Tetrahydrofuran → (S)-(3-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)(cyclopentyl)methanone

HRID 332956Notes

Reaction equation

HRID 332956 reaction equation
Cl.[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][NH2+:19][CH2:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1.C1COCC1.C([O-])(O)=O.[Na+].[CH:33]1([C:38](Cl)=[O:39])[CH2:37][CH2:36][CH2:35][CH2:34]1>O>[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:38]([CH:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)=[O:39])[CH2:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:9])(=[O:10])[N:8]=1

Participants

6

Reactant 4

HCID 8028TetrahydrofuranHCID 78284Cyclopentanecarbonyl chlorideHCID 516892Sodium Bicarbonate2×HCID 86714280(S)-3-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidinium hydrochloride

Product 1

HCID 73213589(S)-(3-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)(cyclopentyl)methanoneYield 52.1%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Procedure

To a solution of (S)-3-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidinium hydrochloride (Example 2a, 528 mg, 1.52 mmol) in H2O:THF (20 mL, 2:1), was added NaHCO3 (640 mg, 7.60 mmol). Upon complete dissolution of the NaHCO3, cyclopentanecarbonyl chloride (945 uL, 7.60 mmol) was added dropwise. The reaction was stirred at room temperature overnight. The precipitate was collected by vacuum filtration and purified by preparative HPLC (10-90% acetonitrile in water). The pure fractions were combined, concentrated then dissolved in a solution of NaHCO3 (250 mg in 10 mL water). After complete dissolution, the mixture was cooled in an ice bath and neutralized with 1N HCl. The resulting white solid was collected by vacuum filtration to provide the desired product (322 mg, 52%) as a white solid. 1H NMR (DMSO-d6, 400 MHz, 80° C.): 1.43 (m, 2H), 1.51-1.80 (m, 10H), 1.90 (m, 1H), 2.09 (m, 1H), 2.96 (m, 2H), 4.01 (br m, 2H), 4.12 (d, J=6.4 Hz, 2H), 6.67 (d, J=7.8 Hz, 1H), 6.77 (d, J=8.3 Hz, 1H), 7.46 (t, J=8.3 Hz, 1H), 7.92 (br s, 2H), 10.70 (br s, 1H). MS=407 (MH+).

Workup

  1. additionwas added dropwise
  2. filtrationThe precipitate was collected by vacuum filtration
  3. custompurified by preparative HPLC (10-90% acetonitrile in water)
  4. concentrationconcentrated
  5. dissolutionthen dissolved in a solution of NaHCO3 (250 mg in 10 mL water)
  6. dissolutionAfter complete dissolution
  7. temperaturethe mixture was cooled in an ice bath
  8. filtrationThe resulting white solid was collected by vacuum filtration

Sources & evidence

ORD record
ord-be684f0935854e35add5137b50a80577
Source dataset
uspto-grants-2014_11
Patent number
US08877922B2

Reaction notes

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