2-(7-chloro[1,8]naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone -Drug Synthesis Database

【结构式】

【分子编号】47678

【品名】2-(7-chloro[1,8]naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone

【CA登记号】

【分子式】C₂₃H₂₂ClN₃O₂

【分子量】407.8994

【元素组成】C 67.73% H 5.44% Cl 8.69% N 10.3% O 7.84%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(VII)

Condensation of 7-hydroxy-1,8-naphthyridin-2-amine (I) with phthalic anhydride (II) in refluxing acetic acid gives N-(7-hydroxy-1,8-naphthyridin-2-yl)phthalimide (III), which is treated with refluxing POCl3 to yield the 7-chloro derivative (IV). Reduction of compound (IV) with KBH4 in dioxane affords 2-(7-chloro-1,8-naphthyridin-2-yl)-3-hydroxyisoindolin-1-one (V), which is condensed with 5-methyl-2-hexanone (VI) by means of NaH in DMF to give (±)-2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)isoindolin-1-one (VII) (racemic pagoclone). The treatment of (VII) with NaOH in dioxane/water yields the racemic benzoic acid (VIII). Optical resolution of racemic (VIII) by means of (+)-ephedrine or cinchonine affords the (+)-isomer (IX), which is finally cyclized to the chiral (+)-indolinone derivative pagoclone by means of SOCl2 and imidazole in dichloromethane.

参考文献中间体

合成目标

【1】 Silvestre, J.S.; Castaner, J.; Leeson, P.A.; Sorbera, L.A.; Pagoclone. Drugs Fut 2001, 26, 7, 651.
【2】 Bourzat, J.-D.; Cotrel, C.; Roussel, G.; Capet, M.; Labaudiniere, R.; Pitchen, P. (Aventis SA); Isoindolinone derivs.. AU 8781911; EP 0274930; FR 2607503; JP 1988154681; US 4960779 .
【3】 David-Comte, M.-T.; Roussel, G. (Aventis Pharma SA); Novel 2-aminonaphthyridine deriv., its preparation and its use. EP 0522969; FR 2678931 .
【4】 David-Comte, M.-T. (Aventis Pharma SA); Dextrorotatory isomer of a deriv. of 2-amino naphthyridine and its preparation. EP 0522971; FR 2678933 .
【5】 David-Comte, M.-T. (Aventis Pharma SA); Process for the preparation of a dextrorotatory isomer of an isoindolinone deriv.. EP 0522972; FR 2678934 .
【6】 David-Comte, M.-T. (Aventis Pharma SA); Process for the preparation of the optical isomers of 2-aminonaphthyridine derivs.. EP 0522970; FR 2678932 .
【7】 Cotrel, C.; Crisan, C.; Jeanmart, C.; Messer, M.N. (Aventis Pharma SA); Heterocyclic compounds. BE 0835325; DE 2550111; FR 2313060; FR 2322600; FR 2322601; FR 2322602; GB 1468497; JP 7670776; JP 7733685; JP 7998790; JP 8040671; JP 8051087; US 4220646 .
【8】 (Aventis Pharma SA); Novel isoindoline derivs., their preparation and compsns. containing them. FR 2229400 .

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)	28994	7-amino[1,8]naphthyridin-2-ol		C₈H₇N₃O	详情	详情
(II)	11900	2-Benzofuran-1,3-dione;1,2-Benzenedicarboxylic Anhydride;1,2-BENZENE DICARBOXYLIC ACID ANHYDRIDE;1,2-BENZENEDICARBONIC ACID, ANHYDRIDE;1,3-DIOXOPHTHALAN;1,3-ISOBENZOFURANDIONE;o-phthalic anhydride; Phthalic anhydride	85-44-9	C₈H₄O₃	详情	详情
(III)	47675	2-(7-hydroxy[1,8]naphthyridin-2-yl)-1H-isoindole-1,3(2H)-dione		C₁₆H₉N₃O₃	详情	详情
(IV)	47676	2-(7-chloro[1,8]naphthyridin-2-yl)-1H-isoindole-1,3(2H)-dione		C₁₆H₈ClN₃O₂	详情	详情
(V)	11334	2-(7-Chloro[1,8]naphthyridin-2-yl)-3-hydroxy-1-isoindolinone		C₁₆H₁₀ClN₃O₂	详情	详情
(VI)	47677	2-Methyl-5-Hexanone; 5-Methyl-2-hexanone; 5-Methyl-2-oxohexane; iso-Amyl methyl ketone; Isopentyl methyl ketone; Methyl isoamyl ketone	110-12-3	C₇H₁₄O	详情	详情
(VII)	47678	2-(7-chloro[1,8]naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone		C₂₃H₂₂ClN₃O₂	详情	详情
(VIII)	47679	(rac)-2-[1-[(7-chloro[1,8]naphthyridin-2-yl)amino]-6-methyl-3-oxoheptyl]benzoic acid		C₂₃H₂₄ClN₃O₃	详情	详情
(IX)	47680	(+)-2-[1-[(7-chloro[1,8]naphthyridin-2-yl)amino]-6-methyl-3-oxoheptyl]benzoic acid		C₂₃H₂₄ClN₃O₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VII)

