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

HRID 1396911Notes

Reaction equation

HRID 1396911 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]([OH:24])=O)[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][N:65]([CH3:78])[C@H:66]1[CH2:70][CH2:69][N:68]([C:71]2[N:76]=[C:75]([NH2:77])[CH:74]=[CH:73][N:72]=2)[CH2:67]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:77][C:75]3[CH:74]=[CH:73][N:72]=[C:71]([N:68]4[CH2:69][CH2:70][C@H:66]([N:65]([CH3:78])[CH3:64])[CH2:67]4)[N:76]=3)=[O:24])[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 68288030HCID 68288030, compoundHCID 86706346(3S)-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidinecarboxylic acid

Product 1

HCID 86706356phenylmethyl (3S)-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-3-[({2-[(3S)-3-(dimethylamino)-1-pyrrolidinyl]-4-pyrimidinyl}amino)carbonyl]-1-pyrazolidinecarboxylateYield 45%

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

4-Methylmorpholine (36.8 μl, 0.335 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 (150 mg, 0.279 mmol) and 4-[4,6-bis(methyloxy)-1,3,5-triazin-2-yl]-4-methylmorpholin-4-ium (110 mg, 0.335 mmol) in acetonitrile (4.7 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 2-[(3S)-3-(dimethylamino)-1-pyrrolidinyl]-4-pyrimidinamine (69.4 mg, 0.335 mmol). After stirring for 2 days at ambient temperature, the reaction mixture was concentrated to yield a residue. The residue was dissolved in DCM. The resulting solution was washed with aqueous saturated Na2SO4 and brine, respectively. The solvent was removed to yield a residue again. The residue was purified by RP-HPLC to yield phenylmethyl (3S)-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-3-[({2-[(3S)-3-(dimethylamino)-1-pyrrolidinyl]-4-pyrimidinyl}amino)carbonyl]-1-pyrazolidinecarboxylate (91 mg, 0.125 mmol, 45% yield). MS (ES+) m/z 727.2 (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 aqueous saturated Na2SO4 and brine
  5. customThe solvent was removed
  6. customto yield a residue again
  7. customThe residue was purified by RP-HPLC

Sources & evidence

ORD record
ord-d8728d221a3c4059b6b40ad4c6971e57
Source dataset
uspto-grants-2014_12
Patent number
US08901119B2

Reaction notes

Loading…