Isaglitazone, Netoglitazone, RWJ-241947, MCC-555, -Drug Synthesis Database

【结构式】

【药物名称】Isaglitazone, Netoglitazone, RWJ-241947, MCC-555

【化学名称】5-[6-(2-Fluorobenzyloxy)naphthalen-2-ylmethyl]thiazolidine-2,4-dione

【CA登记号】161600-01-7, 161599-99-1 (sodium salt)

【分子式】C₂₁H₁₆FNO₃S

【分子量】381.42897

【开发单位】Mitsubishi Pharma (Originator), Johnson & Johnson (Licensee)

【药理作用】Antidiabetic Drugs, ENDOCRINE DRUGS, Type 2 Diabetes Mellitus, Agents for, Insulin Sensitizers, PPARalpha Agonists, PPARgamma Agonists, Thiazolidinediones (Glitazones)

合成路线1 合成路线2

合成路线1

Reduction of 6-hydroxynaphthalen-2-carboxylic acid (I) by means of trimethyl borate and BH3.THF complex obtained by reaction of NaBH4 and dimethyl sulfate in THF yields the naphthyl carbinol derivative (II), which is oxidized to aldehyde (III) with either manganese dioxide in DMF or acetone, mixtures of CuCl2, CuBr2 or FeCl3 with 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) in DMF or O2, TEMPO and a ruthenium catalyst in chlorobenzene. Condensation of aldehyde (III) with thiazolidine-2,4-dione (IV) in 2-methoxyethanol, 2-propanol, DMF or DMSO gives 5-(6-hydroxynaphthalen-2-ylmethylene)thiazolidine-2,4-dione (V), which is then reduced with either H2 over catalyst or cyclohexene to provide 5-(6-hydroxynaphthalen-2-ylmethyl)thiazolidine-2,4-dione (VI). Finally, compound (VI) is condensed with 2-fluorobenzyl chloride (VII) by means of NaH or KH in DMF, DMSO or NMP.

参考文献中间体

【1】 del Fresno, M.; Sorbera, L.A.; Castaner, J.; Silvestre, J.S.; Netoglitazone. Drugs Fut 2002, 27, 2, 132.
【2】 Ohe, T.; Suehiro, I.; Sekiya, T.; Ueno, H. (Mitsubishi Chemical Corp.); Preparation method of naphthalene derivs.. JP 1998139768 .
【3】 Ichikawa, S.; Iwane, H.; Qu, J. (Mitsubishi Chemical Corp.); 6-Hydroxy-2-naphthylcarbinol and process for the preparation thereof. WO 0073252 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	51716	6-Hydroxy-2-naphthoic acid; 2-Naphthol-6-carboxylic Acid	16712-64-4	C₁₁H₈O₃	详情	详情
(II)	51717	6-(hydroxymethyl)-2-naphthol		C₁₁H₁₀O₂	详情	详情
(III)	51718	6-hydroxy-2-naphthaldehyde		C₁₁H₈O₂	详情	详情
(IV)	10883	1,3-Thiazolane-2,4-dione; 2,4-Thiazolidinedione	2295-31-0	C₃H₃NO₂S	详情	详情
(V)	51719	5-[(E)-(6-hydroxy-2-naphthyl)methylidene]-1,3-thiazolidine-2,4-dione		C₁₄H₉NO₃S	详情	详情
(VI)	51720	5-[(6-hydroxy-2-naphthyl)methyl]-1,3-thiazolidine-2,4-dione		C₁₄H₁₁NO₃S	详情	详情
(VII)	51721	alpha-Chloro-2-fluorotoluene; 2-Fluorobenzyl chloride; alpha-Chloro-O-Fluorotoluene; o-Fluorobenzyl chloride; 1-Chloromethyl-2-fluorobenzene	345-35-7	C₇H₆ClF	详情	详情

合成路线2

Reaction of aldehyde (III) with 2-fluorobenzyl alcohol (VIII) by means of triphenylphosphine and diethyl azodicarboxylate (DEAD) in THF furnishes 6-(2-fluorobenzyloxy)naphthalene-2-carbaldehyde (IX) , which is then reduced with NaBH4 in ethanol/THF to give the naphthalenemethanol derivative (X). Halogenation of (X) by means of iodide, triphenylphosphine and imidazole in THF yields the naphthylmethyl iodide derivative (XI), which is finally condensed with thiazolidine-2,4-dione (IV) by means of HMPA and butyl lithium in THF.

参考文献中间体

【1】 del Fresno, M.; Sorbera, L.A.; Castaner, J.; Silvestre, J.S.; Netoglitazone. Drugs Fut 2002, 27, 2, 132.
【2】 Ueno, H.; Oe, T.; Suehiro, I.; Nakamura, F. (Mitsubishi Chemical Corp.); Naphthalene derivs.. EP 0604983; JP 1994247945; US 5594016 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(III)	51718	6-hydroxy-2-naphthaldehyde		C₁₁H₈O₂	详情	详情
(IV)	10883	1,3-Thiazolane-2,4-dione; 2,4-Thiazolidinedione	2295-31-0	C₃H₃NO₂S	详情	详情
(VIII)	51722	2-Fluorobenzyl alcohol	446-51-5	C₇H₇FO	详情	详情
(IX)	51723	6-[(2-fluorobenzyl)oxy]-2-naphthaldehyde		C₁₈H₁₃FO₂	详情	详情
(X)	51724	[6-[(2-fluorobenzyl)oxy]-2-naphthyl]methanol		C₁₈H₁₅FO₂	详情	详情
(XI)	51725	2-[(2-fluorobenzyl)oxy]-6-(iodomethyl)naphthalene; 2-fluorobenzyl 6-(iodomethyl)-2-naphthyl ether		C₁₈H₁₄FIO	详情	详情

Extended Information