7-chloro-4(3H)-quinazolinone -Drug Synthesis Database

【结构式】

【分子编号】50077

【品名】7-chloro-4(3H)-quinazolinone

【CA登记号】

【分子式】C₈H₅ClN₂O

【分子量】180.59328

【元素组成】C 53.21% H 2.79% Cl 19.63% N 15.51% O 8.86%

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：(XIV)

The condensation of (R)-lactic acid (I) with morpholine (II) gives the corresponding morpholide (III), which is protected at the hydroxyl position with dihydropyran (IV) to yield the tetrahydropyranyl ether (V). The Grignard reaction of (V) with 2,4-difluorophenylmagnesium bromide (VI) affords the chiral 1-propanone (VII), which by a Corey's diastereoselective epoxidation with trimethylsulfoxonium iodide is converted into the oxirane (VIII). The opening of the oxirane ring of (VIII) by means of 1,2,4-triazole (IX) and NaH provides the tertiary alcohol (X), which is treated with pyridine p-toluenesulfonate to give the deprotected diol (XI) as a (2R,3R) and (2R,3S) 4:1 diastereomeric mixture, from which the desired (2R,3R)-isomer (XII) was isolated by crystallization. The reaction of (XII) with Ms-Cl and TEA, followed by cyclization with NaOMe, yields the oxirane (XIII), which is finally condensed with 7-chloroquinazolin-4(3H)-one (XIV) by means of K2CO3 in hot NMP.

参考文献中间体

合成目标

【1】 Tasaka, A.; Tamura, N.; Matsushita, Y.; Teranishi, K.; Hayashi, R.; Okonogi, K.; Itoh, K.; Optically active antifungal azoles. I. Synthesis and antifungal activity of (2R,3R)-2-(2,4-difluorophenyl)-3-mercapto-1-(1H-1,2,4-triazol-1-yl)-2-butanol and stereoisomers. Chem Pharm Bull 1993, 41, 6, 1035-42.
【2】 Bartroli Orpi, J.; Anguita Lopez, M. (J. Uriach & Cia., SA); Method for preparing pyrimidone derivs. with antifungal activity. ES 2159488; WO 0166519 .

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)	11591	methyl (2R)-2-hydroxypropanoate	17392-83-5	C₄H₈O₃	详情	详情
(II)	10388	Morpholine	110-91-8	C₄H₉NO	详情	详情
(III)	56718	(2R)-2-hydroxy-1-(4-morpholinyl)-1-propanone		C₇H₁₃NO₃	详情	详情
(IV)	13684	3,4-Dihydro-2H-pyran;2,3-Dihydro-4H-pyran; 5,6-Dihydro-4H-pyran;Dihydropyran	110-87-2	C₅H₈O	详情	详情
(V)	45574	(2R)-1-(4-morpholinyl)-2-(tetrahydro-2H-pyran-2-yloxy)-1-propanone		C₁₂H₂₁NO₄	详情	详情
(VI)	20262	bromo(2,4-difluorophenyl)magnesium		C₆H₃BrF₂Mg	详情	详情
(VII)	56717	(2S)-1-(2,4-difluorophenyl)-2-methyl-3-tetrahydro-2H-pyran-2-yl-1-propanone		C₁₅H₁₈F₂O₂	详情	详情
(VIII)	56719	2-({(1R)-1-[2-(2,4-difluorophenyl)-2-oxiranyl]ethyl}oxy)tetrahydro-2H-pyran; (1R)-1-[2-(2,4-difluorophenyl)-2-oxiranyl]ethyl tetrahydro-2H-pyran-2-yl ether		C₁₅H₁₈F₂O₃	详情	详情
(IX)	13135	1H-1,2,4-Triazole; 1,2,4-Triazole	288-88-0	C₂H₃N₃	详情	详情
(X)	56720	(3R)-2-(2,4-difluorophenyl)-3-(tetrahydro-2H-pyran-2-yloxy)-1-(1H-1,2,4-triazol-1-yl)-2-butanol		C₁₇H₂₁F₂N₃O₃	详情	详情
(XI)	56721	(3R)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2,3-butanediol		C₁₂H₁₃F₂N₃O₂	详情	详情
(XII)	13106	(2R,3R)-2-(2,4-Difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2,3-butanediol		C₁₂H₁₃F₂N₃O₂	详情	详情
(XIII)	31738	1-[[(2R,3S)-2-(2,4-difluorophenyl)-3-methyloxiranyl]methyl]-1H-1,2,4-triazole		C₁₂H₁₁F₂N₃O	详情	详情
(XIV)	50077	7-chloro-4(3H)-quinazolinone		C₈H₅ClN₂O	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

Nitration of quinazolone (I) by reaction with HNO3/H2SO4 affords 7-chloro-6-nitro-4-quinazolone (II), which is then chlorinated with phosphorus oxychloride (POCl3) to provide quinazoline (III). Selective amination of the quinazoline ring of (III) by reaction with 4-chlorophenethylamine (IV) in isopropanol in the presence of Et3N yields compound (V), which is finally converted into the desired compound by condensation with piperazine (VI) in refluxing butanol in the presence of DIEA. Alternatively the target product can be obtained by the following procedure: Condensation of quinazolone derivative (II) with piperazine (VI) in refluxing butanol in the presence of DIEA affords compound (VII), which is treated with POCl3 and finally subjected to condensation with 4-chlorophenethylamine (IV) in isopropanol in the presence of Et3N.

