Processes to produce acalabrutinib

Abstract

The present invention relates to a method for preparing the compound of formula IV, compound of formula XI, and acalabrutinib, a new generation of bruton tyrosine kinase (BTK) inhibitor. ##STR00001##

Claims

1. A process for preparation of compound IV from compound of formula III, ##STR00034## comprising reacting the compound of formula III with an organometallic reagent and trialkyl borate to produce the compound of formula IV, wherein R1 is C.sub.1-20 alkyl or benzyl, and X is Br or I.

2. The process of claim 1, wherein R1 is a substituent selected from the group consisting of methyl, ethyl, propyl, isopropyl and benzyl; and X is Br or I.

3. The process of claim 2, wherein R1 is isopropyl; and X is Br.

4. The process of claim 1, wherein organometallic reagent is selected from the group consisting of butyl lithium, ethyl lithium, pentyl lithium, phenyl lithium, methyl lithium, cyclohexyl lithium, isopropyl magnesium chloride, isopropyl magnesium bromide and the mixtures thereof.

5. The process of claim 4, wherein organometallic reagent is n-butyllithium.

6. A process for preparation of compound III from compound of formula I and compound of formula II, ##STR00035## comprising reacting the compound of formula I with an activating reagent and the compound of formula II in a solvent to produce the compound of formula III; wherein the activating reagent is selected from the group consisting of N,N′-carbonyldiimidazole, methanesulfonyl chloride, p-toluenesulfonyl chloride and p-nitrobenzene sulfonyl chloride; and X is Br or I.

7. The process of claim 6, wherein the solvent is selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, tetrahydrofuran, methyltetrahydrofuran, toluene, xylene, dioxane, dimethyl sulfoxide, N-methylpyrrolidone, sulfolane, methylene chloride and mixtures thereof.

8. The process of claim 7, wherein the solvent is selected from the group consisting of tetrahydrofuran, toluene, and dioxane.

9. A process for preparation of compound IV from compound of formula I and compound of formula II, ##STR00036## comprising steps of coupling of the compound of formula I and the compound of formula II ##STR00037## to produce the compound of formula III; wherein X is Br or I ##STR00038## and reacting the compound of formula III with an organometallic reagent and trialkyl borate to produce the compound of formula IV.

10. A process for preparation of compound VIII from compound of formula VI, ##STR00039## comprising reacting the compound of formula VI with the compound of formula VII or its salt to produce the compound of formula VIII, where Cbz is carboxybenzyl.

11. The process of claim 10, wherein the compound of formula VI is prepared from compound of formula V and oxalyl chloride, ##STR00040##

12. The process of claim 11, wherein the equivalent of oxalyl chloride versus the compound of formula V is from 0.8 to 10.

13. The process of claim 12, wherein the equivalent of oxalyl chloride versus the compound of formula V is from 1.5 to 3.

14. The process of claim 10, wherein the chiral impurity of the compound of formula VIII is not more than 2%.

15. The process of claim 14, wherein the chiral impurity of the compound of formula VIII is not more than 0.5%.

16. A process for preparation of compound X from compound of formula VIII in a solvent, ##STR00041## comprising; reacting the compound of formula VIII ##STR00042## with a dehydrating reagent to produce compound of formula IX ##STR00043## and bromination of the compound of formula IX to produce the compound of formula ##STR00044## where Cbz is carboxybenzyl.

17. The process of claim 16, wherein the solvent is selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, tetrahydrofuran, methyltetrahydrofuran, toluene, xylene, dioxane, dimethyl sulfoxide, N-methylpyrrolidone, sulfolane, methylene chloride and mixtures thereof.

18. The process of claim 17, wherein the solvent is methylene chloride.

19. A process for preparation of compound XI from compound of formula VIII in a solvent, ##STR00045## comprising reacting the compound of formula VIII ##STR00046## with a dehydrating reagent to produce compound of formula IX ##STR00047## and bromination of compound of formula IX to produce the compound of formula X ##STR00048## and reacting the compound of formula X with aqueous ammonia to produce the compound of formula XI ##STR00049## where Cbz is carboxybenzyl.

20. A process for preparation of compound XIV-a or XIV-b from compound of formula IV, ##STR00050## comprising reacting a compound of formula IV with alcohol to produce the compound of formula XIV-a or XIV-b, wherein R1 is C.sub.1-20 alkyl or benzyl.

