Acetic Acid → 5-chloro-3-[((S)-1-methoxycarbonyl-3-methyl-butylamino)-methyl]-4H-chromene-2 carboxylic acid methyl ester
Reaction equation
[CH2:1]([O:3][C:4]([CH:6]1[C:15]([CH:16]=O)=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[Cl:18])[O:7]1)=[O:5])C.[CH3:19][O:20][C:21](=[O:28])[C@@H:22]([NH2:27])[CH2:23][CH:24]([CH3:26])[CH3:25].CCN(C(C)C)C(C)C.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH3:1][O:3][C:4]([C:6]1[O:7][C:8]2[C:13]([CH2:14][C:15]=1[CH2:16][NH:27][C@H:22]([C:21]([O:20][CH3:19])=[O:28])[CH2:23][CH:24]([CH3:26])[CH3:25])=[C:12]([Cl:18])[CH:11]=[CH:10][CH:9]=2)=[O:5]Participants
Reactant 5
Product 1
Reagents, catalysts & solvents 1
Conditions
- Temperature
- 25 °C
Procedure
To a solution of 5-chloro-3-formyl-2H-chromene-2-carboxylic acid ethyl ester (1.0 g, 3.74 mmol) (Example 20, Step 1) in methanol (20 mL) containing molecular sieves (0.7 g) was added commercially available (S)-2-amino-4-methyl-pentanoic acid methyl ester (0.68 g, 3.74 mmol) and N,N′-diisopropylethylamine (1.30 mL, 7.49 mmol). The mixture was stirred at 25° C. for 10 hours. At this time, sodium cyanoborohydride (0.47 g, 7.49 mmol) and acetic acid (0.43 mL, 7.20 mmol) were added simultaneously to the reaction mixture, and the reaction mixture was stirred for additional 16 hours at 25° C. The reaction mixture was then filtered through celite and washed with methanol. The filtrate was concentrated in vacuo. Flash column chromatography (eluant-ethyl acetate:petroleum ether 1:9, Rf=0.6) over neutral alumina afforded 5-chloro-3-[((S)-1-methoxycarbonyl-3-methyl-butylamino)-methyl]-4H-chromene-2 carboxylic acid methyl ester (0.46 g, 31%) as an oil.
Workup
- stirringthe reaction mixture was stirred for additional 16 hours at 25° C
- filtrationThe reaction mixture was then filtered through celite
- washwashed with methanol
- concentrationThe filtrate was concentrated in vacuo
Sources & evidence
- ORD record
- ord-02877b24180d42df85ad7ca3c8dc8469
- Source dataset
- uspto-grants-2012_05
- Patent number
- US08178689B2
Reaction notes
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