PROCESS FOR PREPARING SUBSTITUTED 2-ARYLETHANOLS

Abstract

The invention relates to a process for preparing substituted 2-arylethanols of the formula (I) by reacting Grignard compounds of the formula (II) in the presence of a copper compound with ethylene oxide. Moreover, the invention relates to novel substituted 2-arylethanols of the formula (I).

Claims

1. Process for preparing a compound of formula (I) ##STR00004## in which R.sup.1, R.sup.5 independently of one another represent C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-fluoroalkyl having 1 to 13 fluorine atoms, optionally substituted C.sub.6-C.sub.10-aryl, fluorine, chlorine, a radical NR.sup.6.sub.2, OR.sup.6 or SR.sup.6, where R.sup.6 represents C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.2-fluoroalkyl having 1 to 5 fluorine atoms or phenyl, R.sup.2, R.sup.3, R.sup.4 independently of one another represent hydrogen, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-fluoroalkyl having 1 to 13 fluorine atoms, optionally substituted C.sub.6-C.sub.10-aryl, fluorine, chlorine, a radical NR.sup.6.sub.2, OR.sup.6 or SR.sup.6, where R.sup.6 represents C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.2-fluoroalkyl having 1 to 5 fluorine atoms or phenyl, wherein a compound of the formula (II) ##STR00005## in which the radicals R.sup.1 to R.sup.5 have the meanings given above and X represents chlorine, bromine or iodine, is reacted in the presence of a copper compound with ethylene oxide.

2. Process for preparing a compound of formula (I) according to claim 1, in which R.sup.1, R.sup.5 independently of one another represent C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.2-fluoroalkyl having 1 to 5 fluorine atoms, phenyl optionally substituted by C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy, fluorine or chlorine, fluorine, chlorine or a radical OR.sup.6, where R.sup.6 represents C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.2-fluoroalkyl having 1 to 5 fluorine atoms or phenyl, R.sup.2, R.sup.3, R.sup.4 independently of one another represent hydrogen, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.2-fluoroalkyl having 1 to 5 fluorine atoms, phenyl optionally substituted by C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy, fluorine or chlorine, fluorine, chlorine or a radical OR.sup.6, where R.sup.6 represents C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.2-fluoroalkyl having 1 to 5 fluorine atoms or phenyl.

3. Process for preparing a compound of formula (I) according to claim 1, in which R.sup.1, R.sup.5 independently of one another represent methyl, ethyl, n-propyl, iso-propyl, trifluoromethyl, phenyl optionally substituted by methyl, ethyl, n-propyl, iso-propyl, methoxy, ethoxy or fluorine, fluorine, chlorine or a radical OR.sup.6, where R.sup.6 represents methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, CHF.sub.2, CF.sub.3 or C.sub.2F.sub.5 and R.sup.2, R.sup.3, R.sup.4 independently of one another represent hydrogen, methyl, ethyl, n-propyl, iso-propyl, trifluoromethyl, phenyl optionally substituted by methyl, ethyl, n-propyl, iso-propyl, methoxy, ethoxy or fluorine, fluorine, chlorine or a radical OR.sup.6, where R.sup.6 represents methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, CHF.sub.2, CF.sub.3 or C.sub.2F.sub.5.

4. Process for preparing a compound of formula (I) according to claim 1, in which the compound of formula (I) has the following meanings: 2-(4-chloro-2,6-dimethylphenyl)ethanol, 2-(4-chloro-2,6-diethylphenyl)ethanol, 2-(2,6-dimethyl-4-trifluoromethylphenyl)ethanol, 2-(4-fluoro-2,6-dimethylphenyl)ethanol, 2-(2,6-dimethyl-4-trifluoromethoxyphenyl)ethanol, 2-(2-ethyl-4,6-dimethylphenyl)ethanol, 2-(2,4-diethyl-6-methylphenyl)ethanol, 2-(3-chloro-2,6-dimethylphenyl)ethanol.

5. Process for preparing a compound of formula (I) according to claim 1, wherein the copper compound used is copper(I) iodide, copper(I) bromide, copper(II) bromide or copper(I) chloride.

6. Process for preparing a compound of formula (I) according to claim 1, wherein the copper compound is used in an amount of from 0.1 to 50 mol percent, based on the compound of formula (II).

7. Process for preparing a compound of formula (I) according to claim 1, wherein the copper compound is used in an amount of from 0.5 to 15 mol percent, based on the compound of formula (II).

