Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2001-02-06
2002-06-11
Killos, Paul J. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C548S961000, C549S463000, C549S465000
Reexamination Certificate
active
06403824
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a multi-step process for the preparation of 4,5-diamino shikimic acid derivatives, especially for the preparation of (3R,4R,5S)-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid ethyl ester and its pharmaceutically acceptable addition salts starting from furan as well as new specific intermediates.
BACKGROUND OF THE INVENTION
4,5-diamino shikimic acid derivatives, especially the (3R,4R,5S)-4-acetamido-5-amino-3-(1-ethylpropoxy) -1-cyclohexene-1-carboxylic acid ethyl ester and its pharmaceutically acceptable addition salts are potent inhibitors of viral neuraminidase( J. C. Rohloff et al., J.Org.Chem., 1998, 63, 4545-4550; WO 98/07685).
A multi step synthesis of (3R,4R,5S)-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid ethyl ester from (−)-quinic acid or (−)-shikimic acid is described in (J. C. Rohloff et al, loc.cit.).
Both (−)-quinic acid and (−)-shikimic acid are starting compounds which are rather expensive and hardly accessible in technical quantities. A multi step synthesis capable to run on a technical scale should therefore preferably be based on starting compounds that are more attractive in price and available in technical quantities.
An object of the present invention therefore is to provide such a new access to the 4,5-diamino shikimic acid derivatives mentioned above in good yields and excellent quality.
SUMMARY OF THE INVENTION
It was found that the following synthesis could achieve this object.
The present invention therefore relates to a process for the preparation of a 4,5-diamino shikimic acid derivative of formula
and pharmaceutically acceptable addition salts 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, a process
which is characterized by steps a) through g), wherein
step a)
furan is reacted with an acrylic acid derivative of the formula
wherein R
2
is as above to form a bicyclo compound of formula
wherein R
2
is as above,
step b)
the 2R-exo isomer of the bicyclo compound of formula (III) is separated,
step c)
this 2R-exo isomer of the bicyclo compound of formula (III) is reacted with an azide to form an aziridine of formula
wherein R
2
is as above and wherein R
5
is the organic azide residue then,
step d)
eliminative ring opening is effected to yield a cyclohexene aziridine derivative of formula
wherein R
2
and R
5
are as above,
step e)
a substituent R
6
is introduced in the free OH-position and the aziridine ring is opened to give a cyclohexene derivative of formula
wherein R
1
, R
2
and R
5
are as above and R
6
is a OH-protecting group,
step f)
R
5
is removed to yield a 4-amino cyclohexene derivative of formula
wherein R
1
, R
2
and R
6
are as above
this 4-amino cyclohexene derivative of formula (VII) is finally processed to the 4,5-diamino shikimic acid derivatives of formula (I) by
step g)
comprising either g
11
transformation of the 4-amino cyclohexene derivative of formula (VII) into an aziridine of formula
wherein R
1
and R
2
are as above,
g
12
formation of the azide of formula
wherein R
1
, R
2
, R
3
and R
4
are as above and
g
13
reduction and, if necessary the formation of the pharmaceuticallyacceptable addition salt, or
g
21
transformation of the 4-amino cyclohexene derivative formula (VII)
into a 5-N-substituted-4,5-diamino shikimic acid derivative of formula
wherein R
1
and R
2
are as above and R
7
and R
8
, independent of each other are H or an amino protecting group, with the proviso that not both R
7
and R
8
are H
g
22
acylation of the amino group in position 4 and
g
23
releasing the amino group in position 5 and, if necessary the formation of the pharmaceutically acceptable addition salt.
DETAILED DESCRIPTION OF THE INVENTION
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 somers, heptyl and its isomers, octyl and its isomers, nonyl and its isomers, decyl and its somers, undecyl and its isomers and dodecyl and its isomers.
