METHOD FOR PREPARING COAGULATION FACTOR XIA INHIBITOR AND INTERMEDIATE THEREOF

Abstract

The present disclosure involves a method for preparing a coagulation factor XIa inhibitor and an intermediate thereof. Specifically, the present disclosure involves a method for preparing an oxypyridine amide derivative. The method has the advantages of high yield, good product purity, and mild reaction conditions.

Claims

1. A method for preparing a compound of formula AI, the method comprising a step of reacting a compound of formula III and a compound of formula II, ##STR00026## wherein: ring A is an aryl or heteroaryl; each R.sub.1 is identical or different and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, amino, nitro, cyano, hydroxy, hydroxyalkyl, —C(O)R.sub.5, cycloalkyl, heterocyclyl, aryl and heteroaryl; R.sub.2 is selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, cycloalkyloxy, haloalkoxy, amino, nitro, cyano, hydroxy, hydroxyalkyl and alkylthio; L.sub.1 is an alkylene; each R.sub.3 is identical or different and each is independently selected from the group consisting of hydrogen atom, alkyl, alkoxy, oxo, halogen, haloalkyl, haloalkoxy, amino, nitro, cyano, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(O)R.sub.6, —C(O)OR.sub.6, —NHC(O)R.sub.6, —NHC(O)OR.sub.6, —NR.sub.7R.sub.8, —C(O)NR.sub.7R.sub.8, —CH.sub.2NHC(O)OR.sub.6, —CH.sub.2NR.sub.7R.sub.8, —C(O)OCH(R.sub.7)R.sub.8 and —S(O).sub.mR.sub.6; R.sub.4 is selected from the group consisting of hydrogen atom, deuterium atom, halogen, alkyl, alkoxy, amino, nitro, cyano, hydroxy, hydroxyalkyl, cycloalkyl, cycloalkyloxy, heterocyclyl, aryl and heteroaryl; R.sub.5 is selected from the group consisting of hydrogen atom, alkyl, haloalkyl, alkoxy, haloalkoxy, amino, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R.sub.6 is selected from the group consisting of hydrogen atom, alkyl, haloalkyl, hydroxy, amino, cycloalkyl, heterocyclyl, aryl, heteroaryl and carboxy protecting group; R.sub.7 and R.sub.8 are identical or different and are each independently selected from the group consisting of hydrogen atom, alkyl, haloalkyl, cycloalkyl, heterocyclyl, —C(O)OR.sub.6 and —OC(O)OR.sub.9; R.sub.9 is selected from the group consisting of hydrogen atom, alkyl, alkoxy, haloalkyl, haloalkoxy, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl; LG is a leaving group; n is 0, 1, 2, 3 or 4; m is 0, 1 or 2; and s is 0, 1, 2, 3 or 4.

2. The method according to claim 1, wherein the compound of formula III reacts with the compound of formula II in the presence of an alkaline substance.

3. (canceled)

4. The method according to claim 1, wherein the compound of formula II is ##STR00027##

5. The method according to claim 1, wherein the compound of formula II is ##STR00028## wherein Y is selected from the group consisting of hydrogen atom and carboxy protecting group.

6. The method according to claim 1, wherein the compound of formula II is ##STR00029## wherein Y is selected from the group consisting of hydrogen atom and carboxy protecting group.

7. The method according to claim 1, wherein the compound of formula III is ##STR00030## wherein each R.sub.1 is identical or different and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, amino, nitro, cyano, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R.sub.5 is selected from the group consisting of alkyl, cycloalkyl and haloalkyl.

