PROCESS FOR SYNTHESIZING 2-HYDROXY-6-((2-(1-ISOPROPYL-1H-PYRAZOL-5-YL)-PYRIDIN-3-YL)METHOXY)BENZALDEHYDE
Disclosed herein are processes for synthesizing 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzaldehyde (also referred to herein as Compound (I)) and intermediates used in such processes. Compound (I) binds to hemoglobin and increases its oxygen affinity and hence can be useful for the treatment of diseases such as sickle cell disease.
1 . A process of synthesizing Compound (I):
the process comprising:
Step (i): treating a compound of formula (2):
wherein each R is —CH(CH 2 R 1 )—OR 2 or tetrahydropyran-2-yl optionally substituted with one, two, or three alkyl; and wherein R 1 is hydrogen or alkyl, and R 2 is alkyl;
with an acid to provide compound (1):
Step (ii): reacting compound (1) with a compound of formula (3):
wherein LG is a leaving group under alkylation reacting conditions to provide Compound (I); and
Step (iii): optionally crystallizing Compound (I) from Step (ii) from heptane and methyl tert-butyl ether at 45°+/−5° C. to 55°+/−5° C.
2 . The process of claim 1 further comprising formylating a compound of formula (4):
to provide the compound of formula (2):
wherein each R in compound of formulae compounds (2) and (4) is —CH(CH 2 R 1 )—OR 2 or tetrahydropyran-2-yl optionally substituted with one, two, or three alkyl; and
R 1 is hydrogen or alkyl, and R 2 is alkyl.
3 . The process of claim 2 further comprising reacting compound (5):
with a vinyl ether of formula CHR 1 ═CHOR 2 (wherein R 1 is hydrogen or alkyl and R 2 is alkyl), or 3,4-dihydro-2H-pyran optionally substituted with one, two or three alkyl, in the presence of a weak acid to provide the compound of formula (4):
wherein each R is —CH(CH 2 R 1 )—OR 2 (where R 1 is hydrogen or alkyl and R 2 is alkyl) or tetrahydropyran-2-yl optionally substituted with one, two, or three alkyl.
4 . The process of claim 3 wherein compound (4) prepared according to claim 3 is treated in situ with a formylating agent to provide compound (2).
5 . The process of claim 4 wherein compound (2) prepared according to claim 2 is treated in situ with an acid to provide compound (1).
6 . The process of claim 1 wherein Compound (I) is crystallized from heptane and methyl tert-butyl ether at 45°+/−5° C. to 55+/−5° C. to give Compound (I) in substantially pure Form II characterized by a XRPD pattern comprising a X-ray powder diffraction peak (Cu Kα radiation) at one or more of 13.37°, 14.37°, 19.95° or 23.92±0.2°2θ.
7 . The process of claim 4 wherein Compound (I) is crystallized from heptane and methyl tert-butyl ether at 45°+/−5° C. to 55+/−5° C. to give Compound (I) in substantially pure Form II characterized by a XRPD pattern comprising a X-ray powder diffraction peak (Cu Kα radiation) at one or more of 13.37°, 14.37°, 19.95° or 23.92±0.2°2θ.
8 . The process of claim 5 wherein Compound (I) is crystallized from heptane and methyl tert-butyl ether at 45°+/−5° C. to 55+/−5° C. to give Compound (I) in substantially pure Form II characterized by a XRPD pattern comprising a X-ray powder diffraction peak (Cu Kα radiation) at one or more of 13.37°, 14.37°, 19.950 or 23.92±0.2°2θ.9.
9 . The process of claim 6 wherein Compound (I) is crystallized at 45° C. to 55° C. to give Compound (I) wherein at least 95% by wt of Compound (I) is Form II.
10 . The process of claim 7 wherein Compound (I) is crystallized at 45° C. to 55° C. to give Compound (I) wherein at least 95% by wt of Compound (I) is Form II.
11 . The process of claim 8 wherein Compound (I) is crystallized at 45° C. to 55° C. to give Compound (I) wherein at least 95% by wt of Compound (I) is Form II.
