Synthesis of a compound that modulates kinases
The present disclosure provides processes for the preparation of a compound of formula I: or a salt thereof, active on the receptor protein kinases c-Kit and/or c-Fms and/or Flt3. The disclosure also provides compounds and processes for the preparation of the compounds that are synthetic intermediates to the compound of formula I.
1. A process for preparation of a compound of formula I:
or a salt thereof, comprising:
contacting a compound of formula IV:
or a salt thereof, with a compound of formula V:
or a salt thereof, under reductive amination conditions to provide the compound of formula I or a salt thereof.
2. The process of claim 1 , wherein the reductive amination conditions comprise triethylsilane and trifluoroacetic acid.
3. The process of claim 1 , wherein the reductive amination conditions comprise a solvent selected from the group consisting of acetonitrile, 1,2-dichloroethane, dichloromethane, tetrahydrofuran, 1,2-dimethoxyethane, butyl acetate, acetone, acetonitrile, 2-butanone and dimethylsulfoxide.
4. The process of claim 1 , wherein the compound of formula IV, or a salt thereof, is prepared by subjecting a compound of formula III:
or a salt thereof, to N-deprotection and alcohol reduction conditions to provide the compound of formula IV or a salt thereof, wherein each PG independently is a protecting group.
5. The process of claim 4 , wherein the N-deprotection and alcohol reduction conditions comprise triorganosilane and trifluoroacetic acid.
6. The process of claim 5 , wherein the triorganosilane is selected from the group consisting triethylsilane, tripropylsilane, tent-butyldimethylsilane, triphenylsilane and methyldiphenylsilane.
7. The process of claim 4 , wherein the N-deprotection and alcohol reduction conditions further comprise a solvent selected from the group consisting of acetonitrile, 1,2-dichloroethane, dichloromethane, tetrahydrofuran, 1,2-dimethoxyethane, butyl acetate, acetone, 2-butanone and dimethylsulfoxide.
8. The process of claim 4 , wherein formula III, or a salt thereof; is prepared by contacting a compound of formula A, or a salt thereof, with a compound of formula B, or a salt thereof:
under addition conditions to provide the compound of formula III, or a salt thereof, wherein each PG independently is a protecting group.
9. The process of claim 8 , wherein the addition conditions comprise a base and a catalyst.
10. The process of claim 9 , wherein the base is selected from the group consisting of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, potassium tert-butoxide, potassium tent-pentoxide, cesium carbonate, lithium tert-butoxide, magnesium tert-butoxide, sodium tert-butoxide, sodium hydroxide, potassium hydroxide and lithium hydroxide.
11. The process of claim 9 , wherein the catalyst is selected from the group consisting of tetrabutylammonium hydrogen sulfate, tetrabutylammonium fluoride, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, 18-crown-6 and 15-crown-5.
12. The process of claim 8 , wherein the addition conditions comprise a solvent selected from the group consisting of isopropyl alcohol, toluene, acetonitrile, nitromethane, N,N-dimethylformamide, N,N-dimethylacetamide, dim ethyl sulfoxide, 3-methyl-1-butanol, 2-methoxyethanol, 2-propanol and xylene.
13. The process of claim 8 , wherein the addition conditions comprise a temperature ranging from about 15 to about 25° C.
14. The process of claim 8 , wherein the protecting group is selected from the group consisting of tert-butyloxycarbonyl, benzyloxycarbonyl and 9-fluorenylmethoxycarbonyl.
15. The process of claim 14 , wherein the protecting group is tert-butyloxycarbonyl.
16. The process of claim 1 , wherein compound I, or a salt thereof, is an HCl salt of compound I.