3-Hydroxypropionic acid → 3-(4-(1-(3-Hydroxypropanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)-5(R)(N-(t-butoxycarbonyl)isoxazol-3-ylaminomethyl)oxazolidin-2-one

HRID 1582373

Reaction equation

HRID 1582373 reaction equation
[OH:1][CH2:2][CH2:3][C:4]([OH:6])=O.Cl.[NH:8]1[CH2:13][CH2:12][C:11]([C:14]2[C:19]([F:20])=[CH:18][C:17]([N:21]3[CH2:25][C@H:24]([CH2:26][N:27]([C:35]4[CH:39]=[CH:38][O:37][N:36]=4)[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[O:23][C:22]3=[O:40])=[CH:16][C:15]=2[F:41])=[CH:10][CH2:9]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O.O.C(OCC)(=O)C>[OH:1][CH2:2][CH2:3][C:4]([N:8]1[CH2:13][CH2:12][C:11]([C:14]2[C:19]([F:20])=[CH:18][C:17]([N:21]3[CH2:25][C@H:24]([CH2:26][N:27]([C:35]4[CH:39]=[CH:38][O:37][N:36]=4)[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[O:23][C:22]3=[O:40])=[CH:16][C:15]=2[F:41])=[CH:10][CH2:9]1)=[O:6]

Participants

8

Reactant 4

HCID 681523-Hydroxypropionic acidHCID 81531DiisopropylethylamineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 695846063-(4-(1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)-5(R)(N-(t-butoxy-carbonyl)isoxazol-3-ylaminomethyl)oxazolidin-2-one hydrochloride

Product 1

HCID 571925683-(4-(1-(3-Hydroxypropanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)-5(R)(N-(t-butoxycarbonyl)isoxazol-3-ylaminomethyl)oxazolidin-2-oneYield 74.2%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of 3-hydroxypropionic acid (45 mg, 0.5 mM) in N,N-dimethylformamide (2 ml) was added 3-(4-(1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)-5(R)-(N-(t-butoxy-carbonyl)isoxazol-3-ylaminomethyl)oxazolidin-2-one hydrochloride (256 mg, 0.5 mM, reference example 10), and O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (190 mg, 0.5 mM). The mixture was cooled to 0°, N,N-diisopropylethylamine (129 mg, 1 mM) added, and the mixture stirred 18 hours, allowing the temperature to rise to ambient. The mixture was poured into a mixture of ethyl acetate (40 ml) and water (40 ml), the organic layer separated and washed with aqueous sodium dihydrogen phosphate (2%, 40 ml), sodium bicarbonate (40 ml) and brine (40 ml). Solvent was removed, and the residue chromatographed on a 10 g silica Mega Bond Elut® column, eluting with a mixture of 2.5% methanol in dichloromethane. Relevant fractions were combined and evaporated to give the title product (203 mg). NMR (DMSO-d6) δ: 1.47 (s, 9H); 2.28 (m, 1H); 2.37 (m, 1H); 2.54 (m overlapped by DMSO, 2H); 3.66 (br m, 4H); 3.86 (dd, 1H); 3.95 (dd, 1H); 4.08 (m, 1H); 4.17 (m, 1H); 4.26 (dd, 2H); 4.53 (m, 1H); 5.02 (m, 1H); 5.87 (s, 1H); 6.86 (s, 1H); 7.33 (d, 2H); 8.82 (s, 1H). MS (ESP): 549 (MH+) for C26H30F2N4O7

Workup

  1. temperatureThe mixture was cooled to 0°
  2. customthe organic layer separated
  3. washwashed with aqueous sodium dihydrogen phosphate (2%, 40 ml), sodium bicarbonate (40 ml) and brine (40 ml)
  4. customSolvent was removed
  5. customthe residue chromatographed on a 10 g silica Mega Bond Elut® column
  6. washeluting with a mixture of 2.5% methanol in dichloromethane
  7. customevaporated

Sources & evidence

ORD record
ord-1c6b9c3f2f494ec0aae2224388d961cf
Source dataset
uspto-grants-2004_05
Patent number
US06734200B1

Linked notes

Loading…