Beta-Alanine → Diisopropylethylamine

HRID 1817750Notes

Reaction equation

HRID 1817750 reaction equation
[C:1]1(B(O)O)[C:10]2[C:5](=CC=CC=2)C=CC=1.[Li].[OH-].[Na+].N[CH2:18][CH2:19][C:20](O)=O.[CH2:23]([N:25]=C=NCCCN(C)C)[CH3:24].ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>[Pd].C(Cl)Cl.CN(C)C=O.C(O)C.CO.O1CCOCC1.O1CCCC1>[CH:19]([N:25]([CH:10]([CH3:1])[CH3:5])[CH2:23][CH3:24])([CH3:18])[CH3:20]

Participants

15

Reactant 7

HCID 239Beta-AlanineHCID 14798Sodium HydroxideHCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 2545321-Naphthaleneboronic acidHCID 2724699PyBOPHCID 3028194Lithium

Product 1

HCID 81531Diisopropylethylamine

Reagents, catalysts & solvents 7

HCID 23938PalladiumCatalystHCID 702EthanolSolventHCID 887MethanolSolventHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolventHCID 312751,4-DioxaneSolvent

Procedure

Alternatively, modification of pyrazolone 6 can be carried out in a different order, Scheme 7. Pyrazolone 6 is treated with triflic anhydride (Tf2O) in a polar aprotic solvent such as THF in the presence of a base such as triethylamine at −78° C. to room temperature to afford the intermediate 18. Palladium catalyzed coupling with an appropriate napthyl boronic acid 9 can be carried out at this point using a method analogous to that described above. Final elaboration can be achieved by saponification of the ester 19 using a base such as aqueous lithium or sodium hydroxide in a polar solvent such as tetrahydrofuran, dioxane, methanol, ethanol or a mixture of similar solvents. Coupling of the beta alanine 8 is then achieved using 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC) and 1-hydroxybenzotriazole (HOBt) or benzotriazole-1-yloxytrispyrrolidinophosphonium hexafluorophosphate (PyBOP) and a base, generally diisopropylethylamine, in a solvent such as N,N-dimethylformamide (DMF) or methylene chloride for 3 to 48 hours at ambient temperature to yield the ester of final product I. Removal of the ester when R=Me or Et is accomplished by saponification using a base such as aqueous lithium or sodium hydroxide in a polar solvent such as tetrahydrofuran, dioxane, methanol, ethanol or a mixture of similar solvents. When R is a tert-butyl ester it is most conveniently removed by treatment with trifluoroacetic acid in methylene chloride for 0.5-3 h at ambient temperature. The product is purified from unwanted side products by recrystallization, trituration, preparative thin layer chromatography, flash chromatography on silica gel as described by W. C. Still et al, J. Org. Chem., 43, 2923, (1978), or HPLC. Purification of intermediates is achieved in the same manner. If compound I is racemic (ie R3 is not hydrogen), then this compound can be resolved via chiral hplc using either normal phase or supercritical fluid conditions.

Workup

  1. additiona mixture of similar solvents

Sources & evidence

ORD record
ord-4586ddffa4af41daa3f626691521419c
Source dataset
uspto-grants-2009_10
Patent number
US07598285B2

Reaction notes

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