8. Process for preparing a compound of formula (I) according to claim 1, wherein ethylene oxide is used in an amount between 0.9 and 3 mol equivalents, based on the compound of formula (II).

9. Process for preparing a compound of formula (I) according to claim 1, wherein ethylene oxide is used in an amount between 1 and 2 mol equivalents, based on the compound of formula (II).

10. Compound of formula (I) according to claim 1 in which R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 have the meanings given in the table TABLE-US-00004 R.sup.1 R.sup.2 R.sup.3 R.sup.4 R.sup.5 Me H Cl H Me Me H Cl H Et Et H Cl H Et Me H Cl H n-Pr Et H Cl H n-Pr n-Pr H Cl H n-Pr Me H Cl H iso- Pr Et H Cl H iso- Pr iso- H Cl H iso- Pr Pr iso- H Cl H n-Pr Pr Me H F H Me Me H F H Et Et H F H Et Me H CF.sub.3 H Me Me H CF.sub.3 H Et Et H CF.sub.3 H Et Me H OCF.sub.3 H Me Me H Me H Et Me H Et H Et Me H Et H Me Me Cl H H Me Et Cl H H Me Et H H Cl Me

Description

EXAMPLES

Example 1: 2-(4-Chloro-2,6-dimethylphenyl)ethanol (Compound I-1)

[0061] To a solution of bromo(4-chloro-2,6-dimethylphenyl)magnesium, prepared at 30-35? C. from 50 mmol of 4-chloro-2,6-dimethylbromobenzene, 1 mmol of bromo(4-chloro-2,6-dimethylphenyl)magnesium (to start the Grignard synthesis) and 55.5 mmol of magnesium in 50 ml of tetrahydrofuran, were added 5 mmol of copper(I) iodide. Then, 48 ml of a 2.5-3.3 molar solution of ethylene oxide in tetrahydrofuran (120 mmol, calculated for a concentration of 2.5 M) were metered in at 20? C. over the course of 30 minutes. After 16 hours at 20? C., the reaction mixture was placed on 100 g of ice and adjusted to pH 1 with sulphuric acid. After triple extraction with in each case 50 ml of methylene chloride, the combined organic phases were extracted once by shaking with 30 ml of water, dried over magnesium sulphate and concentrated on a rotary evaporator. There remained an oil, in which, according to GC/MS analysis, the ratio of 2-(4-chloro-2,6-dimethylphenyl)ethanol to 1-(4-chloro-2,6-dimethylphenyl)ethanol was >99:1.

[0062] GC/MS: m/e=184 (M.sup.+ (.sup.35Cl), 25%), 153 (.sup.35Cl, 100%).

[0063] .sup.1H-NMR (600 MHz, d-DSMO): ?=2.28 (s, 6H), 2.75 (m, 2H), 3.45 (m, 2H), 4.74 (m, 1H), 7.0 (s, 2H) ppm.

Example 2: 2-(4-Chloro-2,6-dimethylphenyl)ethanol (Compound I-1)

[0064] To a solution of bromo(4-chloro-2,6-dimethylphenyl)magnesium, prepared at 30-35? C. from 10 mmol of 4-chloro-2,6-dimethylbromobenzene, 1 mmol of bromo(4-chloro-2,6-dimethylphenyl)magnesium (to start the Grignard synthesis) and 11.1 mmol of magnesium in 10 ml of tetrahydrofuran, were added 0.1 mmol of copper(I) iodide. Then, 9.6 ml of a 2.5-3.3 molar solution of ethylene oxide in tetrahydrofuran (24 mmol, calculated for a concentration of 2.5 M) were metered in at 20? C. over the course of 30 minutes. After 16 hours at 20? C., the reaction mixture was placed on 100 g of ice and adjusted to pH 1 with sulphuric acid. After triple extraction with in each case 50 ml of methylene chloride, the combined organic phases were extracted once by shaking with 30 ml of water, dried over magnesium sulphate and concentrated on a rotary evaporator. There remained an oil, in which, according to GC/MS analysis, the ratio of 2-(4-chloro-2,6-dimethylphenyl)ethanol to 1-(4-chloro-2,6-dimethylphenyl)ethanol was >99:1.

