Trifluoroacetic acid → 4-[7-(3-[1,2,4]Triazol-4-yl-propoxy)-quinazolin-4-yl]-piperidine-1-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide

HRID 657259Notes

Reaction equation

HRID 657259 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH2:25][CH2:26][CH2:27][N:28]4[CH:32]=[N:31][N:30]=[CH:29]4)=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:33](O)([C:35]([F:38])(F)F)=O.[Al].CN(CCO)C.Cl.[N+](C1C=CC(OC(=O)[NH:59][C:60]2[CH:61]=[N:62][C:63]([N:66]3[CH2:71][CH2:70][O:69][CH2:68][CH2:67]3)=[CH:64][CH:65]=2)=CC=1)([O-])=O>C(Cl)(Cl)Cl>[N:66]1([C:63]2[N:62]=[CH:61][C:60]([NH:59][C:6]([N:8]3[CH2:13][CH2:12][CH:11]([C:14]4[C:23]5[C:18](=[CH:19][C:20]([O:24][CH2:25][CH2:26][CH2:27][N:28]6[CH:32]=[N:31][N:30]=[CH:29]6)=[CH:21][CH:22]=5)[N:17]=[CH:16][N:15]=4)[CH2:10][CH2:9]3)=[O:7])=[CH:65][CH:64]=2)[CH2:71][CH2:70][O:69][CH2:68][CH2:67]1.[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:35]([F:38])=[CH:33][CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

8

Reactant 5

HCID 6422Trifluoroacetic acidHCID 79022-(Dimethylamino)ethanolHCID 5359268AluminumHCID 59551762HCID 59551762, compoundHCID 69259253HCID 69259253, compound

Product 2

HCID 587707184-[7-(3-[1,2,4]Triazol-4-yl-propoxy)-quinazolin-4-yl]-piperidine-1-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amideHCID 595517364-(7-Fluoro-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester

Reagents, catalysts & solvents 1

HCID 6212ChloroformSolvent

Conditions

Temperature
40 °C

Procedure

The crude 4-[7-(3-[1,2,4]Triazol-4-yl-propoxy)-quinazolin-4-yl]-piperidine-1-carboxylic acid tert-butyl ester, as prepared in the previous step, was treated with TFA (70 μL) at 100° C. in a sealed vial for 10 min (aluminum block). CHCl3 (450 μL) and DMEA (140 μL, 1.3 mmol) were added, and one-half of the resulting homogeneous amber solution was treated with (6-morpholin-4-yl-pyridin-3-yl)-carbamic acid-4-nitrophenyl ester hydrochloride (22 mg, 58 μmol), as prepared in Example 80a, and stirred at 40° C. for 1.5 hr. (The other one-half of the homogenous solution was diverted to the synthesis given in Example 114.) The reaction was then partitioned with 2M K2CO3 (2 mL) and DCM (2 mL), and the aqueous layer was extracted with 9:1 DCM/MeOH (1×2 mL). The combined organic layers were concentrated and the residue was partially purified with a 5 g silica flash cartridge (97:3 acetone/MeOH eluent with 2% DMEA), and further purified with HPLC (C18 column) to provide the title compound as a powder after lyophilization [2.1 mg, 8.1% overall from 4-(7-fluoro-quinazolin-4-yl)-piperidin-1-carboxylic acid tert-butyl ester.] 1H-NMR (400 MHz, 95:5 CDCl3/CD3OD) δ 9.12 (s, 1H), 8.43 (dd, 1H), 8.30 (br s, 2H), 8.13 (m, 2H), 7.32 (m, 1H), 7.26 (dd, 1H), 6.96 (d, 1H), 4.37 (m, 4H), 4.21 (t, 2H), 3.88 (m, 4H), 3.75 (m, 1H), 3.59 (m, 4H), 3.14 (m, 2H), 2.42 (pentet, 2H), 2.16-1.95 (m, 4H). LC/MS (ESI) calcd mass 543.3, found 544.1 (MH)+.

Workup

  1. customas prepared in Example 80a
  2. custom) The reaction was then partitioned with 2M K2CO3 (2 mL) and DCM (2 mL)
  3. extractionthe aqueous layer was extracted with 9:1 DCM/MeOH (1×2 mL)
  4. concentrationThe combined organic layers were concentrated
  5. customthe residue was partially purified with a 5 g silica flash cartridge (97:3 acetone/MeOH eluent with 2% DMEA)
  6. customfurther purified with HPLC (C18 column)

Sources & evidence

ORD record
ord-8bee2a3e66ba4845bd52c1ca64defbc7
Source dataset
uspto-grants-2011_12
Patent number
US08071768B2

Reaction notes

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