2-bromo-1-methyl-4-nitrobenzene -Drug Synthesis Database

【结构式】

【分子编号】38642

【品名】2-bromo-1-methyl-4-nitrobenzene

【CA登记号】7745-93-9

【分子式】C₇H₆BrNO₂

【分子量】216.03418

【元素组成】C 38.92% H 2.8% Br 36.99% N 6.48% O 14.81%

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：(I)

Catalytic hydrogenation of 2-bromo-4-nitrotoluene (I) over Raney-Ni provided aniline (II). Reaction of (II) with chloral hydrate and hydroxylamine gave rise to the isonitrosoacetanilide (III), which was subsequently cyclized to the isatin (IV) by heating in concentrated H2SO4. Oxidative cleavage of isatin (IV) produced the anthranilic acid (V). This was converted to the benzoxazinone (VI) upon refluxing with acetic anhydride. Ring opening of benzoxazinone (VI) with MeOH, followed by acidic hydrolysis of the acetamide function, yielded the anthranilate ester (VII). The quinazoline derivative (VIII) was then obtained by treatment of anthranilate (VII) with chloroformamidine hydrochloride in refluxing diglyme. Finally, displacement of the bromide group of (VIII) with the sodium thiolate of 4-mercaptopyridine (IX) under Ullmann conditions afforded the title pyridyl sulfide.

参考文献中间体

合成目标

【1】 Webber, S.E.; Bleckman, T.M.; Attard, J.; Jones, T.R.; Varney, M.D. (Agouron Pharmaceuticals, Inc.); Antiproliferative quinazolines. EP 0637300; US 5430148; WO 9320055 .
【2】 Webber, S.E.; et al.; Design of thymidylate synthase inhibitors using protein crystal structures: The synthesis and biological evaluation of a novel class of 5-substituted quinazolinones. J Med Chem 1993, 36, 6, 733.

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)	38642	2-bromo-1-methyl-4-nitrobenzene	7745-93-9	C₇H₆BrNO₂	详情	详情
(II)	49517	3-Bromo-p-toluidine; 4-Amino-2-bromotoluene; 3-Bromo-4-methylaniline	7745-91-7	C₇H₈BrN	详情	详情
(III)	49518	N-(3-bromo-4-methylphenyl)-2-(hydroxyimino)acetamide		C₉H₉BrN₂O₂	详情	详情
(IV)	49519	4-bromo-5-methyl-1H-indole-2,3-dione		C₉H₆BrNO₂	详情	详情
(V)	49520	6-amino-2-bromo-3-methylbenzoic acid		C₈H₈BrNO₂	详情	详情
(VI)	49521	5-bromo-2,6-dimethyl-4H-3,1-benzoxazin-4-one		C₁₀H₈BrNO₂	详情	详情
(VII)	49522	methyl 6-amino-2-bromo-3-methylbenzoate		C₉H₁₀BrNO₂	详情	详情
(VIII)	49523	2-amino-5-bromo-6-methyl-4(3H)-quinazolinone		C₉H₈BrN₃O	详情	详情
(IX)	27936	4-Mercaptopyridine; 4-pyridinethiol	4556-23-4	C₅H₅NS	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

The condensation of 2-bromo-4-nitrotoluene (I) with phenylboronic acid (II) by means of Pd(OAc)2 in aqueous acetone gives the biphenyl (III), which is oxidized with KMnO4 in aqueous pyridine yielding the biphenyl-2-carboxylic acid (IV). The condensation of (IV) with L-methionine methyl ester (V) by means of EDC and HOBT affords the amide (VI), which is reduced with SnCl2 to give the 5-aminobiphenyl derivative (VII). The reductocondensation of (VII) with N-(tert-butoxycarbonyl)-S-trityl-L-cysteinal (VIII) by means of NaBH3CN affords the secondary amine (IX), which is finally deprotected with HgCl2 and H2S in methanol to furnish the target ester.

参考文献中间体

合成目标

【1】 Fossum, R.D.; Marugan, J.J.; Vogt, A.; Qian, Y.; Sebti, S.M.; Hamilton, A.D.; Probing the hydrophobic pocket of farnesyltransferase: Aromatic substitution of CAAX peptidomimetics leads to highly potent inhibitors. Bioorg Med Chem 1999, 7, 12, 3011.
【2】 Sebti, S.; Hamilton, A. (University of Pittsburgh); Inhibitors of prenyl transferases. JP 1998512266; WO 9621456 .

