CS243574B1 - Method of alfa-hydroxyphenones' acetals' esters' production - Google Patents

Description

(54) A process for the production of acetal esters of hydroxyphenones

The present invention relates to a process for the preparation of acetal esters of n-hydroxyphenones of the general formula I

OR ^{1 2}

Ar — C — CH — R ¹ (I)

O O

R R where

Ar is phenyl or naphthyl, optionally substituted with 1 to 2 alkyl substituents of 1 to 4 carbon atoms, alkoxy of 1 to 2 carbon atoms, halogen from chloro, bromo, or phenoxy,

R represents alkyl having 1 to 3 carbon atoms or together

R + R represents a -CH 2 CH 2 - group,

R @ ¹ denotes hydrogen or alkyl having 1 to carbon atoms and

R ² represents a R ³ CO or R ³ SO 2 group, wherein R ³ represents a methyl or phenyl or p-tolyl group.

Said compounds of formula I serve as intermediates in the manufacture of substituted arylalkanoic acids. To date, these compounds have been found to be highly effective drugs in the treatment of inflammatory diseases such as rheumatoid arthritis, osteoarthritis, Still's disease with significant antipyretic and analgesic effects (Chronicles of Drugs Discovery, Chapter 7, p. 149, J. Wiley, New York 1981). .

Typical representatives of this class of substances are 2- (4-isobutylphenyl) propionic acid (see, for example, British Patent Specification No. 1,167,198, U.S. Pat. No. 3,385,386), 2- (6-methoxy-2-naphthyl) propionic acid. (U.S. Pat. Nos. 3,904,682 and 3,955,012) and 2- (3-phenoxyphenyl) propionic acid (U.S. Pat. No. 3,600,437).

Higher 2- (substituted aryl-alkanoic acids) have found utility in agriculture both as growth regulators and as insecticides with significant pyrethroid activity (Angew. Chem. Int. Ed. Eng. 11, 460 (1972); J. Pathol. Bacteriol. 85, 361) (1963)).

Hitherto known processes for the preparation of the compounds of formula (I) consist in esterifying the α-hydroxyphenone acetals with alkyl or arylsulfonyl chlorides or acyl halides in a tertiary amine environment (see, e.g., Tetrahedron Lett. 1981, 4 205, Tetrahedron Lett. 1982, 527, Japanese Pat. 57144 234 and 57 146 730). This embodiment presents problems with isolation of the product from the excess organic base used, which also serves as solvent 1 as solvent.

Another disadvantage is the waste water treatment. In the process of EP 64,394, this esterification reaction is carried out with only a small excess of organic base and halogenated hydrocarbons are used as solvent.

The main disadvantage of this process is the disproportionately long reaction times and thus the increased requirements for bulky apparatuses.

Another disadvantage is the need to remove a small amount of undesirable impurities. From this, it is evident that the efficiency of the process is reduced.

These known processes are followed in a positive way by the process according to the invention, which partially or completely removes these deficiencies.

A process for the preparation of acetal esters of .alpha.-hydroxyphenones of the formula I starting from acetals of the formula II

OH

Ar — C — CH — R ¹ (II) / \

O O

R R where

Ar, R and R ¹ are as defined above, by treatment with an acyl halide in the presence of an organic base consists according to the invention in that the reaction is carried out in the presence of an acylating catalyst N-substituted imidazoles or in the 4-substituted pyridine in the reactants of an inert solvent wherein the molar ratio of the reactants alcohol of formula II: acylating agent:

The organic base: the acylation catalyst is 1: 1.0 to 1.5: 1.1 to 2.0: 0.22 to: 0.2, after the reaction is completed, water is added to the reaction mixture, the organic phase is separated off and after processing, the product of formula (I) is obtained.

The progress of the reaction can be monitored by thin layer chromatography. After completion of the reaction, the reaction mixture is diluted with water, the organic phase is separated, dried over anhydrous sodium or magnesium sulphate and, after distilling off the solvents, the product of formula I is obtained in high yield and purity.

The acylating agents used are halides, preferably carboxylic acid chlorides, such as acetic, propionic, benzoic or sulfonic acid chlorides, such as methanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride.

