Pazelliptine, SR-95225B(triHCl), NSC-629464J(triHCl), BD-40, NSC-327471D, -Drug Synthesis Database

【结构式】

【药物名称】Pazelliptine, SR-95225B(triHCl), NSC-629464J(triHCl), BD-40, NSC-327471D

【化学名称】N,N-Diethyl-N'-(6-methyl-5H-pyrido[3',4':4,5]pyrrolo[2,3-g]isoquinolin-10-yl)propane-1,3-diamine
　　　　　　1-[3-(Diethylamino)propyl]amino-5-methyldipyrido[4,3-b][3,4-f]indole
　　　　　　10-[3-(Diethylamino)propylamino]-6-methyl-5H-pyrido[3',4':4,5]pyrrolo[2,3-g]isoquinoline

【CA登记号】65222-35-7

【分子式】C₂₂H₂₇N₅

【分子量】361.49399

【开发单位】Institut Curie (Originator), Sanofi-synthélabo (Licensee)

【药理作用】ONCOLYTIC DRUGS

合成路线1 合成路线2 合成路线3

合成路线1

The acetylation of 2-methyl-3-aminobenzonitrile (I) with acetic anhydride in refluxing acetic acid gives 2-methyl-3-acetylaminobenzonitrile (II), which is reduced with Raney-Ni in refluxing 50% formic acid yielding 2-methyl-3-acetylaminobenzaldehyde (III). The condensation of (III) with malonic acid (IV) by means of piperidine in pyridine affords 2-methyl-3-acetylaminocinn acid (V), which is converted to the corresponding azide (VI) by reaction with ethyl chloroformate and sodium azide by means of triethylamine in acetone. The cyclization of (VI) by heating at 240 C in diphenyl ether gives 1-hydroxy-5-methyl-6-acetylaminoisoquinoline (VII), which is hydrolyzed with HCl in refluxing ethanol to 1-hydroxy-5-methyl-6-aminoisoquinoline (VIII). The condensation of (VIII) with 4-chloro-3-nitropyridine (IX) in DMF affords 1-hydroxy-5-methyl-6-[(3-nitro-4-pyridyl)amino]isoquinoline (X).

参考文献中间体

【1】 Rivalle, C.; Lhoste, J.M.; Bisagni, E.; Duerocq, C.; Synthesis of 10-substituted 5H-pyrido[3',4':4,5]pyrrolo[2,3-g]isoquinolines. J Chem Soc - Perkins Trans I 1979, 142-145.
【2】 Van der Burg, W.J. (Akzo Nobel N.V.); Tetracyclic compounds. BE 0840362; CH 622261; DE 2614406; DK 142498; ES 446634; FR 2305986; GB 1543171; JP 76122099; NL 754075 .
【3】 Hopkins, S.J.; Serradell, M.N.; Castaner, J.; BD-40. Drugs Fut 1984, 9, 2, 96.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	29968	N-(5-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)acetamide		C₁₂H₁₂N₂O₂	详情	详情
(I)	29963	3-amino-2-methylbenzonitrile		C₈H₈N₂	详情	详情
(II)	29964	N-(3-cyano-2-methylphenyl)acetamide		C₁₀H₁₀N₂O	详情	详情
(III)	29965	N-(3-formyl-2-methylphenyl)acetamide		C₁₀H₁₁NO₂	详情	详情
(IV)	12963	Malonic acid	141-82-2	C₃H₄O₄	详情	详情
(V)	29966	(Z)-3-[3-(acetamido)-2-methylphenyl]-2-propenoic acid		C₁₂H₁₃NO₃	详情	详情
(VI)	29967	(Z)-3-[3-(acetamido)-2-methylphenyl]-2-propenoyl azide		C₁₂H₁₂N₄O₂	详情	详情
(VII)	29969	N-(1-hydroxy-5-methyl-6-isoquinolinyl)acetamide		C₁₂H₁₂N₂O₂	详情	详情
(VIII)	29970	6-amino-5-methyl-1-isoquinolinol		C₁₀H₁₀N₂O	详情	详情
(IX)	29971	4-chloro-3-nitropyridine		C₅H₃ClN₂O₂	详情	详情
(X)	29972	5-methyl-6-[(3-nitro-4-pyridinyl)amino]-1-isoquinolinol		C₁₅H₁₂N₄O₃	详情	详情

合成路线2

Compound (X) is reduced with H2 over Pd/C in acetic acid to 1-hydroxy-5-methyl-6-[(3-amino-4-pyridyl)amino]isoquinolin (Xl). The treatment of (XI) with NaNO2 in acetic acid yields 1-(1-hydroxy-5-methyl-6-isoquinolyl)triazolo[4,5-c]pyridine (XII), which is converted into 1-hydroxy-5-methyldipyrido[4,3-b][3,4-f]indole (XIII). The reaction of (XIII) with PCl5 in refluxing POCl3 gives 1-chloro-5-methyldipyrido[4,3-b][3,4-f]indole (XIV), which is finally condensed with 3-(diethylamino)propylamine (XV) by heating at 150 C.

