FR2695637A1 - (E)-2-propyl-2-pentenoic acid prodn. - from 2-bromo-2-propyl-pentanoate ester, useful as anti-epileptic agent - Google Patents

Abstract

Prodn. of (E)-2-propyl-2-pentenoic acid of formula (I) comprises: (a) heating a 2-bromo-2-propyl-pentanoate ester of formula (II) in a polar aprotic amide solvent, opt. contg. H2O in the presence of a basic agent (III) to form a mixt. of (E)- and (Z)-2-propyl-2-pentenoate esters of formula (IV); and (b) saponifying (IV) with an alkali metal hydroxide in an aq. medium, opt. contg. an alcohol ROH, and acidifying the reaction mixt. with a strong acid to obtain (I). In the formulae, R = 1-4C alkyl. (III) comprises: (i) a sec. amine, (ii) a sec. or tert. amine and a weak inorganic base, (iii) an alkali metal carbonate, or (iv) an alkali metal carbonate and an alkali metal halide. (I) is described in Arch. Pharm., 310(4), 394(1977) and J.A.C.S., 93(17), 4242(1971). The solvent is DMF, N,N-dimethylacetamide or N-methylpyrrolidone. The sec. amine is piperidine or piperazine. The tert. amine is NMe3, NEt3, trimethyl-ethylenediamine or 1,4- diazabicyclo(2,2,2)octane. The weak inorganic base is an alkali metal carbonate or alkaline earth metal hydroxide. The alkali metal halide is a chloride or bromide. (III) esp. comprises piperazine and K2CO3. The (III):(II) molar ratio is 0.5-3:1. Step (a) is effected at 30-130 (esp. 70-80) deg.C. Saponification is effected with 1-10 equiv. of NaOH at reflux temp. in an aq. medium contg. 50-150 vol.% ROH, esp. where R = Et. The reaction mixt. is acidified with HCl at -10 to +20 deg.C. Saponification is limited to 90-92% conversion, and unsaponified ester is extracted with a water-immiscible solvent before acidifying the aq. phase. USE/ADVANTAGE - (I) is an anti-epileptic agent. The process gives higher yields (65-80%) than prior art processes (cf. EP 293753) and gives (I) with high purity (at least 98%).

Description

 The present invention relates generally to the preparation of an isomer of 2-propyl pentene-2-oic acid.

In particular, the invention relates to a process for the preparation, in pure form, of (E) -2-propylpentene-2-oic acid of formula

<tb> C <SEP> 2H5-CH <SEP> O
<tb><SEP> CC-OH <SEP> (Isomer <SEP> E) <SEP> I
<tb><SEP> nC, H7
<tb><SEP> 37
<tb> as well as its pharmaceutically acceptable salts.

 This acid of formula I is a known product which has been described in particular in Arch. Pharm. 310 (5) pp 394-403 (1977) and in J.A.C.S. 93, (17) pp 4242-4247 (1971).

 It is a metabolite of valproic acid, a compound known for its anticonvulsant properties and widely used in the treatment of epilepsy.

 The acid of formula I also has significant anti-epileptic activity and a lower degree of teratogenicity than valproic acid.

 Several processes are already known for preparing (E) -2-propylpentene-2-oic acid.

However, most of them have disadvantages such that their use can not be validly considered for an industrial production. Indeed, these different processes involve
- or dangerous reagents such as sodium cyanide, requiring a delicate implementation,
- Or starting compounds already developed and difficult to access, such as 4-hydroxy 5 octanone,
- Or a number of important steps with ultimately a low overall efficiency, of the order of 30%, coupled with a rather heavy implementation because of the reagents used.

 There are, however, processes for the preparation of the (E) -2-propylpentene-2-oic acid in question having a relatively small number of steps and using readily accessible reagents.

However, these processes have disadvantages, the most important of which are characterized by a lack of selectivity in the isomers of 2-propylpentene-2-oic acid formed (geometric and positional isomers) and difficult separation of these isomers resulting in overall returns quite low.

In this regard, the method described in Arch. Pharm. 310 (1977) cited above, according to which
a) dehydrohalogenation of ethyl 2bromo-2-propyl pentanoate under reflux with N, N-diethylaniline and purification by distillation (yield: 76.5).

 b) the ester thus obtained is saponified under reflux with a 1.5M aqueous solution of sodium hydroxide and in the presence of ethanol, treated with sulfuric acid and purified by fractional crystallization from petroleum ether (yield: 25).

The overall yield of this process is very low since of the order of 19 from 2-bromo-2-propyl pentanoate ethyl.

A modification of this method has been described in patent application EP-293 753, according to which
a) the dehydrohalogenation of ethyl 2-bromo-2-propyl pentanoate by means of 1,4-diaza F2,2,2] bicyclooctane in acetonitrile, the reaction taking place for 8 hours at the reflux temperature of the medium, then it is purified by distillation to obtain a 77/23 mixture of (E) and (Z) isomers of ethyl 2-propyl pentene-2-olate (yield: 80%, equivalent to a 62% yield of isomer (E)) ,
b) saponification of the mixture of isomers in question with 10 equivalents of sodium hydroxide in methanol and for 5 days at room temperature to give a quantitative crude mixture 80/20 of (E) -2-propyl acid pentene-2-oic acid / 2-propyl pentene-3-oic acid (n3 isomer) and purification by distillation (yield not specified).

 As a result, the above process makes it possible to obtain crude (E) -2-propylpentene-2-oic acid with a maximum yield of 48t.