12 . The process of claim 1 wherein R is —CH(CH 3 )—O—CH 2 CH 3 and the acid for removal of the R groups is an inorganic acid.
13 . The process of claim 1 wherein R is —CH(CH 3 )—O—CH 2 CH 3 , LG is chloro and the alkylation reaction is carried out in N-methyl-2-pyrrolidinone in the presence of sodium bicarbonate and a catalytic amount of NaI.
14 . The process of claim 3 wherein R is —CH(CH 3 )—O—CH 2 CH 3 , LG is chloro and the alkylation reaction is carried out in N-methyl-2-pyrrolidinone in the presence of sodium bicarbonate and a catalytic amount of NaI.
15 . The process of claim 4 wherein R is —CH(CH 3 )—O—CH 2 CH 3 , LG is chloro and the alkylation reaction is carried out in N-methyl-2-pyrrolidinone in the presence of sodium bicarbonate and a catalytic amount of NaI.
16 . The process of claim 5 wherein R is —CH(CH 3 )—O—CH 2 CH 3 , LG is chloro and the alkylation reaction is carried out in N-methyl-2-pyrrolidinone in the presence of sodium bicarbonate and a catalytic amount of NaI.
17 . The process of claim 6 wherein R is —CH(CH 3 )—O—CH 2 CH 3 , LG is chloro and the alkylation reaction is carried out in N-methyl-2-pyrrolidinone in the presence of sodium bicarbonate and a catalytic amount of NaI.
18 . The process of claim 7 wherein R is —CH(CH 3 )—O—CH 2 CH 3 , LG is chloro and the alkylation reaction is carried out in N-methyl-2-pyrrolidinone in the presence of sodium bicarbonate and a catalytic amount of NaI.
19 . The process of claim 8 wherein R is —CH(CH 3 )—O—CH 2 CH 3 , LG is chloro and the alkylation reaction is carried out in N-methyl-2-pyrrolidinone in the presence of sodium bicarbonate and a catalytic amount of NaI.
20 . The process of claim 9 wherein R is —CH(CH 3 )—O—CH 2 CH 3 , LG is chloro and the alkylation reaction is carried out in N-methyl-2-pyrrolidinone in the presence of sodium bicarbonate and a catalytic amount of NaI.
21 . The process of claim 10 wherein R is —CH(CH 3 )—O—CH 2 CH 3 , LG is chloro and the alkylation reaction is carried out in N-methyl-2-pyrrolidinone in the presence of sodium bicarbonate and a catalytic amount of NaI.
22 . The process of claim 11 wherein R is —CH(CH 3 )—O—CH 2 CH 3 , LG is chloro and the alkylation reaction is carried out in N-methyl-2-pyrrolidinone in the presence of sodium bicarbonate and a catalytic amount of NaI.
23 . The process of claim 1 wherein R is —CH(CH 3 )—O—CH 2 CH 3 , LG is chloro and the alkylation reaction is carried out in N-methyl-2-pyrrolidinone in the presence of sodium bicarbonate and a catalytic amount of NaI and Compound (I) is crystallized from the reaction mixture by addition of water at 40° C. to 50° C. to give substantially pure Form I characterized by a XRPD pattern comprising a X-ray powder diffraction peak (Cu Kα radiation) at one or more of 12.82°, 15.74°, 16.03°, 16.63°, 17.60°, 25.14°, 25.82° and 26.44°±0.2°2θ.
24 . The process of claim 4 wherein R is —CH(CH 3 )—O—CH 2 CH 3 , LG is chloro and the alkylation reaction is carried out in N-methyl-2-pyrrolidinone in the presence of sodium bicarbonate and a catalytic amount of NaI and Compound (I) is crystallized from the reaction mixture by addition of water at 40° C. to 50° C. to give substantially pure Form I characterized by a XRPD pattern comprising a X-ray powder diffraction peak (Cu Kα radiation) at one or more of 12.82°, 15.74°, 16.03°, 16.63°, 17.60°, 25.14°, 25.82° and 26.44°±0.2°2θ.