Example 3: 2-(4-Chloro-2,6-dimethylphenyl)ethanol (Compound I-1)

[0065] To a solution of bromo(4-chloro-2,6-dimethylphenyl)magnesium, prepared at 30-35? C. from 10 mmol of 4-chloro-2,6-dimethylbromobenzene, 1 mmol of bromo(4-chloro-2,6-dimethylphenyl)magnesium (to start the Grignard synthesis) and 11.1 mmol of magnesium in 10 ml of tetrahydrofuran, were added 1 mmol of copper(I) iodide. Then, 9.6 ml of a 2.5-3.3 molar solution of ethylene oxide in tetrahydrofuran (24 mmol, calculated for a concentration of 2.5 M) were metered in at 50? C. over the course of 30 minutes. After 16 hours at 50? C., the reaction mixture was placed on 100 g of ice and adjusted to pH 1 with sulphuric acid. After triple extraction with in each case 50 ml of methylene chloride, the combined organic phases were extracted once by shaking with 30 ml of water, dried over magnesium sulphate and concentrated on a rotary evaporator. There remained an oil, in which, according to GC/MS analysis, the ratio of 2-(4-chloro-2,6-dimethylphenyl)ethanol to 1-(4-chloro-2,6-dimethylphenyl)ethanol was >99:1.

Comparative Example 1: 2-(4-Chloro-2,6-dimethylphenyl)ethanol

[0066] To a solution of bromo(4-chloro-2,6-dimethylphenyl)magnesium, prepared at 30-50? C. from 10 mmol of 4-chloro-2,6-dimethylbromobenzene and 11.1 mmol of magnesium in 10 ml of tetrahydrofuran, were metered in 8.8 ml of a 2.5-3.3 molar solution of ethylene oxide in tetrahydrofuran (22 mmol, calculated for a concentration of 2.5 M) at 50? C. over the course of 30 minutes. After 3 hours at 50? C., the reaction mixture was placed on 100 g of ice and adjusted to pH 1 with sulphuric acid. After triple extraction with in each case 50 ml of methylene chloride, the combined organic phases were extracted once by shaking with 30 ml of water, dried over magnesium sulphate and concentrated on a rotary evaporator. There remained an oil, in which, according to GC/MS analysis, the ratio of 2-(4-chloro-2,6-dimethylphenyl)ethanol to 1-(4-chloro-2,6-dimethylphenyl)ethanol was 87:13.

Comparative Example 2: 2-(4-Chloro-2,6-dimethylphenyl)ethanol

[0067] To a solution of bromo(4-chloro-2,6-dimethylphenyl)magnesium, prepared at 30-35? C. from 10 mmol of 4-chloro-2,6-dimethylbromobenzene, 1 mmol of bromo(4-chloro-2,6-dimethylphenyl)magnesium (to start the Grignard synthesis) and 11.1 mmol of magnesium in 10 ml of tetrahydrofuran, were metered in 9.6 ml of a 2.5-3.3 molar solution of ethylene oxide in tetrahydrofuran (24 mmol, calculated for a concentration of 2.5 M) at 50? C. over the course of 30 minutes. After 16 hours at 50? C., the reaction mixture was placed on 100 g of ice and adjusted to pH 1 with sulphuric acid. After triple extraction with in each case 50 ml of methylene chloride, the combined organic phases were extracted once by shaking with 30 ml of water, dried over magnesium sulphate and concentrated on a rotary evaporator. There remained an oil, in which, according to GC/MS analysis, the ratio of 2-(4-chloro-2,6-dimethylphenyl)ethanol to 1-(4-chloro-2,6-dimethylphenyl)ethanol was 78:22.

Example 4: 2-(4-Chloro-2,6-dimethylphenyl)ethanol (Compound I-1)

[0068] To a solution of 20 mmol of bromo(4-chloro-2,6-dimethylphenyl)magnesium in 20 ml tetrahydrofuran were added 2 mmol of copper(I) bromide. Then, 16 ml of a 2.5-3.3 molar solution of ethylene oxide in tetrahydrofuran (40 mmol, calculated for a concentration of 2.5 M) were metered in at 20? C. over the course of 30 minutes. After 16 hours at 20? C., the reaction mixture was placed on 100 g of ice and adjusted to pH 1 with sulphuric acid. After triple extraction with in each case 50 ml of methylene chloride, the combined organic phases were extracted once by shaking with 30 ml of water, dried over magnesium sulphate and concentrated on a rotary evaporator. There remained an oil, in which, according to GC/MS analysis, the ratio of 2-(4-chloro-2,6-dimethylphenyl)ethanol to 1-(4-chloro-2,6-dimethylphenyl)ethanol was >99:1.