 In addition, when separating the isomers formed at the level of 2-propylpentene-2-oic acid, significant problems can be expected, since it is stated in the patent application in question that the Distillation to be carried out for the purification is delicate and must be carried out by means of a powerful column.

 The development of a process which can be used industrially and which makes it possible to prepare the acid of formula I in pure form, that is to say free from isomers and with good yields, therefore remains a major interest.

 It has surprisingly been found that it is possible to obtain (E) -2-propylpentene-2-oic acid and its pharmaceutically acceptable salts from a 2-bromo-2-propyl pentanoic ester, with yields far superior to those provided by the prior processes and with a degree of purity particularly remarkable.

dans laquelle R représente un radical alkyle en C1-C4, dans un solvant aprotique polaire comportant un groupement amide et en présence d'un agent basique consti tué
- soit d'une amine secondaire,
- soit d'une amine secondaire ou tertiaire et d'une base inorganique faible,
- soit d'un carbonate de métal alcalin éventuellement associé à un halogénure de métal alcalin,
ce qui fournit un mélange d'isomères (E) et (Z) d'esters éthyléniques de formule générale

dans laquelle R a la même signification que précédemment ;;
b) on saponifie le mélange d'isomères (E) et (Z) d'esters ainsi obtenu, au moyen d'un hydroxyde de métal alcalin, dans un milieu réactionnel aqueux, puis on acidifie ce milieu au moyen d'un acide fort, pour obtenir l'acide (E)-2-propyl pentène-2-oïque. According to the invention, (E) 2propylpentene-2-oic acid is prepared by a process involving the following steps
a) an α-brominated ester of general formula is heated

wherein R represents a C1-C4 alkyl radical, in a polar aprotic solvent having an amide group and in the presence of a basic agent consisting of
- a secondary amine,
- a secondary or tertiary amine and a weak inorganic base,
or an alkali metal carbonate optionally combined with an alkali metal halide,
which provides a mixture of (E) and (Z) isomers of ethylenic esters of the general formula

wherein R has the same meaning as before;
b) the mixture of isomers (E) and (Z) of esters thus obtained is saponified, using an alkali metal hydroxide, in an aqueous reaction medium, and then this medium is acidified using a strong acid; to obtain (E) -2-propylpentene-2-oic acid.

 Preferably, use is made of the abbreviated ester of formula II in which R represents the ethyl group, that is to say ethyl 2-bromo-2-propyl pentanoate.

 In general, the dehydrobromination reaction of the ester of formula II, namely the reaction of formation of the ethylenic bond by removal of hydrobromic acid, takes place at a temperature of between 30.degree. C. and 130.degree. temperature between 70 ° C and 80 ° C.

 As the solvent, a polar aprotic solvent having an amide group is used.

 Indeed, it is noted that such a solvent is already proving capable of inducing elimination of HBr at the level of the esters of formula II, unlike other polar aprotic solvents such as acetonitrile.

 Generally, N, N-dimethylformamide, N, N-dimethylacetamide or N-methylpyrrolidone is used as a solvent.

 However, N, N-dimethylformamide is a preferred solvent.

As for the basic agent, it may be
or a secondary amine, preferably a cyclic secondary amine,
or an association formed by a secondary or tertiary amine, preferably a cyclic secondary amine or a cyclic tertiary amine, and a weak inorganic base such as an alkali metal carbonate or an alkaline earth metal hydroxide,
or an alkali metal carbonate optionally combined with an alkali metal halide such as chloride, or preferably bromide.

 As cyclic secondary amine, for example piperidine or piperazine may be mentioned, and as tertiary amine, it is generally possible to use a C 1 -C 4 trialkylamine such as trimethylamine, triethylamine or trimethylethylenediamine, or preferably a cyclic tertiary amine such as 1,4diaza [2,2,2] bicyclooctane (DABCO).

 Also, the weak inorganic base may be an alkali metal carbonate such as lithium, sodium or potassium carbonate, while the alkaline earth metal hydroxide may be for example calcium hydroxide or calcium hydroxide. magnesium.

Preferentially, the basic agents that may be mentioned are piperidine, piperazine, sodium carbonate, potassium carbonate, the secondary amine / alkali metal carbonate couple, the couple
DABCO / alkali metal carbonate or the lithium carbonate / lithium bromide pair.

 The secondary amine / alkali metal carbonate pair constitutes a particularly advantageous basic agent according to the invention, in particular the piperazine / potassium carbonate pair.

 According to the invention, the elimination of HBr is carried out in the presence of 0.5 to 3 moles of basic agent, more generally in the presence of 1 to 2 moles per mole of ester of formula II.

 For example, 0.5 to 1.5 moles of secondary or tertiary amine associated with 1.5 to 0.5 moles of a weak inorganic base can be used.

 If necessary, the HBr removal reaction medium contains water so as to increase its homogeneity, and thus allow greater reaction kinetics.

 The HBr removal method thus described makes it possible to obtain a mixture of isomers (E) and (Z) of esters of formula III having a very high level of isomer (E), since at least 85% , usually a rate of about 90%.

 In addition, these mixtures of (E) and (Z) isomers of formula III esters were found to be free of the corresponding 2-propyl pentene-3-oic ester (3-isomer).

 Likewise, their yields from the α-brominated ester of formula II have been excellent.

 By way of example, mixtures of isomers (E) and (Z) of esters of formula III could be obtained with crude chemical yields generally greater than 95% from 2-bromo-2-propyl pentanoate. ethyl.

 The saponification of the mixture of isomers (E) and (Z) of esters of formula III in question generally takes place in the presence of 1 to 10 equivalents, preferably 1 to 5 equivalents, of an alkali metal hydroxide such as sodium hydroxide.

