PROCESS FOR THE PREPARATION OF ORTHO-HALOGENATED PHENYLALANINE COMPOUNDS

Abstract

Process of ortho-halogenation of phenylalanine compounds by C—H activation.

Claims

1. A process for the preparation of the compound of formula (A), the compound of formula (B), or a mixture thereof: ##STR00006## wherein R.sup.1 is a hydrogen atom, a benzyl group or a C.sub.1-C.sub.6 linear or branched alkyl group, and X is a halogen atom selected from a group consisting of Cl, Br and I, by reaction of the compound of formula (I): ##STR00007## wherein R.sup.1 is a hydrogen atom, and HY.sup.1 is an acid, with a halogenating agent, in the presence of a palladium catalyst and an acid HY.sup.2, in an organic solvent or a mixture of organic solvents.

2. The process according to claim 1, wherein the compounds of formula (I), (A) and (B) are in (S) configuration.

3. The process according to claim 1, wherein R.sup.1 is methyl or ethyl.

4. The process according to claim 1, wherein HY.sup.1 is trifluoroacetic acid.

5. The process according to claim 1, wherein X is Cl or Br.

6. The process according to claim 5, wherein the halogenating agent is one selected from a group consisting of N-bromosuccinimide, N-chlorosuccinimide, N-bromophtalimide and N-chlorophtalimide.

7. The process according to claim 1, wherein the palladium catalyst is used in a sub stoichiometric amount.

8. The process according to claim 1, wherein the palladium catalyst is palladium(II) acetate.

9. The process according to claim 1, wherein the amount of the palladium catalyst is from 5 to 20 mol %.

10. The process according to claim 1, wherein HY.sup.2 is trifluoroacetic acid.

11. The process according to claim 1, wherein the reaction is conducted in the presence of copper (II) acetate.

12. The process according to claim 1, wherein the temperature of the reaction is from 30° C. to 80° C.

13. The process according to claim 1, wherein the organic solvent is a mixture of dichloromethane and hexafluoroisopropanol.

14. The process according to claim 1, wherein the organic solvent is trifluoroacetic acid.

15. The process according to claim 1, wherein a mixture of the compounds (A) and (B) is obtained and subsequently separated into the compounds (A) and (B).

16. The process according to claim 1, further comprising a step of intramolecular aryl amination reaction, to lead to the compound of formula (IIIA), to the compound of formula (IIIB) or to a mixture thereof: ##STR00008## wherein R.sup.1 is a hydrogen atom, a benzyl group or a C.sub.1-C.sub.6 linear or branched alkyl group, and R.sup.2 is H, Cl, Br or I, followed, if the compound of formula (IIIB) is obtained, by a reduction reaction, to lead to the compound of formula (IIIA).

Description

Example 1: Methyl (S)-2-amino-3-(2-bromophenyl)propanoate 1A—Mixture with Methyl (S)-2-amino-3-(2,6-dibromophenyl)propanoate 1B

[0061] A mixture of DCM/HFIP (3 mL, 1:1) solvents was added to palladium acetate (7 mg, 0.03 mmol, 10 mol %) and copper acetate (54 mg, 0.3 mmol, 1 equiv.) into an oven dried tube. NBS (80 mg, 0.45 mmol, 1.5 equiv.), L-Phe-OMe.HTFA (88 mg, 0.3 mmol, 1 equiv.) and trifluoroacetic acid (230 μL, 3 mmol, 10 equiv.) were added to the reaction mixture. The tube was sealed and the reaction was stirred at 50° C. (oil bath temperature) for 16 hours. After cooling to room temperature, the reaction mixture was diluted by DCM (20 mL), quenched with a saturated aqueous solution of Na.sub.2CO.sub.3 (5 mL) and the two layers were separated. The aqueous phase was extracted once with dichloromethane (10 mL). The combined organic layers were washed with a saturated aqueous solution of Na.sub.2CO.sub.3 (5 mL), a solution of brine (5 mL) and dried over Na.sub.2SO.sub.4 before filtration. Bn.sub.2O (14.4 μL, 0.25 equiv.) was added as the internal standard for the determination of the yield by .sup.1H NMR (67% 1A, 34% 1B) if required. The solution was concentrated under vacuum to afford the crude product.

