PROCESS OF MAKING ROXADUSTAT

Abstract

A process of making Roxadustat of the following formula:

##STR00001##

comprising converting a compound of formula VI:

##STR00002##

to Roxadustat, wherein R is a C.sub.1-C.sub.20 alkyl group, and PG is a protective group.

Claims

1. A method of making Roxadustat of the following formula: ##STR00038## comprising converting a compound of formula VI: ##STR00039## to Roxadustat, wherein R is a C.sub.1-C.sub.20 alkyl group, and PG is a protective group.

2. The method of claim 1 wherein the protecting group is selected from the group consisting of benzyloxycarbonyl, p-toluenesulfonyl, benzenesulfonyl, acetyl, and propoxycarbonyl groups.

3. The method of claim 1 wherein the step of converting the compound of formula VI to Roxadustat comprises converting the compound of formula VI to a compound of formula VII: ##STR00040## and then converting the compound of formula VII to Roxadustat.

4. The method of claim 3 wherein the step of converting the compound of formula VI to the compound of formula VII is conducted in the presence of at least one acid.

5. The method of claim 4 wherein the acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, acetic acid, and formic acid.

6. The method of claim 3 wherein the step of converting the compound of formula VII to Roxadustat is conducted with glycine in the presence of a base.

7. The method of claim 6 wherein the base is selected from the group consisting of sodium ethylate, potassium ethylate, sodium tert-butoxide, potassium tert-butoxide, and combinations thereof.

8. The method of claim 1 comprising a step of converting a compound of formula V: ##STR00041## to the compound of formula VI.

9. The method of claim 8 wherein the step of converting the compound of formula V to the compound of formula VI is conducted under oxidative conditions.

10. The method of claim 9 wherein the step of converting the compound of formula V to the compound of formula VI is conducted in the presence of ceric ammonium nitrate as an oxidant.

11. The method of claim 8 comprising a step of converting a compound of formula IV: ##STR00042## to the compound of formula V.

12. The method of claim 11 comprising making the compound of formula IV through the following synthetic scheme: ##STR00043##

13. The method of claim 12 comprising reacting the compound of formula I with oxalyl chloride and ferric chloride to produce the compound of formula II.

14. The method of claim 12 comprising deprotecting the compound of formula II under acidic conditions to produce the compound of formula III.

15. The method of claim 14 wherein the deprotecting is conducted in the presence of an acid selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, acetic acid, formic acid, and combinations thereof.

16. The method of claim 12 comprising reducing the compound of formula III to produce the compound of formula IV.

17. The method of claim 16 wherein the reducing is conducted in the presence of a reducing agent selected from the group consisting of sodium borohydride, lithium borohydride, palladium carbon/hydrogen, Raney Ni/hydrogen, and combinations thereof.

18. A compound of formula VI ##STR00044## wherein R is a C.sub.1-C.sub.20 alkyl group, and PG is a protective group.

19. A process of making the compound of formula VI of claim 18 comprising converting a compound of formula V: ##STR00045## to the compound of formula VI.

20. The process of claim 19 wherein the step of converting the compound of formula V to the compound of formula VI is carried out in the presence of ceric ammonium nitrate as an oxidant.

21. A compound selected from the group consisting of formulae II, III, and V: ##STR00046## wherein R is a C.sub.1-C.sub.20 alkyl group, and PG is a protective group.

Description

DESCRIPTION OF PREFERRED EMBODIMENTS

Examples

Example 1: Synthesis of Compound 6

[0049] ##STR00013##

[0050] To a round-bottom flask were added compound 1 (134.0 g), compound 2 (212.3 g) and DCM (675 mL). DBU (133.8 g) was added dropwise at 5-15° C. After 2 h, the reaction mixture was quenched with H.sub.2O. Acetic acid was added to adjust pH=6˜7. The layers were separated. The aqueous phase was extracted with DCM twice. The organic phases were combined and concentrated. The mixture was added MTBE and stirred at room temperature for 1 h. The suspension was filtered to give compound 3 as an off-white solid (199.2 g, 94.6% yield, 96.0% purity).

