Highly E-selective and effective synthesis of antiarthritic drug candidate S-2474 using quinone methide derivatives.
We have developed an efficient and E-selective synthesis of an antiarthritic drug candidate (E)-(5)-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-ethyl-1,2-isothiazolidine-1,1-dioxide (S-2474; 1), in which alpha-methoxy-p-quinone methide is used as a key intermediate. alpha-Methoxy-p-quinone methide was revealed to be an equivalent to a p-hydroxy protected benzaldehyde. It reacts smoothly with alpha-sulfonyl carbanion to give 1,6-addition intermediates, which can be further processed to provide S-2474 directly in the presence of a base. This procedure gives S-2474 as an almost single isomer on the benzylidene double bond in excellent yield and thus is a very practical method adaptable to large-scale synthesis. The detailed mechanistic aspects are studied and discussed.
Inagaki
Masanao
M
Shionogi Research Laboratories, Shionogi & Company, Ltd., Fukushima-ku, Osaka 553-0002, Japan.
Haga
Nobuhiro
N
Kobayashi
Makoto
M
Ohta
Naoki
N
Kamata
Susumu
S
Tsuri
Tatsuo
T
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry / Q000302:isolation & purification; D018501:Antirheumatic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000302:isolation & purification; D003460:Crystallization; D003499:Cyclic S-Oxides / Q000138:chemical synthesis* / Q000737:chemistry / Q000302:isolation & purification; D045563:Indolequinones; D007211:Indoles / Q000737:chemistry; D011809:Quinones / Q000737:chemistry; D012997:Solvents; D013237:Stereoisomerism; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000302:isolation & purification
C409872:((E)-(5)-(3,5-di-tert-butyl-4-hydroxybenzylidene)- 2-ethyl-1,2-isothiazolidine-1,1-dioxide); D000894:Anti-Inflammatory Agents, Non-Steroidal; D018501:Antirheumatic Agents; D003499:Cyclic S-Oxides; D045563:Indolequinones; D007211:Indoles; D011809:Quinones; D012997:Solvents; D013844:Thiazoles; C068040:quinone methide