21. The process of claim 20, wherein alcohol is selected from the group consisting of methanol, ethanol, propanol, isopropanol, and pinacol; wherein R1 is a substituent selected from the group consisting of methyl, ethyl, propyl and isopropyl.

22. The process of claim 20, wherein alcohol is methanol or pinacol, wherein R1 is methyl.

23. The process for preparation of compound XV from compound of formula I and compound of formula II, ##STR00051## comprising steps of: 1) amide formation of the compound of formula I and the compound of formula II ##STR00052## to produce compound of formula wherein X is Br or I ##STR00053## 2) reacting the compound of formula III with an organometallic reagent and trialkyl borate to produce compound of formula IV, or derivative compound of formula XIV-a, compound of formula XIV-b ##STR00054## wherein R1 is a substituent selected from the group consisting of methyl, ethyl, propyl, isopropyl and benzyl; 3) reacting the compound of formula IV, or derivative compound of formula XIV-a, or compound of formula XIV-b, with the compound of formula XI by transition-metal catalyzed cross coupling reaction to produce the compound of formula XII, where Cbz is carboxybenzyl ##STR00055## 4) removal of Cbz protection group of the compound of formula XII to produce the compound of formula XIII ##STR00056## and 5) amide formation of the compound of formula XIII with but-2-ynoic acid to produce the compound of formula XV.

Description

DETAILED DESCRIPTION OF THE PRESENTLY PREFERRED EMBODIMENTS

EXAMPLES

Example 1: Synthesis of Compound III

(1) ##STR00020##

(2) To a mixture of 4-bromobenzoic acid (2.0 g, compound I-a) and triethylamine (1.11 g) in 1,4-dioxane (16 mL), methanesulfonyl chloride (1.25 g) was added dropwise. The mixture was heated to 40° C. and stirred for 2 h. DMAP (1.35 g) and 2-aminopyridine (1.41 g) was added. The mixture was heated to 60° C. and stirred for 3 h. The reaction mixture was quenched with water (20 mL), and extracted with EtOAc twice (2×20 mL). The combined organic phase was concentrated under vacuum. The crude material was purified by silica gel column chromatography using heptane/EtOAc to afford compound III-a (69% yield).

(3) .sup.1H NMR (400 MHz, DMSO) δ 10.90 (s, 1H), 8.40 (dd, J=4.8, 1.1 Hz, 1H), 8.18 (d, J=8.4 Hz, 1H), 8.03-7.93 (m, 2H), 7.91-7.81 (m, 1H), 7.77-7.67 (m, 2H), 7.26-7.11 (m, 1H).

Example 2: Synthesis of Compound III

(4) ##STR00021##

(5) To a round-bottom flask was added 4-bromobenzoic acid (20.0 g, compound I-a), 1,1′-Carbonyldiimidazole (CDI, 19.34 g) and toluene (200 mL). The mixture was heated to 60° C. and stirred for 2 h. 2-Aminopyridine (14.04 g) was added. The mixture was heated to 100° C. and stirred for 4 h. The reaction mixture was washed with saturated Na.sub.2CO.sub.3 aqueous solution, water (twice), and brine. The organic phase was concentrated to 100 mL, cooled to 0.sup.˜5° C., and then stirred for 1 h. After filtration and drying, compound III-a was obtained as a white solid (23 g, 84% yield).

Example 3: Synthesis of Compound IV

(6) ##STR00022##

(7) To a round-bottom flask was added i-PrMgCI solution in THF (10 mL, 2 M) and THF (20 mL). The mixture was cooled to −20.sup.˜-30° C. n-BuLi solution in n-hexane (16.4 mL, 2.5 M) was added dropwise. After 10 min, a solution of compound III-a (5.00 g) in THF (35 mL) was added into the mixture at −20.sup.˜-30° C. and stirred for 20 min. Trimethyl borate (3.75 g) was added at −20.sup.˜-30° C. The reaction mixture was stirred for 16 h at this temperature. The reaction mixture was quenched with saturated NH.sub.4Cl aqueous solution (50 mL), and extracted with EtOAc three times. The combined organic phase was concentrated and concentrated under vacuum. The crude material was purified by silica gel column chromatography using DCM/MeOH to afford compound IV (2.00 g, 45.8% yield).

(8) .sup.1H NMR (400 MHz, DMSO) δ 10.75 (s, 1H), 8.52-8.36 (m, 1H), 8.35-8.17 (m, 2H), 8.11-7.79 (m, 5H), 7.24-7.12 (m, 1H).

