Methyl chloroformate → 2-[2-fluoro-4-(2-[(1S,2R)-2-{1-[5-(methoxymethyl)pyrimidine-2-yl]piperidin-4-yl]cyclopropyl}ethoxy)phenyl]acetohydrazide

HRID 1474746Notes

Reaction equation

HRID 1474746 reaction equation
[F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:25]=[CH:24][C:23]([CH2:26][O:27][CH3:28])=[CH:22][N:21]=3)[CH2:16][CH2:15]2)[CH:5]=[CH:4][C:3]=1[CH2:29][C:30](O)=[O:31].ClC(OC)=O.O.[NH2:39][NH2:40]>C1COCC1.CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:15][CH2:16][N:17]([C:20]3[N:25]=[CH:24][C:23]([CH2:26][O:27][CH3:28])=[CH:22][N:21]=3)[CH2:18][CH2:19]2)[CH:5]=[CH:4][C:3]=1[CH2:29][C:30]([NH:39][NH2:40])=[O:31]

Participants

7

Reactant 3

HCID 6586Methyl chloroformateHCID 24654Hydrazine hydrate (1:1)HCID 117678258[2-fluoro-4-(2-{(1S,2R)-2-{1-[5-(methoxymethyl)pyrimidin-2-yl]piperidin-4-yl}cyclopropyl}ethoxy)phenyl]acetic acid

Product 1

HCID 1176784992-[2-fluoro-4-(2-[(1S,2R)-2-{1-[5-(methoxymethyl)pyrimidine-2-yl]piperidin-4-yl]cyclopropyl}ethoxy)phenyl]acetohydrazide

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
-10 °C

Procedure

A solution [2-fluoro-4-(2-{(1S,2R)-2-{1-[5-(methoxymethyl)pyrimidin-2-yl]piperidin-4-yl}cyclopropyl}ethoxy)phenyl]acetic acid (500 mg, 1.152 mmol) in 5 mL of THF was cooled to −10° C. TEA (0.177 mL, 1.268 mmol) and methyl chloroformate (0.098 mL, 1.268 mmol) were added and the mixture stirred for 30 minutes at −10° C. The precipitate was filtered and the filtercake washed with 10 mL of THF. The filtrate was collected, 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 resulting mixture was stirred overnight at room temperature, diluted with ethyl acetate (3 mL), washed with water (2 mL), and brine (2 mL). The organic fractions were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via 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. The filtrate was collected and concentrated under reduced pressure to afford the title compound. HPLC/MS; 1.31 min(2 minute run), 458 (M+H)+.

Workup

  1. filtrationThe precipitate was filtered
  2. washthe filtercake washed with 10 mL of THF
  3. customThe filtrate was collected
  4. concentrationconcentrated under reduced pressure
  5. stirringThe resulting mixture was stirred overnight at room temperature
  6. washwashed with water (2 mL), and brine (2 mL)
  7. dry with materialThe organic fractions were dried over sodium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated under reduced pressure
  10. customThe residue was purified via preparative TLC (1000 μM, silica gel)
  11. additionThe band containing the product
  12. customwas collected
  13. washthe silica washed with 10% methanol in DCM
  14. customThe filtrate was collected
  15. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-b7f235417aa5432189d6ba8c9c9b6854
Source dataset
uspto-grants-2015_04
Patent number
US09018224B2

Reaction notes

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