Eformoterol fumarate, Formoterol fumarate, CGP-25827A(free base), YM-08316, BD-40A(anhydrous), Foradil Aerolizer, Foradil Certihaler, Broncoral, Oxeze Turbuhaler, Oxis Turbuhaler, Foradil, Atock, -Drug Synthesis Database

【结构式】

【药物名称】Eformoterol fumarate, Formoterol fumarate, CGP-25827A(free base), YM-08316, BD-40A(anhydrous), Foradil Aerolizer, Foradil Certihaler, Broncoral, Oxeze Turbuhaler, Oxis Turbuhaler, Foradil, Atock

【化学名称】(±)-N-[2-Hydroxy-5-[1(R*)-hydroxy-2-[1(R*)-methyl-2-(4-methoxyphenyl)ethylamino]ethyl]phenyl]formamide fumarate (2:1) monohydrate

【CA登记号】43229-80-7 (anhydrous), 73573-87-2 (anhydrous; free base)

【分子式】C₄₂H₅₄N₄O₁₃

【分子量】822.91768

【开发单位】Yamanouchi (Originator), Schering-Plough (Marketer), AstraZeneca (Licensee), Ferrer (Licensee), Novartis (Licensee), Chiesi (Formulation), ML Laboratories (Formulation), Orion Corp. (Formulation), SkyePharma (Formulation)

【药理作用】Asthma Therapy, Bronchodilators, Chronic Obstructive Pulmonary Diseases (COPD), Treatment of, RESPIRATORY DRUGS, beta2-Adrenoceptor Agonists

合成路线1 合成路线2 合成路线3 合成路线4 合成路线5 合成路线6

合成路线1

The bromination of 4 benzyloxy-3-nitroacetophenone (I) with Br2 in CHCl3 gives 4-benzyloxy-3-nitro-alpha-bromoacetophenone (II), which is then condensed with N-benzyl-N-(1-methyl-2-(p-methoxyphenyl)ethyl]-amine (III) in butanone at 80 C yielding 4-benzyloxy-3-nitro-alpha-[N-benzyl-N-[1-methyl-2-(p-methoxyphenyl)ethyl]amino]acetophenone (IV). The reduction of the carbonyl group of (IV) with NaBH4 in ethanol affords the corresponding nitro alcohol (V), which is reduced again with Fe and HCl in ethanol - water to the amino alcohol (VI). The formylation of (VI) with formic acid in acetic anhydride gives 4-benzyloxy-3-formyl-amino-alpha-[N-benzyl-N-[1-methyl-2-(p-methoxyphenyl)ethyl]aminomethyl]benzyl alcohol (VII), which is finally debenzylated with H2 over Pd/C in ethanol and treated with fumaric acid (A).

参考文献中间体

【1】 Murakami, M.; et al.; alpha-Aminomethylbenzylalkoholderivative. DE 2305092; DE 2366625 .
【2】 Castaner, J.; Weetman, D.F.; BD 40A. Drugs Fut 1977, 2, 10, 639.

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)	23808	Fumaric acid; (E)-2-butenedioic acid	110-17-8	C₄H₄O₄	详情	详情
(I)	20627	1-[4-(benzyloxy)-3-nitrophenyl]-1-ethanone		C₁₅H₁₃NO₄	详情	详情
(II)	32763	1-[4-(benzyloxy)-3-nitrophenyl]-2-bromo-1-ethanone		C₁₅H₁₂BrNO₄	详情	详情
(III)	33904	(2S)-N-benzyl-1-(4-methoxyphenyl)-2-propanamine; N-benzyl-N-[(1S)-2-(4-methoxyphenyl)-1-methylethyl]amine		C₁₇H₂₁NO	详情	详情
(IV)	33900	2-[benzyl[(1S)-2-(4-methoxyphenyl)-1-methylethyl]amino]-1-[4-(benzyloxy)-3-nitrophenyl]-1-ethanone		C₃₂H₃₂N₂O₅	详情	详情
(V)	33901	(1R)-2-[benzyl[(1S)-2-(4-methoxyphenyl)-1-methylethyl]amino]-1-[4-(benzyloxy)-3-nitrophenyl]-1-ethanol		C₃₂H₃₄N₂O₅	详情	详情
(VI)	33902	(1R)-1-[3-amino-4-(benzyloxy)phenyl]-2-[benzyl[(1S)-2-(4-methoxyphenyl)-1-methylethyl]amino]-1-ethanol		C₃₂H₃₆N₂O₃	详情	详情
(VII)	33903	5-((1R)-2-[benzyl[(1S)-2-(4-methoxyphenyl)-1-methylethyl]amino]-1-hydroxyethyl)-2-(benzyloxy)phenylformamide		C₃₃H₃₆N₂O₄	详情	详情

合成路线2

By reduction of a mixture of 1-(3-formylamino-4-hydroxyphenyl)-2-aminoethanol (VIII) and 1-(4-methoxyphenyl)-2-propanone (IX) with H2 over Pt in ethanol, followed by a treatment with fumaric acid (A).

