FR2835524A1 - PROCESS FOR THE PREPARATION OF OMEGA -BROMOALKYLCARBOXYLIC COMPOUNDS - Google Patents

Abstract

The invention relates to a process for preparing ω-bromoalkylcarboxylic acid and their esters, alkyl les-bromoalkanoates, which comprises reacting gaseous HBr with a lactone in the absence of solvent at a temperature above the melting point of the mixture. reaction medium and then esterifying the ω-bromoalkylcarboxylic acid with an alcohol in a solvent medium and without adding a catalyst, so as to extract the water in the form of a ternary water / solvent / alcohol heteroazeotrope by extractive distillation.

Description

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Process for the preparation of co-bromoalkylcarboxylic compounds.

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The invention relates to a process for the preparation of (O-bromoalkylcarboxylic compounds such as 4-bromobutyric acid and their esters, such as ethyl 4-bromobutyrate.

d'Alzheimer, et plus généralement pour la synthèse de composés à activité nootrope. Le 4-bromobutyrate d'éthyle est tout particulièrement utilisé dans la synthèse du LEVETIRACET ( (S)- (-) a-éthyl-2-oxo-1-pyrrotidineacétamide). The m-bromoalkylcarboxylic compounds, in particular their esters, are intermediates for the synthesis of pharmaceutical products recommended, inter alia, for the treatment of cerebral senescence and of disease.

Alzheimer's, and more generally for the synthesis of compounds with nootropic activity. Ethyl 4-bromobutyrate is particularly used in the synthesis of LEVETIRACET ((S) - (-) a-ethyl-2-oxo-1-pyrrotidineacetamide).

lesquelles font le plus souvent appel à la réaction d'un alcool sur un acide Go- bromoalkylcarboxylique pour l'obtention des w-bromoalccinoates d'alkyles, les acides étant généralement obtenus par hydrolyse acide d'm-bromoalkylnitriles, par clivage de lactones avec BBr3, par la réaction de Hunsdiecker ou bien par hydrobromuration de lactones. Many methods have been described for obtaining these compounds,

which most often involve the reaction of an alcohol with a Go-bromoalkylcarboxylic acid to obtain alkyl w-bromoalccinoates, the acids generally being obtained by acid hydrolysis of m-bromoalkylnitriles, by cleavage of lactones with BBr3, by the Hunsdiecker reaction or else by hydrobromination of lactones.

y-bromobutyronitrile avec de l'acide bromhydrique à 48 %, puis en versant le milieu réactionnel dans de l'eau glacée et en extrayant l'acide avec de l'éther, ladite solution éthérée étant ensuite séchée sur sulfate de sodium, puis après évaporation du solvant, le résidu étant distillé sous pression réduite après évaporation du solvant. Thus, Redeuilh G. et al. (Bull. Société Chim. De France, 3-4, part. 2, pages 850-856,1975) obtain, with a yield of 65%, 4-bromobutyric acid by heating at reflux for 18 hours on

y-bromobutyronitrile with 48% hydrobromic acid, then by pouring the reaction medium into ice water and extracting the acid with ether, said ethereal solution then being dried over sodium sulfate, then after evaporation of the solvent, the residue being distilled under reduced pressure after evaporation of the solvent.

 Shigeru Oae (J. A. C. S., 78, pages 4030-4032,1950) directly obtains ethyl 4-bromobutyrate with a yield of 50% from y-bromobutyronitrile by treating said nitrile with methanol in the presence of H2SO4. In this case, there is underproduction of ammonium sulfate.

 In the special drug patent (BSM) No. 3,901 M, the preparation of alkyl 4-bromobutanoates (methyl, butyl, 3-methylbutyl, ethyl) is described by esterification of 4-bromobutyric acid with the corresponding alcohols. presence of HBr. No yield is indicated.

 G. A. Olah et al. (Synthesis, pages 963-965; 1982) obtain different w-bromoolkylcarboxylic acids according to the reaction:

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avec n = 1 (butyrolactone), le rendement est de 98 %, avec n = 2 (valérolactone), le rendement est de 88 %.

with n = 1 (butyrolactone), the yield is 98%, with n = 2 (valerolactone), the yield is 88%.

