Method for synthesizing 2-bromoglutaric acid diester

Abstract

To provide a method for preparing a 2-bromoglutaric acid diester.SOLUTION: The present invention relates to a method comprising forming a 2-hydroxyglutaric acid diester of formula (II) by reacting butyrolactone acid of formula (BA) with an alcohol of formula ROH in the presence of an acid such as sulfuric acid; and brominating the 2-hydroxyglutaric acid diester of formula (II) by bubbling gaseous hydrobromic acid. The present invention further comprises a 2-bromoglutaric acid diester of formula (I) having a purity of 90% or more as measured by HPLC analysis.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a novel process for preparing 2-bromoglutaric acid diesters.

Background Art

[0002] α-Haloglutaric acids and their esters are useful basic building blocks in organic synthesis, whereby it becomes possible to incorporate an α-glutaric acid fragment into a complex molecule via a simple nucleophilic substitution reaction.

[0003] EP 1 931 673 describes novel gadolinium complexes derived from PCTA, which have uses as contrast agents in the field of medical imaging methods. Some of these complexes, particularly in the side chain of gadopiclenol, contain an α-glutaric acid fragment. The synthesis of gadopiclenol (in the form of all mixtures of its stereoisomers) described in EP 1 931 673 involves the alkylation of pycrene with diethyl 2-bromoglutarate, resulting in the intermediate hexaester, which is then hydrolyzed to the corresponding hexaacid, which is then complexed using a source of gadolinium. Gadopiclenol prepared according to the process described in EP 1 931 673 is finally obtained by reacting the gadolinium hexaacid complex with 3-amino-1,2-propanediol.

Chem.

[0004] Diethyl 2-bromoglutarate (hereinafter referred to as EBG) is a relatively unstable compound that decomposes over time under the influence of temperature or in the presence of water. More specifically, this particular α-halo-glutarate ester tends to be hydrolyzed or cyclized, thereby losing its bromine atom. Attempts have been made to purify commercial EBG, develop novel synthetic routes to obtain it in improved purity, or prevent its decomposition, but these have yet to be successful.

[0005] Therefore, the inventors have been searching for an alternative to EBG that is more stable than EBG and, at the same time, sufficiently reactive to achieve, for example, the synthesis of gadopicrenol. Thus, chloro derivatives of glutaric acid, which meet improved stability standards compared to EBG, cannot be satisfactory alternatives because they do not have sufficient reactivity. Iodine derivatives, as far as they are concerned, are more reactive than their bromo analogs, but are also more unstable. Through exploratory research conducted by the inventors, it became possible to select 2-bromoglutarate di-(C3~C6)-alkyl compounds as an alternative to EBG, particularly in the synthesis of gadopicrenol. However, commercially available equivalent products do not have a high enough level of purity to be used in the preparation of pharmaceutical products intended for human administration, such as gadopicrenol. [Overview of the project] [Problems that the invention aims to solve]

[0006] Therefore, there is a need to develop novel processes for preparing 2-bromoglutarate di-(C3~C6)-alkyl compounds that can be obtained with sufficient purity and can be efficiently carried out on an industrial scale.

[0007] Currently, the synthesis of 2-bromoglutaric acid diesters is rarely described in the literature. To the best of the inventors' knowledge, the only document describing the preparation of these compounds is the former Czechoslovakian patent specification 209266B1 (granted in 1983). It generally concerns a process for preparing α-haloglutaric acid or its alkyl diester of the formula R'O2CCH2CH2CH(X)CO2R'' (wherein R' and R'' are (C1-C5) alkyl groups and X corresponds to a bromine atom or a chlorine atom), however, the emphasis thereon is clearly on the preparation of chloro derivatives. These derivatives are obtained by chlorinating glutaric acid diesters in the presence of an antimony-based catalyst. Although the aforementioned document asserts that the described method enables monochlorination at the α-position with better selectivity than conventional processes, the fact remains that a considerable amount of β-chloro or α-dichloro and trichloro derivatives are formed, the selectivity for the α-monochloro reaction product ranges between 63.16% and 86.1% depending on the characteristics of the antimony-based catalyst, and the conversion rate of the starting material ester itself fluctuates between 86.10% and 98.9%. It should be noted that under conditions where the conversion rate of the starting material is at its highest, the resulting α-monochloro reaction product has a selectivity of only 79%. Another significant drawback of this process is the use of highly toxic antimony. [Means for solving the problem]

