Process for preparing 4-chlorobenzyl propargyl ether

Abstract

The present invention relates to a process for preparing 4-chlorobenzyl propargylether comprising a step (a) of reacting 4-chlorobenzyl chloride with propargyl alcohol in the presence of a base and a phase transfer catalyst, wherein the reaction mixture comprises at least two phases, wherein one phase is an organic phase and one phase is an aqueous phase.

Claims

1. A process for preparing a compound of formula I ##STR00004## comprising a step (a) of reacting a compound formula II ##STR00005## with a compound of formula III ##STR00006## in the presence of a base and a phase transfer catalyst in a reaction mixture, wherein the reaction mixture comprises at least two phases, wherein one phase is an organic phase and one phase is an aqueous phase, wherein the base is selected from the group consisting of alkali metal and alkaline earth metal hydroxides, alkali metal and alkaline earth metal oxides, alkali metal and alkaline earth metal carbonates, alkali metal and alkaline earth metal hydrogen carbonates, alkali metal and alkaline earth metal alcoholates, a tertiary amine, a pyridine, a bicyclic amine, and mixtures thereof, and wherein the phase transfer catalyst is selected from the group consisting of benzyltrimethylammonioum chloride, tetraethylammonium chloride, tetrapropylammonium bromide, tetrabutylammonium bromide, and tributylmethylammonium chloride, wherein the process further comprises (b) adding an organic solvent and/or water to the mixture obtained in the reaction step (a), (c) separating the at least two phases of the mixture obtained in step (b), and (f) isolating the compound of formula I from the organic phase obtained in step (c), wherein the phase separation step (c) comprises the separation of three phases, wherein one phase is an organic phase, one phase is an aqueous phase, and one phase is a catalyst-containing phase, wherein the process further comprises isolating the catalyst-containing phase.

2. The process according to claim 1, wherein the process further comprises (d) washing the organic phase obtained in step (c) with an aqueous solution.

3. The process according to claim 1, wherein the process further comprises recycling the catalyst-containing phase for repetition of the process.

4. The process according to claim 1, wherein the isolation of the compound of formula I in step (f) is performed by subjecting an organic phases to a distillation process.

5. The process according to claim 1, wherein the phase transfer catalyst is provided in a molar amount of from 0.5 to 20 mol-% based on the molar amount of the compound of formula II.

6. The process according to claim 1, wherein the base and the compound of formula II are provided in a molar ratio of from 3:1 to 1:1.

7. The process according to claim 1, wherein the base is selected from the group consisting of alkali carbonates, alkali hydroxides, and mixtures thereof.

8. The process according to claim 7, wherein the base comprises sodium hydroxide.

9. The process according to claim 1, wherein the base is sodium hydroxide, which is provided in the form of an aqueous solution.

10. The process according to claim 1, wherein the organic phase comprises an organic solvent selected from the group consisting of alkanes, aromatic solvents, ethers, and mixtures thereof.

11. The process according to claim 1, wherein the compound of formula Ill and the compound of formula II are provided in a molar ratio of from 2:1 to 1:1.

12. The process according to claim 11, wherein the compound of formula Ill and the compound of formula II are provided in the molar ratio of 1.5:1 to 1:1.

13. The process according to claim 1, wherein the reaction step (a) is performed by providing a mixture comprising the compound of formula II and the phase transfer catalyst in an organic solvent, and adding the compound of formula III simultaneously with an aqueous solution of the base.

14. The process according to claim 13, wherein the dosing time for adding the compound of formula Ill simultaneously with the aqueous solution of the base is from 0.5 to 3 hours.

15. The process according to claim 1, wherein the reaction step (a) is performed at a temperature within a range from 10° C. to 40° C.

16. The process according to claim 1, wherein the phase transfer catalyst comprises tributylmethylammonium chloride.

Description

EXAMPLES

(1) The following abbreviations are used: CBC=4-chlorobenzyl chloride, POH=propargyl alcohol, PTC=phase transfer catalyst, BMC=tributylmethylammonium chloride.

Example 1: Catalyst Screening

(2) A mixture of an aqueous sodium hydroxide solution (50%, 2 eq.), a PTC (0.1 eq.) according to Table 1 and toluene (200 g per mole CBC) was precharged in a reaction vessel. A mixture of CBC (16 g, 1 eq.) and POH (1.5 eq.) was added in 60 minutes at a temperature of 40° C. The results for the CBC turnover are provided in Table 1.

(3) TABLE-US-00001 TABLE 1 Entry PTC CBC turnover.sup.a 1 none <1%.sup.b 2 BnMe.sub.3NCl (solid) .sup. 7% 3 Et.sub.4NCl (solid)  9%.sup.c 4 Pr.sub.4NBr (solid) 39%.sup.d 5 BMC (75% in water) 94%.sup.  .sup.aafter dosing only 25% of CBC/POH (for safety reasons to prevent potentially dangerous accumulation) and 10-20 min post-stirring, turnover calculated from peak area (HPLC with UV detection at 205 nm) of CBC vs. 4-chlorobenzyl propargyl ether .sup.bvery pasty mixture, no improvement by doubling the amount of toluene .sup.cPTC not completely dissolved; 38% CBC turnover when water is added (0.033 eq., 33% based on PTC) .sup.d93% CBC turnover after 16 h

Example 2: Reaction with BMC as PTC and Formation and Isolation of the Catalyst-Containing Phase

(4) A mixture of toluene (100 g per mole of CBC), CBC (485 g, 1 eq.), BMC (0.1 eq.) and POH (0.11 eq.) was precharged in a reaction vessel at 30° C. NaOH (50% in H.sub.2O, 2 eq.) and additional POH (0.99 eq.) were added simultaneously over 1 h at 30° C. Stirring was continued for another 3.5 h at 30° C. Toluene (150 g per mole of CBC) and water (200 g per mole of CBC) were added. After stirring for 2 min, a lower aqueous phase, an intermediate catalyst-containing phase (BMC content: 49% by weight by quantitative GC which is 84% by weight of the 0.1 eq. of BMC that was used for the reaction) and an upper organic phase were separated. This organic phase was washed twice with a solution of H.sub.2SO.sub.4 in water (first wash: 0.2% H.sub.2SO.sub.4 by weight, 204 g solution per mole of CBC, second wash: 0.05% H.sub.2SO.sub.4 by weight, 201 g solution per mole of CBC). Removal of low boilers by distillation under reduced pressure gave 4-chlorobenzyl propargyl ether in 92% yield (97% purity by quantitative GC).