GB2153826A - Unsaturated carboxylic acid - Google Patents

Abstract

A process for preparing 8-methyl-6-nonenoic acid (useful as an intermediate) comprises (1) reacting caprolactone with hydrogen bromide and a lower aliphatic alcohol (preferably ethanol); (2) reacting the 6-bromohexanoic ester so formed with triphenylphosphine in a solvent; (3) reacting the triphenylphosphonium salt formed with isobutyraldehyde in accordance with the Wittig reaction; and (4) converting the 8-methyl-6-nonenoic ester formed to the free acid. Steps (3) and (4) can, if desired, be obtained.

Description

SPECIFICATION Unsaturated carboxylic acid This invention relates to the preparation of the unsaturated carboxylic acid, 8-methyl-6-nonenoic acid, which is useful as an intermediate in the synthesis of further valuable compounds.

According to the invention, there is provided a process for the preparation of 8-methyl6-nonenoic acid, comprising the steps of (1) reacting caprolactone with hydrogen bromide and a lower aliphatic alcohol to produce the corresponding 6-bromohexanoic acid ester; (2) converting the 6-bromohexanoic acid ester so formed to the corresponding triphenylphosphonium salt by reaction with triphenylphosphine in a suitable solvent; (3) reacting the triphenylphosphonium salt so formed with isobutyraldehyde in accordance with the Wittig reaction to form the corresponding ester of 8-methyl-6-nonenoic acid; and (4) converting the ester to free 8-methyl-6-nonenoic acid.

Using ethanol in step (1), the reactions involved in the invention can be represented as follows

IBr EtOH ~ OEt Sten 1 t ) B m Caproictone Ethyl 6-bromohexanoate Mf 114 }191 223 Step'2 2 ? Phm Nw 485.3 SteD sCSO bozo Ethyl 8-methyl-6-nonenoate M.W. 198 Step 4 NaOH gl & ethyl-6-nonenoic acrid N.W, 170 If desired, steps (3) and (4) can be combined, the ester being converted to the acid in situ without intermediate isolation of the ester.

While in step (1), any lower aliphatic alcohol having 1 to 3 carbon atoms can be used, ethanol is preferred.

When ethanol is used, the ethyl ester can be directly produced in adequate yield, without the necessity for isolating the free acid first formed.

In step (2), dimethylformamide (DMF) or dioxane is generally used as solvent. However, t-butyl-methyl ether can be used with some advantage, since the salt is deposited as an oily layer from the reaction liquor, although the rate of reaction is slower.

The product obtained by the process of the invention in step (3) has chromatographic mobility and infra-red spectral properties consistent with its being ethyl 8-methyl-6-nonenoate.

It appears to be an essential feature of the process of the invention to use a bromine derivative of the hexanoic acid ester in step (2), since the Wittig reaction between the triphenylphosphonium salt derived from 6-chlorohexanoic acid and isobutyraldehyde under conditions similar to step (3) failed. The Homer-Wittig reaction between the phosphonate derived from 6-chlorohexanoic acid ester and isobutyraldehyde also failed to produce any identifiable product.

The invention is illustrated by the following examples : Example 1 Step (1) Caprolactone monomer was converted into ethyl 6-bromohexanoate by the method described by Vogel (4th Edition, p. 531 ) with minor modifications. A sample of the crude oil product was distilled at b.p.

57-60 C/lmmto give the pure product, g.c. analysis 98.1%, in a yield equivalent to 87.6%. The bulk of the crude product was not distilled but taken on to step (2) without further purification.

Step 62) The crude ester prepared in step (1) (87 grms, 0.39M) and triphenylphosphine (105 grms, 0.4M) were dissolved in DMF (500 mls) and the solution was boiled under refluxfor 8 hours; reaction then appeared to be complete. The solution was concentrated under vacuum at 509C. The oily residue was shaken three times with 200 ml portions of toluene to remove excess triphenylphosphine, and was then dissolved in dichloromethane (500 mix). The solution was washed with 20% brine, dried, and evaporated to dryness.

The viscous residue weighed 150 grms (0.31 M,79.5% yield) and was taken on to step (3) without further purification.

Step (3) The crude phosphonium salt was dissolved in dichloromethane (500 mls) and half of this solution was taken for the subsequent reaction (i.e. 75 grms, 0.155M).

The solution was boiled under a reverse-Dean-and-Stark trap for 0.5 hours to remove any residual water.

After recooling to 25 C anhydrous potassium carbonate (23.1 grms, 0.167M) and 18-Crown-6 (420 mgs) were added. The mixture was stirred for 0.5 hours, reheated to boiling, and, while continuing to boil under reflux, a solution isobutyraldehyde (10.8 grms, 0.15M) in dichloromethane (300 mls) was added dropwise during 6 hours. The mixture was refluxed for a further 0.5 hours and allowed to cool overnight.

G.C. and T.L.C. analysis indicated the presence of a product having the expected chromatographic mobility; however a significant amount of phosphonium salt starting material remained unreacted.

300 mis of the dichloromethane was distilled off until the pot temperature rose to 60 C. Dioxane (200 mls) and anhydrous potassium carbonate (23.1 grms) were added and the mixture was reheated to 65"C. A solution of isobutyraldehyde (10.3 grms) in dioxane (200 mls) was dropped in during 2 hours while maintaining a pot temperature of 65-70 C. The reaction was heated to reflux during 1.5 hours and boiled under reflux (pot temperature, 95"C) for a further one hour.

T.L.C. analysis indicated virtually complete absence of phosphonium salt.