[0008] Therefore, the present invention relates to a process for preparing a 2-bromoglutaric acid diester of the following formula (I): [ka] [In the formula, R represents an (C3-C6) alkyl group.] This includes the following steps: (b) A step of reacting butyrolactonic acid of formula (BA) with an alcohol of formula ROH in the presence of an acid, such as sulfuric acid, to form a 2-hydroxyglutaric acid diester of formula (II); [ka] [ka] and (c) Bromination of the 2-hydroxyglutaric acid diester of formula (II) to the 2-bromoglutaric acid diester of formula (I) by sparging with gaseous hydrobromic acid.

[0009] For the purposes of this invention, the term "(C3-C6) alkyl group" means a linear or branched saturated hydrocarbon-based chain having 3 to 6 carbon atoms. Examples include propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl groups, and in particular the n-butyl group (also called butyl).

[0010] Butyrolactonic acid, represented by formula (BA), is also known as carboxy-γ-butyrolactone.

[0011] In one preferred embodiment, R corresponds to a butyl group, and the process according to the present invention makes it possible to prepare dibutyl 2-bromoglutarate of formula (BBG) (also known as dibutyl 2-bromo-1,5-pentanedioate (CAS No: 104867-13-2)). [ka]

[0012] In one specific embodiment, the process according to the present invention includes a first step (a) in which L-glutamic acid is reacted with sodium nitrite in an aqueous solution to form butyrolactonic acid of formula (BA).

[0013] Step (a) This first step consists of forming butyrolactone acid (BA) from L-glutamic acid, a generally available starting material, by a reaction well known to those skilled in the art.

[0014] L-glutamic acid is introduced into water, and the ratio of the mass of the water used to the mass of the introduced L-glutamic acid is typically greater than 1, especially greater than 1.5, and typically equal to 2. The density of water is equal to 1 g / mL, and in the following description, such a ratio of the mass of water (or, similarly, various other solvents or solutions) to the mass of the solute will be expressed by the expression "volume equivalent" or its abbreviation "vol.eq.".

[0015] The water used in this process is at least water of a quality equivalent to deionized water, and it is preferable to avoid the generation of impurities such as α-chloro impurities. In particular, it may be deionized water or water for injection (WFI).

[0016] The aqueous solution thus obtained is then heated, typically with stirring, to a temperature preferably between 40°C and 70°C, particularly between 45°C and 65°C, preferably between 50°C and 60°C, especially 55°C.

[0017] Then, while maintaining the previously set temperature, an aqueous sodium nitrite solution is gradually added to the L-glutamic acid solution, preferably with stirring.

[0018] The aqueous sodium nitrite solution is such that the amount of water used is, for example, between 0.8 and 5.0 vol.eq., especially between 1.0 and 3.0 vol.eq., and typically 2 vol.eq., based on the mass of sodium nitrite contained therein.

[0019] Sodium nitrite is preferably introduced into the L-glutamic acid solution in particular in a slightly excessive amount compared to the stoichiometric ratio. In so doing, the ratio of the amount of the substance introduced as sodium nitrite to the amount of the substance initially introduced as L-glutamic acid is greater than 1, typically less than 1.5, particularly less than 1.3, and preferably less than 1.2. Put another way, the amount of sodium nitrite introduced is greater than 1 molar equivalent (mol.eq.) based on the amount of L-glutamic acid initially introduced (which itself corresponds to 1 molar equivalent), typically less than 1.5 mol.eq., particularly less than 1.3 mol.eq., and preferably less than 1.2 mol.eq.