The organic base used to neutralize the hydrogen halide reaction is a tertiary amine, preferably triethylamine, diisopropylethylamine or pyridine. Suitable solvents inert to the reactants include chlorinated hydrocarbons having 1 to 2 carbon atoms and 2 to 4 chlorine atoms, such as dichloromethane, dichloroethane, carbon tetrachloride, trichlorethylene or aromatic hydrocarbons, preferably benzene and toluene. The acylation catalysts are based on N-substituted imidazoles containing C 1 -C 3 -alkyl or benzyl or 4 substituted pyridines from the group of dimethylamino-, methyl-, phenoxypyridine.

The process of the invention has a number of advantages. The presence of the acylation catalyst greatly increases the reaction rate and thus substantially reduces reaction times and energy consumption, the product is readily isolated in high yields and purity, available and inexpensive reagents and solvents are used, wastewater does not require expensive purification. From the above, the technological and economic advantages of the process according to the invention are obvious.

The process according to the invention is illustrated by several exemplary embodiments, which are illustrative only and do not limit the scope of the invention in any way.

Example 1

To a mixture of 9 g of the alcohol of formula II wherein Ar = 4-isobutylphenyl, R = R ¹ = CH 3, 10.2 g of p-toluenesulfonyl chloride, 0.21 g 4-dimethylaminopyridine in 80 mL of dichloroethane was added dropwise over 30 minutes 7.2 g of triethylamine. After stirring at 20-25 ° C for 1 hour, the organic phase was separated, washed with water and dried over magnesium sulfate. After evaporation of the solvents, 14.0 g (96%) of the ester of the general formula were obtained

I, wherein Ar-4-isobutylphenyl, R = R ^X = CH 3, R 5 = p-toluenesulfonyl, mp 64-66 ° C.

Example 2

To a solution of 15 g of an alcohol of formula

II, where Ar = 5-bromo-6-methoxy-2-naphthyl, R = Rt = CH3, and 0.39 g of 4-methylpyridine in 150 ml of dichloroethane, dropwise with external ice cooling, 7.2 g of methanesulfonyl chloride and then 5 g of pyridine within 30 minutes. The reaction mixture was stirred for another 30 minutes at room temperature, diluted with 150 ml of water, the organic phase separated and after analogous work-up as in Example 1, crystallization from benzene / heptane gave 17.1 g of the ester of formula I wherein Ar = 5-bromo -6-methoxy-2-naphthyl, Ρ = Ρ ⁴ = = CH 3, R 2 = CH 3 SO ₂ , mp 135-138 ° C. Example 3

To a solution of 2.76 g of the alcohol of formula II wherein Ar = 6-methoxy-2-naphthyl, R = R ¹ = CH 3, 0.082 g of N-methylimidazole, 1.3 g of triethylamine in 25 ml of toluene was stirred at At 0-5 ° C, 1.25 g of methanesulfonyl chloride was added over 10 minutes, and after stirring for an additional half hour at this temperature 243574, the reaction mixture was filtered, the filtrate washed with water and dried over anhydrous sodium sulfate.

Evaporation of the solvents afforded 3.40 g (96%) of the ester of formula I where Ar = 6-methoxy-2-naphthyl, R = R ¹ = CH 3, R ² = CH3SO2, as an oil. NMR Spectrum (CDCl3):

1.18 d (Jhh = 7 Hz),

3.19 s,

3.24 s,

3.35 s,

3,87 s,

5.11 q,

7.06 to 7.30 m,

7.46 to 8.00 m is in accordance with the proposed structure.

Example 4

To a solution of 28.8 g of the alcohol of formula II wherein Ar = 3-phenoxyphenyl, R ¹ -R = CH 3 in 200 ml of toluene, under stirring at 5-10 ° C was added 12.1 g of triethylamine and 1.22 g of 4- dimethylaminopyridine. Then, 13.7 g of methanesulfonyl chloride were added dropwise over 10 minutes and stirred at the same temperature for 20 minutes.

After diluting the reaction mixture 200 ml of ice water, the product was isolated as described in Example 1. 35.8 g (98 percent] of the ester of formula I where Ar = 3-phenoxyphenyl, R = R ¹ = CH 3, R ² = CH3SO2 , in the form of a yellowish oil.

NMR Spectrum (CDCl3):

1.09 s,

3.15 s,

3.36 s,

3.42 s,

5.08 s,

6.60 to 8.24 m is in accordance with the proposed structure.

