2,4-Dimethylbenzaldehyde → HCID 11454345, compound

HRID 2377547Notes

Reaction equation

HRID 2377547 reaction equation
C(O[C:9](=O)[NH:10][CH2:11][C@H:12]([NH:18][C:19](=[O:33])[CH2:20][C:21](=[O:32])[NH:22][C:23]1[S:24][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[N:26][N:27]=1)[C@@H:13]([OH:17])[C:14]#[C:15][CH3:16])C1C=CC=CC=1.[CH3:35][C:36]1[CH:43]=[C:42]([CH3:44])[CH:41]=[CH:40][C:37]=1C=O.C([BH3-])#N.[Na+]>CO.[Pd]>[C:28]([C:25]1[S:24][C:23]([NH:22][C:21](=[O:32])[CH2:20][C:19]([NH:18][C@@H:12]([CH2:11][NH:10][CH2:9][C:37]2[CH:40]=[CH:41][C:42]([CH3:44])=[CH:43][C:36]=2[CH3:35])[C@@H:13]([OH:17])[CH2:14][CH2:15][CH3:16])=[O:33])=[N:27][N:26]=1)([CH3:29])([CH3:30])[CH3:31]

Participants

6

Reactant 3

HCID 618142,4-DimethylbenzaldehydeHCID 5003444Sodium cyanoborohydrideHCID 69287829HCID 69287829, compound

Product 1

HCID 11454345HCID 11454345, compound

Reagents, catalysts & solvents 2

HCID 23938PalladiumCatalystHCID 887MethanolSolvent

Procedure

The compound 5-tert-butyl-[1,3,4]thiadiazol-2-ylamine (67 mg, 0.43 mmol) was dissolved in 6 mL of 1:1 CH2Cl2/DMF. The resultant solution was charged sequentially with the lithium salt of N-[(1S,2S)-1-(benzyloxycarbonylamino-methyl)-2-hydroxy-pent-3-ynyl]-malonamic acid (151 mg, 0.43 mmol, see procedure 21a), N, N-diisopropylethylamine (0.38 mL, 2.1 mmol) and HATU (194 mg, 0.51 mmol). The mixture was stirred for 12 h at RT, concentrated in vacuo, and partitioned between EtOAc and sat. NH4Cl. The aqueous phase was extracted with EtOAc (1×). The combined organic extracts were washed with sat. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography to afford {(2S,3S)-2-[2-(5-tert-butyl-[1,3,4]thiadiazol-2-ylcarbamoyl)-acetylamino]-3-hydroxy-hex-4-ynyl}-carbamic acid benzyl ester as a colorless oil (90 mg, 43% yield). MS found: (M+Na)+=510.4. (23b) A solution of {(2S,3S)-2-[2-(5-tert-butyl-[1,3,4]thiadiazol-2-ylcarbamoyl)-acetylamino]-3-hydroxy-hex-4-ynyl}-carbamic acid benzyl ester (90 mg, 0.19 mmol) in MeOH (4 mL) was charged with 5% Pd/C, Degussa style (18 mg), stirred under H2 (1 atm) for 12 h at RT, filtered, and concentrated in vacuo. The residue was dissolved in MeOH (3 mL). The resultant solution was charged sequentially with 2,4-dimethylbenzaldehyde (0.02 mL, 0.14 mmol) and sodium cyanoborohydride (11 mg, 0.18 mmol), stirred for 12 h at RT, quenched with sat. NaHCO3, and extracted twice with EtOAc. The organic extracts were combined, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification of the residue by reverse-phase HPLC provided the title compound as a white powder after lyopholization. MS found: (M+H)+=476.5.

Workup

  1. filtrationfiltered
  2. concentrationconcentrated in vacuo
  3. dissolutionThe residue was dissolved in MeOH (3 mL)
  4. stirringstirred for 12 h at RT
  5. customquenched with sat. NaHCO3
  6. extractionextracted twice with EtOAc
  7. washwashed with brine
  8. dry with materialdried (Na2SO4)
  9. filtrationfiltered
  10. concentrationconcentrated in vacuo
  11. customPurification of the residue by reverse-phase HPLC

Sources & evidence

ORD record
ord-400d1ffaa6b34ab2a59491701cb8f46f
Source dataset
uspto-grants-2008_12
Patent number
US07468440B2

Reaction notes

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