[0020] The reaction mixture containing sodium nitrite and L-glutamic acid is then typically maintained under stirring at a temperature between 40°C and 70°C, particularly between 45°C and 65°C, preferably between 50°C and 60°C, and particularly at 55°C, for a time between typically 2 hours and 10 hours, preferably between 2 hours and 5 hours, until the various compounds present in the solution are dissolved.

[0021] It is then cooled to a temperature between preferably 10°C and 45°C, more preferably between 10°C and 35°C, particularly between 15°C and 30°C, and preferably between 20°C and 25°C, and then neutralized by adding an acid, for example preferably a 33% m / m hydrochloric acid solution, where the amount of the substance introduced as hydrochloric acid is close to, typically equal to. Thus, the amount of the substance introduced as hydrochloric acid is greater than 1 molar equivalent (mol.eq.) based on the amount of L-glutamic acid initially introduced, typically less than 1.5 mol.eq., particularly less than 1.3 mol.eq., and preferably less than 1.2 mol.eq.

[0022] The reaction mixture thus neutralized is then concentrated typically under vacuum by gradually raising the temperature up to a temperature higher than 50°C, for example up to 60°C.

[0023] In the following description, the term "under vacuum" refers to a pressure between 10 and 500 mbar, particularly between 10 and 350 mbar, preferably between 10 and 150 mbar, and especially between 50 and 100 mbar, while the temperature will be appropriately specified.

[0024] Regarding the vacuum concentration operation to obtain crude butyrolactonic acid (BA) at the completion of step (a), this is typically carried out by gradually raising the temperature to 60°C at a pressure of less than 100 mbar.

[0025] Steps (a) and (b) are preferably carried out in a one-pot embodiment, i.e., without intermediate steps of isolation or purification.

[0026] Step (b) Step (b) aims to form the 2-hydroxyglutaric acid diester of formula (II) by reacting the butyrolactonic acid of formula (BA) with the alcohol of formula ROH. [ka]

[0027] In one preferred embodiment, butyrolactonic acid (BA) is obtained from step (a) described above and is then used in step (b) without purification.

[0028] During this step, the ring-opening of the lactone and the formation of the two ester functional groups -C(O)OR occur in parallel or sequentially.

[0029] It is preferable to introduce alcohol ROH in excess of butyrolactonic acid. Therefore, the amount of ROH introduced is preferably 2 molar equivalents (mol.eq.) or more, particularly 4 mol.eq. or more, preferably between 2 and 10 mol.eq., especially between 4 and 10 mol.eq., typically equal to 5 mol.eq., based on the amount of butyrolactonic acid initially introduced. Note that if butyrolactonic acid is obtained from step (a), the amount of ROH introduced is expressed in relation to the amount of L-glutamic acid initially introduced, and the mol.eq. figure is shown unchanged.

[0030] In one preferred embodiment, step (b) is carried out in the presence of the acetate of formula CH3COOR. The amount of acetate introduced is typically between 0.1 and 0.7 mol.eq., particularly between 0.2 and 0.5 mol.eq., and preferably between 0.3 and 0.4 mol.eq., relative to the amount of alcohol ROH introduced.

[0031] The formation of the two ester functional groups -C(O)OR during step (b) may be advantageously carried out by acid catalysis. Therefore, step (b) is preferably carried out in the presence of a catalytic amount of acid, such as sulfuric acid. Under such conditions, the lactone readily opens its ring to form 2-hydroxyglutaric acid of formula (HG), followed by esterification of its carboxylic acid functional group with the alcohol ROH. [ka]

[0032] Therefore, step (b) of the process according to the present invention further includes the production of a 2-hydroxyglutaric acid diester of formula (II) by the reaction of a 2-hydroxyglutaric acid of formula (HG) with an alcohol of formula ROH.

[0033] Conversely, it is also possible for butyrolactonic acid (BA) to undergo the first esterification reaction before ring opening, forming the esterified lactone shown in formula (BR) below. [ka]

[0034] Therefore, step (b) of the process according to the present invention further includes the production of a 2-hydroxyglutaric acid diester of formula (II) by the reaction of an esterified lactone of formula (BR) with an alcohol of formula ROH.

