Process for the preparation of 3-aryl-2-hydroxy propanoic acid compounds

Abstract

The present disclosure provides a process for synthesis of 3-aryl-2-hydroxy propanoic acid derivatives of formula (S)-1. wherein R.sub.1 represents H or (C.sub.1-C.sub.5) alkyl groups and R.sub.2 represents (C.sub.1-C.sub.5) alkyl groups. ##STR00001##

Claims

1. A process for the preparation of 3-aryl-2-hydroxy propanoic acid compounds of formula (S)-1, wherein R.sub.1 represents H or (C.sub.1-C.sub.5) alkyl groups and R.sub.2 represents (C.sub.1-C.sub.5) alkyl groups, comprising the steps of; ##STR00025## a) subjecting an epoxide (S)-2 to regioselective ring opening with 4-methoxyphenylmagnesium bromide in presence of copper iodide to obtain a secondary alcohol (S)-3; ##STR00026## b) O-alkylating the secondary alcohol (S)-3 using ethyl iodide and a base in anhydrous DMF to give ethylated derivative (S)-4; ##STR00027## c) debenzylating (S)-4 in presence of a debenzylating agent to obtain primary hydroxy compound (S)-5; ##STR00028## d. oxidizing the compound (S)-5 in presence of an oxidizing agent to obtain compound (S)-6; and ##STR00029## e. demethylating the compound (S)-6 using sodium ethanethiolate to obtain (S)-7 followed by esterification using EtOH and HCl to give (S)-1a; f. optionally, esterificating of (S)-7 as obtained in step (e) using anhydrous 2-propanol and SOCl.sub.2 to give (S)-1b.

2. The process according to claim 1, wherein the base used in step (b) is selected from NaOH, KOH, Na.sub.2CO.sub.3, or NaHCO.sub.3.

3. The process according to claim 1, wherein the debenzylating agent used in step (c) is selected from Pd/C, Pd(OH).sub.2, Raney-Ni or TiCl.sub.4 along with dichloromethane.

4. The process according to claim 1, wherein the oxidizing agent used in step (d) is selected from chromium trioxide along with H.sub.2SO.sub.4 or sodium chlorite along with TEMPO and sodium hypochlorite.

5. The process according to claim 1, wherein the compound of (S)-1a is ethyl (2S)-2-ethoxy-3-(4-hydroxyphenyl)propanoate, ##STR00030##

6. The process according to claim 1, wherein the compound of (S)-1b is isopropyl (2S)-2-ethoxy-3-(4-hydroxyphenyl)propanoate, ##STR00031##

7. The process according to claim 1, wherein overall yield of compound of (S)-1a is in the range of 40-45%.

8. The process according to claim 1, wherein overall yield of compound of (S)-1b is in the range of 40-45%.

9. The process according to claim 1, wherein enantiomeric excess (ee) of 3-aryl-2-hydroxy propanoic acid compounds of formula (S)-1 is in the range of 97-99%.

Description

BRIEF DESCRIPTION OF FIGURES

(1) FIG. 1: Chiral HPLC chromatogram of (S)-1b.

DETAILED DESCRIPTION OF INVENTION

(2) The present disclosure provides a process for the synthesis of the compound of formula (S)-1 starting from commercially available (S)-benzyl glycidyl ether in high enantiopurity of ee>99% and chemical yield of more than 43%.

(3) Epoxides constitute one of the most widely used functional groups in organic transformations and serve as important building blocks in the industrial production of a wide variety of organic materials. As part of the study of the utility of epoxides on enantioselective transformations, the inventors of the present disclosure have put their interest in the application of epoxide to the synthesis of important chiral pharmaceuticals in the present disclosure for which protection is sought.

(4) In view of the above, the present disclosure provides a process for the synthesis of the compound of formula (S)-1 starting from commercially available (S)-benzyl glycidyl ether in good overall yield and high enantiopurity of ee>99%.

