METHOD FOR SYNTHESIZING 2-BROMOGLUTARIC ACID DIESTERS

Abstract

The present invention relates to a process for preparing the 2-bromoglutaric acid diester of formula (I) below:

##STR00001##

comprising the formation of the 2-hydroxyglutaric acid diester of formula (II)

##STR00002##

by reaction of butyrolactone acid of formula (BA)

##STR00003##

with the alcohol of formula ROH, in the presence of an acid such as sulfuric acid; and bromination of the 2-hydroxyglutaric acid diester of formula (II), by sparging with gaseous hydrobromic acid.

The present invention also relates to a 2-bromoglutaric acid diester of formula (I), having a degree of purity determined by HPLC analysis of greater than or equal to 90%.

Claims

1. A process for preparing the 2-bromoglutaric acid diester of formula (I) below: ##STR00014## in which R represents a (C .sub.3-C.sub.6)alkyl group, wherein said process comprises the following steps: (b) forming the 2-hydroxyglutaric acid diester of formula (II) ##STR00015## by reacting butyrolactone acid of formula (BA) ##STR00016## with the alcohol of formula ROH, in the presence of an acid such as sulfuric acid; and (c) brominating the 2-hydroxyglutaric acid diester of formula (II), by sparging with gaseous hydrobromic acid, thereby leading to the 2-bromoglutaric acid diester of formula (I).

2. The process of claim 1, wherein step (b) is performed in the presence of the acetate of formula CH.sub.3COOR.

3. The process of claim 1, wherein, during step (b), the water is removed by vacuum distillation.

4. The process of claim 1, wherein in step (b), butyrolactone acid of formula (BA) and the alcohol ROH are introduced in amounts such that the ROH/BA mole ratio is between 2 and 10.

5. The process of claim 1, wherein, on conclusion of step (b), the reaction medium is cooled to a temperature below 15° C. and is left to separate by settling after addition of water so as to obtain the formation of an organic phase and a separate aqueous phase, said aqueous phase then being removed and said organic phase being dehydrated by vacuum distillation and/or concentration under vacuum before being subjected to step (c).

6. The process of claim 1, wherein step (c) comprises the following cycle of steps: setting the temperature of the reaction medium to a value of between 5° C. and 40° C., introducing gaseous hydrobromic acid in an amount of between 1 and 1.5 mol. eq. relative to the amount of butyrolactone acid (BA) used in step (b), vacuum distillation so as to remove water from the reaction medium, restoring the temperature of the reaction medium to a value of between 5° C. and 40° C.

7. The process of claim 1, wherein it comprises a first step (a) of forming butyrolactone acid of formula (BA) by reacting L-glutamic acid with sodium nitrite in aqueous solution.

8. The process of claim 1, wherein the reaction mixture obtained on conclusion of step (c) is subjected to the following additional steps: (d) introducing the reaction mixture obtained on conclusion of step (c) into a basic aqueous solution; (e) separating by settling the solution obtained in step (d), so as to obtain the formation of an organic phase and a separate aqueous phase, said aqueous phase being then removed; (f) concentrating under vacuum the organic phase obtained in step (e), until a temperature of between 65° C. and 75° C. is reached, followed by drying under vacuum; (g) optionally, filtrating; and recovering the 2-bromoglutaric acid diester of formula (I).

9. The process of claim 1, wherein the 2-bromoglutaric acid diester of formula (I) obtained on conclusion of step (c), (f) or (g) is subjected to an additional racemization step by adding a bromine salt.

10. The process of claim 1, wherein R corresponds to an n-butyl group.

11. The process of claim 3, wherein the vacuum distillation operations taking place during steps (b) and (c) are azeotropic distillations.

12. A compound of formula (I) below: ##STR00017## in which R represents a (C.sub.3-C.sub.6)alkyl group, preferably a butyl group, with a degree of purity, determined by HPLC analysis, of greater than or equal to 90%.

