PROCESS FOR PREPARING 2,6-DIALKYLPHENYLACETIC ACIDS

Abstract

The invention relates to a multi-stage process for preparing 2,6-dialkylphenylacetic acids of the general formula (I) by reacting 2,6-dialkylbromobenzenes with (1) magnesium, (2) a formamide, (3) an acid, (4) hydrogenation of the benzaldehyde obtained, (5) activation of the benzyl alcohol obtained, (6) cyanation of the activated benzyl alcohol and (7) hydrolysis of the nitrile obtained.

Claims

1. Process for preparing compounds of formula (I) ##STR00033## in which R.sup.1 and R.sup.2 independently of one another represent C.sub.1-C.sub.6-alkyl, and R.sup.3 represents hydrogen, C.sub.1-C.sub.6-alkyl, fluorine or chlorine, (1) reacting one or more compounds of formula (II) ##STR00034## in which R.sup.1, R.sup.2 and R.sup.3 have the definitions given above, with magnesium in the presence of a solvent to give one or more compounds of formula (III), ##STR00035## in which R.sup.1, R.sup.2 and R.sup.3 have the meanings given above; (2) the one or more compounds of formula (III) are reacted with one or more compounds of formula (IV) ##STR00036## in which R.sup.4 and R.sup.5 independently of one another represent C.sub.1-C.sub.6-alkyl or together represent —(CH.sub.2).sub.2—X—(CH.sub.2).sub.2—, wherein X represents CH.sub.2, oxygen or sulfur, to give a compound of formula (V) ##STR00037## in which R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 have the definitions given above; (3) the one or more compounds of formula (V) are reacted by hydrolysis under acidic conditions to give one or more compounds of formula (VI) ##STR00038## in which R.sup.1, R.sup.2 and R.sup.3 have the definitions given above, (4) one or more compounds of formula (VI) are hydrogenated to give one or more compounds of formula (VII) ##STR00039## in which R.sup.1, R.sup.2 and R.sup.3 have the definitions given above, in the presence of a catalyst; (5) one or more compounds of formula (VII) are reacted to give one or more compounds of formula (VIII) ##STR00040## in which R.sup.1, R.sup.2 and R.sup.3 have the definitions given above, and Y represents chlorine, bromine, OSO.sub.2Me, OSO.sub.2(4-Me-Ph) or OSO.sub.2CF.sub.3, (6) one or more of the compounds of formula (VIII) are reacted with a cyanide of formula (IX)
MCN  (IX), in which M represents lithium, sodium or potassium, to give one or more compounds of formula (X) ##STR00041## in which R.sup.1, R.sup.2 and R.sup.3 have the definitions given above; (7) one or more of the compounds of formula (X) are hydrolysed under acidic or basic conditions to give one or more compounds of formula (I) ##STR00042## in which R.sup.1, R.sup.2 and R.sup.3 have the definitions given above.

2. Process according to claim 1, where R.sup.1 and R.sup.2 independently of one another represent C.sub.1-C.sub.6-alkyl, R.sup.3 represents hydrogen or chlorine, R.sup.4 and R.sup.5 independently of one another represent C.sub.1-C.sub.6-alkyl or together represent —(CH.sub.2).sub.2—X—(CH.sub.2).sub.2—, wherein X represents CH.sub.2, oxygen or sulfur, Y represents chlorine, bromine, OSO.sub.2Me, OSO.sub.2(4-Me-Ph) or OSO.sub.2CF.sub.3, M represents lithium, sodium or potassium.

3. Process according to claim 1, where R.sup.1 and R.sup.2 independently of one another represent methyl or ethyl, R.sup.3 represents hydrogen or chlorine, R.sup.4 and R.sup.5 independently of one another represent C.sub.1-C.sub.6-alkyl or together represent —(CH.sub.2).sub.2—O—(CH.sub.2).sub.2— Y chlorine, bromine, OSO.sub.2Me, OSO.sub.2(4-Me-Ph) or OSO.sub.2CF.sub.3, M represents lithium, sodium or potassium.

