4(3H)-quinazolinone -Drug Synthesis Database

【结构式】

【分子编号】14634

【品名】4(3H)-quinazolinone

【CA登记号】

【分子式】C₈H₆N₂O

【分子量】146.14852

【元素组成】C 65.75% H 4.14% N 19.17% O 10.95%

与该中间体有关的原料药合成路线共 7 条

合成路线1 合成路线2 合成路线3 合成路线4 合成路线5 合成路线6 合成路线7

合成路线1

该中间体在本合成路线中的序号：(IV)

Flubichin (V) is prepared by a reaction of 4(3H)-quinazolinone (IV) with 2',4'-difluoro-4-(2-chloroethoxy)biphenyl (III). Compound (III) can be prepared by reaction of 2',4'-difluoro-4-hydroxybiphenyl (I) with 2-chloroethyl p-toluene sulfonate (II). Methanesulfonate of flubichin is obtained by reaction of flubichin base (V) with methanesulfonic acid in chloroform.

参考文献中间体

合成目标

【1】 Fisnerová, L.; Brunová, B.; Maturová, E.; Grimová, J. (SPOFA - United Pharmaceutical Works); Ether deriv. of 4-[3H]-quinazoline, a process for the preparation thereof, and pharmaceutical compsns. AU 8942880; EP 0367944; JP 1990172977 .
【2】 Rejholec, V.; Flubichin Methanesulfonate. Drugs Fut 1991, 16, 8, 715.

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)	14631	2',4'-difluoro[1,1'-biphenyl]-4-ol		C₁₂H₈F₂O	详情	详情
(II)	14632	2-chloroethyl 4-methylbenzenesulfonate; 2-Chloroethyl-p-toluenesulfonate	80-41-1	C₉H₁₁ClO₃S	详情	详情
(III)	14633	2-chloroethyl 2',4'-difluoro[1,1'-biphenyl]-4-yl ether; 4-(2-chloroethoxy)-2',4'-difluoro-1,1'-biphenyl		C₁₄H₁₁ClF₂O	详情	详情
(IV)	14634	4(3H)-quinazolinone		C₈H₆N₂O	详情	详情
(V)	14635	3-[2-[(2',4'-difluoro[1,1'-biphenyl]-4-yl)oxy]ethyl]-4(3H)-quinazolinone		C₂₂H₁₆F₂N₂O₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XX)

After protection of (XVI) as the N-Boc derivative (XVII), the diol function was cyclized to epoxide (XIX) by treatment with N-tosyl imidazole (XVIII) in the presence of NaH. Epoxide (XIX) opening with the potassium salt of 4-quinazolinone (XX) gave alcohol (XXI). Subsequent Dess-Martin oxidation of (XXI) yielded the epimeric mixture of ketones (XXII). Acid hydrolysis of this mixture furnished the title trans-piperidine along with the cis-isomer, which was isolated in the cyclic hemiacetal form (XXIII). The title compound was also obtained by isomerization of (XXIII) in refluxing MeOH).

参考文献中间体

合成目标

【1】 Ooi, H.e; et al.; A concise enantioselective synthesis of antimalarial febrifugine alkaloids. Org Lett 2001, 3, 6, 953.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XVI)	47844	3-((3S)-3-[[tert-butyl(diphenyl)silyl]oxy]piperidinyl)-1,2-propanediol		C₂₄H₃₅NO₃Si	详情	详情
(XVII)	47845	tert-butyl (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-(2,3-dihydroxypropyl)-1-piperidinecarboxylate		C₁₉H₃₉NO₅Si	详情	详情
(XVIII)	47846	1-[(4-methylphenyl)sulfonyl]-1H-imidazole	2232-08-8	C₁₀H₁₀N₂O₂S	详情	详情
(XIX)	47847	tert-butyl (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-(2-oxiranylmethyl)-1-piperidinecarboxylate		C₁₉H₃₇NO₄Si	详情	详情
(XX)	14634	4(3H)-quinazolinone		C₈H₆N₂O	详情	详情
(XXI)	47848	tert-butyl (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-[2-hydroxy-3-[4-oxo-3(4H)-quinazolinyl]propyl]-1-piperidinecarboxylate		C₂₇H₄₃N₃O₅Si	详情	详情
(XXII)	47849	tert-butyl (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-[2-oxo-3-[4-oxo-3(4H)-quinazolinyl]propyl]-1-piperidinecarboxylate		C₂₇H₄₁N₃O₅Si	详情	详情
(XXIII)	38272	3-[[(3aS,7aS)-2-hydroxyoctahydrofuro[3,2-b]pyridin-2-yl]methyl]-4(3H)-quinazolinone		C₁₆H₁₉N₃O₃	详情	详情

