3-Oxo-azetidine-1-carboxylic acid tert-butyl ester → HCID 71765515, compound

HRID 626828Notes

Reaction equation

HRID 626828 reaction equation
[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:24]4[O:23][CH:22]([CH3:25])[CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][C:18]=4[C:17]([F:33])=[C:16]([Cl:34])[CH:15]=3)[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12.O=[C:36]1[CH2:39][N:38]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:37]1.C([BH3-])#N.[Na+]>Cl.O1CCOCC1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:24]4[O:23][CH:22]([CH3:25])[CH2:21][N:20]([CH:36]5[CH2:37][N:38]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:39]5)[CH2:19][C:18]=4[C:17]([F:33])=[C:16]([Cl:34])[CH:15]=3)[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12

Participants

6

Reactant 3

HCID 15194043-Oxo-azetidine-1-carboxylic acid tert-butyl esterHCID 5003444Sodium cyanoborohydrideHCID 86697521HCID 86697521, compound

Product 1

HCID 71765515HCID 71765515, compound

Reagents, catalysts & solvents 2

HCID 313Hydrochloric AcidSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
60 °C

Procedure

tert-Butyl 9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-fluoro-2-methyl-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (75 mg, 0.15 mmol) was stirred in 4 N HCl in dioxane (5 mL) and evaporated. The residue was stirred in methanol (4 mL) and tert-butyl 3-oxoazetidine-1-carboxylate (110 mg, 0.61 mmol) was added. Sodium cyanoborohydride (86 mg, 1.4 mmol) was added and the mixture was warmed to 60° C. overnight and evaporated. Water was added and the mixture was extracted with ethyl acetate. The extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The reactions were purified by prep HPLC on C-18 column eluting water:acetonitrile gradient buffered pH 10 to give two diastereomers (peak #1 and 2): Peak #1 (Example 26): LCMS calculated for C26H34ClFN7O3 (M+H)+: m/z=546.2; found: 546.2 1H NMR (300 MHz, CD3OD): δ 8.14 (s, 1 H), 7.38 (m, 1 H), 6.32 (m, 1 H), 4.11 (m, 1 H), 3.95 (m, 2 H), 3.78 (m, 2 H), 3.50 (m, 2 H), 2.92 (m, 2 H), 2.65 (m, 1 H), 2.60 (s, 3 H), 1.80 (m, 3 H), 1.42 (s, 9 H), 1.38 (m, 3 H). Peak #2 (Example 27): LCMS calculated for C26H34ClFN7O3 (M+H)+: m/z=546.2; Found: 546.2.

Workup

  1. customevaporated
  2. customevaporated
  3. additionWater was added
  4. extractionthe mixture was extracted with ethyl acetate
  5. washThe extracts were washed with brine
  6. dry with materialdried over sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customThe reactions were purified by prep HPLC on C-18 column
  10. washeluting water
  11. customacetonitrile gradient buffered pH 10 to give two diastereomers (peak #1 and 2)

Sources & evidence

ORD record
ord-a9af9792090642aa9119dee731f57b09
Source dataset
uspto-grants-2016_04
Patent number
US09309251B2

Reaction notes

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