Diisopropylamine → Morpholine-4-carboxylic acid (1-{1-[(3-cyclopropyl-[1,2,4]oxadiazol-5-yl)-hydroxy-methyl]-propylcarbamoyl}-3,3-difluoro-hexyl)-amide

HRID 1455594Notes

Reaction equation

HRID 1455594 reaction equation
[F:1][C:2]([F:20])([CH2:17][CH2:18][CH3:19])[CH2:3][C@H:4]([NH:8][C:9]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:10])[C:5]([OH:7])=O.Cl.[NH2:22][CH:23]([CH2:34][CH3:35])[C@@H:24]([C:26]1[O:30][N:29]=[C:28]([CH:31]2[CH2:33][CH2:32]2)[N:27]=1)[OH:25].C(NC(C)C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>ClCCl>[CH:31]1([C:28]2[N:27]=[C:26]([CH:24]([OH:25])[CH:23]([NH:22][C:5]([CH:4]([NH:8][C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[O:10])[CH2:3][C:2]([F:1])([F:20])[CH2:17][CH2:18][CH3:19])=[O:7])[CH2:34][CH3:35])[O:30][N:29]=2)[CH2:32][CH2:33]1

Participants

6

Reactant 4

HCID 7912DiisopropylamineHCID 2724699PyBOPHCID 57535361(S)-4,4-difluoro-2-[(morpholine-4-carbonyl)-amino]-heptanoic acidHCID 68820971(S)-2-amino-1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-butan-1-ol hydrochloride

Product 1

HCID 86760809Morpholine-4-carboxylic acid (1-{1-[(3-cyclopropyl-[1,2,4]oxadiazol-5-yl)-hydroxy-methyl]-propylcarbamoyl}-3,3-difluoro-hexyl)-amideYield 88.1%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a mixture of (S)-4,4-difluoro-2-[(morpholine-4-carbonyl)-amino]-heptanoic acid (104 mg, 0.35 mmol), (S)-2-amino-1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-butan-1-ol hydrochloride (86.7 mg, 0.37 mmol) and diisopropyl amine (219 mg, 0.42 mmol) in dry dichloromethane (5 mL) is added PyBOP (113 mg, 0.87 mmol). The mixture is stirred at room temperature for 16 hr and the evaporated in vacuum. The residue is diluted with ethyl acetate (25 mL) and washed with saturated NaHCO3 (30 mL), dilute HCl (30 mL), then saturated NaHCO3 (30 mL). The organic layer is dried over magnesium sulfate and concentrated in vacuum. The residue is purified over 12 g silica gel, eluting with ethyl acetate: heptane (2:1 then 1:0) to afford morpholine-4-carboxylic acid (1-{1-[(3-cyclopropyl-[1,2,4]oxadiazol-5-yl)-hydroxy-methyl]-propylcarbamoyl}-3,3-difluoro-hexyl)-amide (146 mg, 88%) as a solid. LC/MS shows 2 isomers, total 100% M+1 474.

Workup

  1. customthe evaporated in vacuum
  2. additionThe residue is diluted with ethyl acetate (25 mL)
  3. washwashed with saturated NaHCO3 (30 mL), dilute HCl (30 mL)
  4. dry with materialThe organic layer is dried over magnesium sulfate
  5. concentrationconcentrated in vacuum
  6. customThe residue is purified over 12 g silica gel
  7. washeluting with ethyl acetate: heptane (2:1

Sources & evidence

ORD record
ord-ac3b1d44e1ee446ba8378fcaf1bdfe9a
Source dataset
uspto-grants-2009_01
Patent number
US07482448B2

Reaction notes

Loading…