 This saponification reaction generally takes place at a temperature ranging from room temperature to the reflux temperature of the medium, preferably at the reflux temperature.

In addition, the saponification reaction is preferably carried out in an aqueous reaction medium containing an alcohol of general formula
R-OH IV in which R has the same meaning as above.

 Preferably, the alcohol of formula III is used in a proportion of 50 to 150% by volume, for example 100%, by volume of water.

 Likewise, from 2 to 10 mol / l of alkali metal hydroxide, for example from 3 to 8 mol / l and generally from 1 to 5 mol of a mixture of isomers (E) and (Z, are preferably used. ) of esters of formula III such as from 1 to 3 mol / l, preferably 1.5 mol / l.

 As for the acidification, this is generally carried out at a temperature of +20 ° C. to -10 ° C., preferably at a temperature of 0 ° C. to -10 ° C.

 According to this method, the crude (E) -2-propylpentene-2-oic acid can be obtained with an excellent chemical yield, since of the order of 65 to 80%, from the α-brominated derivative of formula II . Therefore, the overall yield of the process of the invention is far superior to that obtained according to the prior art.

 In addition, the degree of purity of the acid of formula I thus obtained is very important, since it is greater than 95%.

 If necessary, the purification of this acid of formula I can be improved by one or more recrystallizations in an aqueous medium containing an alcohol of formula IV, a medium similar to that previously defined as a preferred medium for saponification.

 However, a single recrystallization is generally sufficient to obtain a product of very high purity since titrating at least 98% isomer (E) of formula I [isomer (Z) <1.5% and isomer t3 <0.3%].

 After purification, the yield of isomer (E) of 2-propylpentene-2-oic acid remains very high.

 It can be for example of the order of 65 to 70% from the α-brominated ester of formula 11, when the latter is treated with the piperazine / alkali metal carbonate couple as basic agent.

 The preparation of the acid of formula I by saponification from a mixture of isomers (E) and (Z) of esters of formula I can be carried out according to a variant of the method described above.

 This variant is based in particular on the demonstration of a saponification kinetics of the (E) and (Z) isomers of 2-propylpentene-2-oic esters of formula II, which is totally different, since it has been found that the isomer (E) saponifies much more rapidly than the corresponding (Z) isomer.

 Consequently, this difference can be exploited by effectively controlling the saponification rate so as to limit the conversion to a maximum mixture of (E) -2-propyl pentene-2-oic acid and minimal salt of acid salt. (Z) -2-propyl pentene-2-oic acid.

 According to the variant in question, (E) -2-propylpentene-2-oic acid is prepared by saponifying a mixture of (E) and (Z) -isomers up to a conversion level of 90 to 92%. ethylene esters of formula II obtained according to the invention, the saponification being carried out by means of an alkali metal hydroxide in an aqueous reaction medium optionally containing an alcohol of formula IV, by extracting the unsaponified esters by means of a solvent immiscible with water, for example an ether, and by acidifying the aqueous reaction medium with a strong acid after extraction of the unsaponified esters, to obtain essentially (E) -2-propyl pentene-2 acid -oïque.

 If necessary, the acid thus formed can be crystallized once or several times in water and in the presence of an alcohol of formula IV, to obtain (E) -2-propylpentene-2-oic acid in particular form. pure.

 This variant of saponification generally takes place in the presence of 2 to 10 equivalents, preferably 5 equivalents of an alkali metal hydroxide.

This saponification reaction is carried out at a temperature of 30 ° C. to 50 ° C., preferably at a temperature of the order of 40 ° C. in a reaction medium formed of an aqueous medium containing an alcohol of formula
IV, preferably from 50 to 150% by volume, for example 100%, by volume of water and, preferably, from 2 to 10 mol / l of alkali metal hydroxide, for example 7.5 mol / l and preferably from 1 to 3 mol / l, of a mixture of esters of formula 11.

 The other operating conditions are similar to those described above for the general method of saponification.

 The saponification variant thus described makes it possible to obtain the acid of formula I with yields of the order of 75% in repurified product calculated from the ester of formula II. In addition, the pure product thus obtained has a title of (E) -2-propyl pentene-2 oic acid greater than 98t.

d'abord avec le chlorure de thionyle, ensuite avec le brome, et finalement avec un alcool de formule IV, ces réactions ayant lieu dans un solvant aprotique tel que le dichloréthane, pour obtenir les esters désirés.As for the α-brominated esters of formula 11, these can be obtained by treating, in a polar solvent, n-2-propyl pentanoic acid or valproic acid, of formula

first with thionyl chloride, then with bromine, and finally with an alcohol of formula IV, these reactions taking place in an aprotic solvent such as dichloroethane, to obtain the desired esters.

 Finally, the pharmaceutically acceptable salts of (E) -2-propylpentene-2-oic acid can be prepared by reaction in a suitable solvent such as toluene, with an appropriate organic or inorganic base, for example a metal hydroxide. alkali such as sodium hydroxide or an alkali metal carbonate such as sodium carbonate, to form a pharmaceutically acceptable salt, preferably the sodium salt.

The following nonlimiting examples illustrate the invention
Preparation
2-bromo ethyl 2-propyl pentanoate
144 g of 2-n-propylpentanoic acid and 0.5 g of N, N-dimethylformamide are introduced into a Grignard reactor under a nitrogen atmosphere.