[0051] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.47-7.35 (m, 2H), 7.40-7.34 (m, 4H), 7.22-7.13 (m, 1H), 7.06-7.02 (m, 2H), 6.98-6.92 (m, 2H), 3.82 (s, 3H), 2.12 (s, 3H). Mass: [M+H].sup.+: 312.3;

[0052] To a reactor were added MeOH (1 L), compound 3 (100 g) and catalyst Rh (Rc, Sp-Duanphos)(NBD)BF.sub.4 (1 g). The reactor was degassed and refilled with H.sub.2 (2.0 MPa) three times. The mixture was stirred at room temperature under H.sub.2 (3.0˜4.0 MPa) for overnight. The reaction mixture was filtered. The filtrate was concentrated to dryness. The crude product was recrystallized with EtOAc/heptane (150 mL/200 mL) to give compound 6 (92.0 g, 91.5% yield, 100% purity).

[0053] .sup.1H NMR (400 MHz, DMSO-d6) δ 8.38-8.36 (m, 1H), 7.41-7.36 (m, 2H), 7.25-7.21 (m, 2H), 7.15-7.11 (m, 1H), 6.99-6.93 (m, 4H), 4.47-4.41 (m, 1H), 3.60 (s, 3H), 3.02-2.84 (m, 2H), 1.81 (s, 3H).

[0054] Mass: [M+H].sup.+: 314.3.

Example 2: Synthesis of Compound 8

[0055] ##STR00014##

[0056] To a round-bottom flask were added compound 6 (2.8 g) and DCM (28 mL). (COCl).sub.2 (1.3 g) was added dropwise at 20˜30° C. The mixture was stirred for 2 h. FeCl.sub.3 (1.7 g) was added in portions. The mixture was stirred overnight at room temperature. The reaction mixture was quenched with H.sub.2O. The layers were separated. The organic phase was concentrated to dryness. The crude product was purified by silica gel column chromatography eluting with EA/heptane=1/3 to give compound 8 as a light yellow solid (2.4 g, 62.5% yield, 97.0% purity).

[0057] .sup.1H NMR (400 MHz, DMSO-d6) δ 7.44-7.38 (m, 3H), 7.20-7.15 (m, 1H), 7.09-7.08 (m, 1H), 7.06-7.01 (m, 3H), 4.91-4.87 (m, 1H), 3.79 (s, 3H), 3.53-3.47 (m, 1H), 3.30-3.24 (m, 1H), 1.87 (s, 3H).

[0058] Mass: [M+H].sup.+: 368.3.

Example 3: Synthesis of Compound 9

[0059] ##STR00015##

[0060] To a round-bottom flask were added compound 8 (1.4 g), EtOH (14 mL) and H.sub.2SO.sub.4. The mixture was heated and refluxed at 75˜85° C. overnight. The mixture was concentrated, quenched with saturated sodium bicarbonate solution, and extracted with EtOAc (20 mL) twice. The combined organic phase was concentrated to dryness. The crude product was purified by silica gel column chromatography eluting with EA/heptane=1/6 to give compound 9 as a light yellow solid (0.9 g, 80% yield, 97.3% purity).

[0061] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.38-7.34 (m, 2H), 7.21-7.18 (m, 2H), 7.13 (s, 1H), 7.05-7.00 (m, 3H), 4.26-4.20 (m, 1H), 3.84 (s, 3H), 2.98-2.92 (m, 2H), 2.41 (s, 3H).

[0062] Mass: [M+H].sup.+: 296.3.