[0035] As will be obvious to those skilled in the art, the process according to the present invention can also be carried out using 2-hydroxyglutaric acid of formula (HG) or an esterified lactone of formula (BR) instead of butyrolactonic acid (BA) as the starting material for step (b).

[0036] In one preferred embodiment, the water typically produced in the insitz, present in the reaction mixture of step (b), is removed by vacuum distillation until a reaction medium having a mass fraction of water of less than 2% (w / w), preferably less than 1.5% (w / w), and advantageously less than 0.8% (w / w), is obtained.

[0037] The reaction mixture of step (b) further includes, in particular, butyrolactonic acid of formula (BA), an alcohol of formula ROH, and, advantageously, an acetate of formula CH3COOR.

[0038] Vacuum distillation is advantageous if it is performed using vacuum azeotropic distillation.

[0039] For the purposes of the present invention, the term "vacuum azeotropic distillation" means the distillation of an azeotropic mixture carried out at a pressure between 10 and 500 mbar, particularly between 10 and 350 mbar, preferably between 10 and 150 mbar, and especially between 50 and 100 mbar, thereby enabling the removal of one of the components of the azeotropic mixture.

[0040] In the present invention, the azeotropic mixture is a ternary azeotropic mixture of water / ROH / CH3COOR, and water can be removed from the mixture by vacuum azeotropic distillation.

[0041] In one preferred embodiment, R corresponds to a butyl group (Bu), and its azeotropic mixture is a ternary mixture of water / BuOH / CH3COOBu. This azeotropic mixture is characterized by a boiling point at atmospheric pressure that is between 85°C and 95°C, more precisely between 87°C and 93°C, and even more precisely between 89°C and 91.5°C, typically equal to 89.4°C.

[0042] Vacuum azeotropic distillation of the ternary mixture of water / BuOH / CH3COOBu is typically carried out at pressures between 10 and 500 mbar, particularly between 10 and 350 mbar, preferably between 10 and 150 mbar, and especially between 50 and 125 mbar, and at temperatures between 20°C and 100°C, particularly between 30°C and 70°C.

[0043] In one preferred embodiment, upon completion of step (b), the reaction medium is cooled to a temperature below 15°C, particularly below 10°C, and especially between 0°C and 5°C.

[0044] This cooling step is typically carried out after vacuum distillation, which is preferably vacuum azeotropic distillation of the reaction mixture as described above.

[0045] In one preferred embodiment, upon completion of step (b), the cooled reaction medium is left to stand after adding water to separate it by sedimentation, forming an organic phase and a separate aqueous phase, and then the aqueous phase is removed.

[0046] This operation is advantageously performed several times, typically between two and five times, and especially three times.

[0047] The amount of water to be added is expressed relative to the mass of butyrolactonic acid initially used, for example, between 0.1 and 2 vol.eq. Note that if the butyrolactonic acid comes from step (a), the amount of water added is expressed relative to the mass of L-glutamic acid initially introduced, and the vol.eq. number remains unchanged.

[0048] When separation is performed several times using the water addition / sedimentation procedure, the amount of water added in the first cycle is typically between 1 and 2 vol.eq., and the amount of water added in subsequent cycles is typically between 0.1 and 0.5 vol.eq.

[0049] The reaction medium obtained at the completion of step (b), preferably the organic phase recovered after separation by the addition of water / sedimentation, typically contains, in solution in alcohol ROH, 2-hydroxyglutaric acid diester of formula (II) as the main chemical species, and also the esterified lactone of formula (BR), advantageously as a mixture with the acetic acid ester of formula CH3COOR.

[0050] In one preferred embodiment, R corresponds to a butyl group (Bu), and the reaction medium obtained at the completion of step (b), preferably the organic phase recovered after separation by the addition / sedimentation of water, typically contains, in solution in butanol BuOH, dibutyl 2-hydroxyglutarate of formula (BHG) and even butyl butyrolactone ester of formula (BBE) as the main chemical species, advantageously as a mixture with butyl acetate CH3COOBu. [ka]

[0051] In one preferred embodiment, the reaction medium obtained at the completion of step (b), preferably the organic phase recovered after separation by the addition / sedimentation of water, is then dehydrated by vacuum distillation at a pressure between 10 and 500 mbar, particularly between 10 and 350 mbar, preferably between 10 and 150 mbar, and especially between 50 and 100 mbar.

