2-Naphthalenesulfonyl chloride → HCID 3852743, compound

HRID 1893182Notes

Reaction equation

HRID 1893182 reaction equation
[NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[S:23]([NH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]1)(=[O:24])=[O:25]

Participants

4

Reactant 2

HCID 71252-Naphthalenesulfonyl chlorideHCID 100867Ethyl 4-amino-1-piperidinecarboxylate

Product 1

HCID 3852743HCID 3852743, compoundYield 86.5%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Conditions

Temperature
10 °C

Procedure

TEA (0.088 mol, 12.4 ml) was added at 10° C. to a solution of 4-amino-1-piperidinecarboxylic acid, ethyl ester (0.044 mol, 7.6 g) in DCM (110 ml) under N2 flow. A solution of 2-naphtalenesulfonyl chloride (0.044 mol) in DCM (50 ml) was added dropwise. The mixture was stirred at 10° C. for 1 hour and 30 minutes, poured out into ice water and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue was taken up in diethylether, the precipitate was filtered and dried yielding 13.8 g of 4-[(2-naphthalenylsulfonyl)amino]-1-piperidinecarboxylic acid, ethyl ester, melting point 128° C., intermediate 1. b) A mixture of interm. 1 (0.072 mol) in HCl 12N (290 ml) was stirred and refluxed for 48 hours, then cooled to room temperature, poured out into ice water and basified with NH4OH. The precipitate was filtered, washed with water, then with diethyl ether and dried, yielding 15.78 g (76%) of N-4-piperidinyl-2-naphthalenesulfonamide, melting point 172° C., intermediate 2. c) NaH 60% (0.0066 mol) was added portionwise at room temperature to a solution of interm. 2 (0.0033 mol) in THF (10 ml) under N2 flow. The mixture was stirred at room temperature for 1 hour, then cooled to 0° C. A solution of 2-(methylsulfonyl)-5-pyrimidinecarboxylic acid, ethyl ester (0.0043 mol) in THF (8 ml) was added dropwise quickly. The mixture was stirred at room temperature for 2 hours, poured out into ice water and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue (1.64 g) was crystallized from CH3OH/diethyl ether. The precipitate was filtered off and dried, yielding 0.925 g (63%) of 2-[4-[(2-naphthalenylsulfonyl)amino]-1-piperidinyl]-5-pyrimidinecarboxylic acid, ethyl ester, intermediate 3. d) A mixture of interm. 3 (0.0021 mol) and potassium hydroxide (0.0084 mol) in ethanol (20 ml) was stirred and refluxed overnight, then cooled to room temperature, poured out into ice water and acidified with HCl 3N. The precipitate was filtered off and dried, yielding 0.66 g (76%) of 2-[4-[(2-naphthalenylsulfonyl)amino]-1-piperidinyl]-5-pyrimidinecarboxylic acid, melting point >260° C., intermediate 4. e) TEA (0.0019 mol), 1-(3-dimethylaminopropyl)-3-ethyl-carbodimide hydrochloride (0.0019 mol), 1-hydroxybenzotriazole (0.0019 mol) and O-(tetrahydro-2H-pyran-2-yl)-hydroxylamine (0.0019 mol) were added at room temperature to a solution of interm. 4 (0.0014 mol) in DCM/THF 50/50 (20 ml) under N2 flow. The mixture was stirred at room temperature for 24 hours, poured out into ice water. DCM was added. The precipitate was filtered, washed with water and dried, yielding 0.261 g (34%) of 2-[4-[(2-naphthalenylsulfonyl)amino]-1-piperidinyl]-N-[(tetrahydro-2H-pyran-2-yl)oxy]-5-pyrimidinecarboxamide, melting point 226° C., intermediate 5.

Workup

  1. extractionextracted with DCM
  2. customThe organic layer was separated
  3. dry with materialdried (MgSO4)
  4. filtrationfiltered
  5. customthe solvent was evaporated
  6. filtrationthe precipitate was filtered
  7. customdried

Sources & evidence

ORD record
ord-7ecba384547f4a3496fa7791b1ed3c76
Source dataset
uspto-grants-2013_08
Patent number
US08513237B2

Reaction notes

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