25 . The process of claim 5 wherein R is —CH(CH 3 )—O—CH 2 CH 3 , LG is chloro and the alkylation reaction is carried out in N-methyl-2-pyrrolidinone in the presence of sodium bicarbonate and a catalytic amount of NaI and Compound (I) is crystallized from the reaction mixture by addition of water at 40° C. to 50° C. to give substantially pure Form I characterized by a XRPD pattern comprising a X-ray powder diffraction peak (Cu Kα radiation) at one or more of 12.82°, 15.74°, 16.03°, 16.63°, 17.60°, 25.14°, 25.82° and 26.44°0.2°2θ.
26 . The process of claim 6 wherein R is —CH(CH 3 )—O—CH 2 CH 3 , LG is chloro and the alkylation reaction is carried out in N-methyl-2-pyrrolidinone in the presence of sodium bicarbonate and a catalytic amount of NaI and Compound (I) is crystallized from the reaction mixture by addition of water at 40° C. to 50° C. to give substantially pure Form I characterized by a XRPD pattern comprising a X-ray powder diffraction peak (Cu Kα radiation) at one or more of 12.82°, 15.74°, 16.03°, 16.63°, 17.60°, 25.14°, 25.82° and 26.44° 0.2°2θ.
27 . The process of claim 7 wherein R is —CH(CH 3 )—O—CH 2 CH 3 , LG is chloro and the alkylation reaction is carried out in N-methyl-2-pyrrolidinone in the presence of sodium bicarbonate and a catalytic amount of NaI and Compound (I) is crystallized from the reaction mixture by addition of water at 40° C. to 50° C. to give substantially pure Form I characterized by a XRPD pattern comprising a X-ray powder diffraction peak (Cu Kα radiation) at one or more of 12.82°, 15.74°, 16.03°, 16.63°, 17.60°, 25.14°, 25.82° and 26.44°0.2°2θ.
28 . The process of claim 8 wherein R is —CH(CH 3 )—O—CH 2 CH 3 , LG is chloro and the alkylation reaction is carried out in N-methyl-2-pyrrolidinone in the presence of sodium bicarbonate and a catalytic amount of NaI and Compound (I) is crystallized from the reaction mixture by addition of water at 40° C. to 50° C. to give substantially pure Form I characterized by a XRPD pattern comprising a X-ray powder diffraction peak (Cu Kα radiation) at one or more of 12.82°, 15.74°, 16.03°, 16.63°, 17.60°, 25.14°, 25.82° and 26.44°±0.2°2θ.
29 . The process of claim 9 wherein R is —CH(CH 3 )—O—CH 2 CH 3 , LG is chloro and the alkylation reaction is carried out in N-methyl-2-pyrrolidinone in the presence of sodium bicarbonate and a catalytic amount of NaI and Compound (I) is crystallized from the reaction mixture by addition of water at 40° C. to 50° C. to give substantially pure Form I characterized by a XRPD pattern comprising a X-ray powder diffraction peak (Cu Kα radiation) at one or more of 12.82°, 15.74°, 16.03°, 16.63°, 17.60°, 25.14°, 25.82° and 26.44°±0.2°2θ.
30 . The process of claim 10 wherein R is —CH(CH 3 )—O—CH 2 CH 3 , LG is chloro and the alkylation reaction is carried out in N-methyl-2-pyrrolidinone in the presence of sodium bicarbonate and a catalytic amount of NaI and Compound (I) is crystallized from the reaction mixture by addition of water at 40° C. to 50° C. to give substantially pure Form I characterized by a XRPD pattern comprising a X-ray powder diffraction peak (Cu Kα radiation) at one or more of 12.82°, 15.74°, 16.03°, 16.63°, 17.60°, 25.14°, 25.82° and 26.44°±0.2°2θ.
31 . The process of claim 11 wherein R is —CH(CH 3 )—O—CH 2 CH 3 , LG is chloro and the alkylation reaction is carried out in N-methyl-2-pyrrolidinone in the presence of sodium bicarbonate and a catalytic amount of NaI and Compound (I) is crystallized from the reaction mixture by addition of water at 40° C. to 50° C. to give substantially pure Form I characterized by a XRPD pattern comprising a X-ray powder diffraction peak (Cu Kα radiation) at one or more of 12.82°, 15.74°, 16.03°, 16.63°, 17.60°, 25.14°, 25.82° and 26.44°±0.2°2θ.