Example 4: Synthesis of Compound 10

[0063] ##STR00016##

[0064] To a 250 mL reactor were added compound 9, Pd/C (or Raney Ni) and IPAC. The reactor was degassed and refilled with H.sub.2 three times. The mixture was stirred at room temperature under H.sub.2 (4.0˜5.0 MPa) for 3 h. The reaction mixture was filtered, and the filtrate was concentrated to dryness. The crude product was purified by silica gel column chromatography eluting with EtOAc/heptane=1/6 to give compound 10 as a light yellow oil (970 mg, 60.0% yield, 98.5% purity).

[0065] Mass: [M+H].sup.+: 298.3.

Example 5: Synthesis of Compound 12

[0066] ##STR00017##

[0067] To a round-bottom flask were added compound 11 (0.6 g), MeCN (6 mL) and H.sub.2O (6 mL). CAN (3.65 g) was added in portions and the reaction mixture was stirred for 3 h. After completion of the reaction, EtOAc (30 mL) was added, and the layers were separated. The organic phase was concentrated to dryness. The crude product was purified by silica gel column chromatography eluting with EtOAc/heptane=1/8 to give compound 12 as a light yellow solid (150 mg, 21% yield).

[0068] Mass: [M−H.sub.2O+H].sup.+: 464.2.

Example 6: Synthesis of Compound 13

[0069] ##STR00018##

[0070] To a round-bottom flask were added compound 12 (0.13 g), 33% HBr—AcOH solution (1 mL) and phenol (26 mg). The reaction mixture was stirred for 3 h. EtOAc (20 mL) was added, and the layers were separated. The organic phase was washed with 20% potassium carbonate aqueous solution. The organic phase was concentrated to dryness. The crude product was purified by silica gel column chromatography eluting with EtOAc/heptane=1/5 to give compound 13 as a light-yellow solid (10 mg, 11% yield, 98.0% purity).

[0071] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 11.71 (s, 1H), 8.42-8.40 (m, 1H), 7.52-7.42 (m, 4H), 7.28-7.23 (m, 1H), 7.16-7.13 (m, 2H), 4.10 (s, 3H), 2.77 (s, 3H).

[0072] Mass: [M+H].sup.+: 310.1.

Example 7: Synthesis of Compound 7

[0073] ##STR00019##

[0074] To a round-bottom flask were added compound 1 (45.0 g), compound 4 (60.4 g) and DCM (225 mL). DBU (44.4 g) was added dropwise at 0˜10° C. The reaction mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was quenched with H.sub.2O (225 mL). The layers were separated. The organic phase was concentrated to dryness. The crude product was added MTBE (180 mL) and stirred at room temperature for 1 h. The suspension was filtered to give compound 5 as a white solid (566.8 g, 90.4% yield, 100% purity).

[0075] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.48-7.37 (m, 4H), 7.20-7.13 (m, 2H), 7.09-7.06 (m, 2H), 6.98-6.96 (m, 2H), 4.31 (q, J=7.1 Hz, 2H), 2.16 (s, 3H), 1.37 (t, J=7.1 Hz, 3H).

[0076] Mass: [M+H].sup.+: 326.3.

[0077] To a 2 L reactor were added EtOH (1 L), compound 5 (65 g) and catalyst Rh (Rc,Sp-Duanphos) (NBD)BF.sub.4 (0.5 g). The reactor was degassed and refilled with H.sub.2 (2.0 MPa) three times. The mixture was stirred at 40˜50° C. under H.sub.2 (1.8 MPa) overnight. The reaction mixture was filtered. The filtrate was concentrated to dryness. The crude product was recrystallized with EtOAc/heptane to give compound 7 as an off-white solid (59.5 g, 91.0% yield, 100% purity).

[0078] 1H NMR (400 MHz, DMSO-d6) δ 8.37-8.35 (m, 1H), 7.40-7.36 (m, 2H), 7.25-7.23 (m, 2H), 7.14-7.11 (m, 1H), 6.99-6.92 (m, 4H), 4.46-4.40 (m, 1H), 4.07-4.02 (m, 2H), 3.00-2.86 (m, 2H), 1.82 (s, 3H), 1.12 (t, J=7.1 Hz, 3H).