 The mixture is heated to 65 ° C and 128.4 g of thionyl chloride are added over 8 hours while maintaining the temperature of the medium at 65 to 70 ° C. At the end of the addition, the mixture is heated to 95 ° C. and this temperature is maintained for one hour, 40 g of 1,2-dichloroethane are then introduced, heated to 100 ° C. and 164 g of bromine are added over 8 hours. The temperature of the medium is maintained at 110 ° -115 ° C. for one hour after the end of the addition, the reaction mixture is cooled to 80 ° -85 ° C., and 74 g of absolute ethanol are then added over 2 hours 30 minutes. The mixture is refluxed for one hour and then cooled to 20 ° C. before adding 40 g of water.

Decanted, the organic phase is concentrated and the oily residue is distilled [PE: 117-1190 ° C (2.7 × 10
Pa)].

 In this way, 242 g of ethyl 2-bromo-2-propyl pentanoate are obtained.

Yield: 96.5%.

Example 1
Preparation of (E) -2-propylpentene2-oic acid
A) Mixture of isomers (E) and (Z) of ethyl 2-propyl pentene-2-olate
In a reactor of 1 1 equipped with a stirrer, a condenser and heated by a thermostatically controlled oil bath, 251 g (1 mole) of 2-bromo-2-propyl pentanoate are introduced at ambient temperature and with stirring. 500 g of N, N-dimethylformamide, 95 g (1.1 moles) of piperazine, 76 g (0.055 moles) of anhydrous potassium carbonate and 20 g (1.1 moles) of water.

 The medium is heated to 80 ° C ± 1 ° C until complete conversion. After cooling to 20 ° C., 500 g of purified water are hydrolyzed and the mixture is stirred for 15 minutes. The aqueous phase is then removed by decantation.

 In this way, 163 g of a mixture of isomers (E) and (Z) of 2-propyl pentene-2-olate are obtained.

Gross yield: 95.9%
Ester Title (E): 86.4%
Ester yield (E): 82.8t
Isomer ratio: E / Z = 89.7 / 10.3
B) (E) -2-propylpentene-2-oic acid
a) saponification
The mixture of esters (E) and (Z) obtained previously is subjected to saponification by heating under reflux for 1 hour in a 50/50 (vol / vol) hydroethanolic medium and in the presence of 1.15 mole of sodium hydroxide. in pellets.

 After cooling to 0 ° C., the mixture is acidified with 1.3 mol of 37% hydrochloric acid and then ice-cooled to -10 ° C.

 After drying and drying at 20 ° C., 106.3 g of crude (E) -2-propylpentene-2-oic acid are obtained, which represents a yield of 74.8% relative to 2-bromo-2- ethyl propyl pentanoate.

CPG purity: acid titre (E) = 96.4%
as acid (Z) = 2.2%
b) isolation of (E) -2-propyl pentene-2-oic acid
In a three-necked flask of 100 ml, 22 ml of ethanol, 33 ml of water and 7.6 g of crude (E) -2-propylpentene-2-oic acid obtained previously are introduced.

 The mixture is heated under reflux and then cooled slowly over 1 hour, from 30 ° C. to -10 ° C. (E) -2-propylpentene-2-oic acid precipitates towards 0 ° C. After filtration, it is recrystallized from The precipitate obtained is then the same, and then the mixture is re-stained with a 70/30 water / ethanol mixture.

 In this way, 6.76 g of (E) -2-propylpentene-2-oic acid are obtained.

Purification yield: 89%
Yield over ethyl 2-bromo-2-propyl pentanoate: 66.7%
Example 2
Preparation of (E) -2-propylpentene 2-oic acid
A) Mixture of isomers (E) and (Z) of ethyl 2-propyl pentene-2-olate
In a reactor of 1 1 equipped with a stirrer, a condenser and heated by a thermostatically controlled oil bath, 251 g (1 mole) of 2-bromo-2-propyl pentanoate are introduced at ambient temperature and with stirring. 500 g of N, N-dimethylformamide, 95 g (1.1 moles) of piperazine, 76 g (0.55 moles) of anhydrous potassium carbonate and 20 g (1.1 moles) of water.

 The mixture is heated at 70 ° C. ± 1 ° C. for 12 hours (conversion rate: 99%), then cooled to 20 ° C. 500 g of purified water are hydrolyzed by introduction and the mixture is stirred for 15 hours. The aqueous phase is then decanted off.

In this way, 163.2 g of a mixture of isomers (E) and (Z) of 2-propylpentene-2-ethyl ester are obtained in a ratio E / Z: 91/9
Gross yield: 96%
B) (E) -2-propylpentene-2-oic acid
a) saponification
The mixture of esters (E) and (Z) obtained previously is subjected to saponification by heating under reflux for 1 hour in a 50/50 (vol / vol) hydroethanolic medium and in the presence of 1.15 mole of sodium hydroxide. in pellets.

 After cooling to 0 ° C., the mixture is acidified with 1.3 mol of 37% hydrochloric acid and then ice-cooled to -10 ° C.

 After drying and drying at 20 ° C., 107.9 g of crude (E) -2-propylpentene-2-oic acid are obtained, which represents a yield of 76% relative to 2-bromopropyl pentanoate. ethyl.

b) isolation of (E) -2-propyl pentene-2-oic acid
In a three-necked flask of 100 ml, 22 ml of ethanol, 33 ml of water and 7.6 g of crude (E) -2-propylpentene-2-oic acid obtained previously are introduced.

 The mixture is heated under reflux and then cooled slowly over 1 hour, from 30 ° C. to -10 ° C. (E) -2-propylpentene-2-oic acid precipitates towards 0 ° C. After filtration, it is recrystallized from The precipitate obtained is then the same, and then the mixture is re-stained with a 70/30 water / ethanol mixture.