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)	38642	2-bromo-1-methyl-4-nitrobenzene	7745-93-9	C₇H₆BrNO₂	详情	详情
(II)	16593	Phenylboronic acid；Benzeneboronic acid;Phenylboron dihydroxide	98-80-6	C₆H₇BO₂	详情	详情
(III)	38643	2-methyl-5-nitro-1,1'-biphenyl		C₁₃H₁₁NO₂	详情	详情
(IV)	38644	5-nitro[1,1'-biphenyl]-2-carboxylic acid		C₁₃H₉NO₄	详情	详情
(V)	17950	D-Methionine methyl ester; methyl (2S)-2-amino-4-(methylsulfanyl)butanoate hydrochloride	21691-49-6	C₆H₁₃NO₂S	详情	详情
(VI)	38645	methyl (2S)-4-(methylsulfanyl)-2-[[(5-nitro[1,1'-biphenyl]-2-yl)carbonyl]amino]butanoate		C₁₉H₂₀N₂O₅S	详情	详情
(VII)	38656	2,2,2-trichloroethyl (3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)-1-piperidinecarboxylate		C₉H₁₄Cl₃NO₅	详情	详情
(VIII)	17953	tert-butyl (1R)-1-formyl-2-(tritylsulfanyl)ethylcarbamate		C₂₇H₂₉NO₃S	详情	详情
(IX)	38647	methyl (2S)-2-[[(5-[[(2R)-2-[(tert-butoxycarbonyl)amino]-3-(tritylsulfanyl)propyl]amino][1,1'-biphenyl]-2-yl)carbonyl]amino]-4-(methylsulfanyl)butanoate		C₄₆H₅₁N₃O₅S₂	详情	详情

合成路线3

该中间体在本合成路线中的序号：(I)

The condensation of 2-bromo-4-nitrotoluene (I) with phenylboronic acid (II) by means of Pd(OAc)2 in aqueous acetone gives the biphenyl (III), which is oxidized with KMnO4 in aqueous pyridine yielding the biphenyl-2-carboxylic acid (IV). The condensation of (IV) with L-methionine methyl ester (V) by means of EDC and HOBT affords the amide (VI), which is reduced with SnCl2 to give the 5-aminobiphenyl derivative (VII). The reductocondensation of (VII) with N-(tert-butoxycarbonyl)-S-trityl-L-cysteinal (VIII) by means of NaBH3CN affords the secondary amine (IX), which is finally deprotected and hydrolyzed first with LiOH and THF and then with TFA and Et3SiH in dichloromethane to furnish the target free acid.

参考文献中间体

合成目标

【1】 Fossum, R.D.; Marugan, J.J.; Vogt, A.; Qian, Y.; Sebti, S.M.; Hamilton, A.D.; Probing the hydrophobic pocket of farnesyltransferase: Aromatic substitution of CAAX peptidomimetics leads to highly potent inhibitors. Bioorg Med Chem 1999, 7, 12, 3011.
【2】 Sebti, S.; Hamilton, A. (University of Pittsburgh); Inhibitors of prenyl transferases. JP 1998512266; WO 9621456 .

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)	38642	2-bromo-1-methyl-4-nitrobenzene	7745-93-9	C₇H₆BrNO₂	详情	详情
(II)	16593	Phenylboronic acid；Benzeneboronic acid;Phenylboron dihydroxide	98-80-6	C₆H₇BO₂	详情	详情
(III)	38643	2-methyl-5-nitro-1,1'-biphenyl		C₁₃H₁₁NO₂	详情	详情
(IV)	38644	5-nitro[1,1'-biphenyl]-2-carboxylic acid		C₁₃H₉NO₄	详情	详情
(V)	17950	D-Methionine methyl ester; methyl (2S)-2-amino-4-(methylsulfanyl)butanoate hydrochloride	21691-49-6	C₆H₁₃NO₂S	详情	详情
(VI)	38645	methyl (2S)-4-(methylsulfanyl)-2-[[(5-nitro[1,1'-biphenyl]-2-yl)carbonyl]amino]butanoate		C₁₉H₂₀N₂O₅S	详情	详情
(VII)	38656	2,2,2-trichloroethyl (3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)-1-piperidinecarboxylate		C₉H₁₄Cl₃NO₅	详情	详情
(VIII)	17953	tert-butyl (1R)-1-formyl-2-(tritylsulfanyl)ethylcarbamate		C₂₇H₂₉NO₃S	详情	详情
(IX)	38647	methyl (2S)-2-[[(5-[[(2R)-2-[(tert-butoxycarbonyl)amino]-3-(tritylsulfanyl)propyl]amino][1,1'-biphenyl]-2-yl)carbonyl]amino]-4-(methylsulfanyl)butanoate		C₄₆H₅₁N₃O₅S₂	详情	详情

Extended Information