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【结 构 式】 
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【分子编号】32769 【品名】5-((1R)-2-[benzyl[(1R)-2-(4-methoxyphenyl)-1-methylethyl]amino]-1-hydroxyethyl)-2-(benzyloxy)phenylformamide 【CA登记号】 |
【 分 子 式 】C33H36N2O4 【 分 子 量 】524.65992 【元素组成】C 75.55% H 6.92% N 5.34% O 12.2% |
合成路线1
该中间体在本合成路线中的序号：(VIII)The enantioselective reduction of phenacyl bromide (I) with BH3.S(CH3)2 in THF catalyzed by the chiral borolidine (II) (obtained by reaction of (1R,2S)-1-amino-2-indanol (III) with BH3.S(CH3)2 in THF) gives the (R)-2-bromo-1-(4-benzyloxy-3-nitrophenyl)ethanol (IV), which is reduced with H2 over PtO2 in THF/toluene yielding the corresponding amino derivative (V). The reaction of (V) with formic acid and Ac2O affords the formamide (VI), which is condensed with the chiral (R)-N-benzyl-N-[2-(4-methoxyphenyl)-1-methylethyl]amine (VII) in THF/methanol providing the protected target compound (VIII). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C in ethanol. The intermediate the chiral (R)-N-benzyl-N-[2-(4-methoxyphenyl)-1-methylethyl]amine (VII) has been obtained by reductocondensation of 1-(4-methoxyphenyl)-2-propanone (IX) and benzylamine by hydrogenation with H2 over Pd/C in methanol yielding racemic N-benzyl-N-[2-(4-methoxyphenyl)-1-methylethyl]amine (X), which is submitted to optical resolution with (S)-mandelic acid to obtain the desired (R)-enantiomer (VII).
| 【1】 Hett, R.; et al.; Large-scale synthesis of enantio- and diastereomerically pure (R,R)-formoterol. Org Process Res Dev 1998, 2, 2, 96. |
| 【2】 Hett, R.; Senanayake, C.H.; Fang, K.Q.; Wald, S.A.; Redmon, M.P.; Gao, Y. (Sepracor Inc.); Formoterol process. US 6040344 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 | |
| (I) | 32763 | 1-[4-(benzyloxy)-3-nitrophenyl]-2-bromo-1-ethanone | C15H12BrNO4 | 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) | 27559 | (1R,2S)-1-amino-2,3-dihydro-1H-inden-2-ol | C9H11NO | 详情 | 详情 | |
| (IV) | 32765 | (1R)-1-[4-(benzyloxy)-3-nitrophenyl]-2-bromo-1-ethanol | 188690-82-6 | C15H14BrNO4 | 详情 | 详情 |
| (V) | 32766 | (1R)-1-[3-amino-4-(benzyloxy)phenyl]-2-bromo-1-ethanol | C15H16BrNO2 | 详情 | 详情 | |
| (VI) | 32767 | 2-(benzyloxy)-5-[(1R)-2-bromo-1-hydroxyethyl]phenylformamide | C16H16BrNO3 | 详情 | 详情 | |
| (VII) | 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 | |
| (VIII) | 32769 | 5-((1R)-2-[benzyl[(1R)-2-(4-methoxyphenyl)-1-methylethyl]amino]-1-hydroxyethyl)-2-(benzyloxy)phenylformamide | C33H36N2O4 | 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2
该中间体在本合成路线中的序号：(XII)The intermediate N-benzyl-N-[1(R)-methyl-2-(4-methoxyphenyl)ethyl]amine (IV) has been obtained as follows: The reductocondensation of 1-(4-methoxyphenyl)-2-propanone (I) with benzylamine (II) by H2 over Pd/C gives the N-benzyl-N-[1-methyl-2-(4-methoxyphenyl)ethyl]amine (III) as a racemic mixture, which is submitted to optical resolution with L-mandelic acid in methanol to obtain the desired (R)-enantiomer (IV). The reaction of cis-(1R,2S)-1-aminoindan-2-ol (V) with trimethylboroxine in toluene gives the (1R,2S)-oxazaborolidine (VI), which is used as chiral catalyst in the enantioselective reduction of 4-benzyloxy-3-nitrophenacyl bromide (VII) by means of BH3/THF, yielding the chiral bromoethanol derivative (VIII). The reaction of (VIII) with NaOH in aqueous methanol affords the epoxide (IX), which is condensed with the intermediate amine (IV) by heating the mixture at 90 C to provide the adduct (X). The reduction of the nitro group of (X) with H2 over PtO2 gives the corresponding amino derivative (XI), which is acylated with formic acid to afford the formamide compound (XII). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C in ethanol, providing the target compound.
| 【1】 Wilkinson, H.S.; et al.; Modulation of catalyst reactivity for the chemoselective hydrogenation of functionalized nitroarene: Preparation of a key intermediate in the synthesis of (R,R)-formoterol tartrate. Org Process Res Dev 2000, 4, 6, 567. |
| 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) | 10038 | 4-Methoxyphenylacetone; 1-(4-Methoxyphenyl)acetone | 122-84-9 | C10H12O2 | 详情 | 详情 |
| (II) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (III) | 32770 | N-benzyl-N-[2-(4-methoxyphenyl)-1-methylethyl]amine; N-benzyl-1-(4-methoxyphenyl)-2-propanamine | C17H21NO | 详情 | 详情 | |
| (IV) | 32768 | (2R)-N-benzyl-1-(4-methoxyphenyl)-2-propanamine; N-benzyl-N-[(1R)-2-(4-methoxyphenyl)-1-methylethyl]amine | C17H21NO | 详情 | 详情 | |
| (V) | 27559 | (1R,2S)-1-amino-2,3-dihydro-1H-inden-2-ol | C9H11NO | 详情 | 详情 | |
| (VI) | 34898 | (3aR,8aS)-2-methyl-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d][1,3,2]oxazaborole | C10H12BNO | 详情 | 详情 | |
| (VII) | 32763 | 1-[4-(benzyloxy)-3-nitrophenyl]-2-bromo-1-ethanone | C15H12BrNO4 | 详情 | 详情 | |
| (VIII) | 32765 | (1R)-1-[4-(benzyloxy)-3-nitrophenyl]-2-bromo-1-ethanol | 188690-82-6 | C15H14BrNO4 | 详情 | 详情 |
| (IX) | 50312 | (2R)-2-[4-(benzyloxy)-3-nitrophenyl]oxirane; benzyl 2-nitro-4-[(2R)oxiranyl]phenyl ether | C15H13NO4 | 详情 | 详情 | |
| (X) | 50313 | (1R)-2-[benzyl[(1R)-2-(4-methoxyphenyl)-1-methylethyl]amino]-1-[4-(benzyloxy)-3-nitrophenyl]-1-ethanol | C32H34N2O5 | 详情 | 详情 | |
| (XI) | 50314 | (1R)-1-[3-amino-4-(benzyloxy)phenyl]-2-[benzyl[(1R)-2-(4-methoxyphenyl)-1-methylethyl]amino]-1-ethanol | C32H36N2O3 | 详情 | 详情 | |
| (XII) | 32769 | 5-((1R)-2-[benzyl[(1R)-2-(4-methoxyphenyl)-1-methylethyl]amino]-1-hydroxyethyl)-2-(benzyloxy)phenylformamide | C33H36N2O4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VII)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).
| 【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 |