Method for producing (bromomethyl)cyclopropane and (bromomethyl)cyclobutane

Abstract

The present invention relates to a method for obtaining high purity (bromomethyl)cyclopropane and (bromomethyl)cyclobutane, starting respectively with cyclopropylmethanol and cyclobutylmethanol, under synthesis conditions that enable high productivity and high yield.

Claims

1. A method for preparing a compound (A) of the following formula: ##STR00005## in which R is a cyclobutane or cyclopropane group, comprising the following steps: a) solubilizing a triarylphosphite in a polar aprotic solvent, b) adding a bromine compound at a temperature of less than 15° C., c) lowering the temperature to less than 0° C. after completion of the reaction of the bromine with the triarylphosphite, d) adding cyclobutylmethanol or cyclopropylmethanol at a temperature of less than 0° C., e) recovering the compound (A).

2. The method according to claim 1 wherein the polar aprotic solvent is selected from sulfoxides, substituted amides, sulfones and derivatives thereof, used alone or mixed.

3. The method according to claim 1 wherein the polar aprotic solvent is selected from dimethylformamide, sulfolane, dimethylsulfoxide, and mixtures thereof.

4. The method according to claim 1, wherein the triarylphosphite is selected from the group consisting of triphenylphosphite, tris(4-alkylphenyl)phosphites, tris(2,4-alkylphenyl)phosphites, tris(2,4-dihalophenyl)phosphites for which the halogen atoms are chlorine or bromine and tris(2,4-dinitrophenyl)phosphite.

5. The method according to claim 1, wherein the triarylphosphite is triphenylphosphite.

6. The method according to claim 1 wherein the mass ratio of triarylphosphite to polar aprotic solvent is between 1/10 and ⅓.

7. The method according to claim 1 wherein the bromine compound is Br2.

8. The method according to claim 1, comprising an additional step of returning to room temperature and distillation of the compound (A).

9. The method according to claim 8 wherein the compound (A) obtained is subjected to washing and then to drying.

10. The method according to claim 9 wherein washing is carried out using sodium carbonate buffer solution at pH 8.

11. The method according to claim 9 wherein drying is carried out using a desiccant selected from calcium chloride and magnesium chloride.

12. The method according to claim 1 wherein step d) consists in adding cyclobutylmethanol and the compound (A) is (bromomethyl)cyclobutane.

13. The method according to claim 1 wherein step d) consists in adding cyclopropylmethanol and the compound (A) is (bromomethyl)cyclopropane.

14. The method according to claim 4, wherein the tris(4-alkylphenyl)phosphites is tris(4-nonylphenyl)phosphite.

15. The method according to claim 4, wherein the tris(2,4-alkylphenyl)phosphites is tris(2,4-di-terbutylphenyl)phosphite.

16. The method according to claim 6 wherein the mass ratio of triarylphosphite to polar aprotic solvent is between ⅛ and ¼.

Description

EXAMPLES

(1) The raw materials are raw materials available from Sigma Aldrich.

(2) The analytical method consists in gas chromatography (GC) analysis on an HP 5890 Series II apparatus. The chromatographic column is an Optima Delta-6 column (30 m, 0.25 mm, 0.25 μm).

(3) The oven follows the following temperature profile: Initial temperature: 40° C.; Initial time: 5 min; Gradient: 5°/min; Final temperature: 125° C.; Duration 15 min.

(4) The injector temperature is 250° C., that of the detector is 280° C., the volume injected is 1 μl and the pressure is 6 psi. The concentration of the sample is 75 g/l in tetrahydrofuran (THF).

(5) The reactions are carried out in a 20 liter jacketed glass reactor and the distillations are carried out by means of a glass column having 10 theoretical plates.

Example 1

Method According to the Invention for Producing (Bromomethyl)Cyclopropane

(6) Into a clean, dry reactor equipped with a stirrer and under nitrogen are successively loaded 4.63 kg of DMF (5.1 eqV) and then 4.53 kg of triphenylphosphite. 2.34 kg of bromine is then introduced while maintaining the temperature at less than 12° C. The stirring speed is regulated according to the fluidity of the reaction medium. When casting ends, a very thick medium with a yellow solid suspension is obtained.

(7) The set point of the jacket is then adjusted to −12° C. and then 0.96 kg of cyclopropylmethanol is introduced in such a way as not to exceed a temperature of −5° C. On completion of the addition the whole is allowed to return slowly to room temperature. The set point of the jacket is then adjusted to 64° C. for distillation, which is carried out at a pressure of 13 mbar by collecting the first 24 to 30° C. fraction at the top of the column, then the second 30 to 40° C. fraction (partial reflux). Two fractions, F1 (1.38 kg) and F2 (293 g), are collected. The two fractions, after washing with carbonated water and then drying by means of CaCl.sub.2, lead to a final product 2a (mass 1.316 kg) having a GC relative purity of 98.7% with a yield of 73%.

Example 2

Method According to the Invention for Producing (Bromomethyl)Cyclobutane

(8) Into a clean, dry reactor equipped with a stirrer and under nitrogen are successively loaded 5.4 kg of DMF (5.1 eqV) and then 4.53 kg of triphenylphosphite. 2.34 kg of bromine is then introduced while maintaining the temperature at less than 12° C. The stirring speed is regulated according to the fluidity of the reaction medium.

(9) The set point of the jacket is then adjusted to −12° C. and then 1.120 kg of cyclobutylmethanol is introduced in such a way as not to exceed a temperature of −5° C. At the end of the addition the whole is allowed to return slowly to room temperature. After distillation and washing, the final product 2b (mass 1.529 kg) having a GC relative purity of 98.3% is obtained with a yield of 78%.

Example 3

Comparative Example Implementing Triphenylphosphine with Cyclopropylmethanol

(10) Into a clean, dry reactor equipped with a stirrer and under nitrogen are successively loaded 4.63 kg of DMF (5.1 eqV) and then 3.84 kg of triphenylphosphine; the temperature is maintained at 40° C. with stirring for 60 minutes in order to promote solubilization of the triphenylphosphine. Partial reprecipitation is observed during cooling before the addition of Br.sub.2. 2.34 kg of bromine is then introduced while maintaining the temperature at less than 12° C. At the conclusion of the addition of bromine, the medium is very pasty and hard to stir. The set point of the jacket is then adjusted to −12° C. and then 0.96 kg of cyclopropylmethanol is introduced in such a way as not to exceed a temperature of −5° C. Slight fluidification is observed after addition of cyclopropylmethanol, but it is insufficient for the medium, which remains very pasty, to be able to be distilled. The final product is thus not recoverable. The difficulties encountered during this synthesis are related to the poor solubility of triphenylphosphine in DMF.