4-Methylmorpholine → (S)-2-[(S)-4-benzyloxycarbonyl-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butyryl]-3-phenethylcarbamoyl-tetrahydro-pyridazine-1-carboxylic acid benzyl ester

HRID 1668414Notes

Reaction equation

HRID 1668414 reaction equation
[CH2:1]([O:8][C:9](=[O:27])[CH2:10][CH2:11][C@H:12]([N:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=[O:26])[C:13](O)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH2:34]([O:41][C:42]([N:44]1[CH2:49][CH2:48][CH2:47][C@@H:46]([C:50](=[O:60])[NH:51][CH2:52][CH2:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[NH:45]1)=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.CN1CCOCC1>CCOCC.C1COCC1>[CH2:34]([O:41][C:42]([N:44]1[CH2:49][CH2:48][CH2:47][C@@H:46]([C:50](=[O:60])[NH:51][CH2:52][CH2:53][C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=2)[N:45]1[C:13](=[O:14])[C@@H:12]([N:16]1[C:17](=[O:26])[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:24]1=[O:25])[CH2:11][CH2:10][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:27])=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1

Participants

7

Reactant 4

HCID 79724-MethylmorpholineHCID 24819Phosphorus pentachlorideHCID 11100670(2S)-5-(Benzyloxy)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-5-oxopentanoic acidHCID 57612817(S)-3-phenethylcarbamoyl-tetrahydro-pyridazine-1-carboxylic acid benzyl ester

Product 1

HCID 57612765(S)-2-[(S)-4-benzyloxycarbonyl-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butyryl]-3-phenethylcarbamoyl-tetrahydro-pyridazine-1-carboxylic acid benzyl esterYield 99.9%

Reagents, catalysts & solvents 2

HCID 3283Diethyl EtherSolvent2×HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
25 °C

Procedure

To a solution of (S)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-pentanedioic acid 5-benzyl ester (580 mg, 1.59 mmol) in ether (25 mL) at 0° C., is added PCl5 (920 mg, 4.38 mmol) in one portion. After stirring at 25° C. for 40 minutes, ether is removed by evaporation, and the residue is dissolved in 20 mL of THF, and is added to a solution of (S)-3-phenethylcarbamoyl-tetrahydro-pyridazine-1-carboxylic acid benzyl ester (580 mg) and N-methylmorpholine (0.74 mL, 6.77 mmol) in THF (10 mL) at 0° C. slowly. After stirring at room temperature for 2 hours, the reaction mixture is diluted with 100 mL of ether and washed with 2×20 mL of water. The combined organic layers is dried over Na2SO4 and concentrated, and purified by chromatography (CH2Cl2/MeOH:97/3) to give (S)-2-[(S)-4-benzyloxycarbonyl-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butyryl]-3-phenethylcarbamoyl-tetrahydro-pyridazine-1-carboxylic acid benzyl ester (1.13 g, 99.2%) as pale solid. (NMR and MS data confirmed, U-3133-62).

Workup

  1. customether is removed by evaporation
  2. dissolutionthe residue is dissolved in 20 mL of THF
  3. stirringAfter stirring at room temperature for 2 hours
  4. washwashed with 2×20 mL of water
  5. dry with materialThe combined organic layers is dried over Na2SO4
  6. concentrationconcentrated
  7. custompurified by chromatography (CH2Cl2/MeOH:97/3)

Sources & evidence

ORD record
ord-25e57790abd14e4cbc6ec9d7067b5eb3
Source dataset
uspto-grants-2011_08
Patent number
US07989441B2

Reaction notes

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