KINASE ACTIVITY REGULATING COMPOUND INTERMEDIATES PREPARATION METHOD

Abstract

The present application relates to a preparation method of intermediate compounds with formula II and formula III of a compound (N-{3-[3-(9H-purin-6-yl) pyridin-2-ylamino]-4-chloro-2-fluorophenyl}-3-fluoropropane-1-sulfonamide) for regulating kinase activity.

##STR00001##

Claims

1. A compound of Formula VI, or a salt or solvate thereof, ##STR00030## wherein R is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein each group is optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, halogen-substituted lower alkyl, cycloalkyl, halogen-substituted cycloalkyl, lower alkoxy, halogen-substituted lower alkoxy, lower alkylthio, halogen-substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkylamino, and aryl and heteroaryl both of which are optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, amino, lower alkyl, lower alkoxy and lower alkylthio.

2. A Compound of Formula VIII or Formula VIIIa, or a salt or solvate thereof, ##STR00031## wherein R is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein each group is optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, halogen-substituted lower alkyl, cycloalkyl, halogen-substituted cycloalkyl, lower alkoxy, halogen-substituted lower alkoxy, lower alkylthio, halogen-substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkylamino, and heteroaryl which is optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, amino, lower alkyl, lower alkoxy and lower alkylthio.

3. A compound of Formula X, or a salt or solvate thereof, ##STR00032##

4. A method for preparing a compound of Formula III, comprising reacting a compound of Formula X according to claim 3 to prepare the compound of Formula III, ##STR00033##

5. The method according to claim 4, further comprising reacting a compound of Formula IX with N,N-carbonyldiimidazole (CDI), and then adding NH.sub.3 to prepare the compound of Formula X, ##STR00034##

6. The method according to claim 5, further comprising reacting a compound of Formula VIII to prepare the compound of Formula IX, ##STR00035## or reacting a compound of Formula Villa to prepare the compound of Formula IX, ##STR00036## wherein each R is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein each group is optionally substituted with one or more substituents selected from the group consisting of halogen, OH, NH.sub.2, lower alkyl, halogen-substituted lower alkyl, cycloalkyl, halogen-substituted cycloalkyl, lower alkoxy, halogen-substituted lower alkoxy, lower alkylthio, halogen-substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkylamino, and aryl and heteroaryl both of which are optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, amino, lower alkyl, lower alkoxy and lower alkylthio.

7. The method according to claim 6, further comprising reacting a compound of Formula II with 3-fluoro-1-propylsulfonyl chloride to prepare the compound of Formula VIIIa, ##STR00037## wherein R is as defined in claim 6, or reacting the compound of Formula II with 3-fluoro-1-propylsulfonyl chloride to prepare the compound of Formula VIII, ##STR00038## wherein R is as defined in claim 6.

8. The method according to claim 7, wherein further comprising reacting a compound of Formula VI to prepare the compound of Formula II: ##STR00039## wherein R is as defined in claim 6.

9. The method according to claim 8, wherein further comprising: (1) reacting a compound of Formula IV with 2,5-hexanedione to prepare a compound of Formula V, and (2) reacting the compound of Formula V with a compound of Formula VII to prepare the compound of Formula VI, ##STR00040## wherein R is as defined in claim 6, and X is selected from halogen.

10. The method according to claim 7, further comprising the following steps: (1) reacting a compound of Formula IV with 2,5-hexanedione to prepare a compound of Formula V, (2) reacting the compound of Formula V with a compound of Formula VII to prepare a compound of Formula VI, and (3) reacting the compound of Formula VI to prepare the compound of Formula II, ##STR00041## wherein R is as defined in claim 6, and X is selected from halogen.

11. The method according to claim 10, wherein in step (1), the compound of Formula IV is reacted with 2,5-hexanedione in the presence of a catalyst.

