JPS625411B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the structural formula 2-trifluoromethylpropanal represented by

2-Trifluoromethylpropanal (hereinafter referred to as TFMPA) of the present invention is a compound having the physical properties shown below.

n ²⁰ _D : 1.3262 Boiling point: 64-66C/760mmHg ¹ H NMR (CDCl ₃ :TMS): δ 1.31 (doublet, J=7.2Hz, 3H), 3.09 (multiplet,
1H), 9.79 (wide singlet, 1H). ^19F NMR ( _CDCl3 : _CF3COOH ): δ9.91
(Double line, J=9.6Hz). IR (neat): 2850, 2730cm ^-1 (ν _CH ), 1740cm
^-1 (ν _C=O ). High-resolution mass spectrum: Actual value 126.0283. Calculated value 126.0292. The TFMPA of the present invention can be prepared by reacting it with hippuric acid, treating it with a base, hydrogenating it, and then treating it with an acid to produce trifluoroleucine, which is useful as an antibacterial agent. (See Reference Example 1 below).
Furthermore, TFMPA of the present invention is oxidized to trifluoroisobutyric acid (see Reference Example 2 below), and
It can be converted to trifluoroisobutyl alcohol by reduction (see Reference Example 3 below), and trifluoroisobutyl halide can be derived from this trifluoroisobutyl alcohol (see Reference Example 4 below). Furthermore, by converting to trifluoroisobutyric acid halide, trifluoroisobutyroyl groups can be introduced into various compounds. On the other hand, by performing the Stretzker reaction, trifluorovaline can be obtained, and by reaction with acylglycine, trifluoroleucine can be obtained.

Conventionally, as a method for producing an aldehyde having a branched perfluoroalkyl group, a method in which a slightly perfluoroiodoalkane and an enamine are reacted under radical conditions (Japanese Patent Application Laid-Open No. 125314-1982)
However, there is no description of the compound of the present invention, and even if other compounds are used, the proportion is at most 25-50%.
It has been obtained with a yield of only .

As a result of intensive research into fluoro compounds that are highly useful as industrial raw materials, the present inventors discovered TFMPA of the present invention and completed the present invention.

The raw materials for producing TFMPA of the present invention are 3,3,3-trifluoro-1-propene, carbon monoxide, and hydrogen. 3,3,3-trifluoro-1-propene is a compound that is easily available as an industrial raw material.

In producing the TFMPA of the present invention, it is essential to carry out the production in the presence of a group metal complex. These complexes include, for example, Rh
(PPh ₃ ) ₃ Cl, Rh (CO) (PPh ₃ ) ₂ Cl, HRh (CO)
(PPh ₃ ) ₃ , PR ₃ −Rh ₆ (CO) ₁₆ (However, PR ₃ is the third
represents phosphines and phosphites. ) etc. can be used. These complexes can also be used by being supported on a carrier. The amount of the complex to be used can range from 10 ^-2 to 10 ^-6 mol based on 3,3,3-trifluoro-1-propene.
It is desirable to use a solvent when producing TFMPA, such as aromatic solvents such as benzene, toluene, and xylene, aliphatic hydrocarbon solvents such as pentane and hexane, ether solvents such as tetrahydrofuran and dioxane, methanol, and ethanol. Alcohol solvents such as triethylamine, amine solvents such as pyridine, carboxylic acids such as ethyl acetate and acetic acid, and esters thereof can be used.

The reaction can be carried out at normal pressure to 300 atmospheres. The reaction temperature varies depending on the complex used, but is in the range of room temperature to 300°C.

Hereinafter, the present invention will be explained in more detail with reference to Examples and Reference Examples.

Example 1 92.5 mg (0.10 mmol) of chlorotris(triphenylphosphine)rhodium, 1.12 mg (0.10 mmol) of 3,3,3-trifluoro-1-propene (gas volume, 50 mmol), and 10 ml of toluene as a solvent were placed in a 200 ml autoclave. 50 atm carbon monoxide pressure and 50
The reaction was completed by heating and stirring at 100° C. for 44 hours under hydrogen pressure. GLC analysis of the reaction mixture using nonane as an internal standard revealed 46.6 mmol (93%) and 46.6 mmol (93%) of 2-trifluoromethylpropanal and 4,4,4-trifluorobutanal, respectively.
1.94 mmol (4%) was produced. The reaction mixture was distilled, and fractions up to 66°C were collected and rectified to obtain 4.54 g (yield 72%) of pure 2-trifluoromethylpropanal.

