Diisopropylethylamine → Benzyl [2-({[4-((3R,4R,5S)-3-[(tert-butoxycarbonyl)amino]-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-1-yl)pyridin-3-yl]amino}carbonyl)-7-morpholin-4-ylquinolin-3-yl]carbamate

HRID 924442Notes

Reaction equation

HRID 924442 reaction equation
[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:28]([OH:30])=O)=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][C:37]=1[N:38]1[CH2:43][C@H:42]([CH3:44])[C@@H:41]([O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[C@H:40]([NH:53][C:54](=[O:60])[O:55][C:56]([CH3:59])([CH3:58])[CH3:57])[CH2:39]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:56]([O:55][C:54]([NH:53][C@H:40]1[C@H:41]([O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[C@@H:42]([CH3:44])[CH2:43][N:38]([C:37]2[CH:36]=[CH:35][N:34]=[CH:33][C:32]=2[NH:31][C:28]([C:13]2[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:21][C:20]3[C:15](=[CH:16][C:17]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)=[CH:18][CH:19]=3)[N:14]=2)=[O:30])[CH2:39]1)=[O:60])([CH3:57])([CH3:58])[CH3:59]

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 59226553tert-butyl (3R,4R,5S)-1-(3-aminopyridin-4-yl)-4-(tert-butyldimethylsilyloxy)-5-methylpiperidin-3-ylcarbamateHCID 867268923-{[(Benzyloxy)carbonyl]amino}-7-morpholin-4-ylquinoline-2-carboxylic acid

Product 1

HCID 86726893Benzyl [2-({[4-((3R,4R,5S)-3-[(tert-butoxycarbonyl)amino]-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-1-yl)pyridin-3-yl]amino}carbonyl)-7-morpholin-4-ylquinolin-3-yl]carbamateYield 38.7%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

A mixture of 3-{[(benzyloxy)carbonyl]amino}-7-morpholin-4-ylquinoline-2-carboxylic acid (0.005 g, 0.01 mmol), tert-butyl ((3R,4R,5S)-1-(3-aminopyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate (0.0064 g, 0.015 mmol), and HATU (0.012 g, 0.031 mmol) in DMF (0.2 mL) and DIPEA (0.0064 mL, 0.037 mmol) was stirred at room temperature for 2 h. The mixture was quenched with 5 mL of EtOAc and 3 mL of 1 M NaOH. The resulting layers were separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were concentrated under reduced pressure, then purified by preparative HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.05% TFA, at a flow rate of 30 mL/min.) to afford the sub-title compound (0.0032 g, 30%). LCMS calc. for C44H60N7O7Si [M+H]+: m/z=826.4. found: 826.4.

Workup

  1. customThe mixture was quenched with 5 mL of EtOAc and 3 mL of 1 M NaOH
  2. customThe resulting layers were separated
  3. extractionthe aqueous layer was extracted with EtOAc
  4. concentrationThe combined organic extracts were concentrated under reduced pressure
  5. custompurified by preparative HPLC (XBridge™ C18 column
  6. washeluting with a gradient of MeCN/water containing 0.05% TFA, at a flow rate of 30 mL/min.)

Sources & evidence

ORD record
ord-4026de91408b4147af33aa972f110d24
Source dataset
uspto-grants-2016_03
Patent number
US09278950B2

Reaction notes

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