Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2000-11-17
2002-10-08
Rotman, Alan L. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C560S125000
Reexamination Certificate
active
06462226
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a process for the preparation of 4,5-diamino shikimic acid derivatives, especially for the preparation of ethyl (3R, 4R, 5S)-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate and its pharmaceutically acceptable addition salts from 4-amino-5-azido shikimic acid derivatives, especially from ethyl (3R, 4R, 5S)-4-acetamido-5-azido-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate.
BACKGROUND OF THE INVENTION
4,5-diamino shikimic acid derivatives, especially the ethyl (3R, 4R, 5S)-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate and its pharmaceutically acceptable addition salts are potent inhibitors of viral neuraminidase ( J. C. Rohloff et al., J.Org.Chem. 63, 1998, 4545-4550; WO 98/07685).
A reduction of ethyl (3R, 4R, 5S)-4-acetamido-5-azido-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate to ethyl (3R, 4R, 5S)-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate by a hydrogenation in the presence of a Raney nickel catalyst is known in the art (J. C. Rohloffet al, loc.cit.).
It was found that the “5-azido” starting compound from its prior synthesis always contains a small amount of the “2,5-diazido” compound formed by formal addition of hydrazoic acid to the double bond. In the course of the hydrogenation the azido group in 5-position is readily converted to the desired amino group, the transformation of the azido group in 2-position however is very slow. Accordingly a “2-azido-5-amino” intermediate is formed which was shown to be “Ames positive” and therefore suspicious of being mutagenic.
This intermediate cannot be satisfactorily removed with the common purification techniques. Also, the problem cannot be overcome by prolonging the hydrogenation time because the “cyclohexene double bond” becomes hydrogenated, too.
An object of the present invention is, therefore, to provide a process for the preparation of 4,5-diamino shikimic acid derivatives which does not encompass the difficulties known in the art; i.e. a process which allows easy access to the target product in an excellent quality.
DESCRIPTION OF THE INVENTION
It was found that reduction of 4-amino-5-azido shikimic acid derivatives with a phosphine in the presence of a carboxylic acid surprisingly achieved this object.
The present invention therefore relates to a process for the preparation of a 4,5-diamino shikimic acid derivative of formula
and a pharmaceutically acceptable addition salt thereof
wherein
R
1
is an optionally substituted alkyl group,
R
2
is an alkyl group and
R
3
and R
4
, independent of each other are H or an amino protecting group, with the proviso that not both R
3
and R
4
are H;
the process being characterized by the reduction of a 4-amino-5-azido-shikimic acid derivative of formula
with a phosphine in the presence of a carboxylic acid. R
1
, R
2
, R
3
and R
4
have the same meaning in formula II as in formula I. If necessary, the process includes a further transformation of the 4,5-diamino shikimic acid derivative into a pharmaceutically acceptable addition salt thereof.
The term alkyl in R
1
has the meaning of a straight chained or branched alkyl group of 1 to 20 C-atoms, expediently of 1 to 12 C-atoms. Examples of such alkyl groups are methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert. butyl, pentyl and its isomers, hexyl and its isomers, heptyl and its isomers, octyl and its isomers, nonyl and its isomers, decyl and its isomers, undecyl and its isomers and dodecyl and its isomers.
This R
1
alkyl group can be substituted with one or more substituents as defined in e.g. WO 98/07685. Suitable substituents are C
1-6
-alkyl (as defined above), C
1-6
-alkenyl, C
3-6
-cycloalkyl, hydroxy, C
1-6
-alkoxy, C
1-6
-alkoxycarbonyl, F, Cl, Br, and I. Preferred meaning for R
1
is 1-ethylpropyl.
R
2
is a straight chained or branched alkyl group of 1 to 12 C-atoms, expediently of 1 to 6 C-atoms as exemplified above.
The preferred meaning for R
2
is ethyl.