Example 2 Chlorocarbonylbis(triphenylphosphine)rhodium 20.7mg (3.00×10 ^-2 mmol),
3,3,3-trifluoro-1-propene 224ml
(gas volume 10.0 mmol) and solvent toluene 2
ml was placed in a 200 ml autoclave and stirred at 110°C for 16 hours under a carbon monoxide pressure of 40 atm and a hydrogen pressure of 40 atm, and the reaction was completed. 1.20 g of TFMPA crude product by distilling the reaction mixture
(yield 95%).

Example 3 trans-[hydridocarbonyl tris(triphenylphosphine) rhodium ()] 95.7 mg (0.104
mmol), 105 g (1.09 mol) of 3,3,3-trifluoro-1-propene and 200 g (1.09 mol) of toluene as a solvent.
ml was placed in an autoclave No. 1 and heated and stirred at 90° C. for 5 hours under a carbon monoxide partial pressure of 60 atm and a hydrogen partial pressure of 60 atm, and the reaction was completed. 108 g (79%) of TFMPA by distilling the reaction mixture
I got it.

Example 4 Hexalodium hexadecacarbonyl 21.4 mg
(2.0×10 ^-2 mmol), 12.23 g (127 mmol) of 3,3,3-trifluoro-1-propene, and 20 ml of toluene as a solvent were placed in a 200 ml autoclave, and the carbon monoxide partial pressure was set at 50 atm. The reaction was completed by heating and stirring at 80°C for 5 hours under a hydrogen partial pressure of . By distilling the reaction mixture,
15.5 g of TFMPA (yield 97%) was obtained.

Example 5 5% rhodium carbon 209.4 mg (1.0 x 10 ^-1 milligram atoms), triphenyl phosphite 64.4 mg
(2.1×10 ^-2 mmol), 12.1 g (126 mmol) of 3,3,3-trifluoro-1-propene, and 20 ml of toluene as a solvent were placed in a 200 ml autoclave, and the carbon monoxide partial pressure was set at 50 atm. The reaction was completed by heating and stirring at 80°C for 3 hours under a hydrogen partial pressure of . By distilling the reaction mixture,
15.6 g of TFMPA (yield 98%) was obtained.

Reference example 1 Lead acetate trihydrate 2.19g (5.77 mmol), hippuric acid 2.06g (11.5 mmol), acetic anhydride 3.52g
(34.5 mmol) and 1.74 g (13.8 mmol) of TFMPA were heated under reflux in 26 ml of tetrahydrofuran for 4 hours. After cooling, the solvent was distilled off under reduced pressure, and the residue was poured into 100 ml of water and left overnight. The precipitated solid was filtered to obtain 3.10 g (yield 100%) of azlactone crude product of α-benzoylamino-β-(1-trifluoromethyl)ethyl acrylic acid (E/Z=13/
87). This was dissolved in ether, washed several times with water, and then dried over anhydrous sodium sulfate. After distilling off the solvent, 2.06 g (yield 67%) of pure (Z)-azlactone was obtained by recrystallizing from a small amount of n-hexane.

Melting point: 74-75℃. ¹ H NMR (CDCl ₃ :TMS): δ 1.18 (doublet, J=9.0Hz, 3H), 3.90 (multiplet,
1H), 6.46 (double line, J=10Hz, 1H), 7.3
−8.2 (multiplet, 5H). ^19F NMR ( _CDCl3 : _CFCl3 ): δ-72.20 (double line, J=8.5Hz). IR (KBr): 1815cm ^-1 (ν _C=O ), 1685cm ^-1
(ν _C=N ). Mass spectrum: m/e (relative intensity) M ⁺ 269
(15), 105 (100), 77 (43), 51 (14). Elemental analysis: Actual value (%) Calculated value (%) C 57.83 58.00 H 3.77 3.74 N 5.16 5.20 698 mg of (Z)-azlactone synthesized above
(2.59 mmol) was added with 2 ml of an aqueous sodium hydroxide solution (120 mg/2 ml) and heated under reflux for 3 hours. The reaction solution was filtered while hot, acidified with hydrochloric acid, concentrated to 10 ml, and allowed to cool. The precipitated solid was filtered to obtain α-benzoylamino-β-(1-
Trifluoromethyl)ethyl acrylic acid 561mg
(yield 76%).

Melting point: 170-172℃. ¹ H NMR (CD ₃ OD: TMS): δ1.28 (doublet, J=7Hz, 3H), 3.40 (multiplet,
1H), 6.64 (double line, J=10Hz, 1H), 7.3
−8.0 (multiplet, 5H). ^19F NMR ( _CD3OD : _CFCl3 ): δ-72.04 (double line, J=9Hz). IR (KBr): 3250cm ^-1 (ν _NH ), 1715, 1645cm ^-1
(ν _C=O ), 1670cm ^-1 (C=C). Mass spectrum: m/e relative intensity M ⁺ 287
(1), 190 (9), 106 (8), 105 (100),
77(40), 51(10). Elemental analysis: Actual value (%) Calculated value (%) C 54.09 54.36 H 4.16 4.21 N 4.79 4.88 A 30 ml ethanol solution containing 734 mg (2.73 mmol) of the above (Z)-azlactone and 5 mg of sodium ethylate was heated under reflux for 6 hours. The ethanol was distilled off under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent was distilled off to give (Z)-α-benzoylamino-β-(1-
Ethyl trifluoromethyl)ethyl acrylate was obtained in a crude yield of 860 mg (100% yield). 602 mg (yield 70%) of pure product was obtained by recrystallization from chloroform-n-hexane.

