PROCESS FOR THE PREPARATION OF 1-[4-NITRO-2-(TRIFLUOROMETHYL)PHENYL]-ALKANONES

Abstract

The present invention relates to a process for the preparation of 1-[4-nitro-2-(trifluoromethyl)-phenyl]-alkanones and substituted phenoxyphenyl ketones.

Claims

1. A process for the preparation of a compound of formula (I) ##STR00010## wherein R.sup.1 is C.sub.1-C.sub.4-Alkyl; comprising: (i) reacting a compound of formula (II) ##STR00011## with an aqueous solution of an inorganic base selected from hydroxides, carbonates or phosphates of alkali or earth alkali metals, or aluminium hydroxide or any mixtures thereof in the presence of an organic base selected from amidine and guanidine bases, in an inert organic solvent, wherein the reaction is heterophase and the organic base is used in an amount of 0.001 to 0.3 mol equivalents per 1 mol of compound (II).

2. The process of claim 1, wherein the organic base has a general formula (B1) or (B2), ##STR00012## wherein X is —(CH.sub.2).sub.n—, where n is an integer from 2 to 4; Y is —(CH.sub.2).sub.m—, where m is an integer from 2 to 5; A is CH.sub.2, NH or NR′, where R′ is C.sub.1-C.sub.4-alkyl or acyl; R.sup.2, R.sup.3, R.sup.5 and R.sup.6 each independently is hydrogen, C.sub.1-C.sub.4-alkyl or C.sub.3-C.sub.6-cycloalkyl; with a provisio that all four of R.sup.2, R.sup.3, R.sup.5 to R.sup.6 are not hydrogen, and R.sup.7 is H, C.sub.1-C.sub.4-alkyl or C.sub.3-C.sub.6-cycloalkyl.

3. The process of claim 1, wherein the organic base is selected from the group consisting of: 1,8-diazabicyclo[5,4,0]undec-7-en (DBU), 1,5-diazabicyclo[4,3,0]non-5-ene (DBN): 1,5,7-triazabicyclo[4,4,0]dec-5-ene (TBD), 7-methyl-1,5,7-triazabicyclo[4,4,0]dec-5-ene (MTBD); and alkyl guanidines: tetra-methyl guanidine (TMG), tetra-butyl guanidine, penta-methyl guanidine, penta-butyl guanidine, and N′-butyl-N″,N″-dicyclohexylguanidine.

4. The process of claim 1, wherein the organic base is DBN or DBU.

5. The process of claim 1, wherein the organic base is DBU.

6. The process of claim 1, wherein the inorganic base is selected from the group consisting of KOH, NaOH, CsOH, K.sub.2CO.sub.3, Na.sub.2CO.sub.3, and Cs.sub.2CO.sub.3.

7. The process of claim 1, wherein the inorganic base is selected from KOH or NaOH.

8. The process of claim 1, wherein the inorganic base is used in an amount from 0.7 to 5 mole per 1 mole of compound (II).

9. The process of claim 1, wherein the reaction is carried out in a chlorinated aliphatic solvent.

10. The process of claim 1, wherein the reaction is carried out in 1,2-dichloroethane.

11. The process of claim 1, wherein the compound (II) is prepared by (ii) reacting a compound of formula (III) ##STR00013## with nitric acid, wherein the nitric acid is used in an amount of 2 to 20 mole equivalents per 1 mole of the compound (II).

12. The process of claim 11, wherein the step (ii) is carried out in a chlorinated aliphatic solvent.

13. The process of claim 12, wherein the solvent is 1,2-dichloroethane.

14. A process for preparation of a compound (IV) ##STR00014## wherein R.sup.1 is C.sub.1-C.sub.4-alkyl; comprising: (i) providing a compound (I); ##STR00015## (iii) reacting the compound (I) with a phenol derivative of formula (V) ##STR00016## wherein R″ is hydrogen or an alkali metal ion; R.sup.4 is halogen; in the presence of a base.

Description

EXAMPLE 1

Synthesis of Compound (II), R.SUP.1.═CH.SUB.3

[0136] 12.5 mL 100% nitric acid (0.30 mol) was treated with 25 mL 96% sulfuric acid (0.47 mol) with cooling. 2.9 g molten α-methyl-2-(trifluoromethyl)-benzyl alcohol (15 mmol) was added to the mixture within 10 min while keeping the temperature at 0-5° C. After 15 min a solid precipitated from the mixture. The entire mixture was poured into 250 ml cold water and the product extracted with 50 mL CH.sub.2Cl.sub.2. The organic phase was washed with aqueous sodium bicarbonate and water. The CH.sub.2Cl.sub.2was removed by rotary evaporation keeping the temperature below 25° C. The product was obtained as an oil which solidified upon standing in a few minutes. Yield 4.1 g, (14.6 mmol), 97% by qualitative HPLC, essentially pure by NMR.