The term amino protecting group in R
3
and R
4
refers to any protecting group conventionally used and known in the art. They are described e.g. in “Protective Groups in Organic Chemistry”, Theodora W. Greene et al., John Wiley & Sons Inc., New York, 1991, p.315-385. Suitable amino protecting groups are also given in e.g. WO 98/07685.
Preferred amino protecting groups are alkanoyl groups, more preferably lower C
1-6
-alkanoyl such as hexanoyl, pentanoyl, butanoyl (butyryl), propanoyl (propionyl), ethanoyl (acetyl) and methanoyl (formyl). The preferred alkanoyl group, and therefore preferred meaning for R
4
, is acetyl. The preferred meaning for R
4
is H.
The 4-amino-5-azido-shikimic acid derivative of formula (II) as starting compounds of the present process of the invention are accessible as described in J. C. Rohloff et al., loc. cit. and in WO 98/07685.
The preferred 4-amino-5-azido-shikimic acid derivative of formula (II) is the ethyl (3R, 4R, 5S)-4-acetamido-5-azido-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate. Accordingly, the preferred 4,5-diamino shikimic acid derivative of formula (I) is the ethyl (3R, 4R, 5S)-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate and the corresponding salt, ethyl (3R, 4R, 5S)-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate Phosphate (1:1).
The phosphine used can be defined by the formula
P(R
5
)
3
III
wherein R
5
is alkyl.
R
5
expediently is a straight chained or branched C
1-8
alkyl group as defined above.
Phosphines which can suitably be used are trioctyl phosphine, triisobutyl phosphine, tri-n-butyl phosphine, and triethyl phosphine. The most preferred phosphine is tri-n-butyl phosphine.
Although the ratio of phospine to the 4-amino-5-azido-shikimic acid derivative of formula (II) is not critical to the production of the desired 4,5-diamino shikimic acid derivative of formula (I), the phosphine is preferably added in stoichiometric amounts or in a slight excess of up to 1.05 equivalents relating to the starting amount of the 4-amino-5-azido-shikimic acid derivative of formula (II). One of skill in the art may adjust to relative amounts of phosphine and the 4-amino-5-azido-shikimic acid derivative of formula (II) to optimize them for the particular reaction conditions used.
Typically, the reduction is performed in a polar protic solvent which forms the reaction medium. Any conventional polar protic solvent can be used, such as alcohols, preferably aqueous ethanol or aqueous tetrahydrofuran, most preferably aqueous ethanol. However, the choice of solvent is not critical to production of the desired 4,5-diamino shikimic acid derivative of formula (I), and one of skill would be able to perform the reduction in other solvents using general knowledge of the art.
The reaction temperature is another non-critical variable; for instance, the reduction performs satisfactorily at room temperature. The preferred reaction temperature mainly depends on the phosphine used but most preferably lies in the range of −20° C. to 30° C., with between 0 and 25° C. being particularly preferred.
It can be favorable to perform the reaction at two temperature levels, thereby having the lower temperature range given above for the addition of the phosphine and thereafter having a slightly higher temperature of up to room temperature to bring the reaction to completion.
Catalytic amounts of a carboxylic acid present during the reduction were found to suppress the ester hydrolysis which otherwise takes place to a small extent of some percent and thereby leads to an undesirable impurity. The term “carboxylic acid” refers to any compound having one or more free carboxylic acid groups. Preferably, the carboxylic acid is an aliphatic carboxylic acid, having from 2 to 8 carbon atoms, such as acetic acid, oxalic acid, propionic acid, malonic acid, butyric acid, succinic acid, maleic acid, fumaric acid, valeric acid, glutaric acid, caproic acid, adipic acid, heptanoic acid, and caprylic acid.
The carboxylic acid is preferably present in the reduction reaction in an amount
Hoffmann-La Roche Inc.
Johnston George W.
Rotman Alan L.
Sackey Ebenezer
Tramaloni Dennis P.
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