4. Process according to claim 1, where R.sup.1 and R.sup.2 independently of one another represent methyl or ethyl, R.sup.3 represents hydrogen or chlorine, R.sup.4 and R.sup.5 independently of one another represent methyl or n-butyl or together represent —(CH.sub.2).sub.2—O—(CH.sub.2).sub.2—, Y represents chlorine or bromine, M represents sodium or potassium.

5. Process according to claim 1, where R.sup.1 and R.sup.2 represent methyl, R.sup.3 represents chlorine, R.sup.4 and R.sup.5 represent methyl, Y represents chlorine or bromine, M represents sodium.

6. Process according to claim 1, where R.sup.1 and R.sup.2 represent methyl, R.sup.3 represents hydrogen, R.sup.4 and R.sup.5 represent methyl, Y represents chlorine or bromine, M represents sodium.

7. Process according to claim 1, wherein, for the hydrogenation in (4), one or more catalysts with the metal ruthenium, cobalt or nickel are employed.

8. Process according to claim 1, wherein, for the hydrogenation in (4), Raney cobalt is used as catalyst.

9. Process according to claim 1, wherein, for the hydrogenation in (4), Raney nickel is used as catalyst.

10. Process according to claim 1, wherein, for the hydrogenation in (4), [2-(aminomethyl)pyridine](dichloro)(diphenylphosphinobutane)ruthenium (II) is used as catalyst.

11. Compound of formula (V) ##STR00043## in which R.sup.1 and R.sup.2 independently of one another represent C.sub.1-C.sub.6-alkyl, and R.sup.3 represents hydrogen, C.sub.1-C.sub.6-alkyl, fluorine or chlorine, R.sup.4 and R.sup.5 independently of one another represent C.sub.1-C.sub.6-alkyl or together represent —(CH.sub.2).sub.2—X—(CH.sub.2).sub.2—, wherein X represents CH.sub.2, oxygen or sulfur, excluding the compound of formula (V) in which R.sup.1 and R.sup.2 represent methyl, R.sup.3 represents hydrogen and R.sup.4 and R.sup.5 represent methyl.

12. Compound of formula (VIII) ##STR00044## in which R.sup.1 and R.sup.2 independently of one another represent C.sub.1-C.sub.6-alkyl, and R.sup.3 represents hydrogen, C.sub.1-C.sub.6-alkyl, fluorine or chlorine, and Y represents OSO.sub.2Me, OSO.sub.2(4-methylphenyl) or OSO.sub.2CF.sub.3, excluding the following compounds ##STR00045##

13. Compound of formula (VIII) according to claim 12, in which R.sup.1 and R.sup.2 independently of one another represent methyl or ethyl, R.sup.3 represents hydrogen or chlorine, and Y represents OSO.sub.2Me, OSO.sub.2(4-methylphenyl) or OSO.sub.2CF.sub.3.

14. Compound of formula (VIII) according to claim 12, in which R.sup.1 and R.sup.2 represent methyl, R.sup.3 represents hydrogen or chlorine, and Y represents OSO.sub.2Me, OSO.sub.2(4-methylphenyl) or OSO.sub.2CF.sub.3.

15. Compound of formula (VIII) according to claim 12, in which R.sup.1 and R.sup.2 represent methyl, R.sup.3 represents chlorine, and Y represents OSO.sub.2Me, OSO.sub.2(4-methylphenyl) or OSO.sub.2CF.sub.3.

16. Compound of formula (VIII) according to claim 12, in which R.sup.1 and R.sup.2 represent methyl, R.sup.3 represents hydrogen, and Y represents OSO.sub.2Me, OSO.sub.2(4-methylphenyl) or OSO.sub.2CF.sub.3.

Description

EXAMPLES

Example 1: (4-chloro-2,6-dimethylphenyl)magnesium bromide

[0173] ##STR00015##

[0174] 2.67 g [109.9 mmol] of magnesium turnings and a small crystal of iodine are initially charged in a 250 ml three-necked flask under argon. The flask contents are heated by a hot air gun, with stirring, until iodine vapour is visible. Approximately 10 ml of a solution of 21.7 g [99 mmol] of 4-chloro-2,6-dimethylbromobenzene in 100 ml tetrahydrofuran (THF) are added thereto and heated to 50° C. until the start of reaction becomes discernible. The remaining reactant solution is then slowly metered in, with the internal temperature being kept at 50° C. by cooling. Stirring is subsequently continued for a further hour.

