Diisopropylethylamine → N-((1R,2S,5R)-5-(isopropylamino)-2-((3S)-2-oxo-3-((6-(trifluoromethyl)-4-quinazolinyl)amino)-1-pyrrolidinyl)cyclohexyl)acetamide

HRID 2242331Notes

Reaction equation

HRID 2242331 reaction equation
[NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@@H:10]([N:13]([CH:15]([CH3:17])[CH3:16])C)[CH2:9][C@H:8]2[NH:18][C:19](=[O:21])[CH3:20])[C:3]1=[O:22].C(N(C(C)C)CC)(C)C.Cl[C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([C:43]([F:46])([F:45])[F:44])[CH:41]=2)[N:36]=[CH:35][N:34]=1>CC#N>[CH:15]([NH:13][C@H:10]1[CH2:9][C@@H:8]([NH:18][C:19](=[O:21])[CH3:20])[C@@H:7]([N:4]2[CH2:5][CH2:6][C@H:2]([NH:1][C:33]3[C:42]4[C:37](=[CH:38][CH:39]=[C:40]([C:43]([F:45])([F:46])[F:44])[CH:41]=4)[N:36]=[CH:35][N:34]=3)[C:3]2=[O:22])[CH2:12][CH2:11]1)([CH3:16])[CH3:17]

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 210750954-Chloro-6-(trifluoromethyl)quinazolineHCID 44185161N-((1R,2S,5R)-2-((S)-3-amino-2-oxopyrrolidin-1-yl)-5-(isopropyl(methyl)amino)cyclohexyl)acetamide

Product 1

HCID 24794624N-((1R,2S,5R)-5-(isopropylamino)-2-((3S)-2-oxo-3-((6-(trifluoromethyl)-4-quinazolinyl)amino)-1-pyrrolidinyl)cyclohexyl)acetamideYield 85%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent2×

Procedure

Example 1, Alternative Preparation, Step 8: To a mixture of acetamide 11 (28.5 g, HCl salt, 73.6% free base assay), acetonitrile (100 mL), N,N,-di-isopropyl-N-ethylamine (61 mL) at room temperature was added a solution of 13 (˜21.2 g) in MeCN (˜450 mL). The homogeneous mixture was held overnight. Upon reaction completion (HPLC), the mixture was concentrated in vacuo to approx. 125 mL. A 9.5% aqueous solution of acetic acid (240 mL) was added and the aqueous phase was extracted with methylene chloride. The aqueous phase was separated and methyl tert-butyl ether (450 mL) was added, followed by 2N aqueous lithium hydroxide solution to adjust to pH>11.5. The organic layer was separated, washed with water and filtered. Approx. half of the ether phase was diluted with methyl tert-butyl ether (˜250 mL) and concentrated in vacuo. Heptane (45 mL) was added slowly below 60° C., followed by seed crystals of Example 1 (0.4 g). Additional heptane (125 mL) was added and the mixture was slowly cooled to room temperature and the resulting slurry was held overnight. The product was isolated by filtration, the cake was washed with heptane and dried in vacuo to constant weight to give N-((1R,2S,5R)-5-(isopropylamino)-2-((S)-2-oxo-3-(6-(trifluoromethyl)-quin-azolin-4-ylamino)pyrrolidin-1-yl)cyclohexyl)acetamide 14 (15.0 g, 85% yield).

Workup

  1. customExample 1, Alternative Preparation, Step 8
  2. customUpon reaction completion (HPLC)
  3. concentrationthe mixture was concentrated in vacuo to approx. 125 mL
  4. additionA 9.5% aqueous solution of acetic acid (240 mL) was added
  5. extractionthe aqueous phase was extracted with methylene chloride
  6. customThe aqueous phase was separated
  7. additionmethyl tert-butyl ether (450 mL) was added
  8. customThe organic layer was separated
  9. washwashed with water
  10. filtrationfiltered
  11. additionApprox. half of the ether phase was diluted with methyl tert-butyl ether (˜250 mL)
  12. concentrationconcentrated in vacuo
  13. additionHeptane (45 mL) was added slowly below 60° C.
  14. additionAdditional heptane (125 mL) was added
  15. waitthe resulting slurry was held overnight
  16. customThe product was isolated by filtration
  17. washthe cake was washed with heptane
  18. customdried in vacuo to constant weight

Sources & evidence

ORD record
ord-e7fdfe4dfcf04da686390b494b44c1a8
Source dataset
uspto-grants-2010_03
Patent number
US07671062B2

Reaction notes

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