2-amino-6-bromopyridine; 6-bromo-2-pyridinamine; 6-bromo-2-pyridinylamine -Drug Synthesis Database

【结构式】

【分子编号】41341

【品名】2-amino-6-bromopyridine; 6-bromo-2-pyridinamine; 6-bromo-2-pyridinylamine

【CA登记号】19798-81-3

【分子式】C₅H₅BrN₂

【分子量】173.01218

【元素组成】C 34.71% H 2.91% Br 46.18% N 16.19%

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：(II)

2-Amino-6-bromopyridine (II) was prepared by reaction of 2,6-dibromopyridine (I) with ammonium hydroxide in a pressure bomb at 170 C. The amino group of (III) was subsequently blocked as the pyrrole derivative (IV) by condensation with 2,5-hexanedione (III). Diazotization of p-aminophenyl ethanol (V) followed by treatment with KI gave iodo derivative (VI). Subsequent reaction of (VI) with SOCl2 provided chloride (VII). Arylpyridine (VIII) was obtained by lithiation of bromopyridine (IV) with BuLi, followed by conversion to the corresponding organozinc compound with ZnCl2 and palladium-catalyzed coupling with iodide (VII). Pyrrole ring cleavage in (VIII) upon treatment with hydroxylamine furnished aminopyridine (IX). Subsequent condensation with N-Boc-piperazine (X) provided adduct (XI). After acid cleavage of the Boc group of (XI), alkylation of the resulting piperazine with phenacyl chloride (XII) yielded the title compound. Alternatively, the title compound was obtained by condensation of chloride (IX) with N-phenacylpiperazine (XIII).

参考文献中间体

合成目标

【1】 Qian, W.; Lowe, J.A.; Volkmann, R.A.; et al.; A new class of selective and potent inhibitors of neuronal nitric oxide synthase. Bioorg Med Chem Lett 1999, 9, 17, 2569.
【2】 Lowe, J.A. III; Whittle, P.J. (Pfizer Inc.); 6-Phenylpyridyl-2-amine derivs.. EP 0891332; JP 1999510513; WO 9736871 .

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)	10159	2,6-Dibromopyridine	626-05-1	C₅H₃Br₂N	详情	详情
(II)	41341	2-amino-6-bromopyridine; 6-bromo-2-pyridinamine; 6-bromo-2-pyridinylamine	19798-81-3	C₅H₅BrN₂	详情	详情
(III)	24848	acetonyl acetone;1,2-Diacetylethane;a,b-Diacetylethane;2,5-Diketohexane;Diacetonyl;Acetonylacetone;2,5-Dioxohexane;2,5-hexanedione	110-13-4	C₆H₁₀O₂	详情	详情
(IV)	41342	2-bromo-6-(2,5-dimethyl-1H-pyrrol-1-yl)pyridine		C₁₁H₁₁BrN₂	详情	详情
(V)	14019	p-Aminophenylethanol; 2-(4-Aminophenyl)-1-ethanol	104-10-9	C₈H₁₁NO	详情	详情
(VI)	30973	2-(4-iodophenyl)-1-ethanol		C₈H₉IO	详情	详情
(VII)	41343	1-(2-chloroethyl)-4-iodobenzene		C₈H₈ClI	详情	详情
(VIII)	41344	2-[4-(2-chloroethyl)phenyl]-6-(2,5-dimethyl-1H-pyrrol-1-yl)pyridine		C₁₉H₁₉ClN₂	详情	详情
(IX)	41345	6-[4-(2-chloroethyl)phenyl]-2-pyridinamine; 6-[4-(2-chloroethyl)phenyl]-2-pyridinylamine		C₁₃H₁₃ClN₂	详情	详情
(X)	13225	N-tert-Butoxycarbonyl piperazine; tert-butyl 1-piperazinecarboxylate;tert-butyl piperazine-1-carboxylate	143238-38-4	C₉H₁₈N₂O₂	详情	详情
(XI)	41346	tert-butyl 4-[4-(6-amino-2-pyridinyl)phenethyl]-1-piperazinecarboxylate		C₂₂H₃₀N₄O₂	详情	详情
(XII)	38669	2-chloro-1-phenyl-1-ethanone	532-27-4	C₈H₇ClO	详情	详情
(XIII)	41347	1-phenyl-2-(1-piperazinyl)-1-ethanone		C₁₂H₁₆N₂O	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

