Methods of Making Tolebrutinib
Disclosed herein are improved synthetic routes for making (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (tolebrutinib). Also disclosed herein are novel compounds used in the synthesis of (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one.
1 . A method of preparing a compound of Formula (I):
or a salt thereof, comprising:
reacting a compound of Formula (A-oxalate hydrate):
to form the compound of Formula (I), wherein the reaction comprises the following steps:
(i) to a solution of the compound Formula (A-oxalate hydrate) adding 3-chloropropanoic acid; and
(ii) to the mixture of (i), adding 1,8-diazabicyclo[5.4.0]undec-7-ene;
to prepare the compound of Formula (I).
2 . The method of claim 1 , wherein step (i) is performed in the presence of potassium carbonate, diisopropylethylamine, and propylphosphonic acid anhydride in dichloromethane.
3 . The method of claim 1 or 2 , wherein step (ii) is performed in dichloromethane.
4 . The method of any one of claims 1-3 , further comprising step (iii): washing the mixture of (ii) with hydrochloride.
5 . The method of claim 4 , further comprising step (iv): dehydrating the organic layer obtained from (iii).
6 . The method of claim 5 , further comprising step (v): adding seeds of compound (I)-HCl to the organic layer of (iv).
7 . The method of claim 6 , further comprising step (vi): adding ethyl acetate to the mixture of (v) at a temperature ranging from 0 to 25° C.
8 . The method of claim 7 , further comprising step (vii): filtering the solid from the mixture of (vi) and adding dichloromethane and sodium bicarbonate to the mixture.
9 . The method of claim 8 , further comprising step (viii): filtering and concentrating the mixture of (vii).
10 . The method of any one of claims 1-9 , wherein the compound of Formula (A-oxalate hydrate) is prepared by reacting a compound of Formula (A):
or a salt thereof, with oxalic acid in a mixture of ethanol and water.
11 . A method of preparing a compound of Formula (A-oxalate hydrate):
comprising:
reacting a compound of Formula (A):
or a salt thereof, with oxalic acid in a mixture of ethanol and water to form the compound of Formula (A-oxalate hydrate).
12 . The method of claim 10 or 11 , wherein the reaction comprises the addition of crystalline seeds of the compound of Formula (A-oxalate hydrate).
13 . The method of claim 9 , wherein the filtrate of (viii) comprises the compound of Formula (I), or a salt thereof, that is substantially free of an impurity compound of Formula (I)-Im:
wherein n is equal to or greater than 1.
14 . The method of claim 9 , wherein the filtrate of (viii) yields a product that comprises the compound of Formula (I), or a salt thereof, and an impurity amount ranging from 0 to 1.4%.
15 . The method of claim 14 , wherein the impurity amount ranges from 0 to 0.9%.
16 . The method of claim 14 or 15 , wherein the impurity amount ranges from 0 to 0.4%.
17 . The method of any one of claims 14-16 , wherein the impurity is a compound of Formula (I)-Im:
wherein n is equal to or greater than 1.
18 . A compound of Formula (I):
or a salt thereof, that comprises an impurity in an amount ranging from 0 to 1.4%.
19 . The compound of claim 18 , wherein the impurity amount ranges from 0 to 0.9%.
20 . The compound of claim 18 or 19 , wherein the impurity amount ranges from 0 to 0.4%.
21 . A compound of Formula (I):
or a salt thereof, that is substantially free of an impurity compound of Formula (I)-Im:
wherein n is equal to or greater than 1.
22 . The compound of claim 21 , wherein the compound of Formula (I), or a salt thereof, comprises the impurity in an amount ranging from 0 to 1.4%.
23 . The compound of claim 21 or 22 , wherein the compound of Formula (I), or a salt thereof, comprises the impurity in an amount ranging from 0 to 0.9%.
24 . The compound of any one of claims 21-23 , wherein the compound of Formula (I), or a salt thereof, comprises the impurity in an amount ranging from 0 to 0.4%.
25 . The compound of any one of claims 18-20 , wherein the impurity is a compound of Formula (I)-Im:
or a salt thereof, wherein n is equal to or greater than 1.
26 . A composition comprising a compound of Formula (I) prepared by the method of claim 1 , wherein the composition is substantially free of an impurity compound of Formula (I)-Im:
wherein n is equal to or greater than 1.
27 . The composition of claim 26 , wherein the composition comprises at least 97% by weight or by HPLC analysis the compound of Formula (I).
28 . The composition of claim 26 or 27 , wherein the composition comprises an impurity in an amount ranging from 0 to 1.4% by weight or by HPLC analysis.
29 . The composition of any one of claims 26-28 , wherein the impurity amount ranges from 0 to 0.9% by weight or by HPLC analysis.
30 . The composition of any one of claims 26-29 , wherein the impurity amount ranges from 0 to 0.4% by weight or by HPLC analysis.
31 . The composition of any one of claims 26-30 , wherein the impurity is a compound of Formula (I)-Im:
or a salt thereof, wherein n is greater than 1.
32 . A compound of Formula (I)-Im:
or a salt thereof, wherein n is equal to or greater than 1.
33 . A compound of Formula (A-oxalate hydrate):
wherein the compound is about 90% pure.
34 . The compound of claim 33 , wherein the compound is 95% pure.
35 . The compound of claim 33 or 34 , wherein the compound is 98% pure.
36 . A crystalline form of a compound of Formula (A-oxalate hydrate):
37 . The crystalline form of claim 36 , having an ORTEP structure that is substantially in accordance with that shown in FIG. 1 .
38 . The crystalline form of claim 36 or 37 , wherein the stoichiometry between the compound of Formula (A) and water is 2:6.