CN102140063B - A kind of method synthesizing derivative of trifluoromethyl acrylic acid - Google Patents

Abstract

The present invention relates to a kind of new method synthesizing derivative of trifluoromethyl acrylic acid.This method adopts commercially available trifluoroacetic acid (or its ester) and aldehyde to be raw material, and with titanium tetrachloride for catalyst, organic amine is acid binding agent, can obtain the target product of more than 80% yield under room temperature.This synthetic route raw material is easy to get, and reaction condition is gentle, and the configuration of obtained product is mainly Z formula, has the regioselectivity being up to more than 99%.

Description

A kind of method of synthesizing trifluoromethacrylic acid derivative

technical field

The present invention relates to a new method for synthesizing trifluoromethacrylic acid derivatives.

Background technique

Due to their potential applications in medicine and agrochemicals, compounds containing trifluoromethyl groups have long been favored by research institutions and industries, among which trifluoromethyl acrylic compounds have attracted much attention.

Trifluoromethylacrylic compounds can not only be used as synthetic monomers for polymers, but also can be easily converted into β-amino acids (Tetrahedron2006, 62, 11760-11765), therefore, it is of great practical importance to study the synthetic methods of such compounds value.

Known methods for synthesizing trifluoromethylacrylic acid compounds include: 1. Wittig method (J. Fluorine Chem. 2002, 113, 177-183), using trifluoropyruvate (ester) and Wittig reagent as raw materials. The yield is generally 50-60%, the regioselectivity of the reaction is poor, the product is a Z/E mixture, and the raw materials that can be made into Wittig reagent are very limited, so its application is very limited. 2. Diazotized trifluoromethyl propionate reacts with aldehyde under the action of tributyl antimony and copper acetylacetonate. This method not only uses the highly toxic antimony reagent, but also the raw materials are not easy to obtain, the yield is not high, the selectivity is general, and the reaction steps are complicated (Tetrahedron2006, 62, 11760-11765). 3. Combining Wittig method with trifluoromethylation, bromoalkenes are first synthesized by Wittig method, and then obtained by trifluoromethylation reaction. This method has too many steps, and the trifluoromethylation reaction of bromoalkenes is still not mature enough (Tetrahedron Lett. 2000, 41, 2953-2955; J. Org. Chem. 2007, 72, 2678-2681).

Although, trifluoromethylacrylic acid compounds can also be prepared by dehydration reaction of trifluoromethyl hydroxypropionic acid derivatives. However, the preparation conditions of the corresponding alcohols are very harsh, and the catalyst used is expensive, and the reaction is usually carried out at -78 ° C, and the requirements for the functional group in the reaction starting material are also more stringent (Org.Lett.2010, 12, 4474-4477 ; Org. Lett. 2006, 8, 1129-1131). Undoubtedly, the development of synthetic routes with easy-to-obtain raw materials, simple synthetic routes and convenient operation is a problem that researchers in this research field need to solve.

Contents of the invention

The purpose of the present invention is to provide a kind of easy synthetic method of synthesizing trifluoromethacrylic acid derivative for the deficiencies in the prior art. This synthesis method is characterized in that commercially available trifluoropropionic acid and its derivatives and aldehydes are directly used as raw materials, and the reaction is completed in an organic solvent in the presence of a catalyst and an organic base acid-binding agent. Place

The raw materials used in the method are trifluoropropionic acid and its derivatives, and the commercially available trifluoropropionic acid and trifluoropropionate can be directly used; the aldehydes used are mainly aromatic aldehydes.

The method for synthesizing trifluoromethacrylic acid derivatives of the present invention is to prepare trifluoromethacrylic acid derivatives by reacting trifluoropropionic acid or trifluoropropionate I and aldehyde II in the presence of a catalyst and an organic base in an organic solvent. Material III, described trifluoropropionic acid or trifluoropropionic acid ester I, aldehyde II and trifluoromethacrylic acid derivative III have the following structural formula respectively:

Wherein R represents phenyl and phenyl substituted by R ² ; said R ² is halogen, NO ₂ , C1-4 alkoxy, C1-4 perfluoroalkyl or C1-6 alkyl; R ² Preferred are Br, NO ₂ , methoxy, trifluoromethyl or p-tert-butyl.

R ¹ represents H or a C1-4 alkyl group.

The catalyst is titanium tetrachloride or its solution in organic solvent.

