Process for synthesis of a phenoxy diaminopyrimidine compound
Disclosed herein is a novel process for preparing Compound A free base, 5-((2,4-diaminopyrimidin-5-yl)oxy)-4-iso-propyl-2-methoxybenzenesulfonamide, and a citrate salt of Compound A with simplified chemistry and a high overall yield: Compound A. In one embodiment, the overall yield from the starting material 2-isopropylphenol to Compound A citrate salt is greater than 50%. In another embodiment, the overall yield is greater than 60%. Also disclosed herein are novel salts and solvates of Compound A.
1. A process for preparing Compound A free base of the following formula:
comprising a step of converting 2-isopropylphenol to 4-bromo-2-isopropylphenol hemi-DABCO co-crystal as shown below:
2. The process of claim 1 , wherein the conversion to the 4-bromo-2-isopropylphenol hemi-DABCO co-crystal is carried out in the presence of NBS and MSA.
3. The process of claim 1 , further comprising a step of converting the 4-bromo-2-isopropylphenol hemi-DABCO co-crystal to the methoxy phenol compound, 2-isopropyl-4-methxoy phenol, as shown below:
4. The process of claim 3 , wherein the conversion to the 2-isopropyl-4-methxoy phenol is carried out in the presence of NaOMe and with CuBr as a catalyst.
5. The process of claim 4 , wherein the conversion is carried out in the presence of MeOH and DMF.
6. The process of claim 3 , further comprising a step of reacting the 2-isopropyl-4-methxoy phenol with ClCH 2 CN to form the cyanoether compound, 2-(2-isopropyl-4-methoxyphenoxy)acetonitrile, as shown below:
7. The process of claim 6 , wherein the reaction to form the cyanoether compound is carried out at a temperature from about 20° C. to about 60° C.
8. The process of claim 6 , further comprising a step of converting the cyanoether compound, 2-(2-isopropyl-4-methoxyphenoxy)acetonitrile, to the diaminopyrimidine compound, 5-(2-isopropyl-4-methoxyphenoxy)pyrimidine-2,4-diamine:
9. The process of claim 8 , wherein the conversion to 5-(2-isopropyl-4-methoxyphenoxy)pyrimidine-2,4-diamine is carried out in the presence of potassium tert-butoxide in NMP and the cyanoether compound is in a solution in ethyl formate and toluene.
10. The process of claim 9 , wherein the conversion to 5-(2-isopropyl-4-methoxyphenoxy)pyrimidine-2,4-diamine is carried out further in the presence of guanidine hydrochloride.
11. The process of claim 8 , further comprising a step of reacting the 5-(2-isopropyl-4-methoxyphenoxy)pyrimidine-2,4-diamine with ClSO 3 H followed by NH 4 OH to form Compound A free base, 5-((2,4-diaminopyrimidin-5-yl)oxy)-4-isopropyl-2-methoxybenzenesulfonamide, as shown below:
12. The process of claim 11 , wherein the reaction between 5-(2-isopropyl-4-methoxyphenoxy)pyrimidine-2,4-diamine and ClSO 3 H is carried out in the presence of MeCN.
13. A process for preparing Compound A free base comprising the following steps:
(a) converting 2-isopropylphenol to 4-bromo-2-isopropylphenol hemi-DABCO co-crystal:
(b) converting the 4-bromo-2-isopropylphenol hemi-DABCO co-crystal to 2-isopropyl-4-methxoy phenol shown below in the presence of NaOMe:
(c) reacting the 2-isopropyl-4-methxoy phenol with ClCH 2 CN to form the cyanoether compound, 2-(2-isopropyl-4-methoxyphenoxy)acetonitrile:
(d) converting the 2-(2-isopropyl-4-methoxyphenoxy)acetonitrile to 5-(2-isopropyl-4-methoxyphenoxy)pyrimidine-2,4-diamine:
and
(e) reacting 5-(2-isopropyl-4-methoxyphenoxy)pyrimidine-2,4-diamine with ClSO 3 H followed by NH 4 OH to form Compound A free base, 5-((2,4-diaminopyrimidin-5-yl)oxy)-4-isopropyl-2-methoxybenzenesulfonamide:
14. The process of claim 13 , further comprising converting the Compound A free base to Compound A citrate salt in the presence of glycolic acid and MeOH:
15. The process of claim 14 , wherein the overall yield from 2-isopropylphenol to Compound A citrate salt is greater than 50%.
16. Crystalline Compound A citrate methanol solvate 1 having an XRPD pattern of FIG. 8 .
17. A process for preparing 4-bromo-2-isopropylphenol hemi-DABCO co-crystal comprising a step of converting 2-isopropylphenol to 4-bromo-2-isopropylphenol hemi-DABCO co-crystal as shown below:
18. The process of claim 17 , wherein the conversion to the 4-bromo-2-isopropylphenol hemi-DABCO co-crystal is carried out in the presence of NBS and MSA.
19. The process of claim 17 , further comprising a step of converting the 4-bromo-2-isopropylphenol hemi-DABCO co-crystal to the methoxy phenol compound, 2-isopropyl-4-methxoy phenol, as shown below:
20. The process of claim 19 , wherein the conversion to the 2-isopropyl-4-methxoy phenol is carried out in the presence of NaOMe and with CuBr as a catalyst.