[0137] .sup.1H-NMR: (500 MHz, CDCl.sub.3): 8.58 (d, 1H, J=2.0 Hz), 8.48 (dd, 1H, J=8.6, 2.0 Hz), 7.89 (d, 1H, J=8.6 Hz), 6.32 (q, 1H, J=6.6 Hz), 1.65 (d, 3H, J=6.6 Hz) ppm.

[0138] .sup.13C-NMR: (125 MHz, CDCl.sub.3): 20.8, 76.3 (q, J=2.5 Hz), 121.9 (q, J=6.0 Hz), 122.7 (q, J=275 Hz), 127.6, 127.7, 128.7 (q, J=33.1 Hz), 145.9, 147.5

EXAMPLE 2

Synthesis of Compound (II), R.SUP.1.═CH.SUB.3

[0139] 10 g 65% nitric acid (0.10 mol) was treated with 31 g 98% sulfuric acid (0.31 mol) with cooling. 5.0 g molten α-methyl-2-(trifluoromethyl)-benzyl alcohol (26 mmol) was added to the mixture while the temperature was allowed to reach 50-55° C. The mixture cooled down to 23° C. and was post-stirred for 1 h before it was poured into 65 g of cold water. The temperature reached 55° C. The precipitated product was filtered and washed with 15 g water, followed by 2×15 g 5% aqueous sodium bicarbonate solution and 2×15 g water. The product was dried at 60° C./80 mbar. Yield 6.5 g, (24.3 mmol), 97% by qualitative HPLC, essentially pure by NMR.

EXAMPLE 3

Synthesis of Compound (II), R.SUP.1.═CH.SUB.3

[0140] 28.5 g 99% nitric acid (0.45 mmol) was added slowly to 105 g 98% sulfuric acid (1.05 mol) with cooling. 61.5 g 1,2-dichloroethane was added. 28.5 g α-methyl-2-(trifluoromethyl)-benzyl alcohol (0.15 mol), dissolved in 28.5 g 1,2-dichloroethane, was added within 48 min while keeping the temperature at 19-23° C. The biphasic mixture was post-stirred for 5 h. The phases were separated. The organic phase contained 98% yield of the desired product by quantitative HPLC.

EXAMPLE 4

Synthesis of Compound (II), R.SUP.1.═CH.SUB.3

[0141] 18.4 g 98% sulfuric acid (184 mmol) is added to nitric acid 11.7 g 99% nitric acid (184 mmol) at 0° C. to form nitrating acid. α-methyl-2-(trifluoromethyl)-benzyl alcohol (5 g, 26.3 mmol) is dissolved in 1,2-dichloromethane (15 mL). Said solution and the nitrating acid are dosed to a continuous reactor maintained at 40° C. with a rate of an approximately 2 mL/min per solution. The reactor is rinsed with 1,2-dichloromethane (12 mL) after the dosing is finished. The combined phases are collected, the organic phase is separated and characterized via HPLC. The content of the desired product is 20.9% w/w (yield 91%).

EXAMPLE 5

Synthesis of Compound (II), R.SUP.1.═CH.SUB.3

[0142] α-methyl-2-(trifluoromethyl)-benzyl alcohol (28.5 g, 150 mmol) was dissolved in 1,2-dichloroethane (90 g) and the solution cooled to 0° C. A mixture of 11.2 g nitric acid (99%, 0.18 mol, 1.2 eq) and 17.7 g sulfuric acid (98%, 0.18 mol, 1.2 eq) was added within 27 min under intensive stirring, keeping the temperature at 0-5° C. Stirring was continued for 90 min at 5° C. and the phases were separated. The upper organic phase containing α-methyl-2-(trifluoromethyl)-benzyl nitrate was left in the reactor. A mixture of 14.0 g nitric acid (99%, 0.22 mol, 1.5 eq) and 29.4 g sulfuric acid (98%, 0.30 mol, 2.0 eq) was added within 30 min under intensive stirring, keeping the temperature at 2-9° C. The mixture was post-stirred over night at 15-20° C. The phases were separated and the organic phase (109.9 g) was analyzed. The content of the desired product was 34.2% w/w (134 mmol, yield 89%).

[0143] The isolated dry product (compound (I)) is shock-sensitive.

EXAMPLE 6

Synthesis of Compound (I), R.SUP.1.═CH.SUB.3

[0144] 2.1 g DBU (14 mmol, 5 mol %) was placed together with 32 g water and 55.5 g 1,2-dichloroethane (DCE) in a reaction vessel at 15° C. A solution of 1-[4-nitro-2-(trifluoromethyl)phenyl]ethyl nitrate in DCE (251.2 g, 30.5 wt %, 273 mmol) was added under vigorous stirring at a rate of 1.1 mL/min. In parallel, an aqueous solution of KOH (103 g, 50 wt %, 917 mmol, 3.36 eq) is added at such a rate that kept the pH constant at 14. After complete addition, the mixture was warmed to 20° C. and stirred overnight. 172 g water was added and the phases were separated. The organic phase was washed with aqueous sulfuric acid (35 g, 2.7 wt %, 10 mmol, 3.5 mol %). Quantitative HPLC revealed the presence of 59.0 g 1-[4-nitro-2-(trifluoromethyl)phenyl]ethanone in the organic phase (253 mmol, 93% yield).