 In this way, 7 g of (E) 2-propylpentene-2-oic acid are obtained.

Purification yield: 92%
Yield over ethyl 2-bromo-2-propyl pentanoate: 70%
Examples 3 to 5
Preparation of (E) -2-propylpentene 2-oic acid
A) Mixture of isomers (E) and (Z) of ethyl 2-propyl pentene-2-olate
In a reactor of 1 1 equipped with a stirrer, a condenser and heated by a thermostatically controlled oil bath, 251 g (1 mole) of 2-bromo-2-propyl pentanoate are introduced at ambient temperature and with stirring. 500 g of N, N-dimethylformamide, M moles of piperazine, 76 g (0.55 moles) of anhydrous potassium carbonate and 20 g (1.1 moles) of water.

 The reaction medium is heated at a temperature T for X hours.

 After cooling to 20 ° C., 500 g of purified water are hydrolyzed and the mixture is stirred for 15 minutes and the aqueous phase is then decanted off.

 In this way, a mixture of (E) and (Z) isomers of ethyl 2-propylpentene-2-oate is obtained in the form of a colorless oily residue.

Using the method described above, the following results were obtained:

<tb> Example <SEP> M <SEP> T (C) <SEP> X (h) <SEP> Rate <SEP> of <SEP> Report <SEP> of
<tb><SEP> (mole) <SEP> conver- <SEP> isomers
<tb><SEP> (%) <SEP> E / Z <SEP> *
<tb><SEP> 3 <SEP> 1,1 <SEP> 80 <SEP> 8 <SEP> 100 <SEP> 90/10
<tb><SEP> 4 <SEP> 1 <SEP> - <SEP> 75 <SEP> 10 <SEP> 100 <SEP> 90.5 / 9.5 <SEP>
<tb><SEP> 5 <SEP> 0.55 <SEP> 75-95 <SEP> 19 <SEP> 98 <SEP> 89/11
<tb> * determined by nuclear magnetic resonance (NMR) in CDCl3 (300 Mhz) triplet 6.75 and 5.80 ppm.

B) (E) -2-propylpentene-2-oic acid
This compound was obtained according to the method described in Example 1B.

Example 6
Preparation of the acid (E-2-propyl pentene2-oic
A) Mixture of isomers (E) and (Z) of ethyl 2-propyl pentene-2-olate
In a Grignard reactor, 1.0 kg (4 moles) of ethyl 2-bromo-2-propylpentanoate, 2.0 kg (12.51 moles) of N, N-dimethylformamide and 0.275 kg (2 moles) were charged. ) of potassium carbonate. The mixture is brought to 75 ° C., then 0.494 kg (4.4 mol) of powdered DABCO and 0.32 kg of water are introduced, The temperature is raised to 75 ° C. ± 3 ° C. in the mass at 1 ° C. hour and the reaction medium is maintained at 75 ° C. ± 2 ° C. for 7 hours. It is cooled to 20 ° C. and then hydrolyzed, without exceeding the temperature of 40 ° C., by casting the medium in 2.4 kg of water. previously cooled to 10 C. The surface of the ester is decanted and after removal of the lower aqueous layer, washed with 0.5 kg of water.

 In this way, 0.66 kg of a mixture of isomers (E) and (Z) of ethyl 2-propyl pentene-2-olate are obtained.

Gross yield: 97%
E / Z isomer ratio = 90/10.

 Following the same procedure as above, a mixture of (E) and (Z) isomers of ethyl 2-propylpentene-2-olate was prepared in a 89/11 ratio.

PE: 750C (1.3.103 Pa) d at 20 ° C: about 0.92
B) 2-propylpentene-2-oic acid
a) saponification
20.4 ml of water, 12 g of sodium hydroxide pellets and 20.4 ml of ethanol are introduced under argon into a Grignard reactor. The mixture is heated to 40 ° C. and 10.21 g of a 90/10 mixture of (E) / (Z) isomers of ethyl 2-propylpentene-2-olate are added rapidly. reaction medium at this temperature for 130 minutes, the conversion of ester to acid is then about 90% (control by gas chromatography) is added to the reaction medium 100 ml of purified water and 30 ml of diisopropyl ether The aqueous phase is decanted and extracted once more with 30 ml of diisopropyl ether, the aqueous phase is acidified with 35 ml of 37% hydrochloric acid and extracted with 3 times 50 ml of diisopropyl ether. organic and washed with 3 times 50 ml of water, dried over sodium sulphate and concentrated on a rotary evaporator (temperature <30 ° C.).

 In this way, 7.7 g of crude 2-propylpentene-2-oic acid are obtained.

Yield: 90.3%
By NMR in CDCl 3 (300 MHz), the isomeric ratio E / Z = 94/6 (triplet at 6.8 and 6 ppm) is determined.

b) isolation of (E) -2-propyl pentene-2-oic acid
In a three-necked flask of 100 ml, 22 ml of ethanol, 33 ml of water and 7.6 g of crude 2-propylpentene-2-oic acid obtained previously are introduced.

 The mixture is heated under reflux and then cooled slowly over 1 hour, from 30 ° C. to -10 ° C. (E) -2-propylpentene-2-oic acid precipitates towards 0 ° C. After filtration, it is recrystallized from The precipitate obtained is then the same, and then the mixture is re-stained with a 70/30 water / ethanol mixture.

 In this way, 6.5 g of (E) -2-propylpentene-2-oic acid are obtained.