Benzoylation: Methyl (S)-2-benzamido-3-(2-bromophenyl)propanoate 1C and Methyl (S)-2-benzamido-3-(2,6-dibromophenyl)propanoate 1D

[0062] The crude 1A and 1B mixture was solubilized in DCM (3 mL) and a saturated aqueous solution of K.sub.2CO.sub.3 (3 mL) and benzoic anhydride (136 mg, 0.6 mmol, 2 equiv. based on starting 1A and 1B mixture) was added. The tube was sealed and the reaction was vigorously stirred (1200 rpm) at room temperature for 2 hours. The mixture was diluted with DCM (20 mL), washed with water (5 mL), a saturated aqueous solution of Na.sub.2CO.sub.3 (5 mL) and eventually a solution of brine (5 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated under vacuum. The yields were measured by .sup.1H-NMR spectroscopy by means of Bn.sub.2O as an internal standard (49% 1C, 39% 1D). The crude reaction mixture was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate 9:1 to 8:2) to afford 1C as a white solid (50 mg, 46% over two-steps) and 1D as a white solid (50 mg, 38% over two-steps).

[0063] Methyl (S)-2-benzamido-3-(2-bromophenyl)propanoate 1C:

[0064] R.sub.f=0.16 (PE/AcOEt: 9/1).

[0065] .sup.1H NMR (300 MHz; CDCl.sub.3) δ.sub.H 7.75-7.72 (m, 2H), 7.57-7.38 (m, 4H), 7.28-7.21 (m, 2H), 7.15-7.08 (m, 1H), 6.67 (brd, J=7.7 Hz, 1H), 5.14-5.07 (m, 1H), 3.76 (s, 3H), 3.44 (dd, J=6.1, 14.0 Hz, 1H), 3.34 (dd, J=7.6, 14.0 Hz, 1H). .sup.13C NMR (75 MHz; CDCl.sub.3) δ.sub.C 172.2 (C), 167.1 (C), 136.1 (C), 133.8 (C), 133.1 (CH), 131.3 (CH), 131.4 (CH), 129.0 (CH), 128.7 (CH), 127.8 (CH), 127.2 (CH), 125.1 (C), 53.2 (CH or CH.sub.3), 52.7 (CH or CH.sub.3), 38.0 (CH.sub.2).

[0066] HRMS (ESI.sup.+): calculated for C.sub.17H.sub.17BrNO.sub.3 [(M+H).sup.+]: 362.0386; found: 362.0394.

Example 2: Methyl (S)-2-amino-3-(2-bromophenyl)propanoate 1A—Mixture with Methyl (S)-2-amino-3-(2,6-dibromophenyl)propanoate 1B

[0067] A mixture of DCM/HFIP (10 mL, 1:1) solvents was added to palladium acetate (22 mg, 0.1 mmol, 10 mol %) in an open vessel or a sealed tube. NBS (196 mg, 1.1 mmol, 1.1 equiv.), L-Phe-OMe.HTFA (293 mg, 1 mmol, 1 equiv.) and trifluoroacetic acid (766 μL, 10 mmol, 10 equiv.) were added to the reaction mixture. The reaction was stirred at 50° C. (oil bath temperature) for 16 hours. After cooling to room temperature, the reaction mixture was diluted with DCM (60 mL), quenched with a saturated aqueous solution of Na.sub.2CO.sub.3 (15 mL) and the two layers were separated. The aqueous phase was extracted once with dichloromethane (20 mL). The combined organic layers were washed with a saturated aqueous solution of Na.sub.2CO.sub.3 (15 mL), then a solution of brine (15 mL) and dried over Na.sub.2SO.sub.4 before filtration. Bn.sub.2O (48 μL, 0.25 equiv.) was added as the internal standard for the determination of the yield by .sup.1H NMR (sealed tube: 57% 1A, 21% 1B, open vessel: 54% 1A, 20% 1B). The solution was concentrated under vacuum to afford the crude product.

