Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-08-30
2001-10-23
Lambkin, Deborah C. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C548S541000
Reexamination Certificate
active
06307059
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a novel process for preparing a protected 4-aminomethyl-pyrrolidin-3-one, novel intermediates produced during this process, and its use in the preparation of quinolone antibiotics.
BACKGROUND ART
Compounds of formula (1):
in which P
1
and P
2
are protecting groups are useful as intermediates for preparing compounds of formula (2).
wherein R is C
1-4
alkyl or C
1-4
haloalkyl, and salts therof e.g. the dihydrochloride salts;
which are in turn useful as intermediates for preparing quinolone antibiotics, such as those disclosed in U.S. Pat No. 5,633,262 and EP 688772A1. The intermediate of formula (2) in which R is methyl is of particular use in the production of the compound (R,S)-7-(3-aminomethyl-4-methoxyiminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-n aphthyridine-3-carboxylic acid and salts thereof, especially (R,S)-7-(3-aminomethyl-4-syn-methoxyimino-pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid methanesulfonate and hydrates thereof including the sesquihydrate disclosed in WO 98/42705.
EP 688772A1 discloses a process for the production of a compound of formula (2) as depicted in Scheme 1:
in Scheme 1 Boc represents t-butoxycarbonyl, and has the same meaning throughout the present specification.
There are however several drawbacks with the process of scheme 1, particularly if it is to be used on a tens to hundreds of kilogramme scale for commercial production, these include:
a) The process is somewhat inefficient since the use of a reducing agents, such as, platinum under hydrogen atmosphere, palladium metal, lithium aluminum hydride(LAH), lithium borohydride(LiBH
4
), sodium borohydride(NaBH
4
), or NaBH
4
-trifluoroacetic acid complex, etc., reduces both the ketone and cyano groups, requiring reoxidation of the alcohol to regenerate the ketone.
b) Reducing agents other than NaBH
4
-trifluoroacetic acid complex do not completely reduce the cyano group, resulting in the production of several side products and thus a reduction in yield and purity. Although the use of NaBH
4
-trifluoroacetic acid complex as a reducing agent may improve the yield and purity of the product, its use results in the discontinuous generation of hydrogen gas. Therefore, explosion risk cannot be adequately prevented by simple exhaust-incineration equipment, and it is not easy to apply this reduction process to production on a large scale. In addition, since the process for preparing the complex itself has many problems, such as formation of side products, etc., it is inappropriate for use on a large scale.
c) Side reactions which are not observed in small scale production occur more frequently in a large scale production which leads to a reduction in yield. The undesired side products, some of which are not clearly identified, make the separation and/or purification of the desired product difficult. Side products which have been identified include the compound of formulae (3) and (4):
It is assumed that the side products (3) and (4) are produced by reactions of the starting 4-cyano-1-(N-t-butoxy-carbonyl)pyrrolidin-3-one with sodium borohydride and trifluoroacetic acid. The by-product of formula (3) is particularly troublesome as it is not easily removed by recrystallization.
d) The pyridine-sulfur trioxide complex used during the oxidation of the hydroxy group is expensive, making it unsuitable for use on an industrial or commercial scale. In addition, the dimethylsulfide formed as a side product during the oxidation is not environmentally acceptable.
e) When a transition metal catalyst such as platinum is used in hydrogenation reaction, the reaction does not well proceeded using a catalytic amount of platinum and a low pressure of hydrogen, and thus cannot be used commercially.
Thus, it is desirable to find an alternative process for the production of the compounds of formulae (1) and (2), particularly one in which an &agr;-cyanoketone derivative can be selectively reduced in such a way that the subsequent reoxidation of the hydroxy group is not required.
The present invention is based on the finding that the cyano group of an &agr;-cyanoketone derivative can be selectively reduced to effectively produce the compound of formula (1) using Raney-nickel under hydrogen as reducing agent. The reaction conditions used in this process are very mild and thus can be used for industrial production. The use of a Raney-nickel catalyst gives several advantages over the prior art process described above, for example it does not require the additional oxidation reaction, also, the formation of side products markedly decreases compared with the process using NaBH
4
as a reducing agent, which leads to a stoichiometric reaction and a good yield.
DISCLOSUE OF THE INVENTION
The present invention provides a process for preparing a compound of formula (1):
in which P
1
and P
2
are protecting groups; comprising
a) reaction of a compound of formula (5):
wherein P
1
is defined for formula (1); with a Raney-nickel catalyst in a solvent under hydrogen to produce a compound of formula (6):
wherein P
1
is defined for formula (1);
b) protecting the amino group to produce a compound of formula (7):
wherein P
1
and P
2
are defined for formula (1); and
c) selective reduction of the double bond to produce the compound of formula (1).
The present invention also provides the novel intermediates of formulae (6) and (7).
DETAILED DESCRIPTION OF THE INVENTION
The process of the invention is summarized in Scheme 2:
The above process is more specifically explained hereinafter.
In step a)—reduction of the cyano group, the solvent is preferably an alcohol or ether, e.g. methanol or isopropanol, which have been found to improve the reaction rate. However, suitable solvents are not restricted to alcohols and ethers, and various inert solvents which do not adversely affect the reaction can be used providing the hydrogen pressure is controlled. The solvent may be used in an amount of 2 to 20 times by volume, preferably 2 to 5 times by volume with respect to the compound of formula (5). The reaction is advantageously conducted in the presence of one or more additives selected from the group consisting of ammonia water, gaseous ammonia and acetic acid, etc. These additives may be used in an amount of 2 molar equivalents or more, preferably 2 to 4 molar equivalents with respect to the compound of formula (5). The use of these additives has been shown to improve the purity of the resulting compounds of formula (6).
The step a) reaction is suitably carried out under hydrogen pressures ranging from atmospheric to about 50 atms, preferably from 4 to 10 atms, and suitably at temperatures ranging from room temperature to 60° C. Various types of Raney-nickels can be used as the catalyst in this reduction reaction, however, Raney-nickel of W-2 type or a similar type thereof is preferably used.
In step b)—protection of the amino group, any suitable amino protecting group may be used. The protecting group is preferably removable under acidic conditions. Examples of protecting groups include formyl, acetyl, trifluoroacetyl, benzoyl, para-toluenesulfonyl, methoxycarbonyl, ethoxycarbonyl, t-buthoxycarbonyl, benzyloxycarbonyl, para-methoxybenzyl, trityl, tetrahydropyranyl and pivaloyl. Particular protecting groups that may be mentioned include acetyl, t-buthoxycarbonyl, and pivaloyl. The preferred protecting group for both P
1
and P
2
is t-butoxycarbonyl. Protection of the amino group may be achieved using conditions familiar to those skilled in the art. For example by reaction of the compound of formyla (6) with a suitable base, e.g. selected from the group consisting of lithium t-butoxide, lithium isopropoxide, potassium t-butoxide, sodium t-butoxide, and lithium chloride, sodium hydroxide and potassium hydroxide. The base is suitably used in an amount of 2.0 molar equivalents or more, preferably 2.0 to 4.0 molar equivalents with respect to the compound of formula (6). Any solvents conventionally used in organic reactions,
Chang Jay Hyok
Kim Won Sup
Lee Tae Hee
Moon Kwang Yul
D'Souza Andrea M.
Henderson Loretta J.
King William T.
Kinzig Charles M.
Lambkin Deborah C.
LandOfFree
Process for preparing a protected 4-aminomethyl-pyrrolidi-3-one 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 preparing a protected 4-aminomethyl-pyrrolidi-3-one, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for preparing a protected 4-aminomethyl-pyrrolidi-3-one will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2588227