Purification yield: 85.5%
Yield over ethyl 2-bromo-2-propyl pentanoate: 74.9%
Purity determined by capillary GC: title = 98.9%
PF: 38%
Impurities: Isomer (Z): 0.7
isomers3: 0.4%
Example 7
Preparation of (E) -2-propylpentene2-oic acid
A) Mixture of isomers (E) and (Z) of ethyl 2-propyl pentene-2-olate
Following the same procedure as that described in Example 6A, starting from 25.1 g (0.1 mole) of ethyl 2-bromo-2-propyl pentanoate, 50 g of N-methyl pyrrolidone, 6.9 g. g (0.05 mol) of potassium carbonate, 12.4 g (0.11 mol) of DABCO and 8 g of water were obtained after heating for 8 hours at 75 ° C. a mixture of isomers (E ) and (Z) ethyl 2-propyl pentene-2-oate containing 2,4t of starting ester.

E / Z isomer ratio = 87.4 / 9.6.

B) (E) -2-propylpentene-2-oic acid
This compound was obtained according to the method described in Example 1B.

Example 8
Preparation of (E) -2-propylpentene2-oic acid
A) Mixture of (E) and (Z) isomers of ethyl 2-propyl pentene-2-olate
Following the same procedure as that described in Example 6A, starting from 25.1 g (0.1 mole) of ethyl 2-bromo-2-propylpentanoate, 50 g of N, N-dimethylacetamide, 6, 9 g (0.05 mol) of potassium carbonate, 12.4 g (0.11 mol) of DABCO and 8 g of water were obtained after heating for 14 hours at 75 ° C. a mixture of isomers ( E) and (Z) ethyl 2-propyl penten-2-olate.

E / Z isomer ratio = 91 / 8.8.

B) (E) -2-propylpentene-2-oic acid
This compound was obtained according to the method described in Example 1B.

Example 9
Preparation of (E) -2-propylpentene2-oic acid
A) Mixture of (E) and (Z) isomers of ethyl 2-propyl pentene-2-olate
In a reactor of 1 1 equipped with a stirrer, a condenser and heated by a thermostatically controlled oil bath, 251 g (1 mole) of 2-bromo-2-propyl pentanoate are introduced at ambient temperature and with stirring. ethyl, 500 g of N, N-dimethylformamide, and 170 g (2 moles) of piperidine. The medium is heated to 75 ° C + 1 ° C until complete conversion.

 After cooling to 20 ° C., 500 g of purified water are hydrolyzed and the mixture is stirred for 15 minutes and the aqueous phase is then decanted off.

 In this way, 160 g of a mixture of isomers (E) and (Z) of 2-propyl pentene-2-olate are obtained.

Gross yield: 94%
Ester Title (E): 85.8%
Ester yield (E): 80.6%
E / Z isomer ratio = 90/10
B) (E) -2-propylpentene-2-oic acid
a) saponification
The mixture of esters (E) and (Z) obtained previously is subjected to saponification by heating under reflux for 1 hour in a 50/50 (vol / vol) hydroethanolic medium and in the presence of 1.15 mole of sodium hydroxide. in pellets.

 After cooling to 0 ° C., the mixture is acidified with 1.3 mol of 37% hydrochloric acid and then ice-cooled to -10 ° C.

 After drying and drying at 20 ° C., 96 g of crude (E) -2-propylpentene-2-oic acid are obtained, which represents a yield of 67.6% relative to 2-bromo-2-propylpentanoate. ethyl.

CPG purity: acid content (E) = 98.8%
as acid (Z) = 0.8%
b) isolation of (E) -2-propyl pentene-2-oic acid
In a three-necked flask of 100 ml, 22 ml of ethanol, 33 ml of water and 7.6 g of crude (E) -2-propylpentene-2-oic acid obtained previously are introduced.

 The mixture is heated under reflux and then cooled slowly over 1 hour, from 30 ° C. to -10 ° C. (E) -2-propylpentene-2-oic acid precipitates towards 0 ° C. After filtration, it is recrystallized in the same conditions the precipitate obtained, then it is backpacked with a 70/30 water / ethanol mixture.

 In this way, 7.06 g of (E) -2-propylpentene-2-oic acid are obtained.

Purification yield: 93%
Yield over ethyl 2-bromo-2-propyl pentanoate: 63.2%
Examples 10 to 13
Preparation of (E) -2-propylpentene2-oic acid
A) Mixture of isomers (E) and (Z) of ethyl 2-propyl pentene-2-olate
In a reactor of 1 1 equipped with a stirrer, a condenser and heated by a thermostatically controlled oil bath, 251 g (1 mole) of 2-bromo-2-propyl pentanoate are introduced at ambient temperature and with stirring. ethyl, 500 g of N, N-dimethylformamide, and M moles of piperazine.

 The reaction medium is heated at a temperature T for X hours.

 After cooling to 20 ° C., 500 g of purified water are hydrolyzed and the mixture is stirred for 15 minutes and the aqueous phase is then decanted off.

 In this way, a mixture of (E) and (Z) isomers of ethyl 2-propylpentene-2-oate is obtained in the form of a colorless oily residue.

