Ethylaziridine derivatives and their preparation methods

Details Ethylaziridine derivatives and their preparation methods Ethylaziridine derivatives and their preparation methods

2002-02-18

2003-06-03

McKane, Joseph K. (Department: 1626)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S967000, C548S968000, C548S969000

Reexamination Certificate

active

06573388

ABSTRACT:

This application is a 371 of PCT/KR00/00876 Aug. 10, 2000.
FIELD OF THE INVENTION
This invention is related to new ethylazindine derivatives and their preparation. The compounds are useful synthetic intermediates for the synthesis of HIV protease inhibitors and oligopeptide mimetics.
BACKGROUND OF THE INVENTION
HIV is a retrovirus delivering the genetic information in the form of RNA. Therapeutic agents for the virus include reverse transcriptase inhibitors and HIV protease inhibitors, which do not kill the virus in cells, rather inhibit the replication of the virus. Moreover, rapid emergence of viral strains resistant against the chemotherapeutics requires development of therapeutic agents of new structure.
HIV protease inhibitors which have been developed so far include Roche's Saquinavir [EP 432695 A (1991)], Glaxo-Weilcome's Amprenavir [U.S. Pat. No. 941,982 (1992)], Merck's Indinavir [U.S. Pat. No. 789,508 (1991)]. Abbott's Ritronavir [U.S. Pat. No. 998,114 (1992)], and Agouron's Nelfinavir [U.S. Pat. No. 5,484,926 (1996)]. These compounds are used for the prevention or treatment of AIDS caused by HIV viral infection.
Most of these HIV protease inhibitors belong to the hydroxyethylamine (HEA) class inhibitors. Except Nelfinavir, Saquinavir, Palinavir, and Amorenavir have benzyl group at the C(2) of the hydroxyethylamine backbone.
Intermediates for the synthesis of HIV protease inhibitors reported so far are (2R)-[1′(S)-azido-2-phenylethyl]oxirane (J. Med. Chem. 1993, 36, 292-294) and 3(S)-amino-1,2(S)-epoxy-4-phenylbutane. However, these intermediates are normally derived from phenylaianine and inevitably installs benzyl group onto the backbone of the HEA backbone. On the other hand, Nelfinavir possesses phenylthiomethyl group instead of the benzyl one onto the HEA backbone, thus requires a different intermediate such as 3(S)-amino-1,2(S)-epoxy-4-phenyl thiobutane.
Therefore, a new-intermediate is required for the introduction of benzyl as well as phenylthiomethyl or other substituents for the development of new HIV protease inhibitors.
The object of this invention is to provide a new ethylaziridine derivative which is capable of introducing various substituents. Another object of this invention is to provide important intermediates for the synthesis of HIV protease inhibitors.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is concerned with the ethylaziridine derivatives of formula I and their preparation methods. The new ethylaziridine derivatives are prepared from tartaric acid with amino and alcohol groups protected and the termini substituted with halogen and alkoxy groups. These aziridine derivatives can be utilized as core intermediates for the preparation of HIV protease inhibitors.
In the formula above,
R
1
and R
2
are respetively, H, alkyl, aryl, arylalkyl, or heteroatom which is bound to an alkyl, aryl or arylakyl group;
R
3
is H, alkyl, aryl, arylakyl, or amino protecting group forming C
5-7
monocyclic heterocycle or C
7-11
bicyclic heterocycle with nitrogen atom;
X and Y are respetively, H, C
1-4
alkyl, arylalkyl, aryl, or heteroatom which is bound to alkyl, aryl or arylakyl;
R
4
is silyl protecting group optionally substituted with alkyl group, or alcohol protecting group which includes alkoxycarbonyl, aryloxycarbonyl, methoxymethyl, tetrahydropyranyl, methoxyethoxy methyl or ethoxyvinylethyl;
Z is F, Cl, Br, I, or —OR
5
; and
R
5
is SO
n
R
6
, where n=0, 1 or 2, and R
6
is alkyl or aryl.
The synthetic method for ethylaziridine derivatives of general formula (I′) where R
1
, R
2
, X and Y are H is as follows.
In the case where tartaric acid is used as a starting material:
(1) D-methyl tartrate is prepared from the reaction of D-tartaric acid and SOCl
2
in methanol.
