4-Methylmorpholine → phenylmethyl (3S)-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-3-[({6-[(2R)-2,4-dimethyl-1-piperazinyl]-4-pyrimidinyl}amino)carbonyl]-1-pyrazolidinecarboxylate

HRID 1396920Notes

Reaction equation

HRID 1396920 reaction equation
CN1CCOCC1.[CH:8]1([CH2:13][C@H:14]([CH2:35][N:36]([CH:45]=[O:46])[O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:15]([N:17]2[C@H:21]([C:22](O)=[O:23])[CH2:20][CH2:19][N:18]2[C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9]1.COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[CH3:64][C@@H:65]1[CH2:70][N:69]([CH3:71])[CH2:68][CH2:67][N:66]1[C:72]1[N:77]=[CH:76][N:75]=[C:74]([NH2:78])[CH:73]=1>C(#N)C.C(Cl)Cl>[CH:8]1([CH2:13][C@H:14]([CH2:35][N:36]([CH:45]=[O:46])[O:37][CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:15]([N:17]2[C@H:21]([C:22]([NH:78][C:74]3[CH:73]=[C:72]([N:66]4[CH2:67][CH2:68][N:69]([CH3:71])[CH2:70][C@H:65]4[CH3:64])[N:77]=[CH:76][N:75]=3)=[O:23])[CH2:20][CH2:19][N:18]2[C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9]1

Participants

7

Reactant 4

HCID 79724-MethylmorpholineHCID 27340604-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-iumHCID 682877206-[(2R)-2,4-dimethyl-1-piperazinyl]-4-pyrimidinamineHCID 86706346(3S)-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidinecarboxylic acid

Product 1

HCID 86706363phenylmethyl (3S)-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-3-[({6-[(2R)-2,4-dimethyl-1-piperazinyl]-4-pyrimidinyl}amino)carbonyl]-1-pyrazolidinecarboxylateYield 18%

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

4-Methylmorpholine (73.6 μl, 0.670 mmol) was added into the solution of (3S)-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidinecarboxylic acid (300 mg, 0.558 mmol) and 4-[4,6-bis(methyloxy)-1,3,5-triazin-2-yl]-4-methylmorpholin-4-ium (220 mg, 0.670 mmol) in acetonitrile (9.3 ml). The resulting solution was cooled to 0° C., and it was stirred at 0° C. for 15 min. To the reaction mixture was added 6-[(2R)-2,4-dimethyl-1-piperazinyl]-4-pyrimidinamine (139 mg, 0.670 mmol). After stirring for 2 days at ambient temperature, the reaction mixture was concentrated to yield a residue. The residue was dissolved in DCM, and the resulting solution was washed with Na2SO4 (sat.) and brine. The solvent was removed to give a residue again. The residue was purified by RP-HPLC to give an impure product. The impure product was purified by using Silica Gel chromatography (DCM/MeOH/NH4OH=9/1/0.002) to yield phenylmethyl (3S)-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-3-[({6-[(2R)-2,4-dimethyl-1-piperazinyl]-4-pyrimidinyl}amino) carbonyl]-1-pyrazolidinecarboxylate (71 mg, 0.098 mmol, 18% yield). MS (ES+) m/z 727.1 (MH+).

Workup

  1. stirringAfter stirring for 2 days at ambient temperature
  2. concentrationthe reaction mixture was concentrated
  3. customto yield a residue
  4. washthe resulting solution was washed with Na2SO4 (sat.) and brine
  5. customThe solvent was removed
  6. customto give a residue again
  7. customThe residue was purified by RP-HPLC
  8. customto give an impure product
  9. customThe impure product was purified

Sources & evidence

ORD record
ord-d00c1fad151c465da8c6be7e7c8adbf7
Source dataset
uspto-grants-2014_12
Patent number
US08901119B2

Reaction notes

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