Triethylamine → N-[2-({1-[6-(methyloxy)-1,5-naphthyridin-4-yl]-3-pyrrolidinyl}thio)ethyl]-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxamide

HRID 1992526Notes

Reaction equation

HRID 1992526 reaction equation
[CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[N:13]1[CH2:17][CH2:16][CH:15]([S:18][CH2:19][CH2:20][NH2:21])[CH2:14]1.C(N(CC)CC)C.ClC(OCC)=O.[O:35]=[C:36]1[CH2:41][S:40][C:39]2[CH:42]=[CH:43][C:44]([C:46](O)=[O:47])=[N:45][C:38]=2[NH:37]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[N:13]1[CH2:17][CH2:16][CH:15]([S:18][CH2:19][CH2:20][NH:21][C:46]([C:44]2[CH:43]=[CH:42][C:39]3[S:40][CH2:41][C:36](=[O:35])[NH:37][C:38]=3[N:45]=2)=[O:47])[CH2:14]1

Participants

8

Reactant 5

HCID 8471Triethylamine2×HCID 10928Ethyl chloroformateHCID 516892Sodium BicarbonateHCID 218737873-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylic acidHCID 58955135HCID 58955135, compound

Product 1

HCID 11518898N-[2-({1-[6-(methyloxy)-1,5-naphthyridin-4-yl]-3-pyrrolidinyl}thio)ethyl]-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxamideYield 39%

Reagents, catalysts & solvents 2

HCID 6212ChloroformSolventHCID 6344DichloromethaneSolvent

Procedure

The hydrochloride salt of [2-({1-[6-(methyloxy)-1,5-naphthyridin-4-yl]-3-pyrrolidinyl}thio)ethyl]amine (from Example 7b) (300 mg, 0.88 mmol) was dissolved in DCM (5 mL) with triethylamine (0.31 mL, 2.2 mmol) and cooled in an ice bath. The cooled solution was treated with ethyl chloroformate (0.15 mL, 1.59 mmol) and triethyl amine (0.79 mL, 5.3 mmol) and stirred for 1 h. 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylic acid (222 mg, 1.06 mmol) was added. After stirring at 25° C. for 12 h, the reaction mixture was diluted with chloroform and poured into saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with chloroform, and the combined organic layers were washed with brine, dried over magnesium sulfate, concentrated and purified by column chromatography (silica, 0-10% MeOH in CDCl3 (1% NH4OH) to afford the title compound as a white solid (170 mg, 39%): LC/MS m/z 497 (M+H)+; 1H NMR (CDCl3, 400 MHz) δ 8.33 (d, J=4.4 Hz, 1H), 8.29 (br, 1H), 8.2 (d, J=9.0 Hz, 1H), 8.02-8.06 (m, 1H), 7.88 (d, J=7.8 Hz, 1H), 7.81 (d, J=7.8 Hz, 1H), 7.09 (d, J=9.0 Hz, 1H), 6.47 (d, J=4.4 Hz, 1H), 4.47-4.49 (m, 1H), 3.95-4.15 (m, 6H), 3.75-3.81 (m, 2H), 3.64-3.70 (m, 2H), 3.13-3.17 (m, 1H), 2.92-2.94 (m, 2H), 2.47-2.52 (m, 1H), 2.11-2.19 (m, 1H).

Workup

  1. temperaturecooled in an ice bath
  2. stirringAfter stirring at 25° C. for 12 h
  3. extractionThe aqueous layer was extracted with chloroform
  4. washthe combined organic layers were washed with brine
  5. dry with materialdried over magnesium sulfate
  6. concentrationconcentrated
  7. custompurified by column chromatography (silica, 0-10% MeOH in CDCl3 (1% NH4OH)

Sources & evidence

ORD record
ord-0fcc44fe267b459ba44e85baa1cdb6ed
Source dataset
uspto-grants-2010_01
Patent number
US07648984B2

Reaction notes

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