Method for producing 4,4,7-trifluoro-1,2,3,4-tetrahydro-5H-1-benzazepine compound and intermediate used in the method
The present invention provides a method for producing a 4,4,7-trifluoro-1,2,3,4-tetrahydro-5H-1-benzazepine compound which has an superior agonistic activity to an arginine vasopressin V2 receptor and is useful as an active ingredient for a pharmaceutical composition for preventing and/or treating urinary frequency, urinary incontinence, enuresis, central diabetes insipidus, nocturia, nocturnal enuresis, or the like; and useful intermediates for use in the methods. The production method of the present invention is suitable for the industrial production of a medicament, because of a smaller number of steps, a higher yield, and a lower cost, as compared with the methods in the related art.
1. A method for producing a compound of formula (1) shown in a reaction scheme below, comprising:
a step of reacting a compound of formula (5) with thionyl chloride (4) to produce a compound of formula (3); and
a step of amidating the compound of formula (3) by reacting with 2-aminoethanol (2):
wherein Me represents methyl.
2. A method for producing a compound of formula (1) shown in a reaction scheme below, comprising:
a step of producing a compound of formula (6) from a compound of formula (8) and a compound of formula (7);
a step of producing a compound of formula (5) from the compound of formula (6);
a step of producing a compound of formula (3) by reacting the compound of formula (5) with thionyl chloride (4); and
a step of amidating the compound of formula (3) by reacting with 2-aminoethanol (2):
wherein Me represents methyl and R 1 represents lower alkyl.
3. The method for producing a compound of formula (1) according to claim 2 , using the compound of formula (8) produced by:
(X-1) a method for producing the compound of formula (8) shown in a reaction scheme below, consisting of:
a step of producing a compound of formula (9) from a compound of formula (11) and diphenylphosphonoacetic acid (10), and
a step of producing the compound of formula (8) from the compound of formula (9):
wherein Ts represents p-toluenesulfonyl, Ph represents phenyl, and R 1 represents lower alkyl; or
(X-2) a method for producing the compound of formula (8) shown in a reaction scheme below, consisting of:
a step of producing a compound of formula (9-S) by reacting a compound of formula (11) with diethylphosphonoacetic acid (18), and treating the obtained crude product with dicyclohexylamine (17) in methanol, and
a step of producing the compound of formula (8) from the compound of formula (9-S):
wherein Ts represents p-toluenesulfonyl, Et represents ethyl, and R 1 represents lower alkyl.
4. The method for producing the compound of formula (1) according to claim 3 , using the compound of formula (11) produced by:
(Y-1) a method for producing the compound of formula (11) shown in a reaction scheme below, consisting of:
a step of producing a compound of formula (14) from a compound of formula (16) and methyl 4-chlorobutyrate (15),
a step of producing a compound of formula (13) from the compound of formula (14),
a step of producing a compound of formula (12) from the compound of formula (13), and
a step of producing the compound of formula (11) from the compound of formula (12):
wherein Ts represents p-toluenesulfonyl and Me represents methyl.
5. The method for producing the compound of formula (1) according to claim 4 , wherein in the production method (Y-1), the compound of formula (13) is produced without isolating the compound of formula (14), and the compound of formula (12) is produced without isolating the compound of formula (13).
6. The method for producing the compound of formula (1) according to any one of claims 2 to 5 , using the compound of formula (7) produced by any one of:
(Z-1) a method for producing the compound of formula (7) shown in a reaction scheme below, consisting of:
a step of producing a compound of formula (7a) from a compound of formula (7c) and (2R)-2-fluoropropanol (7b), and
a step of producing the compound of formula (7) from the compound of formula (7a):
wherein Lv represents leaving group, Me represents methyl, iPr represents isopropyl, and R represents isopropyl or (2R)-2-fluoropropyl;
(Z-2) a method for producing the compound of formula (7) shown in a reaction scheme below, which is
a step of producing the compound of formula (7) from the compound of formula (7e) and (2R)-2-fluoropropanol (7b):
wherein Lv represents a leaving group and Me represents methyl; or
(Z-3) a method for producing the compound of formula (7) shown in a reaction scheme below, consisting of:
a step of producing a compound of formula (7g) from a compound of formula (7i) and (S)-glycidyl 3-nitrobenzenesulfonate (7h),
a step of producing a compound of formula (7f) by hydrogenation reaction of the compound of formula (7g), and
a step of producing the compound of formula (7) from the compound of formula (7f):
wherein R 2 represents lower alkyl and Me represents methyl.