Example 5

Following the procedure of Example 1, 2.28 g of the alcohol of formula II wherein Ar = 4-t-butylphenyl, R = CH3, ^R1 = CH (CH3) 2, 1.2 g of pyridine, 0.17 g of 4- of phenoxypyridine, 1.72 g of methanesulfonyl chloride in 20 mL of dichloromethane prepared 3.4 g (95%) of an ester of formula I wherein Ar = tert-butylphenyl, R = CH3, R1 = CH (CH3) 2, R2 = CH3SO2, 1.1 . Mp 84-87 ° C.

Example 6

The procedure of Example 1, from 5.6 g of the alcohol of formula II wherein Ar = 4-isobutylphenyl, R = C2H5, ^R1 = CH3, 2.22 g of triethylamine, 0.12 g of 4-dimethylaminopyridine and 3, 88 g benzenesulfonyl chloride in 30 ml of chloroform to afford 7.64 g of the ester of formula I wherein Ar = 4-isobutylphenyl, R = C2H5, R ¹ = R ² = CH5 CeHsSO2.

NMR Spectrum:

0.89 d (J _H '= 7.1 Hz),

1,12 t,

1,64 t,

2,42 d,

3.96 q,

4,22 q,

5.03 q,

6.75 to 7.42 m,

7.84 d coPass with the proposed structure.

Example 7

To a mixture of 2.77 g of an alcohol of formula II wherein Ar = 6-methoxy-2-naphthyl, R = R * = CH ₃ , 0.1 g of N-benzylimidazole, 1.2 g of pyridine in 50 ml of 1.2 -dichloroethane, while stirring at 10 ° C, was added 1.18 g of acetyl chloride in 5 ml of 1,2-dichloroethane. After work-up as in example 1 yielded 2.99 g (94%] of the product of formula I where Ar - 6-methoxy-2-naphthyl, R = R = CH5, R ² = CH5CO whose NMR spectrum was in accordance with the proposed structure.

Example 8

To a solution of 5.0 g of an alcohol of formula II wherein Ar = 4-isobutylphenyl, R ¹ = R ² = CH 2 CH 2, R ¹ = CH 3 in 100 mL of dichloromethane was added with stirring at 20 ° C 0.24 g of 4-dimethylaminopyridine and 2,4 g of pyridine and then 4.22 g of benzoyl chloride in one portion. After stirring for 2 hours, 0.5 ml of water was added and after 15 minutes 10 ml of water, the organic phase was separated, washed and dried, the solvents were distilled off to give 6.37 g (90%) of the product of formula I where Ar = 4-isobutylphenyl R ¹ = CH 2 CH 2, R ¹ = CH ² , R ² = C 6 H 5 CO, m.p. 96-101 ° C.

Claims (4)

SUBJECT A process for preparing acetal esters of α-hydroxyphenones of the general formula I OR ² Ar — C — CH — R ¹ (I) / \ O O R R where Ar is phenyl or naphthyl, optionally substituted with 1 to 2 alkyl substituents of 1 to 4 carbon atoms, alkoxy of 1 to 2 carbon atoms, halogen from chloro, bromo, or phenoxy, R represents alkyl having 1 to 3 carbon atoms or together R + R represents a -CH 2 CH 2 - group, R ¹ · represents hydrogen or alkyl containing 1-3 carbon atoms and R ² represents R ³ CO or SO 2 R ³ group wherein R ³ is methyl or phenyl or p-tolyl, α-acetals of hydroxyfenonů 0becného formula II OH Ar — C — CH — R ¹ (II) / \ O O R R I will invent where Ar, R ¹ and R ¹ are as defined above, by the action of acyl halides in the presence of an organic base, characterized in that the reaction is carried out in the presence of an acylation catalyst based on N-substituted imidazole containing C 1 -C 3 alkyl or benzyl; dimethylamino-, phenoxy- or methylpyridine in the medium to the inert solvent reactants, wherein the molar ratio of the alcohol of the formula II: acylating agent: organic base: acylating catalyst is from 1: 1.0 to 1.5:: 1.1 to 2.0: 0.02 to 0.2, after which the reaction mixture is diluted with water after completion of the reaction and the product of formula I is isolated from the organic phase. 2. Process according to claim 1, characterized in that aromatic hydrocarbons or chlorinated hydrocarbons having 1 to 2 carbon atoms and 2 to 4 chlorine atoms are used as solvents inert to the reactants. 3. The process according to claim 1, wherein from 0.05 to 0.1 mol of acylation catalyst is used per mole of alcohol of formula II. 4. The process of claim 1, wherein the reaction is carried out at a temperature of 0 to 35 ° C.