Hydrochloric Acid → HCID 24759017, compound

HRID 1879234Notes

Reaction equation

HRID 1879234 reaction equation
[CH3:1][N:2]([CH3:33])[CH2:3][CH2:4][CH2:5][N:6]([S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=1)(=[O:24])=[O:23])[C@@H:7]([C:12]([O:14]CC1C=CC=CC=1)=O)[C:8]([CH3:11])([CH3:10])[CH3:9].O1CCCCC1[O:40][NH2:41].CCN=C=NCCCN(C)C.Cl.C1C=NC2N(O)N=NC=2C=1.O.O.O.O.O.O.O.O.O.O.C(=O)(O)[O-].[Na+].Cl>CO.[Pd].CN(C=O)C>[CH3:1][N:2]([CH3:33])[CH2:3][CH2:4][CH2:5][N:6]([S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=1)(=[O:24])=[O:23])[C@@H:7]([C:12]([NH:41][OH:40])=[O:14])[C:8]([CH3:11])([CH3:10])[CH3:9]

Participants

10

Reactant 6

HCID 313Hydrochloric AcidHCID 181649HOAtHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 5142091O-(Tetrahydropyran-2-yl)hydroxylamineHCID 58017454HCID 58017454, compoundHCID 86637425Sodium bicarbonate decahydrate

Product 1

HCID 24759017HCID 24759017, compoundYield 100%

Reagents, catalysts & solvents 3

HCID 23938PalladiumCatalystHCID 887MethanolSolvent2×HCID 6228DimethylformamideSolvent2×

Procedure

To a de-gassed solution of benzyl N[3-(dimethylamino)propyl]-N-[(3-methoxyphenyl)sulfonyl]-3-methyl-D-valinate (500 mg, 0.634 mmol) in methanol (10 mL), catalytic palladium on carbon (10% on activated carbon, 7 mg, 0.063 mmol) is added and the reaction mixture is stirred vigorously under hydrogen for 78 h. The reaction mixture is diluted with anhydrous DMF (5 mL), concentrated in vacuo to remove methanol. To the DMF solution of the acid intermediate, O-(tetrahydro-2H-pyranyl)hydroxylamine (149 mg, 1.27 mmol), EDC·HCl (249 mg, 1.27 mmol), and HOAt (173 mg, 1.27 mmol) are added at rt. The reaction was allowed to stir at rt for 18 h and was complete by LC/MS. To the reaction mixture, sodium bicarbonate decahydrate (779 mg, 2.64 mmol) is added and is stirred vigorously for 30 min. The decahydrate crystals are filtered, and the filterate is concentrated in vacuo, and purified by silica gel chromatography eluting with 15-100% EtOAc/heptanes to obtain 250 mg of the THP-protected hydroxamide intermediate. (81% yield over 2 steps). To the solution of the intermediate in methanol (1 mL), concentrated hydrochloric acid solution (37% in water, 840 mL, 0.70 mmol) is added dropwise. The reaction mixture is stirred for 15 min, resulting in the precipitation of slightly pink white solid. The precipitate is washed with methanol and ether, then dried in vacuo to give the desired product as a white solid (227 mg, 100% yield). 1H NMR (400 MHz, d6-DMSO) δ ppm 10.82 (s, 1H), 9.86 (br s, 1H), 8.91 (s, 1H), 7.52-7.90 (m, 2H), 7.35 (m, 1H), 7.24 (m, 2H), 3.98 (m, 1H), 3.97 (s, 1H), 3.85 (s, 3H), 3.07 (ddd, J=12, 4, 4Hz, 1H), 2.97 (m, 2H), 2.73 (br s, 6H), 2.13 (m, 1H), 1.94 (m, 1H), 1.01 (s, 9H). Mass spectrum (402.20; M+1).

Workup

  1. concentrationconcentrated in vacuo
  2. customto remove methanol
  3. stirringto stir at rt for 18 h
  4. stirringis stirred vigorously for 30 min
  5. filtrationThe decahydrate crystals are filtered
  6. concentrationthe filterate is concentrated in vacuo
  7. custompurified by silica gel chromatography
  8. washeluting with 15-100% EtOAc/heptanes
  9. customto obtain 250 mg of the THP-protected hydroxamide intermediate
  10. stirringThe reaction mixture is stirred for 15 min
  11. customresulting in the precipitation of slightly pink white solid
  12. washThe precipitate is washed with methanol and ether
  13. customdried in vacuo

Sources & evidence

ORD record
ord-a5d240b1afd440d68f607db269eb8d83
Source dataset
uspto-grants-2012_11
Patent number
US08314148B2

Reaction notes

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