Phosgene → [1-(4-fluorobenzyl)cyclobutyl]methyl(1S)-5-{[(dimethylamino)sulfonyl]amino}-1-{1-hydroxy-2-oxo-2-[(3-pyridinylmethyl)amino]ethyl}pentylcarbamate

HRID 1180758Notes

Reaction equation

HRID 1180758 reaction equation
[F:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][C:7]2([CH2:11][OH:12])[CH2:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[C:15](Cl)(Cl)=[O:16].Cl.Cl.[NH2:21][C@@H:22]([CH2:35][CH2:36][CH2:37][CH2:38][NH:39][S:40]([N:43]([CH3:45])[CH3:44])(=[O:42])=[O:41])[CH:23]([OH:34])[C:24]([NH:26][CH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1)=[O:25].C(N(CC)CC)C>O1CCCC1.C1(C)C=CC=CC=1>[CH3:45][N:43]([CH3:44])[S:40]([NH:39][CH2:38][CH2:37][CH2:36][CH2:35][C@H:22]([NH:21][C:15](=[O:16])[O:12][CH2:11][C:7]1([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:14][CH:13]=2)[CH2:8][CH2:9][CH2:10]1)[CH:23]([OH:34])[C:24](=[O:25])[NH:26][CH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1)(=[O:41])=[O:42]

Participants

7

Reactant 4

HCID 6371PhosgeneHCID 8471TriethylamineHCID 58979657HCID 58979657, compoundHCID 69237893(3S)-3-amino-7-{[(dimethylamino)sulfonyl]amino}-2-hydroxy-N-(3-pyridinylmethyl)heptanamide dihydrochloride

Product 1

HCID 58979653[1-(4-fluorobenzyl)cyclobutyl]methyl(1S)-5-{[(dimethylamino)sulfonyl]amino}-1-{1-hydroxy-2-oxo-2-[(3-pyridinylmethyl)amino]ethyl}pentylcarbamateYield 59.1%

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

To 110 mg (0.57 mmol) of [1-(4-fluorobenzyl)cyclobutyl]methanol in 2 mL of tetrahydrofuran was added 0.59 mL (1.1 mmol) of 1.93 M phosgene in toluene and the reaction stirred at room temperature overnight. The mixture was concentrated under reduced pressure and added to a solution of 250 mg (0.57 mmol) of (3S)-3-amino-7-{[(dimethylamino)sulfonyl]amino}-2-hydroxy-N-(3-pyridinylmethyl)heptanamide dihydrochloride and 0.28 mL of triethylamine in 4 mL of tetrahydrofuran. The mixture was filtered through a frit and the wash concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 7:3 acetone:hexanes to leave 200 mg (59%) of [1-(4-fluorobenzyl)cyclobutyl]methyl(1S)-5-{[(dimethylamino)sulfonyl]amino}-1-{1-hydroxy-2-oxo-2-[(3-pyridinylmethyl)amino]ethyl}pentylcarbamate. 1H NMR (300 MHz, DMSO-d6) δ 8.38-8.55 (m, 2H), 7.65 (m, 1H), 6.7.00-7.40 (m, 7H), 6.55 (d, J=9 Hz, 1H), (5.83 (d, J=6 Hz) and 5.72 (J=6 Hz), 1H), 4.31 (m, 2H), 4.00 (m, 1H), 3.71-3.88 (m, 2H), 3.42 under water peak (m, 2H), 2.74-2.90 (m, 3H), 2.66 (s, 6H), 1.70-1.95 (m, 6H), 1.25-1.59 (m, 6H). ES-LCMS m/z 594 (M+H).

Workup

  1. concentrationThe mixture was concentrated under reduced pressure
  2. filtrationThe mixture was filtered through a frit
  3. concentrationthe wash concentrated under reduced pressure
  4. customThe residue was purified by silica gel chromatography
  5. washeluting with 7:3 acetone

Sources & evidence

ORD record
ord-81a4cd6cd7b04fd1b288c792e08121bd
Source dataset
uspto-grants-2007_10
Patent number
US07282512B2

Reaction notes

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