[(2R)-3-(2-{2-chloro-5-fluoro-6-[(9aR)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl][(phenylmethyl)oxy]formamide → [(2R)-3-(2-{2-chloro-5-fluoro-6-[(9aR)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl]hydroxyformamide

HRID 1366566Notes

Reaction equation

HRID 1366566 reaction equation
[Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10](=[O:30])[C@H:11]([CH2:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:12][N:13]([O:16]CC2C=CC=CC=2)[CH:14]=[O:15])[C:5]([F:31])=[C:4]([N:32]2[CH2:41][CH2:40][N:39]3[C@@H:34]([CH2:35][O:36][CH2:37][CH2:38]3)[CH2:33]2)[N:3]=1>CO.[OH-].[OH-].[Pd+2]>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10](=[O:30])[C@H:11]([CH2:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:12][N:13]([OH:16])[CH:14]=[O:15])[C:5]([F:31])=[C:4]([N:32]2[CH2:41][CH2:40][N:39]3[C@@H:34]([CH2:35][O:36][CH2:37][CH2:38]3)[CH2:33]2)[N:3]=1

Participants

4

Reactant 1

HCID 86636989[(2R)-3-(2-{2-chloro-5-fluoro-6-[(9aR)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl][(phenylmethyl)oxy]formamide

Product 1

HCID 58000693[(2R)-3-(2-{2-chloro-5-fluoro-6-[(9aR)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl]hydroxyformamideYield 63%

Reagents, catalysts & solvents 2

HCID 9942167Palladium hydroxideCatalystHCID 887MethanolSolvent

Procedure

To a solution of [(2R)-3-(2-{2-chloro-5-fluoro-6-[(9aR)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl][(phenylmethyl)oxy]formamide (2.3947 g, 4.058 mmol) in MeOH (40 mL) was added 20% Pd(OH)2/C (50% water, 240 mg). The mixture was hydrogenated under balloon pressure for 2.5 h, and then filtered through a 0.2 μm membrane. The solution was concentrated in vacuo, and the residue was purified by Gilson RPLC (10% MeCN in water to 65% MeCN in water; 8 min gradient). The desired fractions were combined, and the MeCN was removed in vacuo. The resulting mixture was extracted with EtOAc (2×150 mL), and the combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was then crystallized from EtOAc-hexanes to provide [(2R)-3-(2-{2-chloro-5-fluoro-6-[(9aR)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl]hydroxyformamide (1.2759 g, 63%) as a pale pink solid. LCMS: (M+H)+: 500.1.

Workup

  1. filtrationfiltered through a 0.2 μm membrane
  2. concentrationThe solution was concentrated in vacuo
  3. customthe residue was purified by Gilson RPLC (10% MeCN in water to 65% MeCN in water; 8 min gradient)
  4. customthe MeCN was removed in vacuo
  5. extractionThe resulting mixture was extracted with EtOAc (2×150 mL)
  6. dry with materialthe combined organic phase was dried over anhydrous Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customThe residue was then crystallized from EtOAc-hexanes

Sources & evidence

ORD record
ord-6c510dbdabd142ca96af76bd18ff956b
Source dataset
uspto-grants-2011_02
Patent number
US07893056B2

Reaction notes

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