METHOD FOR THE SYNTHESIS OF QUINOLINE DERIVATIVES

• Main Authors: SISKO, JOSEPH, KOWALSKI, CONRAD, MELLINGER, MARK
• Format: Patent
• Language: English; Russian
• Published: 29.08.2002
• Edition: 7
• Subjects: CHEMISTRY; HETEROCYCLIC COMPOUNDS; HUMAN NECESSITIES; HYGIENE; MEDICAL OR VETERINARY SCIENCE; METALLURGY; ORGANIC CHEMISTRY; PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES; SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS ORMEDICINAL PREPARATIONS

1. A method for preparing a compound of formula (I): or a pharmaceutically acceptable salt form thereof, wherein: Ar is phenyl, R is C1-6 alkyl, R1 and R2 are independently hydrogen; R3 is hydrogen; R4 is hydroxy; R5 is phenyl, comprising: 1) adding a compound of formula (III): to base in a suitable solvent, to form a first reaction mixture, adding to the first reaction mixture a compound of formula (II): to form a second reaction mixture, and heating the second reaction mixture to form a compound of formula (IV): 2) isolating the compound of formula (IV) and then reacting the compound of formula (IV), in a suitable solvent, with a base to form a third reaction mixture, cooling the third reaction mixture, and adding thionyl chloride to form a fourth reaction mixture; 3) adding a compound of formula (V): to the fourth reaction mixture to form a fifth reaction mixture; 4) heating the fifth reaction mixture; and 5) optionally converting the compound of formula (I) to a pharmaceutically acceptable salt thereof, wherein Ar, R, R1, R2, R3, R4, and R5 as used in a compound of formulae (II) through (V) are as defined for a compound of formula (I). 2. A method for preparing (-)-(S)-N-(α-ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-carboxamide comprising: 1) reacting 3-hydroxy-2-phenylquinoline-4-carboxylic acid, in a suitable solvent, with triethyl amine to form a first reaction mixture, cooling the first reaction mixture, and adding thionyl chloride to form a second reaction mixture comprising 6,14,22,30-tetraphenyl[1,5,9,13]tetraoxahexadecino[2,3-c:6,7-c': 10,11-c'': 14,15c''']tetraquinoline-8,16,24,32-tetrone and ethyl 3-acetoxy-2-phenylquinoline-4-carboxylate; 2) adding (S)-1-phenylpropylamine to the second reaction mixture to form a third reaction mixture comprising (-)-(S)-N-(α-ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-carboxamide and (S)-2-phenyl-4-[[(1-phenylpropyl)amino]carbonyl]-3-quinolinyl-3-hydroxy-2-phenyl-4-quinolinecarboxylate; 3) heating the third reaction mixture; and 4) optionally converting (-)-(S)-N-(α-ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-carboxamide to a pharmaceutically acceptable salt. 3. A compound of formula (VII): wherein: Ar is phenyl, R is hydrogen, and R'4 is OH or OAc group. 4. The compound of formula (VII) according to Claim 3, which is 5. A compound of formula (VIII): wherein: Ar and R are as defined for a compound of formula (I) as claimed in Claim 1; and n is 1 or 3. 6. The method as claimed in Claim 1, wherein the compound of formula (I) is (-)-(S)-N-(α-ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-carboxamide. 7. A compound which is (-)-(S)-N-(α-ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-carboxamide, hydrochloride salt. 8. A method for preparing a compound of formula (Ia): or a pharmaceutically acceptable salt thereof, wherein: Ar is phenyl, R is C1-6 alkyl, R1 and R2 are independently hydrogen; R3 is hydrogen; R4 is hydroxy; R5 is phenyl, comprising: 1) adding a compound of formula (III): to base in a suitable solvent, to form a first reaction mixture, adding to the first reaction mixture a compound of formula (IIa): to form a second reaction mixture, and heating the second reaction mixture to form a compound of formula (IVa): 2) isolating the compound of formula (IVa) and then reacting the compound of formula (IVa), in a suitable solvent, with a base to form a third reaction mixture, cooling the third reaction mixture, and adding a carbonyl-activating agent to form a fourth reaction mixture; 3) adding a compound of formula (Va): to the fourth reaction mixture to form a fifth reaction mixture; 4) heating the fifth reaction mixture; and 5) optionally converting the compound of formula (I) to a pharmaceutically acceptable salt thereof, wherein Ar, R, R1, R2, R3, R4, and R5 as used in a compound of formulae (IIa), and (IVa) through (Va) are as defined for a compound of formula (Ia). 9. A method for preparing a compound of formula (VII) according to Claim 3, comprising: 1) adding a compound of formula (III): to at least 2-6 equivalents of aqueous base in a suitable solvent, to form a first reaction mixture, adding to the first reaction mixture a compound of formula (II'): to form a second reaction mixture, and heating the second reaction mixture to form a compound of formula (IV'): 2) isolating the compound of formula (IV') and then reacting the compound of formula (IV'), in a suitable solvent, with an amine base to form a third reaction mixture; 3) cooling the third reaction mixture below approximately 5 degree C, and adding a carbonyl-activating agent to form a fourth reaction mixture, comprising the compound of formula (VII). 10. A method according to Claim 9, wherein the aqueous base on stage 1 is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, or barium hydroxide. 11. A method according to Claim 10, wherein for forming of the first reaction mixture 4 equivalents of the aqueous base are used. 12. A method according to Claim 9, wherein the amine base on stage 2 is selected from triethylamine or diisopropylethylamine. 13. A method according to Claim 9, additionally comprising adding the amine compound of formula (V), as it is determined in Claim 1, to fourth reaction mixture to form fifth reaction mixture. 14. A method according to Claim 13, additionally comprising heating the fifth reaction mixture to form the compound of formula (I), as it is determined in Claim 1. 15. A method according to Claim 14, additionally comprising converting the compound of formula (I) into a pharmaceutically acceptable salt thereof. 16. The compound according to Claim 5, which is selected from 6,14-diphenyl [1,5]dioxocino [2,3-c:6,7-c']diquinoline-8,16-dione or 6,14,22,30-tetraphenyl [1,5,9,13]tetraoxahexadecino [2,3-c:6,7-c':10,11-c'':14,15-c''']tetraquinoline-8,16,24,32-tetrone. Данное изобретение относится к новым промежуточным веществам и способам получения фармацевтически активных соединений хинолина, включая (-)-(S)-N-(α-этилбензил)-3-гидрокси-2-фенилхинолин-4-карбоксамид.