The organic base used in the method includes various organic amines, mainly pyridine, hexahydropyridine, triethylamine, N-methylmorpholine or hexamethyldisilazane, and the preferred base is triethylamine.

The organic solvent used in this method is recommended to be a polar organic solvent, such as polar organic solvents such as THF (tetrahydrofuran), dichloromethane, chloroform or toluene, and the preferred solvent is THF.

Adopt the method of the present invention, the molar ratio of general described trifluoropropionic acid or trifluoropropionic acid ester I, aldehyde II, catalyst and organic base is 1: 0.5-3: 1-4: 2-10; The preferred molar ratio of trifluoropropionic acid or trifluoropropionate I, aldehyde II, catalyst and organic base is 1:1.5:1.5:4

The reaction temperature used in this method is generally -10°C to 40°C, and a more preferred reaction temperature is room temperature (eg, 15-30°C).

The reaction time is preferably 5-40 hours.

The main configuration of the trifluoromethacrylic acid derivative III is the Z formula, and has a regioselectivity of up to 99%.

This method adopts commercially available trifluoropropionic acid (or its ester, or its amide) and aldehyde as raw material, with titanium tetrachloride as catalyst, organic amine as acid-binding agent, can obtain more than 80% yield at room temperature target product. The raw materials of the synthesis method are easy to obtain, the reaction conditions are mild, the configuration of the obtained product is mainly Z formula, and the highest regioselectivity is 99%. The obtained compound can be used in the fields of medicine, material and biology.

detailed description

The present invention is specifically described below through the examples, it is necessary to point out that the present examples are only used to further illustrate the present invention, and can not be interpreted as limiting the protection scope of the present invention, those skilled in the art can according to the above-mentioned present invention The content of the invention makes some non-essential improvements and adjustments.

(1), screening example of synthetic conditions

1. Optimum ratio selection of reactants

Embodiment 1: Synthesis of Z-p-bromostyryl trifluoropropionic acid

In the reaction flask, add 111 mg (0.6 mmol) of p-bromobenzaldehyde, 2 mL of anhydrous THF, 35 μL of trifluoropropionic acid (0.4 mmol, the molar ratio of p-bromobenzaldehyde to trifluoropropionic acid is 1.5:1), -10 Add 0.8mL TiCl ₄ (1MinCH ₂ Cl ₂ ) at ℃, stir the reaction for 0.5h, slowly add 180μL (1.6mmol) of N-methylmorpholine dropwise, stir the reaction at room temperature for 40h, stop the reaction, add 3mL water to quench the reaction, dichloro Extracted with methane, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The crude product was separated by flash column chromatography (eluent, _{CH2Cl2 :} MeOH=15:1) to obtain white solid Z-p-bromostyryl Trifluoropropionic acid, yield 69%, Z/E>0.99.

Product NMR data: ¹ HNMR (300MHz, DMSO-d6) ε: 8.08 (s, 1H), 7.67 (d, J=8.1Hz, 2H), 7.37 (d, J=8.1Hz, 2H); ¹⁹ FNMR ( 282 MHz, DMSO-d6) ε: -56.52.

Example 2:

Change the ratio of p-bromobenzaldehyde to trifluoropropionic acid in Example 1 to 1:1, and synthesize Z-p-bromostyryl trifluoropropionic acid according to the steps and conditions of Example 1, with a yield of 44% , Z/E=87/13.

Example 3:

The ratio of p-bromobenzaldehyde and trifluoropropionic acid in Example 1 was changed to 1: 1.5, and according to the steps and conditions of Example 1, Z-p-bromostyryl trifluoropropionic acid was synthesized with a yield of 53% , Z/E=79/21.

Example 4:

Change the ratio of p-bromobenzaldehyde to trifluoropropionic acid in Example 1 to 1: 2, and synthesize Z-p-bromostyryl trifluoropropionic acid according to the steps and conditions of Example 1, with a yield of 64% , Z/E=72/28.

Example 5:

Change the ratio of p-bromobenzaldehyde to trifluoropropionic acid in Example 1 to 1:3, and synthesize Z-p-bromostyryl trifluoropropionic acid according to the steps and conditions of Example 1, with a yield of 54% , Z/E=68/32.

2. Alkali dosage selection

Embodiment 6:

The ratio of trifluoropropionic acid and N-methylmorpholine in Example 1 was changed to 1:1, according to the steps and conditions of Example 1, no product was generated, and the reclaimed products were all raw materials.

