyst comprises one or more of tetrabutylammonium fluoride, KF, csF, potassium tert-butoxide, naBF ₄ and triethylamine.

5. The process for producing an intermediate compound according to any one of claims 2 to 4, wherein the molar ratio of ethyl glyoxylate to trifluoromethyltrimethylsilane is 1:1 to 1.5, preferably 1:1 to 1.2.

6. The process for producing an intermediate compound according to any one of claims 2 to 5, wherein the catalyst is used in an amount of 5 to 20mol% based on the molar amount of the trifluoromethyltrimethylsilane; preferably 5 to 10mol%.

7. A synthesis method of 3, 3-trifluoro lactic acid is characterized in that the synthesis route is as follows:

the synthesis steps comprise:

s1: dropwise adding an acid solution into the intermediate compound (I) at room temperature to obtain 3, 3-trifluoromethyl-2-hydroxy-ethyl propionate;

S2: dropwise adding an alkali solution into 3, 3-trifluoromethyl-2-hydroxy-ethyl propionate to obtain sodium 3, 3-trifluoromethyl-2-hydroxy-propionate;

s3: acidizing 3, 3-trifluoromethyl-2-hydroxy-sodium propionate to obtain 3, 3-trifluoro lactic acid.

8. The method for synthesizing 3, 3-trifluorolactic acid according to claim 7, wherein in S2, the temperature is controlled to be 40-80 ℃; preferably 50 to 60 ℃.

9. The method for synthesizing 3, 3-trifluoro lactic acid according to claim 7 or 8, wherein in S1, the acid solution is 5-20wt% diluted hydrochloric acid and/or diluted sulfuric acid solution;

And/or in the step S2, the alkali solution is one or more of 5-30wt% sodium hydroxide solution, potassium hydroxide solution and potassium carbonate solution; preferably, the molar ratio of the alkali solution to the ethyl 3, 3-trifluoromethyl-2-hydroxy-propionate is 1 to 1.2, calculated as OH ^-: 1, a step of;

And/or in the step S3, the acidification treatment adopts one or more of hydrochloric acid, sulfuric acid, glacial acetic acid and dilute nitric acid; preferably, the acidification treatment uses a molar ratio of acid to sodium 3, 3-trifluoromethyl-2-hydroxy-propionate of 1 to 1.2, calculated as H ⁺: 1.

10. The method for synthesizing 3, 3-trifluoro lactic acid according to claims 7 to 9, wherein the synthetic route is as follows:

the method specifically comprises the following steps:

1) Mixing ethyl glyoxylate, trifluoromethyl trimethylsilane, aprotic polar solvent and catalyst, and reacting at-30 to-5 ℃ to obtain 3, 3-trifluoromethyl-2-trimethylsiloxy-ethyl propionate;

2) Dropwise adding an acid solution into 3, 3-trifluoromethyl-2-trimethylsiloxy-ethyl propionate at room temperature to obtain 3, 3-trifluoromethyl-2-hydroxy-ethyl propionate;

3) Dropwise adding an alkali solution into 3, 3-trifluoromethyl-2-hydroxy-ethyl propionate to obtain sodium 3, 3-trifluoromethyl-2-hydroxy-propionate;

4) Acidizing 3, 3-trifluoromethyl-2-hydroxy-sodium propionate to obtain 3, 3-trifluoro lactic acid.