7. The method for producing a compound of formula (1)
comprising using the compound of formula (8) produced by the method shown in (X-1) according to claim 3 and a compound of formula (7) produced by a reaction scheme below, consisting of:
a step of producing a compound of formula (7a) from a compound of formula (7c) and (2R)-2-fluoropropanol (7b), and
a step of producing a compound of formula (7) from the compound of formula (7a):
wherein Lv represents leaving group, Me represents methyl, iPr represents isopropyl, and R represents isopropyl or (2R)-2-fluoropropyl.
8. The method for producing a compound of formula (1) according to claim 2 ,
comprising using the compound of formula (8) produced by the method shown in (X-2) according to claim 3 and a compound of formula (7) produced by a reaction scheme below, consisting of:
a step of producing a compound of formula (7a) from a compound of formula (7c) and (2R)-2-fluoropropanol (7b), and
a step of producing a compound of formula (7) from the compound of formula (7a):
wherein Lv represents leaving group, Me represents methyl, iPr represents isopropyl, and R represents isopropyl or (2R)-2-fluoropropyl.
9. The method for producing a compound of formula (1)
comprising using the compound of formula (8) produced by the method shown in (X-1) according to claim 3 and compound of formula (7) produced by a reaction scheme below, which is
a step of producing the compound of formula (7) from the compound of formula (7e) and (2R)-2-fluoropropanol (7b):
wherein Lv represents a leaving group and Me represents methyl.
10. The method for producing a compound of formula (1)
comprising using the compound of formula (8) produced by the method shown in (X-2) according to claim 3 and the compound of formula (7) produced by a reaction scheme below, which is
a step of producing the compound of formula (7) from the compound of formula (7e) and (2R)-2-fluoropropanol (7b):
wherein Lv represents a leaving group and Me represents methyl.
11. The method for producing a compound of formula (1)
comprising using the compound of formula (8) produced by the method shown in (X-1) according to claim 3 and a compound of formula (7) produced by a reaction scheme below consisting of:
a step of producing a compound of formula (7g) from a compound of formula (7i) and (S)-glycidyl 3-nitrobenzenesulfonate (7h),
a step of producing a compound of formula (7f) by hydrogenation reaction of the compound of formula (7g), and
a step of producing the compound of formula (7) from the compound of formula (7f):
wherein R 2 represents lower alkyl and Me represents methyl.
12. The method for producing a compound of formula (1)
comprising using the compound of formula (8) produced by the method shown in (X-2) according to claim 3 and a compound of formula (7) produced by a reaction scheme below consisting of:
a step of producing a compound of formula (7g) from a compound of formula (7i) and (S)-glycidyl 3-nitrobenzenesulfonate (7h),
a step of producing a compound of formula (7f) by hydrogenation reaction of the compound of formula (7g), and
a step of producing the compound of formula (7) from the compound of formula (7f):
wherein R 2 represents lower alkyl and Me represents methyl.
13. The method for producing the compound of formula (1) according to any one of claims 7 to 12 , using the compound of formula (11) produced by a method shown in a reaction scheme below, consisting of:
a step of producing a compound of formula (14) from a compound of formula (16) and methyl 4-chlorobutyrate (15),
a step of producing a compound of formula (13) from the compound of formula (14),
a step of producing a compound of formula (12) from the compound of formula (13), and
a step of producing the compound of formula (11) from the compound of formula (12):
wherein Ts represents p-toluenesulfonyl and Me represents methyl.
14. The method for producing the compound of formula (1) according to claim 13 , wherein in the production method (Y-1), the compound of formula (13) is produced without isolating the compound of formula (14), and the compound of formula (12) is produced without isolating the compound of formula (13).
15. (2Z)-{4,4,7-Trifluoro-1-[4-{[(2R)-2-fluoropropyl]oxy}-2-(trifluoromethyl)benzoyl]-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene}acetyl chloride.
16. Methyl 5-fluoro-2-{(4-methoxy-4-oxobutyl)[(4-methylphenyl)sulfonyl]amino}benzoate.