This alkyl group can be substituted with one or more substituents as defined in e.g. WO 98/07685. Suitable substituents are alkyl of 1 to 20 C-atoms (as defined above), alkenyl with 2 to 20 C-atoms, cycloalkyl with 3 to 6 C-atoms, hydroxy, alkoxy with 1 to 20 C-atoms, alkoxycarbonyl with 1 to 20 C-atoms, 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.
Preferred meaning for R
2
is ethyl.
The substituent R
6
refers to any substituent for OH groups conventionally used and known in the art such as hydroxyl-protecting groups. They are described e.g. in “Compendium of Organic Methods” or in “Advanced Organic Chemistry”, ed. March J., John Wiley & Sons, New York, 1992, 353-357.
Preferably R
6
is a sulfonyl group, more preferably optionally substituted aryl sulfonyl or alkyl sulfonyl such as p-toluenesulfonyl, p-nitrobenzenesulfonyl, p-bromo benzenesulfonyl, trifluoromethanesulfonyl or methanesulfonyl, most preferably methanesulfonyl.
The term amino protecting group in R
3
and R
4
or R
7
and R
8
refers to any substituent conventionally used and known in the art for protecting amino groups. They are described e.g. in “Protective Groups in Organic Chemistry”, Theodora W. Greene et al., John Wiley &Sons Inc., New York, 1991, 315-385. Suitable substituents are also given in e.g. the WO 98/07685.
Preferred substituents for R
3
and R
4
are alkanoyl groups, more preferably lower alkanoyl with 1 to 6 C-atoms such as hexanoyl, pentanoyl, butanoyl (butyryl), propanoyl (propionyl), ethanoyl (acetyl) and methanoyl (formyl). Preferred alkanoyl group and therefore preferred meaning for R
3
is acetyl and for R
4
is H.
Preferred substituent for R
7
and R
8
is straight chained or branched alkenyl with 2 to 6 C-atoms, preferably allyl or an analog thereof. Suitable analog of allyl is an allyl group which is substituted on the &agr;-, &bgr;- or &ggr;-carbon by one lower alkyl, lower alkenyl, lower alkynyl or aryl group. Suitable examples are e.g. 2-methylallyl, 3,3-dimethylallyl, 2-phenylallyl, or 3-methylallyl. Most preferred meaning for R
7
is allyl and for R
8
is H.
Preferred 4,5-diamino shikimic acid derivative of formula (I) is the (3R,4R,5S)-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid ethyl ester and the ethyl (3R,4R,5S)-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate Phosphate (1:1).
Step a)
Step a) comprises a Diels-Alder reaction of furan with an acrylic acid derivative. Diels-Alder reactions per se are known to the skilled in the art (see e.g. Tetrahedron Letters, 23, 1982, 5299-5302). The present conversion can therefore be performed following the methods and conditions described in the art.
Suitable derivatives of an acrylic acid are the esters and the amides, preferably the esters, more preferably lower alkyl esters of acrylic acid.
Usually this type of reaction needs the presence of Lewis acids. Suitable Lewis acids are magnesium halogenides such as magnesium chloride, magnesium bromide or magnesium iodide or zinc halogenides such as zinc chloride, zinc bromide or zinc iodide. Preferred Lewis acid was found to be zinc chloride.
As a rule catalytic amounts of the Lewis acid are applied, however it was surprisingly found that stoechiometric amounts or even an excess of the Lewis acid, preferably of zinc chloride within a reasonable time lead to an excellent exo/endo ratio of the bicyclo compound of formula (III) of up to 9:1.
Preferably stoichiometric amounts of zinc chloride are used.
Convenient solvent for step a) is the reactant acrylic acid derivative itself, used in an excess of up
Abrecht Stefan
Karpf Martin
Trussardi Rene
Wirz Beat
Hoffmann-La Roche Inc.
Johnston George W.
Killos Paul J.
Tramaloni Dennis P.
LandOfFree
Process for the preparation for 4,5-diamino shikimic acid... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Process for the preparation for 4,5-diamino shikimic acid..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for the preparation for 4,5-diamino shikimic acid... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2947005