2-Bromo-3-methylpyridine; 2-Bromo-3-picoline -Drug Synthesis Database

【结构式】

【分子编号】57602

【品名】2-Bromo-3-methylpyridine; 2-Bromo-3-picoline

【CA登记号】3430-17-9

【分子式】C₆H₆BrN

【分子量】172.02438

【元素组成】C 41.89% H 3.52% Br 46.45% N 8.14%

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：(I)

2-Bromo-3-methylpyridine (I) is converted to the corresponding N-oxide (II) by treatment with m-chloroperbenzoic acid in CH2Cl2. Reaction of N-oxide (II) with trimethylsilyl cyanide and dimethylcarbamoyl chloride gives rise to the 2-cyanopyridine (III). Subsequent radical bromination of (III) using NBS and AIBN affords the bromomethyl pyridine (IV). Lithiation of 1-methyl-2-(triethylsilyl)imidazole (V), followed by condensation with 4-cyanobenzaldehyde (VI), provides carbinol (VII). This is then condensed with bromide (IV) in the presence of Ag2O to give ether (VIII). 5-Bromo-2,2-difluorobenzodioxole (IX) is lithiated with butyllithium in cold Et2O and subsequently treated with triisopropyl borate to afford, after aqueous work-up, the arylboronic acid (X). Finally, Mitsunobu coupling between boronic acid (X) and the bromopyridine (VIII) provides the title compound.

参考文献中间体

合成目标

【1】 Wang, L.; Hasvold, L.; Tong, Y.; et al.; Discovery of potent and orally active farnesyltransferase inhibitors. 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 129.
【2】 Sham, H.L.; Rockway, T.W.; Li, T.; Mantei, R.A.; Li, Q.; Lin, N.-H.; Wang, L.; Wang, W.; Wang, X.; Sullivan, G.M.; Wang, G.T.; Gwaltney, S.L. II; Claiborne, A.K.; Hasvold, L.A.; Tong, Y. (Abbott Laboratories Inc.); Farnesyltransferase inhibitors. US 2002115640; WO 0274747 .

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)	57602	2-Bromo-3-methylpyridine; 2-Bromo-3-picoline	3430-17-9	C₆H₆BrN	详情	详情
(II)	57603	2-bromo-3-methyl-1-pyridiniumolate		C₆H₆BrNO	详情	详情
(III)	57604	6-bromo-5-methyl-2-pyridinecarbonitrile		C₇H₅BrN₂	详情	详情
(IV)	57605	6-bromo-5-(bromomethyl)-2-pyridinecarbonitrile		C₇H₄Br₂N₂	详情	详情
(V)	57606	1-methyl-5-(triethylsilyl)-1H-imidazole		C₁₀H₂₀N₂Si	详情	详情
(VI)	17552	4-formylbenzonitrile; 4-Cyanobenzaldehyde	105-07-7	C₈H₅NO	详情	详情
(VII)	57607	4-[hydroxy(1-methyl-1H-imidazol-5-yl)methyl]benzonitrile		C₁₂H₁₁N₃O	详情	详情
(VIII)	57608	6-bromo-5-{[(4-cyanophenyl)(1-methyl-1H-imidazol-5-yl)methoxy]methyl}-2-pyridinecarbonitrile		C₁₉H₁₄BrN₅O	详情	详情
(IX)	57609	5-Bromo-2,2-difluoro-1,3-benzodioxole；4-Bromo-1,2-[(difluoromethylene)dioxy]benzene	33070-32-5	C₇H₃BrF₂O₂	详情	详情
(X)	57610	2,2-difluoro-1,3-benzodioxol-5-ylboronic acid		C₇H₅BF₂O₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XXII)

Intermediate (XVI) is prepared by Suzuki coupling of 2-bromo-3-methylpyridine (XXII) with 3-(tert-butoxycarbonyl)phenylboronic acid (XXIII) in the presence of PdCl2(dppf) and K2CO3 in toluene at 65 °C to give tert-butyl 3-(3-methylpyridin-2-yl)benzoate (XXIV), which upon oxidation of the pyridine ring using urea-hydrogen peroxide and phthalic anhydride in EtOAc/H2O furnishes the pyridine-N-oxide (XXV). Finally, compound (XXV) is submited to rearrangement with Ms2O in the presence of pyridine in acetonitrile at 70 °C followed by quenching with ethanolamine .

参考文献中间体

合成目标

【1】 Siesel, D. (Vertex Pharmaceuticals, Inc.). Processes for producing cycloalkylcarboxamido-pyridine benzoic acids. CN 101910134, EP 2231606, JP 2011506332, KR 201010132, US 2009176989, US 8124781, US 2012190856, WO 2009076142.

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)	68642	tert-butyl 3-(6-amino-3-methylpyridin-2-yl)benzoate		C₁₇H₂₀N₂O₂	详情	详情
(XXII)	57602	2-Bromo-3-methylpyridine; 2-Bromo-3-picoline	3430-17-9	C₆H₆BrN	详情	详情
(XXIII)	68646	3-(tert-butoxycarbonyl)phenylboronic acid;3-tert-Butoxycarbonylphenylboronic acid	220210-56-0	C₁₁H₁₅BO₄	详情	详情
(XXIV)	68648	tert-butyl 3-(3-methylpyridin-2-yl)benzoate		C₁₇H₁₉NO₂	详情	详情
(XXV)	68647	2-(3-(tert-butoxycarbonyl)phenyl)-3-methylpyridine 1-oxide		C₁₇H₁₉NO₃	详情	详情

Extended Information