Triethylamine → 4-[4-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-benzoylamino]-piperidine-1-carboxylic acid tert-butyl ester

HRID 1676554Notes

Reaction equation

HRID 1676554 reaction equation
[CH:1]1([N:5]2[CH2:11][C:10]([F:13])([F:12])[C:9](=[O:14])[N:8]([CH3:15])[C:7]3[CH:16]=[N:17][C:18]([NH:20][C:21]4[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=4)=[N:19][C:6]2=3)[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.[CH3:61][C:62]([O:65][C:66]([N:68]1[CH2:73][CH2:72][CH:71]([NH2:74])[CH2:70][CH2:69]1)=[O:67])([CH3:64])[CH3:63]>ClCCl.CN(C)C=O>[C:62]([O:65][C:66]([N:68]1[CH2:73][CH2:72][CH:71]([NH:74][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][C:21]([NH:20][C:18]3[N:17]=[CH:16][C:7]4[N:8]([CH3:15])[C:9](=[O:14])[C:10]([F:12])([F:13])[CH2:11][N:5]([CH:1]5[CH2:4][CH2:3][CH2:2]5)[C:6]=4[N:19]=3)=[CH:22][CH:23]=2)[CH2:70][CH2:69]1)=[O:67])([CH3:61])([CH3:63])[CH3:64]

Participants

7

Reactant 4

HCID 8471TriethylamineHCID 12682914-Amino-1-Boc-piperidineHCID 445472064-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-benzoic acidHCID 178484293HCID 178484293, compound

Product 1

HCID 670764154-[4-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-benzoylamino]-piperidine-1-carboxylic acid tert-butyl esterYield 55.7%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Procedure

A mixture of 0.093 g (0.23 mmole) of 4-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-benzoic acid (I-11), 0.093 g (0.92 mmole) of triethylamine, 0.133 g (0.35 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate and 5 mL of dimethylformamide was stirred for 15 minutes and then 0.070 g (0.35 mmole) of 4-amino-1-piperidinecarboxylic acid 1,1-dimethylethyl ester was added. The mixture was stirred for 3 hours, then taken up in 50 mL of dichloromethane and washed twice with 100 mL of water and then 100 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with hexane-ethyl acetate (gradient 50:50-0:100) to give 0.075 g of 4-[4-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-benzoylamino]-piperidine-1-carboxylic acid tert-butyl ester.

Workup

  1. stirringThe mixture was stirred for 3 hours
  2. washwashed twice with 100 mL of water
  3. dry with materialThe organic layer was dried over anhydrous sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated under reduced pressure
  6. customThe residue was purified by silica gel chromatography
  7. washeluting with hexane-ethyl acetate (gradient 50:50-0:100)

Sources & evidence

ORD record
ord-4a77f3b5c22f4fbda41b8e42dfdfd677
Source dataset
uspto-grants-2011_08
Patent number
US08003785B2

Reaction notes

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