Process for the preparation of amino acid derivatives

Details Process for the preparation of amino acid derivatives Process for the preparation of amino acid derivatives

2000-04-21

2002-06-04

Geist, Gary (Department: 1623)

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

Organic compounds

Carboxylic acid esters

C560S027000, C560S038000, C560S155000, C560S157000, C562S443000, C562S555000

Reexamination Certificate

active

06399809

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a process for the preparation of amino acid derivatives of the general formula I
where R
1
is C
1-6
-alkyl or C
3-6
-cycloalkyl and R
2
is C
1-6
-alkyl, phenyl, heteroaryl-, (CH
2
)
1-3
-phenyl or —(CH
2
)
1-4
—COOR, or R
1
and R
2
together are —(CH
2
)
2-6
, —(CH
2
)
2
—O—(CH
2
)
2
— or
or R
1
is hydrogen and R
2
is a tertiary hydrocarbon radical having from 4 to 10 carbon atoms,
R
3
is hydrogen or an alkyl radical having 1-4, in particular 1 or 2, carbon atoms and R
4
is OR, where R in R
2
and R
4
is an aliphatic, aromatic or araliphatic radical having from 1 to 8 carbon atoms, or NR′R″, where R′ is hydrogen or an aliphatic, aromatic or araliphatic radical having from 1 to 8 carbon atoms and R″ is hydrogen or an aliphatic, aromatic or araliphatic radical having from 1 to 8 carbon atoms which may or may not be different from R′,
from the corresponding malonic acid monoester amides of the general formula II by Hofmann degradation using a hypohalite in an aqueously basic medium in the presence of an alcohol or amine
where R
1
, R
2
and R
3
are as defined above.
If R
1
is different to R
2
, the compounds of the general formula II as well as the compounds of the general formula I are chiral. Thus, the racemates of the compounds of the general formula II also give the racemates of the amino acid derivatives of the general formula I. On the other hand, the corresponding enantiomerically pure compounds of the general formula II, where R
1
is not equal to R
2
, also give the corresponding enantiomerically pure compounds of the general formula I.
2. Background of the Invention
Amino acids and derivatives thereof are of great importance for the synthesis of pharmacologically active compounds (A. S. Bommarius, M. Schwarm and K. Drauz, J. Mol. Catalysis B; Enzymatic 5 (1998) 1-11). In addition to the naturally occurring amino acids, the importance of unnatural amino acids and derivatives thereof is also increasing. For example, the synthesis of highly effective pharmaceutical products requires derivatives of specific unnatural amino acids. The development of suitable synthesis processes for the preparation of specific amino acids is thus of great interest.
Of the unnatural amino acids, the 2,2-dialkylaminoacetic acids, as unnatural amino acids, are of great importance for the synthesis of specific peptides. The additional alkyl group in the 2-position compared with the natural amino acids leads to conformative rigidity of the corresponding peptide bond and as a result influences in a manner which is relevant the tertiary structure of the overall peptide (D. Obrecht, M. Altorfer, U. Bohdal, J. Daly, W. Huber, A. Labhardt, C. Lehmann, K. Muller, R. Ruffieux, P. Schonholzer, C. Spiegler, C. Zumbrunn, Biopolymers 42(5), 575-626 (1997); M. Crisma, G. Valle, M. Pantano, F. Formaggio, G. M. Bonora, C. Toniolo, J. Kamphius, Recl. Trav. Chim. Pays-Bas 114(7), 325-31 (1995); S. Prasad, B. R. Rao, P. Balaram, Biopolymers 35(1), 11-20, (1995)).
2,2-Dialkylaminoacetic acids have also been used as lipophilic amino acids for the construction of peptides, which are important as potential active ingredient candidates (P. M. Hardy, l. N. Lingham, Int. J. Peptide Protein Res. 21, 392-405 (1983)).
Moreover, European Patent Application EP-A 770 613 describes the synthesis of 5,5-disubstituted imidazolidin-2,4-diones, which are used as immunodilators. Their synthesis starts from the corresponding 2,2-dialkyl amino acid esters.
Substituted hydantoin compounds, which can be prepared simply from the compounds of the general formula I where R
4