Melting point: 97-98℃. ¹ H NMR (CDCl ₃ :TMS): δ1.34 (triplet, J=7Hz, 3H), 1.37 (doublet, J=
7Hz, 3H), 3.50 (multiplet, 1H), 4.31
(Quadruplet, J=7Hz, 2H), 6.56 (Doublet, J=10Hz, 1H), 7.3-8.0 (Multiplet,
6H). ^19F NMR ( _CDCl3 : _CFCl3 ): δ-72.40 (double line, J=8.5Hz). IR (KBr): 3250cm ^-1 (ν _NH ), 1735, 1645cm
^-1 (ν _C=O ), 1682cm ^-1 (C=C). Mass spectrum: m/e (relative intensity) M ⁺ 315
(2), 218 (12), 105 (100), 77 (33), 51
(7). Elemental analysis: Actual value (%) Calculated value (%) C 56.96 57.14 H 5.04 5.12 N 4.39 4.44 (Z)-α-benzoylamino-β-(1-trifluoromethyl)ethyl acrylic in a normal atmospheric hydrogenation apparatus. 134 mg (0.467 mmol) of acid, 100 mg of 10% palladium on carbon and 10 ml of ethanol as solvent
was added and stirred at 20°C for 14 hours under a hydrogen pressure of 1 atm, and the reaction was completed. The catalyst was filtered off, and the filtrate was concentrated to obtain 135 mg (100% yield) of N-benzoyl-5',5',5'-trifluoroleucine (diastereomer ratio 82:18).

Melting point: 173-178℃. ¹ H NMR (CD ₃ OD: TMS): δ1.23 (doublet, J=6.5Hz, 3H), 1.8−2.7 (multiplet,
3H), 4.80 (multiplet, 1H), 7.3−8.1 (multiplet, 5H). ^19F NMR ( _CD3OD : _CFCl3 ): δ-73.15 (double line, J=9Hz), -73.38 (double line, J=9Hz)
9Hz). IR (KBr): 3300cm ^-1 (ν _NH ), 1730, 1625cm
^-1 (ν _C=O ). Mass spectrum: m/e (relative intensity) M ⁺ 289
(1), 244 (5), 179 (8), 105 (100),
77(33), 51(10). Elemental analysis: Actual value (%) Calculated value (%) C 53.82 53.98 H 4.86 4.88 N 4.81 4.84 (Z)-α-benzoylamino-β-(1-trifluoromethyl)ethyl acrylic in a normal atmospheric hydrogenation apparatus. Ethyl acid 315 mg (1.00 mmol), 10%
297 mg of palladium on carbon and 15 ml of ethanol were added, and the mixture was stirred at 25°C under a hydrogen pressure of 1 atmosphere for 31 hours, and the reaction was completed. After filtering off the catalyst, ethanol was distilled off to obtain 317 mg of N-benzoyl-5',5',5'-trifluoroleucine ethyl ester (yield 100%).
(diastereomer ratio 84:16) was obtained.

Melting point: 54-57℃. ¹ H NMR (CDCl ₃ :TMS): δ1.28 (double line, J=7Hz, 3H), 1.31 (triplet line, J=
7Hz, 3H), 2.00 (multiple line, 2H), 2.30
(multiplet, 1H), 4.26 (quartet, 2H), 4.95
(multiplet, 1H), 6.79 (wide doublet, 1H),
7.3−8.0 (multiplet, 5H). ^19F NMR ( _CDCl3 : _CFCl3 ): δ-74.10 (double line, J=9Hz), -74.20 (double line, J=9Hz), -74.20 (double line, J=9Hz)
9Hz). IR (KBr): 3310cm ^-1 (ν _NH ), 1735, 1635cm
^-1 (ν _C=O ). Mass spectrum: m/e (relative intensity) M ⁺ 317
(0.5), 244 (12), 105 (100), 77 (41),
51(13). Elemental analysis: Actual value (%) Calculated value (%) C 56.65 56.78 H 5.66 5.72 N 4.36 4.41 Add 5 ml of 6N hydrochloric acid to 100 mg (0.346 mmol) of N-benzoyl-5',5',5'-trifluoroleucine and 100 After heating at °C for 24 hours, the reaction solution was dried under reduced pressure. Add 1 ml of boiling water and carefully neutralize with aqueous ammonia using a Congo Red indicator.
Alcohol was added and cooled. Precipitated 5′, 5′,
Filter off the white solid of 5′-trifluoroleucine,
Further, the filtrate was dried under reduced pressure, and the resulting solid was washed several times with cold water and then with alcohol to obtain 5',5',5'-trifluoroleucine. The total yield was 51.2 mg (80% yield).

