Diisopropylethylamine → HCID 25164123, compound

HRID 1929309Notes

Reaction equation

HRID 1929309 reaction equation
[NH2:1][C@@H:2]([CH3:21])[C:3]([NH:5][CH:6]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]=[CH:9][N:8]([CH3:19])[C:7]1=[O:20])=[O:4].[OH:22][C@@H:23]([CH:27]([CH3:29])[CH3:28])[C:24](O)=[O:25].O.OC1C2N=NNC=2C=CC=1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC>ClCCl>[OH:22][C@@H:23]([CH:27]([CH3:29])[CH3:28])[C:24]([NH:1][C@H:2]([C:3](=[O:4])[NH:5][C@H:6]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]=[CH:9][N:8]([CH3:19])[C:7]1=[O:20])[CH3:21])=[O:25]

Participants

7

Reactant 5

HCID 81531DiisopropylethylamineHCID 853180(S)-2-Hydroxy-3-methylbutanoic acidHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 68476876HCID 68476876, compoundHCID 178526939HCID 178526939, compound

Product 1

HCID 25164123HCID 25164123, compoundYield 92.1%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
1 °C

Procedure

The (S)-2-amino-N-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-azepin-3-yl)-propionamide (406 g, 1.423 mol) is combined with dichloromethane (3 L) and the solution cooled to 0-2° C. To this solution is added (S)-2-hydroxy-3-methyl-butyric acid (168.1 g, 1.423 mol), hydroxybenzotriazole hydrate (239.7 g, 1.565 mol) and diisopropylethylamine (310 mL, 1.779 mol) which provides a slight exotherm. The contents are cooled back to about 4° C. and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (286.5 g, 1.494 mol) is added. The reaction contents are allowed to gradually warm to room temperature. High-performance liquid chromatography analysis at 4.5 hours (temperature at 14° C.) indicates about 5% unreacted starting amine present. After stirring an additional 1-1.5 hour, the reaction contents are quenched into water (1000 mL) and the layers are separated. The dichloromethane layer is further extracted with water (1000 mL), 0.1 N HCl (1000 mL), saturated sodium bicarbonate (1000 mL) and finally saturated aqueous sodium chloride. The dichloromethane layer is then dried over magnesium sulfate, filtered and concentrated via rotary evaporation to provide the crude diastereomeric mixture (505 g) of the coupled product as tan foam. The isomers are separated by chiral chromatography employing a Chiralpak® AD column eluting with 100% methanol. Upon removal of the elution solvent from the isomer fractions, approximately 210 g of the first eluting isomer is recovered as a tan foam and for the desired isomer 2, approximately 220 g (44%) is recovered, also as a tan powder. The second eluting isomer is the desired (S,S,S)-diastereomer. Approximately 140 g of the title compound is taken up in acetone (1000 mL) and water (95 mL). The solution is heated on the rotary evaporator until no suspended particles are observed. The solution is transferred to a flask, equipped with overhead stirring, and water (2750 mL) is gradually added over 15 minutes. The resulting slurry is allowed to cool to room temperature, then filtered and the cake is rinsed with 20% acetone/water solution (650 mL). After vacuum drying at 40° C. overnight, approximately 102 g of the title example is recovered.

Workup

  1. customprovides a slight exotherm
  2. temperatureThe contents are cooled back to about 4° C.
  3. customThe reaction contents
  4. temperatureto gradually warm to room temperature
  5. customthe reaction contents
  6. customare quenched into water (1000 mL)
  7. customthe layers are separated
  8. extractionThe dichloromethane layer is further extracted with water (1000 mL), 0.1 N HCl (1000 mL), saturated sodium bicarbonate (1000 mL) and finally saturated aqueous sodium chloride
  9. dry with materialThe dichloromethane layer is then dried over magnesium sulfate
  10. filtrationfiltered
  11. concentrationconcentrated via rotary evaporation

Sources & evidence

ORD record
ord-bfacb153f9a840638bc3a20df2f954cf
Source dataset
uspto-grants-2012_05
Patent number
US08188069B2

Reaction notes

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