After cooling, the reaction mixture was diluted with 20% brine (400 mls) and extracted three times with ethyl acetate (400 mls, 2 x 200 mix). The combined extracts were washed to neutrality with 20% brine, dried and evaporated to dryness. The residue was extracted with cyclohexane (3 x 200 mix), to separate the product from the co-produced triphenylphosphine oxide, and the extracts were reconcentrated to a small volume and allowed to stand overnight. After filtration from a further small amount of triphenylphosphine oxide, the productwes recovered by distillation.

Yield: 16.9 grms; b.p. 50-60"C/0.2-0.4 mm, 55% of theory; G.C. analysis: about 95% major impurity low boiler about 1.5%; T.L.C. analysis shows trace impurities; I.R. analysis was consistent with the expected structure.

Step (4) The ethyl ester produced in step (3) was treated with aqueous sodium hydroxide and the free acid liberated from the salt formed by acidification, and recovered by extraction.

Example 2 The process was carried out as in Example 1, except that the steps (3) and (4) were combined, the ester formed being converted in situ into the free acid.

The reaction mixture at the end of step (3) was directly treated with aqueous sodium hydroxide. This resulted in a reaction mixture which was much easier to work up since the product acid is, of course, soluble in aqueous alkali. Organic impurities, e.g. triphenylphosphine oxide can be removed by filtration and washing, and the free acid recovered by extraction from the acidified aqueous layer and distillation. The overall yield of distilled free acid was 81%.

Example 3 The process was carried out as in Example 1, except that in step (2), t-butylmethyl ether was used as the solvent. Although about 2 days reaction time was required to achieve a reasonable conversion, and the reaction is much slower than using DMF as solvent as in Example 1, but has the advantage that the precipitated oily salt can be separated merely by decanting the liquor. An average yield of 90% was obtained over three runs by recycling the liquor.

Example 4 Step 1: Ethyl 6-bromohexanoate Caprolactone (2087 grms) (18.28M) was brought into reaction with a mixture of 48% hydrobromic acid (9.6 t) and 96% sulphuric acid (2.32 J). The product was taken into carbon tetrachloride (5 { ) and the washed and dried extract was mixed with ethanol (1.5 f ) and p-toluene sulphonic acid (200 grms) and reacted by the azeotropic distillation method.

After a standard work-up, the crude concentrate (3897 grms, g.c. 96%) was distilled in vacuum to give ethyl 6-bromohexanoate, 3503 grms. (86%), g.c. 98.3%.

Step 2 : Phosphonium salt A mixture of ethyl 6-bromohexanoate (1708 grms, 7.66M), triphenylphosphine (2009 grms, 7.66M) and dioxane (2.5 C) was boiled under gentle reflux for 48 hours until no starting material remained.

Steps 314: Cis-8-methyl-6-nonenoic acid The solution from Step (3) was diluted, under nitrogen, with dioxane (4.4 e) and dichloromethane (2.3 t), potassium carbonate (1.59 Kg., 1 1.5M), isobutyraldehyde (830 grms, 11 .5M) and 18-crown-6 (10.5 grms, 0.5M%) were added and the mixture was boiled under gentle reflux for 48 hours, when utilisation of phosphonium salt was virtually complete. After cooling, 30% w/w aqueous sodium hydroxide (2043 grms, 1 5.32M) was added and the mixture was reheated to 50 to hydrolyse the product ester. When hydrolysis was complete, the mixture was recooled, diluted with water (4 e) and concentrated by distillation to remove most of the dioxane.The precipitated triphenylphosphine oxide was filtered off and washed well with 5% sodium hydroxide and water.

The combined alkaline mother liquors and washings were extracted twice with toluene (3 t, 2 P)to remove any remaining neutral impurities and the acidified with cooling at less than 20"C to pH 1-2 with concentrated hydrochloric acid.

The liberated product acid was extracted into ethyl acetate (three extracts) and the combined extracts were washed neutral with water, dried and concentrated.

The concentrate (1700 grms) was dissolved in cyclohexane (1500 grms) with warming. On cooling to ambient temperature a crystalline impurity deposited and was filtered off. The mother liquors were reconcentrated.

The residue was subjected to a careful fractional distillation to give cis-methyl-6-nonenoic acid, 872.5 grms, (67%), g.c. 99.3%, I.R. spectrum showing absence of trans-isomer.

The cis-isomer can be converted to the trans-isomer, if required, by known methods.

Claims (7)

1. A process for the preparation of 8-methyl-6-nonenoic acid, comprising the steps of : (1) reacting caprolactonewith hydrogen bromide and a lower aliphatic alcohol to produce the corresponding 6-bromohexanoic acid ester; (2) converting the 6-bromohexanoic acid ester so formed to the corresponding triphenylphosphonium salt by reaction with triphenylphosphine in a suitable solvent; (3) reacting the triphenylphosphonium salt so formed with isobutyraldehyde in accordance with the Wittig reaction to form the corresponding ester of 8-methyl-6-nonenoic acid; and (4) converting the ester to free 8-methyl-6-nonenoic acid.

2. A process as claimed in Claim 1, wherein the lower aliphatic alcohol used in step (1) is ethanol.

3. A process as claimed in Claim 1, or Claim 2, wherein steps (3) and (4) are combined, the ester being converted to the acid in situ without intermediate isolation.

4. A process as claimed in any one of Claims 1 to 3, wherein dimethylformamide or dioxane is used as the solvent in step (2).

5. A process as claimed in any one of Claims 1 to 3, wherein t-butyl-methyl ether is used as the solvent in step (2).

6. A process for the preparation of 8-methyl-6-nonenoic acid, substantially as herein before described with reference to any one of Examples 1 to 4.

7. 8-methyl-6-nonenoic acid prepared by a process as claimed in any one of Claims 1 to 6.