With n = 1, if H20 is replaced by CH3OH, methyl 4-bromobutyrate is obtained with a yield of 65%.

agi EtOzC (CH2) n C02H Ag+) Et02C (CH2) nC02Ag brotne brome) Et02C (CH2) n Br + AgBr + CO2

Ainsi, dans le brevet suisse CH 202 417, le 8-bromooctanoate d'éthyle est obtenu avec un rendement de 77 % par rapport au sel d'argent du monoester méthylique de l'acide azelaique. The acids <D-bromoo! ky) carboxy) iques et) eurs esters can be obtained by the Hunsdiecker reaction:

acted EtOzC (CH2) n C02H Ag +) Et02C (CH2) nC02Ag brotne bromine) Et02C (CH2) n Br + AgBr + CO2

Thus, in Swiss patent CH 202 417, ethyl 8-bromooctanoate is obtained with a yield of 77% relative to the silver salt of the methyl monoester of azelaic acid.

The most commonly used method for obtaining the alkyl 4bromobutyrates (III) consists in esterifying the 4-bromobutyric acid (I) obtained by opening the Y-butyrolacton with HBr according to the reactions:

R representing a linear or branched hydrocarbon radical having a number of carbon atoms ranging from 1 to 4.

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porter a reflux pendant 7 heures, un mélange de 500 ml d'méthanol absolu, 81 g d'HBr sec (1 mole) et 42 g de &gamma;-butyrolactone (0,48 mole). Ensuite, ils distillent sous pression réduite et obtiennent 57 g de 4-bromobutyrate d'éthyle soit un rendement de 58 %. Thus, JP Berry et al. (J. Org. Chem., Vol. 37, n 26, page 4396.1972) describe a process for the preparation of ethyl 4-bromobutyrate which consists in

bring to reflux for 7 hours, a mixture of 500 ml of absolute methanol, 81 g of dry HBr (1 mole) and 42 g of &gamma; -butyrolactone (0.48 mole). Then, they distill under reduced pressure and obtain 57 g of ethyl 4-bromobutyrate, ie a yield of 58%.

bullage dans 500 ml d'éthanol absolu jusqu'à ce que 819 (1 mole) d'HBr ait été absorbé. WA Reckhow and b. S. Tarbell (J. Amer. Chem. Soc. 74, page 4961, 1952) proceed somewhat differently but obtain an identical yield of ethyl 4-bromobutyrate. They introduce dry HBr by

bubbling in 500 ml of absolute ethanol until 819 (1 mole) of HBr has been absorbed.

 To this ethanolic solution of HBr, they add 43 g (0.5 mole) of &gamma; -butyrolactone and the solution is brought to reflux in a water bath for 4 hours. The excess ethanol is removed and the residue is distilled under reduced pressure. They obtain 55 g of a clear colorless oil having a boiling point of 76-78 "C under 7 mm of mercury.

 The major drawback is to use large quantities of ethyl alcohol which serves as reagent and solvent. In addition, yields are low.

 Another way to obtain alkyl, especially ethyl, 4-bromobutyrate consists in using the method described in Japanese patent application No. JP-A-52-93713.

 A mixture of 40 g of &gamma; -butyrolactone (0.465 mole), 59 g of ethyl alcohol and 114 g of NaBr is cooled to 0 C. To this mixture is added dropwise at a temperature ranging from 0 to 5 C. , 108 g of concentrated H2SO4, then the mixture is stirred for 30 minutes at this temperature.

 Stirring is continued for 6 hours at 250C - 30oC. Then add 300 g of water. An oily phase is obtained which is separated from the aqueous phase by decantation and which is distilled to give 78% of ethyl 4-bromobutyrate corresponding to a yield of 85%.

 If the ethanol is replaced by methanol, in the process described above, 68 g of methyl 4-bromobutyrate are obtained, corresponding to a yield of approximately 75%.

des traitements coûteux des effluents (BBr3, sels d'argent des acides, bromonitriles, H2S04). All of these methods have many drawbacks. They use expensive reagents, which are difficult to access industrially, and which require

expensive effluent treatments (BBr3, silver salts of acids, bromonitriles, H2SO4).

The yields and selectivities are low.