12. The method according to claim 10, wherein in step (3), the compound of Formula VI is reacted in the presence of a reagent selected from the group consisting of hydroxylamine hydrochloride, hydroxylamine hydrochloride and a base, and hydrochloric acid and a base, wherein hydrochloric acid is first added to react for a period of time, and then the base was added, when the reagent is hydrochloric acid and the base.

13. A method for preparing a compound of Formula VIII according to claim 2, comprising reacting a compound of Formula II with 3-fluoro-1-propylsulfonyl chloride to prepare the compound of Formula VIII, ##STR00042## wherein R is as defined in claim 2.

14. A method for preparing a compound of Formula VIIIa according to claim 2, comprising reacting a compound of Formula II with 3-fluoro-1-propylsulfonyl chloride to prepare the compound of Formula VIIIa, ##STR00043## wherein R is as defined in claim 2. ##STR00044##

15. The method according to claim 5, further comprising reacting a compound of Formula VIII to prepare the compound of Formula IX, ##STR00045## or reacting a compound of Formula VIIIa to prepare the compound of Formula IX, ##STR00046## wherein each R is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein each group is optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, halogen-substituted lower alkyl, cycloalkyl, halogen-substituted cycloalkyl, lower alkoxy, halogen-substituted lower alkoxy, lower alkylthio, halogen-substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkylamino, and heteroaryl which is optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, amino, lower alkyl, lower alkoxy and lower alkylthio. ##STR00047##

16. A method for preparing a compound of Formula X according to claim 3, comprising reacting a compound of Formula IX with N,N-carbonyldiimidazole, and then adding NH.sub.3 to prepare the compound of Formula X, ##STR00048##

17. The method according to claim 4, further comprising reacting a compound of Formula IX with N,N-carbonyldiimidazole, and then adding NH.sub.3 to prepare a compound of Formula X ##STR00049##

18. The method according to claim 4, further comprising the following steps: (1) reacting a compound of Formula IV with 2,5-hexanedione to prepare a compound of Formula V, (2) reacting the compound of Formula V with a compound of Formula VII to prepare a compound of Formula VI, (3) reacting the compound of Formula VI to prepare a compound of Formula II, (4) reacting the compound of Formula II with 3-fluoro-1-propylsulfonyl chloride to prepare a compound of Formula VIII, (5) reacting the compound of Formula VIII to prepare a compound of Formula IX, and (6) reacting the compound of Formula IX with N,N-carbonyldiimidazole, and then adding NH.sub.3 to prepare a compound of Formula X, ##STR00050##

19. The method according to claim 4, further comprising the following steps: (1) reacting a compound of Formula IV with 2,5-hexanedione to prepare a compound of Formula V, (2) reacting the compound of Formula V with a compound of Formula VII to prepare a compound of Formula VI, (3) reacting the compound of Formula VI to prepare a compound of Formula II; (4) reacting the compound of Formula II with 3-fluoro-1-propylsulfonyl chloride to prepare a compound of Formula VIIIa, (5) reacting the compound of Formula VIIIa to prepare a compound of Formula IX, and (6) reacting the compound of Formula IX with N,N-carbonyldiimidazole, and then adding NH.sub.3 to prepare a compound of Formula X, ##STR00051##

Description

EXAMPLES

Example 1

Preparation of 1-(4-chloro-2-fluorophenyl)-2,5-dimethyl-1H-pyrrole (Formula V)

[0166] ##STR00021##

[0167] To a 5 L three-necked reaction flask equipped with a water segregator was added 4-chloro-2-fluoroaniline (598 g, 4.11 mol), 2,5-hexanedione (518 g, 4.54 mol) and toluene (3.0 L), and stirred for 10 minutes until the system was uniformly mixed. A catalytic amount of p-toluenesulfonic acid (1.4 g) was added, and heated under reflux for 2 hours. After cooling to room temperature, the system was washed successively with water (1 L) and saturated brine (1 L), and was dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was removed through concentration in vacuo. The resulting residue was concentrated under reduced pressure to obtain a colourless and clear liquid (850 g, 92% yield). The liquid product was rapidly solidified upon cooling.