Example 4: Synthesis of Compound IV

(9) ##STR00023##

(10) To a round-bottom flask was added compound III-a (1.98 g) and THF (20 mL). The mixture was cooled to −60.sup.˜-70° C. n-BuLi solution in n-hexane (6.8 mL, 2.5 M) was added at −60.sup.˜-70° C., followed by addition of triisopropyl borate (2.72 g). After completion of the reaction, saturated NH.sub.4Cl aqueous solution (100 mL) was added to quench the reaction. The mixture was extracted with EtOAc twice (2×200 mL). The combined organic phase was washed with brine, and concentrated under vacuum. The crude material was purified by reslurrying in EtOAc/Heptane to get compound IV (0.92 g, 53% yield).

Example 5: Synthesis of Compound IV

(11) ##STR00024##

(12) To a mixture compound III-a (1.01 g), triisopropyl borate (1.36 g) and THF (10 mL) at −60.sup.˜-70° C. n-BuLi solution in n-hexane (6 mL, 2.5 M) was added slowly. Additional triisopropyl borate (0.81 g, 1 mL) was added simultaneously. After completion of the reaction, saturated NH.sub.4Cl aqueous solution (50 mL) was added to quench the reaction. The mixture was extracted with EtOAc twice (2×100 mL). The combined organic phase washed with brine. The organic phase was concentrated under vacuum. The crude material was purified by reslurrying in EtOAc/Heptane to afford compound IV (0.76 g, 86% yield).

Example 6: Synthesis of Compound IV

(13) ##STR00025##

(14) To a mixture of compound III-a (50 g), triisopropyl borate (84.9 g) and THF (500 mL) at −60.sup.˜-70° C., n-BuLi solution in n-hexane (378 mL, 2.5 M) was added. After completion of the reaction, 10% NH.sub.4Cl aqueous solution (500 mL) was added to quench the reaction. The mixture was extracted with EtOAc (2×500 mL). The combined organic phase was washed with brine and concentrated under vacuum. The crude material was purified by reslurrying in IPAc/Heptane to afford compound IV (39 g, 90% yield).

Example 7: Synthesis of Compound XIV-b

(15) ##STR00026##

(16) To a round-bottom flask was added compound IV (17.2 g), pinacol (12.6 g) and methanol (70 mL). The mixture was stirred for 2 h at 40.sup.˜50° C. The reaction mixture was cooled to 5° C. and stirred for 1 h. After filtration and drying, compound XIV-b was obtained as white solid (14.5 g, 63% yield).

(17) .sup.1H NMR (400 MHz, DMSO) δ 10.82 (s, 1H), 8.40-8.38 (m, 1H), 8.23-8.20 (m, 1H), 8.06-8.02 (m, 2H), 7.87-7.77 (m, 3H), 7.18-7.14 (m, 1H), 1.31 (s, 12H).

Example 8: Synthesis of Compound IV

(18) ##STR00027##

(19) To a mixture of compound III-b (2.00 g), triisopropyl borate (2.90 g) and THF (20 mL) at −60.sup.˜-70° C., n-BuLi solution in n-hexane (8.64 mL, 2.5 M) was added. After completion of the reaction, saturated NH.sub.4Cl aqueous solution (50 mL) was added to quench the reaction. The mixture was extracted with EtOAc (2×100 mL). The combined organic phase was washed with brine and concentrated under vacuum. the crude material was purified by reslurrying in EtOAc/Heptane to afford compound IV (0.92 g, 62% yield).

Example 9: Synthesis of Compound VIII

(20) ##STR00028##

(21) To a mixture of compound V (5.0 g), dichloromethane (DCM, 50 mL) and DMF (0.25 mL) in a 100 mL three-neck flask, SOCl.sub.2 (9.6 g, 4 eq) was added. The reaction mixture was stirred at RT. After completion of the reaction, the solvent was removed by concentration. DCM (20 mL) was added to prepare a solution of compound VI in DCM.

(22) To a mixture of compound VII (3 g), DCM (30 mL, 6 vol) and TEA (12.2 g, 6 eq) in a 100 mL three-neck flask at 0.sup.˜10° C., the solution of compound VI in DCM obtained in above step was added dropwise. The reaction mixture was warmed to RT. After the reaction was completed, water (100 mL, 20 vol) was added to quench the reaction. The mixture was extracted with DCM (2×50 mL). The combined organic phase was washed with saturated NH.sub.4Cl aqueous solution (50 mL, 10 vol) and saturated NaHCO.sub.3 aqueous solution (50 mL, 10 vol), and concentrated under vacuum. The crude material was recrystallized from IPAc/Heptane to afford compound VIII (6.0 g, 96% yield, 99.7% chiral purity).

