Practical synthesis of benzoxazinones useful as HIV reverse...

Details Practical synthesis of benzoxazinones useful as HIV reverse... Practical synthesis of benzoxazinones useful as HIV reverse...

2000-08-30

2002-02-19

Raymond, Richard L. (Department: 1624)

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

Organic compounds

Carboxylic acid esters

C560S030000

Reexamination Certificate

active

06348616

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates generally to novel methods for the synthesis of benzoxazinone compounds which are useful as human immunodeficiency virus (HIV) reverse transcriptase inhibitors.
BACKGROUND OF THE INVENTION
Reverse transcription is a common feature of retrovirus replication. Viral replication requires a virally encoded reverse transcriptase to generate DNA copies of viral sequences by reverse transcription of the viral RNA genome. Reverse transcriptase, therefore, is a clinically relevant target for the chemotherapy of retroviral infections because the inhibition of virally encoded reverse transcriptase would interrupt viral replication.
A number of compounds are effective in the treatment the human immunodeficiency virus (HIV) which is the retrovirus that causes progressive destruction of the human immune system with the resultant onset of AIDS. Effective treatment through inhibition of HIV reverse transcriptase is known for both nucleoside based inhibitors, such as azidothymidine, and non-nucleoside based inhibitors. Benzoxazinones have been found to be useful non-nucleoside based inhibitors of HIV reverse transcriptase. The benzoxazinone of the formula (VI-a):
is not only a highly potent reverse transcriptase inhibitor, it is also efficacious against HIV reverse transcriptase resistance. Due to the importance of benzoxazinones as reverse transcriptase inhibitors, synthetic processes for their production need to be developed.
Thompson et al,
Tetrahedron Letters
1995, 36, 937-940, describe the asymmetric synthesis of an enantiomeric benzoxazinone by a highly enantioselective acetylide addition followed by cyclization with a condensing agent to form the benzoxazinone shown above.
European Patent Application 582,455 A1 describes the synthesis of benzoxazinones via a three step process.
This general method teaches (1) metallation of the pivalamide of parachloroaniline with n-butyllithium followed by nucleophilic substitution with an ester to form a ketone, (2) synthesis of a tertiary carbinol by Grignard addition to the ketone, and (3) cyclization of the unprotected amine with the carbinol by addition of a condensing agent to form a benzoxazinone.
Young et al, PCT International Patent Application Number WO 9520389 A1 describe benzoxazinones useful in the inhibition of HIV reverse transcriptase, the prevention or treatment of infection by HIV and the treatment of AIDS. Application WO 9520389 A1 discloses methods of synthesis which are commensurate with EP 582,455 A1 above. Additionally, Young et al,
Antimicrobial Agents and Chemotherapy
1995, 39, 2602-2605, in discussing the clinical benefit, the in vitro activity, and the pharmacokinetic activity of benzoxazinone (VI-a) in the treatment of HIV as an HIV reverse transcriptase inhibitor disclose an abbreviated synthesis of benzoxazinone (VI-a) commensurate with EP 582,455 A1 above wherein the tertiary carbinol is synthesized by addition of a cyclopropyl-ethynyl-lithium reagent before cyclizing the unprotected amine with the carbinol by addition of a condensing agent.
Muchowski and Venuti,
J. Org. Chem
. 1980, 45, 4798-4801, describe the ortho functionalization of N-(tert-butoxycarbonyl)aniline by a corresponding dilithio species using only tert-butyllithium as a practical means of synthesis of ortho-substituted anilines. This reference teaches away from the use of sec-butyllithium and n-butyllithium. The following references describe procedures for ortho lithiation on N-Boc-4-chloro-anilines using tert-butyllithium: Reed et al,
Tetrahedron Letters
1988, 29, 5725-8; Cho et al,
J. Org. Chem
. 1991, 56, 7288-91; Berger et al, Heterocycles 1993, 36, 2051-8; Iwao, Heterocycles 1994, 38, 45-50; and Reuter et al,
Tetrahedron Lett
. 1994, 35, 4899-902.
Karlsson et al,
Tetrahedron Letters
