Diisopropylethylamine → 2,2-Dimethyl-propionic acid 1-(hydroxy-{4-[3-isopropoxy-5-(thiazol-2-ylcarbamoyl)-phenoxy]-phenyl}-phosphinoyloxy)-ethyl ester

HRID 1431028Notes

Reaction equation

HRID 1431028 reaction equation
[CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:19]=[C:20]([C:22](=[O:29])[NH:23][C:24]2[S:25][CH:26]=[CH:27][N:28]=2)[CH:21]=1)[O:8][C:9]1[CH:14]=[CH:13][C:12]([P:15](=[O:18])([OH:17])[OH:16])=[CH:11][CH:10]=1)([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[C:39]([O:45][CH:46](I)[CH3:47])(=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41]>C(#N)C.C(Cl)Cl>[OH:18][P:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][C:7]2[CH:19]=[C:20]([C:22](=[O:29])[NH:23][C:24]3[S:25][CH:26]=[CH:27][N:28]=3)[CH:21]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH:6]=2)=[CH:10][CH:11]=1)([O:17][CH:46]([O:45][C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41])[CH3:47])=[O:16]

Participants

6

Reactant 3

HCID 81531DiisopropylethylamineHCID 133930641-Iodoethyl 2,2-dimethylpropanoateHCID 58529006{4-[3-Isopropoxy-5-(thiazol-2-ylcarbamoyl)-phenoxy]-phenyl}-phosphonic acid

Product 1

HCID 585288962,2-Dimethyl-propionic acid 1-(hydroxy-{4-[3-isopropoxy-5-(thiazol-2-ylcarbamoyl)-phenoxy]-phenyl}-phosphinoyloxy)-ethyl esterYield 10%

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolventHCID 6344DichloromethaneSolvent

Procedure

A mixture of {-4-[3-isopropoxy-5-(thiazol-2-ylcarbamoyl-)phenoxy]-phenyl}-phosphonic acid (250 mg, 0.58 mmol) and DIEA (0.193 mL, 1.16 mmol) in 6 mL of acetonitrile was stirred for 15 min and then 1-iodoethyl pivalate (177 mg, 0.69 mmol) was added. The resulting mixture was stirred for 2 h at rt, then diluted with CH2Cl2, washed with 1 M aqueous NaHSO4, dried (MgSO4) and evaporated. The residue was dissolved in 3:1 acetonitrile/water and subjected to MPLC purification through a 25 g C18 column eluting with % acetonitrile in water (time): 15-50 (15 min). Lyophilization of the eluent containing the desired product provided 31 mg (10%) of the title compound as an amorphous solid: 1H NMR (500 MHz, DMSO-d6): δ 0.91 (s, 9H), 1.29 (d, 6H, J=6 Hz), 1.30 (d, 3H, J=6 Hz), 4.73 (septet, 1H, J=6 Hz), 6.34 (br s, 1H), 6.75 (s, 1H), 7.01 (d, 2H, 1=7 Hz), 7.24 (s, 1H), 7.28 (d, 1H, J=3 Hz), 7.45 (s, 1H), 7.56 (d, 1H, J=3 Hz), 7.63 (br s, 2H), 12.61 (br s, 1H); LCMS (m/z): 563.4 [C26H31N2O8PS+H]+. Anal. calcd. for (C26H31N2O8PS+1H2O): C, 53.79; H, 5.73; N, 4.82. Found: C, 52.93; 11, 5.93; N, 5.92.

Workup

  1. stirringThe resulting mixture was stirred for 2 h at rt
  2. washwashed with 1 M aqueous NaHSO4
  3. dry with materialdried (MgSO4)
  4. customevaporated
  5. dissolutionThe residue was dissolved in 3:1 acetonitrile/water
  6. customsubjected to MPLC purification through a 25 g C18 column
  7. washeluting with % acetonitrile in water (time)
  8. custom15-50 (15 min)
  9. additionLyophilization of the eluent containing the desired product

Sources & evidence

ORD record
ord-4d366df929c54c0db7f45af236120bcb
Source dataset
uspto-grants-2015_01
Patent number
US08940927B2

Reaction notes

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