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 Furthermore, the methods using alcoholic solutions of HBr inevitably produce alkyl bromides.

puis dans une seconde étape b) à estérifier l'acide #-bromoalkylcarboxylique (I) en co-bromoalcanoate d'alkyle (III) au moyen d'un alcool ROH selon la réaction (2) :

où R représente un radical éthyl, propyl ou isopropyl et n = 1,2 ou 3 ledit procédé étant caractérisé par le fait que, - dans l'étape a), réalisée en absence de solvant, l'on introduit en continu de l'HBr dans un réacteur contenant une lactone (II) maintenue a une température supérieure àl la température de fusion du milieu réactionnel, puis que l'on strippe l'HBr résiduel par balayage à l'azote et que l'on dégaze l'acide < a- bromoalkylcarboxylique brut (I) obtenu par mise sous pression réduite, puis que, - dans l'étape b), réalisée sans ajout de catalyseur, l'on charge un solvant d'estérification sur l'acide co-bromoalkylcarboxylique dégazé obtenu en a), puis que l'on charge ensuite tout ou partie de l'alcool ROH dans le mélange précédent que l'on porte a reflux total sous agitation, sous pression atmosphérique, puis que l'on soutire l'eau formée par distillation extractive, tout en introduisant le complément (éventuel) d'alcool ROH qui est utilisé selon un rapport molaire alcool total mis en #uvre / acide #-bromoalkylcarboxylique (I), allant de 1,5 a 5, et de préférence, allant de 2 ci 3,5. The Applicant has now found a process for the preparation of # -bromoalkylcarboxylic acids and their esters, the alkyl # -bromoalkanoates not having the drawbacks mentioned above which consists in preparing in a first step a) ro-bromoalkylcarboxylic acid (I) by reacting the hydrogen bromide gas HBr-with a lactone (II) according to reaction (1):

then in a second step b) esterifying the # -bromoalkylcarboxylic acid (I) into an alkyl co-bromoalkanoate (III) using an alcohol ROH according to reaction (2):

where R represents an ethyl, propyl or isopropyl radical and n = 1,2 or 3 said process being characterized in that, - in step a), carried out in the absence of solvent, is continuously introduced HBr in a reactor containing a lactone (II) maintained at a temperature above the melting temperature of the reaction medium, then the residual HBr is stripped by nitrogen sweeping and the acid is degassed < a- crude bromoalkylcarboxylic (I) obtained by placing under reduced pressure, then, - in step b), carried out without addition of catalyst, an esterification solvent is loaded on the degassed co-bromoalkylcarboxylic acid obtained in a), then all or part of the alcohol ROH is then loaded into the preceding mixture which is brought to total reflux with stirring, at atmospheric pressure, then the water formed is drawn off by extractive distillation , while introducing the (if any) ROH alcohol supplement that is used according to a total alcohol molar ratio used / # bromoalkylcarboxylic acid (I), ranging from 1.5 to 5, and preferably ranging from 2 to 3.5.

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 According to the present invention, the term “extractive distillation” is understood to mean the distillation of the ternary water heteroazeotrope Isolvant lol alcohol ROH, which leads by decantation to an aqueous lower phase drawn off continuously and to an upper organic phase which is recycled to the reaction medium.

 According to the present invention, a rapid evaporation is then carried out, at atmospheric pressure, of the excess alcohol and of the solvent which can advantageously be recycled in a subsequent operation.

 The crude alkyl m-bromoakanoate obtained is heated under reduced pressure in order to remove the alcohol and / or the residual solvent (exhaustion).

 According to the present invention, purification is then carried out by distillation which consists in topping and then flash distillation under reduced pressure at a temperature such that the bottom temperature is lower than the degradation temperature of the ester (III). Advantageously, the top fraction can be recycled, which improves the yield of ester (III).

 According to the present invention, step a) can optionally be carried out in the presence of a small catalytic amount of water or an aqueous solution of hydrobromic acid.

préférence, va de 35 C a 60 C. Dans l'étape a), l'HBr est introduit dans la lactone (II) mise en oeuvre selon un rapport molaire HBr/ ! actone (H) attant de 1 a 2,5 et de préférence, allant de 1,1 à 1,8. According to the present invention, step a) is carried out at a temperature as defined above, which can range from 20 ° C. to 100 ° C. and, from

preferably ranges from 35 C to 60 C. In step a), the HBr is introduced into the lactone (II) used in a molar ratio HBr /! actone (H) ranging from 1 to 2.5 and preferably ranging from 1.1 to 1.8.

inférieure a 100 C et, de préférence, a une température allant de 70 C à 100 C. Esterification step b) is carried out at an equal temperature or

less than 100 C and preferably at a temperature ranging from 70 C to 100 C.

