CS217075B1 - For the preparation of alkyleethers of 2-exe-3-methylpentane - Google Patents

Abstract

A method for preparing 2-exs3-methylpentanoic acid esters by reacting secondary butylmagnesium chloride with an alkyl halide, where alkyl means methyl to hexyl, at a temperature of 0 to - 50 °C, preferably at a temperature of -15 to - 20 °C. The invention can be used in the healthcare sector.

Description

The present invention relates to a process for the preparation of 2-exo-3-methylpentanoic acid alkyl esters wherein alkyl is methyl to hexyl, by reacting a secondary butylmagnesiumislerleride and an alkyl alavelan, wherein alkyl is methyl to hexyl.

Esters of 2-eno-3-methylpentanoic acid are the starting material for the free acid synthesis, which prepares them most frequently for alkaline hydrolysis. This acid is the keteansleg of the essential amino acid iaeleucine and can be used in the form of suitable pigments wherever it is desired to replace the corresponding amino acid with its metabolite,

Several methods for the preparation of 2-exe-3-methylpentanoic esters are described in 1 teratum; one of the most feasible (Wielamd T.s Ber. 81, 314 (1948)) utilizes Grignadeva's reaction of secondary butylmagnealuachleride with ethyl oxalate according to achematutes

CH - CH - C1 1) Mg CH - CH - CO - COOR ³ I -> ³ l CH _{3 -} CH ₂ 2) (COOR) g CHyCHg (I)

CH ₃ -CH-CO-COOH

AND

CH ₃ -CH ₂ (II)

Tate's simple method is based on accessible aurovia and is not very challenging experimentally; according to the procedure described in the literature ee Grignard's reaction is carried out under cooling with running water and yields an eoketeeater (the compounds of formula I where R CgHH) in 20% yield from which is carried out by hydrolysis to give ε-keto acid (compound II) in total yield 17 up to 18% calculated on the starting chloride.

Low total yields of 2-oxo-3-methylpentanevé 4 ^3-50% according to the invention a process for preparing alkyleaterů this acid, where alkyl is methyl through hexyl, reacting the secondary butylnagnesiumchleridu e oxalate alkylnatým, where alkyl is methyl through hexyl, at temperatures from 0 to 50 ° C, preferably -15 to -20 ° C and with good stirring

The basic effect of the present invention is that by lowering the temperature of the reaction mixture and yielding the said reaction, it roughly triples. country r ^r Grignard reaction mixture after the distillation is desired koteeateru formula I (R ^»CH3-C g ^H 13) alkylaatým oxalate, C, 5-Diex-3,6-dimethyloctane, and other agents which distillation can be very difficult to separate. The koteeater content of this mixture can be monitored by gas chromatography. However, further cleaning of the keteeater to prepare the free acid is not necessary; the crude product is subjected to hydrelysis with a hydroxide solution by extracting an alkaline solution to separate all neutral portions and extracting the acidified solution and distillation to give pure 2-oxo-3-methylpentanoic acid in a yield of 45-50%, calculated on starting 2-chlorobutap.

Example 1

To a 12.2 g (0.5 mill) magnesium layer overlaid with 50 mL dry ether was added dropwise a solution of 46.3 g (0.5 mill) of 2-chlorobutane in 65 mL dry ether at a rate such that the reaction mixture ae spontaneously maintained at moderate reflux. . Reakoe was started by adding one to two drops of bromine. After mixing the ebeu components, the mixture was refluxed for 1-2 hours. The Grignard reagent thus prepared was poured into a separatory funnel after cooling and added dropwise to a solution of 81 ml (0.6 ml) of ethyl oxalate in 175 ml of dry ether. The temperature (inside the flask) was maintained at -15 to -20 ° C during the reaction (cooling to a lower temperature does not matter, higher temperatures strongly reduce yields). A dry ice bath was used to cool. After mixing the two components, the reaction mixture was allowed to warm to room temperature spontaneously with stirring and allowed to stand for 12 hours. The reaction mixture was quenched by adding 150 ml of 10% hydrochloric acid while stirring and cooling to 5-10 ° C. The ether layer was separated, the aqueous layer was shaken four times with 100 ml of ether and the combined washings were washed twice with 100 ml of water, dried over magnesium sulfate, evaporated and the residue distilled in a water pump vacuum. Distillate was collected up to 110 ° C; predominantly fraction and b.p.

up to 110 ° C (1.6 kPa) (distillate is yellow, since it contains yellow ε-diketone - 4 - 1,5-dioxa-3,6-dimethylectane). A total of 72 g of this distillate was obtained which, according to gas chromatography, contained 51% of the 6-ketoeater. This mixture was poured into 200 ml of 10% potassium hydroxide with stirring and gradually neutralized by dropwise addition of concentrated potassium hydroxide until permanently alkaline over 1-2 hours. The alkaline solution together with the remaining yellow oil was shaken twice with 150 ml of ether and the colorless aqueous solution acidified. * 20% sulfuric acid. The strongly acidic solution together with the precipitated oil was shaken four times with chloroform, the combined chloroform extracts were filtered and evaporated. The residue was distilled in a water pump vacuum, yielding 29 g (44.5%, calculated on the starting chloride) of 2-oxo-3- acid. methylpentane, tv 78-80 ° C / 1.6 kPa, m.p. Deň: 32 ° C.

@ 1 H-NMR in dioxane (ppm) .delta.1.20 (3H, .delta. CH), 1.50 to 2.60 (2H, m, _CH2), 4.20 (1H, m, CH).

In several repeated experiments the yield of this acid was in the range of 29-32 g (44.5-50%).

Example 2

A reaction carried out in the same manner as in Example 1, but maintaining the temperature of the reaction mixture at 0 to -10 ° C, yielded 16 g (25%) of 2-oxo-3-methylpentanoic acid.

Example 3

A reaction carried out in the same manner as in Example 1, but maintaining the temperature of the reaction mixture at -30 to -35 ° C, afforded 30 g (47%) of 2-oxo-3-methylpentanoic acid. Example 4

A Grignard reagent prepared from 46.3 g (0.5 mol) of 2-chlorobutane as described in Example 1 was added dropwise to a mixture of 155 g (0.6 mol) of hexyl oxalate and 175 ml of dry ether. The temperature of the screening mixture was maintained at -15 to -25 ° C. After decomposition with hydrochloric acid, the ether layer was separated, the aqueous layer was washed four times with 100 ml ether, the combined ether was washed twice with 100 ml water and evaporated. The residue was poured with stirring into 200 ml of 10% potassium hydroxide and salkalisevan was added dropwise with concentrated potassium hydroxide until permanently alkaline. This alkaline hydrate was further treated as in Example 1 to give 28 g (43%) of 2-oxe-3-methylpentanoic acid.

Claims (1)

A process for the preparation of 2-oxo-3-methylpentanoic acid alkyl esters wherein alkyl is methyl to hexyl by reacting a secondary butylmagneeiunch chloride with alkyl oxalate, wherein alkyl is methyl to hexyl, characterized in that the reaction is carried out at temperatures of 0 to -50 ° C, and preferably at a temperature of -15 to -20 ° C.