13. The compound as claimed in claim 12, wherein R corresponds to an n-butyl group.

14. The compound of claim 12, wherein its degree of purity is greater than or equal to 95%.

15. The compound of claim 12, wherein its degree of purity is greater than or equal to 97%.

16. The process of claim 1, wherein the acid in step (b) is sulfuric acid.

17. The process of claim 6, wherein vacuum distillation is carried out for a time between 3h and 8h.

18. The process of claim 6, wherein the cycle of steps are repeated from 3 to 8 times.

19. The process of claim 8, wherein the solution obtained in step (d) has a pH typically between 7.5 and 9.5.

20. The process of claim 9, wherein the bromine salt is LiBr or tetrabutylammonium bromide.

Description

FIGURES

[0086] FIG. 1 shows the mass spectrum of BBG.

EXAMPLES

[0087] The following abbreviations are used:

TABLE-US-00001 BBG: dibutyl 2-bromoglutarate Bu: butyl ee: enantiomeric excess HPLC: High Performance Liquid Chromatography NMR: nuclear magnetic resonance TBAB: tetrabutylammonium bromide

I. Synthesis of Dibutyl 2-bromoglutarate

I.1. Protocol

[0088] 147.1 g (1 mol) of L-glutamic acid are dissolved in 294 g of water. This solution is heated to 55° C.±5° C. 76 g (1.1 mol) of sodium nitrite dissolved in 152 g of water are slowly added. Contact is maintained for at least 2 hours at 55° C.±5° C. until dissolution is complete, and the solution is then cooled to 20-25° C. After neutralization with about 122 g (1.1 mol) of 33% hydrochloric acid, the medium is concentrated under vacuum (< 100 mbar) by gradually increasing the temperature to 60° C.

[0089] The butyrolactone acid obtained is esterified with 370 g (5 mol) of butanol in the presence of 206 g of butyl acetate and 1.47 g (0.015 mol) of sulfuric acid under azeotropic distillation and under vacuum. The reaction medium is then cooled to 0-5° C. and taken up in 221 g of water. The lower aqueous phase is removed and the organic phase washed twice more with 30 g of water. The organic phase obtained contains a mixture of butyl hydroxyglutarate/butyl ester of butyrolactone (HPLC s/s: 90/10). The mixture is dehydrated by azeotropic distillation under 50-100 mbar and then concentrated by removing the equivalent of 195 g of solvent.

[0090] The bromination is performed by performing the following operations five times in succession: sparging with 100 g (1.2 mol) of hydrobromic acid at 20±10° C., azeotropic distillation under vacuum for at least 5 hours. The reaction medium is washed with an aqueous solution of 6 g of potassium hydrogen carbonate dissolved in about 60 g of water. The aqueous phase is discarded and the organic phase is washed with water and then concentrated under vacuum until a temperature of about 70° C. is reached. BBG is obtained in a yield of 90% and a purity of 97.1% s/s as determined by HPLC.

I.2. Characterization of BBG

[0091] Boiling point 115-120° C./0.2-0.3 mmHg, i.e. about 380° C. at atmospheric pressure. [0092] NMR performed on a JEOL 500 MHz machine: [0093] .sup.1H NMR (CDCl.sub.3, 400 MHz) 4.34-4.39 (m, 1H, Br-CH-COO), 4.16-4.22 (m, 2H, Br-CH-COOCH.sub.2), 4.06-4.11 (m, 2H, CH.sub.2-COOCH.sub.2), 2.50-2.59 (m, 2H, OOC-CH.sub.2-CH.sub.2-CHBr), 2.25-2.43 (m, 2H, OOC-CH.sub.2-CH.sub.2-CHBr), 1.55-1.69 (m, 4H, CH.sub.2—CH.sub.2—CH.sub.2), 1.34-1.45 (m, 4H, CH.sub.3—CH.sub.2—CH.sub.2), 0.92-0.96 (m, 6H, CH.sub.3—CH.sub.2—CH.sub.2) [0094] Mass spectrometry

[0095] The presence of bromine in the molecule was confirmed by a mass spectrum performed using a Waters QDa mass spectrometer coupled to a Waters I-Class UHPLC machine. The mass spectrum recording was performed in positive electrospray mode at a cone voltage of 10 V.