(5) The 3-aryl-2-hydroxy propanoic acid derivatives of (S)-1 according to the present disclosure encompasses ethyl (2S)-2-ethoxy-3-(4-hydroxyphenyl)propanoate (EEHP) (S)-1a and isopropyl (2S)-2-ethoxy-3-(4-hydroxyphenyl)propanoate (IEHP) (S)-1b.

(6) The present disclosure provides a retrosynthetic analysis of compound of formula (S)-1 as shown in Scheme 5. The secondary alcohol (S)-3 can be visualized as a key intermediate for the synthesis which can be elaborated to primary hydroxy derivative (S)-5 using simple O-alkylation and debenzylation steps. Further, (S)-5 derivative can be transformed to the target molecule (S)-1 via oxidation followed by demethylation and esterification protocols. The key intermediate (S)-3 in turn can be obtained from commercially available (S)-benzyl glycidyl ether (S)-2.

(7) ##STR00018##

(8) The present disclosure commences with the commercially available, (S)-benzyl glycidylether (S)-2 which was subjected to regioselective ring opening with 4-methoxyphenylmagnesium bromide in the presence of catalytic amount of CuI in anhydrous THF at 20 C. to obtain the requisite key intermediate (S)-3 (Scheme 6). Further, O-ethylation on substrate (S)-3 was considered to be important, because of the fact that base mediated ethylation of -hydroxy esters generally leads to epimerization at C-2 carbon. However, surprisingly, in the present case, the O-ethylation of protected secondary alcohol (S)-3 went smoothly with ethyliodide using sodium hydride as a base in DMF to produce O-ethylated derivative (S)-5 in 93% yield without any loss in optical purity. Therefore, it is important to consider that O-ethylation of protected hydroxyl derivative (S)-4 provides an attractive alternative to the alkylation of -hydroxy ester derivatives to avoid the risk of epimerization at C-2 carbon. Further, compound (S)-4 was subjected to debenzylation followed by oxidation with sodium chlorite catalyzed by TEMPO and bleach in an acetonitrile-phosphate buffer (pH 6.8) afforded acid (S)-6 in 86% yield.

(9) Finally, demethylation of compound (S)-6 was accomplished using NaH/EtSH in DMF at 130 C. to provide the acid (S)-7 in 86% yield. Other deprotection conditions such as BBr.sub.3, HI etc were not favored as they are known to produce unwanted side products. Finally, the acid (S)-7 was esterified using ethanol under acidic condition to afford EEHP ((S)-1a) in 90% yield.

(10) Similarly, IEHP ((S)-1b) was obtained by esterification of the acid (S)-7 with isopropanol (yield 85%; ee>99%). The structure of (S)-1a & (S)-1b was confirmed by its IR, 1H NMR, .sup.13C NMR, and mass spectroscopic analysis. The enantiomeric excess of compounds (S)-1b and the intermediate (S)-3a was determined by chiral HPLC analysis.

(11) ##STR00019##

(12) The process for the synthesis of 3-aryl-2-hydroxy propanoic acid derivatives comprises: (a) regioselective ring opening of epoxide (S)-2 with 4-methoxyphenylmagnesium bromide to afford secondary alcohol of formula (S)-3;

(13) ##STR00020## (b) O-alkylation of secondary alcohol (S)-3 of step (a) to give ethylated derivative (S)-4 without any loss in optical purity of final compound;

(14) ##STR00021## (c) debenzylation of compound (S)-4 of step (b) to furnish primary hydroxy compound (S)-5;

(15) ##STR00022## (d) oxidation of compound (S)-5 of step (c) to afford acid derivative (S)-6 and

(16) ##STR00023## (e) demethylating of compound (S)-6 of step (d) followed by esterification to furnish the targeted compound of formula (S)-1.