 According to the present invention, the esterification solvent is chosen from solvents making it possible to lead to a ternary heteroazeotrope with water and the esterification alcohol under the pressure and temperature conditions used in step b).

 By way of illustration of such solvents, mention will be made of cyclohexane, heptane, benzene, toluene, chloroform, trichlorethylene. Cyclohexane will be used in particular.

The solvent according to the present invention should be used in an amount such that it can ensure the formation of the ternary heteroazeotrope while allowing the boiling temperature of the reaction medium to be kept below or equal to 100 C, at atmospheric pressure .

The process of the present invention applies very particularly to the synthesis of ethyl 4-bromobutyrate from γ-butyrolactone.

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 The process which is the subject of the present invention makes it possible to obtain o-bromoatkytcarboxytic acids and their esters, in particular, ethyl or isopropyl, in a very selective manner with high yields, while in particular minimizing underproduction. of alkyl bromides and the retrogradation of co-bromoalkylcarboxylic acids (or their esters) to their corresponding lactones.

 The direct hydrobromination of lactones with HBr gas in the absence of solvent according to the process of the present invention makes it possible to obtain the cobromoalkylcarboxylic acids with a very high productivity and a purity sufficient for their subsequent use.

 The synthesis of esters with heteroazeotropic extraction of water makes it possible to considerably limit the aqueous effluents.

 In addition, the esterification is carried out without adding catalyst.

 The following examples illustrate the invention.

la) Préparation de l'acide 4-brotnobutyrique
La synthèse est réalisée dans un réacteur en verre de 1,5 litre équipé d'une agitation mécanique, d'une introduction d'HBr gaz, d'un système d'inertage à l'azote et d'une sonde de température et surmonté d'un réfrigérant à double circulation (eau glycole). La sortie du réfrigérant (évents) est connectée à un laveur à eau pour absorber l'HBr en excès. Le chauffage (ou le refroidissement) du réacteur est assuré au moyen d'un bain d'huile thermostat. Le débit d'HBr est régulé via un débitmètre massique. EXAMPLE 1:

la) Preparation of 4-brotnobutyric acid
The synthesis is carried out in a 1.5 liter glass reactor equipped with mechanical stirring, an introduction of HBr gas, a nitrogen inerting system and a temperature probe and overcome a dual circulation refrigerant (glycol water). The refrigerant outlet (vents) is connected to a water washer to absorb excess HBr. The reactor is heated (or cooled) by means of a thermostat oil bath. The flow of HBr is regulated via a mass flow meter.

 The whole assembly is inerted with nitrogen, then the circulation of glycol water cooled to 0 ° C. is started in the refrigerant, 10 moles of y-butyrolactone are loaded into the reactor, then the stirring is started, the mixture is heated at 40 ° C., then the introduction of the HBr gas is started at the bottom of the reactor at a flow rate of 2 mol / h while maintaining the reaction medium at 40 ° C. with stirring.

a 1 mol/h. The flow of HBr is thus maintained at 2 mol / h for 4 h then is reduced

at 1 mol / h.

After the overall introduction of 12.5 moles of HBr, the injection of HBr is stopped and the reaction medium is placed under a nitrogen sweep at 40 ° C. for 30 min, then under a pressure of 133 mbar for an additional 30 min.

 1667 g of 4-bromobutyric acid are thus obtained with a purity greater than 99% with a residual content of gam-gamma -butyrolactone less than 0.5% (analyzes by vapor phase chromatography and by NMR).

 The molar yield of 4-bromobutyric acid relative to the # 019-butyrolactone used is thus 98.8%.

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 This 4-bromobutyric acid is either recovered and stored as it is at room temperature for subsequent use or is kept in solution in cyclohexane at 30 oC pending its esterification. In the latter case, at the end of the reaction, 340 g of cyclohexane are poured into the reactor.

"double double enveloppe réfrigérée, lui-même surmonté d'un réfrigérant à double circulation (eau glycolée). 1b-Préparationdu4-bromobutyrated'éthyle
The esterification is carried out in a 1.5 liter glass reactor equipped with mechanical stirring, a liquid supply system by metering pump, a nitrogen inerting system and a temperature probe and surmounted by an adiabatic distillation column of the Oldershaw type with 20 trays. The column head is connected to a decanter a

"refrigerated double jacket, itself topped with a dual circulation refrigerant (glycol water).