[0079] Mass: [M+H].sup.+: 328.3.

Example 8: Synthesis of Compound 15

[0080] ##STR00020##

[0081] To a round-bottom flask were added compound 7 (160 g) and DCM (1.28 L). (COCl).sub.2 (69.0 g) was added dropwise at room temperature. The mixture was stirred for 2 h. FeCl.sub.3 (96.1 g) was added in portions at −15° C.˜−10° C. The mixture was warmed to room temperature and stirred for 2 h. H.sub.2O (800 mL) and DCM (1.6 L) were added, and the layers were separated. One eighth of the organic phase was concentrated to dryness. The crude product was added EtOH (200 mL) and stirred for 3 h. The suspension was filtered to give compound 14 (8.1 g, 34.8% yield, 95.5% purity). Seven eighths of the organic phase was concentrated to dryness and added EtOH (1.26 L) and sulfuric acid (0.14 L). The mixture was heated to 70˜80° C. and stirred overnight. The mixture was quenched with saturated sodium bicarbonate solution. The pH of the mixture was adjusted to 6˜7. The layers were separated. The organic layer was concentrated to dryness. The crude product was purified by silica gel column chromatography eluting with EA/heptane=1/20 to give compound 15 as a yellow oil (110 g, 83.0% yield, 98.0% purity).

Compound 14:

[0082] Mass: [M+H].sup.+: 382.2;

Compound 15:

[0083] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.37-7.33 (m, 2H), 7.20-7.17 (m, 2H), 7.14-7.11 (m, 1H), 7.04-6.99 (m, 3H), 4.29 (q, J=7.1 Hz, 2H), 4.26-4.19 (m, 1H), 3.03-2.86 (m, 2H), 2.40 (d, J=2.0 Hz, 3H), 1.32 (t, J=7.1 Hz, 3H).

[0084] Compound 15 Mass: [M+H].sup.+: 310.2.

Example 9: Synthesis of Compound 16

[0085] ##STR00021##

[0086] To a 250 mL reactor were compound 15 (15 g), 10% Pd/C (1.5 g) and EtOH (120 mL). The reactor was degassed and refilled with H.sub.2 three times. The mixture was stirred at room temperature under H.sub.2 (5.0 MPa) for 2 h. The mixture was filtered. The filtrate was concentrated to dryness. The crude product 16 was a yellow oil liquid (13.8 g, 91.3% yield, 95.4% purity).

[0087] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.33-7.29 (m, 2H), 7.09-7.05 (m, 2H), 6.99-6.96 (m, 2H), 6.88-6.87 (m 1H), 6.82-6.79 (m, 1H), 4.28-4.22 (m, 2H), 4.13-4.11 m, 1H), 3.74-3.70 (m, 1H), 3.07-2.92 (m, 2H), 2.02 (s, 1H), 1.46 (d, J=6.5 Hz, 3H), 1.32 (t, J=7.1 Hz, 3H).

[0088] Mass: [M+H].sup.+: 312.3.

Example 10: Synthesis of Compound 17

[0089] ##STR00022##

[0090] To a round-bottom flask were added compound 17 (22.4 g), DCM (150 mL), TEA (10.2 g) and tosyl chloride (19.24 g). The mixture was stirred at 40˜50° C. overnight. The reaction mixture was quenched with H.sub.2O (100 mL). The layers were separated. The organic phase was concentrated to dryness. The crude product was purified by silica gel column chromatography eluting with EtOAc/heptane=1/8 to give compound 17 as a white solid (25.1 g, 74.1% yield, 99.35% purity).