参考文献中间体

【1】 Tanoury GJ, Hett R,Kessler D,et aL 2002. Taking advantage of polymorphism to effect an impurity removalt: development of a thermodynamic crystal form of (R,R)-fonnoterol tartnte. Org Proc Res Dev,6 (6)．855~862
【1】 Murase, K.; et al.; JP 7512040 .
【2】 Castaner, J.; Weetman, D.F.; BD 40A. Drugs Fut 1977, 2, 10, 639.

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)	23808	Fumaric acid; (E)-2-butenedioic acid	110-17-8	C₄H₄O₄	详情	详情
(I)	66381	(1R,2S)-1-Amino-2-indanol	7480-35-5	C₉H₁₁NO	详情	详情
(II)	32764	(3aR,8aS)-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d][1,3,2]oxazaborole		C₉H₁₀BNO	详情	详情
(III)	32765	(1R)-1-[4-(benzyloxy)-3-nitrophenyl]-2-bromo-1-ethanol	188690-82-6	C₁₅H₁₄BrNO₄	详情	详情
(IV)	32766	(1R)-1-[3-amino-4-(benzyloxy)phenyl]-2-bromo-1-ethanol		C₁₅H₁₆BrNO₂	详情	详情
(V)	32767	2-(benzyloxy)-5-[(1R)-2-bromo-1-hydroxyethyl]phenylformamide		C₁₆H₁₆BrNO₃	详情	详情
(VI)	32738	tert-butyl (2S,3S)-2-[(2-[[2-([[(1S,2S)-1-(tert-butoxycarbonyl)-2-methylbutyl]amino]carbonyl)phenyl]disulfanyl]benzoyl)amino]-3-methylpentanoate		C₃₄H₄₈N₂O₆S₂	详情	详情
(VII)	32769	5-((1R)-2-[benzyl[(1R)-2-(4-methoxyphenyl)-1-methylethyl]amino]-1-hydroxyethyl)-2-(benzyloxy)phenylformamide		C₃₃H₃₆N₂O₄	详情	详情
(VIII)	33905	5-[(1R)-2-amino-1-hydroxyethyl]-2-hydroxyphenylformamide		C₉H₁₂N₂O₃	详情	详情
(VIII)	66382	N-[2-Hydroxy-5-[1(R)-hydroxy-2-[2-(4-methoxyphenyl)-1(R)-methylethylamino]ethyl]phenyl]formamide	67346-49-0	C₁₉H₂₄N₂O₄	详情	详情
(IX)	10038	4-Methoxyphenylacetone; 1-(4-Methoxyphenyl)acetone	122-84-9	C₁₀H₁₂O₂	详情	详情

合成路线3

参考文献中间体

【1】 Tanoury GJ, Hett R,Kessler D,et aL 2002. Taking advantage of polymorphism to effect an impurity removalt: development of a thermodynamic crystal form of (R,R)-fonnoterol tartnte. Org Proc Res Dev,6 (6)．855~862
【1】 Murase, K.; et al.; JP 7512040 .
【2】 Castaner, J.; Weetman, D.F.; BD 40A. Drugs Fut 1977, 2, 10, 639.

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)	23808	Fumaric acid; (E)-2-butenedioic acid	110-17-8	C₄H₄O₄	详情	详情
(I)	66381	(1R,2S)-1-Amino-2-indanol	7480-35-5	C₉H₁₁NO	详情	详情
(II)	32764	(3aR,8aS)-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d][1,3,2]oxazaborole		C₉H₁₀BNO	详情	详情
(III)	32765	(1R)-1-[4-(benzyloxy)-3-nitrophenyl]-2-bromo-1-ethanol	188690-82-6	C₁₅H₁₄BrNO₄	详情	详情
(IV)	32766	(1R)-1-[3-amino-4-(benzyloxy)phenyl]-2-bromo-1-ethanol		C₁₅H₁₆BrNO₂	详情	详情
(V)	32767	2-(benzyloxy)-5-[(1R)-2-bromo-1-hydroxyethyl]phenylformamide		C₁₆H₁₆BrNO₃	详情	详情
(VI)	32738	tert-butyl (2S,3S)-2-[(2-[[2-([[(1S,2S)-1-(tert-butoxycarbonyl)-2-methylbutyl]amino]carbonyl)phenyl]disulfanyl]benzoyl)amino]-3-methylpentanoate		C₃₄H₄₈N₂O₆S₂	详情	详情
(VII)	32769	5-((1R)-2-[benzyl[(1R)-2-(4-methoxyphenyl)-1-methylethyl]amino]-1-hydroxyethyl)-2-(benzyloxy)phenylformamide		C₃₃H₃₆N₂O₄	详情	详情
(VIII)	33905	5-[(1R)-2-amino-1-hydroxyethyl]-2-hydroxyphenylformamide		C₉H₁₂N₂O₃	详情	详情
(VIII)	66382	N-[2-Hydroxy-5-[1(R)-hydroxy-2-[2-(4-methoxyphenyl)-1(R)-methylethylamino]ethyl]phenyl]formamide	67346-49-0	C₁₉H₂₄N₂O₄	详情	详情
(IX)	10038	4-Methoxyphenylacetone; 1-(4-Methoxyphenyl)acetone	122-84-9	C₁₀H₁₂O₂	详情	详情