8. The method according to claim 1, wherein the compound of formula III is ##STR00031##

9. The method according to claim 1, wherein the compound of formula III is ##STR00032##

10. The method according to claim 1, wherein the method further comprises a step of reacting a compound of formula IV and a compound of formula V to obtain the compound of formula II, ##STR00033## wherein R.sub.11 is selected from the group consisting of —OR.sub.9 and halogen; and LG′ and LG are identical or different and are each selected from the group consisting of halogen, substituted sulfonyloxy, R.sub.iR.sub.jN—, hydroxy, R.sub.kS—, substituted or unsubstituted phosphoryloxy and substituted formyloxy, wherein R.sub.i and R.sub.j are each independently selected from the group consisting of hydrogen atom, C.sub.1-C.sub.6 alkyl and amino protecting group, and R.sub.k is selected from the group consisting of hydrogen atom and C.sub.1-C.sub.6 alkyl.

11. A compound of formula IIb, ##STR00034## wherein LG is a leaving group; and Y is selected from the group consisting of hydrogen atom and carboxy protecting group; and and when LG is a hydroxy, Y is not a methyl.

12. A compound of formula IIc, ##STR00035## wherein LG is a leaving group; and Y is selected from the group consisting of hydrogen atom and carboxy protecting group.

13. A method for preparing a compound of formula IIb ##STR00036## the method comprising a step of reacting a compound of formula IVb or a salt thereof and a compound of formula Vb or a salt thereof, ##STR00037## wherein R.sub.11 is selected from the group consisting of —OR.sub.9 and halogen; R.sub.9 is selected from the group consisting of hydrogen atom, alkyl, alkoxy, haloalkyl, haloalkoxy, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl; and LG′ and LG are identical or different and are each selected from the group consisting of halogen, substituted sulfonyloxy, R.sub.iR.sub.jN—, hydroxy, R.sub.kS—, substituted or unsubstituted phosphoryloxy and substituted formyloxy, wherein R.sub.i and R.sub.j are each independently selected from the group consisting of hydrogen atom, C.sub.1-C.sub.6 alkyl and amino protecting group, and R.sub.k is selected from the group consisting of hydrogen atom and C.sub.1-C.sub.6 alkyl.

14. A method for preparing a compound of formula IIc, ##STR00038## the method comprising a step of reacting a compound of formula IVc or a salt thereof and a compound of formula Vb or a salt thereof, ##STR00039## wherein R.sub.11 is selected from the group consisting of —OR.sub.9 and halogen; R.sub.9 is selected from the group consisting of hydrogen atom, alkyl, alkoxy, haloalkyl, haloalkoxy, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl; and LG′ and LG are identical or different and are each selected from the group consisting of halogen, substituted sulfonyloxy, R.sub.iR.sub.jN—, hydroxy, R.sub.kS—, substituted or unsubstituted phosphoryloxy and substituted formyloxy, wherein R.sub.i and R.sub.j are each independently selected from the group consisting of hydrogen atom, C.sub.1-C.sub.6 alkyl and amino protecting group, and R.sub.k is selected from the group consisting of hydrogen atom and C.sub.1-C.sub.6 alkyl.

15. A method for preparing a compound of formula I or the pharmaceutically acceptable salt thereof, the method comprising a step of reacting the compound of formula IIIb and the compound of formula IIb to obtain a compound of formula BI, wherein LG is a leaving group, and wherein Y is selected from the group consisting of hydrogen atom and carboxy protecting group, ##STR00040##

16. The method according to claim 15, wherein the compound of formula IIIb reacts with the compound of formula IIb in the presence of an alkaline substance.

17. The method according to claim 15, wherein the method further comprises a step for preparing the compound of formula IIb.

18. The method according to claim 15, wherein LG is a substituted sulfonyloxy, and the method further comprises a step of converting a compound of formula IId into the compound of formula IIb, ##STR00041##

19. The method according to claim 15, wherein Y is a carboxy protecting group, and the method further comprises a step of removing the carboxy protecting group of the compound of formula BI.

