1-Hydroxybenzotriazole → 4-[(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester

HRID 633797Notes

Reaction equation

HRID 633797 reaction equation
[O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12]([OH:14])=O)[CH:10]=[CH:11][C:5]=2[S:4][CH2:3]1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([NH:28][C:12]([C:9]2[CH:10]=[CH:11][C:5]3[S:4][CH2:3][C:2](=[O:1])[NH:7][C:6]=3[CH:8]=2)=[O:14])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]

Participants

7

Reactant 5

HCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 7609933-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboxylic acidHCID 12682914-Amino-1-Boc-piperidineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochloride

Product 1

HCID 711180944-[(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl)-amino]-piperidine-1-carboxylic acid tert-butyl esterYield 64.7%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid (556 mg, 2.45 mmol, 1.0 eq) is added at room temperature to a stirred solution of 4-amino-piperidine-1-carboxylic acid tert-butyl ester (500 mg, 2.45 mmol, 1.0 eq) in N,N-dimethylformamide (20 mL), followed by 1-hydroxybenzotriazole (421 mg, 2.69 mmol, 1.1 eq), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (550 mg, 2.81 mmol, 1.15 eq) and N,N-diisopropylethylamine (962 μL, 5.50 mmol, 2.25 eq). After 15 hours stirring at room temperature, solvent is evaporated and the residue is extracted with dichloromethane (3×30 mL) and water (30 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a crude product that is purified by column chromatography (silica gel, eluent: cyclohexane:ethyl acetate:methanol, 1:3:0 to 0/9/1, v/v/v) to afford 4-[(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester as a light yellow solid (621 mg, 62% yield).

Workup

  1. customsolvent is evaporated
  2. extractionthe residue is extracted with dichloromethane (3×30 mL) and water (30 mL)
  3. dry with materialThe combined organic layers are dried over sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customto give a crude product that
  7. customis purified by column chromatography (silica gel, eluent: cyclohexane:ethyl acetate:methanol, 1:3:0 to 0/9/1, v/v/v)

Sources & evidence

ORD record
ord-ff15d5a931464099947bd40619392fe9
Source dataset
uspto-grants-2016_04
Patent number
US09321788B2

Reaction notes

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