[0168] .sup.1H NMR (CDCl.sub.3):7.28-7.18 (3H, m), 5.93 (2H, s), 2.00 (6H, s).

Example 2

Preparation of ethyl 6-chloro-3-(2,5-dimethyl-1H-pyrrol-1-yl)-2-fluorobenzoate (Formula VI-0)

[0169] ##STR00022##

[0170] To a 3 L three-necked reaction flask equipped with a constant pressure dropping funnel was added the compound of Formula V (224 g, 1.00 mol) and dried tetrahydrofuran (1.3 L), was stirred for 5 minutes until the system was uniformly mixed. The reaction system was degassed by using nitrogen gas and cooled to 30 C., and thereto was added n-butyllithium solution (2.4 mol/L, 438 mL) slowly and dropwise upon keeping the reaction temperature of the system below 30 C. After the addition was completed, the system was stirred continuously for 1 hour at this temperature. Ethyl chloroformate (217 g, 2.00 mol) was dissolved in dried tetrahydrofuran (220 mL), degassed by using nitrogen gas, and cooled to 30 C. Then, to the above system was added the solution of ethyl chloroformate dropwise under the protection of nitrogen gas, during which the reaction temperature of the system was kept below 30 C. After the addition was completed, the system was stirred continuously for 30 minutes, and thereto was added a saturated aqueous solution of ammonium chloride (450 mL), and then the system was naturally warmed to room temperature. Ethyl acetate (1.5 L) and water (3.0 L) were added, and the phases were separated. The aqueous phase was extracted with ethyl acetate (1.5 L). The organic phase was combined, washed with saturated brine (2.0 L), and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was removed through concentration in vacuo. The resulting residue was concentrated under reduced pressure to obtain a colorless and clear liquid (266 g, yield: 90%). The liquid product was rapidly solidified upon cooling.

[0171] .sup.1H NMR (CDCl.sub.3):7.33-7.23 (2H, m), 5.93 (2H, s), 4.47 (2H, q), 2.00 (6H, s), 1.43-1.39 (3H, m).

Example 3

Preparation of ethyl 3-amino-6-chloro-2-fluorobenzoate compound (Formula II-0)

[0172] ##STR00023##

[0173] To a 3 L three-necked reaction flask were added the compound of Formula VI-0 (286 g, 0.96 mol), ethanol (1.2 L) and water (400 mL), and uniformly stirred. Triethylamine (389 g, 3.84 mol) and hydroxylamine hydrochloride (997 g, 14.4 mol) were added. The reaction system was vigorously stirred at a temperature of 80 C. for 24 hours, concentrated under reduced pressure to remove most of ethanol. Water (3.0 L) and ethyl acetate (1.5 L) were added, and stirred, and the phases were separated. The resulting aqueous phase was extracted with ethyl acetate(1. L) twice. The organic phase was combined, washed with saturated brine (2 L), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a colorless liquid (140 g, yield: 90%).

[0174] .sup.1H NMR (CDCl.sub.3): 6.97 (1H, dd, J=8.8 Hz, J=0.8 Hz), 6.73 (1H, t, J=9.2 Hz), 4.44 (2H, q, J=6.8 Hz), 3.84 (2H, s), 1.41-1.38 (3H, m).

Example 4

Preparation of ethyl 6-chloro-2-fluoro-3-[3-fluoro-N-(3-fluoro-propylsulfonyl)propylsulfonamido]benzoate (Formula VIII-0)

[0175] ##STR00024##

[0176] To a 3 L three-necked reaction flask were added the compound of Formula II-0 (162 g, 0.74 mol), triethylamine (244 g, 2.22 mol), and dichloromethane (970 mL), and stirred for 10 minutes until the system was uniformly mixed. Then 3-fluoro-1-propylsulfonyl chloride (244 g, 1.52 mol) was added slowly and dropwise, upon controlling the reaction temperature of the system below 20 C. After the addition was completed, the system was stirred at room temperature for 3 hours. The reaction solution was washed successively with 1 mol/L hydrochloric acid (2.5 L), water (2.0 L) and saturated brine (1.0 L), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a light brown liquid (329 g, 95%).