(17) ##STR00024##

(18) The present disclosure provides a process for the synthesis of the compound of formula (S)-1 depicted in Scheme 6 comprising the steps: (a) subjecting the epoxide (S)-2 to the regioselective ring opening with 4-methoxyphenylmagnesium bromide in presence of CuI to afford secondary alcohol (S)-3 in 83% yield; (b) O-alkylation of secondary alcohol (S)-3 using ethyl iodide and base in anhydrous DMF to give ethylated derivative (S)-4 in 93% yield without any loss in optical purity of final compound; (c) debenzylation of compound (S)-4 to furnish primary hydroxy compound (S)-5 in 88% yield; (d) oxidizing compound (S)-5 using TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxyl) and bleach in acetonitrile-phosphate buffer (pH 6.8) condition to afford the corresponding acid (S)-6 in 86% yield; and (e) demethylating of compound (S)-6 using sodium ethanethiolate followed by esterification using EtOH/HCl to give (S)-1a or IPA/SOCl.sub.2 to give (S)-1b.

(19) The base in step (b) is selected from NaOH, KOH, Na.sub.2CO.sub.3 and NaHCO.sub.3. In a more preferred embodiment, the base is NaOH.

(20) The agent for debenzylation is step (c) is selected from Pd/C, Pd(OH).sub.2, Raney-Ni and TiCl.sub.4/dichloromethane, preferably TiCl.sub.4/dichloromethane.

(21) The oxidizing agent of step (d) is selected from chromium trioxide/H.sub.2SO.sub.4, (bis(acetoxy)iodo)benzene)/TEMPO and sodium chlorite, preferably sodium chlorite/2,2,6,6-tetramethyl-1-piperidinyl oxyl (TEMPO)/bleach conditions.

(22) The structure of (S)-1a & (S)-1b was confirmed by its IR, .sup.1H NMR, .sup.13C NMR, and mass spectroscopic analysis. The enantiomeric purity was determined by chiral HPLC analysis as seen in FIG. 1.

EXAMPLES

(23) The following examples are given by way of illustrations and therefore, should not be construed to limit the scope of the present investigation.

(24) Solvents were purified and dried by standard procedures prior to use. IR spectra were obtained from Perking Elmer Spectrum one spectrophotometer. .sup.1H NMR and .sup.13C NMR spectra were recorded on a Bruker AC-200 NMR spectrometer. Spectra were obtained in CDCl.sub.3. Monitoring of reactions was carried out using TLC plates Merck Silica Gel 60 F254 and visualization with UV light (254 and 365 nm), I.sub.2 and anisaldehyde in ethanol as development reagents. Optical rotations were measured with a JASCO P 1020 digital polarimeter. Mass spectra were recorded at ionization energy 70 eV on API Q Star Pulsar spectrometer using electrospray ionization. Enantiomeric excess was determined by chiral HPLC.

Example 1

Preparation of (S)-1-(benzyloxy)-3-(4-methoxyphenyl) propan-2-ol referred as (S)-3

(25) To a pre-cooled (20 C.) solution of (S)-benzyl glycidyl ether (S)-2 (4.5 g, 27.4 mmol) and CuI (0.1 g) in dry THF (30 mL) was added 4-methoxyphenylmagnesium bromide (12 mL, 54.8 mmol) in THF (20 ml) drop-wise for about one hour. Subsequently, the reaction mixture was allowed to attain ambient temperature, usually 30 C. and continued the stirring for additional 4 h. After completion of the reaction (indicated by TLC), aqueous NH.sub.4Cl 5 ml was added, after which the reaction mixture was filtered, and washed with ethyl acetate. The solvent was removed under reduced pressure and the crude product was subjected to column chromatography (silica gel, petroleum ether/acetone, 95:5) to yield (S)-3 as colorless oil. (6.1 g; 83%); [].sub.D.sup.25=+11.3 (c 1.1, CHCl.sub.3); IR (CHCl.sub.3): 3387, 3019, 2977, 2933, 1612, 1496, 1454, 1370, 1296, 1216, 1104, 929, 757 cm.sup.1; .sup.1H NMR (200 MHz, CDCl.sub.3): .sub.H=2.76 (d, J=6.5 Hz, 2H), 3.43 (dd, J=9.5, 6.8 Hz, 1H), 3.54 (dd, J=9.5, 3.5 Hz, 1H), 3.79 (s, 3H), 3.95-4.07 (m, 1H), 4.54 (s, 2H), 6.86 (d, J=8.6 Hz, 2H), 7.10 (d, J=8.6 Hz, 2H), 7.31-7.37 (m, 5H); .sup.13C NMR (50 MHz, CDCl.sub.3): .sub.C=158.2 (C), 138.0 (C), 138.2 (CH, 2 carbons), 129.8 (C), 128.4 (CH, 2 carbons), 127.7 (CH, 3 carbons), 113.9 (CH, 2 carbons), 73.5 (CH.sub.2), 73.3 (CH.sub.2), 71.5 (CH), 55.3 (CH.sub.3), 38.9 (CH.sub.2); MS: m/z 295 [M+Na].sup.+.

