4-Toluenesulfonyl chloride → HCID 59359875, compound

HRID 2407180Notes

Reaction equation

HRID 2407180 reaction equation
[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([OH:11])[N:5]=[C:4]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])[N:3]=1.N1C(C)=CC(C)=CC=1C.[S:26](Cl)([C:29]1[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=1)(=[O:28])=[O:27].O.C(#N)C>C(#N)C.CCCCCC.C(Cl)Cl.O>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([O:11][S:26]([C:29]2[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[N:5]=[C:4]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])[N:3]=1

Participants

9

Reactant 4

HCID 73974-Toluenesulfonyl chlorideHCID 79532,4,6-Trimethylpyridine2×HCID 18373917Acetonitrile--water (1/1)HCID 178450380HCID 178450380, compound

Product 1

HCID 59359875HCID 59359875, compoundYield 52%

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 6342AcetonitrileSolventHCID 6344DichloromethaneSolventHCID 8058HexaneSolvent

Conditions

Temperature
60 °C

Procedure

A solution of 4-amino-2-butoxy-5-nitro-6-hydroxypyrimidine BL (nitrate salt form, 8.00 g, 27.5 mmol, 1.00 equiv, see note below) in acetonitrile (80.0 ml) was treated with 2,4,6-collidine (distilled under vacuum from NaH, 10.90 ml, 82.4 mmol, 3.00 equiv), followed by TsCl (26.21 g, 0.138 mol, 5.00 equiv). The reaction was stirred for 4 h at 60° C. By this point, 95% conversion to the product was observed using LC-MS as the analytical method (Water/Acetonitrile (with trace AcOH) 95:5-2:98 on a C-18 gemini column). The reaction was added dropwise to a 0° C. mixture of H2O (400 mL) and CH2Cl2 (200 mL). After 10 min, the mixture was extracted (3×200 mL CH2Cl2). All organic layers were combined, dried (Na2SO4), filtered, and concentrated to a total volume of 50 mL. The crude solution of product was purified by directly loading onto a 330 g column of silica gel, followed by chromatography (Eluent hexane/EtOAc 9:1→0:100) giving semipure BM contaminated with 2,4,6-Collidine. The oily solid was taken up in hexane (50 mL) and agitated, then filtered over glass frits. The filter cake was washed with several 30 mL portions of hexane until no collidine was present, giving pure product BM (5.44 g, 52% yield). 1H NMR in CDCl3 was obtained, along with LCMS analysis. 1H NMR (CDCl3, 400 MHz): δ (ppm) 7.99 (d, J=8.2 Hz, 2H), 7.95 (s, broad, 1H), 7.39 (d, J=8.2 Hz, 2H), 6.19 (s, broad, 1H), 4.26 (t, J=7.4 Hz, 2H), 2.48 (s, 3H), 1.73 (app. quintet, J=7.4 Hz, 2H), 1.43 (app. sextet, J=7.4 Hz, 2H), 0.96 (t, J=7.4 Hz, 3H).

Workup

  1. additionThe reaction was added dropwise to a 0° C.
  2. waitAfter 10 min
  3. extractionthe mixture was extracted (3×200 mL CH2Cl2)
  4. dry with materialdried (Na2SO4)
  5. filtrationfiltered
  6. concentrationconcentrated to a total volume of 50 mL
  7. customThe crude solution of product was purified
  8. customgiving semipure BM
  9. stirringagitated
  10. filtrationfiltered over glass frits
  11. washThe filter cake was washed with several 30 mL portions of hexane until no collidine
  12. customgiving pure product BM (5.44 g, 52% yield)
  13. custom1H NMR in CDCl3 was obtained, along with LCMS analysis

Sources & evidence

ORD record
ord-5a1360c45a984344b6ac33730e3c278d
Source dataset
uspto-grants-2014_08
Patent number
US08809527B2

Reaction notes

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