[0091] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.67-7.65 (m, 2H), 7.35-7.31 (m, 2H), 7.21-7.19 (m, 2H), 7.13-7.09 (m, 1H), 7.03-7.01 (m, 1H), 6.93-6.90 (m, 2H), 6.78-6.75 (m, 1H), 6.65-6.64 (m, 1H), 4.93 (q, J=7.0 Hz, 1H), 4.56-4.53 (m, 1H), 4.23 (q, J=7.1 Hz, 2H), 3.01-2.96 (m, 2H), 2.38 (s, 3H), 1.48 (d, J=7.0 Hz, 3H), 1.29 (t, J=7.1 Hz, 3H).

[0092] Mass: [M+H].sup.+: 466.3.

Example 11: Synthesis of Compound 18

[0093] ##STR00023##

[0094] To a round-bottom flask were added compound 17 (1.6 g), MeCN (16 mL) and H.sub.2O (16 mL). CAN (9.44 g) was added in portions. The reaction mixture was stirred for 3 h. EtOAc (100 mL) was added. The layers were separated. The organic phase was concentrated to dryness. The crude product was purified by silica gel column chromatography eluting with EtOAc/heptane=1/8 to give compound 18 as a light-yellow solid (0.95 g, 58% yield).

[0095] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.94-7.92 (m, 3H), 7.48-7.44 (m, 2H), 7.34-7.26 (m, 3H), 7.13-7.10 (m, 2H), 6.99-6.96 (m, 1H), 6.71-6.70 (m, 1H), 4.86 (q, J=6.8 Hz, 1H), 4.35-4.29 (m, 2H), 2.46 (s, 3H), 1.27 (d, J=6.8 Hz, 3H), 1.24 (t, J=6.8 Hz, 3H).

[0096] Mass: [M−H.sub.2O+H].sup.+: 478.2.

Example 12: Synthesis of Compound 30

[0097] ##STR00024##

[0098] To a round-bottom flask were added compound 18 (0.2 g), 33% HBr—AcOH solution (2 mL) and phenol (39.4 mg). The mixture was stirred at room temperature. After completion of the reaction, EtOAc (20 mL) was added. The layers were separated. The organic layer was washed with 20% potassium carbonate aqueous solution. The organic phase was concentrated to dryness. The crude product was purified by silica gel column chromatography eluting with EtOAc/heptane=1/5 to give compound 30 as a light yellow solid (90 mg, 67% yield, 95.0% purity).

[0099] .sup.1H NMR (400 MHz, DMSO-d6) δ 11.61 (s, 1H), 8.31-8.29 (m, 1H), 7.57-7.56 (m, 1H), 7.53-7.47 (m, 3H), 7.29-7.25 (s, 1H), 7.20-7.18 (m, 2H), 4.45 (d, J=7.1 Hz, 2H), 2.63 (s, 3H), 1.39 (t, J=7.1 Hz, 3H).

[0100] Mass: [M+H].sup.+: 324.1.

Example 13: Synthesis of Compound 19

[0101] ##STR00025##

[0102] To a round-bottom flask were added THF (80 mL), H.sub.2O (80 mL), compound 16 (8.01 g) and potassium bicarbonate (3.9 g). The mixture was cooled to 0˜10° C. CbzCl (5.33 g) was added in portions. The mixture was stirred at room temperature for 1 h. The layers were separated. The organic phase was dried with anhydrous sodium sulfate. After filtration and concentration, the crude product was purified by silica gel column chromatography eluting with EtOAc/heptane=1/15 to give compound 19 as an oil (7.7 g, 70% yield, 99.05% purity).

[0103] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.40-7.34 (m, 7H), 7.17-7.11 (m, 2H), 7.03-7.01 (m, 2H), 6.89-6.81 (m, 2H), 5.33-5.10 (m, 3H), 4.74-4.22 (m, 2H), 4.07-4.04 (m, 1H), 3.19-3.12 (m, 2H), 1.52 (d, J=6.9 Hz, 3H), 1.32-1.15 (m, 3H). Mass: [M+H]+: 446.3.

