Method for producing triazolopyridine compound
The present invention relates to a novel method for producing a triazolopyridine compound or a salt thereof having a PHD inhibitory action and useful for treating or preventing diseases caused by decreased production of EPO, or the like. The present invention provides a method for producing 2-({[7-hydroxy-5-(2-phenylethyl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl]carbonyl}amino)acetic acid comprising a step of reacting Compound [VI]: wherein R 61 , R 62 and R 111 are as defined in the specification, or a salt thereof.
1. A method for producing Compound (1):
or a pharmaceutically acceptable salt thereof, the method comprising:
a step of hydrolyzing and then decarboxylating Compound [VI]:
or a salt thereof, wherein:
R 61 , R 62 and R 111 are each independently selected from C 1-6 alkyl and benzyl; and
X 91 is selected from halogen, p-toluenesulfonyloxy, methanesulfonyloxy, trifluoromethanesulfonyloxy, and trifluoroacetyloxy; to give Compound [IV]:
or a salt thereof, wherein X 91 is as defined above,
a step of reacting Compound [IV] or a salt thereof with a glycine derivative to give Compound [III]:
or a salt thereof, wherein:
R 31 is selected from C 1-6 alkyl and benzyl; and
X 91 is as defined above;
a step of reacting Compound [III] or a salt thereof with a base to give a salt of Compound (1), and
a step of reacting the said salt of Compound (1) with an acid to give Compound (1).
2. The production method according to claim 1 further comprising:
a step of reacting Compound [VII]:
or a salt thereof, wherein:
X 92 is selected from halogen, p-toluenesulfonyloxy, methanesulfonyloxy, trifluoromethanesulfonyloxy, and trifluoroacetyloxy; and
X 91 and R 111 are as defined above;
with a benzylmalonic acid derivative to give Compound [VI] or a salt thereof.
3. The production method according to claim 2 further comprising:
a step of reacting Compound [XI]:
wherein R 111 is as defined above and may be the same or different, with cyanamide or a salt thereof to give Compound [X]:
or a salt thereof, wherein R 111 is as defined above,
a step of converting a hydroxy group of Compound [X] or a salt thereof to a leaving group to give Compound [IX]:
or a salt thereof, wherein X 91 , X 92 and R 111 are as defined above,
a step of sequentially reacting Compound [IX] or a salt thereof with N,N-dimethylformamide dialkylacetal, hydroxylamine or a salt thereof to give Compound [VIII]:
or a salt thereof, wherein X 91 , X 92 and R 111 are as defined above, and
a step of subjecting Compound [VIII] or a salt thereof to a dehydration reaction to give Compound [VII] or a salt thereof.
4. The production method according to claim 1 wherein Compound [VI] or a salt thereof is Compound (6):
or a salt thereof, Compound [IV] or a salt thereof is Compound (4):
or a salt thereof, Compound [III] or a salt thereof is Compound (3):
or a salt thereof, and the said salt of Compound (1) is Compound (2):
5. The production method according to claim 4 further comprising:
a step of reacting Compound (7):
or a salt thereof with a benzylmalonic acid derivative to give Compound (6) or a salt thereof.
6. The production method according to claim 5 further comprising:
a step of reacting Compound (11):
with cyanamide or a salt thereof to give Compound (10):
or a salt thereof,
a step of chlorinating a hydroxy group of Compound (10) or a salt thereof to give Compound (9):
or a salt thereof,
a step of reacting Compound (9) or a salt thereof with hydroxylamine or a salt thereof to give Compound (8):
or a salt thereof, and
a step of subjecting Compound (8) or a salt thereof to a dehydration reaction to give Compound (7) or a salt thereof.
7. A method for producing Compound [VI]:
or a salt thereof, wherein:
R 61 , R 62 , and R 111 are each independently selected from C 1-6 alkyl and benzyl; and
X 91 is selected from halogen, p-toluenesulfonyloxy, methanesulfonyloxy, trifluoromethanesulfonyloxy, and trifluoroacetyloxy;
the method comprising:
a step of reacting Compound [VII]:
or a salt thereof, wherein:
X 92 is selected from halogen, p-toluenesulfonyloxy, methanesulfonyloxy, trifluoromethanesulfonyloxy, and trifluoroacetyloxy; and
X 91 and R 111 are as defined above;
with a benzylmalonic acid derivative to give Compound [VI] or a salt thereof.
8. A method for producing Compound [IV]:
or a salt thereof, wherein X 91 is selected from halogen, p-toluenesulfonyloxy, methanesulfonyloxy, trifluoromethanesulfonyloxy, and trifluoroacetyloxy, the method comprising:
a step of reacting Compound [VII]:
or a salt thereof, wherein:
X 92 is selected from halogen, p-toluenesulfonyloxy, methanesulfonyloxy, trifluoromethanesulfonyloxy, and trifluoroacetyloxy;
R 111 is selected from C 1-6 alkyl and benzyl; and
X 91 is as defined above;
with a benzylmalonic acid derivative to give Compound [VI]:
or a salt thereof; wherein:
R 61 and R 62 are each independently selected from C 1-6 alkyl and benzyl; and
X 91 and R 111 are as defined above; and
a step of hydrolyzing and then decarboxylating Compound [VI] or a salt thereof to give Compound [IV] or a salt thereof.
9. Compound [VI]:
or a salt thereof, wherein:
R 61 , R 62 and R 111 are each independently selected from C 1-6 alkyl and benzyl; and
X 91 is selected from halogen, p-toluenesulfonyloxy, methanesulfonyloxy, trifluoromethanesulfonyloxy, and trifluoroacetyloxy.