6-methyl-3-pyridinol; 5-Hydroxy-2-methylpyridine -Drug Synthesis Database

【结构式】

【分子编号】25748

【品名】6-methyl-3-pyridinol; 5-Hydroxy-2-methylpyridine

【CA登记号】1121-78-4

【分子式】C₆H₇NO

【分子量】109.12772

【元素组成】C 66.04% H 6.47% N 12.84% O 14.66%

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：(XV)

Finally, compound (VIII) is condensed with either trimethyl(6-methyl-3-pyridyl)tin (XIII) or the boronate ester lithium salt (XIV) by means of Pd(PPh3)4 to afford etoricoxib. The metalated pyridine (XIII) is obtained by esterification of 3-hydroxy-6-methylpyridine (XV) with triflic anhydride to give the corresponding triflate (XVI), which is treated with hexamethylditin to afford the target tin intermediate (XIII). The boronate lithium salt (XIV) is prepared by treatment of 5-bromo-2-methylpyridine (XVII) with n-BuLi followed by addition of triisopropyl borate.

参考文献中间体

合成目标

【1】 Castañer, R.M.; Silvestre, J.S.; Sorbera, L.A.; Castañer, J.; Etoricoxib. Drugs Fut 2001, 26, 4, 346.
【2】 Friesen, R.W.; Brideau, C.; Chan, C.C.; Charleson, S.; Deschenes, D.; Dube, D.; Ethier, D.; Fortin, R.; Gauthier, J.Y.; Girard, Y.; Gordon, R.; Greig, G.M.; Riendeau, D.; Savoie, C.; Wang, Z.; Wong, E.; Visco, D.; Xu, L.J.; Young, R.N.; 2-Pyridinyl-3-(4-methylsulfonyl)phenylpyridines: Selective and orally active cyclooxygenase-2 inhibitors. Bioorg Med Chem Lett 1998, 8, 19, 2777.
【3】 Dube, D.; Fortin, R.; Friesen, R.; Wang, Z.; Gauthier, J.Y. (Merck Frosst Canada Inc.); Substd. pyridines as selective cyclooxygenase-2 inhibitors. EP 0912518; JP 1999514008; US 5861419; WO 9803484 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VIII)	18565	2,5-dichloro-3-[4-(methylsulfonyl)phenyl]pyridine; 4-(2,5-dichloro-3-pyridinyl)phenyl methyl sulfone		C₁₂H₉Cl₂NO₂S	详情	详情
(XIII)	25750	2-methyl-5-(trimethylstannyl)pyridine		C₉H₁₅NSn	详情	详情
(XIV)	45704	Lauroyl chloride	112-16-3	C₁₅H₂₇BLiNO₃	详情	详情
(XV)	25748	6-methyl-3-pyridinol; 5-Hydroxy-2-methylpyridine	1121-78-4	C₆H₇NO	详情	详情
(XVI)	25749	6-methyl-3-pyridinyl trifluoromethanesulfonate		C₇H₆F₃NO₃S	详情	详情
(XVII)	18566	5-bromo-2-methylpyridine	3430-13-5	C₆H₆BrN	详情	详情

合成路线2

该中间体在本合成路线中的序号：(LXXII)

Rearrangement of 5-bromo-2-methylpyridine 1-oxide (LXVII) with trifluoroacetic anhydride gives (5-bromopyridin-2-yl)methyl trifluoroacetate (LXVIII), which, without isolation, is hydrolyzed in MeOH solution, yielding (5-bromopyridin-2-yl)methanol trifluoroacetate salt (LXIX). Basification of compound (LXIX) with K2CO3 followed by chlorination with SOCl2 affords 5-bromo-2-(chloromethyl)pyridine (LXX), which is subsequently condensed with diethyl phosphite in the presence of LiHMDS, affording phosphonate (LXXI). Finally, Suzuki coupling of bromopyridine derivative (LXXI) with 3-fluorophenylboronic acid (V) by means of Na2CO3 and Pd/C in H2O at 75 °C provides the phenylpyridine compound (XII) .
O-Protection of 6-methyl-3-pyridinol (LXXII) with TIPSCl in DMF gives the corresponding silyl ether (LXXIII), which is then condensed with diethyl chlorophosphate (LXXIV) in the presence of BuLi and DIEA in THF, yielding diethyl phosphonate (II) .

参考文献中间体

合成目标

【1】 Chackalamannil, S., Wang, Y., Greenlee, W.J. et al. Discovery of a novel, orally active himbacine-based thrombin receptor antagonist (SCH 530348) with potent antiplatelet activity. J Med Chem 2008, 51(11): 3061-4.
【2】 Wu, G., Sudhakar, A.R., Wang, T. et al. (Schering Corp.). Exo- and diastereo- selective synthesis of himbacine analogs. CA 2594871, EP 1848705, EP 2196454, EP 2196468, EP 2206697, JP 2008526972, US 2006247450, WO 2006076415.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(II)	68703	diethyl ((5-((triisopropylsilyl)oxy)pyridin-2-yl)methyl)phosphonate		C₁₉H₃₆NO₄PSi	详情	详情
(V)	68704	3-fluorophenylboronic acid;3-Fluorobenzeneboronic acid	768-35-4	C₆H₆BFO₂	详情	详情
(XII)	68705	diethyl ((5-(3-fluorophenyl)pyridin-2-yl)methyl)phosphonate		C₁₆H₁₉FNO₃P	详情	详情
(LXVII)	68760	5-bromo-2-methylpyridine 1-oxide；5-bromo-2-Picoline-1-oxide；3-Bromo-6-methylpyridine 1-oxide;5-bromo-2-methylpyridine N-oxide;5-Bromo-2-picoline N-oxide	31181-64-3	C₆H₆BrNO	详情	详情
(LXVIII)	68761	(5-bromopyridin-2-yl)methyl trifluoroacetate；(5-bromopyridin-2-yl)methyl 2,2,2-trifluoroacetate		C₈H₅BrF₃NO₂	详情	详情
(LXIX)	68762	(5-bromopyridin-2-yl)methanol 2,2,2-trifluoroacetate		C₆H₆BrNO.C₂HF₃O₂	详情	详情
(LXX)	68763	5-bromo-2-(chloromethyl)pyridine	168823-76-5	C₆H₅BrClN	详情	详情
(LXXI)	68764	diethyl ((5-bromopyridin-2-yl)methyl)phosphonate		C₁₀H₁₅BrNO₃P	详情	详情
(LXXII)	25748	6-methyl-3-pyridinol; 5-Hydroxy-2-methylpyridine	1121-78-4	C₆H₇NO	详情	详情
(LXXIV)	68765	2-methyl-5-((triisopropylsilyl)oxy)pyridine		C₁₅H₂₇NOSi	详情	详情
(LXXV)	23623	Chlorophosphoric acid ethyl ester；Phosphorochloridic acid diethyl ester；Diethyl chlorophosphate;diethyl phosphorochloridate	814-49-3	C₄H₁₀ClO₃P	详情	详情

Extended Information