合成路线3

该中间体在本合成路线中的序号：(VI)

The enantioselective reduction of 2-allyl-1-(benzyloxycarbonyl)piperidin-3-one (I) by means of Baker's yeast and sucrose in ethanol/water gives a mixture of unreacted (R)-piperidinone (II) and the desired (2S,3S)-piperidinol (III), which are easily separated by chromatography. The bromination of (III) with NBS in acetonitrile yields the furo piperidine (IV), which is treated with potassium tert-butoxide and NBS in methanol to afford the methoxy compound (V). The condensation of (V) with quinazolinone (VI) by means of K2CO3 in DMF provides the adduct (VII), which is deprotected by hydrogenation with H2 over Pd/C in methanol to give isofebrifugine (VIII). Finally, this compound is converted into the target febrifugine by treatment with water at 80 C.

参考文献中间体

合成目标

【1】 Takeuchi, Y.; et al.; Asymmetric synthesis of (+)-febrifugine and (+)-isofebrifugine using yeast reduction. Tetrahedron 2001, 57, 7, 1213.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	51238	benzyl 2-allyl-3-oxo-1-piperidinecarboxylate	C₁₆H₁₉NO₃	详情	详情
(II)	51239	benzyl (2R)-2-allyl-3-oxo-1-piperidinecarboxylate	C₁₆H₁₉NO₃	详情	详情
(III)	51240	benzyl (2S,3S)-2-allyl-3-hydroxy-1-piperidinecarboxylate	C₁₆H₂₁NO₃	详情	详情
(IV)	51241	benzyl (3aS,7aS)-2-(bromomethyl)hexahydrofuro[3,2-b]pyridine-4(2H)-carboxylate	C₁₆H₂₀BrNO₃	详情	详情
(V)	51242	benzyl (3aS,7aS)-2-(bromomethyl)-2-methoxyhexahydrofuro[3,2-b]pyridine-4(2H)-carboxylate	C₁₇H₂₂BrNO₄	详情	详情
(VI)	14634	4(3H)-quinazolinone	C₈H₆N₂O	详情	详情
(VII)	51243	benzyl (3aS,7aS)-2-hydroxy-2-[[4-oxo-3(4H)-quinazolinyl]methyl]hexahydrofuro[3,2-b]pyridine-4(2H)-carboxylate	C₂₄H₂₅N₃O₅	详情	详情
(VIII)	38272	3-[[(3aS,7aS)-2-hydroxyoctahydrofuro[3,2-b]pyridin-2-yl]methyl]-4(3H)-quinazolinone	C₁₆H₁₉N₃O₃	详情	详情

合成路线4

该中间体在本合成路线中的序号：(XXIV)

The desulfurization of (XXI) with H2O2 and CaCO3 gives the chiral allylpiperidine (XXII), which is epoxidized by oxidation with OsO4, reaction of Ts-OH and treatment with K2CO3 to yield the epoxide (XXIII). The condensation of (XXIII) with quinazolinone (XXIV) by means of KOH in methanol affords the substituted propanol (XXV), which is oxidized with DMP to provide the propanone derivative (XXVI). Finally, compound (XXVI) is deprotected by treatment with refluxing 6N HCl to give the target febrifugine.

参考文献中间体

合成目标

【1】 Taniguchi, T.; Ofasawara, K.; A diastereocontrolled synthesis of (+)-febrifugine: A potent antimalarial piperidine alkaloid. Org Lett 2000, 2, 20, 3193.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XXI)	50262	3-hydroxypropyl methanesulfonate	C₄H₁₀O₄S	详情	详情
(XXII)	51264	benzyl (2R,3S)-2-allyl-3-(benzyloxy)-1-piperidinecarboxylate	C₂₃H₂₇NO₃	详情	详情
(XXIII)	51265	benzyl (2R,3S)-3-(benzyloxy)-2-(2-oxiranylmethyl)-1-piperidinecarboxylate	C₂₃H₂₇NO₄	详情	详情
(XXIV)	14634	4(3H)-quinazolinone	C₈H₆N₂O	详情	详情
(XXV)	51266	benzyl (2R,3S)-3-(benzyloxy)-2-[2-hydroxy-3-[4-oxo-3(4H)-quinazolinyl]propyl]-1-piperidinecarboxylate	C₃₁H₃₃N₃O₅	详情	详情
(XXVI)	51267	benzyl (2R,3S)-3-(benzyloxy)-2-[2-oxo-3-[4-oxo-3(4H)-quinazolinyl]propyl]-1-piperidinecarboxylate	C₃₁H₃₁N₃O₅	详情	详情