1989, 30, 2653-6, describe a cyclization process for synthesizing five membered cyclic carbamates from an aliphatic N-2-Boc-amino alcohol resulting in a monocyclic oxazolidone.
The formation of benzoxazinones by intramolecular nucleophilic alkoxide ion attack on ethyl and p-nitrophenyl carbamates has been described in the literature for the study of intramolecular enzyme-catalyzed reactions (see Hutchins and Fife,
J. Am. Chem. Soc
. 1973, 95, 3786-90). The rates of ring closure and phenoxide ion release from the ethyl and p-nitrophenyl esters of 2-hydroxymethyl-N-methylcarbanilic acid and 2-hydroxymethylcarbanilic acid were measured in water at 25° under conditions which required excess potassium hydroxide concentrations.
Doller et al, PCT International Application Number WO 93/14054 describes a process for the production of substituted trifluoromethyl ketones of formula (XIV)
by oxidation of the corresponding substituted trifluoromethyl alcohols.
The above methods for the syntheses of benzoxazinones use toxic, difficult to handle reagents and relatively expensive materials. Thus, it is desirable to discover new synthetic routes to benzoxazinones on a large scale which avoid toxic, difficult to handle reagents and provide high yields of desired benzoxazinones.
Accordingly, the present invention provides an improved synthetic process for the preparation of benzoxazinones. The process of the present invention eliminates use of highly toxic condensing agents such as phosgene and provides for a more efficient intramolecular cyclization using a stoichiometric equivalent of strong base. The present invention eliminates the use of highly toxic ceric ammonium nitrate or replaces messy HCl/EtOH/LiOH for the removal of camphanic acid with a considerably cleaner DMSO/H
2
O reaction.
The present invention provides novel processes for the addition of cyclopropylethynyl radical to N-Boc-aniline via the cyclopropylethynyl lithium or cyclopropylethynyl trifluoromethyl ketone to produce the carbinol necessary for the intramolecular cyclization reaction.
The present invention provides for intermediates as stable solids purifiable by recrystallization. None of the above-cited references describe the methods of the present invention for the synthesis of benzoxazinones useful as inhibitors of HIV reverse transcriptase.
SUMMARY OF THE INVENTION
The present invention concerns processes for the preparation of benzoxazinone compounds which are useful as HIV reverse transcriptase inhibitors. The processes of the present invention provide high yields, can be conducted on a kilogram scale, and yield stable intermediates. The invention further provides for a facile intramolecular cyclization under mild condition to form benzoxazinone compounds.
There is provided by this invention a process for the preparation of compounds of formula (VI) and derivatives thereof:
wherein X, R
2
, and R
3
are as defined below, said process comprising one or more of the following:
(1) (substitution) reacting a compound of formula (I):
 wherein R
1
is an amine protecting group, which forms a carbamate with the amine,
 with sec-butyllithium or another suitable lithiating agent, and ethyl trifluoroacetate in a suitable aprotic solvent, to form a compound of formula (II):
(2) (addition) reacting a compound of formula (II) with cyclopropylethynyl lithium, which has been generated in situ by the reaction of 5-chloro-1-pentyne with n-butyllithium, in a suitable aprotic solvent, to form a compound of formula (III):
(3) (cyclization) contacting a compound of formula (III) with n-butyllithium or a suitable strong base, to form a compound of formula (IV)
(4) (chiral resolution) reacting a compound of formula (IV) with sodium hydride and camphanic acid chloride or a suitable chiral amine protecting group and separating the diastereomers to form a compound of formula (V):
 wherein R
4
is a chiral amine protecting group, and
(5) (nitrogen deprotection) contacting a compound of formula (V) with dimethylsulfoxide and water to form a compound of formula (VI).
DETAILED DESCRIPTION OF THE INVENTION
In a first embodiment, the present invention provides a novel process for the preparation of compounds of formula (IV) and derivatives thereof:
wherei

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