Using the method described above, the following results were obtained:

<tb> Example <SEP>: <SEP> M <SEP>: <SEP> T <SEP> (C) <SEP>: <SEP> X <SEP> (h) <SEP>: <SEP> Rate <SEP > of <SEP>: <SEP> Report <SEP> of
<tb><SEP>: (mole) <SEP>: <SEP>: <SEP>: <SEP> conversion <SEP>: <SEP> isomers
<tb><SEP>:<SEP> (%) <SEP> E / Z <SEP> ^ <SEP>
<tb><SEP> 10 <SEP>: <SEP> 2 <SEP>: <SEP> 75 <SEP>: <SEP> 6 <SEP>: <SEP> 100 <SEP> 89.7 / 10.3
<tb><SEP> 11 <SEP>: <SEP> 1,1 <SEP>: <SEP> 75 <SEP>: <SEP> it <SEP>: <SEP> 97 <SEP>: <SEP> 89, 5 / 9.5
<tb><SEP> 12 <SEP>: <SEP> 2 <SEP>: <SEP> 70 <SEP>: <SEP> 8 <SEP> 97 <SEP>: <SEP> 91/9
<tb><SEP> 13 <SEP>: <SEP> 1,1 <SEP>: <SEP> 80 <SEP>: <SEP> 10 <SEP>: <SEP> 99 <SEP>: <SEP> 89, 5 / 10.5
<tb> * determined by NMR in CDCl3 (300 Mhz): triplet 6.75 and 5.80 ppm.

B) (E) -2-propylpentene-2-oic acid
This compound was obtained according to the method described in Example 1B.

Examples 14 to 17
Preparation of (E) -2-propylpentene2-oic acid
A) Mixture of (E) and (Z) isomers of ethyl 2-propyl pentene-2-olate
In a reactor equipped with a stirrer, a condenser and heated with a thermostatically controlled oil bath, 25.1 g (0.1 mol) of 2-bromo-2-propyl are introduced at ambient temperature and with stirring. ethyl pentanoate, V ml of N, N-dimethylformamide, Y mole of lithium carbonate and Z mole of lithium chloride.

 The reaction medium is placed under nitrogen and, with stirring, the mixture is heated at a temperature T for X hours. The monitoring of the reaction by C.P.G.

reveals an almost complete conversion of the α-brominated ester.

After cooling to 20 ° C., the medium is slowly hydrolyzed by adding a mixture of 37 ml of 36% hydrochloric acid and 63 ml of water. The aqueous phase is extracted with 25 ml of diisopropyl ether and decanted. The organic phase is washed with twice 100 ml of water and then concentrated, on a rotary evaporator, the organic phase obtained.

In this way, a mixture of (E) and (Z) isomers of ethyl 2-propylpentene-2-olate is obtained.

<Tb>

Ex. <SEP> V <SEP>: <SEP><SEP> Y <SEP>. <SEP><SEP> Z <SEP>: <SEP> T <SEP>: <SEP><SEP> X <SEP> Render- <SEP>% <SEP><SEP> by <SEP> CPC <SEP>: <SEP> Report <SEP>
<tb><SEP><SEP>:<SEP> of <SEP>
<tb><SEP> crude <SEP>: (a) <SEP> Isomer <SEP> isomers <SEP>
<tb><SEP> (%) <SEP> (E) <SEP> E / Z <SEP> (%)
<tb> 14 <SEP> 100 <SEP> 0.21 <SEP> 0.05 <SEP><SEP> 8080 <SEP><SEP> 88 <SEP> 100 <SEP>: <SEP> 1 <SEP> 84 , 3 <SEP> 88.3 / 11.7 <SEP>
<tb><SEP> (15.6g) <SEP> (2.1g) <SEP>(<SEP>
<tb> 15 <SEP>: <SEP> 400 <SEP>: <SEP> 0.21 <SEP>: <SEP> 0.05 <SEP>: <SEP> 80 <SEP>: <SEP> 8 <SEP >: <SEP> 100 <SEP>: <SEP> 1 <SEP>: <SEP> 84.3 <SEP>: <SEP> 88/12
<tb> 16 <SEP> 200 <SEP>: <SEP> 021 <SEP><SEP> - <SEP> 90 <SEP> 11 <SEP> 98 <SEP> 1 <SEP> 83.5 <SEP> 87 / 13 <SEP>
<tb> 17 <SEP>: <SEP> 400 <SEP>: <SEP> 0.21 <SEP>: <SEP> 0.05 <SEP>: <SEP> 80 <SEP>: <SEP> 10 <SEP >: <SEP> 100 <SEP>: 0.2 <SEP>: <SEP> 84.6 <SEP> 88/12
<tb> (a): ethyl 2-bromo-2-propylpentanoate.

B) (E) -2-propylpentene-2-oic acid
This compound was obtained according to the method described in Example 1B.

Example 18
Preparation of (E) -2-propylpentene 2-oic acid
A) Mixture of isomers (E) and (Z) of ethyl 2-propyl pentene-2-olate
In a reactor equipped with a stirrer, a condenser and heated with a thermostatically controlled oil bath, 251 g (1 mole) of ethyl 2-bromo-2-propyl pentanoate and 250 g of N, N- dimethylformamide. 53 g (0.5 mole) of ground sodium carbonate, 250 g of N, N-dimethylformamide and 40 g of water are added with stirring. The reaction medium is brought to 1200C in 1 hour and maintained at this temperature for 5 hours.

It is then cooled to 13 ° C. GPC carried out on an aliquot of the mixture (3 ml) reveals an E / Z isomer ratio of the desired ester = 85.1 / 14.9. 500 g of water, bringing the temperature to 30 ° C, then cooled to 20 ° C. Decanted and washed twice with 200 g of a 10% aqueous sodium chloride solution (weight / weight After a new decantation, 166 g of a mixture of isomers (E) and (Z) of ethyl 2-propyl pentene-2-olate are obtained.

Gross yield: 97.6%
Ester Title (E): 83.3%
Title in ester (Z): 15.3%
E / Z isomer ratio: 84.5 / 15.5
B) (E) -2-propylpentene-2-oic acid
a) saponification
In a Grignard reactor, 158 g (0.93 mol) of the mixture of isomers (E) and (Z) of esters obtained previously, 42.8 g of sodium hydroxide pellets, 75.9 g are introduced. ethanol and 94.8 g of water.

