HCID 68765224, compound → HCID 69809772, compound

HRID 529069Notes

Reaction equation

HRID 529069 reaction equation
[CH:1]1([Mg]Br)[CH2:3][CH2:2]1.Br[C:7]1[CH:8]=[C:9]2[C:15]3([CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[CH2:14][N:13]([C:28]3[C:29]4[C@H:36]([CH3:37])[CH2:35][CH2:34][C:30]=4[N:31]=[CH:32][N:33]=3)[C:10]2=[CH:11][CH:12]=1>C1COCC1.CCOC(C)=O.[Zn+2].[Br-].[Br-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]1([C:7]2[CH:8]=[C:9]3[C:15]4([CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH2:17][CH2:16]4)[CH2:14][N:13]([C:28]4[C:29]5[C@H:36]([CH3:37])[CH2:35][CH2:34][C:30]=5[N:31]=[CH:32][N:33]=4)[C:10]3=[CH:11][CH:12]=2)[CH2:3][CH2:2]1

Participants

7

Reactant 2

HCID 68765224HCID 68765224, compoundHCID 178418630HCID 178418630, compound

Product 1

HCID 69809772HCID 69809772, compoundYield 57%

Reagents, catalysts & solvents 4

HCID 10421208Zinc bromideCatalystHCID 178418397HCID 178418397, compoundCatalystHCID 8028TetrahydrofuranSolvent3×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
-78 °C

Procedure

To a stirred suspension of ZnBr2 (41 mg, 0.18 mmol) in THF (0.5 mL) was added dropwise a 0.5 M solution of cyclopropylmagnesium bromide in THF (0.36 mL, 0.18 mmol) at about −78° C. under nitrogen. After being stirred at about −78° C. for about 30 min, the resulting solution was allowed to warm to about 0° C. A solution of (R)-tert-butyl 5-bromo-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (38 mg, 0.076 mmol) and Pd(PPh3)4 (4.4 mg, 0.0038 mmol) in THF (0.3 mL) was added. The resulting mixture was heated to about 60° C. overnight. After cooling, the mixture was diluted with EtOAc, washed with water and brine, dried and concentrated. The residue was purified by reverse phase preparative HPLC to give (R)-tert-butyl 5-cyclopropyl-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (20 mg, 57%). LCMS (APCI+) m/z 461 [M+H]+; Rt=3.24 min.

Workup

  1. temperatureto warm to about 0° C
  2. temperatureThe resulting mixture was heated to about 60° C. overnight
  3. temperatureAfter cooling
  4. washwashed with water and brine
  5. customdried
  6. concentrationconcentrated
  7. customThe residue was purified by reverse phase preparative HPLC

Sources & evidence

ORD record
ord-7b624602f8844c03b504cf7233b931ef
Source dataset
uspto-grants-2016_05
Patent number
US09346805B2

Reaction notes

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