Triethylamine → (R)-N-(2,2-Dimethoxyethyl)-3-(3-(1-methyl-1H-pyrazol-4-yl)phenethoxy)-N-(3-methylbutan-2-yl)propanamide

HRID 909905Notes

Reaction equation

HRID 909905 reaction equation
C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[CH3:19][N:20]1[CH:24]=[C:23]([C:25]2[CH:26]=[C:27]([CH:36]=[CH:37][CH:38]=2)[CH2:28][CH2:29][O:30][CH2:31][CH2:32][C:33]([OH:35])=O)[CH:22]=[N:21]1.[CH3:39][O:40][CH:41]([O:49][CH3:50])[CH2:42][NH:43][C@@H:44]([CH:46]([CH3:48])[CH3:47])[CH3:45].C(N(CC)CC)C>C1COCC1.C(#N)C.C(OCC)(=O)C>[CH3:39][O:40][CH:41]([O:49][CH3:50])[CH2:42][N:43]([C@@H:44]([CH:46]([CH3:47])[CH3:48])[CH3:45])[C:33](=[O:35])[CH2:32][CH2:31][O:30][CH2:29][CH2:28][C:27]1[CH:36]=[CH:37][CH:38]=[C:25]([C:23]2[CH:22]=[N:21][N:20]([CH3:19])[CH:24]=2)[CH:26]=1

Participants

8

Reactant 4

HCID 8471TriethylamineHCID 111923Propylphosphonic anhydrideHCID 58168508(R)-N-(2,2-dimethoxyethyl)-3-methylbutan-2-amineHCID 592904613-(3-(1-methyl-1H-pyrazol-4-yl)phenethoxy)propanoic acid

Product 1

HCID 67075774(R)-N-(2,2-Dimethoxyethyl)-3-(3-(1-methyl-1H-pyrazol-4-yl)phenethoxy)-N-(3-methylbutan-2-yl)propanamide

Reagents, catalysts & solvents 3

HCID 6342AcetonitrileSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
25 °C

Procedure

A solution of T3P (1.86 mL) dissolved in THF (1.57M) was added in one portion to a stirred solution of 3-(3-(1-methyl-1H-pyrazol-4-yl)phenethoxy)propanoic acid [Example 2a, Step i)] (567 mg), (R)—N-(2,2-dimethoxyethyl)-3-methylbutan-2-amine [Preparation 4] (307 mg), and triethylamine (2.44 mL) in acetonitrile (6 mL) at 25° C. The resulting solution was stirred at 25° C. for 15 min. The reaction mixture was diluted with ethyl acetate (50 mL), and washed with saturated sodium hydrogen carbonate (20 mL). The organic layer was dried over magnesium sulfate, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0-100% ethyl acetate in isohexane, then elution gradient 5-10% methanol in ethyl acetate to afford the subtitled compound as a gum (210 mg). 1H NMR (400 MHz, CD3OD) δ 7.92 and 7.91 (2×s, 1H), 7.77 (s, 1H), 7.40-7.37 (m, 1H), 7.36-7.32 (m, 1H), 7.23 and 7.22 (2×t, J=7.7 Hz, 1H), 7.05 (d, J=7.6 Hz, 1H), 4.59 and 4.43 (2×t, J=5.4 Hz, 1H), 3.90 (s, 3H), 3.75-3.45 (m, 5H), 3.36 (d, J=1.5 Hz, 2H), 3.35, 3.34, 3.33, 3.32 (4×s, 6H), 2.84 and 2.84 (2×t, J=7.0 Hz, 2H), 2.76-2.61 (m, 2H), 1.98-1.86 and 1.79-1.66 (2×m, 1H), 1.16 and 1.14 (2×d, J=7.0 Hz, 3H), 0.90 and 0.88 (2×d, J=6.8 Hz, 3H), 0.79 and 0.75 (2×d, J=6.8 Hz, 3H), a ˜1:1 mixture of rotamers is observed.

Workup

  1. washwashed with saturated sodium hydrogen carbonate (20 mL)
  2. dry with materialThe organic layer was dried over magnesium sulfate
  3. filtrationfiltered
  4. customevaporated
  5. customto afford crude product
  6. customThe crude product was purified by flash silica chromatography, elution gradient 0-100% ethyl acetate in isohexane
  7. washelution gradient 5-10% methanol in ethyl acetate

Sources & evidence

ORD record
ord-2a68b9b72bb94af0b95512feabbe503e
Source dataset
uspto-grants-2011_09
Patent number
US08017602B2

Reaction notes

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