The isoindolinone (VII) (racemic pagoclone) can also be obtained by reaction of isoindolinone (V) with SOCl2 in DMF to provide 3-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)isoindolin-1-one (X), which is condensed with 3-oxo-6-methylheptanoic acid ethyl ester (XI) by means of NaH in DMF to yield 2-[2-(7-chloro-1,8-naphthyridin-2-yl)-3-oxoisoindolin-1-yl-6-methyl-3-oxoheptanoic acid ethyl ester (XII). Finally, this compound is decarboxylated to the indolinone (VII) by means of LiCl in refluxing DMSO/water. The racemic benzoic acid (VIII) can also be obtained by hydrolysis of the heptanoic ester (XII) with concentrated sulfuric acid to give the corresponding free acid (XIII), which is finally decarboxylated and hydrolyzed by means of NaOH in water.

参考文献中间体

合成目标

【1】 Silvestre, J.S.; Castaner, J.; Leeson, P.A.; Sorbera, L.A.; Pagoclone. Drugs Fut 2001, 26, 7, 651.
【2】 Bourzat, J.-D.; Cotrel, C.; Roussel, G.; Capet, M.; Labaudiniere, R.; Pitchen, P. (Aventis SA); Isoindolinone derivs.. AU 8781911; EP 0274930; FR 2607503; JP 1988154681; US 4960779 .
【3】 David-Comte, M.-T. (Aventis Pharma SA); Dextrorotatory isomer of a deriv. of 2-amino naphthyridine and its preparation. EP 0522971; FR 2678933 .
【4】 David-Comte, M.-T.; Roussel, G. (Aventis Pharma SA); Novel 2-aminonaphthyridine deriv., its preparation and its use. EP 0522969; FR 2678931 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(V)	11334	2-(7-Chloro[1,8]naphthyridin-2-yl)-3-hydroxy-1-isoindolinone	C₁₆H₁₀ClN₃O₂	详情	详情
(VII)	47678	2-(7-chloro[1,8]naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone	C₂₃H₂₂ClN₃O₂	详情	详情
(VIII)	47679	(rac)-2-[1-[(7-chloro[1,8]naphthyridin-2-yl)amino]-6-methyl-3-oxoheptyl]benzoic acid	C₂₃H₂₄ClN₃O₃	详情	详情
(X)	47681	3-chloro-2-(7-chloro[1,8]naphthyridin-2-yl)-1-isoindolinone	C₁₆H₉Cl₂N₃O	详情	详情
(XI)	47682	Ethyl isoamylacetoacetate; ethyl 6-methyl-3-oxoheptanoate	C₁₀H₁₈O₃	详情	详情
(XII)	47683	ethyl 2-[2-(7-chloro[1,8]naphthyridin-2-yl)-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-6-methyl-3-oxoheptanoate	C₂₆H₂₆ClN₃O₄	详情	详情
(XIII)	47684	2-[2-(7-chloro[1,8]naphthyridin-2-yl)-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-6-methyl-3-oxoheptanoic acid	C₂₄H₂₂ClN₃O₄	详情	详情

合成路线3

该中间体在本合成路线中的序号：(VII)

The optical resolution of racemic pagoclone (VII) can also be performed by reaction with (-)-(1R,2R,3S,5R)-pinanediol (XIV) by means of PPTS in refluxing dichloroethane to give the ketal (XV) as a diastereomeric mixture separated by crystallization. Finally, hydrolysis of the desired diastereomer (XVI) with 12N HCl affords the (+)-enantiomer, pagoclone.

参考文献中间体

合成目标

【1】 Silvestre, J.S.; Castaner, J.; Leeson, P.A.; Sorbera, L.A.; Pagoclone. Drugs Fut 2001, 26, 7, 651.
【2】 Barreau, M.; Cotrel, C.; Dubroeucq, M.-C.; Manfre, F. (Aventis Pharma SA); Method for preparing enantiomers of an isoindolinone deriv.. WO 9313098 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VII)	47678	2-(7-chloro[1,8]naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone		C₂₃H₂₂ClN₃O₂	详情	详情
(XIV)	16644	(-)-Pinanediol; (1R,2R,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]heptane-2,3-diol	20536-52-1	C₁₀H₁₈O₂	详情	详情
(XV)	47685	(rac)-2-(7-chloro[1,8]naphthyridin-2-yl)-3-[[(1R,2R,6S,8R)-4-isopentyl-2,9,9-trimethyl-3,5-dioxatricyclo[6.1.1.0(2,6)]dec-4-yl]methyl]-1-isoindolinone		C₃₃H₃₈ClN₃O₃	详情	详情
(XVI)	47686	(+)-2-(7-chloro[1,8]naphthyridin-2-yl)-3-[[(1R,2R,6S,8R)-4-isopentyl-2,9,9-trimethyl-3,5-dioxatricyclo[6.1.1.0(2,6)]dec-4-yl]methyl]-1-isoindolinone		C₃₃H₃₈ClN₃O₃	详情	详情

Extended Information