Propylphosphonic anhydride → N-Cyclopentyl-N-(2,2-dimethoxyethyl)-3-(3-(1-propyl-1H-pyrazol-4-yl)phenethoxy)propanamide

HRID 909932Notes

Reaction equation

HRID 909932 reaction equation
C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[CH2:19]([N:22]1[CH:26]=[C:25]([C:27]2[CH:28]=[C:29]([CH:38]=[CH:39][CH:40]=2)[CH2:30][CH2:31][O:32][CH2:33][CH2:34][C:35]([OH:37])=O)[CH:24]=[N:23]1)[CH2:20][CH3:21].[CH3:41][O:42][CH:43]([O:51][CH3:52])[CH2:44][NH:45][CH:46]1[CH2:50][CH2:49][CH2:48][CH2:47]1.C(=O)([O-])O.[Na+]>C1COCC1.C(#N)C.C(N(CC)CC)C>[CH:46]1([N:45]([CH2:44][CH:43]([O:51][CH3:52])[O:42][CH3:41])[C:35](=[O:37])[CH2:34][CH2:33][O:32][CH2:31][CH2:30][C:29]2[CH:38]=[CH:39][CH:40]=[C:27]([C:25]3[CH:24]=[N:23][N:22]([CH2:19][CH2:20][CH3:21])[CH:26]=3)[CH:28]=2)[CH2:47][CH2:48][CH2:49][CH2:50]1

Participants

8

Reactant 4

HCID 111923Propylphosphonic anhydrideHCID 516892Sodium BicarbonateHCID 58168622N-(2,2-dimethoxyethyl)cyclopentanamineHCID 592904323-(3-(1-propyl-1H-pyrazol-4-yl)phenethoxy)propanoic acid

Product 1

HCID 59290380N-Cyclopentyl-N-(2,2-dimethoxyethyl)-3-(3-(1-propyl-1H-pyrazol-4-yl)phenethoxy)propanamide

Reagents, catalysts & solvents 3

HCID 6342AcetonitrileSolventHCID 8028TetrahydrofuranSolventHCID 8471TriethylamineSolvent

Conditions

Temperature
22 °C

Procedure

A solution of T3P (0.637 mL, 1.57M) dissolved in THF was added to a stirred solution of 3-(3-(1-propyl-1H-pyrazol-4-yl)phenethoxy)propanoic acid [Example 18, Step ii)] (151 mg), triethylamine (0.906 mL) and N-(2,2-dimethoxyethyl)cyclopentanamine [Preparation 9] (106 mg) in acetonitrile (2 mL) at 22° C. under air. The resulting solution was stirred at 22° C. for 30 min. The reaction mixture was neutralised with saturated sodium hydrogen carbonate and extracted with DCM. The organic was filtered through a phase separator cartridge and evaporated to afford crude product. The crude product was purified by flash silica chromatography using elution gradient 0 to 100% ethyl acetate in isohexane to the subtitled compound (150 mg) as an oil. MS [M+H-MeOH]+=426 (MultiMode+) 1H NMR (300 MHz, CD3OD) δ 8.00 (s, 1H), 7.83 (s, 1H), 7.43 (s, 1H), 7.39 (d, J=7.9 Hz, 1H), 7.26 (t, J=7.6 Hz, 1H), 7.09 (d, J=7.5 Hz, 1H), 4.60 and 4.41 (2×t, J=5.2 Hz, 1H), 4.31-4.18 (m, 1H), 4.14 (t, J=7.0 Hz, 2H), 3.80-3.67 (m, 4H), 3.39 and 3.26 (2×d, J=5.3 Hz, 2H), 3.38 (s, 3H), 3.36 (s, 3H), 2.88 (t, J=6.6 Hz, 2H), 2.69 (t, J=6.2 Hz, 2H), 1.92 (sextet, J=7.2 Hz, 2H), 1.85-1.47 (m, 8H), 0.95 (t, J=7.4 Hz, 3H), a ˜1:1 mixture of rotamers is observed.

Workup

  1. extractionextracted with DCM
  2. filtrationThe organic was filtered through a phase separator cartridge
  3. customevaporated
  4. customto afford crude product
  5. customThe crude product was purified by flash silica chromatography
  6. washelution gradient 0 to 100% ethyl acetate in isohexane to the subtitled compound (150 mg) as an oil
  7. additionMS [M+H-MeOH]+=426 (MultiMode+) 1H NMR (300 MHz, CD3OD) δ 8.00 (s, 1H), 7.83 (s, 1H), 7.43 (s, 1H), 7.39 (d, J=7.9 Hz, 1H), 7.26 (t, J=7.6 Hz, 1H), 7.09 (d, J=7.5 Hz, 1H), 4.60 and 4.41 (2×t, J=5.2 Hz, 1H), 4.31-4.18 (m, 1H), 4.14 (t, J=7.0 Hz, 2H), 3.80-3.67 (m, 4H), 3.39 and 3.26 (2×d, J=5.3 Hz, 2H), 3.38 (s, 3H), 3.36 (s, 3H), 2.88 (t, J=6.6 Hz, 2H), 2.69 (t, J=6.2 Hz, 2H), 1.92 (sextet, J=7.2 Hz, 2H), 1.85-1.47 (m, 8H), 0.95 (t, J=7.4 Hz, 3H), a ˜1:1 mixture of rotamers

Sources & evidence

ORD record
ord-0d052d9ba18e496191ebbc9be8087ef0
Source dataset
uspto-grants-2011_09
Patent number
US08017602B2

Reaction notes

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