Example 3: Methyl (S)-2-amino-3-(2,6-dibromophenyl)propanoate 1B

[0068] TFA (3 mL) solvent was added to palladium acetate (14 mg, 0.06 mmol) into an oven dried tube. NBS (107 mg, 0.6 mmol, 2 equiv.) and L-Phe-OMe.HTFA (88 mg, 0.3 mmol, 1 equiv.) were added to the reaction mixture. The tube was sealed and the reaction was stirred at 50° C. (oil bath temperature) for 16 hours. After cooling to room temperature, the reaction mixture was diluted with DCM (20 mL), quenched with a saturated aqueous solution of Na.sub.2CO.sub.3 (40 mL) and the two layers were separated. The aqueous phase was extracted once with dichloromethane (10 mL). The combined organic layers were washed with a saturated aqueous solution of Na.sub.2CO.sub.3 (5 mL), a solution of brine (5 mL) and dried over Na.sub.2SO.sub.4 before filtration. Bn.sub.2O (14.4 μL, 0.25 equiv.) was added as the internal standard for the determination of the yield by .sup.1H NMR (72% 1B) if required. The solution was concentrated under vacuum to afford 1B as a crude product.

Benzoylation: Methyl (S)-2-benzamido-3-(2,6-dibromophenyl)propanoate 1D

[0069] The crude 1B compound was solubilized in DCM (3 mL), and a saturated aqueous solution of K.sub.2CO.sub.3 (3 mL) and benzoic anhydride (136 mg, 0.6 mmol, 2 equiv. based on crude 1B) was added to the reaction medium. The tube was sealed and the reaction was vigorously stirred (1200 rpm) at room temperature for 2 hours. The reaction mixture was diluted with DCM (20 mL), washed with water (5 mL), a saturated aqueous solution of Na.sub.2CO.sub.3 (5 mL) and eventually a solution of brine (5 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated under vacuum. The yield was measured by .sup.1H-NMR spectroscopy by means of Bn.sub.2O as an internal standard (69% 1D). The crude reaction mixture was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate 9:1 to 8:2) to afford 1D as a white solid (86 mg, 65%).

[0070] R.sub.f=0.19 (PE/AcOEt: 9/1).

[0071] .sup.1H NMR (300 MHz; CDCl.sub.3) δ.sub.H 7.78-7.73 (m, 2H), 7.53-7.45 (m, 3H), 7.43-7.37 (m, 2H), 6.95 (t, J=8.0 Hz, 1H), 6.82 (brd, J=8.4 Hz, 1H), 5.42-5.24 (m, 1H), 3.79 (s, 3H), 3.65-3.54 (m, 2H). .sup.13C NMR (75 MHz; CDCl.sub.3) δ.sub.C 172.2, 167.1, 135.7, 133.7, 132.6, 131.9, 129.9, 128.6, 127.2, 126.2, 52.9, 51.6, 38.9. HRMS (ESI.sup.+): calculated for C.sub.17H.sub.16.sup.79Br.sub.2NO.sub.3 [(M+H).sup.+]: 439.9491; found: 439.9497.

Example 4: Methyl (S)-2-amino-3-(2-chlorophenyl)propanoate 2A—Mixture with Methyl (S)-2-amino-3-(2,6-dichlorophenyl)propanoate 2B

[0072] A mixture of DCM/HFIP (3 mL, 1:1) solvents was added to palladium acetate (7 mg, 0.03 mmol, 10 mol %) into an oven dried tube. NCS (60 mg, 0.45 mmol, 1.5 equiv.), L-Phe-OMe. HTFA (88 mg, 0.3 mmol, 1 equiv.) and trifluoroacetic acid (230 μL, 3 mmol, 10 equiv.) were added to the reaction mixture. The tube was sealed and the reaction was stirred at 50° C. (oil bath temperature) for 16 hours. After cooling to room temperature, the reaction mixture was diluted in DCM (20 mL), quenched with a saturated aqueous solution of Na.sub.2CO.sub.3 (5 mL) and the two layers were separated. The aqueous phase was extracted once with dichloromethane (10 mL). The combined organic layers were washed with a saturated aqueous solution of Na.sub.2CO.sub.3 (5 mL), then a solution of brine (5 mL) and dried over Na.sub.2SO.sub.4 before filtration. Bn.sub.2O (14.4 μL, 0.25 equiv.) was added as the internal standard for the determination of the yield by .sup.1H NMR (78% 2A, 27% 2B) if required. The solution was concentrated under vacuum to afford the crude product.