Example 2: (4-chloro-2,6-dimethylphenyl)magnesium bromide

[0175] ##STR00016##

[0176] 20.05 g [0.825 mol] of magnesium turnings are initially charged in a 2 1 jacketed vessel under argon. Firstly, 50 ml of the solution from example 1 are added thereto at 25° C., and then 25 g of a solution of 164.6 g [0.75 mol] of 4-chloro-2,6-dimethylbromobenzene in 565 ml THF are added thereto. The start of the reaction is clear by the exothermy. The remaining amount of the reactant solution is then metered in within 2.5 hours such that the internal temperature does not exceed 33° C. At the end, further stirring is then carried out at 35° C. for one hour. Stirring a small batch sample into a THF solution of iodine and subsequent HPLC analysis shows complete conversion of the 4-chloro-2,6-dimethylbromobenzene.

Example 3: (4-chloro-2,6-dimethylphenyl)(dimethylamino)methoxide magnesium bromide

[0177] ##STR00017##

[0178] A solution of 54.8 g [0.75 mol] of N,N-dimethylformamide (DMF) in 185 ml of THF is metered in to the solution from example 2 in a 2 1 jacketed vessel at 27-35° C. within approximately one hour. Stirring is subsequently continued for a further hour at 27-35° C. The product obtained is used in the next step without further work-up.

Example 4: 4-chloro-2,6-dimethylbenzaldehyde

[0179] ##STR00018##

[0180] 402 g of semiconcentrated hydrochloric acid are metered into the reaction mixture from example 3 in a 2 1 jacketed vessel at 15° C. so that the pH drops to 1. The reaction mixture is emptied, the phases are separated, the aqueous phase is extracted three times with in each case 200 ml of methyl tert-butyl ether (MBTE), the combined organic phases are washed with 100 ml of saturated aqueous sodium chloride solution, drying is carried out over sodium sulfate and concentration is carried out under reduced pressure. 131.5 g of yellowish solid are obtained. After removal of the low-boiling impurities at 100° C. and 6 mbar, 123.4 g of yellowish solid remain which contains 90.7% of the title compound according to GC analysis, which corresponds to a yield of 83% of theory, based on the starting material in example 2.

[0181] GC/MS: m/e=167 ((M-1)+, .sup.35Cl, 100%), 139 (M-29, 45%).

[0182] .sup.1H-NMR (600 MHz, CDCl.sub.3): δ=2.59 (s, 6H), 7.09 (s, 2H), 10.55 (s, 1H) ppm.

[0183] Melting point: 59° C.

Example 5: 4-Chloro-2,6-dimethylbenzyl alcohol

[0184] ##STR00019##

[0185] 120.8 g of 4-chloro-2,6-dimethylbenzaldehyde with a purity of 89.2% [0.639 mol] in 480 ml of ethanol are initially charged in a 2 1 autoclave. 3.6 g of Raney cobalt (Actimet: in each case washed three times with water and ethanol) are added thereto, the autoclave is closed, flushed twice with argon and hydrogenation is then carried out for 16 hours at 100° C. and 30 bar of hydrogen pressure. After cooling to room temperature and venting, the reaction mixture is filtered through Celite and the filtrate is concentrated under reduced pressure. 115.6 g of product are obtained which consists of 90.4% of the title compound according to quantitative .sup.1H-NMR, which corresponds to a yield of 95.8% of theory.

[0186] GC/MS: m/e=170 (M.sup.+, .sup.35Cl, 35%), 152 (M-18, .sup.35Cl, 100%).

[0187] .sup.1H-NMR (600 MHz, d.sub.6-DMSO): δ=2.34 (s, 6H), 4.44 (d, J=5.3 Hz, 2H), 4.75 (t, J=5.3 Hz, 1H), 7.06 (s, 2H) ppm.

[0188] Melting point (on 98.3% purified compound): 110.6° C.