Embodiment 7:

Change the ratio of trifluoropropionic acid and N-methylmorpholine in Example 1 to 1: 2, according to the steps and conditions of Example 1, synthesize Z-p-bromostyryl trifluoropropionic acid, yield 2%, Z/E>0.99.

Embodiment 8:

Change the ratio of trifluoropropionic acid and N-methylmorpholine in Example 1 to 1: 3, according to the steps and conditions of Example 1, synthesize Z-p-bromostyryl trifluoropropionic acid, yield 32%, Z/E > 0.99. .

Embodiment 9:

The ratio of trifluoropropionic acid and titanium tetrachloride in Example 1 was changed to 1: 1.5, and according to the steps and conditions of Example 1, Z-p-bromostyryl trifluoropropionic acid was synthesized with a yield of 81% , Z/E>0.99. .

3. Selection of catalyst dosage

Example 10:

The ratio of trifluoropropionic acid and titanium tetrachloride in Example 1 was changed to 1: 2.5, and according to the steps and conditions of Example 1, Z-p-bromostyryl trifluoropropionic acid was synthesized with a yield of 67% , Z/E>0.99. .

Example 11:

The ratio of trifluoropropionic acid and titanium tetrachloride in Example 1 was changed to 1: 3, and according to the steps and conditions of Example 1, Z-p-bromostyryl trifluoropropionic acid was synthesized with a yield of 64% , Z/E>0.99.

Example 12:

The ratio of trifluoropropionic acid and titanium tetrachloride in Example 1 was changed to 1: 4, and according to the steps and conditions of Example 1, Z-p-bromostyryl trifluoropropionic acid was synthesized with a yield of 53% , Z/E>0.99.

4. Selection of alkali varieties

Example 13:

The N-methylmorpholine in Example 1 was changed to triethylamine, and according to the steps and conditions of Example 1, Z-p-bromostyryl trifluoropropionic acid was synthesized with a yield of 89%, Z/E> 0.99.

Example 14:

The N-methylmorpholine in Example 1 was changed to piperidine, and according to the steps and conditions of Example 1, no product was generated, and the recovered products were all raw materials.

Example 15:

The N-methylmorpholine in Example 1 was changed to hexamethyldisilazane, and according to the steps and conditions of Example 1, no product was generated, and the recycled products were all raw materials.

5. Selection of solvent type

Example 16:

The THF (tetrahydrofuran) in Example 13 was changed to chloroform, and according to the steps and conditions of Example 1, Z-p-bromostyryl trifluoropropionic acid was synthesized with a yield of 67% and Z/E>0.99.

Example 17:

The THF (tetrahydrofuran) in Example 13 was changed to toluene, and according to the steps and conditions of Example 1, Z-p-bromostyryl trifluoropropionic acid was synthesized with a yield of 62% and Z/E>0.99.

Example 18:

The temperature in Example 13 was changed from -10°C to 0°C, and according to the steps and conditions of Example 1, Z-p-bromostyryl trifluoropropionic acid was synthesized with a yield of 89% and Z/E>0.99.

6. Selection of reaction temperature

Example 19:

The temperature in Example 13 was changed from -10°C to room temperature, and according to the steps and conditions of Example 1, Z-p-bromostyryl trifluoropropionic acid was synthesized with a yield of 90% and Z/E>0.99.

(2), embodiment after optimizing synthetic conditions

1. Using aryl aldehyde and trifluoropropionic acid as raw materials

Example 20: Synthesis of Z-p-nitrostyryl trifluoropropionic acid

Using p-nitrobenzaldehyde instead of p-bromobenzaldehyde in Example 19, according to the steps and conditions of Example 19, Z-p-nitrostyryl trifluoropropionic acid was synthesized with a yield of 83%, Z/E> 0.99.

Product NMR data: ¹ HNMR (300MHz, DMSO-d6)ε: 8.25(d, J=8.4Hz, 2H), 7.85(s, 1H), 7.58(d, J=8.4Hz, 2H); ¹⁹ FNMR( 282 MHz, DMSO-d6) ε: -55.82.

Example 21: Synthesis of Z-p-methoxystyryl trifluoropropionic acid

With p-methoxybenzaldehyde instead of p-bromobenzaldehyde in Example 19, according to the steps and conditions of Example 19, Z-p-methoxystyryl trifluoropropionic acid was synthesized with a yield of 87%, Z/ E>0.99.

