4-Methylmorpholine → [Butyl-(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzoyl)-amino]-acetic acid ethyl ester

HRID 1061329Notes

Reaction equation

HRID 1061329 reaction equation
O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.Cl.CN(C)CCCN=C=NCC.[CH2:29]([O:31][C:32](=[O:39])[CH2:33][NH:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH3:30].CN1CCOCC1.[NH2:47][CH2:48][C@@H:49]([C:51]1[CH:52]=[CH:53][C:54]([OH:62])=[C:55]([NH:57][S:58]([CH3:61])(=[O:60])=[O:59])[CH:56]=1)[OH:50].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.CN(C)C=O.C(O)(=O)C>[CH2:29]([O:31][C:32](=[O:39])[CH2:33][N:34]([CH2:35][CH2:36][CH2:37][CH3:38])[C:12](=[O:14])[C:11]1[CH:10]=[CH:9][C:8]([N:5]2[CH2:4][CH2:3][CH:2]([NH:47][CH2:48][C@H:49]([OH:50])[C:51]3[CH:52]=[CH:53][C:54]([OH:62])=[C:55]([NH:57][S:58]([CH3:61])(=[O:60])=[O:59])[CH:56]=3)[CH2:7][CH2:6]2)=[CH:16][CH:15]=1)[CH3:30]

Participants

11

Reactant 7

HCID 79724-MethylmorpholineHCID 516892Sodium BicarbonateHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 5049666Sodium triacetoxyborohydrideHCID 10607047Ethyl 2-(butylamino)acetateHCID 12047933(R)-N-(5-(2-amino-1-hydroxyethyl)-2-hydroxyphenyl)methanesulfonamideHCID 220640224-(4-Oxopiperidin-1-yl)benzoic acid

Product 1

HCID 10627245[Butyl-(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzoyl)-amino]-acetic acid ethyl ester

Reagents, catalysts & solvents 3

HCID 176Acetic AcidSolventHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Procedure

A mixture of 4-(4-oxo-piperidine-1-yl)-benzoic acid (which was obtained in Example 151) (0.30 g, 1.37 mmol), 1-[3-(dimethylamino)propyl-3-ethylcarbodiimide hydrochloride (0.53, 2.74 mmol) and N-butylglycine ethyl ester (0.44 g, 2.7 mmol) was stirred in methylene chloride (70 mL). N-methylmorpholine (0.28 g, 2.74 mol) was added dropwise and the mixture was stirred overnight. The mixture was then washed with 0.05 N hydrochloric acid and water. The resulting solution was dried with magnesium sulfate and concentrated to give a gum. The gum was dissolved in dimethylformamide (15 mL) and then treated with N-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (0.25 g, 1 mmol) (which was obtained in Example 10), sodium triacetoxyborohydride (0.85 g, 4 mmol) and acetic acid (0.3 mL). After stirring at room temperature under a nitrogen atmosphere for 2 hours the mixture was poured into a saturated aqueous sodium bicarbonate. The aqueous layer was extracted with n-butanol and the concentrated gum was purified by silica gel chromatography (methanol/methylene chloride) to give the title compound as a white solid; mp >60° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 0.70-1.60 (m, 12H), 1.75-1.95 (m, 2H), 2.50-3.50 (m, 7H), 2.91 (s, 3H), 3.60-3.75 (m, 2H), 4.00-4.15 (m, 4H), 4.47 (dd, J=8.0, 4.3 Hz, 1H), 6.81 (d, J=8.5 Hz, 1H), 6.90-7.00 (m, 3H), 7.05-7.25 (m, 3H); MS (ES) m/z: 591.3 (MH+); HRMS Calcd. for C29H43N4O7S(MH+): 591.2847. Found: 591.2840.

Workup

  1. washThe mixture was then washed with 0.05 N hydrochloric acid and water
  2. dry with materialThe resulting solution was dried with magnesium sulfate
  3. concentrationconcentrated
  4. customto give a gum
  5. stirringAfter stirring at room temperature under a nitrogen atmosphere for 2 hours the mixture
  6. extractionThe aqueous layer was extracted with n-butanol
  7. customthe concentrated gum was purified by silica gel chromatography (methanol/methylene chloride)

Sources & evidence

ORD record
ord-935e7acd38fc47df8af1ba7b9031c029
Source dataset
uspto-grants-2003_02
Patent number
US06525202B2

Reaction notes

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