Example 6: 4-Chloro-2,6-dimethylbenzyl alcohol

[0189] ##STR00020##

[0190] A solution of 1 g of 4-chloro-2,6-dimethylbenzaldehyde with a purity of 94% in 10 ml of tetrahydrofuran is added to an autoclave and 8 mg of [2-(aminomethyl)pyridine](dichloro)(diphenylphosphinobutane)ruthenium (II) (CAS 850424-32-7) and 16 μl of a 1.7 M solution of potassium tert-butoxide in THF are added thereto. The autoclave is flushed twice with 10 bar argon and 50 bar of hydrogen is then applied thereto for 18 hours at 50° C. After cooling to room temperature and venting, the title compound is obtained with a purity of 91.7% according to GC/MS analysis.

[0191] GC/MS: m/e=170 (M.sup.+, .sup.35Cl, 35%), 152 (M-18, .sup.35Cl, 100%).

Example 7: 2-(Bromomethyl)-5-chloro-1,3-dimethylbenzene

[0192] ##STR00021##

[0193] 8.53 g [50 mmol] of 4-chloro-2,6-dimethylbenzyl alcohol in 60 ml of 48% strength aqueous hydrobromic acid are heated for 4 hours at 92° C. The reaction mixture is cooled to room temperature and 50 ml of methylene chloride are added thereto. The phases are separated and the aqueous phase is extracted twice with 50 ml of methylene chloride each time. The combined organic phases are extracted by shaking with 50 ml of water and then 30 ml of saturated sodium bicarbonate solution, dried over sodium sulfate, and concentrated under reduced pressure. This gives 12.22 g of a solid which, according to GC/MS analysis, contains 91.1% of the title compound, which corresponds to a yield of 95.3% of theory.

[0194] GC/MS: m/e=232 (M.sup.+, .sup.35Cl, .sup.79Br, 5%), 153 (M-79, 100%).

Example 8: 2-(Chloromethyl)-5-chloro-1,3-dimethylbenzene

[0195] ##STR00022##

[0196] 14.94 g [0.19 mol] of thionyl chloride are initially charged, heated to 72° C. and a warm (74° C.) solution of 16.47 g [0.0965 mol] of 4-chloro-2,6-dimethylbenzyl alcohol in 75 ml of toluene are added dropwise thereto within an hour. Further stirring is subsequently carried out for 90 minutes at 72° C. The excess thionyl chloride is distilled off, the residue is filtered over some Celite and concentrated under reduced pressure. This gives 20.21 g of a greenish solid which, according to GC/MS analysis, contains 87.2% of the title compound, which corresponds to a yield of 96.5% of theory.

[0197] GC/MS: m/e=188 (M.sup.+, .sup.35Cl, 12%), 153 (M-35, 100%), 119 (M-36, 72%).

[0198] .sup.1H-NMR (600 MHz, CDCl.sub.3): δ=2.33 (s, 6H), 4.53 (s, 2H), 6.97 (s, 2H) ppm.

[0199] Melting point: 63.5-64° C.

Example 9: (4-Chloro-2,6-dimethylphenyl)acetonitrile

[0200] ##STR00023##

[0201] A solution of 70.8 g of 2-(chloromethyl)-5-chloro-1,3-dimethylbenzene of a purity of 74.4% is initially charged in 105 ml of toluene, 35 ml of water and 1.13 g of Aliquat336 are added thereto, the mixture is heated to 65° C. and a solution of 16.38 g [0.334 mol] of sodium cyanide in 55 ml of water is metered thereinto with vigorous stirring. Stirring is subsequently carried out for 16 hours at 80° C. The phases are separated at room temperature, the organic phase is washed with 120 ml of saturated aqueous sodium bicarbonate solution and two times 100 ml of water, drying is carried out over sodium sulfate and concentration is carried out under reduced pressure. This gives 61.9 g of a solid which, according to quantitative .sup.1H-NMR, contains 69.8% of the title compound, which corresponds to a yield of 86.3% of theory. Recrystallization from 100 ml of isopropanol gives 33.1 g of a solid which, according to GC/MS analysis, contains 99.2% of the title compound, which corresponds to a yield of 65.6% of theory.

[0202] GC/MS: m/e=179 (M.sup.+, .sup.35Cl, 57%), 152 (M-27, 100%), 144 (70%), 118 (90%).

