Methyl chloroformate → 2-[4-(2-{(1S,2R)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethoxy)-2-fluorophenyl]-acetohydrazide

HRID 1474745Notes

Reaction equation

HRID 1474745 reaction equation
[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27](O)=[O:28])=[C:22]([F:30])[CH:21]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.ClC(OC)=O.O.[NH2:37][NH2:38]>C1COCC1.CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:37][NH2:38])=[O:28])=[C:22]([F:30])[CH:21]=3)[CH2:10][CH2:9]2)=[N:4][CH:3]=1

Participants

7

Reactant 3

HCID 6586Methyl chloroformateHCID 24654Hydrazine hydrate (1:1)HCID 89583888[4-(2-{(1S,2R)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethoxy)-2-fluorophenyl]acetic acid

Product 1

HCID 895840202-[4-(2-{(1S,2R)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethoxy)-2-fluorophenyl]-acetohydrazide

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
-10 °C

Procedure

A solution of [4-(2-{(1S,2R)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethoxy)-2-fluorophenyl]acetic acid (500 mg, 1.152 mmol) in 5 mL of THF cooled to −10° C. and TEA (0.177 mL, 1.268 mmol) was added. Methyl chloroformate (0.098 mL, 1.268 mmol) was added and the mixture stirred for 30 minutes at −10° C. The mixture was filtered and the filtercake washed with 10 mL THF. The filtrate was collected and concentrated under reduced pressure. The residue (265 mg, 0.539 mmol) was dissolved in 1 mL of DMF and hydrazine monohydrate (0.052 mL, 1.077 mmol) added. The mixture was stirred overnight at room temperature. The mixture was diluted with ethyl acetate (3 mL) and washed with water (2 mL) and brine (2 mL). The organics fractions were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified using preparative TLC (1000 μM, silica gel) developing with 5% methanol in DCM. The band containing the product was collected and the silica washed with 10% methanol in DCM to elute the product. The solution was concentrated under reduced pressure to afford the title compound. HPLC/MS; 1.22 min(2 minute run), 448 (M+H)+.

Workup

  1. filtrationThe mixture was filtered
  2. washthe filtercake washed with 10 mL THF
  3. customThe filtrate was collected
  4. concentrationconcentrated under reduced pressure
  5. stirringThe mixture was stirred overnight at room temperature
  6. washwashed with water (2 mL) and brine (2 mL)
  7. dry with materialdried over sodium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated under reduced pressure
  10. customThe residue was purified
  11. additionThe band containing the product
  12. customwas collected
  13. washthe silica washed with 10% methanol in DCM
  14. washto elute the product
  15. concentrationThe solution was concentrated under reduced pressure

Sources & evidence

ORD record
ord-43a19b3303ce4ea4806ff2d6ab3907a0
Source dataset
uspto-grants-2015_04
Patent number
US09018224B2

Reaction notes

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