[0145] .sup.1H-NMR: (500 MHz, CDCl.sub.3): 8.58 (d, 1H, J=2.1 Hz), 8.48 (dd, 1H, J=8.6, 2.3 Hz), 7.65 (d, 1H, J=8.6 Hz), 2.63 (s, 3H) ppm.

EXAMPLE 7

Synthesis of Compound (I), R.SUP.1.═CH.SUB.3

[0146] A solution of 1-[4-nitro-2-(trifluoromethyl)phenyl]ethyl nitrate in DCE (276.4 g, 28.0 wt %, 276 mmol) was placed in a reaction vessel. 2.1 g DBU (14 mmol, 5 mol %) was added together with 32 g water at 15° C. Under vigorous stirring, an aqueous solution of NaOH (23.2 g, 50 wt %, 290 mmol, 1.05 eq) is added at such a rate that allows to keep the temperature of the reaction mixture below 20° C. After complete addition, the mixture was warmed to 20° C. and stirred for 3 h. A second portion of aqueous NaOH (11.1 g, 50 wt %, 138 mmol, 0.5 eq) was added and the mixture stirred overnight to bring the reaction to completion. 174 g water and 56 g DCE was added and the phases were separated. The organic phase was washed with aqueous sulfuric acid (35.4 g, 2.8 wt %, 10 mmol, 3.6 mol %). Quantitative HPLC revealed the presence of 62.5 g 1-[4-nitro-2-(trifluoromethyl)phenyl]ethanone in the organic phase (268 mmol, 97% yield).

COMPARATIVE EXAMPLE 1

Inorganic Base with Addition of the Phase Transfer Catalyst

[0147] A solution of 1-[4-nitro-2-(trifluoromethyl)phenyl]ethyl nitrate in DCE (7.1 g, 28.2 wt %, 7.2 mmol) was mixed with aqueous NaOH solution (1.0 g, 30 wt %, 7.5 mmol) and 0.19 g tetrabutylammonium bromide (0.6 mmol, 8 mol %). The mixture was stirred at 20° C. Qualitative HPLC showed the following composition (area %):

TABLE-US-00001 1-[4-nitro-2-(trifluoro- Starting material 45.3% 13.4 min methyl)phenyl]ethyl nitrate 1-[4-nitro-2-(trifluoro- Product 39.4% 10.1 min methyl)phenyl]ethanone 1-[4-hydroxy-2-(trifluoro- Side product A 6.0%  6.9 min methyl)phenyl]ethanone 1-[4-nitro-2-(trifluoro- Side product B 4.9%  9.4 min methyl)phenyl]ethanol

COMPARATIVE EXAMPLE 2

Inorganic Base Without Addition of DBU

[0148] A solution of 1-[4-nitro-2-(trifluoromethyl)phenyl]ethyl nitrate in DCE (2.4 g, 23.8 wt %, 2.0 mmol) was diluted with 4.9 g THF. Aqueous KOH solution (0.42 g, 50 wt %, 3.7 mmol) was added and the mixture stirred for 24 h at 20° C. Qualitative HPLC showed the following composition (area %):

TABLE-US-00002 1-[4-nitro-2-(trifluoro- Starting material 72.9% 13.4 min methyl)phenyl]ethyl nitrate 1-[4-nitro-2-(trifluoro- Product 17.6% 10.1 min methyl)phenyl]ethanone 1-[4-nitro-2-(trifluoro- Side product B 1.7%  9.4 min methyl)phenyl]ethanol 1-[4-nitro-2-(trifluoro- Side product C 2.9%  5.9 min methyl)phenyl]ethanol

EXAMPLE 8

Synthesis of Compound (IV), R.SUP.1.═CH.SUB.3

[0149] ##STR00009##

[0150] To a stirred solution of 4-nitro-2-trifluoromethyl-acetophenone (5 g, 0.02 mol) in DMF (225 mL) at 25° C. was added a potassium carbonate (2 g, 0.015 mol) and 4-chlorophenol (2.9 g, 0.022 mol). The reaction mixture was heated to 125° C. and stirred for 3 h at this temperature. Thereafter, the reaction mixture cooled down to 25° C. Water (25 mL) and toluene (25 mL) were added. The organic layer was separated, washed with aqueous NaOH (10 mL, 0.02 mol), then with water (15 mL) and concentrated under vacuum to compound give 4-(4-chlorophenyloxy)-2-trifluoromethyl-acetophenone (6 g, Yield:86.37% HPLC purity: 96.88%) as a dark brown oil.