 After inerting the entire installation with nitrogen, half of the 4-bromobutyric acid / cyclohexane mixture obtained above is transferred to the reactor, then 300 9 of additional cyclohexane and 200 g of absolute ethanol are charged.

 After stirring, the mixture is brought to total reflux, and, as soon as a decantation is observed in the decanter at the top of the column, the drawing off of the lower phase is started while recycling the upper organic phase in the reactor and simultaneously, the introduction of the additional ethanol is started via the metering pump at a flow rate of 50 g / h.

 The heating and the introduction of ethanol are thus maintained for 12 h until almost complete extraction of the water formed (end of decantation).

Throughout this period, the temperature of the reaction medium remains between 75 "C and 85 C and the temperature at the top of the column between 60 C and 64" C.

 At the end of extraction, the withdrawn phase represents 545 g and the conversion of 4-bromobutyric acid is greater than 99%.

 The excess ethanol and the cyclohexane of the reaction mixture are then evaporated at atmospheric pressure and then under reduced pressure (133 mbar) while maintaining a bottom temperature below 100 C. After concentration, the title of ethyl 4-bromobutyrate in crude esterification is greater than 96% and the residual contents of 4-bromobutyric acid and butyrolactone are respectively less than 0.5% and 1.5%.

 The ethyl 4-bromobutyrate is then distilled under reduced pressure at 10 mbar while maintaining a bottom temperature below 100 C. After having extracted a top fraction of 116.5 g consisting of 95% of ethyl 4-bromobutyrate and 5% of gam-butyrolactone (recyclable), which is obtained by flash distillation

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 with a bottom temperature of 95 ° C. and a head temperature of 76 ° C., 727.5 g of ethyl 4-bromobutyrate with a purity equal to 99.5%, which corresponds to a yield of 4-bromobutyrate d 'ethyl of 75% relative to the y-butyrolactone used. The recycling of the heads advantageously makes it possible to bring the yield to around 85%.

Préparation de l'acide 5-brotno volérique
On utilise un montage expérimental analogue à celui mis en oeuvre dans l'exemple la-mais avec un réacteur en verre de 250 ml. EXAMPLE 2:

Preparation of 5-brotno voleric acid
An experimental setup similar to that used in Example 1a-but is used with a 250 ml glass reactor.

 After having inerted the entire assembly with nitrogen, 150 g of o-valerolactone (1.5 mol) are loaded into the reactor and 16 g of 48.1% aqueous HBr solution. After placing the reaction mixture with stirring at 55 ° C., 211 g of anhydrous HBr are then introduced over 5 hours (average flow rate of the order of 0.5 mol / h) while maintaining the reaction temperature at 55 ° C.

 At the end of the introduction of the HBr, the reaction medium is kept under stirring at 55 ° C. for an additional 30 min then is degassed by flushing with nitrogen for 1 h.

bromovalérique d'une pureté de 98 % correspondant à un rendement molaire de 97, 4 % par rapport a ! a o-vatérotactone initia) e. The conversion of # -valerolactone is then greater than 99.5% and thus 292.2 g of crude 5-bromovaleric acid are obtained, containing approximately 7% of water and of HBr but of an organic purity greater than 98 %. After topping this crude at 55 oC under a pressure of 20 mmHg, 270 g of acid are recovered.

bromovaleric with a purity of 98% corresponding to a molar yield of 97.4% relative to a! a o-vaterotactone initia) e.

2b-Preparation û / 5 - / * C / M7 / a6 </ 'C //? ? The esterification is carried out with an assembly similar to that used in Example 1b. 222 g of 5-bromovaleric acid obtained above (1.2 mol), 138 g of ethanol (3 mol) and 200 ml of cyclohexane are successively loaded into the reactor. The reaction mixture with stirring is heated until the reflux of the ternary azeotrope (cyclohexane-ethanol-water) at the head of the distillation column is reached: - column head temperature: 66.1-66.7 C, - reaction temperature: 73-78 C.