[0052] This is advantageous because it involves vacuum azeotropic distillation of a water / ROH / CH3COOR mixture, particularly water / BuOH / CH3COOBu, which allows for the removal of water from the mixture.

[0053] In one preferred embodiment, the reaction medium obtained at the completion of step (b), preferably the organic phase recovered after separation by the addition / sedimentation of water, is advantageously dehydrated by vacuum distillation at a pressure between 10 and 500 mbar, particularly between 10 and 350 mbar, preferably between 10 and 150 mbar, particularly between 50 and 100 mbar, and then concentrated under vacuum before proceeding to step (c) to remove a mixture of ROH / CH3COOR, particularly some of BuOH / CH3COOBu.

[0054] The amount of the mixture removed is typically between 1 and 2 vol.eq. based on the mass of the butyrolactonic acid initially used, or, if the butyrolactonic acid was obtained from step (a), based on the mass of the L-glutamic acid initially introduced.

[0055] In the following description, the operations of cooling, separation by addition / sedimentation of water, dehydration by vacuum distillation, and / or concentration under vacuum, as mentioned above, should be considered as an integral part of step (b) if they are performed.

[0056] Steps (b) and (c) are preferably carried out in a one-pot embodiment, i.e., without intermediate isolation or purification steps.

[0057] Step (c) Step (c) aims to form the 2-bromoglutaric acid diester of formula (I) by bromidating the 2-hydroxyglutaric acid diester of formula (II) obtained in step (b).

[0058] As will be clear to those skilled in the art from the detailed description of step (b), the reaction medium obtained at the completion of step (b) typically contains, in solution in alcohol ROH, 2-hydroxyglutaric acid diester of formula (II) as the main chemical species, along with the esterified lactone of formula (BR), preferably with acetic acid ester of formula CH3COOR. It is included as a mixture.

[0059] Therefore, although step (c) aims to form the 2-bromoglutaric acid diester of formula (I) by brominating the 2-hydroxyglutaric acid diester of formula (II), the formation of the 2-hydroxyglutaric acid diester of formula (II) by the reaction of the esterified lactone of formula (BR) with the alcohol ROH can typically continue during this step, and the ring-opening of the lactone is made easier by introducing a brominating agent into the reaction medium.

[0060] Step (c) is typically initiated by setting the temperature of the reaction medium to a value between 5°C and 40°C, preferably between 10°C and 30°C, and especially between 20°C.

[0061] Next, gaseous hydrobromic acid is gradually introduced into the reaction medium by sparging.

[0062] In one preferred embodiment, the amount of gaseous hydrobromic acid introduced is typically between 1 and 1.5 mol.eq., particularly between 1.2 and 1.3 mol.eq., based on the amount of butyrolactonic acid used in step (b) or the amount of L-glutamic acid initially introduced in step (a).

[0063] In one preferred embodiment, the reaction medium obtained after introducing gaseous hydrobromic acid is then dehydrated by vacuum distillation typically for 3 to 8 hours, and more favorably for 5 to 7 hours, at a pressure typically between 10 and 500 mbar, particularly between 10 and 350 mbar, preferably between 10 and 150 mbar, and especially between 50 and 100 mbar.

[0064] It is advantageous that the vacuum distillation is a vacuum azeotropic distillation of a water / ROH / CH3COOR mixture, particularly water / BuOH / CH3COOBu. Such vacuum azeotropic distillation makes it possible to remove water from the mixture.

[0065] Next, the temperature of the reaction medium is returned to a value typically between 5°C and 40°C, preferably between 10°C and 30°C, and especially 20°C.