Example 2

Preparation of (S)-1-(3-(benzyloxy)-2-ethoxypropyl)-4-methoxybenzene referred as (S)-4

(26) In a 50 mL two-necked round bottomed flask sodium hydride (0.9 g, 36.5 mmol) was taken under N.sub.2 atmosphere, and washed with pet ether followed by addition of dry DMF (15 mL). It was cooled to 0 C., then compound (S)-3 (4 g, 14.6 mmol) in dry DMF (3 mL) was added slowly. After stirring for 10 minutes, ethyl iodide (2.4 mL, 29.2 mmol) in 2 mL dry DMF was added slowly to the reaction mixture and again stirred at 0 C. for 1 h. After completion of the reaction (indicated by TLC), reaction was quenched with ice-cold water, extracted with ethyl acetate (315 mL). The combined organic layer was dried, concentrated under reduced pressure and purified using column chromatography (silica gel, petroleum ether/acetone, 97:3) to yield (S)-4 as colorless oil. (4.2 g; 93%); [].sub.D.sup.25=3.9 (c 1, CHCl.sub.3); IR (CHCl.sub.3): 3387, 3019, 2977, 2933, 1612, 1496, 1454, 1370, 1296, 1216, 1104, 929, 757 cm.sup.1; .sup.1H NMR (200 MHz, CDCl.sub.3): .sub.H=1.14 (t, J=6.7 Hz, 3H), 2.76-2.81 (m, 2H), 3.42-3.50 (m, 3H), 3.55-3.63 (m, 2H), 3.79 (s, 3H), 4.54 (s, 2H), 6.79 (d, J=8.6 Hz, 2H), 7.10 (d, J=8.6 Hz, 2H), 7.31-7.36 (m, 5H); .sup.13C NMR (50 MHz, CDCl.sub.3): .sub.C=157.3 (C), 137.7 (C), 130.1 (C), 129.7 (CH, 2 carbons), 127.6 (CH, 2 carbons), 127.0 (CH, 2 carbons), 126.8 (CH), 112.9 (CH, 2 carbons), 79.2 (CH), 72.6 (CH.sub.2), 70.9 (CH.sub.2), 64.8 (CH.sub.2), 54.8 (CH.sub.3), 36.6 (CH.sub.2), 14.9 (CH.sub.3); MS: m/z 323 [M+Na]+.

Example 3

Preparation of (S)-2-ethoxy-3-(4-methoxyphenyl) propan-1-ol referred to as (S)-5

(27) To a solution of compound (S)-4 (4 g, 15.3 mmol) in dry DCM (10 mL) at 0 C. was added slowly TiCl.sub.4 (2.5 mL, 23.0 mmol) under N.sub.2 atmosphere. Subsequently, the reaction mixture was allowed to stir for 4 h at room temperature (30 C.). The reaction was quenched with saturated NH.sub.4Cl solution and the mixture was allowed to stand for 1 h. The organic layer was separated and washed with 0.1 N HCl, saturated NaHCO.sub.3 solution and brine. The organic layer was dried, concentrated under reduced pressure and purified using column chromatography (silica gel, petroleum ether/acetone, 80:20) to yield (S)-5 as colorless oil. (2.8 g; 88%); [].sub.D.sup.25=+2.8 (c 1.8 CHCl.sub.3); IR (CHCl.sub.3): 3420, 3019, 1635, 1514, 1215, 1113, 928, 770, 669 cm.sup.1; .sup.1H NMR (200 MHz, CDCl.sub.3): .sub.H=1.23 (t, J=6.9 Hz, 3H), 2.64-2.82 (m, 2H), 3.47-3.61 (m, 5H), 3.80 (s, 3H), 3.91-3.95 (m, 1H), 6.86 (d, J=8.5 Hz, 2H), 7.15 (d, J=8.5 Hz, 2H); .sup.13C NMR (50 MHz, CDCl3): .sub.C=157.0 (C), 130.3 (CH, 2 carbons), 130.3 (C), 113.8 (CH, 2 carbons), 81.1 (CH), 65.2 (CH.sub.2), 63.2 (CH.sub.2), 55.2 (CH.sub.3), 36.4 (CH.sub.2), 15.5 (CH.sub.3); MS: m/z 211 [M+H].sup.+.

