Methylation of Mcl-1 compounds

Abstract

To provide methylation of an Mcl-1 compound.SOLUTION: A process for synthesis of compound A or a salt or solvate thereof comprises forming a mixture of a specific base, a compound B or a salt or solvate thereof, a specific organic solvent and water, and further mixing methyl halide therewith.SELECTED DRAWING: Figure 1

Claims

1. Compound A, its salt, or solvate: 【Chemistry 1】 A method for synthesizing, (0) A step of adding water to compound B, a salt thereof, or a solvate to form a water-containing solution, 【change】 The molar ratio of water to compound B is in the range of 0.5:1 to 3:

1. Compound B is compound B': 【Chemistry 2】 (In the formula, M is an alkali metal.) The salt having the structure is formed in the following steps: (a)(i) A base selected from the group consisting of non-nucleophilic bases, alkali metal hydride bases, alkali metal hydroxide bases, organolithium bases, and any combination thereof; (ii) Water-containing solution formed in step (0); and (iii) Organic solvents including ether solvents, nonpolar solvents, or any combination thereof The process of mixing to form a mixture; (b) A step of mixing the mixture from step (a) with MeX (where X is a halogen) to form a mixture containing compound A. A method that includes this.

2. The method according to claim 1, wherein the base comprises lithium hexamethyldisilazide ("HMDS"), sodium HMDS, potassium HMDS, lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-amilate, sodium tert-amilate, potassium tert-amilate, potassium hydride, sodium hydride, potassium hydroxide, sodium hydroxide, lithium hydroxide, 2,2,6,6-tetramethylpiperidine (TMP), LiTMP, n-butyllithium (n-BuLi), n-hexyllithium, 1,1,3,3-tetramethylguanidine (TMG), 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU), 1,5-diazabicyclo[4.3.0]nona-5-ene, or any combination thereof.

3. The method according to claim 2, wherein the base comprises lithium hexamethyldisilazide HMDS, sodium HMDS, potassium HMDS, or any combination thereof.

4. The method according to claim 3, wherein the base comprises potassium hexamethyldisilazide ("KHMDS").

5. The method according to any one of claims 1 to 4, wherein the molar ratio of the base pair compound B is in the range of 1:1 to 5:

1.

6. The method according to claim 5, wherein the molar ratio of the base pair compound B is in the range of 2.5:1 to 4:

1.

7. The method according to claim 5, wherein the molar ratio of the base pair compound B is 3.0:1 to 3.5:

1.

8. The method according to claim 5, wherein the molar ratio of the base pair compound B is 3.2:

1.

9. The method according to any one of claims 1 to 8, wherein the organic solvent is selected from the group consisting of tetrahydrofuran ("THF"), 2-methyltetrahydrofuran, cyclopentyl methyl ether, tert-butyl methyl ether, 1,2-dimethoxyethane, toluene, hexane, heptane, 1,4-dioxane, and combinations thereof.

10. The method according to claim 9, wherein the organic solvent contains THF.

11. The method according to claim 10, wherein the molar ratio of water to compound B is in the range of 1:1 to 3:

1.

12. The method according to claim 10, wherein the molar ratio of water to compound B is 1.4:1 to 1.6:

1.

13. The method according to any one of claims 1 to 12, wherein X is yogide.

14. The method according to any one of claims 1 to 13, wherein the molar ratio of MeX to compound B is in the range of 1:1 to 4:

1.

15. The method according to claim 14, wherein the molar ratio of MeX to compound B is 2.7:

1.

16. The method according to any one of claims 1 to 15, wherein the base is mixed with the solution in step (a) for a period of 5 seconds to 6 hours.

17. The method according to any one of claims 1 to 15, wherein the base is mixed with the solution within 5 seconds in step (a).

18. The method according to claim 17, wherein the base is mixed with the solution within 1 second in step (a).

19. The method according to any one of claims 1 to 18, wherein the mixture in step (a) is stirred for 1 second to 12 hours.

20. The method according to claim 19, wherein the mixture in step (a) is stirred for 1 second to 20 minutes.

21. The method according to any one of claims 1 to 20, wherein the MeX is mixed with the mixture of step (a) over a period of time from 1 second to 6 hours.

22. The method according to any one of claims 1 to 20, wherein the MeX is mixed with the mixture of step (a) within 5 seconds.

23. The method according to claim 22, wherein the MeX is mixed with the mixture of step (a) within 1 second.

24. The method according to any one of claims 1 to 23, wherein the mixture in step (b) is stirred for 1 minute to 12 hours.

25. The method according to claim 24, wherein the mixture in step (b) is stirred for 1 to 20 minutes.

26. The method according to claim 1, wherein the alkali metal is lithium, sodium, or potassium.

27. The method according to claim 26, wherein the alkali metal is potassium.

28. The method according to claim 1, wherein compound B' is prepared by mixing compound B with an organic solvent selected from the group consisting of an alkali hydroxide base and an ether solvent, a nonpolar solvent, and any combination thereof to form a mixture containing compound B'.

29. The method according to claim 28, wherein the alkali hydroxide base is selected from the group consisting of potassium hydroxide, sodium hydroxide, lithium hydroxide, and combinations thereof.

30. The method according to claim 28 or 29, wherein the molar ratio of the alkali hydroxide base pair compound B is in the range of 0.5:1 to 3:

1.

31. The method according to claim 30, wherein the molar ratio of the alkali hydroxide base pair compound B is 1.5:

1.

32. The method according to claim 28, wherein the organic solvent is selected from the group consisting of tetrahydrofuran ("THF"), 2-methyltetrahydrofuran, cyclopentyl methyl ether, tert-butyl methyl ether, 1,2-dimethoxyethane, toluene, hexane, heptane, 1,4-dioxane, and combinations thereof.

33. The method according to claim 32, wherein the organic solvent contains THF.

34. The method according to any one of claims 28 to 33, wherein the mixture containing compound B' is stirred for 1 to 48 hours.

35. The method according to any one of claims 1 to 34, further comprising the step of quenching the mixture of step (b) with a secondary amine base.

36. The method according to claim 35, wherein the secondary amine base is selected from the group consisting of N,N-diethylamine, morpholine, piperidine, pyrrolidine, piperazine, and combinations thereof.

37. The method according to any one of claims 1 to 36, wherein each mixing step occurs at a temperature in the range of 0°C to 40°C.

38. The method according to claim 37, wherein the temperature of each mixing step is in the range of 15°C to 25°C.

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