Example 5: 2-(4-Chloro-2,6-dimethylphenyl)ethanol (Compound I-1)

[0069] The procedure was as in Example 4 but now using 1 mmol of copper(II) bromide instead of Cu(I)Br. The ratio of 2-(4-chloro-2,6-dimethylphenyl)ethanol to 1-(4-chloro-2,6-dimethylphenyl)ethanol was >99:1.

Example 6: 2-(4-Chloro-2,6-dimethylphenyl)ethanol (Compound I-1)

[0070] The procedure was as in Example 4 but now using 1 mmol of copper(I) chloride instead of Cu(I)Br. The ratio of 2-(4-chloro-2,6-dimethylphenyl)ethanol to 1-(4-chloro-2,6-dimethylphenyl)ethanol was >99:1.

Example 7: 2-(2,6-Dimethylphenyl)ethanol

[0071] To a solution of 2,6-dimethylphenylmagnesium, prepared at 30-35? C. from 20 mmol of 2,6-dimethylbromobenzene and 22.2 mmol of magnesium in 10 ml of tetrahydrofuran, were added 0.2 mmol of copper(I) iodide. Then, 8.8 ml of a 2.5-3.3 molar solution of ethylene oxide in tetrahydrofuran (22 mmol, calculated for a concentration of 2.5 M) were metered in at 20? C. over the course of 30 minutes. After 16 hours at 20? C., the reaction mixture was placed on 100 g of ice and adjusted to pH 1 with sulphuric acid. After triple extraction with in each case 50 ml of methylene chloride, the combined organic phases were extracted once by shaking with 30 ml of water, dried over magnesium sulphate and concentrated on a rotary evaporator. There remained an oil, in which, according to GC/MS analysis, the ratio of 2-(2,6-dimethylphenyl)ethanol to 1-(2,6-dimethylphenyl)ethanol was 97.5:2.5.

Comparative Example 3: 2-(2,6-Dimethylphenyl)ethanol

[0072] Into a solution of 2,6-dimethylphenylmagnesium, prepared at 40-55? C., towards the end for a few minutes at 65? C., from 200 mmol of 2,6-dimethylbromobenzene and 222 mmol of magnesium in 100 ml of tetrahydrofuran, were introduced 215 mmol of ethylene oxide at 30-35? C. over the course of about 2 hours. After 3 hours at 60? C., the reaction mixture was placed on 200 g of ice and adjusted to pH 1 with sulphuric acid. After triple extraction with in each case 50 ml of methylene chloride, the combined organic phases were extracted once by shaking with 30 ml of water, dried over magnesium sulphate and concentrated on a rotary evaporator. There remained an oil, in which, according to GC/MS analysis, the ratio of 2-(2,6-dimethylphenyl)ethanol to 1-(2,6-dimethylphenyl)ethanol was 81:19.

Use Example 1: 4-Chloro-2,6-dimethylphenylacetic acid

[0073] To a solution of 5 g of 2-(4-chloro-2,6-dimethylphenyl)ethanol (24 mmol, purity 90%) in 20 g of acetonitrile were added 38 mg of 2,2,6,6-tetramethylpiperidinyloxyl (0.24 mmol) at room temperature. To this solution were added, at 45? C., 0.8 ml of 11.05% strength sodium hypochlorite solution and then 4.3 g of sodium chlorite (36 mmol), dissolved in 12.5 g of a phosphate buffer (10.65 g of Na.sub.2HPO.sub.4 and 10.21 g of KH.sub.2PO.sub.4 per 1000 ml of water) were added dropwise over the course of one hour using a metering pump. When the addition was complete, the mixture was after-stirred for 30 min and cooled to 5-10? C. and 3 g of sodium sulphite were added in portions. The reaction mixture was then after-stirred for one hour and adjusted to pH 13.5 with 45% strength sodium hydroxide solution and the resulting suspension was extracted twice with in each case 25 ml of MTBE. The aqueous phase was adjusted to pH 3.38 with 10% strength hydrochloric acid and extracted three times with in each case 30 ml of MTBE. The combined organic phases of the acid extraction were dried and concentrated. This gave 4.3 g of product (87% of theory; purity 98% according to HPLC and quant. NMR).