Pyridine → 5-[(4aR,7aR)-2-Amino-6-[5-fluoro-4-(2-hydroxypropan-2-yl)pyrimidin-2-yl]-4a,5,6,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-7a(4H)-yl]thiophene-2-carbonitrile

HRID 338159Notes

Reaction equation

HRID 338159 reaction equation
[C:1]([C:3]1[S:7][C:6]([C@:8]23[CH2:16][N:15]([C:17]4[N:22]=[C:21]([C:23]([OH:26])([CH3:25])[CH3:24])[C:20]([F:27])=[CH:19][N:18]=4)[CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH:28]C(=O)C2C=CC=CC=2)=[N:9]3)=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.Cl.CON>C(O)C>[NH2:28][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:14][N:15]([C:17]3[N:22]=[C:21]([C:23]([OH:26])([CH3:25])[CH3:24])[C:20]([F:27])=[CH:19][N:18]=3)[CH2:16][C@:8]2([C:6]2[S:7][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[N:9]=1

Participants

5

Reactant 3

HCID 1049PyridineHCID 521874O-Methylhydroxylamine hydrochlorideHCID 86762238N-{(4aR,7aR)-7a-(5-Cyanothiophen-2-yl)-6-[5-fluoro-4-(2-hydroxypropan-2-yl)pyrimidin-2-yl]-4,4a,5,6,7,7a-hexahydropyrrolo[3,4-d][1,3]thiazin-2-yl}benzamide

Product 1

HCID 867622495-[(4aR,7aR)-2-Amino-6-[5-fluoro-4-(2-hydroxypropan-2-yl)pyrimidin-2-yl]-4a,5,6,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-7a(4H)-yl]thiophene-2-carbonitrileYield 90%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Conditions

Temperature
55 °C

Procedure

To a stirred solution of N-{(4aR,7aR)-7a-(5-cyanothiophen-2-yl)-6-[5-fluoro-4-(2-hydroxypropan-2-yl)pyrimidin-2-yl]-4,4a,5,6,7,7a-hexahydropyrrolo[3,4-d][1,3]thiazin-2-yl}benzamide (364 mg, 0.697 mmol) in ethanol (14 mL) is added pyridine (563 μL, 6.96 mmol) and O-methylhydroxylamine hydrochloride (582 mg, 6.96 mmol). The solution is heated to 55° C. under an atmosphere of nitrogen for 21 hours. The resulting solution is allowed to cool for a few minutes then concentrated under reduced pressure. Dichloromethane (30 mL) is added and again the solution is concentrated under reduced pressure. The residue is diluted with ethyl acetate (50 mL), water (25 mL), and saturated aqueous sodium bicarbonate (10 mL). The phases are separated and the ethyl acetate phase is dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica gel chromatography, eluting with dichloromethane/ethyl acetate, 70:30 for 20 minutes, and then a gradient to 0:100 to give the title compound (261 mg, 90%) as a white foam. MS/ES (m/z) 419.0 (M+H).

Workup

  1. temperatureto cool for a few minutes
  2. concentrationthen concentrated under reduced pressure
  3. additionDichloromethane (30 mL) is added
  4. concentrationagain the solution is concentrated under reduced pressure
  5. additionThe residue is diluted with ethyl acetate (50 mL), water (25 mL), and saturated aqueous sodium bicarbonate (10 mL)
  6. customThe phases are separated
  7. dry with materialthe ethyl acetate phase is dried over sodium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated under reduced pressure
  10. customThe residue is purified by silica gel chromatography
  11. washeluting with dichloromethane/ethyl acetate, 70:30 for 20 minutes

Sources & evidence

ORD record
ord-6cd358322d38416ba38cfeeae3ef59f9
Source dataset
uspto-grants-2014_11
Patent number
US08889856B2

Reaction notes

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