Benzoylation: Methyl (S)-2-benzamido-3-(2-chlorophenyl)propanoate 2C and Methyl (S)-2-benzamido-3-(2,6-dichlorophenyl)propanoate 2D

[0073] The crude 2A and 2B mixture was solubilized in DCM (3 mL), and a saturated aqueous solution of K.sub.2CO.sub.3 (3 mL) and benzoic anhydride (136 mg, 0.6 mmol, 2 equiv. based on crude 2A and 2B mixture) was added to the reaction medium. The tube was sealed and the reaction was vigorously stirred (1200 rpm) at room temperature for 2 hours. The reaction mixture was diluted with DCM (20 mL), washed with water (5 mL), a saturated aqueous solution of Na.sub.2CO.sub.3 (5 mL) and eventually a solution of brine (5 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated under vacuum. The yields were measured by .sup.1H-NMR spectroscopy by means of Bn.sub.2O as an internal standard (61% 2C, 26% 2D). The crude reaction mixture was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate 9:1 to 8:2) to afford 2C as a white solid (55 mg, 58%) and 2D as a white solid (31 mg, 29%).

[0074] Methyl (S)-2-benzamido-3-(2-chlorophenyl)propanoate 2C: R.sub.f=0.18 (PE/AcOEt: 9/1). .sup.1H NMR (300 MHz; CDCl.sub.3) δ.sub.H 7.76-7.72 (m, 2H), 7.53-7.35 (m, 4H), 7.27-7.17 (m, 3H), 6.66 (brd, J=7.5 Hz, 1H), 5.13-5.06 (m, 1H), 3.76 (s, 3H), 3.43 (dd, J=6.1, 13.9 Hz, 1H), 3.34 (dd, J=7.3, 13.9 Hz, 1H). .sup.13C NMR (75 MHz; CDCl.sub.3) δ.sub.C 172.2 (C), 167.1 (C), 134.6 (C), 134.3 (C), 133.9 (C), 131.9 (CH), 131.6 (CH), 129.8 (CH), 128.8 (CH), 128.7 (CH), 127.2 (CH), 53.2 (CH or CH.sub.3), 52.7 (CH or CH.sub.3), 35.6 (CH.sub.2).

[0075] Methyl (S)-2-benzamido-3-(2,6-dichlorophenyl)propanoate 2D : R.sub.f=0.21 (PE/AcOEt: 9/1). .sup.1H NMR (300 MHz; CDCl.sub.3) δ.sub.H 7.70-7.66 (m, 2H), 7.47-7.41 (m, 1H), 7.38-7.32 (m, 2H), 7.25-7.19 (m, 2H), 7.07 (dd, J=8.6, 7.5 Hz, 1H), 6.72 (d, J=8.3 Hz, 1H), 5.24-5.15 (m, 1H), 3.73 (s, 3H), 3.48 (dd, J=6.3, 13.7 Hz, 1H), 3.42 (dd, J=9.4, 13.7 Hz, 1H). .sup.13C NMR (75 MHz; CDCl.sub.3) δ.sub.C 172.3, 167.2, 136.1, 133.8, 132.9, 131.9, 129.1, 128.7, 128.5, 127.2, 52.9, 51.6, 33.8. HRMS (ESI.sup.+): calculated for C.sub.17H.sub.16.sup.35Cl.sub.2NO.sub.3 [(M+H).sup.+]: 352.0502; found: 352.0503.

Example 5: Preparation of Compounds 3-9

[0076] A mixture of DCM/HFIP (1:1) solvents was added to palladium acetate (10 mol %) in a sealed tube. NXS (1.1 equiv.), L-Phe-OR.sup.1.HTFA (1 equiv.) and trifluoroacetic acid (10 equiv.) were added to the reaction mixture. With NBS or NCS, the reaction was stirred at 50° C. (oil bath temperature) for 16 hours; with NIS, the reaction was stirred at 40° C. After cooling to room temperature, the reaction mixture was diluted with DCM, quenched with a saturated aqueous solution of Na.sub.2CO.sub.3 and the two layers were separated. The aqueous phase was extracted once with dichloromethane. The combined organic layers were washed with a saturated aqueous solution of Na.sub.2CO.sub.3, then a solution of brine and dried over Na.sub.2SO.sub.4 before filtration. An internal standard was used for the determination of the yield by .sup.1H NMR.

##STR00005##

TABLE-US-00001 Compound R.sup.1 X Ratio A:B (RMN .sup.1H) 3 Bn Br 56:21 4 Bn Cl 62:26 5 Et Br 66:20 6 Et Cl 78:15 7 iPr Br 48:23 8 iPr Cl 43:21 9 Me I 50:11