 The reaction medium is brought to the reflux temperature for 1 hour, then cooled to 20 ° C. It is then acidified by adding 129 g of 37% hydrochloric acid, and then cooled to 0 ° C., which causes crystallization. Sprayed at -10 ° C., drained and rinsed with a mixture of 52 g of ethanol / 132 g of water, ice-cold mixture at -10 ° C., then dried at 20 ° C. under 1.33 × 10 4 ( 100 mm Hg).

 In this way, 85.6 g of dry (E) -2-propylpentene-2-oic acid are obtained.

Yield: 64.9%
CPG purity: acid titre (E) = 95.9%
as acid (Z) = 3.2%
titre in isomers3 = 0,5%
b) isolation of (E) -2-propyl pentene-2-oic acid
Following the method described in Example 1B, the crude (E) -2-propylpentene-2-oic acid obtained previously was purified. From 77.5 g of crude acid, 68 g of dry purified acid were obtained in the form of an off-white solid.

Purification yield: 87.74%
Yield from ethyl 2-bromo-2-propyl pentanoate: 57%
CPG purity: acid titre (E) = 99.8%
title in acid (Z) = 0,15% titre in isomer 3 = undetected

Claims (26)

 1. Process for the preparation of (E) -2-propylpentene-2-oic acid of formula

 (E-isomer) and its pharmaceutically acceptable salts, characterized in that  a) an α-brominated ester of general formula is heated

 in which R represents a C 1 -C 4 alkyl radical, in a polar aprotic solvent comprising an amide group, optionally containing water, and in the presence of a basic agent consisting of  - a secondary amine,  - a secondary or tertiary amine and a weak inorganic base,  or an alkali metal carbonate optionally combined with an alkali metal halide,  which provides a mixture of (E) and (Z) isomers of ethylenic esters of the general formula

 in which R has the same meaning as above.  R-OH in which R has the same meaning as above, this medium is acidified with a strong acid to obtain (E) -2-propyl pentene-2-oic acid, and then form, if desired, a pharmaceutically acceptable salt of this acid.  b) the mixture thus obtained is saponified by means of an alkali metal hydroxide in an aqueous reaction medium optionally containing an alcohol of general formula  2. Method according to claim 1, characterized in that R represents the ethyl radical.  3. Process according to claim 1 or 2, characterized in that the polar aprotic solvent comprising an amide group is N, N-dimethylformamide, N, N-dimethylacetamide or N-methylpyrrolidone.  4. Process according to claim 1 or 2, characterized in that the secondary amine is a cyclic secondary amine.  5. Process according to claim 4, characterized in that the cyclic secondary amine is piperidine or piperazine.  6. Process according to claim 1 or 2, characterized in that the tertiary amine is a C1-C4 trialkylamine.  7. Process according to claim 6, characterized in that the tertiary amine is trimethylamine, triethylamine or trimethylethylenediamine.  8. Process according to claim 1 or 2, characterized in that the tertiary amine is 1,4-diaza (2,2,2] bicyclooctane.  9. Process according to claim 1 or 2, characterized in that the weak inorganic base is an alkali metal carbonate or an alkaline earth metal hydroxide.  10. The method of claim 9, characterized in that the alkali metal carbonate is lithium carbonate, sodium or potassium, and the alkaline earth metal hydroxide is calcium hydroxide or magnesium hydroxide.  11. The method of claim 1 or 2, characterized in that the alkali metal halide is chloride or bromide.  12. The method of claim 1 or 2, characterized in that the basic agent consists of a secondary amine and a weak inorganic base.  13. The method of claim 12, characterized in that the basic agent consists of piperazine and an alkali metal carbonate.  14. The method of claim 12 or 13, characterized in that the basic agent consists of piperazine and potassium carbonate.  15. Process according to one of claims 1 to 14, characterized in that from 0.5 to 3 moles of basic agent are used per mole of α-brominated ester.  16. Process according to one of Claims 1 to 13, characterized in that the α-brominated ester is heated at a temperature of 30 ° C to 130 ° C.  17. Process according to claim 16, characterized in that the α-brominated ester is heated at a temperature of 70 ° C to 80 ° C.  18. The method of claim 1 or 2, characterized in that the saponification takes place at a temperature between room temperature and the reflux temperature of the medium.  19. The method of claim 18, characterized in that the saponification takes place at the reflux temperature of the medium.  20. Process according to one of claims 1, 2, 18 or 19, characterized in that the saponification is carried out using 1 to 10 equivalents of alkali metal hydroxide.  21. The method of claim 1 or 2, characterized in that the alkali metal hydroxide is sodium hydroxide.  22. Method according to one of claims 1, 2 or 18 to 21, characterized in that the aqueous reaction medium contains from 50 to 150% by volume of an alcohol of general formula  R-OH in which R has the same meaning as in claim 1.  23. Process according to claim 1 or 2, characterized in that the acidification takes place at a temperature of +20 ° C to -10 ° C.  24. The method of claim 1 or 2, characterized in that the strong acid is hydrochloric acid.  25. Process according to claim 1 or 2, characterized in that the saponification is carried out to a degree of conversion of 90 to 92%, the unsaponified esters are extracted using a solvent immiscible with the solvent. water, and then the aqueous reaction medium is acidified after extraction of the unsaponified esters.  26. Process according to claim 1 or 2, characterized in that the pharmaceutically acceptable salt is formed by reaction of (E) -2-propylpentene-2-oic acid with an organic or inorganic basic compound.