[0066] In one preferred embodiment, the cycle of operations described above is repeated 3 to 8 times, preferably 4 to 6 times: setting the temperature of the reaction medium to a value between 5°C and 40°C; introducing gaseous hydrobromic acid in an amount typically between 1 and 1.5 mol.eq., based on the amount of butyrolactonic acid used in step (b) or the amount of L-glutamic acid initially introduced in step (a); removing water from the reaction medium by vacuum distillation over a period of 3 to 8 hours; and returning the temperature of the reaction medium to a value between 5°C and 40°C.

[0067] The reaction medium obtained at the completion of step (c) typically contains, in solution in alcohol ROH, 2-bromoglutaric acid diester of formula (I), preferably as a mixture with acetic acid ester of formula CH3COOR.

[0068] In one preferred embodiment, R corresponds to a butyl group, and the reaction medium obtained at the completion of step (c) typically contains dibutyl bromoglutarate of formula (BBG) 2-bromoglutarate in solution in butanol BuOH, preferably as a mixture with butyl acetate CH3COOBu.

[0069] Alternatively, hydrobromic acid can be produced in azeotropic distillation. In this alternative method, a bromine salt, typically NaBr or KBr, is introduced into the reaction medium instead of gaseous hydrobromic acid, and then a strong acid, such as concentrated sulfuric acid (>96%), is added.

[0070] A skilled professional in this field would know how to adopt the subsequent processing steps and, in particular, how to remove any present salts, such as sulfates in this alternative embodiment.

[0071] Steps (d) to (e) In one preferred embodiment of the process according to the present invention, the reaction mixture obtained at the completion of step (c) is subjected to the following additional steps: (d) The reaction mixture obtained at the completion of step (c) is introduced into a basic aqueous solution (the solution thus obtained typically has a pH between 7.5 and 9.5); (e) Separating the solution obtained in step (d) by sedimentation to form an organic phase and a separated aqueous phase, and then removing the aqueous phase; (f) The organic phase obtained in step (e) is concentrated under vacuum until it reaches a temperature between 65°C and 75°C, and then dried under vacuum; (g) In some cases, filtration may be performed. A step to recover the 2-bromoglutarate diester of formula (I).

[0072] In one alternative embodiment, steps (d) and (e) are omitted, and step (f) is performed directly on the reaction mixture obtained at the completion of step (c), and optionally, the filtration step (g) is followed thereafter.

[0073] Step (d), in particular, may be carried out by adding the reaction mixture obtained at the completion of step (c) to an aqueous solution of bicarbonate (also called hydrogen bicarbonate) ions, but the amounts of potassium bicarbonate or sodium bicarbonate and water used can be determined by a skilled professional such that at the completion of step (d), the solution has a pH typically between 7.5 and 9.5, particularly between 8 and 9, so that separation between the aqueous phase and the organic phase can be carried out in step (e).

[0074] The organic phase obtained in step (e), or the reaction mixture obtained at the completion of step (c), is then concentrated in step (f) under vacuum at a pressure typically between 10 and 500 mbar, particularly between 10 and 350 mbar, preferably between 10 and 150 mbar, especially between 50 and 100 mbar, until a temperature higher than 50°C, especially higher than 60°C, for example 70°C, to remove some of the ROH / CH3COOR mixture, and then dried under vacuum at a pressure typically between 10 and 350 mbar, preferably between 50 and 150 mbar, especially between 50 and 100 mbar, until a temperature higher than 50°C, especially higher than 60°C, for example 70°C, is reached.

[0075] A filtration step (g) may be carried out after this step, which can be done using various methods well known to those skilled in the art.

[0076] The process according to the present invention makes it possible to obtain 2-bromoglutaric acid diester of formula (I) in a yield of greater than 85%, preferably greater than 90%, and in purity of 90% or more, particularly 93% or more, typically 95% or more, preferably 97% or more, especially 98% or more, and preferably 99% or more, as measured by HPLC analysis.

[0077] In one preferred embodiment, R corresponds to a butyl group, and the process according to the present invention makes it possible to prepare dibutyl 2-bromoglutarate of formula (BBG) in the yield and purity described above.