参考文献中间体

【1】 Rivalle, C.; Lhoste, J.M.; Bisagni, E.; Duerocq, C.; Synthesis of 10-substituted 5H-pyrido[3',4':4,5]pyrrolo[2,3-g]isoquinolines. J Chem Soc - Perkins Trans I 1979, 142-145.
【2】 Van der Burg, W.J. (Akzo Nobel N.V.); Tetracyclic compounds. BE 0840362; CH 622261; DE 2614406; DK 142498; ES 446634; FR 2305986; GB 1543171; JP 76122099; NL 754075 .
【3】 Hopkins, S.J.; Serradell, M.N.; Castaner, J.; BD-40. Drugs Fut 1984, 9, 2, 96.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(X)	29972	5-methyl-6-[(3-nitro-4-pyridinyl)amino]-1-isoquinolinol		C₁₅H₁₂N₄O₃	详情	详情
(XI)	29973	6-[(3-amino-4-pyridinyl)amino]-5-methyl-1-isoquinolinol		C₁₅H₁₄N₄O	详情	详情
(XII)	29974	5-methyl-6-(1H-[1,2,3]triazolo[4,5-c]pyridin-1-yl)-1-isoquinolinol		C₁₅H₁₁N₅O	详情	详情
(XIII)	29975	6-methyl-5H-pyrido[3',4':4,5]pyrrolo[2,3-g]isoquinolin-10-ol		C₁₅H₁₁N₃O	详情	详情
(XIV)	29976	10-chloro-6-methyl-5H-pyrido[3',4':4,5]pyrrolo[2,3-g]isoquinoline		C₁₅H₁₀ClN₃	详情	详情
(XV)	29977	N-(3-aminopropyl)-N,N-diethylamine; N(1),N(1)-diethyl-1,3-propanediamine	104-78-9	C₇H₁₈N₂	详情	详情

合成路线3

1-hydroxy-5-methyl-6-[(3-nitro-4-pyridyl)amino]isoquinoline (X) is heated with phosphorous chloride oxide to give 1-chloro-5-methyl-6-[(3-nitro-4-pyridyl)amino]isoquinoline (XVI), which is reduced with H2 over Raney-Ni giving 6-[(3-amino-4-pyridyl)amino]-1-chloro-5-methylisoquinoline (XVII). This compound is treated with sodium nitrite to give 1-(1-chloro-5-methyl-6-isoquinolyl)triazolo[4,5-c]pyridine (XVIII), which is cyclized to 1-chloro-5-methylpyrido[4,3-b][3,4-f]indole (XIV), which is finally condensed with 3-(diethylamino)propylamine (XV) by heating at 150 C.

参考文献中间体

【1】 Rivalle, C.; Lhoste, J.M.; Bisagni, E.; Duerocq, C.; Synthesis of 10-substituted 5H-pyrido[3',4':4,5]pyrrolo[2,3-g]isoquinolines. J Chem Soc - Perkins Trans I 1979, 142-145.
【2】 Hopkins, S.J.; Serradell, M.N.; Castaner, J.; BD-40. Drugs Fut 1984, 9, 2, 96.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(X)	29972	5-methyl-6-[(3-nitro-4-pyridinyl)amino]-1-isoquinolinol		C₁₅H₁₂N₄O₃	详情	详情
(XIV)	29976	10-chloro-6-methyl-5H-pyrido[3',4':4,5]pyrrolo[2,3-g]isoquinoline		C₁₅H₁₀ClN₃	详情	详情
(XV)	29977	N-(3-aminopropyl)-N,N-diethylamine; N(1),N(1)-diethyl-1,3-propanediamine	104-78-9	C₇H₁₈N₂	详情	详情
(XVI)	29978	N-(1-chloro-5-methyl-6-isoquinolinyl)-N-(3-nitro-4-pyridinyl)amine; 1-chloro-5-methyl-N-(3-nitro-4-pyridinyl)-6-isoquinolinamine		C₁₅H₁₁ClN₄O₂	详情	详情
(XVII)	29979	N-(3-amino-4-pyridinyl)-N-(1-chloro-5-methyl-6-isoquinolinyl)amine; N(4)-(1-chloro-5-methyl-6-isoquinolinyl)-3,4-pyridinediamine		C₁₅H₁₃ClN₄	详情	详情
(XVIII)	29980	1-chloro-5-methyl-6-(1H-[1,2,3]triazolo[4,5-c]pyridin-1-yl)isoquinoline		C₁₅H₁₀ClN₅	详情	详情

Extended Information