[0177] .sup.1H NMR (CDCl.sub.3):7.40-7.39 (1H, m), 7.35-7.28 (1H, m), 4.65-4.63 (2H, m), 4.53-4.44 (4H, m), 3.80-3.68 (4H, m), 2.37-2.27 (4H, m), 1.43-1.38 (3H, m).

Example 5

Preparation of 6-chloro-2-fluoro-3-(3-fluoro-propylsulfonamido)benzoic acid (Formula IX)

[0178] ##STR00025##

[0179] To a 5 L three-necked flask were added the compound of Formula VIII-0 (309 g, 0.66 mol) and tetrahydrofuran (1.5 L), and stirred at room temperature for 10 minutes until the system was uniformly mixed. The system was cooled in an ice-water bath, and then 2 mol/L aqueous solution of potassium hydroxide (1.65 L, 3.3 mol) was added dropwise, during which the reaction temperature of the system was controlled below 10 C. The ice-water bath was removed after the addition was completed, and the system was stirred at room temperature for 3 days. The system was placed in an ice-water bath again, and then a concentrated hydrochloric acid was added dropwise until a pH value is less than 3, during which the temperature of the system was controlled below 10 C. The system was filtered, and the resulting solid was slurried in 2 L water, filtered again, washed with 2-3 L water, and dried to obtain the product (309 g, 95%).

[0180] .sup.1H NMR (CDCl.sub.3):10.04 (1H, s), 7.50 (1H, t, J=8.8 Hz), 7.39 (1H, dd, J=8.8 Hz, J=1.2 Hz), 4.60 (1H, t, J=5.6 Hz), 4.48 (1H, t, J=5.6 Hz), 3.28-3.24 (2H, m), 2.16-2.03 (2H, m).

Example 6

Preparation of ethyl 6-chloro-2-fluoro-3-(3-fluoro-propylsulfonamido)benzoate (Formula VIIIa-0)

[0181] ##STR00026##

[0182] To a 3 L three-necked reaction flask were added the compound of Formula II-0 (190 g, 0.87 mol), pyridine (345 g, 4.36 mol) and dichloromethane (1.9 L), and stirred for 10 minutes until the system was uniformly mixed. Then, a solution of 3-fluoro-1-propylsulfonyl chloride (168 g, 1.05 mol) in dichloromethane (0.34 L) was added slowly and dropwise, during which the reaction temperature of the system was controlled at 20-25 C. After the addition was completed, the system was warmed to 30 C., and reacted at this temperature for 24h. The reaction solution was washed successively with 4 mol/L hydrochloric acid (1.9 L) and saturated brine (1 L), and the organic phase was concentrated in vacuo to obtain a reddish brown liquid (298 g).

[0183] .sup.1H NMR (CDCl.sub.3):7.48 (1H, t), 7.36 (1H, dd), 4.64-4.62 (2H, m),4.58 (1H, t), 4.47 (1H, t), 3.28-3.24 (2H, m), 2.16-2.03 (2H, m), 1.41-1.38 (3H, m).

Example 7

Preparation of 6-chloro-2-fluoro-3-(3-fluoro-propylsulfonamido)benzoic acid (Formula IX)

[0184] ##STR00027##

[0185] To a 5 L three-necked flask were added the compound of Formula VIIIa-0 (298 g, 0.87 mol) and tetrahydrofuran (1.5 L), and stirred at room temperature for 10 minutes until the system was uniformly mixed. The system was cooled to below 0 C., and 2 mol/L aqueous solution of potassium hydroxide (1.7 L) was added dropwise, during which the reaction temperature of the system was controlled below 10 C. After the addition was completed, the system was stirred at a temperature of 35 C. for 3 days, and then cooled, and subsequently the concentrated hydrochloric acid was added dropwise until a pH value is less than 3, during which the temperature of the system was controlled below 10 C. The phases were separated, and the aqueous phase was back-extracted with ethyl acetate (0.6 L) twice. The organic phase was combined, washed with saturated brine (0.9 L), concentrated in vacuo, and dried to obtain the product (259 g, 95%).