Example 14: Synthesis of Compound 20

[0104] ##STR00026##

[0105] To a round-bottom flask were added compound 19 (6 g), MeCN (60 mL) and H.sub.2O (60 mL). CAN (36.9 g) was added in portions. The reaction mixture was stirred for 3 h. EtOAc (200 mL) was added. The layers were separated. The organic phase was concentrated to dryness. The crude product was purified by silica gel column chromatography eluting with EtOAc/heptane=1/5 to give compound 20 as a light yellow solid (3.65 g, 56% yield, 95.0% purity).

[0106] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.94-7.78 (m, 1H), 7.51-7.46 (m, 2H), 7.41-7.27 (m, 7H), 7.24-7.15 (m, 3H), 7.02-6.97 (m, 1H), 5.47-5.46 (m, 1H), 5.27-5.19 (m, 2H), 4.06-4.01 (m, 2H), 1.49-1.34 (m, 3H), 1.10-1.06 (m, 3H).

[0107] Mass: [M−H.sub.2O+H].sup.+: 458.3.

Example 15: Synthesis of Compound 30

[0108] ##STR00027##

[0109] To a round-bottom flask were added compound 18 (3.5 g), acetic acid (12 mL) and 33% HBr—AcOH solution (12 mL). The mixture was stirred at room temperature. After completion of the reaction, EtOAc (100 mL) was added and the layers were separated. The organic phase was washed with 20% potassium carbonate aqueous solution. The organic phase was concentrated to dryness. The crude product was purified by silica gel column chromatography eluting with EtOAc/heptane=1/5 to give compound 30 as a light yellow solid (2.05 g, 86% yield, 99.5% purity).

[0110] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 11.61 (s, 1H), 8.31-8.29 (m, 1H), 7.57-7.56 (m, 1H), 7.53-7.47 (m, 3H), 7.29-7.25 (s, 1H), 7.20-7.18 (m, 2H), 4.45 (d, J=7.1 Hz, 2H), 2.63 (s, 3H), 1.39 (t, J=7.1 Hz, 3H).

[0111] Mass: [M+H].sup.+: 324.1.

Example 16: Synthesis of Compound 21

[0112] ##STR00028##

[0113] To a round-bottom flask were added compound 16 (8.0 g), DCM (80 mL), TEA (5.2 g) and p-TsCl (6.9 g). The mixture was stirred at 40° C. overnight. The mixture was quenched with H.sub.2O (80 mL). The layers were separated. The organic phase was concentrated to dryness. The crude product was purified by silica gel column chromatography eluting with EtOAc/heptane=1/9 to give compound 21 as an oil (8.9 g, 77.3% yield, 100% purity).

[0114] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.79-7.77 (m, 2H), 7.53-7.48 (m, 1H), 7.42-7.40 (m, 2H), 7.33-7.31 (m, 2H), 7.11-7.10 (m, 1H), 7.02-7.00 (m, 1H), 6.91-6.89 (m, 2H), 6.78-6.75 (m, 1H), 6.64-6.63 (m, 1H), 4.97-4.92 (m, 1H), 4.57-4.53 (m, 1H), 4.26-4.20 (m, 2H), 3.16-2.97 (m, 2H), 1.50-1.47 (m, 3H), 1.31-1.26 (m, 3H).

[0115] Mass: [M+H].sup.+: 452.7.

Example 17: Synthesis of Compound 22

[0116] ##STR00029##

[0117] To a round-bottom flask were added compound 21 (6 g), MeCN (60 mL) and H.sub.2O (60 mL). CAN (36.9 g) was added in portions. The reaction mixture was stirred for 3 h. EtOAc (60 mL) was added. The layers were separated. The organic phase was concentrated to dryness. The crude product was purified by silica gel column chromatography eluting with EtOAc/heptane=1/8 to give compound 22 as a light yellow solid (2.9 g, 47% yield, 93.0% purity).