32 . The process of claim 1 wherein R is —CH(CH 3 )—O—CH 2 CH 3 , the acid for the removal of R group is hydrochloric acid, LG is chloro and the alkylation reaction is carried out in N-methyl-2-pyrrolidinone in the presence of sodium bicarbonate and a catalytic amount of NaI and Compound (I) is crystallized from the reaction mixture by addition of water at 40° C. to 46° C. to give Compound (I) that at least 95% by weight Form I characterized by a XRPD pattern comprising a X-ray powder diffraction peak (Cu Kα radiation) at one or more of 12.82°, 15.74°, 16.03°, 16.63°, 17.60°, 25.14°, 25.82° and 26.44°±0.2°2θ.
33 . The process of claim 4 wherein R is —CH(CH 3 )—O—CH 2 CH 3 , the acid for the removal of R group is hydrochloric acid, LG is chloro and the alkylation reaction is carried out in N-methyl-2-pyrrolidinone in the presence of sodium bicarbonate and a catalytic amount of NaI and Compound (I) is crystallized from the reaction mixture by addition of water at 40° C. to 46° C. to give Compound (I) that at least 95% by weight Form I characterized by a XRPD pattern comprising a X-ray powder diffraction peak (Cu Kα radiation) at one or more of 12.82°, 15.74°, 16.03°, 16.63°, 17.60°, 25.14°, 25.82° and 26.44°±0.2°2θ.
34 . The process of claim 5 wherein R is —CH(CH 3 )—O—CH 2 CH 3 , the acid for the removal of R group is hydrochloric acid, LG is chloro and the alkylation reaction is carried out in N-methyl-2-pyrrolidinone in the presence of sodium bicarbonate and a catalytic amount of NaI and Compound (I) is crystallized from the reaction mixture by addition of water at 40° C. to 46° C. to give Compound (I) that at least 95% by weight Form I characterized by a XRPD pattern comprising a X-ray powder diffraction peak (Cu Kα radiation) at one or more of 12.82°, 15.74°, 16.03°, 16.63°, 17.60°, 25.14°, 25.82° and 26.44°±0.2°2θ.
35 . The process of claim 7 wherein R is —CH(CH 3 )—O—CH 2 CH 3 , the acid for the removal of R group is hydrochloric acid, the weak acid is pyridinium tosylate, the formylating agent is n-BuLi and DMF, LG is chloro and the alkylation reaction is carried out in N-methyl-2-pyrrolidinone in the presence of sodium bicarbonate and a catalytic amount of NaI and Compound (I) is crystallized from the reaction mixture by addition of water at 40° C. to 46° C. to give Compound (I) that at least 95% by weight Form I characterized by a XRPD pattern comprising a X-ray powder diffraction peak (Cu Kα radiation) at one or more of 12.82°, 15.74°, 16.03°, 16.63°, 17.60°, 25.14°, 25.82° and 26.44°±0.2°2θ.
36 . The process of claim 8 wherein R is —CH(CH 3 )—O—CH 2 CH 3 , the acid for the removal of R group is hydrochloric acid, the weak acid is pyridinium tosylate, the formylating agent is n-BuLi and DMF, LG is chloro and the alkylation reaction is carried out in N-methyl-2-pyrrolidinone in the presence of sodium bicarbonate and a catalytic amount of NaI and Compound (I) is crystallized from the reaction mixture by addition of water at 40° C. to 46° C. to give Compound (I) that at least 95% by weight Form I characterized by a XRPD pattern comprising a X-ray powder diffraction peak (Cu Kα radiation) at one or more of 12.82°, 15.74°, 16.03°, 16.63°, 17.60°, 25.14°, 25.82° and 26.44°±0.2°2θ.
37 . An intermediate of formula (2):
wherein each R is —CH(CH 2 R 1 )OR 2 ; and
wherein R 1 is hydrogen or alkyl, and R 2 is alkyl.