20. A method for preparing a compound of formula VI or the pharmaceutically acceptable salt thereof, the method comprising a step of reacting the compound of formula IIIc and the compound of formula IIc to obtain a compound of formula BVI, wherein LG is a leaving group, and wherein Y is selected from the group consisting of hydrogen atom and carboxy protecting group, ##STR00042##

21. The method according to claim 20, wherein the compound of formula IIIc reacts with the compound of formula IIc in the presence of an alkaline substance.

22. The method according to claim 20, wherein the method further comprises a step for preparing the compound of formula IIc.

23. The method according to claim 20, LG is a substituted sulfonyloxy, and the method also comprises a step of converting a compound of formula IIe into the compound of formula IIc, ##STR00043##

24. The method according to claim 20, wherein Y is a carboxy protecting group, and the method further comprises a step of removing the carboxy protecting group of the compound of formula BVI.

25. A compound of formula IVd, ##STR00044## wherein Y1 is selected from the group consisting of hydrogen atom and carboxy protecting group; and Y2 is selected from the group consisting of hydrogen atom and hydroxy protecting group.

26. A method for preparing a compound of formula Ivd, ##STR00045## the method comprising a step of converting a compound of formula IVe into the compound of formula IVd, ##STR00046##

Description

DETAILED DESCRIPTION OF THE INVENTION

[0113] The present disclosure will be explained in detail below in conjunction with the specific examples, allowing those skilled in the art to understand the disclosure comprehensively. The specific examples are only used to illustrate the technical solution of the present disclosure, and will not limit the present disclosure in any way.

Example 1

[0114] ##STR00022##

[0115] Step 1

[0116] Compound 1 (40.1 g, 292.41 mmol) was dissolved in 500 mL of DMF, followed by the addition of potassium carbonate (40.41 g, 292.41 mmol). The reaction solution was cooled in an ice bath, followed by the addition of propenyl bromide (35.37 g, 292.41 mmol). The reaction solution was reacted at room temperature. After completion of the reaction, 1500 mL of water was added to the reaction solution, and the resulting solution was extracted with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution and water successively, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=10:1). The product was collected and concentrated to obtain compound 2 (33.7 g, yield: 65%).

[0117] MS m/z (LC-MS): 178.2[M+1]

[0118] Step 2

[0119] Compound 2 (532 mg, 3 mmol), D-phenyllactic acid (compound 3, 500 mg, 3 mmol) and methylboronic acid (18 mg, 0.3 mmol) were added to a reaction flask, followed by the addition of 20 mL of toluene and 108 μL of water. The reaction solution was warmed up to 140° C., and reacted under reflux. After completion of the reaction, the reaction solution was cooled to room temperature, followed by the addition of 100 mL of dichloromethane. The solution was washed with 0.5 M hydrochloric acid solution and 1 M sodium bicarbonate solution successively, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by Combiflash (eluent: 100% dichloromethane) to obtain compound 4 (829 mg, yield: 84.9%).

[0120] MS m/z (LC-MS): 326.2[M+1]

[0121] Step 3

[0122] Compound 4 (4.3 g, 13.22 mmol) was dissolved in 50 mL of tetrahydrofuran. The resulting solution was purged with argon, cooled in an ice bath, followed by the addition of triethylamine (2.67 g, 26.43 mmol) and the dropwise addition of methylsulfonyl chloride (2.27 mg, 19.82 mmol). The reaction solution was reacted in an ice bath. After completion of the reaction, 1 M dilute hydrochloric acid solution was added to the reaction solution to quench the reaction. Two phases were separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the resulting crude product was pulped in methyl tert-butyl ether, filtered, and dried to obtain compound 5 (4.6 g, yield: 86.27%).