 The azeotrope is then continuously extracted at the top of the column and decanted at 10 C. The lower aqueous phase is drawn off and the upper organic phase is continuously recycled in the reactor via a pump. After 2 h of extraction, the temperature at the top of the column thus increases to 75-77 C for a reaction temperature of 94-97 C.

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 The mass of the decanted phase obtained is 135.7% to 15.4% water corresponding to a conversion of 5-bromovaleric acid by 96.7%.

 After concentration of the reaction medium, the ethyl 5-bromovalerate is then recovered by distillation under reduced pressure (Sample: 78 C / 80 "C at 5 mbar).

Claims (13)

 where R represents an ethyl, propyl or isopropyl radical and n = 1, 2 or 3; said process being characterized in that, - in step a), carried out in the absence of solvent, there is continuously introduced HBr into a reactor containing a lactone (II) maintained at a temperature above the temperature of fusion of the reaction medium, then stripping the residual HBr by sweeping with nitrogen and degassing the crude o-bromoalkylcarboxylic acid (I) obtained by placing under reduced pressure, then, - in l step b), carried out without addition of catalyst, an esterification solvent is loaded onto the degassed # -bromoalkylcarboxylic acid obtained in a), then all or part of the alcohol ROH is then loaded into the previous mixture which is brought to total reflux with stirring, at atmospheric pressure, then which the water formed is drawn off by extractive distillation, while introducing the complement (possible)

 then in a second step b) a esterifying the co-bromoalkylcarboxylic acid (I) into an alkyl o-bromoalkanoate (III) using an alcohol ROH according to reaction (2):

 CLAIMS - * - * - * - * - * - * - * -. Process for the preparation of # -bromoalkylcarboxylic acids and their esters, the alkyl # -bromoalkanoates which consists in preparing in a first step a) the # -bromoalkylcarboxylic acid (I) by reacting the hydrogen bromide gas- HBr-with a lactone (II) according to reaction (1): <Desc / Clms Page number 11>  alcohol ROH which is used according to a molar ratio of total alcohol used / o-bromoalkylcarboxylic acid, ranging from 1.5 to 5; and then a rapid evaporation is carried out, at atmospheric pressure, of the excess alcohol and of the solvent which are then exhausted under reduced pressure and then the alkyl # -bromoalkanoate (III) is purified by distillation .

2. Method according to claim 1, characterized in that the # - alkyl bromoalkanoate (III) is subjected to a purification by distillation which consists of a topping then a flash distillation under reduced pressure at a temperature such that the temperature of foot is lower than the degradation temperature of the alkyl bromoalkanoate (III). 3. Method according to claim 1 or 2, characterized in that step a) is carried out at a temperature ranging from 20 "C to 100 C and, preferably, at a temperature ranging from 35 C to 60 C. 4. Method according to one of claims 1 to 3, characterized in that the HBr gas is introduced into the actone (II) used according to a HBr / lactone (II) molar ratio ranging from 1 to 2.5 and, from preferably ranging from

 1, 1 to 1, 8. 5. Method according to one of claims 1 to 4, characterized in that step b) of esterification is carried out at a temperature equal to or less than 100 C. 6. Method according to claim 5, characterized in that step b) of esterification is carried out at a temperature ranging from 70 C Ci 100 C. 7. Method according to one of claims 1 to 6, characterized in that the esterification solvent is chosen from solvents leading to a ternary heteroazeotrope with water and ROH under the pressure and temperature conditions used in the step b). 8. Method according to claim 7, characterized in that the esterification solvent is cyclohexane, heptane, benzene, toluene, chloroform or trichlorethylene. <Desc / Clms Page number 12> 9. Method according to one of claims 7 or 8, characterized in that the esterification solvent is cyclohexane. 10. Method according to any one of claims 1 to 9, characterized in that the total alcohol molar ratio used #uvre / o-bromoalkyl acid

 carboxylic (I) ranges from 2 to 3, 5. 11. Method according to one of claims 1 to 10, characterized in that, after having loaded the esterification solvent, a part of all the alcohol used is loaded. 12. Method according to any one of claims 1 to 11, characterized in that, in addition, step a1 is carried out in the presence of a small amount of water or an aqueous solution of hydrobromic acid. 13. Method according to one of claims 1 to 12, characterized in that in the formula of the lactone (II), n = 1 or 2 and R of the alcohol ROH is an ethyl radical.