合成路线5

该中间体在本合成路线中的序号：(XX)

After protection of (XVI) as the N-Boc derivative (XVII), the diol function was cyclized to epoxide (XIX) by treatment with N-tosyl imidazole (XVIII) in the presence of NaH. Epoxide (XIX) opening with the potassium salt of 4-quinazolinone (XX) gave alcohol (XXI). Subsequent Dess-Martin oxidation of (XXI) yielded the epimeric mixture of ketones (XXII). Acid hydrolysis of this mixture furnished the trans-piperidine (XXIII) along with the title cis-isomer, which was isolated in the cyclic hemiacetal form.

参考文献中间体

合成目标

【1】 Ooi, H.e; et al.; A concise enantioselective synthesis of antimalarial febrifugine alkaloids. Org Lett 2001, 3, 6, 953.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XVI)	47844	3-((3S)-3-[[tert-butyl(diphenyl)silyl]oxy]piperidinyl)-1,2-propanediol		C₂₄H₃₅NO₃Si	详情	详情
(XVII)	47845	tert-butyl (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-(2,3-dihydroxypropyl)-1-piperidinecarboxylate		C₁₉H₃₉NO₅Si	详情	详情
(XVIII)	47846	1-[(4-methylphenyl)sulfonyl]-1H-imidazole	2232-08-8	C₁₀H₁₀N₂O₂S	详情	详情
(XIX)	47847	tert-butyl (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-(2-oxiranylmethyl)-1-piperidinecarboxylate		C₁₉H₃₇NO₄Si	详情	详情
(XX)	14634	4(3H)-quinazolinone		C₈H₆N₂O	详情	详情
(XXI)	47848	tert-butyl (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-[2-hydroxy-3-[4-oxo-3(4H)-quinazolinyl]propyl]-1-piperidinecarboxylate		C₂₇H₄₃N₃O₅Si	详情	详情
(XXII)	47849	tert-butyl (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-[2-oxo-3-[4-oxo-3(4H)-quinazolinyl]propyl]-1-piperidinecarboxylate		C₂₇H₄₁N₃O₅Si	详情	详情
(XXIII)	47850	3-[3-[(2R,3S)-3-hydroxypiperidinyl]-2-oxopropyl]-4(3H)-quinazolinone		C₁₆H₁₉N₃O₃	详情	详情

合成路线6

该中间体在本合成路线中的序号：(VI)

参考文献中间体

合成目标

【1】 Takeuchi, Y.; et al.; Asymmetric synthesis of (+)-febrifugine and (+)-isofebrifugine using yeast reduction. Tetrahedron 2001, 57, 7, 1213.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	51238	benzyl 2-allyl-3-oxo-1-piperidinecarboxylate	C₁₆H₁₉NO₃	详情	详情
(II)	51239	benzyl (2R)-2-allyl-3-oxo-1-piperidinecarboxylate	C₁₆H₁₉NO₃	详情	详情
(III)	51240	benzyl (2S,3S)-2-allyl-3-hydroxy-1-piperidinecarboxylate	C₁₆H₂₁NO₃	详情	详情
(IV)	51241	benzyl (3aS,7aS)-2-(bromomethyl)hexahydrofuro[3,2-b]pyridine-4(2H)-carboxylate	C₁₆H₂₀BrNO₃	详情	详情
(V)	51242	benzyl (3aS,7aS)-2-(bromomethyl)-2-methoxyhexahydrofuro[3,2-b]pyridine-4(2H)-carboxylate	C₁₇H₂₂BrNO₄	详情	详情
(VI)	14634	4(3H)-quinazolinone	C₈H₆N₂O	详情	详情
(VII)	51243	benzyl (3aS,7aS)-2-hydroxy-2-[[4-oxo-3(4H)-quinazolinyl]methyl]hexahydrofuro[3,2-b]pyridine-4(2H)-carboxylate	C₂₄H₂₅N₃O₅	详情	详情

合成路线7

该中间体在本合成路线中的序号：(XIV)

