Process for the preparation of substituted phenoxyphenyl alcohols

Abstract

The present invention relates to a process for the preparation of the compounds of formula II ##STR00001##
using a lanthanoid salt.

Claims

1. A process for the preparation of the compounds of formula II ##STR00010## comprising the following step: (i) reacting a substituted phenoxy phenyl compound of the formula III ##STR00011## with a Grignard reagent RMg-Hal.sup.3 (IV) and a ketone R.sup.1C(O)CH.sub.2Hal.sup.1 (V) in the presence of a lanthanoid salt; wherein the variables R.sup.1, R.sup.4, Hal.sup.1, Hal.sup.2, Hal.sup.3 and R are defined as follows: R1 is selected from C.sub.1-C.sub.6-alkyl and C.sub.3-C.sub.8-cycloalkyl; R4 is halogen; and Hal.sup.1, Hal.sup.2, Hal.sup.3 are independently from one another halogen; and R is C.sub.1-C.sub.4-alkyl or C.sub.3-C.sub.6-cycloalkyl.

2. The process of claim 1, wherein the lanthanoid salt is a Cerium (III) salt.

3. The process of claim 2, wherein the Cerium (III) salt is CeCl.sub.3 or Ce(iPrO).sub.3.

4. The process of claim 1, wherein the reacting in step (i) comprises reacting in a solvent comprising tetrahydrofuran (THF).

5. An intermediate compound of formula II according to claim 1.

6. A process for the preparation of the compounds of formula I ##STR00012## comprising the following steps: (i) preparing a compound II according to claim 1; (ii) reacting the compound of the formula II resulting from step (i) with 1H-1,2,4-triazole in the presence of a base to obtain compounds I, wherein R.sup.2 is hydrogen (compounds I-1) ##STR00013## and, for obtaining compounds, wherein R.sup.2 is different from hydrogen (compounds I-2): (iii) derivatizing the compound of formula (I-1) as defined in step (ii) under basic conditions with R.sup.2-LG, wherein LG is a nucleophilically replaceable leaving group; to result in compounds (I-2); wherein the variables R.sup.1 and R.sup.4 are defined in claim 1, and R.sup.2 is hydrogen, C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl or C.sub.2-C.sub.6-alkynyl; wherein the aliphatic moieties of R.sup.2 are not further substituted or do carry one, two, three or up to the maximum possible number of identical or different groups R.sup.12a which independently are selected from halogen, OH, CN, nitro, C.sub.1-C.sub.4-alkoxy, C.sub.3-C.sub.8-cycloalkyl, C.sub.3-C.sub.8-halocycloalkyl and C.sub.1-C.sub.4-halogenalkoxy.

7. The process of claim 6, wherein the product resulting from step (ii) or (iii), respectively, is crystallized from toluene and/or ortho-xylene and/or an aliphatic alcohol and/or carbonic acid ester and/or a dipolar aprotic solvent.

8. The process of claim 7, wherein the aliphatic alcohol is selected from methanol, ethanol, n-propanol, iso-propanol, n-butanol, isobutanol and any mixture thereof.

9. The process of claim 7, wherein n-butyl acetate or ethyl acetate or any mixture thereof is used for crystallization.

10. The process of claim 7, wherein the dipolar aprotic solvent is selected from DMF, NMP, and dimethylacetamide.

11. The process of claim 6, wherein R.sup.2 is H, R.sup.1 is CH.sub.3 and R.sup.4 is Cl.

Description

EXAMPLES

(1) The following examples further illustrate the present invention and do not restrict the invention in any manner.

