Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2003-12-23
2004-10-12
Morris, Patricia L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06803467
ABSTRACT:
The present invention relates to novel compounds which are of use in the production of pharmaceutically active compounds, for example, quinolone carboxylic acid derivatives having antibacterial activity.
EP 688772 discloses novel naphthyridine carboxylic acid derivatives having antibacterial activity, including anhydrous (R,S)7-(3-aminomethyl4-methoxyiminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid of the formula:
WO 98142705 discloses (R,S)-7-(3-aminomethyl-4syn-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.
PCT/KR99/00099 (published after the priority date of the present application) discloses a process for the production of 4-aminomethyl-3-alkoxyiminopyrrolidines and salts thereof from aminomethylpyrrolidin-3-one and the corresponding alkoxylamine. Suitable salts of the 4-aminomethyl-3-alkoxyiminopyrrolidines are described as the hydrochloride, trifluoroacetate and sulfate salts.
The present invention relates to novel 4aminometyl-3-alkoxyiminopyrrolidine salts which arm of use in the synthesis of pharmaceutically active compounds.
According to the invention there is provided a compound of formula (I):
wherein R is C
1-4
alkyl or C
1-4
haloalkyl.
The compound of formula (I) is preferably 4-aminomethyl-3-methoxyiminopyrrolidinium dimethanesulfonate.
According to a further aspect of the invention there is provided a process for the production of a compound of formula (I) which comprises reaction of a compound of formula (II):
wherein R is as defined for formula (I) and P
1
and P
2
, which may be the same or different, are amino protecting groups, with metlanesulfonic acid.
Suitable protecting groups P
1
and P
2
include any suitable amino protecting groups which are removable by treatment with methanesulfonic acid. The preferred protecting group for both P
1
and P
2
is t-butoxycarbonyl.
The reaction of the compound of formula (II) and methanesulfonic acid is suitably carried out at a temperature between about 10° C. and about 50° C., more preferably at a temperature of 40-45° C.
The amount of methanesulfonic acid used to effect the deprotection of the compound of formula (II) is suitably 2 to 4 equivalents. For example, 2.4 equivalents, suitably used at a temperature of between 35° C. and 40° C.; or 3 equivalents, suitably used at ambient temperature. More preferably 2.5 equivalents used at a temperature of 40-45° C.
The reaction is suitably carried out in a solvent, for example, an alcohol such as methanol, ethanol, isopropanol or n-propanol, dichloromethane, acetonitrile, acetone, methyl iso-butyl ketone, DME, THF, tert-butylmethyl ether, dioxane or ethyl acetate or a mixture of any of these. The solvent is preferably methanol. Suitably, up to 10 equivalents by volume of solvent may be used, e.g. about 4 equivalents.
The compounds of formula (II) may be prepared by the processes described in U.S. Pat. No. 5,633,262, EP 688772 and PCT/KR99/00099.
The compounds of formula (I) are useful as an intermediates for preparing quinolone antibacterials particularly those described in U.S. Pat. No. 5,633,262 and EP 688772. Thus according to a further aspect of the invention there is provided a process for the production of a compound of formula (III), or a pharmaceutically acceptable salt and/or hydrate thereof:
wherein R is as defined for formula (I), which comprises reaction of a compound of formula (I), with a compound of formula (IV):
wherein X is a leaving group, e.g. a halogen atom, preferably chlorine; and optionally forming a pharmaceutically acceptable salt and/or hydrate thereof.
Other suitable leaving groups X will be apparent to those skilled in the art.
The reaction of the compounds of formulae (I) and (IV) is preferably conducted in the presence of a base e.g. triethylamine. The reaction of the compounds of formulae (I) and (IV) is preferably conducted in a solvent, e.g. acetonitrile, an aqueous solvent such as aqueous acetonitrile or an aqueous alcohol and more preferably water. When water is used as solvent for this process the resulting compound of formula (III) is of superior quality to that obtained using other solvents. This leads to an improvement in the quality of the resulting drug substance as well as a process that may offer environmental advantages. Further details regarding the reaction of the compounds of formula (I) and (IV) can be found in U.S. Pat. No. 5,633,262 and EP 688772. The compounds of formula (IV) may be synthesisied as described in U.S. Pat. No. 5,633,262 and EP 688772.
The compound of formula (III) produced according to this aspect of the invention is preferably (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 or a hydrate thereof, preferably the sesquihydrate, as disclosed in WO 98/42705. The methanesulfonate and hydrates thereof may be synthesised from the free acid as described in WO 98/42705 and WO 00/17199.
The compounds of the invention have the advantage that they are stable, i.e. not hygroscopic. They can be isolated from the reaction in higher yield and purity than the corresponding dibydrochloride or free base. The dimesylate salts can be recrystallised if necessary, whereas the corresponding dihydrochloride or free base has not been successfully recrystallised. The dimesylate salts can be used to produce quinolone antibacterials of high purity and several advantages result from using this intermediate. For example, when the resulting drug substance is (R,S)-7-3-aminomethyl-4-syn-methoxyiminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid methanesulfonate or a hydrate thereof it has improved colour and significantly lower levels of high molecular weight impurities compared to the drug substance produced using the corresponding dihydrochloride or free base as intermediate.
All publications, including but not limited to patents and patent applications cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.
The invention is illustrated by the following examples. However, it should be understood that the examples are intended to illustrate but not in any manner limit the scope of the invention.
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Grinter Trevor
Howie Simon
Finnegan Henderson Farabow Garrett & Dunner L.L.P.
LG Life Sciences Limited
Morris Patricia L.
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