Methods of Synthesis of Chiral 3,5-Disubstituted Morpholine Compounds and Intermediates Useful Therein
Provided herein are diastereomer-selective synthetic methods and intermediates for making chiral 3,5-disubstituted morpholine compounds, which are useful for the preparation of compounds useful as mitochondrial-derived activator of caspases (SMAC) mimetics for the treatment of proliferative diseases such as cancer.
1 . A compound of Formula (VI),
or a pharmaceutically acceptable salt, solid form, enantiomer, isotopologue, or solvate thereof,
wherein
R 1 and R 2 are independently unsubstituted or substituted C 1-5 alkyl.
2 . The compound of claim 1 , wherein R 1 and R 2 are independently unsubstituted or substituted C 1-4 alkyl.
3 . The compound of claim 1 , wherein R 1 and R 2 are independently unsubstituted linear or branched C 1-4 alkyl.
4 . (canceled)
5 . The compound of claim 1 , wherein R 1 and R 2 are methyl.
6 . A solid form comprising the compound of claim 1 .
7 . A crystal form comprising the compound of claim 5 , wherein the crystal form has an X-ray powder diffraction pattern comprising one, two or three peaks at 22.5, 27.1, or 27.3±0.2° 2θ.
8 . The crystal form of claim 7 , wherein the X-ray powder diffraction pattern further comprises one, two or three peaks at 15.3, 22.4, or 24.2±0.2° 2θ.
9 . The crystal form of claim 7 , wherein the crystal form has a melting point at a temperature from about 91° C. to about 93° C.
10 . The crystal form of claim 7 , wherein the crystal form is anhydrous.
11 . A method for preparing a compound of Formula (VIII):
or a pharmaceutically acceptable salt, solid form, enantiomer, isotopologue, or solvate thereof,
wherein the method comprises contacting a compound of Formula (VII):
with hydrogen (H 2 ) in the presence of a catalyst in a solvent, wherein
R 1 and R 2 are independently unsubstituted or substituted C 1-5 alkyl.
12 . The method of claim 11 , wherein the solvent is methanol, ethanol, or isopropanol.
13 . The method of claim 11 , wherein the catalyst is Pd(OH) 2 /C or Pd/C.
14 . The method of claim 11 , wherein the pressure of the hydrogen (H 2 ) is about 1 to about 10 atm and the contacting proceeds at a temperature from about 25° C. to about 55° C.
15 . The method of claim 14 , wherein the pressure of the hydrogen (H 2 ) is about 1 to about 5 atm.
16 . The method of claim 14 , wherein the pressure of the hydrogen (H 2 ) is about 1 to about 3 atm.
17 . The method of claim 11 , wherein the compound of Formula (VII) is prepared by contacting a compound of Formula (VI):
with an acid.
18 . The method of claim 17 , wherein the acid is TfOH and the contacting proceeds at a temperature from about 20° C. to about 140° C.
19 . The method of claim 17 , wherein the compound of Formula (VI) is prepared by contacting a mixture of a compound of Formula (IV):
and
a compound of Formula (V):
with a reducing agent.
20 . The method of claim 19 , wherein the reducing agent is NaBH 4 and the contacting proceeds in a solvent selected from the group consisting of methanol, ethanol, isopropanol, and a mixture thereof at a temperature from about 15° C. to about 35° C.
21 . The method of claim 17 , wherein the compound of Formula (VI) is a solid form.
22 . The method of claim 17 , wherein R 1 and R 2 are methyl.
23 . The method of claim 22 , wherein the compound of Formula (VI) is a crystalline form comprising the compound of Formula (VI), wherein the crystal form has an X-ray powder diffraction pattern comprising one, two or three peaks at 22.5, 27.1, or 27.3±0.2° 2θ.
24 . The method of claim 23 , wherein the X-ray powder diffraction pattern further comprises one, two, or three peaks at 15.3, 22.4, or 24.2±0.2° 2θ.
25 . The method of claim 23 , wherein the crystal form has a melting point at a temperature from about 91° C. to about 93° C.
26 . The method of claim 23 , wherein the crystal form is anhydrous.
27 . The method of claim 19 , wherein the mixture of a compound of Formula (IV) and a compound of Formula (V) is prepared by contacting a compound of Formula (II):
with a compound of Formula (III):
in the presence of a suitable base in a suitable solvent.
28 . The method of claim 27 , wherein the suitable base is 2,6-lutidine; the suitable solvent is dichloromethane; and the contacting proceeds at a temperature from about 0° C. to about 40° C.
29 . The method of claim 27 , wherein the compound of Formula (II) is prepared by contacting a compound of Formula (I),
with PhCHO in the presence of a suitable base in a suitable solvent.
30 . The method of claim 29 , wherein the suitable base is NaHCO 3 ; the suitable solvent is methanol; and the contacting proceeds at a temperature from about 20° C. to about 40° C.