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)
comprising:
(a) reacting a compound of formula (5) with thionyl chloride
and
(b) reacting the resulting product with 2-aminoethanol.
2. The method of claim 1 , wherein the resulting product from step (a) that is reacted in step (b) comprises impurities.
3. The method of claim 2 , wherein the yield of the produced compound of formula (1) is greater than a yield of a produced compound of formula (1) obtained by reacting the compound of formula (5) with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 2-aminoethanol.
4. The method of claim 1 , further comprising
producing a compound of formula (6) from a compound of formula (8) and a compound of formula (7);
producing a compound of formula (5) from the compound of formula (6);
wherein R 1 represents lower alkyl.
5. The method of claim 4 , further comprising
producing a compound of formula (9) from a compound of formula (11) and diphenylphosphonoacetic acid (10), and
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
reacting a compound of formula (11) with diethylphosphonoacetic acid, and treating the obtained crude product with dicyclohexylamine in methanol, and
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.
6. The method of claim 5 , further comprising
producing a compound of formula (14) from a compound of formula (16) and methyl 4-chlorobutyrate (15),
producing a compound of formula (13) from the compound of formula (14),
producing a compound of formula (12) from the compound of formula (13), and
producing the compound of formula (11) from the compound of formula (12):
wherein Ts represents p-toluenesulfonyl and Me represents methyl.