Condensation of 2-amino-6-bromopyridine (I) with ethoxycarbonyl isothiocyanate (II) in CH2Cl2 gives 1-(6-bromopyridin-2-yl)-3-(ethoxycarbonyl) thiourea (III), which by cyclization with hydroxylamine hydrochloride (IV) in the presence of DIEA in EtOH/MeOH yields 2-amino-5-bromo[1,2,4]triazolo[1,5-a]pyridine (V). N-Acylation of amine (V) with cyclopropanecarbonyl chloride (VI) using Et3N in acetonitrile, and subsequent treatment with methanolic ammonia, results in the carboxamide (VII) . Suzuki coupling of compound (VII) with 4-(hydroxymethyl)phenylboronic acid (VIII) in the presence of PdCl2(dppf) and K2CO3 in dioxane/H2O at 90 °C, followed by bromination with PBr3 in CHCl3, affords the benzyl bromide intermediate (IX), which is finally condensed with thiomorpholine-1,1-dioxide (X) using DIEA in CH2Cl2/MeOH .
Alternatively, condensation of (4-bromomethylphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (XI) with thiomorpholine 1,1-dioxide (X) by means of DIEA in CH2Cl2/MeOH gives intermediate (XII), which finally undergoes Suzuki coupling with aryl bromide (VII) in the presence of PdCl2(dppf) and K2CO3 in dioxane/H2O at 90 °C .

参考文献中间体

合成目标

【1】 Menet, C.J.M., Smits, K.K. (Galapagos NV). 5-Phenyl-[1,2,4]triazolo[1,5-a]pyridine-2-yl carboxamides as JAK inhibitors. CN 102482273, EP 2445911, JP 2012530766, KR 2012107919, US 201331319, US 8088764, WO 2010149769.
【2】 Menet, C.J.M., Smits, K.K. (Galapagos NV). Novel compound useful for the treatment of degenerative and inflammatory diseases. US 2012142678, US 8563545.
【3】 Van ‘t Klooster, G.A.E., Brys, R.C.X., Van Rompaey, L.J.C., Namour, F.S. (Galapagos NV). Aminotriazolopyridine for use in the treatment of inflammation, and pharmaceutical composition thereof. US 2013345209, WO 2013189771.

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)	41341	2-amino-6-bromopyridine; 6-bromo-2-pyridinamine; 6-bromo-2-pyridinylamine	19798-81-3	C₅H₅BrN₂	详情	详情
(II)	25964	1-[(isothiocyanatocarbonyl)oxy]ethane	16182-04-0	C₄H₅NO₂S	详情	详情
(III)	67818	1-(6-bromopyridin-2-yl)-3-(ethoxycarbonyl)thiourea		C₉H₁₀BrN₃O₂S	详情	详情
(IV)	65957	Hydroxylamine hydrochloride; Hydroxylammonium chloride; Oxammonium hydrochloride	5470-11-1	H₃NO.HCl	详情	详情
(V)	67819	2-amino-5-bromo[1,2,4]triazolo[1,5-a]pyridine		C₆H₅BrN₄	详情	详情
(VI)	14061	Cyclopropanecarbonyl chloride; Cyclopropanecarboxylic acid chloride	4023-34-1	C₄H₅ClO	详情	详情
(VII)	67820	N-(5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide		C₁₀H₉BrN₄O	详情	详情
(VIII)	67821	4-(hydroxymethyl)phenylboronic acid	59016-93-2	C₇H₉BO₃	详情	详情
(IX)	67822	N-(5-(4-(bromomethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide		C₁₇H₁₅BrN₄O	详情	详情
(X)	67823	thiomorpholine-1,1-dioxide	39093-93-1	C₄H₉NO₂S	详情	详情
(XI)	67824	(4-bromomethylphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane	138500-85-3	C₁₃H₁₈BBrO₂	详情	详情
(XII)	67825	4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)thiomorpholine 1,1-dioxide		C₁₇H₂₆BNO₄S	详情	详情

Extended Information