Example 4

Preparation of (S)-2-ethoxy-3-(4-methoxyphenyl) propanoic acid referred to as (S)-6

(28) A mixture of (S)-5 (1 g, 4.4 mmol), TEMPO (2,2,6,6-Tetramethylpiperidine 1-oxyl) (0.034 g, 0.22 mmol), acetonitrile (20 mL), and sodium phosphate buffer (16 mL, 0.67 M, pH 6.7) was heated to 35 C. Then sodium chlorite (0.6 g dissolved in 2 mL water, 6.4 mmol) and dilute bleach (Sodium hypochlorite) (4-6%, 2 mL diluted in 4 mL water) were added simultaneously over 1 h. The reaction mixture was stirred at 35 C. until the reaction is complete (6 h, TLC), then cooled to room temperature. Water (20 mL) was added and the pH is adjusted to 8 with 2N NaOH. The reaction is quenched by pouring into ice cold Na.sub.2SO.sub.3 solution maintained at <20 C. After stirring for 30 min at room temperature, ethyl acetate (20 mL) was added and continued the stirring for additional 15 min. The organic layer was separated and discarded. More ethyl acetate (20 mL) was added, and the aqueous layer was acidified with 2N HCl to pH 3-4. The organic layer was separated, washed with water (215 mL), brine (20 mL) and concentrated under reduced pressure to afford the carboxylic acid (S)-6 (0.85 g, 86%); [].sub.D.sup.25=15.3 (c 2.7 CHCl.sub.3); IR (CHCl.sub.3): 3412, 3020, 1614, 1425, 1216, 1110, 1031, 928, 758 cm.sup.1; .sup.1H NMR (200 MHz, CDCl.sub.3): .sub.H=1.19 (t, J=7.0 Hz 3H), 2.90-3.15 (m, 2H), 3.39-3.65 (m, 2H), 3.80 (s, 3H), 4.03-4.16 (m, 1H), 6.87 (d, J=8.5 Hz 2H), 7.20 (d, J=8.5 Hz, 2H); .sup.13C NMR (50 MHz, CDCl3): .sub.C=176.3 (CO), 158.5 (C), 130.4 (CH, 2 carbons), 128.6 (C), 113.7 (CH, 2 carbons), 79.7 (CH), 66.7 (CH.sub.2), 55.1 (CH.sub.3), 37.8 (CH.sub.2), 14.9 (CH.sub.3); MS: m/z 247 [M+Na].sup.+.

Example 5

Preparation of Ethyl (S)-2-ethoxy-3-(4-hydroxyphenyl)propanoate referred to as (S)-1a

