Hydrazine hydrate (1:1) → HCID 66991310, compound

HRID 2367317Notes

Reaction equation

HRID 2367317 reaction equation
[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([NH:15][CH3:16])[N:12]=[C:11]([N:17]3[CH:21]([CH3:22])[CH2:20][CH:19]([C:23]([NH:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:24])[CH2:18]3)[CH:10]=2)=[CH:5][C:4]=1F)#[N:2].O.[NH2:35][NH2:36]>CCO>[NH2:2][C:1]1[C:3]2[C:4](=[CH:5][C:6]([C:9]3[N:14]=[C:13]([NH:15][CH3:16])[N:12]=[C:11]([N:17]4[C@H:21]([CH3:22])[CH2:20][C@H:19]([C:23]([NH:25][CH2:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)=[O:24])[CH2:18]4)[CH:10]=3)=[CH:7][CH:8]=2)[NH:36][N:35]=1

Participants

4

Reactant 2

HCID 24654Hydrazine hydrate (1:1)2×HCID 58504640HCID 58504640, compound

Product 1

HCID 66991310HCID 66991310, compound

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Conditions

Temperature
100 °C

Procedure

To a suspension of racemic (3S,5R)-1-[6-(4-cyano-3-fluorophenyl)-2-(methylamino)-4-pyrimidinyl]-5-methyl-N-(phenylmethyl)-3-pyrrolidinecarboxamide (360 mg total, 0.81 mmol) in EtOH (50 mL) at room temperature was added hydrazine monohydrate (2 mL) in one portion. The suspension was heated in an oil bath to 100° C. for 20 hours. LCMS showed there was still 40% starting material remaining. To the mixture was added 2 mL of hydrazine monohydrate, followed by heating to 100° C. for another 24 h. LCMS showed conversion complete. The mixture was cooled to room temperature, and filtered through celite. The filtrate was concentrated in vacuo, and the resulting residue was taken up in 8 mL of water to form a suspension, which was briefly sonicated. The mixture was filtered. The solids collected were combined with another run starting with 190 mg of racemic (3S,5R)-1-[6-(4-cyano-3-fluorophenyl)-2-(methylamino)-4-pyrimidinyl]-5-methyl-N-(phenylmethyl)-3-pyrrolidinecarboxamide. The combined crude products were purified by silica gel column chromatography using gradient elution of 1% A in CHCl3 to 75% A in CHCl3. A was a mixture of 800/80/3200 CH3OH/NH4OH/CHCl3. Trituration of the purified material in a mixture of CHCl3 (2 mL) and hexane (8 mL), followed by drying under vacuum at 65° C. for 14 hours afforded the title compound (228 mg) as a beige powder. LC-MS (ES) m/z=457 [M+H]+. 1H NMR (400 MHz, CD3OD): δ 1.42 (d, J=6.1 Hz, 3H), 2.00-2.06 (m, 1H), 2.52-2.58 (m, 1H), 2.99 (s, 3H), 3.00-3.10 (m, 1H), 3.68-3.73 (m, 1H), 3.95-4.10 (bs, 1H), 4.21-4.33 (bs, 1H), 4.39-4.47 (m, 2H), 6.23 (s, 1H), 7.25-7.37 (m, 5H), 7.52 (dd, J=8.5, 1.1 Hz, 1H), 7.75 (d, J=8.6 Hz, 1H), 7.85 (s, 1H).

Workup

  1. temperatureby heating to 100° C. for another 24 h
  2. temperatureThe mixture was cooled to room temperature
  3. filtrationfiltered through celite
  4. concentrationThe filtrate was concentrated in vacuo
  5. customto form a suspension, which
  6. customwas briefly sonicated
  7. filtrationThe mixture was filtered
  8. customThe solids collected
  9. customwere purified by silica gel column chromatography
  10. washelution of 1% A in CHCl3 to 75% A in CHCl3
  11. additiona mixture of 800/80/3200 CH3OH/NH4OH/CHCl3
  12. additionTrituration of the purified material in a mixture of CHCl3 (2 mL) and hexane (8 mL)
  13. customby drying under vacuum at 65° C. for 14 hours

Sources & evidence

ORD record
ord-fb3d940234d949cd8cf2805bc7bd1deb
Source dataset
uspto-grants-2014_04
Patent number
US08697685B2

Reaction notes

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