Thiourea → (4aS,8aS)-8a-(2,4-difluoro-5-(pyrimidin-5-yl)phenyl)-4,4a,5,6,7,8a-hexahydropyrano[2,3-d][1,3]thiazin-2-amine

HRID 1907434Notes

Reaction equation

HRID 1907434 reaction equation
[Si](O[CH2:9][CH2:10][CH2:11][C:12](=[CH2:29])[C:13]([C:15]1[CH:20]=[C:19]([C:21]2[CH:22]=[N:23][CH:24]=[N:25][CH:26]=2)[C:18]([F:27])=[CH:17][C:16]=1[F:28])=[O:14])(C(C)(C)C)(C)C.[NH2:30][C:31]([NH2:33])=[S:32].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CC(O)=O.C1COCC1>[F:28][C:16]1[CH:17]=[C:18]([F:27])[C:19]([C:21]2[CH:26]=[N:25][CH:24]=[N:23][CH:22]=2)=[CH:20][C:15]=1[C@@:13]12[O:14][CH2:9][CH2:10][CH2:11][C@@H:12]1[CH2:29][S:32][C:31]([NH2:33])=[N:30]2

Participants

6

Reactant 3

HCID 2723790ThioureaHCID 2724141Tetrabutylammonium FluorideHCID 866853465-((Tert-butyldimethylsilyl)oxy)-1-(2,4-difluoro-5-(pyrimidin-5-yl)phenyl)-2-methylenepentan-1-one

Product 1

HCID 86762169(4aS,8aS)-8a-(2,4-difluoro-5-(pyrimidin-5-yl)phenyl)-4,4a,5,6,7,8a-hexahydropyrano[2,3-d][1,3]thiazin-2-amineYield 2.354%

Reagents, catalysts & solvents 2

HCID 176Acetic AcidSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a solution of 5-((tert-butyldimethylsilyl)oxy)-1-(2,4-difluoro-5-(pyrimidin-5-yl)phenyl)-2-methylenepentan-1-one (Preparation 16, 606 mg, 1.448 mmol) in HOAc (7239 μL) was added thiourea (441 mg, 5.79 mmol), and a suspension was formed. The reaction mixture was stirred at rt for 12 h, and a clear yellowish solution was formed. TBAF (2172 μL, 2.172 mmol) in THF was added, and the reaction mixture was stirred at rt for 5 h, followed by heating at 60° C. for 12 h. This crude reaction mixture was purified by reverse phase preparative HPLC on a Luna C18 column (10 μM, 30×100 mm) eluting with 0-100% B (A: 10% MeOH/90% water/0.1% TFA; B: 90% MeOH/10% water/0.1% TFA) over 12 min to give a mixture of two isomers. This mixture was purified by preparative TLC on silica gel (0.50 mm thickness) eluting with 90% DCM/9% MeOH/1% ammonium hydroxide to give (4aS,8aS)-8a-(2,4-difluoro-5-(pyrimidin-5-yl)phenyl)-4,4a,5,6,7,8a-hexahydropyrano[2,3-d][1,3]thiazin-2-amine (13 mg, 0.034 mmol, 2.354% yield) as a white solid. 1H NMR (500 MHz, CHLOROFORM-d) δ 9.22 (s, 1H), 8.91 (d, J=1.4 Hz, 2H), 7.43 (t, J=8.5 Hz, 1H), 7.02 (dd, J=10.8, 10.2 Hz, 1H), 5.0-4.5 (broad s, 2H), 4.00-3.92 (m, 1H), 3.88-3.80 (m, 1H), 2.95 (dd, J=12.6, 4.0 Hz, 1H), 2.81-2.71 (m, 1H), 2.67 (dd, J=12.6, 2.8 Hz, 1H), 2.01-1.83 (m, 2H), 1.75-1.57 (m, 2H). MS (M+H)+: 363.03.

Workup

  1. customa suspension was formed
  2. customa clear yellowish solution was formed
  3. stirringthe reaction mixture was stirred at rt for 5 h
  4. temperatureby heating at 60° C. for 12 h
  5. customThis crude reaction mixture
  6. customwas purified by reverse phase preparative HPLC on a Luna C18 column (10 μM, 30×100 mm)
  7. washeluting with 0-100% B (A: 10% MeOH/90% water/0.1% TFA
  8. customB: 90% MeOH/10% water/0.1% TFA) over 12 min to give
  9. additiona mixture of two isomers
  10. customThis mixture was purified by preparative TLC on silica gel (0.50 mm thickness)
  11. washeluting with 90% DCM/9% MeOH/1% ammonium hydroxide

Sources & evidence

ORD record
ord-b7bc2b9ba4af40f898f69a45cf72f844
Source dataset
uspto-grants-2013_12
Patent number
US08598161B2

Reaction notes

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