Sodium Iodide → (2S,3S,5R)-4-[5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoyloxymethoxycarbonyl]-2-(3,5-difluorophenyl)-3,5-dimethyl-2-morpholinol

HRID 2357759Notes

Reaction equation

HRID 2357759 reaction equation
Cl[CH2:2][O:3][C:4]([N:6]1[C@H:11]([CH3:12])[CH2:10][O:9][C@:8]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)([OH:13])[C@@H:7]1[CH3:22])=[O:5].[CH:23]1[CH:24]=[C:25]([CH2:28][NH:29][C:30]2[C:35]([C:36]([OH:38])=[O:37])=[CH:34][C:33]([S:39]([NH2:42])(=[O:41])=[O:40])=[C:32]([Cl:43])[CH:31]=2)[O:26][CH:27]=1.[Cs].[I-].[Na+].CCCCCCC>O1CCCC1.C(OCC)(=O)C>[NH2:42][S:39]([C:33]1[C:32]([Cl:43])=[CH:31][C:30]([NH:29][CH2:28][C:25]2[O:26][CH:27]=[CH:23][CH:24]=2)=[C:35]([CH:34]=1)[C:36]([O:38][CH2:2][O:3][C:4]([N:6]1[C@H:11]([CH3:12])[CH2:10][O:9][C@:8]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)([OH:13])[C@@H:7]1[CH3:22])=[O:5])=[O:37])(=[O:41])=[O:40]

Participants

7

Reactant 4

HCID 5238Sodium IodideHCID 8900HeptaneHCID 59613210(2S,3S,5R)-2-(3,5-difluorophenyl)-2-hydroxy-3,5-dimethylmorpholine-4-carboxylic acid chloromethyl esterHCID 86613437Furosemide cesium

Product 1

HCID 16214883(2S,3S,5R)-4-[5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoyloxymethoxycarbonyl]-2-(3,5-difluorophenyl)-3,5-dimethyl-2-morpholinolYield 13.3%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
60 °C

Procedure

To a stirring solution of (2S,3S,5R)-2-(3,5-difluorophenyl)-2-hydroxy-3,5-dimethylmorpholine-4-carboxylic acid chloromethyl ester (1410) (2.24 g, 6.67 mmol) in 150 mL of anhydrous tetrahydrofuran was added the furosemide cesium salt (10c) (3.09 gm, 6.67 mmol) and sodium iodide (1.10 gm, 7.34 mmol). The mixture was heated to ˜60° C. and monitored by TLC (1:1 heptane:ethyl acetate). After heating for 6 hours, TLC analysis indicated a slowing down of product formation with starting materials remaining. The reaction was halted so as not to allow by-product formation. The solvent was removed from the crude yellow mixture, and it was dried onto silica gel. This crude material was purified on an Optix Companion Automated Chromatography system using an 80 gm silica cartridge and eluting with ethyl acetate/heptane (0 to 70% over 50 minutes). This material was dried on a vacuum pump for 24 hours and afforded 0.560 g of (2S,3S,5R)-4-[5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoyloxymethoxycarbonyl]-2-(3,5-difluorophenyl)-3,5-dimethyl-2-morpholinol (1420) as a light yellow foamy solid. Melting point range was 105° C. to 110° C. Elemental analysis calculated for [C26H26N3 0.3 EtOAc]: C, 49.76; H, 4.36; N, 6.4. found C, 50.08; H, 4.65; N, 6.23. 1H NMR (400 MHz, CDCl3) δ 0.86-0.89 (t, 3H), 1.34 (m, 3H), 3.60-3.67 (m, 1H), 4.23 (m, 1H), 4.33 (m, 1H), 4.45-4.46 (d, 2H), 4.47 (s, 1H), 5.07-5.11 (d, 2H), 6.00-6.05 (dd, 2H), 6.28 (s, 1H), 6.35 (s, 1H), 6.75-6.79 (t, 1H), 6.89 (m, 1H), 7.12-7.14 (br. d, 2H), 7.37-7.39 (d, 1H), 8.53 (br. d., 1H), 8.63 (s, 1H).

Workup

  1. temperatureAfter heating for 6 hours
  2. customThe solvent was removed from the crude yellow mixture, and it
  3. customwas dried onto silica gel
  4. customThis crude material was purified on an Optix Companion Automated Chromatography system
  5. washeluting with ethyl acetate/heptane (0 to 70% over 50 minutes)
  6. customThis material was dried on a vacuum pump for 24 hours

Sources & evidence

ORD record
ord-c0cdc877811d4c418151490d3ae1b264
Source dataset
uspto-grants-2010_07
Patent number
US07763612B2

Reaction notes

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