Process for preparation of propionic acid derivatives

Details Process for preparation of propionic acid derivatives Process for preparation of propionic acid derivatives

1999-03-16

2001-01-16

Rotman, Alan L. (Department: 1612)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S301000

Reexamination Certificate

active

06175018

ABSTRACT:

The present invention relates to a process for the preparation of (R)(+)-2-[4-(5-chloro-3-fluoropyridin-2-yloxy)-phenoxy]-propionic acid propinyl ester.
(R)(+)-2-[4-(5-chloro-3-fluoropyridin-2-yloxy)-phenoxy]-propionic acid propinyl ester possesses herbicidal activity and is described for example in EP-A-0 248 968. [4-(5-chloro-3-fluoropyridin-2-yloxy)-phenoxy]-propionic acid derivatives may be produced for example in accordance with EP-A-0 439 857, by reacting 5-chloro-2,3-difluoropyridine with corresponding 4-hydroxypropionic acid esters in the presence of a water-free base and in the absence of a solvent. However, this process is unsuitable for producing (R)(+)-2-[4-(5-chloro-3-fluoropyridin-2-yloxy)-phenoxy]-propionic acid propinyl ester, since the triple bonding of the hydroxypropionic acid ester is inclined to form polymers under the conditions of the process and under basic conditions. In addition, this process is especially problematic as regards the safety aspect, since the reaction mixture can only be heated without solvents at some risk, owing to the high thermal potential of this triple bond.
According to EP-A-0 248 968, pages 12 to 14, (R)(+)-2-[4-(5-chloro-3-fluoropyridin-2-yloxy)-phenoxy]-propionic acid propinyl ester is obtained whereby
a) in a first step, a compound of formula A
in dimethyl sulphoxide is reacted with a mixture of hydroquinone and potassium hydroxide in dimethyl sulphoxide to form a compound of formula B
this compound
b) in a second step, in dimethyl sulphoxide, is reacted in the presence of potassium carbonate with S(−)-lactic acid methyl ester tosylate to form the compound of formula C
this compound
c) in a third step, in dioxane, is reacted in the presence of sodium hydroxide solution to form the compound of formula D
this compound
d) in a fourth step, in toluene, is reacted with thionyl chloride to form the compound of formula (E)
which finally, without further isolation, this compound
e) is reacted with a mixture of triethylamine and propinol in toluene to form (R)(+)-2-[4-(5-chloro-3-fluoropyridin-2-yloxy)-phenoxy]-propionic acid propinyl ester.
This process has the major disadvantage that, because of the four-stage reaction procedure, complicated separation and purification steps are necessary. This leads to substantial losses of yield. In addition, while the process is being carried out, the solvent has to be changed twice. This necessitates additional time-consuming and expensive distillation steps. The known process is therefore not the optimum one especially for application on a large scale.
The aim of the present invention is therefore to provide a process which enables (R)(+)-2-[4-(5-chloro-3-fluoropyridin-2-yloxy)-phenoxy]-propionic acid propinyl ester to be produced in a more simple manner, in higher purity and in higher yields.
It has now been found that (R)(+)-2-[4-(5-chloro-3-fluoropyridin-2-yloxy)-phenoxy]-propionic acid propinyl ester of formula I
can be produced in a particularly advantageous manner by converting a compound of formula II
in an inert organic solvent, without isolation of the intermediate products, with M
2
CO
3
, in which M is sodium or potassium, into the compound of formula III
wherein M is sodium or potassium, reacting this compound with the compound of formula IV
to form the compound of formula V
wherein M is sodium or potassium, and converting this compound with a compound of formula VI
wherein Z signifies a leaving group such as phenylsulphonyl, tosyl, methylsulphonyl, nosyl, bromophenyl, Cl-, Br- or CICO-, into the compound of formula I.
The starting compounds may be used in stoichiometric quantities. It is preferable to use the compound of formula IV in an excess of 0.05 to 0.3 equivalents, most preferably 0.1 equivalents, based on the compound of formula III. The compound of formula VI is preferably employed in an excess of 0.05 to 0.15 equivalents.
Within the scope of the present invention, M in M
2
CO
3
is preferably potassium.
Suitable inert organic solvents within the scope of the present invention are in particular ketones, esters and ethers. Dimethyl formamide, dimethyl sulphoxide, N-methyl pyrrolidone or acetonitrile are especially suitable as solvents. Dimethyl formamide and acetonitrile are preferred in particular, most preferably dimethyl formamide. In a preferred embodiment of the process according to the invention, in formula VI, Z is chlorine. The process according to the invention can be carried out at elevated temperatures, especially at 40 to 120° C. A temperature range of 60° to 90 ° C., most preferably 70 to 75° C., is preferred.
The reaction of formula II with formula IV may be carried out in the presence of a phase transfer catalyst in order to speed up the reaction. Suitable phase transfer catalysts are for example quatemary ammonium salts, quatemary phosphonium salts or crown ethers.
The starting compounds of formulae II, IV and VI are known or may be produced by known processes. The compound of formula IV is described for example in EP-A-0 248 968, and the compound of formula II in EP-A-0 083 556. Compounds of formula VI, wherein Z is chlorine, may be produced for example according to J. Am. Chem. Soc. 77, 1831(1955), whereby suitable bases for this reaction are pyridine and preferably 5-ethyl-2-methylpyridine.
The process according to the invention is distinguished from known processes in particular by the fact that it can be carried out as a one-pot process without changing the solvent. In this way, not only is the expenditure on apparatus considerably lower, but by avoiding complex separation and distillation steps, there is also a substantial saving in time. In addition, the substantial reduction in solvent residues achieved with the process according to the invention is particularly advantageous from an ecological point of view. The lower thermal loading of the product reduces the formation of undesired by-products and the particularly selective course of the reaction enables a more precise dosaging of the reactants to be achieved, which in turn leads to a higher yield and a product with considerably improved purity.


REFERENCES:
patent: 5002604 (1991-03-01), Schurter et al.
patent: 592804 (1987-12-01), None
patent: 0 083 556 (1983-07-01), None
patent: 0 248 968 (1987-12-01), None
patent: 0 439 857 (1991-08-01), None
Ettlinger MG, et al. “The Mustard Oil of Rape Seed, Allylcarbinyl Isothiocyanate, and Synthetic Isomers” J Am Chem Soc, 77, pp. 1831-1836 (1955).
J. Chem. Res. Miniprint 7, 1992, pp. 1601-1615.
Ann. Chim. (Paris) 13, No. 1, 1956, pp. 161-213.
J. App. Chem. USSR, 65, No. 12.2, 1992, pp. 2310-2314.
J. Med. Chem. 20, No. 12, 1977, pp. 1584-1588.
Heterocycles, 32, No. 10, 1991, pp. 1947-1953.

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