=OR, where R is an aliphatic, aromatic or araliphatic radical having from 1 to 8 carbon atoms (B. A. Dressmann, L. A. Spangle, W. Kaldor, Tetrahedron Lett. 937-940 (1996)) are generally of great importance as pharmaceutical products or precursors. In the pharmaceutical field, anticonvulsive, antiinflammatory (J. Med. Chem. 8,239 (1965); Arzneim. Forsch./Drug Res. 27(11), 1942 (1977); Pharmazie 38,341 (1983), J. Med. Chem. 28,601 (1985)) and antitumor effects (J. Med. Chem. 18,846 (1975); Arzneim. Forsch./Drug Res. 34(1), 663 (1984)) in particular are known.
The synthesis of ethyl 2,2-di-n-propylaminoacetate has been described starting from ethyl cyanoacetate (J. Chinese Chem. Soc. 8, 81-91 (1941)), shown in Equation 1 below:
Equation 1
For this purpose, the ethyl cyanoacetate was first converted into the enolate using sodium ethoxide, and then reacted with 2 equivalents of propyl bromide. The ethyl 2,2-di-n-propylcyanoacetate 2, obtained in a yield of 68%, was then converted into the 2,2-di-n-propylmalonic acid monoamide ethyl ester 3 in a yield of 75% using sulfuric acid. Reaction with a mixture of sodium hydroxide solution and bromine in chloroform then gave the 2,2-di-n-propyl-n-bromomalonic acid monoamide ethyl ester 4 in a yield of 89%. The latter was then converted into the target compound 5 using an excess of sodium hydroxide solution by Hofmann degradation in a yield of 79%. The overall yield starting from ethyl cyanoacetate was thus 36%.
The synthesis of this compound, which can also be called di-n-propylglycine ethyl ester, was later optimized (P. M. Hardy, l. N. Lingham, Int. J. Peptide Protein Res. 21, 392-405 (1983)). The synthesis of ethyl 2,2-di-n-propylcyanoacetate 2 gave a yield of 81%, while the subsequent reaction to give the 2,2-di-n-propylmalonic acid monoamide ethyl ester 3 gave a yield of 82%. Following further reaction with bromine and NaOH in CHCl
3
at low temperature, the N-bromoamide 4 was not isolated, but, following treatment with a 4-fold excess of sodium hydroxide solution, the corresponding isocyanate 6 in a distillative yield of 81% was obtained. The latter was then refluxed with an excess of 3M HCl. Subsequent alkalinization with sodium hydroxide solution gave the amino ester 5 in a yield of 87%. The overall yield of this synthesis was about 47% starting from cyanoacetic ester 1.
Hardy et al. emphasize that the isolation of the isocyanate and the subsequent acidic hydrolysis to give the amino ester 5 is of great advantage since in this method the formation of a urea derivative 7, which is very problematic during work-up, is avoided. This is because, under alkaline conditions, some of the reaction product 5 reacts with the isocyanate 6 to give the problematic urea derivative 7, which, furthermore, considerably reduces the yield.
Despite the higher yield which Hardy et al. achieved with their synthesis strategy, the process according to equation 1 has a number of problems. For example, the carrying out of the Hofmann degradation in chloroform using a mixture of bromine and sodium hydroxide solution is surely only suitable as a laboratory method. Also, a reaction temperature of −15° C. can only be attained in industry at great expense. Another disadvantage of the process is the need to isolate the isocyanate in order to prevent the formation of the urea derivative 7. This is, firstly, an additional step and, secondly, requires subsequent acidic hydrolysis to give the amino acid ester 5. In this connection, salt is again produced in stoichiometric amounts since it is necessary to alkalinize the reaction mixture prior to extraction of the product.
Against the backdrop of the large synthesis expenditure for the preparation of 5, the overall yield of 47% in total starting from cyanoacetic ester 1 is thus unsatisfactory. The yield of the Hofmann degradation reaction of 3 to produce 5 is about 70%.
Another method for the preparation of the amino ester 5 starts from a racemic norvaline, an unnatural amino acid (EP 770613), shown in Equation 2 below:
Equation 2
Here, the amino acid is first converted into the ester. Then, by reaction with benzaldehyde, an imine is synthesized, which is converted to the di-n-propylglycine ester by deprotonation using n-butyllithium and alkylation using propyl iodide with subsequent hydrolysis. The overall yield for all of the stages is only 53%.
Apart from the fact th

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