potassium 4-aminobenzenolate -Drug Synthesis Database

【结构式】

【分子编号】49911

【品名】potassium 4-aminobenzenolate

【CA登记号】

【分子式】C₆H₆KNO

【分子量】147.21808

【元素组成】C 48.95% H 4.11% K 26.56% N 9.51% O 10.87%

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：(VI)

Reaction of picolinic acid (I) with hot thionyl chloride in DMF gives 4-chloropyridine-2-carbonyl chloride (II), which is treated with methanol to give ester (III). Subsequent displacement of the methyl ester function with methylamine provides amide (IV). Alternatively, acid chloride (II) is directly converted into amide (IV) by reaction with a cold solution of methylamine. In a different synthetic procedure, amide (IV) can be obtained from 4-chloropyridine (V) via the Menisci reaction using N-methylformamide and hydrogen peroxide in the presence of FeSO4 and H2SO4. Coupling of the amide (IV) with potassium 4-aminophenolate (VI) -obtained by treatment of 4-aminophenol (VII) with potassium tert-butoxide- in hot DMF yields the pyridyloxyaniline (VIII). Aniline (VIII) is finally condensed with either 4-chloro-3-(trifluoromethyl)phenyl isocyanate (IX) in CH2Cl2 or 4-chloro-3-(trifluoromethyl)aniline (X) by means of CDI in CH2Cl2.

参考文献中间体

合成目标

【1】 Sorbera, L.A.; Castaner, J.; Bozzo, J.; Leeson, P.A.; BAY-43-9006. Drugs Fut 2002, 27, 12, 1141.
【2】 Monahan, M.-K.; Sibley, R.; Natero, R.; Dumas, J.; Bankston, D.; Riedl, B.; A scaleable synthesis of BAY 43-9006: A potent Raf kinase inhibitor for the treatment of cancer. Org Process Res Dev 2002, 6, 6, 777.
【3】 Smith, R.A.; Monahan, M.-K.; Riedl, B.; Scott, W.J.; Khire, U.; Lowinger, T.B.; Natero, R.; Sibley, R.N.; Wood, J.E.; Renick, J.; Dumas, J. (Bayer Corp.); omega-Carboxy aryl substd. diphenyl ureas as p38 kinase inhibitors. WO 0041698 .
【4】 Lowinger, T.B.; Monahan, M.-K.; Dumas, J.; Scott, W.J.; Khire, U.; Wood, J.E.; Renick, J.; Riedl, B.; Smith, R.A.; Natero, R.; Sibley, R.N. (Bayer Corp.); omega-Carboxyaryl substd. diphenyl ureas as raf kinase inhibitors. EP 1140840; WO 0042012 .

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)	29950	2-pyridinecarboxylic acid；picolinic acid;Pyridine-2-carboxylic acid	98-98-6	C₆H₅NO₂	详情	详情
(II)	49908	4-chloropyridine-2-carbonyl chloride hydrochloride;(4-Chloro-2-pyridinecarbonyl Chloride Hydrochloride);4-Chloro-2-pyridinecarbonyl Chloride Hydrochlorid	51727-15-2	C₆H₃Cl₂NO.HCl	详情	详情
(III)	49909	methyl 4-chloro-2-pyridinecarboxylate	24484-93-3	C₇H₆ClNO₂	详情	详情
(IV)	49910	4-chloro-N-methyl-2-pyridinecarboxamide；4-chloro-N-methylpyridine-2-carboxamide;4-chloro-N-methylpicolinamide;4-Chloro-N-methylpicolinamide;2-(N-Methylcarbamoyl)-4-chloropyridine;4-Chloropyridine-2-carboxylicacid methylamide;N-Methyl-4-chloro-2-pyridinecarboxamide;N-Methyl-4-chloropicolinamide	220000-87-3	C₇H₇ClN₂O	详情	详情
(V)	32889	4-chloropyridine	7379-35-3	C₅H₄ClN	详情	详情
(VI)	49911	potassium 4-aminobenzenolate		C₆H₆KNO	详情	详情
(VII)	49912	4-(4-aminophenoxy)-N-methyl-2-pyridinecarboxamide	284462-37-9	C₁₃H₁₃N₃O₂	详情	详情
(VII)	49912	4-(4-aminophenoxy)-N-methyl-2-pyridinecarboxamide	284462-37-9	C₁₃H₁₃N₃O₂	详情	详情
(VIII)	37868	1-chloro-4-isocyanato-2-(trifluoromethyl)benzene; 4-chloro-3-(trifluoromethyl)phenyl isocyanate	327-78-6	C₈H₃ClF₃NO	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I), (II)

The title compound has been prepared by solid-phase combinatorial synthesis. The protected diaminopropionic acid (I) is attached to 2-chlorotrityl resin, producing the resin-bound amino acid (II). The N-Fmoc group of (II) is then selectively removed by treatment with piperidine in DMF producing (III). Condensation of amine (III) with N-ethoxycarbonyl-2-methyl-3-piperidinothioacrylamide (IV) results in the thiouracil derivative (V). This is converted into the thiocyanate (VI) upon treatment with cyanogen bromide in the presence of diisopropylethylamine. Further displacement of the thiocyanate group of (VI) with N-(2-benzimidazolyl)-1,3-propanediamine (VII) leads to the aminopyrimidone resin (VIII). Finally, acidic cleavage from the solid support (VIII) gives rise to the desired compound.

参考文献中间体

合成目标

【1】 Zechel, C.; Backfisch, G.; Delzer, J.; Geneste, H.; Graef, C.; Hornberger, W.; Kling, A.; Lange, U.E.W.; Lauterbach, A.; Seitz, W.; Subkowski, T.; Highly potent and selective alphaVbeta3-receptor antagonists: Solid-phase synthesis and SAR of 1-substituted 4-amino-1H-pyrimidin-2-ones. Bioorg Med Chem Lett 2003, 13, 2, 165.

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), (II)	49911	potassium 4-aminobenzenolate		C₆H₆KNO	详情	详情
(III)	18008	(2S)-3-amino-2-[[(benzyloxy)carbonyl]amino]propionic acid; N(alpha)-Z-L-2,3-diaminopropionic acid	35761-26-3	C₁₁H₁₄N₂O₄	详情	详情
(IV)	63377	ethyl 2-methyl-3-(1-piperidinyl)-2-propenethioylcarbamate		C₁₂H₂₀N₂O₂S	详情	详情
(V)	63378	3-[5-methyl-2-oxo-4-thioxo-3,4-dihydro-1(2H)-pyrimidinyl]-N-{[(phenylmethyl)oxy]carbonyl}alanine		C₁₆H₁₇N₃O₅S	详情	详情
(VI)	63379	3-[4-(cyanosulfanyl)-5-methyl-2-oxo-1(2H)-pyrimidinyl]-N-{[(phenylmethyl)oxy]carbonyl}alanine		C₁₇H₁₆N₄O₅S	详情	详情
(VII)	63380	N~1~-(1H-benzimidazol-2-yl)-1,3-propanediamine		C₁₀H₁₄N₄	详情	详情
(VIII)	63381	3-[4-{[3-(1H-benzimidazol-2-ylamino)propyl]amino}-5-methyl-2-oxo-1(2H)-pyrimidinyl]-N-{[(phenylmethyl)oxy]carbonyl}alanine		C₂₆H₂₉N₇O₅	详情	详情

Extended Information