[0203] .sup.1H-NMR (600 MHz, d.sub.6-DMSO): δ=2.34 (s, 6H), 3.89 (s, 2H), 7.2 (s, 2H) ppm.

[0204] Melting point: 87.6° C.

Example 10: (4-Chloro-2,6-dimethylphenyl)acetic acid

[0205] ##STR00024##

[0206] 28.1 g of (4-chloro-2,6-dimethylphenyl)acetonitrile of a purity of 82% and 45.6 g of (4-chloro-2,6-dimethylphenyl)acetonitrile of a purity of 84.8% are initially charged in 300 ml of ethanol, 122 g of 45% sodium hydroxide solution are added thereto and stirring is carried out for 48 h under reflux. After cooling to room temperature, the reaction mixture is placed on ice and adjusted to a pH of 1 with concentrated hydrochloric acid, the solid is suctioned off, washed with water and dried. This gives 76.04 g of solid which, according to quantitative .sup.1H-NMR, has a purity of 86.8%, which corresponds to a yield of 96.8% of theory.

[0207] GC/MS: m/e=198 (M.sup.+, .sup.35Cl, 23%), 153 (M-45, 100%), 115 (23%).

[0208] .sup.1H-NMR (600 MHz, d.sub.6-DMSO): δ=2.34 (s, 6H), 3.58 (s, 2H), 7.1 (s, 2H) ppm.

[0209] Melting point (after recrystallization): 188.7° C.

Example 11: (2,6-dimethylphenyl)magnesium bromide

[0210] ##STR00025##

[0211] 4.01 g [165 mmol] of magnesium turnings and a small crystal of iodine are initially charged in a 250 ml three-necked flask under argon. The flask contents are heated by a hot air gun, with stirring, until iodine vapour is visible. Approximately 10 ml of a solution of 27.76 g [150 mmol] of 2,6-dimethylbromobenzene in 150 ml tetrahydrofuran (THF) are added thereto and heated to 50° C. until the start of reaction becomes discernible. The remaining reactant solution is then slowly metered in, with the internal temperature being kept at 50° C. by cooling. Stirring is subsequently continued for a further hour.

Example 12: (2,6-dimethylphenyl)magnesium bromide

[0212] ##STR00026##

[0213] 66.62 g [2.741 mol] of magnesium turnings are initially charged in a 6 1 jacketed vessel under argon. Firstly, the solution from example 11 is added thereto at 25° C., and then 800 ml of THF. 100 g of a solution of 461.2 g [2.492 mol] of 2,6-dimethylbromobenzene in 1200 ml of THF are then added thereto at 30° C. The start of the reaction is clear by the exothermy. The remaining amount of the reactant solution is then metered in within 100 minutes such that the internal temperature does not exceed 33° C. At the end, further stirring is then carried out at 35° C. for two hours. Stirring a small batch sample into a THF solution of iodine and subsequent HPLC analysis shows complete conversion of the 2,6-dimethylbromobenzene.

Example 13: (2,6-dimethylphenyl)(dimethylamino)methoxide magnesium bromide

[0214] ##STR00027##

[0215] A solution of 193.1 g [2.642 mol] of DMF in 500 ml of THF is metered in to the solution from example 12 in a 6 1 jacketed vessel at 24-29° C. within approximately 90 minutes. Stirring is subsequently continued for a further hour at 27° C. The product obtained is used in the next step without further work-up.

Example 14: 2,6-Dimethylbenzaldehyde

[0216] ##STR00028##

[0217] 1500 g of semiconcentrated hydrochloric acid are metered in to the reaction mixture from example 13 in a 6 1 jacketed vessel at 15-20° C. so that the pH drops to 1, and the mixture is stirred for a further three hours at room temperature. The reaction mixture is emptied, the phases are separated, the aqueous phase is extracted twice with in each case 500 ml of MTBE, the combined organic phases are washed with 500 ml of saturated aqueous sodium chloride solution, drying is carried out over sodium sulfate and concentration is carried out under reduced pressure. This gives 318.7 g of yellowish solid which, according to quantitative .sup.1H-NMR, contains 84.0% of the title compound, which corresponds to a yield of 75.5% of theory, based on the starting material in example 12.