合成路线4

参考文献中间体

【1】 Tanoury GJ, Hett R,Kessler D,et aL 2002. Taking advantage of polymorphism to effect an impurity removalt: development of a thermodynamic crystal form of (R,R)-fonnoterol tartnte. Org Proc Res Dev,6 (6)．855~862

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VI)	32738	tert-butyl (2S,3S)-2-[(2-[[2-([[(1S,2S)-1-(tert-butoxycarbonyl)-2-methylbutyl]amino]carbonyl)phenyl]disulfanyl]benzoyl)amino]-3-methylpentanoate		C₃₄H₄₈N₂O₆S₂	详情	详情
(IX)	10038	4-Methoxyphenylacetone; 1-(4-Methoxyphenyl)acetone	122-84-9	C₁₀H₁₂O₂	详情	详情
(X)	32770	N-benzyl-N-[2-(4-methoxyphenyl)-1-methylethyl]amine; N-benzyl-1-(4-methoxyphenyl)-2-propanamine		C₁₇H₂₁NO	详情	详情

合成路线5

参考文献中间体

【1】 Zhao LQ，Zhao DM，Zhang YF．et al.2000．Synthesis of 2-adrenoceptor agonist formoterol.中国药物化学杂志，10 (4): 285 --287

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)	32763	1-[4-(benzyloxy)-3-nitrophenyl]-2-bromo-1-ethanone		C₁₅H₁₂BrNO₄	详情	详情
(II)	50312	(2R)-2-[4-(benzyloxy)-3-nitrophenyl]oxirane; benzyl 2-nitro-4-[(2R)oxiranyl]phenyl ether		C₁₅H₁₃NO₄	详情	详情
(III)	66383	1-(4-Methoxyphenyl)propan-2-amine	50505-80-1	C₁₀H₁₅NO	详情	详情
(IV)	66384	1-(4-(benzyloxy)-3-nitrophenyl)-2-((1-(4-methoxyphenyl)propan-2-yl)amino)ethanol		C₂₅H₂₈N₂O₅	详情	详情
(V)	66385	1-(3-amino-4-(benzyloxy)phenyl)-2-((1-(4-methoxyphenyl)propan-2-yl)amino)ethanol hydrochloride		C₂₅H₃₀N₂O₃.HCl	详情	详情
(VI)	66386	N-(2-(benzyloxy)-5-(1-hydroxy-2-((1-(4-methoxyphenyl)propan-2-yl)amino)ethyl)phenyl)formamide hydrochloride		C₂₆H₃₁ClN₂O₄	详情	详情
(VII)	23808	Fumaric acid; (E)-2-butenedioic acid	110-17-8	C₄H₄O₄	详情	详情

合成路线6

参考文献中间体

【1】 Campos F.Bosch MP,Guerrero A. 2000．An efficient enantioselective synthesis of(R, R)-formoterol,a potent bronchodilator, using lipases. Tetrahedron: Asymm, 11 (13): 2705～2717

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)	66388	(R)-N-(1-(4-methoxyphenyl)propan-2-yl)prop-1-en-2-amine		C₁₃H₁₉NO	详情	详情
(II)	66387	(R)-1-(4-methoxyphenyl)propan-2-amine	58993-79-6	C₁₂H₁₇NO₂	详情	详情
(III)	66389	2-(benzyloxy)-5-(2-bromo-1-hydroxyethyl)benzoic acid		C₁₆H₁₅BrO₄	详情	详情
(IV)	66390	(R)-1-(4-(benzyloxy)-3-nitrophenyl)-2-bromoethyl acetate		C₁₇H₁₆BrNO₅	详情	详情
(V)	32765	(1R)-1-[4-(benzyloxy)-3-nitrophenyl]-2-bromo-1-ethanol	188690-82-6	C₁₅H₁₄BrNO₄	详情	详情
(VI)	50312	(2R)-2-[4-(benzyloxy)-3-nitrophenyl]oxirane; benzyl 2-nitro-4-[(2R)oxiranyl]phenyl ether		C₁₅H₁₃NO₄	详情	详情
(VII)	66391	(R)-1-(4-(benzyloxy)-3-nitrophenyl)-2-(((R)-1-(4-methoxyphenyl)propan-2-yl)amino)ethanol		C₂₅H₂₈N₂O₅	详情	详情
(VIII)	66392	(R)-1-(3-amino-4-(benzyloxy)phenyl)-2-(((R)-1-(4-methoxyphenyl)propan-2-yl)amino)ethanol		C₂₅H₃₀N₂O₃	详情	详情
(IX)	66393	N-(2-(benzyloxy)-5-((R)-1-hydroxy-2-(((R)-1-(4-methoxyphenyl)propan-2-yl)amino)ethyl)phenyl)formamide		C₂₆H₃₀N₂O₄	详情	详情
(X)	66382	N-[2-Hydroxy-5-[1(R)-hydroxy-2-[2-(4-methoxyphenyl)-1(R)-methylethylamino]ethyl]phenyl]formamide	67346-49-0	C₁₉H₂₄N₂O₄	详情	详情

Extended Information