4-Methylmorpholine → HCID 131727610, compound

HRID 731312Notes

Reaction equation

HRID 731312 reaction equation
C(O[C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=[O:5])C.[CH3:20][S:21]([NH:24][C:25]1[CH:40]=[CH:39][C:28]2[NH:29][C:30]([CH2:35][C:36](O)=[O:37])=[CH:31][S:32](=[O:34])(=[O:33])[C:27]=2[CH:26]=1)(=[O:23])=[O:22].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.[H-].[Na+]>CN(C)C=O.Cl>[F:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][N:11]2[C@@H:7]3[C@@H:6]([CH2:10][CH2:9][CH2:8]3)[C:4]([OH:5])=[C:35]([C:30]3[NH:29][C:28]4[CH:39]=[CH:40][C:25]([NH:24][S:21]([CH3:20])(=[O:23])=[O:22])=[CH:26][C:27]=4[S:32](=[O:33])(=[O:34])[CH:31]=3)[C:36]2=[O:37])=[CH:18][CH:17]=1

Participants

8

Reactant 5

HCID 79724-MethylmorpholineHCID 24758Sodium hydrideHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 25231427HCID 25231427, compoundHCID 59853605(7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1lambda6-benzo[1,4]thiazin-3-yl)-acetic acid

Product 1

HCID 131727610HCID 131727610, compoundYield 21.3%

Reagents, catalysts & solvents 2

HCID 313Hydrochloric AcidSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
25 °C

Procedure

A solution of cis-2-(4-fluoro-benzylamino)-cyclopentanecarboxylic acid ethyl ester (prepared as described in Example 11, 154 mg, 0.580 mmol), (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,4]thiazin-3-yl)-acetic acid (175 mg, 0.527 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (117 mg, 0.609 mmol) in anhydrous N,N-dimethylformamide (6 mL) was treated with N-methylmorpholine (123 mg, 134 μL, 1.22 mmol). The reaction was stirred for 1 h at 25° C., diluted with 1.0 M aqueous hydrochloric acid solution (20 mL), and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was taken up in ethanol (6 mL) and treated with a 60% oil dispersion of sodium hydride (93 mg, 3.87 mmol). The reaction was heated at 70° C. for 1 h, allowed to cool to 25° C., and quenched with 1.0 M aqueous hydrochloric acid solution (50 mL). The resulting mixture was extracted with ethyl acetate (3×50 mL), and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude oil was purified by prep-HPLC [Column: Thomson C18 ODSA, 5 micron, 50×21.2 mm ID; 45-70% acetonitrile in water; 30 mL/min flow rate for 4 min run] to afford the desired product, cis-N-{3-[1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-2,4a,5,6,7,7a-hexahydro-1H-[1]pyrindin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,4]thiazin-7-yl}-methanesulfonamide (60 mg, 0.112 mmol, 21%), as a light yellow solid. 1H NMR (400 MHz, CDCl3) 1H NMR (400 MHz, Acetone-d6) δ: 1.34-1.47 (m, 1H), 1.50-1.91 (m, 4H), 2.32-2.42 (m, 1H), 2.96-3.03 (m, 1H), 3.11 (s, 3H), 3.83-3.94 (m, 1H), 4.54-4.67 (m, 1H), 4.97-5.07 (m, 1H), 5.37-5.78 (m, 2H), 7.07-7.14 (m, 2H), 7.36-7.54 (m, 3H), 7.66-7.71 (m, 1H), 7.81-7.83 (m, 1H), 8.95 (bs, 1H). LC-MS calcd for C24H24FN3O6S2 533.6, found 534.3 [M+H+].

Workup

  1. extractionextracted with ethyl acetate (3×50 mL)
  2. dry with materialThe combined organic layers were dried over magnesium sulfate
  3. filtrationfiltered
  4. concentrationconcentrated in vacuo
  5. temperatureThe reaction was heated at 70° C. for 1 h
  6. temperatureto cool to 25° C.
  7. customquenched with 1.0 M aqueous hydrochloric acid solution (50 mL)
  8. extractionThe resulting mixture was extracted with ethyl acetate (3×50 mL)
  9. dry with materialthe combined organic layers were dried over magnesium sulfate
  10. filtrationfiltered
  11. concentrationconcentrated in vacuo
  12. customThe crude oil was purified by prep-HPLC [Column: Thomson C18 ODSA, 5 micron, 50×21.2 mm ID; 45-70% acetonitrile in water; 30 mL/min flow rate for 4 min run]

Sources & evidence

ORD record
ord-9aadea0261bd4fc68bf28b111c567351
Source dataset
uspto-grants-2009_09
Patent number
US07582626B2

Reaction notes

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