(23) NMR sample was obtained by column chromatography: .sup.1H NMR (400 MHz, DMSO) δ 8.65-8.35 (m, 3H), 7.42-7.20 (m, 5H), 5.13-4.97 (m, 2H), 4.63-4.40 (m, 2H), 4.35-4.22 (m, 1H), 3.55-3.35 (m, 2H), 2.25-2.05 (m, 1H), 1.97-1.74 (m, 3H).

Example 10: Synthesis of Compound VIII

(24) ##STR00029##

(25) To a 1000 mL three-necked bottom flask was added compound V (30 g), DCM (300 mL) and DMF (0.5 mL). SOCl.sub.2 (28 g, 2 eq) was added and the reaction mixture was stirred at RT. After completion of the reaction, the solvent was removed by concentration. The residual was added toluene (60 mL) and evaporated in vacuo. DCM (120 mL) was added to obtain a solution of compound VI in DCM.

(26) To a mixture of compound VII (18 g), DCM (180 mL) and TEA (73 g, 6 eq) in a 1000 mL three-neck flask at 0.sup.˜10° C. the solution of compound VI in DCM obtained from the above step was added dropwise. The reaction mixture was warmed to RT. After the reaction was completed, water (600 mL) was added to quench the reaction. The mixture was extracted with DCM (2×300 mL). The combined organic phase was washed with saturated NH.sub.4Cl aqueous solution (300 mL) and saturated NaHCO.sub.3 aqueous solution (300 mL), and Concentrated under vacuum. The crude material was purified by silica gel column chromatography and recrystallized from IPAc/Heptane to afford compound VIII (28.5 g, 76% yield, 92.7% chiral purity).

Example 11: Synthesis of Compound VIII

(27) ##STR00030##

(28) To a mixture of compound V (49.8 g), DCM (500 mL) and DMF (5 mL) in a 500 mL three-neck flask, oxalyl chloride (38 g, 1.5 eq) was added at 0.sup.˜10° C. The reaction mixture was warmed to RT. After completion of the reaction, the solvent was removed by concentration. DCM (200 mL) was added to obtain the compound VI solution in DCM.

(29) To a mixture of compound VII (30 g), DCM (240 mL) and TEA (6 eq) in a 1000 mL three-neck flask at 0.sup.˜10° C., the solution of compound VI in DCM obtained from the above step was added dropwise, the reaction mixture was warmed to RT. After the reaction was completed, water (300 mL) was added to quench the reaction. The organic phase was washed with 1N HCl aqueous solution (500 mL), saturated NaHCO.sub.3 aqueous solution (500 mL) and water (500 mL). The organic phase was concentrated under vacuum. The crude product was recrystallized from IPAc/Heptane to afford compound VIII (61 g, 98% yield, 99.7% chiral purity).

Example 12: Synthesis of Compound XI

(30) ##STR00031##

(31) To a 250 mL round-bottom flask was added compound VIII (5 g), DCM (125 mL) and DMF (1 eq). The mixture was cooled to 0.sup.˜10° C. POCl.sub.3 (10 g, 5 eq) was added. The reaction mixture was warmed to RT. After the reaction was completed, ice water (50 mL) and saturated NaHCO.sub.3 aqueous solution (50 mL) were added to quench the reaction. The organic phase was washed with saturated NH.sub.4Cl aqueous solution (50 mL) to give a solution of compound IX in DCM.

(32) After being dried by azeotropic distillation, the solution of compound IX solution in DCM was added NBS (2.1 g, 0.9 eq). After reaction completion, the reaction mixture was washed with saturated NH.sub.4Cl aqueous solution (30 mL), saturated NaHCO.sub.3 aqueous solution (30 mL) and water (50 mL) to give the compound X solution in DCM. The solvent evaporated in vacuo to give crude compound X.

(33) The crude compound X was transferred to a pressure reactor. Isopropanol (100 mL) and ammonium hydroxide (50 mL) were added. The mixture was heated to 120° C. The solvents were removed after reaction completion. IPAc and water were added. The mixture was extracted with 1 N HCl aqueous solution twice. The pH of the combined aqueous phase was adjusted to 8.sup.˜9 with 30% NaOH aqueous solution. The mixture was extracted with IPAc. Recrystallization in IPAc/Heptane afforded compound XI (3.53 g, 63.6% overall yield).

