Diisopropylethylamine → 1-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-piperidine-4-carboxylic acid (2-hydroxy-2-methyl-propyl)-amide

HRID 1842005Notes

Reaction equation

HRID 1842005 reaction equation
[O:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[O:4][C@@H:3]([C:11]2[CH:26]=[CH:25][C:14]([CH2:15][N:16]3[CH2:21][CH2:20][CH:19]([C:22]([OH:24])=O)[CH2:18][CH2:17]3)=[CH:13][CH:12]=2)[CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:51][CH2:52][C:53]([CH3:56])([OH:55])[CH3:54].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[OH:55][C:53]([CH3:56])([CH3:54])[CH2:52][NH:51][C:22]([CH:19]1[CH2:20][CH2:21][N:16]([CH2:15][C:14]2[CH:25]=[CH:26][C:11]([C@@H:3]3[O:4][C:5]4=[N:6][CH:7]=[CH:8][CH:9]=[C:10]4[O:1][CH2:2]3)=[CH:12][CH:13]=2)[CH2:17][CH2:18]1)=[O:24]

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 951022-Propanol, 1-amino-2-methyl-HCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 683590441-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-piperidine-4-carboxylic acid

Product 1

HCID 717371791-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-piperidine-4-carboxylic acid (2-hydroxy-2-methyl-propyl)-amide

Reagents, catalysts & solvents 1

HCID 31374DimethylacetamideSolvent2×

Procedure

To a solution of Intermediate K (50 mg, 0.14 mmol) in DMA (1 mL) is added HATU (59 mg, 0.16 mmol) followed by 1-amino-2-methyl-propan-2-ol (14 mg, 0.16 mmol) as a solution in DMA (1 mL) and DIEA (0.10 mL, 0.56 mmol) and the mixture stirred at rt overnight. Add water (0.1 mL) and purify by reversed phase HPLC eluting with 10-90% MeCN in water (+0.1% TFA). The concentrated pooled fractions are dissolved in 1:1 methanol/DCE and passed through a carbonate resin cartridge to provide the title compound 255 as a free base. (LC/MS method 16: ES+ m/z 426.5 [M+H]+, Rt=1.48 min)

Workup

  1. customAdd water (0.1 mL) and purify by reversed phase HPLC
  2. washeluting with 10-90% MeCN in water (+0.1% TFA)
  3. dissolutionThe concentrated pooled fractions are dissolved in 1:1 methanol/DCE

Sources & evidence

ORD record
ord-d6b8e4d852504bb2a89154ec7c5d96fb
Source dataset
uspto-grants-2015_02
Patent number
US08946203B2

Reaction notes

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