tert-butyl 4-[[(7-chloro-3-methyl-2-[[(methylsulfonyl)oxy]methyl]-4-oxo-3,4-dihydro-6-quinazolinyl)methyl](2-propynyl)amino]benzoate -Drug Synthesis Database

【结构式】

【分子编号】46871

【品名】tert-butyl 4-[[(7-chloro-3-methyl-2-[[(methylsulfonyl)oxy]methyl]-4-oxo-3,4-dihydro-6-quinazolinyl)methyl](2-propynyl)amino]benzoate

【CA登记号】

【分子式】C₂₆H₂₈ClN₃O₆S

【分子量】546.04364

【元素组成】C 57.19% H 5.17% Cl 6.49% N 7.7% O 17.58% S 5.87%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(XV)

Bromination of 3-chloro-4-methylaniline (I) in HOAc-Et2O afforded a mixture of the desired 2-bromo-5-chloro-4-methylaniline (II) and the dibromo derivative (III), which were separated by column chromatography. In an alternative procedure, aniline (I) was converted to the acetanilide (IV), which was then brominated to give (V). Subsequent acid hydrolysis of amide (V) provided the bromo aniline (II). Treatment of (II) with CuCN in hot NMP furnished nitrile (VI). This was hydrolyzed to the corresponding carboxylic acid (VII) using potassium hydroperoxide generated in situ. Cyclization of (VII) with chloroacetonitrile in the presence of NaOMe generated the quinazolinone system (VIII). The acetate ester (IX) was then obtained by displacement of the chloride group of (VIII) with cesium acetate in hot DMF. Further N-alkylation of quinazoline (IX) using methyl iodide and NaH produced (X). The bromomethyl derivative (XI) was prepared by benzylic bromination of (X) with N-bromosuccinimide in the presence of benzoyl peroxide. Condensation of bromide (XI) with tert-butyl 4-(N-propargylamino)benzoate (XII) yielded adduct (XIII). The acetate ester of (XIII) was then hydrolyzed with NaOH to give the hydroxymethyl quinazoline (XIV), which was subsequently converted to the mesylate (XV) upon treatment with methanesulfonic anhydride and Et3N.

参考文献中间体

合成目标

【1】 Bavetsias, V.; et al.; The design and synthesis of water-soluble analogues of CB30865, a quinazolin-4-one-based antitumor agent. J Med Chem 2002, 45, 17, 3692.
【2】 Bavetsias, V.; Jackman, A.; Skelton, L. (Cancer Research Campaign Technology Ltd.); Anti-cancer dihydroquinazoline derivs.. WO 0050417 .

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)	26794	3-Chloro-4-methylaniline; 4-Amino-2-chlorotoluene	95-74-9	C₇H₈ClN	详情	详情
(II)	46858	2-bromo-5-chloro-4-methylaniline; 2-bromo-5-chloro-4-methylphenylamine		C₇H₇BrClN	详情	详情
(III)	46859	2,6-dibromo-3-chloro-4-methylaniline; 2,6-dibromo-3-chloro-4-methylphenylamine	84483-22-7	C₇H₆Br₂ClN	详情	详情
(IV)	46860	N-(3-chloro-4-methylphenyl)acetamide	7149-79-3	C₉H₁₀ClNO	详情	详情
(V)	46861	N-(2-bromo-5-chloro-4-methylphenyl)acetamide		C₉H₉BrClNO	详情	详情
(VI)	46862	2-amino-4-chloro-5-methylbenzonitrile		C₈H₇ClN₂	详情	详情
(VII)	46863	2-amino-4-chloro-5-methylbenzoic acid		C₈H₈ClNO₂	详情	详情
(VIII)	46864	7-chloro-2-(chloromethyl)-6-methyl-4(3H)-quinazolinone		C₁₀H₈Cl₂N₂O	详情	详情
(IX)	46865	(7-chloro-6-methyl-4-oxo-3,4-dihydro-2-quinazolinyl)methyl acetate		C₁₂H₁₁ClN₂O₃	详情	详情
(X)	46866	(7-chloro-3,6-dimethyl-4-oxo-3,4-dihydro-2-quinazolinyl)methyl acetate		C₁₃H₁₃ClN₂O₃	详情	详情
(XI)	46867	[6-(bromomethyl)-7-chloro-3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methyl acetate		C₁₃H₁₂BrClN₂O₃	详情	详情
(XII)	46868	tert-butyl 4-(2-propynylamino)benzoate		C₁₄H₁₇NO₂	详情	详情
(XIII)	46869	tert-butyl 4-[([2-[(acetoxy)methyl]-7-chloro-3-methyl-4-oxo-3,4-dihydro-6-quinazolinyl]methyl)(2-propynyl)amino]benzoate		C₂₇H₂₈ClN₃O₅	详情	详情
(XIV)	46870	tert-butyl 4-[[[7-chloro-2-(hydroxymethyl)-3-methyl-4-oxo-3,4-dihydro-6-quinazolinyl]methyl](2-propynyl)amino]benzoate		C₂₅H₂₆ClN₃O₄	详情	详情
(XV)	46871	tert-butyl 4-[[(7-chloro-3-methyl-2-[[(methylsulfonyl)oxy]methyl]-4-oxo-3,4-dihydro-6-quinazolinyl)methyl](2-propynyl)amino]benzoate		C₂₆H₂₈ClN₃O₆S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XV)

Displacement of the mesylate group of (XV) with N-methylpiperazine (XVI) produced the disubstituted piperazine (XVII). The tert-butyl ester of (XVII) was cleaved to the corresponding carboxylic acid (XVIII) by means of trifluoroacetic acid in CH2Cl2. Then coupling of (XVIII) with 3-(aminomethyl)pyridine (XIX) gave rise to the title amide.

参考文献中间体

合成目标

【1】 Bavetsias, V.; et al.; The design and synthesis of water-soluble analogues of CB30865, a quinazolin-4-one-based antitumor agent. J Med Chem 2002, 45, 17, 3692.
【2】 Bavetsias, V.; Jackman, A.; Skelton, L. (Cancer Research Campaign Technology Ltd.); Anti-cancer dihydroquinazoline derivs.. WO 0050417 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XV)	46871	tert-butyl 4-[[(7-chloro-3-methyl-2-[[(methylsulfonyl)oxy]methyl]-4-oxo-3,4-dihydro-6-quinazolinyl)methyl](2-propynyl)amino]benzoate		C₂₆H₂₈ClN₃O₆S	详情	详情
(XVI)	10061	1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine	109-01-3	C₅H₁₂N₂	详情	详情
(XVII)	46872	tert-butyl 4-[([7-chloro-3-methyl-2-[(4-methyl-1-piperazinyl)methyl]-4-oxo-3,4-dihydro-6-quinazolinyl]methyl)(2-propynyl)amino]benzoate		C₃₀H₃₆ClN₅O₃	详情	详情
(XVIII)	46873	4-[([7-chloro-3-methyl-2-[(4-methyl-1-piperazinyl)methyl]-4-oxo-3,4-dihydro-6-quinazolinyl]methyl)(2-propynyl)amino]benzoic acid		C₂₆H₂₈ClN₅O₃	详情	详情
(XIX)	18731	3-pyridinylmethanamine; 3-pyridinylmethylamine	3731-52-0	C₆H₈N₂	详情	详情

Extended Information