Product NMR data: ¹ HNMR (300MHz, DMSO-d6)ε: 8.04(s, 1H), 7.46(d, J=8.4Hz, 2H), 7.02(d, J=8.4Hz, 2H), 3.81(s , 3H); ¹⁹ FNMR (282 MHz, DMSO-d6) ε: -56.54.

Example 22: Synthesis of Z-styryl trifluoropropionic acid

Using benzaldehyde instead of p-bromobenzaldehyde in Example 19, according to the steps and conditions of Example 19, Z-styryl trifluoropropionic acid was synthesized with a yield of 91% and Z/E>0.99.

NMR data of the product: ¹ HNMR (300MHz, DMSO-d6) ε: 8.10 (s, 1H), 7.44 (s, 5H); ¹⁹ FNMR (282MHz, DMSO-d6) ε: -56.42.

Example 23: Synthesis of Z-p-tert-butylstyryl trifluoropropionic acid

Replace the p-bromobenzaldehyde in Example 19 with p-tert-butylbenzaldehyde, according to the steps and conditions of Example 19, synthesize Z-p-tert-butylstyryl trifluoropropionic acid, yield 86%, Z/ E>0.99.

Product NMR data: ¹ HNMR (300MHz, DMSO-d6)ε: 7.99(s, 1H), 7.46(d, J=8.1Hz, 2H), 7.36(d, J=8.1Hz, 2H), 1.29(s , 9H); ¹⁹ FNMR (282 MHz, DMSO-d6) ε: -56.39.

2. Using aryl aldehyde and methyl trifluoropropionate as raw materials

Example 24: Synthesis of Z-methyl p-bromostyryl trifluoropropionate

Using methyl trifluoropropionate instead of trifluoropropionic acid in Example 19, according to the steps and conditions of Example 19, Z-p-bromostyryl methyl trifluoropropionate was synthesized with a yield of 89%, Z/ E=96/4.

Product NMR data: ¹ HNMR (300MHz, CDCl3) ε: 8.01(s, 1H), 7.54(d, J=8.1Hz, 2H), 7.26(d, J=8.1Hz, 2H), 3.90(s, 3H ); ¹⁹ FNMR (282 MHz, CDCl ₃ ) ε: -57.56.

Example 25: Synthesis of Z-methyl p-nitrostyryl trifluoropropionate

Substitute p-nitrobenzaldehyde for p-bromobenzaldehyde in Example 19, replace trifluoropropionic acid in Example 19 with methyl trifluoropropionate, and synthesize Z-p-nitrobenzaldehyde according to the steps and conditions of Example 19 Methyl styryl trifluoropropionate, yield 86%, Z/E=93/7.

Product NMR data: ¹ HNMR (300MHz, CDCl ₃ )ε: 8.27(d, J=8.4Hz, 2H), 8.13(s, 1H), 7.52(d, J=8.4Hz, 2H), 3.94(s, 3H); ¹⁹ FNMR (282 MHz, CDCl ₃ ) ε: -57.72.

Example 26: Synthesis of Z-p-methoxystyryl methyl trifluoropropionate

Replace the p-bromobenzaldehyde in Example 19 with p-methoxybenzaldehyde, replace the trifluoropropionic acid in Example 19 with methyl trifluoropropionate, and synthesize Z-para Methoxystyryl methyl trifluoropropionate, yield 91%, Z:E=95/5.

Product NMR data: ¹ HNMR (300MHz, CDCl ₃ )ε: 8.01(s, 1H), 7.42(d, J=9.0Hz, 2H), 6.91(d, J=9.0Hz, 2H), 3.87(s, 3H), 3.84 (s, 3H); ¹⁹ FNMR (282 MHz, CDCl ₃ ) ε: -58.46.

Example 27: Synthesis of Z-styryl methyl trifluoropropionate

Replace the p-bromobenzaldehyde in Example 19 with benzaldehyde, replace the trifluoropropionic acid in Example 19 with methyl trifluoropropionate, and synthesize Z-styryl trifluoro Methyl propionate, yield 96%, Z/E=93/7.

NMR data of the product: ¹ HNMR (300MHz, CDCl ₃ ) ε: 8.11 (s, 1H), 7.40 (s, 5H), 3.90 (s, 3H); ¹⁹ FNMR (282 MHz, CDCl ₃ ) ε: -57.75.

Example 28: Synthesis of Z-methyl trifluoromethylstyryl trifluoropropionate

Replace the p-bromobenzaldehyde in Example 19 with p-trifluoromethylbenzaldehyde, replace the trifluoropropionic acid in Example 19 with methyl trifluoropropionate, according to the steps and conditions of Example 19, synthesize Z- Methyl p-trifluoromethylstyryl trifluoropropionate, yield 92%, Z/E=99/1.