[0123] MS m/z (LC-MS): 404.1[M+1]

Example 2

[0124] ##STR00023##

[0125] Step 1

[0126] Compound IIIb (6.54 g, 23.55 mmol, prepared according to the method disclosed in the patent application WO2018041122) was dissolved in 200 mL of tetrahydrofuran, followed by the addition of tetrabutylammonium iodide (7.84 g, 23.55 mmol) and potassium tert-butoxide (3.96 g, 35.32 mmol). Under an argon atmosphere, the solution was cooled to 0° C., followed by the addition of compound 5 (9.5 g, 23.55 mmol). The reaction solution was kept at this temperature and reacted. After completion of the reaction, 1 M hydrochloric acid solution was added to the reaction solution to quench the reaction, followed by the addition of 50 ml of ethyl acetate and 100 ml of water under stirring. Two phases were separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate:dichloromethane=10:3:1) to obtain compound 6 (8.1 g, yield: 58.8%, optical purity: 95.7%).

[0127] Step 2

[0128] Compound 6 (8.10 g, 13.85 mmol) was dissolved in 81 mL of tetrahydrofuran, and the solution was cooled to 0° C. under an argon atmosphere. Pyrrolidine (984.67 mg, 13.85 mmol) and tetrakis(triphenylphosphine) palladium (1.60 g, 1.38 mmol) were added, and the reaction solution was stirred at 0° C. After completion of the reaction, 1 M hydrochloric acid solution was added to the reaction solution to quench the reaction. 40 ml of water was added, and the solution was stirred and filtered. Two phases were separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and 80 mL of methanol was added to the resulting residue. The solution was warmed up to 50° C., and pulped for 30 minutes. The solution was naturally cooled to room temperature, stirred for 30 minutes, and filtered. The filter cake was collected, and dried to obtain the compound of formula I (6.48 g, yield: 85.88%, optical purity: 93.8%).

Example 3

[0129] ##STR00024##

[0130] Step 1

[0131] 40 g of (R)-malic acid was added to a reaction flask, followed by the addition of 250 g of trifluoroacetic anhydride. The reaction solution was reacted at room temperature for 2 hours, followed by the removal of solvent by evaporation. BnOH (167 mL) was added, and the reaction solution was stirred at room temperature. After completion of the reaction, sodium bicarbonate solution was added to the system, which was then extracted with ethyl acetate. The aqueous phase was adjusted to be acidic with hydrochloric acid, and extracted with ethyl acetate. The organic phases were collected, combined, and concentrated to obtain compound 8 (69 g).

[0132] Step 2

[0133] Compound 8 (69 g) was added to a reaction flask, followed by the addition of 65.1 g of acetic anhydride and 490 mg of anhydrous ferric chloride. The reaction solution was reacted at room temperature. After completion of the reaction, acetonitrile was added to the reaction solution. The solution was added to saturated sodium bicarbonate solution, stirred, and extracted with ethyl acetate. The aqueous phase was adjusted to be acidic with hydrochloric acid, and extracted with ethyl acetate. The organic phases were collected, combined, and concentrated to obtain compound 9 (56.5 g, yield: 70%).

[0134] Step 3

[0135] Compound 9 (56.5 g) was added to a reaction flask, followed by the addition of 200 mL of tetrahydrofuran. The solution was cooled to 0° C., followed by the dropwise addition of 10.0 M borane dimethyl sulfide solution (42 mL). After completion of the addition, the reaction solution was stirred at room temperature. After completion of the reaction, methanol was added to quench the reaction. The system was concentrated to obtain compound 10 (49.4 g, yield: 92%).

[0136] Step 4

[0137] Compound 10 (29 g), tert-butyl trichloroacetimide (37.6 g) and dichloromethane (230 mL) were added to a reaction flask, and stirred to dissolve. The solution was cooled to −40° C., followed by the addition of TBSOTf (3.9 mL). After completion of the reaction, triethylamine was added to quench the reaction. The system was concentrated, and the resulting residue was pulped in ethyl acetate, filtered, and concentrated to obtain compound 11 (23.4 g, yield: 66%).