Example 1: Synthesis of Compound I-1, Wherein R.SUP.1 .is CH.SUB.3 .and R.SUP.4 .is Cl

(2) CeCl.sub.3*7H.sub.2O (100 g, 268 mmol) was dried in a vacuum oven at 80 C. with a N.sub.2 sweep for 8 h and subsequently dried at 100 C. with a N.sub.2 sweep for 12 h. The material was determined to be CeCl.sub.3*H.sub.2O based on weight loss. The material was pulverized in a mortis and pestle and stored in an air tight glass flask. CeCl.sub.3*H.sub.2O (14 g, 53 mmol) was transferred to a jacketed 250 mL flask and dried at 140 C. with a N.sub.2 sweep for 36 h. The reactor was cooled to 40 C. followed by the addition of THF (100 mL). After stirring for 2 h, the reaction was cooled to 15 C. Under N.sub.2, compound III, wherein Hal.sup.2 is Br and R.sup.4 is Cl (17.7 g, 99%, 50 mmol) was dissolved into THF (50 mL, 2M) and warmed to 30 C. i-PrMgCl (30 mL, 2 M, 60 mmol) was added dropwise and the mixture was stirred for an additional 1 h. HPLC analysis verified the consumption of the bromide educt. This solution was added dropwise to the CeCl.sub.3 mixture at 15 C. After addition, the mixture was warmed to 0 C. and stirred for 1 hr. The reaction was cooled to 15 C. Chloroacetone (8.5 g, 96%, 96 mmol) in THF (50 mL, 2 M) was added dropwise. The mixture was allowed to warm to 0 C. and stir for 1 hr. The reaction was quenched with H.sub.2O (2 g) and allowed to warm to room temperature. The crude material was distilled under reduced pressure at 40 C. to remove THF. MTBE (100 g) was added and the slurry was filtered. The solids were washed twice with MTBE (250 g). Solvents were removed under reduced pressure providing compound II, wherein Hal.sup.1 is Cl, R.sup.1 is CH.sub.3 and R.sup.4 is Cl, as a clear oil. The alcohol (31 mmol) was dissolved into DMF (30 mL, 1M). 1,2,4-triazole (2.8 g, 40 mmol) and NaOH (3 g, 76 mmol) were added. The reaction was warmed to 125 C. and monitored by HPLC. HPLC analysis of the crude product indicated a 1:10 ratio of symmetrical isomer I to the desired end product I (mefentrifluconazole). The yield of the desired product was 74.7%.

Example 2: Synthesis of Compound II Wherein Hal.SUP.1 .is Cl, R.SUP.1 .is CH.SUB.3 .and R.SUP.4 .is Cl

(3) As explained in Example 1 but using 1.1 eq of CeCl.sub.3 instead of 0.5 eq CeCl.sub.3 and adding the Grignard to the CeCl.sub.3 mixture at 20 instead of 15 C. After the addition of the chloroacetone, the mixture was allowed to warm to 0 C. and stirred for 1 hr, then it was stirred another 12 h at 22 C. The ratio of the desired product to the side product 1-(4-chlorophenoxz)-3-(trifluorome-thyl)benzene (also called side-product B) was 78:22.

Example 3: Synthesis of Compound II Wherein Hal.SUP.1 .is Cl, R.SUP.1 .is CH.SUB.3 .and R.SUP.4 .is Cl

(4) As explained in Example 1 but using 1.1 eq of CeCl.sub.3 instead of 0.5 eq CeCl.sub.3 and drying it at 140 C. with a N.sub.2 sweep for 60 h. The ratio of the desired product to the side product B was 75:25.

Example 4: Synthesis of Compound II Wherein Hal.SUP.1 .is Cl, R.SUP.1 .is CH.SUB.3 .and R.SUP.4 .is Cl

(5) As explained in Example 1 but using 1.1 eq of CeCl.sub.3 instead of 0.5 eq CeCl.sub.3 and drying it at 140 C. with a N.sub.2 sweep for 60 h. After the addition of the chloroacetone, the mixture was allowed to warm to 0 C. and stir for 1 hr, then it was allowed to stirred another 3 days at 5 C. The ratio of the desired product to the side product B was 80:20.

Comparison Example 1: Synthesis of Compound II Wherein Hal.SUP.1 .is Cl, R.SUP.1 .is CH.SUB.3 .and R.SUP.4 .is Cl, not Using Any Lanthanoid Salt

(6) The example as carried out in analogy to Example 1, but no lanthanoid salt was used. Also, in the reaction with iPrMgCl, THF and toluene were used as solvents, and the chloroacetone was added as solution in toluene. The reaction resulted in a yield of around 6% of the desired compound II.