Preparation of N-protected N-alkylated amino acids

Details Preparation of N-protected N-alkylated amino acids Preparation of N-protected N-alkylated amino acids

1995-10-06

1996-12-24

Conrad, Joseph

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acid esters

560 24, 560 29, 560 32, C07C26906

Patent

active

055875068

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/EP94/03480, filed Oct. 22, 1994.
The present invention relates to a novel process for preparing N-protected N-alkylated amino acids. N-Methylated amino acids are important constituents of peptides with high biological activity. Examples of such peptides are cyclosporins (Angew. Chem. 97 (1985) 88) and Dolastatins (Nat. Prod. 44 (1981) 482).
The preparation of N-monomethylated amino acids without using N-protective groups has achieved no practical importance. The processes described in the literature require the use of reagents which are costly and difficult to handle (methyl iodide, sodium hydride) in excess (Can. J. Chem. 55 (1977) 906). In addition, the esterification of the acid functionality which often occurs at the same time is unwanted and interfering (J. Org. Chem. 35 (1970) 1912).
N-Protected N-methylated amino acid derivatives are particularly advantageous for use in peptide chemistry because the methylated amino group is unable to react and the acid functionality does not have to be liberated. The most practicable process to date was introduced by Runge (WO 90/06914). In this case, t-butyloxy-carbonyl-protected amino acids are mixed with methyl iodide and the methylation takes place after addition of potassium tert-butanolate. However, both the chosen protective group and the methylating agent in the process described in WO 90/06914 are not optimal for preparing larger amounts of N-protected N-methylated amino acids. Use of the benzyloxycarbonyl protective group (abbreviated to Z hereinafter) in place of the t-butyloxycarbonyl protective group results in the desired N-alkylated amino acid in only very moderate yield besides many byproducts. Replacement not only of the protective group but also of the methylating agent (dimethyl sulfate in place of methyl iodide) results in no product being isolated.
We have found, surprisingly, that by changing the sequence of addition of the reagents and by changing the alkylating agent it is possible to prepare N-Z-protected N-alkylamino acids in very good yield and in high optical purity.
The present invention relates to a process for preparing N-protected N-alkylated amino acids of the formula I: ##STR2## where R.sup.s is a conventional protective group for peptide synthesis, derivative thereof, -alkynyl or unsubstituted or C.sub.1-4 -alkyl-substituted phenyl or benzyl, and ##STR3## where R.sup.1, R.sup.2 and R.sup.5 have the abovementioned meanings, to a solution of sodium or potassium tert-butanolate in a non-protic organic solvent and subsequently adding dimethyl or diethyl sulfate.
The process is suitable for preparing-both the racemic compounds and the enantiomerically pure compounds.
Preferred meanings of the substituents in the formula I are: C.sub.1-6 -alkyl such as CH.sub.3 --, CH.sub.3 --CH.sub.2 --CH.sub.2 --, --CH(CH.sub.3)--CH.sub.2 --CH.sub.3, --CH.sub.2 --CH(CH.sub.3).sub.2, C.sub.6 H.sub.5 --CH.sub.2 -- and, very particularly, --CH(CH.sub.3).sub.2.
R.sup.1 radicals which may be mentioned for functional derivatives of proteinogenous amino acids are: H.sub.4 OCH.sub.2 --C.sub.6 H.sub.5, --CH.sub.2 --O--CH.sub.3, --CH.sub.2 --O--C(CH.sub.3).sub.3, --CH.sub.2 --O--Si(CH.sub.3).sub.3, --CH.sub.2 --O--CH.sub.2 --C.sub.6 H.sub.5, --CH.sub.2 --C.sub.6 H.sub.4 O--Si(CH.sub.3).sub.3, --CH(CH.sub.3)--O--CH.sub.3, --CH(CH.sub.3)--O--C(CH.sub.3).sub.3, --CH(CH.sub.3)--O--Si(CH.sub.3).sub.3, --CH(CH.sub.3)--O--CH.sub.2 --C.sub.6 H.sub.5, --CH .sub.2 --S--C(C.sub.6 H.sub.5).sub.3, --CH.sub.2 --S--CH(C.sub.6 H.sub.5).sub.2, --CH.sub.2 --S--CH.sub.2 --C.sub.6 H.sub.5, --CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 N--(CO).sub.2 C.sub.6 H.sub.4, --CH.sub.2 --CH.sub.2 --CH.sub.3, --CH(CH.sub.3)--CH.sub.2 --CH.sub.3, --CH.sub.2 --CH.sub.2 --CH.sub.2 --CH.sub.3, --CH.sub.2 --CH(CH.sub.3).sub.2, --C(CH.sub.3).sub.3, C.sub.2-4 -alkenyl such as --CH.sub.2 --CH.dbd.CH.sub.2, C.sub.2-4 -alkynyl such as --CH.sub.2 --C.tbd.CH, or C.sub.6 H.sub.5 --, --C.sub.6 H.sub.4 --CH.sub.3, preferably Z, DMZ (.alpha.,.alpha. dimethyl-benzyloxycarbonyl), BZ (

REFERENCES:
Hlavacek, et al. Collect.Czech. Chem. Commun. 53(11A)2473-94 1988.
Marino, et al. J. Chem. Soc. Chem. Commun. No. 6, 357-58 1972.

Affiliated with

Also associated with

Rating

Preparation of N-protected N-alkylated amino acids does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Preparation of N-protected N-alkylated amino acids, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Preparation of N-protected N-alkylated amino acids will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-1179701