The enantioselective condensation of the silylated 4-hydroxy-2-butanone (I) with the silylated enol ester (II) by means of Sn(OTf)2 and the chiral pyrrolidine (III) gives the chiral benzylated trihydroxyester (IV), which is partially dehydroxylated with thiocarbonyl diimidazole (TCDI) and tributyltin hydride in refluxing toluene to yield the protected dihydroxy ester (V). The reduction of (V) with DIBAL in dichloromethane affords the corresponding alcohol (VI), which is oxidized with oxalyl chloride and TEA in DMSO/dichloromethane to provide the aldehyde (VII). The condensation of (VII) with the enol ether (IX) and 2-methoxyaniline (VIII) by means of Yb(OTf)3 in THF/water gives the beta aminoketone (X), which is cyclized by means of HF, PPh3, CBr4 and cerium ammonium nitrate (CAN) in acetonitrile/water to yield the chiral piperidine (XI). The bromination of (XI) with Br2 and HBr in HOAc affords the bromo derivative (XII), which is treated with Boc2O to provide the N-protected piperidine (XIII). The condensation of (XIII) with quinazolin-4(3H)-one (XIV) by means of KOH gives the adduct (XV), which is finally deprotected and cyclized by treatment with refluxing 6N HCl to afford the target isofebrifugine.

参考文献中间体

合成目标

【1】 Wataya, Y.; Ueno, M.; Suzuki, R.; Kim, H.-S.; Kobayashi, S.; Ishitani, H.; Catalytic asymmetric synthesis of antimalarial alkaloids febrifubine and isofebrifugine and their biological actvity. J Org Chem 1999, 64, 18, 6833.
【2】 Kobayashi, S.; Kim, H.-S.; Wataya, Y. (Japan Science and Technology Corp.); Febrifugine and isofebrifugine and processes for the preparation of both. EP 1076057; WO 0052005 .

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)	44768	4-[[tert-butyl(dimethyl)silyl]oxy]-2-butanone		C₁₀H₂₂O₂Si	详情	详情
(II)	44769	benzyl (Z)-2-phenoxy-2-[(trimethylsilyl)oxy]ethenyl ether; [[(Z)-2-(benzyloxy)-1-phenoxyethenyl]oxy](trimethyl)silane		C₁₈H₂₂O₃Si	详情	详情
(III)	51268	N-(1-naphthyl)-N-[(2S)pyrrolidinylmethyl]amine; N-[(2S)pyrrolidinylmethyl]-1-naphthalenamine		C₁₅H₁₈N₂	详情	详情
(IV)	44771	phenyl (2S,3R)-2-(benzyloxy)-5-[[tert-butyl(dimethyl)silyl]oxy]-3-hydroxypentanoate		C₂₄H₃₄O₅Si	详情	详情
(V)	44773	phenyl (2S)-2-(benzyloxy)-5-[[tert-butyl(dimethyl)silyl]oxy]pentanoate		C₂₄H₃₄O₄Si	详情	详情
(VI)	41269	2-(2-fluoro-4'-hydroxy[1,1'-biphenyl]-4-yl)acetic acid		C₁₄H₁₁FO₃	详情	详情
(VII)	44774	(2S)-2-(benzyloxy)-5-[[tert-butyl(dimethyl)silyl]oxy]pentanal		C₁₈H₃₀O₃Si	详情	详情
(VIII)	25193	2-methoxyphenylamine; 2-methoxyaniline	517-28-2	C₇H₉NO	详情	详情
(IX)	17354	isopropenyl methyl ether; 2-methoxy-1-propene	116-11-0	C₄H₈O	详情	详情
(X)	41270	8-(acetamido)-2,3-dihydro-1,4-benzodioxine-5-carboxylic acid		C₁₁H₁₁NO₅	详情	详情
(XI)	51271	1-[(2S,3S)-3-(benzyloxy)piperidinyl]acetone		C₁₅H₂₁NO₂	详情	详情
(XII)	51272	1-[(2S,3S)-3-(benzyloxy)piperidinyl]-3-bromoacetone		C₁₅H₂₀BrNO₂	详情	详情
(XIII)	51273	tert-butyl (2S,3S)-3-(benzyloxy)-2-(3-bromo-2-oxopropyl)-1-piperidinecarboxylate		C₂₀H₂₈BrNO₄	详情	详情
(XIV)	14634	4(3H)-quinazolinone		C₈H₆N₂O	详情	详情
(XV)	51274	tert-butyl (2S,3S)-3-(benzyloxy)-2-[2-oxo-3-[4-oxo-3(4H)-quinazolinyl]propyl]-1-piperidinecarboxylate		C₂₈H₃₃N₃O₅	详情	详情

Extended Information