Methanol → HCID 86633436, compound

HRID 1172805Notes

Reaction equation

HRID 1172805 reaction equation
[Cl:1][C:2]1[N:6]2[C:7]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([C:20]([N:22]4[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]4)=[O:21])[CH:14]=3)=[CH:8][NH:9][C:10](=[O:11])[C:5]2=[CH:4][C:3]=1[Cl:29].Cl.[F:31][C:32]1([F:36])[CH2:35][NH:34][CH2:33]1.CCN(C(C)C)C(C)C.[OH2:46].[CH3:47][OH:48]>C1COCC1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[F:31][C:32]([F:36])([F:19])[C:47]([O-:48])=[O:46].[Cl:1][C:2]1[N:6]2[C:7]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([CH:14]=3)[C:20]([N:22]3[CH2:23][CH2:24][CH:25]([NH+:34]4[CH2:35][C:32]([F:36])([F:31])[CH2:33]4)[CH2:26][CH2:27]3)=[O:21])=[CH:8][NH:9][C:10](=[O:11])[C:5]2=[CH:4][C:3]=1[Cl:29]

Participants

8

Reactant 5

HCID 887MethanolHCID 962WaterHCID 81531DiisopropylethylamineHCID 27582473,3-Difluoroazetidine hydrochlorideHCID 68688927HCID 68688927, compound

Product 1

HCID 86633436HCID 86633436, compound

Reagents, catalysts & solvents 2

HCID 11026Titanium isopropoxideCatalystHCID 8028TetrahydrofuranSolvent

Procedure

To a solution of 6,7-dichloro-4-{4-fluoro-3-[(4-oxopiperidin-1-yl)carbonyl]benzyl}pyrrolo[1,2-a]pyrazin-1(2H)-one (Example 232, which was prepared as described in Example 13) (1 eq) in THF (0.6 M) were added titanium(IV) isopropoxide (1.6 eq), 3,3-difluoroazetidine hydrochloride (1.6 eq) and DIPEA (1.6 eq). The reaction mixture was stirred for 30 minutes at RT and then a solution of NaBH3(CN) (1.3 eq) in MeOH (0.16 M) was added. After 30 minutes water was added, and the resulting precipitate was filtered and washed with MeOH. The filtrate was evaporated and purified by RP-HPLC (column Symmetry RP 18, 7 μm, 19×300 mm, gradient A: H2O+0.1% TFA; B: MeCN+0.1% TFA) and the pooled fractions were evaporated under reduced pressure to yield the title compound. 1H NMR (300 MHz, DMSO-d6+TFA, 300K) δ 10.94-10.88 (1H, m), 7.38-7.10 (4H, m), 6.64-6.55 (1H, m), 4.91-4.78 (4H, m), 4.62-4.50 (1H, m), 4.44-4.25 (2H, m), 3.61-3.32 (2H, m), 3.10-2.90 (1H, m), 2.82-2.66 (1H, m), 2.10-1.72 (2H, m), 1.48-1.0 (2H, m). MS (ES+) C23H21Cl2F3N4O2 requires: 512/514, found: 513/515 (M+H)+.

Workup

  1. filtrationthe resulting precipitate was filtered
  2. washwashed with MeOH
  3. customThe filtrate was evaporated
  4. custompurified by RP-HPLC (column Symmetry RP 18, 7 μm, 19×300 mm
  5. customB: MeCN+0.1% TFA) and the pooled fractions were evaporated under reduced pressure

Sources & evidence

ORD record
ord-64ebebdbb7ea4b17a5e48410031e4ba9
Source dataset
uspto-grants-2010_11
Patent number
US07834015B2

Reaction notes

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