[0096] The mass spectrum obtained is shown in FIG. 1.

[0097] The doublets with a difference of 2 confirm the presence of bromine in the molecule. The mass at 323-325 corresponds to the parent peak, and the mass at 249-251 to the loss of butoxide.

I.3. HPLC Analysis

[0098] Equipment: [0099] HPLC machine consisting of a pumping system, an injector, a chromatography column, a UV detector and a data station. [0100] Spherisorb ODS 2, 250 × 4.6 mm - 5 .Math.m column. [0101] 96% Sulfuric acid Suprapur® (Merck 1.00714 or equivalent). [0102] Acetonitrile (HPLC gradient grade, J.T Baker reference 8143 or equivalent). [0103] Deionized water (Elga HPLC grade, or equivalent). [0104] Method: [0105] Mobile phase: [0106] Route A: 100% acetonitrile [0107] Route B: 0.1 % v/v aqueous sulfuric acid solution [0108] Preparation of the samples: [0109] 0.2 g of BBG to be analyzed is placed in a 20 mL volumetric flask, followed by a sufficient amount of acetonitrile to make 20 mL of solution.

TABLE-US-00002 Analytical conditions: Column temperature 25° C. Sample temperature Ambient Flow rate 1.0 mL/min Injection volume 20 .Math.l UV detection 220 nm Analysis time 70 min

TABLE-US-00003 Gradient: Time % acetonitrile % H.sub.2SO.sub.4 (0.1%) 0 1 99 5 1 99 20 60 40 50 80 20 60 80 20 62 1 99 70 1 99

II. Racemization of Dibutyl 2-bromoglutarate

[0110] During the synthesis, the asymmetric carbon retains its configuration and becomes partially racemized on bromination. The BBG is typically obtained with an enantiomeric excess ranging from 50% to 80%. If the BBG obtained is not racemic, it is possible to racemize it using a bromine salt.

II.1. With LiBr

[0111] Racemization of the BBG with 1 mol% LiBr by contact for 2 hours at 60° C.

[0112] Washing of the racemic BBG with 2 × 2 weight equivalents of 0.1 M sodium bicarbonate solution at 25° C.

[0113] Washing with 0.5 weight equivalent of water under vacuum (pressure ≤ 30 mbar) and temperature of the reaction medium at ≤ 70° C.

[0114] This process was applied with 3418 g of BBG and 9.22 g of LiBr in 97.9% yield.

[0115] Chiral HPLC monitoring was performed to achieve racemization. [0116] Equipment: [0117] HPLC apparatus equipped with a UV detector. [0118] Chiralpak IC 5 .Math.m 250 × 4.6 mm column from Daicel. [0119] Method: [0120] Mobile phase: 95% heptane/5% isopropyl alcohol [0121] Preparation of the samples: [0122] 50 mg of BBG to be analyzed are placed in a 10 mL volumetric flask, followed by a sufficient amount of heptane to make 10 mL of solution. [0123] Analytical conditions: [0124] HPLC in normal phase, elution of the mobile phase in isocratic mode.

TABLE-US-00004 Flow rate 0.7 mL/min Injection volume 10 .Math.l UV detection 270 nm

[0125] Calculation of the enantiomeric excess:

TABLE-US-00005 % peak area % enantiomeric excess Conditions Enantiomer 1 Enantiomer 2 Starting material 21.46 78.54 -57.08 Contact 2 h/60° C. 48.96 51.04 -2.08 Contact 2 h30/60° C. 49.68 50.32 -0.64

II.2. With TBAB

[0126] It was shown that racemization is also possible with TBAB under the same conditions as with LiBr, without solvent and at room temperature.

[0127] 3.2 g of TBAB are added to 323 g of BBG. The medium is stirred for at least 5 hours to reach an ee < 1%. The TBAB is removed by two successive washes with 150 ml of water. The BBG is concentrated under vacuum at a temperature below 70° C.