[0218] GC/MS: m/e=133 ((M-1).sup.+, .sup.35Cl, 100%), 105 (M-29, 100%).

[0219] .sup.1H-NMR (600 MHz, CDCl.sub.3): δ=2.55 (s, 6H), 7.15 (m, 2H), 7.39 (m, 1H), 10.53 (s, 1H) ppm.

Example 15: 2,6-Dimethylbenzyl alcohol

[0220] ##STR00029##

[0221] 318.7 g of the compound from example 14 as a solution in 1300 ml of ethanol were initially charged in a 5 1 autoclave. 3.9 g of Raney cobalt (Actimet) are added thereto, which has been washed twice with water and three times with ethanol, the closed autoclave is flushed twice with argon and hydrogenation is then carried out for 34 hours at 100° C. and 30 bar of hydrogen pressure. The reaction mixture is subsequently filtered through Celite and then concentrated under reduced pressure. This gives 299.6 g of a solid which, according to GC/MS analysis, contains 74.7% of the title compound, which corresponds to a yield of 74% of theory.

[0222] GC/MS: m/e=138 (Mt, 20%), 118 (100%).

Example 16: 2-(Chloromethyl)-1,3-dimethylbenzene

[0223] ##STR00030##

[0224] 91.4 g [0.768 mol] of thionyl chloride in 100 ml of toluene are initially charged, heated to 72° C. and a solution of 100 g of 2,6-dimethylbenzyl alcohol of a purity of 74.7% in 700 ml of toluene is added dropwise thereto within an hour. Further stirring is subsequently carried out for one hour at 72° C. The excess thionyl chloride is distilled off, the residue is filtered over some Celite and concentrated under reduced pressure. This gives 107.2 g of a brown oil which, according to GC/MS analysis, contains 71.0% of the title compound, which corresponds to a yield of 89.7% of theory.

[0225] GC/MS: m/e=154 (M.sup.+, .sup.35Cl, 17%), 119 (M-35, 100%),

Example 17: 2,6-Dimethylphenylacetonitrile

[0226] ##STR00031##

[0227] A solution of 105.6 g of 2-(chloromethyl)-1,3-dimethylbenzene of a purity of 68.9% is initially charged in 150 ml of toluene, 50 ml of water and 1.9 g of Aliquat336 are added thereto, the mixture is heated to 65° C. and a solution of 27.68 g [0.565 mol] of sodium cyanide in 80 ml of water is metered thereinto with vigorous stirring. Stirring is subsequently carried out for 16 hours at 80° C. A further 0.85 g of Aliquat336 and 2.3 g of sodium cyanide are then added thereto and stirring is carried out for 18 hours at 80° C. The phases are separated at room temperature, the organic phase is washed with 120 ml of saturated aqueous sodium bicarbonate solution and two times 100 ml of water, drying is carried out over sodium sulfate and concentration is carried out under reduced pressure. This gives 85 g of crude product which, according to GC/MS analysis, contains 79.3% of the title compound, which corresponds to a yield of 98.6% of theory.

[0228] GC/MS: m/e=145 (M.sup.+, 40%), 118 (M-27, 100%).

Example 18: 2,6-Dimethylphenylacetic acid

[0229] ##STR00032##

[0230] 11 g of 2,6-dimethylphenylacetonitrile of a purity of 94% are initially charged in a mixture of 100 ml of triethylene glycol and 25 ml of water. 28.1 g of (85%) KOH pellets are added thereto and stirring is carried out for 18 hours at 120° C. The mixture is left to cool to 50° C., 500 ml of ice-cold water are then stirred into the reaction mixture, the reaction mixture is adjusted to a pH of 1 with 32% hydrochloric acid, the solid is filtered off, washed twice with in each case 75 ml of water, and dried. This gives 9.89 g of solid which, according to HPLC analysis, contains 96.3% of the title compound, which corresponds to a yield of 81.7% of theory.

[0231] GC/MS(sil.): m/e=236 (M.sup.+(sil.), 7%), 221 (M.sup.+(sil.)-15, 10%), 192 (10%), 119 (13%), 73(100%).