Product NMR data: ¹ HNMR (300MHz, CDCl ₃ )ε: 8.12(s, 1H), 7.67(d, J=8.1Hz, 2H), 7.48(d, J=8.1Hz, 2H), 3.92(s, 3H); ¹⁹ FNMR (282 MHz, CDCl ₃ )ε: -58.49, -63.40.

Example 29: Synthesis of Z-p-tert-butylstyryl methyl trifluoropropionate

Replace the p-bromobenzaldehyde in Example 19 with p-tert-butylbenzaldehyde, replace the trifluoropropionic acid in Example 19 with methyl trifluoropropionate, and synthesize Z-para Methyl tert-butylstyryl trifluoropropionate, yield 98%, Z/:E=96/4.

Product NMR data: ¹ HNMR (300MHz, CDCl ₃ )ε: 8.07(s, 1H), 7.43(d, J=9.0Hz, 2H), 7.38(d, J=9.0Hz, 2H), 3.90(s, 3H), 1.33 (s, 9H); ¹⁹ FNMR (282 MHz, CDCl ₃ ) ε: -58.45.

Claims (10)

1. A method for synthesizing trifluoromethacrylic acid derivatives, characterized in that in an organic solvent, at -10°C to 40°C, by trifluoropropionic acid or trifluoropropionate II and aldehyde I in the catalyst and In the presence of an organic base, react for 5-40 hours to obtain trifluoromethacrylic acid derivative III; The molar ratio of the trifluoropropionic acid or trifluoropropionate II, aldehyde I, organic base and catalyst is 1:0.5-3:2-10:1-4; Described trifluoropropionic acid or trifluoropropionate II, aldehyde I and trifluoromethacrylic acid derivative III have the following structural formulas respectively: Wherein R represents phenyl and phenyl substituted by R ² ; said R ² is halogen, NO ₂ , C1-4 alkoxy, C1-4 perfluoroalkyl or C1-6 alkyl; R ¹ represents H or C1-4 alkyl; Described catalyst is titanium tetrachloride; And the organic base is an organic base selected from the following group: triethylamine, N-methylmorpholine; And the molar ratio of trifluoropropionic acid or trifluoropropionate II to aldehyde I is 1:1.5; And the molar ratio of the trifluoropropionic acid or trifluoropropionate II to the organic base is 1:4. 2. The method according to claim 1, characterized in that the configuration of the trifluoromethacrylic acid derivative III is formula Z. 3. The method according to claim 1, characterized in that the catalyst is dissolved in an organic solvent. 4. The method according to claim 1, characterized in that said organic solvent is THF, methylene dichloride, chloroform or toluene. 5. The method according to claim 1, characterized in that said organic base is triethylamine. 6. The method according to claim 1, characterized in that said organic solvent is THF, chloroform or toluene. 7. The method according to claim 1, characterized in that said reaction is carried out at 0-40°C. 8. method according to claim 1 is characterized in that described organic base is triethylamine; Described organic solvent is tetrahydrofuran; The mole of described trifluoropropionic acid or trifluoropropionate II and catalyzer The ratio is 1:2. 9. A method for synthesizing trifluoromethacrylic acid derivatives, characterized in that in an organic solvent, react 5-40 hours by trifluoropropionic acid or trifluoropropionate II and aldehyde I in the presence of a catalyst and an organic base Obtain trifluoromethacrylic acid derivative III; Described trifluoropropionic acid or trifluoropropionate II, aldehyde I and trifluoromethacrylic acid derivative III have the following structural formulas respectively: Wherein R represents phenyl and phenyl substituted by R2 ^; said ^R2 is halogen, _NO2 , C1-4 alkoxy, C1-4 perfluoroalkyl or C1-6 alkyl; R ¹ represents H or C1-4 alkyl; Described catalyst is titanium tetrachloride; And the organic base is an organic base selected from the following group: triethylamine, N-methylmorpholine; Described organic solvent is THF, methylene dichloride, chloroform or toluene; And the molar ratio of trifluoropropionic acid or trifluoropropionate II, aldehyde I, catalyst and organic base is 1:1.5:1.5:4; the reaction temperature is 15-30°C. 10. The method according to any one of claims ^1-9 , characterized in that said R represents H.