Pirbuterol hydrochloride, CP-24314-1, Exirel, -Drug Synthesis Database

【结构式】

【药物名称】Pirbuterol hydrochloride, CP-24314-1, Exirel

【化学名称】2-tert-Butylamino-1-(5-hydroxy-6-hydroxymethyl-2-pyridyl)ethanol dihydrochloride

【CA登记号】38029-10-6, 38677-81-5 (free base)

【分子式】C₁₂H₂₂Cl₂N₂O₃

【分子量】313.22674

【开发单位】Pfizer (Originator)

【药理作用】Asthma Therapy, Bronchodilators, RESPIRATORY DRUGS, beta2-Adrenoceptor Agonists

合成路线1 合成路线2

合成路线1

A new method for the synthesis of pirbuterol hydrochloride has been described: By reaction of 2-phenyl-4H-1,3-dioxino[5,4-b]pyridine-6-carbaldehyde (I) with methyltriphenylphosphonium bromide (II) and NaOH in toluene to give 2-phenyl-6-vinyl-4H-1,3-dioxino[5,4-b]pyridine (III), which is treated with m-chloroperbenzoic acid (IV) in methylene chloride to give 6-(1,2-epoxyethyl)-2-phenyl-4H-1,3-dioxino[5,4-b]pyridine N-oxide (V). Compound (V) can also be obtained from 6-(1,2-epoxyethyl)-2-phenyl-4H-1,3-dioxino[5,4-b]pyridine (VI) by reaction with m-chloroperbenzoic acid (IV) as before. The reaction of (V) with tert-butylamine (VII) in methanol affords 6-(1-hydroxy-2-tert-butylaminoethyl)-2-phenyl-4H-1,3-dioxino[5,4-b]pyridine N-oxide (VIII), which is first treated with H2 over Pd/C in methanol and then with HCl in ethyl acetate to give pirbuterol hydrochloride.

参考文献中间体

【1】 Masset, S.S.; Cue, B.W. (Pfizer Inc.); Process and intermediates for preparing pirbuteol and analogs. EP 0058069; EP 0058070; EP 0058071; EP 0058072; JP 57150665 .

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)	30711	2-phenyl-4H-[1,3]dioxino[5,4-b]pyridine-6-carbaldehyde		C₁₄H₁₁NO₃	详情	详情
(II)	30484	Methyl(triphenyl)phosphonium bromide	1779-49-3	C₁₉H₁₈BrP	详情	详情
(III)	30712	2-phenyl-6-vinyl-4H-[1,3]dioxino[5,4-b]pyridine		C₁₅H₁₃NO₂	详情	详情
(V)	30713	6-(2-oxiranyl)-2-phenyl-4H-[1,3]dioxino[5,4-b]pyridin-5-ium-5-olate		C₁₅H₁₃NO₄	详情	详情
(VI)	30714	6-(2-oxiranyl)-2-phenyl-4H-[1,3]dioxino[5,4-b]pyridine		C₁₅H₁₃NO₃	详情	详情
(VII)	17895	2-Amino-2-methylpropane; tert-butylamine; 2-methyl-2-propanamine	75-64-9	C₄H₁₁N	详情	详情
(VIII)	30715	6-[2-(tert-butylamino)-1-hydroxyethyl]-2-phenyl-4H-[1,3]dioxino[5,4-b]pyridin-5-ium-5-olate		C₁₉H₂₄N₂O₄	详情	详情

合成路线2

The reaction of 3-hydroxypyridine (I) first with formaldehyde and NaOH in water, and then with benzyl bromide (A) in ethanol gives 3-benzyloxy-2,6-bis(hydroxymethyl)pyridine hydrochloride (II), which is oxidized with MnO2 in refluxing benzene yielding 2-hydroxmethyl-3-benzyloxy-6-pyridincarboxaldehyde (III). The condensation of (III) with tertbutylisonitrile (B) and acetic acid in refluxing CHCl3 affords N-tertbutyl-2-(5-benzyloxy-6-hydroxymethyl-2-pyridil)-2-acetoxyacetamide (IV), which is hydrolyzed with 12N HCl yielding N-tertbutyl-2-(5-benzyloxy-6-hydroxymethyl-2-pyridil)-2-hydroxyacetamide (V). The reduction of the amide group of (V) with diborane in THF gives 2-hydroxymethyl-3-benzyloxy-6-(1-hydroxy-2-tertbutylaminoethyl)pyridine (VI), which is finally debenzylated with H2 over Pd/C in methanol.

参考文献中间体

【1】 Barth, W.; 2-Hydroxymethyl-3-hydroxy-6-(1-hydroxy-2-aminoethyl)pyridines. DE 2204195; FR 2125309; GB 1367668; GB 1367669; US 3700681; US 3763173 .
【2】 Castaner, J.; Thorpe, P.; Pirbuterol. Drugs Fut 1977, 2, 1, 60.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(A)	12912	1-(Bromomethyl)benzene; Alpha-bromotoluene	100-39-0	C₇H₇Br	详情	详情
(B)	33871	pivalonitrile	630-18-2	C₅H₉N	详情	详情
(I)	12911	3-Hydroxypyridine; 3-Pyridinol	109-00-2	C₅H₅NO	详情	详情
(II)	33869	[3-(benzyloxy)-6-(hydroxymethyl)-2-pyridinyl]methanol		C₁₄H₁₅NO₃	详情	详情
(III)	33870	5-(benzyloxy)-6-(hydroxymethyl)-2-pyridinecarbaldehyde		C₁₄H₁₃NO₃	详情	详情
(IV)	33872	1-[5-(benzyloxy)-6-(hydroxymethyl)-2-pyridinyl]-2-(tert-butylamino)-2-oxoethyl acetate		C₂₁H₂₆N₂O₅	详情	详情
(V)	33873	2-[5-(benzyloxy)-6-(hydroxymethyl)-2-pyridinyl]-N-(tert-butyl)-2-hydroxyacetamide		C₁₉H₂₄N₂O₄	详情	详情
(VI)	33874	1-[5-(benzyloxy)-6-(hydroxymethyl)-2-pyridinyl]-2-(tert-butylamino)-1-ethanol		C₁₉H₂₆N₂O₃	详情	详情

Extended Information