[0078] Therefore, the present invention further relates to a 2-bromoglutarate diester of the following formula (I) having a purity of 90% or more, particularly 93% or more, typically 95% or more, preferably 97% or more, especially 98% or more, and advantageously 99% or more, as measured by HPLC analysis: [ka] [In the formula, R represents a (C3-C6) alkyl group, preferably a butyl group.]

[0079] Racemization step The 2-bromoglutaric acid diester of formula (I) can be obtained in various enantiomer excesses. If it is not a racemic mixture, it can be racemized in an additional racemization step using a bromine salt, such as LiBr or tetrabutylammonium bromide, according to methods well known to those skilled in the art. [Brief explanation of the drawing]

[0080] [Figure 1] This is the mass spectrum of BBG. [Modes for carrying out the invention]

[0081] Examples The following abbreviations are used:

[0082] [Table 1]

[0083] Synthesis of I:2-dibutyl bromoglutarate I.1: Protocol Dissolve 147.1 g (1 mol) of L-glutamic acid in 294 g of water. Heat this solution to 55°C ± 5°C. Gradually add 76 g (1.1 mol) of sodium nitrite dissolved in 152 g of water. Maintain this contact state at 55°C ± 5°C for at least 2 hours until dissolution is complete, then cool the solution to 20-25°C. Neutralize with approximately 122 g (1.1 mol) of 33% hydrochloric acid, and then concentrate the medium under vacuum (less than 100 mbar) while gradually raising the temperature to 60°C.

[0084] The obtained butyrolactonic acid was subjected to azeotropic distillation and vacuum under the presence of 206 g of butyl acetate and 1.47 g (0.015 mol) of sulfuric acid, using 370 g (5 mol) of butanol. Esterification is performed. The reaction medium is then cooled to 0-5°C and added to 221g of water. The aqueous phase at the bottom is removed, and the organic phase is washed at least twice with 30g of water. The resulting organic phase contains a mixture of butyl hydroxyglutarate / butyrolactone butyl ester (HPLC s / s: 90 / 10). The mixture is dehydrated by azeotropic distillation at 50-100 mbar and concentrated by removing an amount equivalent to 195g of solvent.

[0085] Bromination is carried out by performing the following procedure five times in succession: Sparging 100 g (1.2 mol) of hydrobromic acid under vacuum by azeotropic distillation at 20 ± 10 °C for at least 5 hours. Washing the reaction medium with an aqueous solution of 6 g of potassium bicarbonate dissolved in approximately 60 g of water. Discarding the aqueous phase, washing the organic phase with water, and then concentrating under vacuum until the temperature reaches approximately 70 °C. BBG is obtained in 90% yield and with a purity of 97.1% s / s as measured by HPLC.

[0086] I.2: Characterization of BBG - Boiling point: 115-120°C / 0.2-0.3 mmHg, which is approximately 380°C (at atmospheric pressure). - NMR (performed using JEOL's 500MHz instrument): 1 H NMR(CDCl3,400MHz)4.34-4.39(m,1H,Br-CH-COO),4.16-4.22(m,2H,Br-CH-COOCH2),4.06-4.11(m,2H,CH2-COOCH2),2.50-2.59(m,2H,OOC-CH2-CH 2-CHBr),2.25-2.43(m,2H,OOC-CH2-CH2-CHBr),1.55-1.69(m,4H,CH2-CH2-CH2),1.34-1.45(m,4H,CH3-CH2-CH2),0.92-0.96(m,6H,CH3-CH2-CH2) - Mass spectrometry The presence of bromine in the molecule was confirmed by mass spectrometry performed using a Waters QDa mass spectrometer equipped with a Waters I-Class UHPLC instrument. Mass spectrometry was recorded in positive electrospray mode with a cone voltage of 10V. The obtained mass spectrum is shown in Figure 1. The double line with a difference of 2 indicates the presence of bromine in that molecule. The masses at 323-325 correspond to the parent peak, while the masses at 249-251 correspond to the cleavage of the butoxide.