Example 8

Preparation of 6-chloro-2-fluoro-3-(3-fluoro-propylsulfonamido)benzamide (Formula X)

[0186] ##STR00028##

[0187] To a 3 L three-necked reaction flask were added the compound of Formula IX (239 g, 0.76 mol), N,N-carbonyldiimidazole (184 g, 1.14 mol) and dried tetrahydrofuran (1.2 L), and heated under reflux for 1 hour. After the reaction was completed, the system was cooled to 0 C., and water (500 mL) was added. The system was stirred at 0 C., and ammonia gas was introduced into the system until the reaction was completed. 500 mL ice water was added, and the concentrated hydrochloric acid was added dropwise to adjust a pH value to 3-4, during which the temperature of the system was controlled to below 15 C. by using an ice-water bath. the phases were separated, and the aqueous phase was extracted with ethyl acetate (1 L) twice. The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was stirred for 2 hours after adding 240 mL ethanol, filtered, and dried to obtain the product (208 g, yield: 87%),of which the purity through HPLC detection is greater than 99% (area normalization method).

[0188] .sup.2H NMR (CDCl.sub.3):9.98 (1H, s), 8.14 (1H, s), 7.87 (1H, s), 7.44-7.42 (1H, m), 7.35-7.32 (1H, m), 4.60 (1H, t, J=5.6 Hz), 4.48 (1H, t, J=5.6 Hz), 3.26-3.22 (2H, m), 2.14-2.06 (2H, m).

Example 9

Preparation of N-(3-amino-4-chloro-2-fluorophenyl)-3-fluoropropane-1-sulfonamide (Formula III)

[0189] ##STR00029##

[0190] To a 3 L three-necked reaction flask were added the compound of Formula X (176 g, 0.56 mol) and tetrahydrofuran (880 ml), and stirred for 10 minutes until the system was uniformly mixed. The system was placed in an ice-water bath, and 4 mol/L aqueous solution of sodium hydroxide (1400 mL, 5.60 mol) was added, and then stirred for 10 minutes. An aqueous solution of sodium hypochlorite (1.05 L, 10% chlorine content) cooled below 5 C. was added portion-wise to the system over 5 minutes, and stirred for an additional 1 hour. The ice-water bath was removed, and the was naturally warmed to room temperature. The system was stirred for an additional 4-5 hours, and sodium thiosulfate (1.12 kg, 4.51 mol) was added, and stirred for 20 minutes until the sodium thiosulfate was completely dissolved. The reaction system was placed in an ice-water bath again, and then the concentrated hydrochloric acid was added dropwise to a pH value of 5-6, during which the temperature of the system was controlled below 20 C. The phases were separated, and the aqueous phase was extracted with ethyl acetate (700 mL) twice. The organic phase was combined, washed successively with water (1.0 L) and saturated brine (1.0 L), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was slurried in 260 mL ethanol, and filtered. The filter cake was washed with about 50-60 ml ethanol, and dried to obtain a white solid (120 g, 75% yield), of which the purity through HPLC detection was greater than 99.5% (area normalization method).

[0191] .sup.1H NMR (CDCl.sub.3):9.66 (1H, s), 7.04 (1H, dd, J=8.4 Hz , J=1.6 Hz), 6.57 (1H, t, J=8.4 Hz), 4.60 (1H, t, J=6.0 Hz), 4.48 (1H, t, J=6.0 Hz), 3.19-3.16 (2H, m), 2.15-2.02 (2H, m).