CarbaMic acid, [(1S)-3-Methyl-1-(2-Methylpropyl)-2-oxo-3-butenyl]-, 1,1-diMethylethyl ester (9CI) Chemical Properties

Boiling point:

350.4±25.0 °C(Predicted)

Density 

0.964±0.06 g/cm3(Predicted)

storage temp. 

2-8°C

form 

Solid

pka

11.05±0.46(Predicted)

Appearance

White to light yellow Solid

InChI

InChI=1S/C14H25NO3/c1-9(2)8-11(12(16)10(3)4)15-13(17)18-14(5,6)7/h9,11H,3,8H2,1-2,4-7H3,(H,15,17)/t11-/m0/s1

InChIKey

BRMIWZWAGRRHEN-NSHDSACASA-N

SMILES

C(OC(C)(C)C)(=O)N[C@@H](CC(C)C)C(=O)C(C)=C

CarbaMic acid, [(1S)-3-Methyl-1-(2-Methylpropyl)-2-oxo-3-butenyl]-, 1,1-diMethylethyl ester (9CI) Usage And Synthesis

Uses

tert-Butyl ((S)-2,6-Dimethyl-3-oxohept-1-en-4-yl)carbamate is an intermediate in the synthesis of (S)-2-Amino-4-methyl-1-((S)-2-methyloxiran-2-yl)pentan-1-one Trifluoroacetate Salt which is an impurity of carfilzomib (C183460). Carfilzomib is a second-generation proteasome inhibitor that is used as a treatment in relapsed and refractory multiple myeloma.

Synthesis

The general procedure for the synthesis of tert-butyl (S)-(2,6-dimethyl-3-oxohept-1-en-4-yl)carbamate from the compound (CAS: 6386-71-6) and N-(tert-butoxycarbonyl)-L-leucine N-methoxy-N-methyl amide is as follows: the second molecular fragment (the right-handed fragment) can be prepared in parallel or sequentially. The method involves the conversion of amino terminally protected amino acids to Weinreb amides followed by an alkenylation reaction. Specific operations include, first, reacting the amino-terminally protected amino acid with a reagent (e.g., MeNHOMe-HCl, EDCl, NMM, HoBt, in DMF for 12 hr. in 80% yield) to prepare the carboxyl-terminal Weinreb amide of the amino acid. Subsequently, α',β-unsaturated ketones were obtained by reacting the Weinreb amide with an alkenylating agent (e.g., lithium propen-2-yl). In the case of epoxy enzymes synthesis, for example, Boc-Leu Weinreb amides can be reacted with propen-2-yl lithium to produce the corresponding α',β-unsaturated ketones. Propen-2-yl lithium can be prepared by reacting 2-bromopropene with tert-butyl lithium in a nonprotonic solvent (e.g., ether) at a low temperature (-78°C) for at least 30 minutes (e.g., 2.5 hours) to give the α',β-unsaturated ketone in high yield (92%).

References

[1] Patent: US6831099, 2004, B1. Location in patent: Page column 13-14