[0118] Mass: [M−H.sub.2O+H].sup.+: 464.3.

Example 18: Synthesis of Compound 30

[0119] ##STR00030##

[0120] To a round-bottom flask were added compound 22 (2.9 g), 33% HBr—AcOH solution (12 mL) and phenol (0.59 g). The mixture was stirred at room temperature. After completion of the reaction, EtOAc (30 mL) was added. The layers were separated. The organic phase was washed with 20% potassium carbonate aqueous solution. The organic phase was concentrated to dryness. The crude product was purified by silica gel column chromatography eluting with EtOAc/heptane=1/5 to give compound 30 as a light yellow solid (1.51 g, 74% yield, 96.2% purity).

[0121] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 11.61 (s, 1H), 8.31-8.29 (m, 1H), 7.57-7.56 (m, 1H), 7.53-7.47 (m, 3H), 7.29-7.25 (s, 1H), 7.20-7.18 (m, 2H), 4.45 (d, J=7.1 Hz, 2H), 2.63 (s, 3H), 1.39 (t, J=7.1 Hz, 3H).

[0122] Mass: [M+H].sup.+: 324.1.

Example 19: Synthesis of Compound 23

[0123] ##STR00031##

[0124] To a reactor were compound 15 (6.0 g), EtOH (60 mL), acetic anhydride (3.96 g) and 10% Pd/C (0.6 g). The reactor was degassed and refilled with H.sub.2 three times. The mixture was stirred at room temperature under H.sub.2 (3.0˜4.0 MPa). After completion of the reaction, the mixture was filtered. The filtrate was concentrated to dryness. The crude product was purified by silica gel column chromatography eluting with EtOAc/heptane=1/6 to give compound 23 as a white solid (4.2 g, 57.0% yield, purity 97.5%).

[0125] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.39-7.34 (m, 2H), 7.19-7.14 (m, 2H), 7.04-7.01 (m, 2H), 6.91-6.82 (m, 2H), 5.64-4.22 (m, 2H), 4.26-4.22 (m, 2H), 3.17-3.14 (m, 2H), 2.26-2.17 (m, 3H), 1.58-1.42 (m, 3H), 1.44-1.31 (m, 3H).

[0126] Mass: [M+H].sup.+: 354.3.

Example 20: Synthesis of Compound 24

[0127] ##STR00032##

[0128] To a round-bottom flask were added compound 23 (1 g), MeCN (10 mL) and H.sub.2O (10 mL). CAN (7.8 g) was added in portions. The reaction mixture was stirred at room temperature for 3 h. EtOAc (30 mL) was added. The layers were separated. The organic phase was concentrated to dryness. The crude product was purified by silica gel column chromatography eluting with EtOAc/heptane=1/5 to give compound 24 as a light yellow solid (0.6 g, 55% yield, 98.0% purity).

[0129] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.99-7.97 (m, 1H), 7.47-7.43 (m, 2H), 7.27-7.25 (m, 1H), 7.13-7.11 (m, 2H), 7.00-6.98 (m, 1H), 6.81-6.80 (m, 1H), 5.20 (s, 1H), 5.05-5.04 (m, 1H), 4.22-4.19 (m, 2H), 5.64-4.22 (m, 2H), 4.26-4.22 (m, 2H), 3.17-3.14 (m, 2H), 2.26-2.17 (m, 3H), 1.58-1.42 (m, 3H), 1.44-1.31 (m, 3H).

[0130] Mass: [M+H].sup.+: 384.6.

Example 21: Synthesis of Compound 30

[0131] ##STR00033##

[0132] To a round-bottom flask were compound 24 (30 mg), THF (2 mL) and p-toluene sulfonic acid (15 mg). The mixture was stirred and heated to 60˜70° C. The target product was detected by HPLC and LCMS.

