Method for producing (2S)-2-[(1H-pyrazol-1-yl)methyl]-1,3-oxazinane derivative

1. A process for producing (2S)-(2-{[3-(5-fluoropyridin-2-yl)-1H-pyrazol-1-yl]methyl}-1,3-oxazinan-3-yl)[5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone hydrate represented by formula (1):

comprising

(a) reacting a compound represented by formula (2):

with glyoxylic acid to convert them into a compound represented by formula (3):

(b) condensing the compound represented by formula (3) with a compound represented by formula (4):

wherein R 1 represents a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, a optionally substituted C 2-6 alkynyl group, an optionally substituted C 3-6 cycloalkyl group, an optionally substituted C 3-6 cycloalkenyl group, an optionally substituted C 1-6 alkoxy group, an optionally substituted C 2-6 alkenyloxy group, an optionally substituted C 2-6 alkynyloxy group, an optionally substituted C 3-6 cycloalkoxy group, an optionally substituted C 3-6 cycloalkenyloxy group, an optionally substituted aryl group, an optionally substituted heteroaryl group, a saturated or partially saturated heterocyclyl group which is optionally substituted, or an optionally substituted C 7-12 aralkyloxy group, and X represents a halogen atom, to convert them into a compound represented by formula (5):

(c) converting the compound represented by formula (5) into a compound represented by formula (6):

wherein “chiral amine” represents an optically active amine capable of forming a salt with carboxylic acid;

(d) converting the compound represented by formula (6) into a compound represented by formula (7):

(e) converting the compound represented by formula (7) into a compound represented by formula (8):

wherein R 2 represents a protective group for carboxylic acid;

(f) converting the compound represented by formula (8) into a compound represented by formula (9):

(g) condensing the compound represented by formula (9) with a compound represented by formula (10):

to convert them into a compound represented by formula (11):

(h) converting the compound represented by formula (11) into a compound represented by formula (12):

(i) reacting a compound represented by formula (13):

wherein R 3 represents a protective group for pyrazole,

with a compound represented by formula (14):

to convert them into a compound represented by formula (15):

(j) converting the compound represented by formula (15) into a compound represented by formula (16):

(k) reacting the compound represented by formula (16) with R 4 SO 2 —X or (R 4 SO 2 ) 2 O to convert them into a compound represented by formula (17):

wherein R 4 represents an optionally substituted alkyl group, or an optionally substituted aryl group; and

(l) reacting the compound represented by formula (12) with the compound represented by formula (17) to convert them into the compound represented by formula (1).

2. A process for producing a compound represented by formula (5):

wherein R 1 represents a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, a optionally substituted C 2-6 alkynyl group, an optionally substituted C 3-6 cycloalkyl group, an optionally substituted C 3-6 cycloalkenyl group, an optionally substituted C 1-6 alkoxy group, an optionally substituted C 2-6 alkenyloxy group, an optionally substituted C 2-6 alkynyloxy group, an optionally substituted C 3-6 cycloalkoxy group, an optionally substituted C 3-6 cycloalkenyloxy group, an optionally substituted aryl group, an optionally substituted heteroaryl group, a saturated or partially saturated heterocyclyl group which is optionally substituted, or an optionally substituted C 7-12 aralkyloxy group,

comprising:

(a) condensing the compound represented by formula (2)

with the compound represented by formula (4)

wherein X represents a halogen atom,

to convert them into a compound represented by formula (18):

and

(b) reacting the compound represented by formula (18) with glyoxylic acid to convert them into the compound represented by formula (5).

3. A process for producing a compound represented by formula (5):

wherein R 1 represents a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, a optionally substituted C 2-6 alkynyl group, an optionally substituted C 3-6 cycloalkyl group, an optionally substituted C 3-6 cycloalkenyl group, an optionally substituted C 1-6 alkoxy group, an optionally substituted C 2-6 alkenyloxy group, an optionally substituted C 2-6 alkynyloxy group, an optionally substituted C 3-6 cycloalkoxy group, an optionally substituted C 3-6 cycloalkenyloxy group, an optionally substituted aryl group, an optionally substituted heteroaryl group, a saturated or partially saturated heterocyclyl group which is optionally substituted, or an optionally substituted C 7-12 aralkyloxy group,

comprising:

(a) reacting the compound represented by formula (2)

with a glyoxylic acid ester to convert them into a compound represented by formula (19):

wherein R 2 represents a protective group for carboxylic acid;

(b) condensing the compound represented by formula (19) with the compound represented by formula (4)

wherein X represents a halogen atom,

to convert them into a compound represented by formula (20):

and

(c) converting the compound represented by formula (20) into the compound represented by formula (5).

4. A compound represented by formula (21):

wherein R 5 represents an optionally substituted C 7-12 aralkyl group; or an enantiomer thereof, or a salt thereof.

5. A compound represented by formula (22):

wherein R 2 represents a protective group for carboxylic acid and R 5 represents an optionally substituted C 7-12 aralkyl group; or an enantiomer thereof.