Dichloromethane → (2-{[(4-Aminomethyl-2-hydroxymethyl-benzyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-pyridin-3-yl)-carbamic acid tert-butyl ester

HRID 251271Notes

Reaction equation

HRID 251271 reaction equation
C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:5]=1[CH2:12][N:13]([CH2:24][C:25]1[C:30]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:29][CH:28]=[CH:27][N:26]=1)[CH:14]1[C:23]2[N:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:17][CH2:16][CH2:15]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].C(C(C(C([O-])=O)O)O)([O-])=O.C(Cl)Cl>C1COCC1>[C:35]([O:34][C:32](=[O:33])[NH:31][C:30]1[C:25]([CH2:24][N:13]([CH2:12][C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH2:11])=[CH:9][C:4]=2[CH2:3][OH:2])[CH:14]2[C:23]3[N:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH2:17][CH2:16][CH2:15]2)=[N:26][CH:27]=[CH:28][CH:29]=1)([CH3:38])([CH3:36])[CH3:37]

Participants

6

Reactant 4

HCID 6344DichloromethaneHCID 38061142,3-DihydroxybutanedioateHCID 21226445Aluminium lithium hydrideHCID 672715862-{[(3-tert-Butoxycarbonylamino-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-5-cyano-benzoic acid methyl ester

Product 1

HCID 67271682(2-{[(4-Aminomethyl-2-hydroxymethyl-benzyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-pyridin-3-yl)-carbamic acid tert-butyl esterYield 37.4%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

2-{[(3-tert-Butoxycarbonylamino-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-5-cyano-benzoic acid methyl ester (0.4532 g, 0.86 mmol) was dissolved in dry THF (5 mL) and flushed with Ar. At 0° C., 1.0 M LiAlH4 in THF (8.6 mL, 8.6 mmol) was added dropwise to the solution and was stirred at room temperature for 6 hours. The reaction was cooled to 0° C. and saturated aqueous KNa Tartrate (Rochelle's salt, 10 mL) was added slowly, and then CH2Cl2 (100 mL) was added. The phases were separated and the aqueous phase was extracted with CH2Cl2 (8×75 mL). The organic extracts were dried (Na2SO4) and concentrated. Purification of the crude material by column chromatography on silica gel (20:1:1 CH2Cl2-MeOH—NH4OH) provided 0.1620 g (37%) of (2-{[(4-aminomethyl-2-hydroxymethyl-benzyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-pyridin-3-yl)-carbamic acid tert-butyl ester as a yellow solid. 1H NMR (CDCl3) δ 1.54 (s, 9H), 1.62 (s, 6H), 1.97-2.06 (m, 1H), 2.25-2.26 (m, 1H), 2.69-2.82 (m, 2H), 2.95-2.97 (m, 1H), 3.62-3.72 (m, 1H), 3.80 (s, 2H), 3.85-3.99 (m, 3H), 4.22-4.26 (m, 1H), 4.48-4.52 (m, 1H), 7.08-7.23 (m, 4H), 7.39-7.37 (m, 1H), 8.17-8.19 (m, 1H), 8.45-8.51 (m, 1H), 8.65-8.69 (m, 1H), 9.41-9.44 (m, 1H). Deprotection with TFA using General Procedure F gave COMPOUND 406 as a white solid. 1H NMR (CDCl3) δ 1.64-1.68 (m, 4H), 2.02-2.13 (m, 2H), 2.17-2.26 (m, 1H), 2.64-2.69 (m, 1H), 2.77-2.88 (m, 1H), 3.61-3.69 (m, 3H), 3.82-3.88 (m, 3H), 4.06 (d, 1H, J=12.9 Hz), 4.18 (d, 1H, J=11.1 Hz), 4.58 (d, 1H, J=11.4 Hz), 4.92 (s, 2H), 6.93-6.96 (m, 1H), 6.99-7.04 (m, 1H), 7.06-7.10 (m, 1H), 7.13-7.16 (m, 1H), 7.22-7.29 (m, 2H), 7.37 (d, 1H, J=7.5 Hz), 7.91 (d, 1H, J=3.9 Hz), 8.35 (d, 1H, J=3.9 Hz). 13C NMR (CDCl3) δ 19.54, 21.88, 29.55, 46.47, 54.64, 55.47, 58.18, 63.17, 122.36, 122.63, 124.08, 126.62, 130.67, 131.64, 135.21, 135.32, 137.99, 138.29, 142.08, 142.92, 143.78, 143.88, 146.91, 157.29. ES-MS m/z 404 (M+H). Anal. Calcd. for C24H29N5O.0.8H2O.0.1CH2Cl2: C, 67.88; H, 7.28; N, 16.42. Found: C, 67.85; H, 7.3; N, 16.27.

Workup

  1. customflushed with Ar
  2. temperatureThe reaction was cooled to 0° C.
  3. customThe phases were separated
  4. extractionthe aqueous phase was extracted with CH2Cl2 (8×75 mL)
  5. dry with materialThe organic extracts were dried (Na2SO4)
  6. concentrationconcentrated
  7. customPurification of the crude material by column chromatography on silica gel (20:1:1 CH2Cl2-MeOH—NH4OH)

Sources & evidence

ORD record
ord-880dfbf039f2434f9dc73a205d446763
Source dataset
uspto-grants-2011_01
Patent number
US07863293B2

Reaction notes

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