1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide → (2Z)-3-(5-chloro-6-{[(3R)-1-cyclopentyl-3-pyrrolidinyl]amino}-3-pyridinyl)-2-fluoro-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

HRID 226441Notes

Reaction equation

HRID 226441 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4](/[CH:19]=[C:20](\[F:24])/[C:21]([OH:23])=O)[CH:5]=[N:6][C:7]=1[NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:10]1.[O:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[O:31][NH2:32].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.C(OCC)(C)=O.O>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:19]=[C:20](\[F:24])/[C:21]([NH:32][O:31][CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30][O:25]2)=[O:23])[CH:5]=[N:6][C:7]=1[NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:10]1

Participants

7

Reactant 4

HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 5142091O-(Tetrahydropyran-2-yl)hydroxylamineHCID 68960084(2Z)-3-(5-chloro-6-{[(3R)-1-cyclopentyl-3-pyrrolidinyl]amino}-3-pyridinyl)-2-fluoroacrylic acid

Product 1

HCID 86603746(2Z)-3-(5-chloro-6-{[(3R)-1-cyclopentyl-3-pyrrolidinyl]amino}-3-pyridinyl)-2-fluoro-N-(tetrahydro-2H-pyran-2-yloxy)acrylamideYield 73.6%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 22728543Water ethylacetateSolvent

Procedure

A mixture of (2Z)-3-(5-chloro-6-{[(3R)-1-cyclopentyl-3-pyrrolidinyl]amino}-3-pyridinyl)-2-fluoroacrylic acid (658 mg), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (229 mg), HOBt (264 mg) and EDCI (303 mg) in DMF (15 ml) was stirred at ambient temperature for 15 hours. The reaction mixture was poured into a mixture of AcOEt-H2O and the organic layer was washed with brine and dried over MgSO4. The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-MeOH (95:5). The eluted fractions containing the desired product were collected and evaporated in vacuo to give (2Z)-3-(5-chloro-6-{[(3R)-1-cyclopentyl-3-pyrrolidinyl]amino}-3-pyridinyl)-2-fluoro-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (620 mg).

Workup

  1. washthe organic layer was washed with brine
  2. dry with materialdried over MgSO4
  3. customThe solvent was evaporated in vacuo
  4. customthe residue was chromatographed on silicagel
  5. washeluting with AcOEt-MeOH (95:5)
  6. additionThe eluted fractions containing the desired product
  7. customwere collected
  8. customevaporated in vacuo

Sources & evidence

ORD record
ord-167c89b847ee497d8f2884efc0e94e9e
Source dataset
uspto-grants-2009_07
Patent number
US07557127B2

Reaction notes

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