(34) .sup.1HNMR (400 MHz, DMSO) δ 7.68 (m, 1H), 7.44-7.07 (m, 4H), 6.96 (m, 1H), 6.76 (d, J=7.0 Hz, 1H), 6.65 (s, 2H), 5.32 (ddd, J=10.8, 7.5, 4.0 Hz, 1H), 5.12-4.64 (m, 2H), 3.54 (ddd, J=23.5, 15.8, 8.7 Hz, 2H), 2.38-2.06 (m, 2H), 2.04-1.83 (m, 2H).

Example 13: Synthesis of Compound XI

(35) ##STR00032##

(36) To a mixture of compound VIII (5 g) and acetonitrile (30 mL) at 50.sup.˜60° C., PCl.sub.5 (5 g, 1.8 eq) was added. The reaction mixture was stirred for 20 h at 50.sup.˜60° C. DCM (25 mL) and water (25 mL) were added to quench the reaction. The organic phase was washed with water (25 mL) and concentrated to about 15 mL. DCM (35 mL) was added to give a solution of compound IX in DCM.

(37) The solution of compound IX in DCM was added dibromohydantoin (1.7 g, 0.45 eq) and stirred for 2 h at 20.sup.˜30° C. The reaction mixture was washed with water (25 mL) and concentrated under vacuum. The crude material was purified by recrystallization from IPA/H.sub.2O to give compound X (5.0 g).

(38) To a pressure reactor, compound X (3.0 g), isopropanol (54 mL) and ammonium hydroxide (18 mL) were added. The mixture was heated to 120° C. After reaction completion of the, the solvent was removed. IPAc and 1 N HCl aqueous solution were added. The layers were separated. The pH of the aqueous phase was adjusted to >10 with 30% NaOH aqueous solution and extracted with DCM. The DCM phase was concentrated. The material was purified by recrystallization from MeOH/H.sub.2O to give compound XI (1.17 g, 35.1% overall yield).

Example 14: Synthesis of Compound XV

(39) ##STR00033##

(40) A mixture of compound XI (4.14 g, 10 mmol), compound IV (2.66 g, 11 mmol), dioxane (34 mL) and K.sub.2CO.sub.3 aqueous solution (4.14 g K.sub.2CO.sub.3 in 15 mL water) was added Pd(dppf)Cl.sub.2 (73 mg, 0.1 mmol) under nitrogen. The mixture was stirred for 3 h at 90.sup.˜100° C. The organic phase was separated and concentrated. The residue was purified by silica gel column chromatography using heptane/EtOAc to afford compound XII (4.9 g, 92% yield).

(41) To a round-bottom flask was added compound XII (2.4 g), acetic acid (12 mL) and HBr (33% in acetic acid, 12 mL). The mixture was stirred for 2 h at 20.sup.˜30° C. Water (300 mL) and DCM (100 mL) was added. The aqueous phase was separated and washed with DCM (100 mL). The aqueous phase was adjusted to pH>10 with 30% NaOH aqueous solution and extracted with DCM (150 mL). The DCM phase was concentrated to give compound XIII (1.64 g, 91% yield).

(42) To a round-bottom flask was added compound XIII (0.50 g, 1.25 mmol), 2-butynoic acid (0.11 g, 1.31 mmol), HATU (0.48 g, 1.25 mmol), DCM (10 mL) and triethylamine (0.50 g, 5 mmol). The mixture was stirred for 3 h at 20.sup.˜30° C. The reaction mixture was washed with water (5 mL) and concentrated. The residue was purified by silica gel column chromatography using DCM/MeOH to afford compound XV (0.5 g, 90% yield).

(43) .sup.1H NMR (400 MHz, DMSO) δ 10.82 (s, 1H), 8.42-8.39 (m, 1H), 8.26-8.15 (m, 3H), 7.90-7.73 (m, 4H), 7.21-7.11 (m, 2H), 6.25-6.05 (m, 2H), 5.75-5.40 (m, 1H), 3.90-3.55 (m, 2H), 2.47-2.20 (m, 2H), 2.20-2.10 (m, 1H), 2.07-1.90 (m, 3H), 1.63 (s, 1H).

(44) Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, one of skill in the art will appreciate that certain changes and modifications may be practiced within the scope of the appended claims. In addition, each reference provided herein is incorporated by reference in its entirety to the same extent as if each reference was individually incorporated by reference. Where a conflict exists between the instant application and a reference provided herein, the instant application shall dominate.