[0138] MS m/z (LC-MS): 331.05[M+23]

[0139] Step 5

[0140] Compound 11 (26.5 g), 10% Pd/C (7.9 g) and tetrahydrofuran (86 mL) were added to a reaction flask and stirred. A hydrogenation reaction was carried out at 1 atm. After completion of the reaction, the reaction solution was filtered, and purified by column chromatography (eluent: DCM:CH.sub.3OH=5:1) to obtain compound 12 (15.8 g, yield: 85%).

[0141] MS m/z (LC-MS): 219.05[M+1]

[0142] Step 6

[0143] Compound 12 (6.04 g), dichloromethane (60 mL) and DMF (0.1 mL) were added to a reaction flask, followed by the addition of 3.5 mL of oxalyl chloride. The reaction solution was heated to 30° C., and reacted for one hour. The reaction solution was concentrated to dryness, and dissolved in 30 mL of dichloromethane for later use.

[0144] 5.03 g of compound 2, 50 mL of dichloromethane and 11.43 mL of DIEA were added to a reaction flask and stirred, and then the above dichloromethane solution was added. After completion of the reaction, 100 mL of dichloromethane was added. The solution was washed with saturated sodium bicarbonate solution, and dried over anhydrous sodium sulfate. The organic phase was concentrated to obtain compound 13 (9.5 g).

[0145] MS m/z (LC-MS): 378.10[M+1]

[0146] Step 7

[0147] Compound 13 (9.18 g) and isopropanol (90 mL) were added to a reaction flask, followed by the addition of 6.72 g of potassium carbonate. The reaction solution was heated to 50° C. and stirred. After completion of the reaction, the reaction solution was filtered. The filtrate was concentrated to dryness, and 100 mL of methyl tert-butyl ether was added to dissolve the residue. The solution was filtered, and the filtrate was concentrated to dryness to obtain compound 14 (7.76 g).

[0148] MS m/z (LC-MS): 336.10[M+1]

[0149] Step 8

[0150] Compound 14 (7.76 g) and dichloromethane (80 mL) were added to a reaction flask, followed by the addition of 6.43 mL of triethylamine and 7.69 g of p-nitrobenzenesulfonyl chloride. The reaction solution was stirred at room temperature. After completion of the reaction, 100 mL of dichloromethane was added. The solution was washed with saturated sodium bicarbonate solution and saturated ammonium chloride solution successively, and dried over anhydrous sodium sulfate. The reaction system was concentrated, and the residue was pulped in n-heptane:dichloromethane=50:1 (30 mL), filtered, and dried to obtain compound 15 (8.23 g).

[0151] MS m/z (LC-MS): 521.00[M+1]

Example 4

[0152] ##STR00025##

[0153] Step 1

[0154] Compound IIIc (50 mg, prepared according to the method disclosed in the patent application WO2018041122) was dissolved in 1 mL of dioxane, followed by the addition of compound 15 (9.5 g, 23.55 mmol) and Cs2CO3 powder (168 mg). The reaction solution was reacted at room temperature. After completion of the reaction, the reaction solution was filtered. The filtrate was concentrated to dryness, and the resulting residue was purified by column chromatography (eluent: ethyl acetate:petroleum ether=1:1) to obtain compound 16 (65 mg, optical purity: 96.5%).

[0155] Step 2

[0156] Compound 16 (1 g) was dissolved in 6 mL of tetrahydrofuran, followed by the addition of 0.148 mL of pyrrolidine and 24 mg of Pd(dppf)Cl2 under stirring. The reaction solution was reacted at room temperature. After completion of the reaction, an appropriate amount of methyl tert-butyl ether was added, and the solution was extracted with saturated aqueous sodium carbonate solution. The aqueous phase was washed with methyl tert-butyl ether, adjusted to be acidic with hydrochloric acid, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain compound VI (0.84 g, yield: 90.6%, optical purity: 98%).

[0157] Since the present disclosure has been described according to specific embodiments, certain modifications and equivalent changes are obvious to those skilled in the art and are included in the scope of the present disclosure.