[0087] I.3.: HPLC analysis · Device: - An HPLC system consists of a pumping system, injector, chromatography column, UV detector, and data station. - Spherisorb ODS 2, 250 × 4.6 mm - 5 μm column. - 96% sulfuric acid, Suprapur® (Merck, 1.00714 or equivalent). - Acetonitrile (HPLC gradient grade, JT Baker, reference no. 8143 or equivalent). - Deionized water (Elga HPLC grade, or equivalent).

[0088] · How: - Mobile phase: Route A: 100% acetonitrile Route B: 0.1% v / v sulfuric acid aqueous solution - Sample preparation: Place 0.2 g of the analyte BBG into a 20 mL volumetric flask, then add a sufficient amount of acetonitrile to make a 20 mL solution.

[0089] - Analysis conditions:

[0090] [Table 2]

[0091] - Gradient:

[0092] [Table 3]

[0093] II. Racemization of 2-dibutyl bromoglutarate During the synthesis, the chiral carbon maintains its stereochemistry and is partially racemized during bromination. Typically, BBG with an enantiomer excess ranging from 50% to 80% is obtained. If the resulting BBG is not racemic, it can be racemized using a brominated salt.

[0094] II.1: Use of LiBr Racemization of BBG by contact with 1 mol% LiBr at 60°C for 2 hours. Wash the racemic BBG with 2 × 2 weight equivalents of 0.1 M sodium bicarbonate solution at 25°C.

[0095] Washing is performed under vacuum (pressure: 30 mbar or less) with 0.5 weight equivalents of water at a reaction medium temperature of 70°C or less.

[0096] This process was applied to 3418g of BBG and 9.22g of LiBr, yielding a 97.9% yield.

[0097] Racemization was achieved by performing chiral HPLC monitoring.

[0098] · Device: - HPLC system with UV detector. - Chiralpak IC-5μm-250×4.6mm column (manufactured by Daicel)

[0099] · How: - Mobile phase: 95% heptane / 5% isopropyl alcohol - Sample preparation: Place 50 mg of the BBG to be analyzed into a 10 mL volumetric flask, then add a sufficient amount of heptane to make a 10 mL solution. - Analysis conditions: Normal-phase HPLC, mobile phase elution: isocratic mode.

[0100] [Table 4]

[0101] - Calculation of enantiomer excess: %ee=(peak area 1 - peak area 2) / (peak area 1 + peak area 2)×100

[0102] [Table 5]

[0103] II.2.: Use of TBAB It was found that racemization is possible at room temperature without using a solvent, even when using TBAB, under the same conditions as with LiBr.

[0104] Add 3.2 g of TBAB to 323 g of BBG. Stir the medium for at least 5 hours until the ee reaches less than 1%. Remove the TBAB by washing twice in succession with 150 mL of water. Concentrate the BBG under vacuum at a temperature below 70°C. Preferred embodiments of the present invention are described below. Section 1. A process for preparing the 2-bromoglutarate diester of the following formula (I),

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Claims

1. The compound of the following formula (I), 【Chemistry 1】 [In the formula, R represents a propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentyl, or hexyl group] A compound having a purity of 90% or higher as measured by HPLC analysis under the following conditions. [conditions] ·Device: - The HPLC system consists of a pumping system, injector, chromatography column, UV detector, and data station. - ODS, 250 x 4.6 mm - 5 μm column. ・ Method: - Mobile phase: Route A: 100% acetonitrile Route B: 0.1% v / v sulfuric acid aqueous solution - Sample preparation: Place 0.2 g of the compound of formula (I) to be analyzed into a 20 mL volumetric flask, and then add a sufficient amount of acetonitrile to make a 20 mL solution. - Analysis conditions: 【change】 - Gradient: 【change】

2. The compound according to claim 1, characterized in that R corresponds to an n-butyl group.

3. The compound according to claim 1 or 2, characterized in that its purity is 95% or higher.

4. The compound according to any one of claims 1 to 3, characterized in that its purity is 97% or higher.

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