L-Prolinol → 4-{7-[2-(2-Hydroxymethyl-pyrrolidin-1-yl)-ethoxy]-quinazolin-4-yl}-piperidine-1-carboxylic acid (4-pyrrolidin-1-yl-phenyl)-amide

HRID 657267Notes

Reaction equation

HRID 657267 reaction equation
C([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]OS(C)(=O)=O)=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[NH:32]1[CH2:36][CH2:35][CH2:34][C@H:33]1[CH2:37][OH:38].Cl.[N+](C1C=CC(OC(=O)[NH:51][C:52]2[CH:57]=[CH:56][C:55]([N:58]3[CH2:62][CH2:61][CH2:60][CH2:59]3)=[CH:54][CH:53]=2)=CC=1)([O-])=O>CS(C)=O.O>[N:58]1([C:55]2[CH:56]=[CH:57][C:52]([NH:51][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][N:32]6[CH2:36][CH2:35][CH2:34][CH:33]6[CH2:37][OH:38])=[CH:21][CH:22]=5)[N:17]=[CH:16][N:15]=4)[CH2:10][CH2:9]3)=[O:5])=[CH:53][CH:54]=2)[CH2:59][CH2:60][CH2:61][CH2:62]1

Participants

6

Reactant 3

HCID 640091L-ProlinolHCID 595517384-[7-(2-Methanesulfonyloxy-ethoxy)-quinazolin-4-yl]-piperidine-1-carboxylic acid tert-butyl esterHCID 68891845HCID 68891845, compound

Product 1

HCID 732186114-{7-[2-(2-Hydroxymethyl-pyrrolidin-1-yl)-ethoxy]-quinazolin-4-yl}-piperidine-1-carboxylic acid (4-pyrrolidin-1-yl-phenyl)-amide

Reagents, catalysts & solvents 2

HCID 679Dimethyl SulfoxideSolventHCID 962WaterSolvent

Conditions

Temperature
120 °C

Procedure

To a solution of 4-[7-(2-methanesulfonyloxy-ethoxy)-quinazolin-4-yl]-piperidine-1-carboxylic acid tert-butyl ester (40.6 mg, 0.09 mmol) in DMSO (0.4 mL) was added (S)-(+)-2-pyrrolidinemethanol (90.9 mg, 0.9 mmol). The mixture was stirred at 120° C. overnight and subsequently partitioned between EtOAc and water. The combined organic extracts were washed with brine, dried over Na2SO4 and evaporated. The residue was treated with 50% TFA/CH2Cl2 (8 mL) for 2 h, the solvents (TFA/CH2Cl2) were removed under reduced pressure and half of the residue was re-dissolved in CH2Cl2. DIPEA (55 μL) was added to the above solution, followed by (4-pyrrolidin-1-yl-phenyl)-carbamic acid 4-nitro-phenyl ester hydrochloride (19.6 mg, 0.054 mmol), which was prepared as described in Example 74a. The reaction mixture was stirred for 1 h, diluted with water. The organic phase was collected and the solvents were evaporated. The crude residue was purified by flash column chromatography on silica gel (15% MeOH/EtOAc as eluent) to afford a white solid (10 mg, 40.8% overall yield). 1H NMR (CD3OD) δ 9.03 (s, 1H), 8.35 (d, J=9.44 Hz, 1H), 7.40 (dd, J=9.25 and 2.54 Hz, 1H), 7.34 (d, J=2.48 Hz, 1H), 7.13 (d, J=8.87 Hz, 2H), 6.54 (d, J=8.96 Hz, 2H), 4.29-4.36 (4H), 3.92 (m, 1H), 3.60 (dd, J=10.98 and 4.81 Hz, 1H), 3.52 (dd, J=11.00 and 5.90 Hz, 1H), 3.40 (m, 1H), 3.27 (m, 1H), 3.24 (t, J=6.61 Hz, 4H), 3.15 (td, J=12.57 and 2.55 Hz, 2H), 2.88 (dt, J=13.67 and 5.50 Hz, 1H), 2.71 (m, 1H), 2.47 (m, 1H), 1.90-2.09 (9H), 1.79 (m, 2H), 1.66 (m, 1H). Calcd for C31H41N6O3 (MH+) 545.3, found 545.3.

Workup

  1. customsubsequently partitioned between EtOAc and water
  2. washThe combined organic extracts were washed with brine
  3. dry with materialdried over Na2SO4
  4. customevaporated
  5. additionThe residue was treated with 50% TFA/CH2Cl2 (8 mL) for 2 h
  6. customthe solvents (TFA/CH2Cl2) were removed under reduced pressure and half of the residue
  7. dissolutionwas re-dissolved in CH2Cl2
  8. additionDIPEA (55 μL) was added to the above solution
  9. customwas prepared
  10. stirringThe reaction mixture was stirred for 1 h
  11. customThe organic phase was collected
  12. customthe solvents were evaporated
  13. customThe crude residue was purified by flash column chromatography on silica gel (15% MeOH/EtOAc as eluent)
  14. customto afford
  15. customa white solid (10 mg, 40.8% overall yield)

Sources & evidence

ORD record
ord-549ab20e8f534ab69de421646538d6d3
Source dataset
uspto-grants-2011_12
Patent number
US08071768B2

Reaction notes

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