(29) To a suspension of NaH (0.4 g, 60% disp. in min oil, 10 mmol) in DMF (5 mL) was added EtSH (Ethanethiol) (0.75 g, 12.0 mmol) under an N.sub.2 atmosphere. After 30 min, a solution of acid (S)-6 (0.44 g, 2.0 mmol) in DMF (5 mL) was added. After 48 hrs at 130 C., the reaction mixture was quenched with a saturated solution of NaHCO.sub.3 (40 mL) and washed with CH.sub.2Cl.sub.2 (320 mL). The aqueous phase was acidified with HCl (1 M) and extracted with EtOAc (320 mL). The combined organic phase was washed with brine (220 mL), dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford demethylated product (S)-7. To a stirred solution of (S)-7 (0.3 g) in EtOH (10 mL) was added conc. HCl (0.2 mL, 12 M) and the resulting mixture was heated to reflux at 80 C. for 3 h in a vessel well equipped with dean stark assembly for azeotropic removal of water formed in the reaction restoring the volume of ethanol. After completion of the reaction (Indicated by TLC), reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate. The organic phase was washed with saturated NaHCO.sub.3 solution and brine. The organic layer was dried, concentrated under reduced pressure and purified using column chromatography (silica gel, petroleum ether/ethyl acetate, 95:05) to afford (S)-1a 0.3 g, 90%) [].sub.D.sup.25=26.9 (c 0.4, CHCl.sub.3), [lit. [].sub.D.sup.25=21.3 (c 1.45, CHCl.sub.3) for 93% ee]; .sup.1H NMR (200 MHz, CDCl.sub.3): .sub.H=1.17 (t, J=6.9 Hz, 3H), 1.23 (t, J=6.9 Hz, 3H), 2.90 (d, J=7.0 Hz, 2H), 3.32-3.44 (m, 1H), 3.53-3.65 (m, 1H), 3.98 (t, J=6.6 Hz, 1H), 4.15 (dd, J=14.2, 7.0 Hz, 2H), 5.09 (bs, 1H), 6.77 (d, J=8.5 Hz, 2H), 7.13 (d, J=8.5 Hz, 2H); MS: m/z 239 [M+H]+261 [M+Na]+.

Example 7

Preparation of Isopropyl (S)-2-ethoxy-3-(4-hydroxyphenyl)propanoate referred to as (S)-1b

(30) To a stirred solution of (S)-7 (0.3 g, 1.4 mmol) in anhydrous 2-propanol (5 mL) was added thionyl chloride (0.2 mL, 2.6 mmol) slowly at room temperature (30 C.). The mixture was stirred for 2 h at 60 C. and solvent was removed under reduced pressure. Ethyl acetate was added and the organic layer was washed with 10% NaHCO.sub.3 solution (215 mL), dried, concentrated under vacou and purified using column chromatography (silica gel, petroleum ether/ethyl acetate, 95:05). to furnish (S)-1b as oil (0.3 g; 85%); [].sub.D.sup.25=19.4 (c 1.02 CHCl.sub.3) ee 99%; IR (CHCl.sub.3): 3392, 3019, 2400, 1601, 1216, 1116, 928, 757 cm.sup.1; .sup.1H NMR (200 MHz, CDCl.sub.3): .sub.H=1.14-1.26 (m, 9H), 2.96 (d, J=6.6 Hz, 2H), 3.31-3.46 (m, 1H), 3.53-3.68 (m, 1H), 3.96 (t, J=6.6 Hz, 1H), 4.95-5.13 (m, 1H), 5.74 (bs, 1H), 6.75 (d, J=8.5 Hz, 2H), 7.11 (d, J=8.5 Hz, 2H); .sup.13C NMR (50 MHz, CDCl3): .sub.C=172.3 (CO), 154.5 (C), 130.5 (CH, 2 carbons), 128.8 (C), 115.1 (CH, 2 carbons), 80.4 (CH), 68.5 (CH), 66.0 (CH.sub.2), 38.3 (CH.sub.2), 21.7 (CH.sub.3), 21.6 (CH.sub.3), 15.0 (CH.sub.3); MS: m/z 275 [M+Na].sup.+. [The ee was determined by chiral HPLC analysis: Kromasil 5-Amycoat (2504.6 mm) column; eluent: pet ether/ethanol=95/05; flow rate: 0.5 mL/min; detector 220 nm [(R) isomer t.sub.R=16.53 min; (S) isomer t.sub.R=19.01 min].

ADVANTAGES OF THE INVENTION

(31) 1. Commercially available starting material.

(32) 2. High enantiopurity (ee>99%) and good overall yield (>43%).