¹ H NMR (D ₂ O:TSP): δ1.22 (double line,
J=6.8Hz, 3H), 1.6−2.9 (multiplet,
3H), 3.84 (wide triple line, J=7Hz,
2H). ¹⁹ F NMR (D ₂ O: CF ₃ COOH): δ5.53 (double line, J=9Hz), 5.65 (double line, J=9
Hz). IR (KBr): 1600cm ^-1 , 1420cm ^-1 (ν _COO −). Mass spectrum: m/e (relative intensity) M ⁺ 185
(0), 140 (100), 120 (16), 100 (25),
74(26), 43(23). The reaction was carried out in exactly the same manner as above using 127 mg (0.40 mmol) of N-benzoyl-5',5',5'-trifluoroleucine ethyl ester, and 5',
5',5'-trifluoroleucine 55.5 mg (yield 75
%) was obtained.

Reference Example 2 520 mg (4.13 mmol) of TFMPA was added to 4.1 ml of 2.2N sulfuric acid, cooled to 0°C, and 460 mg (2.91 mmol) of potassium permanganate was added little by little. 30
After stirring for a minute, 2.5 ml of 3.8N sulfuric acid was added, followed by sodium bisulfite until the reaction solution became colorless. The reaction solution was extracted with ether, the extract was dried over anhydrous sodium sulfate, the ether was distilled off, and 2-trifluoromethylpropionic acid 512
mg (yield 87%).

¹ H NMR (CDCl ₃ :TMS): δ1.48 (doublet, J=7.2Hz, 3H), 3.28 (multiplet,
1H), 10.18 (wide singlet, 1H). ^19F NMR ( _CDCl3 : _CFCl3 ): δ-70.57 (double line, J=8.1Hz). IR (neat): 1725cm ^-1 (ν _C=O ). Reference example 3 600 mg (15.8 mmol) of lithium aluminum hydride was suspended in 15 ml of ether, cooled to 0°C, and 15 ml of 6.00 g (47.6 mmol) of TFMPA was suspended in 15 ml of ether.
Ether solution was added dropwise. After heating under reflux for 1 hour, the mixture was hydrolyzed with dilute hydrochloric acid, extracted with ether, and the extract was dried over anhydrous sodium sulfate. Distillation of this ether solution yielded 6.10 g of crude 2-trifluoromethylpropanol (yield: 100
%)was gotten. Furthermore, it was preparatively purified using gas chromatography to produce 5.51 g of pure alcohol (yield:
90%).

^1H NMR (CDCl ₃ :TMS): δ1.18 (doublet, J=7Hz, 3H), 1.66 (singlet,
1H), 2.39 (multiple line, 1H), 3.68 (multiple line, J=11.4Hz, J=5.7Hz, 1H), 3.88
(Double double line, J=11.4Hz, J=5.8Hz,
1H). ^19F NMR ( _CDCl3 : _CFCl3 ): δ-7.181 (double line, J=9.0Hz). IR (neat): 3350cm ^-1 (ν _OH ). Reference Example 4 A solution of 2.30 g (18.0 mmol) of 2-trifluoromethylpropanol obtained in Reference Example 3 and 5.70 g (21.8 mmol) of triphenylphosphine in dimethylformamide (18 ml) was cooled to 0°C, and bromine was dissolved in orange. It was added until the color disappeared. After collecting volatile components under reduced pressure and pouring them into water, ether extraction,
It was washed with water and dried with calcium chloride. Distillation of this ether solution yielded 2.24 g of crude 2-trifluoromethylpropyl bromide (yield: 65
%)was gotten. The product was fractionated and purified by gas chromatography to obtain 1.86 g (yield 54%) of pure bromide.

¹ H NMR (CDCl ₃ :TMS): δ1.31 (doublet, J=6.9Hz, 3H), 2.60 (multiplet,
1H), 3.23 (double double line, J=10.5Hz, J=
9.0Hz, 1H), 3.62 (double double line, J=10.5
Hz, J=4.0Hz, 1H). ^19F NMR ( _CDCl3 : _CFCl3 ): δ-72.87 (double line, J=8.4Hz).

Claims (1)

[Claims] 1 2-trifluoromethylpropanal