参考文献中间体

合成目标

【1】 Matsumoto, M.; Hayashi, H.; Tomizawa, H.; Obara, F.; Nagasaki, T.; Tobe, M.; Isoba, Y.; Structure-activity relationships of quinazoline derivatives: Dual-acting compounds with inhibitory activities toward both TNF-alpha production and T cell proliferation. Bioorg Med Chem Lett 2001, 11, 4, 545.

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)	50077	7-chloro-4(3H)-quinazolinone		C₈H₅ClN₂O	详情	详情
(II)	50078	7-chloro-6-nitro-4(3H)-quinazolinone		C₈H₄ClN₃O₃	详情	详情
(III)	50079	4,7-dichloro-6-nitroquinazoline		C₈H₃Cl₂N₃O₂	详情	详情
(IV)	38459	methyl (2R,3R)-3-amino-2-(3-cyanobenzyl)butanoate		C₁₃H₁₆N₂O₂	详情	详情
(V)	50080	N-(7-chloro-6-nitro-4-quinazolinyl)-N-(4-chlorophenethyl)amine; 7-chloro-N-(4-chlorophenethyl)-6-nitro-4-quinazolinamine		C₁₆H₁₂Cl₂N₄O₂	详情	详情
(VI)	10355	Diethylenediamine; Piperazine	110-85-0	C₄H₁₀N₂	详情	详情
(VII)	50081	6-nitro-7-(1-piperazinyl)-4(3H)-quinazolinone		C₁₂H₁₃N₅O₃	详情	详情

合成路线3

该中间体在本合成路线中的序号：(VI)

Quinazolinone (VI) was prepared by condensation of 4-chloroanthranilic acid (V) with hot formamide. Subsequent electrophilic nitration of (VI) provided the 6-nitroquinazolinone (VII) as the major regioisomer. Displacement of the 7-chloro of (VII) upon heating with ethylamine in a sealed tube gave rise to the nitro amine (VIII). The 4-chloroquinazoline derivative (IX) was then obtained by chlorination of (VIII) with phosphorus oxychloride. Condensation of (IX) with the intermediate benzylamine (IV) furnished adduct (X). The nitro group of (X) was then reduced by catalytic hydrogenation to yield the phenylenediamine derivative (XI). Finally, condensation of phenylenediamine (XI) with carbon disulfide in the presence of Et3N generated the target imidazoquinazoline, which was isolated as the dihydrochloride salt.

参考文献中间体

合成目标

【1】 Fujino, K.; et al.; Development of a practical synthetic route of a PDE V inhibitor KF31327. Org Process Res Dev 2001, 5, 4, 426.
【2】 Fujino, K.; et al.; Process development of a PDE V inhibitor KF31327. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst ORGN 612.
【3】 Onoda, Y.; Nomoto, Y.; Ohno, T.; Yamada, K.; Ichimura, M. (Kyowa Hakko Kogyo Co., Ltd.); Imidazoquinazoline derivs.. EP 0863144; WO 9808848 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IV)	54825	{1-[2-(aminomethyl)phenyl]-4-piperidinyl}methanol		C₁₃H₂₀N₂O	详情	详情
(V)	52504	4-Chloro-2-aminobenzoic acid; 2-Amino-4-chlorobenzoic acid; 2-Carboxy-5-chloroaniline; 3-Amino-4-carboxy-1-chlorobenzene; 4-Chloroanthranilic acid	89-77-0	C₇H₆ClNO₂	详情	详情
(VI)	50077	7-chloro-4(3H)-quinazolinone		C₈H₅ClN₂O	详情	详情
(VII)	50078	7-chloro-6-nitro-4(3H)-quinazolinone		C₈H₄ClN₃O₃	详情	详情
(VIII)	54826	7-(ethylamino)-6-nitro-4(3H)-quinazolinone		C₁₀H₁₀N₄O₃	详情	详情
(IX)	54827	4-chloro-N-ethyl-6-nitro-7-quinazolinamine; N-(4-chloro-6-nitro-7-quinazolinyl)-N-ethylamine		C₁₀H₉ClN₄O₂	详情	详情
(X)	54828	{1-[2-({[7-(ethylamino)-6-nitro-4-quinazolinyl]amino}methyl)phenyl]-4-piperidinyl}methanol		C₂₃H₂₈N₆O₃	详情	详情
(XI)	54829	{1-[2-({[6-amino-7-(ethylamino)-4-quinazolinyl]amino}methyl)phenyl]-4-piperidinyl}methanol		C₂₃H₃₀N₆O	详情	详情

Extended Information