Sodium Thiosulfate → 2-({Bis[(phenylmethyl)oxy]phosphoryl}oxy)ethyl {[(3S,11aR)-8-({[(2,4-difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl carbonate

HRID 1430723Notes

Reaction equation

HRID 1430723 reaction equation
C(N(C(C)C)[P:5]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(C)C.[C:25](=[O:61])([O:57][CH2:58][CH2:59][OH:60])[O:26][CH2:27][O:28][C:29]1[C:30](=[O:56])[C:31]([C:44]([NH:46][CH2:47][C:48]2[CH:53]=[CH:52][C:51]([F:54])=[CH:50][C:49]=2[F:55])=[O:45])=[CH:32][N:33]2[C:38]=1[C:37](=[O:39])[N:36]1[C@@H:40]([CH3:43])[CH2:41][O:42][C@@H:35]1[CH2:34]2.N1C=NN=N1.C1C=C(Cl)C=C(C(OO)=[O:75])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[C:25](=[O:61])([O:26][CH2:27][O:28][C:29]1[C:30](=[O:56])[C:31]([C:44]([NH:46][CH2:47][C:48]2[CH:53]=[CH:52][C:51]([F:54])=[CH:50][C:49]=2[F:55])=[O:45])=[CH:32][N:33]2[C:38]=1[C:37](=[O:39])[N:36]1[C@@H:40]([CH3:43])[CH2:41][O:42][C@@H:35]1[CH2:34]2)[O:57][CH2:58][CH2:59][O:60][P:5]([O:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:75]

Participants

7

Reactant 5

HCID 24477Sodium ThiosulfateHCID 70297m-Chloroperbenzoic acidHCID 196621Bis(benzyloxy)(diisopropylamino)phosphine2×HCID 44625951{[(3S,11aR)-8-({[(2,4-difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl 2-hydroxyethyl carbonateHCID 178418441HCID 178418441, compound

Product 1

HCID 671827752-({Bis[(phenylmethyl)oxy]phosphoryl}oxy)ethyl {[(3S,11aR)-8-({[(2,4-difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl carbonate

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

Dibenzyl N, N-diisopropyl-phosphoramidite was added to a mixture of {[(3S,11aR)-8-({[(2,4-difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl 2-hydroxyethyl carbonate (49.4 mg, 0.094 mmol) and tetrazole (79 mg, 1.13 mmol) in dichloromethane at ambient temperature and stirred 3 hours. Additional dibenzyl N,N-diisopropyl-phosphoramidite (0.08 mL) was added and the mixture was stirred for 14 hours at ambient temperature. The reaction was cooled in an ice-water bath, and m-CPBA (130 mg, 0.755 mmol) was added carefully and the mixture was stirred for 30 minutes letting the ice-bath expire. Sodium thiosulfate solution was added, and the mixture was extracted with dichloromethane, washed with sodium bicarbonate solution and brine, and dried over sodium sulfate. Purification by silica gel chromatography afforded the title compound as a colorless residue. 1H NMR (CDCl3) δ 10.17 (m, 1H), 8.28 (s, 1H), 7.35-7.23 (m, 11H), 6.78 (m, 2H), 5.95 (d, J=6.4 Hz, 1H), 5.89 (d, J=6.4 Hz, 1H), 5.20 (dd, J=10, 3.6 Hz, 1H), 5.03-4.60 (m, 3H), 4.58 (m, 1H), 4.45-4.12 (m, 5H), 3.73 (m, 1H), 3.58 (m, 1H), 1.30 (d, J=6.4 Hz, 3H). ES+ MS: 784 (M+1).

Workup

  1. stirringthe mixture was stirred for 14 hours at ambient temperature
  2. temperatureThe reaction was cooled in an ice-water bath
  3. stirringthe mixture was stirred for 30 minutes
  4. extractionthe mixture was extracted with dichloromethane
  5. washwashed with sodium bicarbonate solution and brine
  6. dry with materialdried over sodium sulfate
  7. customPurification by silica gel chromatography

Sources & evidence

ORD record
ord-e7d308c118d744288babcf9d736ac3ad
Source dataset
uspto-grants-2015_01
Patent number
US08940912B2

Reaction notes

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