[0133] Mass: [M+H].sup.+: 324.1.

Example 22: Synthesis of Compound 25

[0134] ##STR00034##

[0135] To a round-bottom flask were added compound 16 (12 g), DCM (120 mL), TEA (5.8 g) and benzoyl chloride (8.2 g). The mixture was stirred at room temperature. After completion of the reaction, the mixture was quenched with H.sub.2O (30 mL). The layers were separated. The organic phase was concentrated to dryness. The crude product was purified by silica gel column chromatography eluting with EtOAc/heptane=1/5 to give compound 25 as a white solid (14.5 g, 89.7% yield, 97.5% purity).

[0136] .sup.1H NMR (400 MHz, DMSO-d6) δ 7.48-7.22 (m, 8H), 7.13-6.78 (m, 5H), 5.54-4.72 (m, 2H), 4.24-3.98 (m, 2H), 3.38-3.32 (m, 1H), 3.19-3.10 (m, 1H), 1.48-1.35 (m, 3H), 1.29-1.08 (m, 3H).

[0137] Mass: [M+H].sup.+: 416.3.

Example 23: Synthesis of Compound 26

[0138] ##STR00035##

[0139] To a round-bottom flask were added compound 16 (10 g), THF (150 mL), H.sub.2O (150 mL), sodium bicarbonate (4.0 g), and propyl chlorocarbonate (4.7 g). The mixture was stirred at room temperature. After completion of the reaction, EtOAc (200 mL) was added. The layers were separated. The organic phase was concentrated to dryness. The crude product was purified by silica gel column chromatography eluting with EtOAc/heptane=1/8 to give compound 26 as a light yellow oil (9.9 g, 77.0% yield, 99.8% purity).

[0140] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.38-7.33 (m, 2H), 7.16-7.10 (m, 2H), 7.03-7.00 (m, 2H), 6.89-6.84 (m, 2H), 5.30-5.13 (m, 1H), 4.70-4.49 (m, 1H), 4.26-4.18 (m, 2H), 4.11-4.02 (m, 2H), 3.17-3.12 (m, 2H), 1.75-1.60 (m, 2H), 1.52-1.45 (m, 3H), 1.33-1.26 (m, 3H), 1.01-0.92 (m, 3H).

[0141] Mass: [M+H].sup.+: 398.3.

Example 24: Synthesis of Compound 27

[0142] ##STR00036##

[0143] To a round-bottom flask were added compound 26 (6 g), MeCN (60 mL) and H.sub.2O (60 mL). CAN (41.4 g) was added in portions. The reaction mixture was stirred for 3 h. EtOAc (100 mL) was added. The layers were separated. The organic phase was concentrated to dryness. The crude product was purified by silica gel column chromatography eluting with EtOAc/heptane=1/8 to give compound 27 as a light yellow solid (4.9 g, 96.3% yield, 75.0% purity).

[0144] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.02-7.90 (m, 1H), 7.48-7.43 (m, 2H), 7.30-7.26 (m, 1H), 7.14-7.10 (m, 2H), 7.01-6.98 (m, 1H), 6.83-6.81 (m, 1H), 5.38-5.32 (m, 1H), 4.27-4.26 (m, 2H), 4.20-4.09 (m, 2H), 1.76-1.66 (m, 2H), 1.57-1.54 (m, 3H), 1.23-1.19 (m, 2H), 1.01-0.97 (m, 3H).

[0145] Mass: [M−H.sub.2O+H].sup.+: 410.3.

Example 25: Synthesis of Roxadustat

[0146] ##STR00037##

[0147] To a pressure tube were added compound 30 (2 g), glycine (1.4 g) and sodium methylate. The reaction mixture was heated to 110-120° C. for 4 h. The reaction was cooled to room temperature. The target compound roxadustat was confirmed by HPLC and LC-MS.

[0148] Compound Roxadustat: Mass: [M−H].sup.−: 351.1.