Ethanol → AZD9977

HRID 1054183Notes

Reaction equation

HRID 1054183 reaction equation
[F:1][C:2]1[CH:30]=[CH:29][C:5]2[N:6]([C:16]([C:18]3[CH:19]=[CH:20][C:21]4[O:26][CH2:25][C:24](=[O:27])[NH:23][C:22]=4[CH:28]=3)=[O:17])[C@@H:7]([CH2:10][C:11]([O:13]CC)=O)[CH2:8][O:9][C:4]=2[CH:3]=1.[CH3:31][NH2:32].C(O)C>CO.CC(O)C>[F:1][C:2]1[CH:30]=[CH:29][C:5]2[N:6]([C:16]([C:18]3[CH:19]=[CH:20][C:21]4[O:26][CH2:25][C:24](=[O:27])[NH:23][C:22]=4[CH:28]=3)=[O:17])[C@@H:7]([CH2:10][C:11]([NH:32][CH3:31])=[O:13])[CH2:8][O:9][C:4]=2[CH:3]=1

Participants

6

Reactant 3

HCID 702EthanolHCID 6329MethylamineHCID 131736335Ethyl {(3S)-7-fluoro-4-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl]-3,4-dihydro-2H-1,4-benzoxazin-3-yl}acetate3×

Product 1

HCID 118599727AZD9977

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 3776IsopropanolSolvent

Procedure

Ethyl {(3S)-7-fluoro-4-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl]-3,4-dihydro-2H-1,4-benzoxazin-3-yl}acetate (Intermediate 14a, 1648 g) was taken up in methanol (10 L). Methylamine in ethanol (33 wt %, 20 eq., 7490 mL) was added at <30° C. The resulting solution was stirred at rt for 18 h. LCMS analysis indicated the reaction was not complete. The reaction was stirred for a further 4 h at rt after which HPLC indicated that <1% Intermediate 14a and its corresponding methyl ester remained (combined). The solvent was removed in vacuo to give the crude product as a tan solid (1719.2 g). This was combined with 376 g crude product from another batch and the combined crude product (2095 g) was taken up in IPA (20950 mL) and heated to reflux. A solution was not obtained. The suspension was sampled and the sample cooled and filtered for XRPD analysis. This indicated the product was of the desired form (type 2). HPLC analysis of the filtered material indicated a purity of 99.2% confirming purification had been successful. The suspension was cooled to room temperature over night. The solid was filtered, washed with IPA (3×2 L) and pulled dry. Further drying in a vacuum oven at 60° C. yielded the title product as an off-white solid (1632.5 g). 1H NMR indicated a purity of >95% (0.18% residual IPA). This material was combined with the product from another smaller scale recrystallisation (input 250 g crude) to give a total of 1820.7 g of the title compound.

Workup

  1. stirringThe reaction was stirred for a further 4 h at rt after which HPLC
  2. customThe solvent was removed in vacuo
  3. customto give the crude product as a tan solid (1719.2 g)
  4. temperatureheated to reflux
  5. customA solution was not obtained
  6. aliquotThe suspension was sampled
  7. temperaturethe sample cooled
  8. filtrationfiltered for XRPD analysis
  9. custompurification
  10. temperatureThe suspension was cooled to room temperature over night
  11. filtrationThe solid was filtered
  12. washwashed with IPA (3×2 L)
  13. custompulled dry
  14. customFurther drying in a vacuum oven at 60° C.

Sources & evidence

ORD record
ord-69b9167fe5824bb39edb1b84f0ae0247
Source dataset
uspto-grants-2016_07
Patent number
US09394291B2

Reaction notes

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