(2) 4,5-Dimethoxycarbonyl acetonide compound is obtained from the reaction of D-methyl tartrate and 2,2-dimethoxypropane in the presence of para-toluenesulfonic acid in dichloromethane.
(3) 2,3-O-Isopropylidene-D-threitol is obtained from the reduction of 4,5-dimethoxycarbonyl acetonide with sodium borohydride in methanol.
(4) 2,3-O-Isopropylidene-D-threitol is treated with triethylamine, lithium halide, and methanesulfonyl halide in acetonitrile to yield 1,4-dihalobutane-2(S),3(S)-diol.
(5) 1,4-Dihalobutane-2(S),3(S)-diol sulfate is prepared from the reaction of 1,4-dihalobutane-2(S),3(S)-diol with either thionyl chloride in chloroform followed by oxidation using ruthenium chloride and sodium periodate, or imidazole sulfuryl chloride in carbon tetrachloride.
(6) 1,4-Dihalobutane-2(S),3(S)-diol sulfate is treated with potassium phthalimide in DMF to provide N-[1,4-dihalo-2(S)-hydroxy-3(R)-butyl]phthalimide.
(7) N-[1,4-Dihalo-2(S)-hydroxy-3(R)-butyl]phthalimide was treated with 80% hydrazine monohydrate in isopropanol to remove the phthalimide protecting group and the resulting free amine was converted to 2(R)-(alkyloxycarbonyl)amino-1,4-dihalo-3(S)-hydroxybutane upon reaction with an acid anhydride in presence of triethylamine in tetrahydrofuran (THF).
(8) Reaction of 2(R)-(alkyloxycarbonyl)amino-1,4-dihalo-3(S)-hydroxybutane with hydroxyl protecting groups such as chlorosilane or chlorocarbonyl group provides 2(S)-silyl(or carbonyl)oxy-3(R)-alkyloxycarbonylamino-1,4-dihalobutane.
(9) N-alkyloxycarbonyl-2(R)-[1(S)-silyloxy-2-haloethyl]aziridine is prepared from the reaction of 2(S)-silyl(or carbonyl)oxy-3(R)-alkyloxycarbonylamino-1,4-dihalobutane with sodium hydride in THF.
Above preoaration method is depicted in Scheme (1-a).
When the same sequence is repeated starting from L-tartaric acid, the following compound of general formula (I-b) can be prepared.
Two isomers of formula (I-a) arnd formula (I-b) are depicted as formula (I′) as below.
This invention also provides the following compound of general formula (II).
wherein:
R
3
is H, alkyl, aryl, arylaikyl, or amino protecting group forming C
5-7
monocyclic heterocycle or C
7-11
bicyclic heterocycle with nitrogen atom;
R
4
is silyl protecting group optionally substituted with alkyl group, or alcohol protecting group which includes alkoxycarbonyl, aryloxycarbonyl, methoxymethyl, tetrahydropyranyl, methoxyethoxy methyl or ethoxyvinylethyl;
Z is F, Cl, Br, I, or —OSO
n
R
5
where n=0, 1 or 2, and R
5
is alkyl or aryl; and
R
7
is phenyl, phenyl substituted with hydroxy, halogen, alkyl or alkoxy group at the para position, phenylthio, pyridyl, piperidyl, cyclohexyl, C
1-4
alkyl, alkenyl, or alkenyl substituted with phenyl.
Compound of general formula (II) is prepared from ethylaziridine derivative of general formula (I′) by the following reaction.
In the above reaction, R
3
, R
4
, Z, and R
7
are same as defined above and M is alkali metal or alkali earth metal halide.
Also this invention provides new compounds of the following formula (III).
wherein,
R
3
is H, alkyl, aryl, arylakyl, or amino protecting group forming C
5-7
monocyclic heterocycle or C
7-11
bicyclic heterocycle with nitrogen atom; and
R
7
is phenyl, phenyl substituted with hydroxy, halogen, alkyl or alkoxy group at the para position, phenylthio, pyridyl, piperidyl, cyclohexyl, C
1-4
alkyl, alkenyl, or alkenyl substituted with phenyl.
Compounds of general formula (III) are prepared from compounds of general formula (II) by the reaction with tetrabutylammonium fluoride (TBAF).
Also afore-mentioned Amprenavir and Nelfinavir can be prepared from compound formula (II) and formula (III) through reactions of Scheme 4 and Scheme 5, respectively. Compounds of formula (II) and (III) are synthetic intermediates for Amprenavir when R
7
is phenyl, and for Nelfinavir when R
7
is phenylthio group, respectively.


REFERENCES:
patent: 3890302 (1975-06-01), Kotera et al.
patent: 5112990 (1992-05-01), Sharpless et al.
patent: 5484926 (1996-01-01), Dressman et al.
Tetrahedron Letter, vol. 32, No. 16, pp. 1897-1898 (1991).
Synlett, vol. 6, pp. 527-529 (1992).
J. Chem. Soc. Perkin Trans. 1, vol. 21, 2863-2870 (

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