Process for preparing...

Details Process for preparing... Process for preparing...

2002-04-25

2004-11-30

Peselev, Elli (Department: 1623)

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

Organic compounds

Carbohydrates or derivatives

C536S018500

Reexamination Certificate

active

06825327

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to processes for preparing C-4″ substituted derivatives of 9-deoxo-9a-aza-9a-homoerythromycin A (hereinafter, “azalide(s)”) that are useful as antibacterial and antiprotozoal agents in mammals, including man, as well as in fish and birds. This invention also relates to processes for preparing stable intermediates of the subject azalides, as well as to a crystalline salt of an intermediate in the process for preparing the subject azalides. This invention also relates to pharmaceutical compositions containing the novel compounds made by the subject processes and to methods of treating bacterial infections and protozoa infections in mammals, fish and birds by administering the novel compounds produced by the subject processes to mammals, fish and birds requiring such treatment.
Macrolide antibiotics are known to be useful in the treatment of a broad spectrum of bacterial infections and protozoa infections in mammals, fish and birds. Such antibiotics include various derivatives of erythromycin A such as azithromycin which is commercially available and is referred to in U.S. Pat. Nos. 4,474,768 and 4,517,359, both of which are incorporated herein by reference in their entirety. Like azithromycin and other macrolide antibiotics, the macrolide compounds of the present invention possess potent activity against various bacterial infections and protozoa infections as described below.
The production of the subject azalides at commercial scale has presented several difficulties, including, but not limited to, poor yields and instability of some synthetic intermediates, as well as the presence of undesirable impurities.
SUMMARY OF THE INVENTION
The present invention relates to a process for preparing a compound of the formula 1
or a pharmaceutically acceptable salt thereof, which comprises:
reacting a compound of formula 2
with an amine of the formula HNR
8
R
15
, in an organic solvent comprising isopropanol;
wherein the reaction is carried out at a temperature of at least about 40° C.;
wherein:
R
3
is —CH
2
NR
8
R
15
;
R
8
is C
1
-C
10
alkyl; and
R
15
is H or C
1
-C
10
alkyl.
In a preferred embodiment of the process, R
8
is propyl and R
15
is H. In a particularly preferred embodiment, R
8
is n-propyl and R
15
is H.
In a particularly preferred embodiment, the organic solvent is isopropanol.
In another preferred embodiment, the invention relates to a process for
preparing a compound of the formula 1a or a pharmaceutically acceptable salt thereof,
by reacting a compound of formula 2 with n-propylamine in an organic solvent comprising isopropanol; wherein the reaction is carried out at a temperature of at least about 40° C. In a particularly preferred embodiment thereof, the organic solvent is isopropanol.
It is to be noted that the terms “solution” and “mixture”, as used herein, unless otherwise indicated, are used interchangeably without regard to the state of dispersion of the components thereof. The phrase “organic solvent comprising isopropanol” as used herein, unless otherwise indicated, means a non-aqueous solvent or mixture of non-aqueous solvents, wherein at least one solvent is isopropanol. In this application, the term “compound of formula 1” includes both the compound of formula 1 and the compound of formula 1a. The compound of formula 1a is a particularly preferred embodiment of the compound of formula 1, to which all of the embodiments and preferred embodiments of the processes described herein apply.
In an embodiment of the processes described herein, the temperature is less than about 95° C., and in a preferred embodiment thereof, the temperature is less than about 80° C. In a more preferred embodiment thereof, the temperature is from about 50° C. to about 76° C. In a particularly preferred embodiment thereof, the temperature is from about 50° C. to about 55° C.
In a preferred embodiment of the processes described herein, the reaction is carried out at about atmospheric pressure. In this application, the term “atmospheric pressure” means a pressure within the normal range of meteorologic atmospheric pressure for a particular altitude, while the term “elevated pressure” means a pressure above atmospheric pressure. In another embodiment of the processes described herein, the reaction is carried out at elevated pressure. In another embodiment of the invention, triethylamine may be present in addition to isopropanol.
In addition to applicants' preferred embodiments, the reaction of the compound of formula 2 with an amine to produce the compound of formula 1 has been successfully performed in solvents other than those comprising isopropanol. Accordingly, this invention also relates to a method for preparing a compound of formula 1 by reacting a compound of formula 2 with an amine of the formula HNR
8
R
15
, in an organic solvent, wherein the solvent is selected from the group consisting of benzyl alcohol, acetone, methylisobutylketone, DMSO, t-butanol, n-butanol, diisopropylether, a mixture of MTBE and DMF, and combinations thereof, wherein the reaction is carried out at a temperature of at least about 40° C. The reaction may be carried out at elevated pressures, but is preferably carried out at about atmospheric pressure. In a further embodiment thereof, the reaction is accelerated by the addition of a catalytic amount of a Lewis acid. In an embodiment thereof, the Lewis acid is a reagent such as magnesium bromide, potassium iodide, lithium perchlorate, magnesium perchlorate, lithium tetrafluoroborate, pyridinium hydrochloride, or tetrabutylammonium iodide. Preferably, the Lewis acid is magnesium bromide.
In an embodiment of the processes described herein, the molar amount of amine is at least about five times the molar amount of the compound of formula 2. In another embodiment of the processes described herein, the concentration of amine in isopropanol is at least about 5 molal. In a particularly preferred embodiment, the concentration of n-propylamine is approximately 6-7 molal in isopropanol.
In an embodiment of the above processes, the compound of formula 2 is reacted with the amine for at least about 24 hours. In a preferred embodiment thereof, the molar amount of the amine is at least about five times the molar amount of the compound of formula 2 and the compound of formula 2 is reacted with the amine for at least about 24 hours. In a more preferred embodiment thereof, the temperature is from about 50° C. to about 80° C. In a still more preferred embodiment thereof, the molar amount of the amine is about twenty times the molar amount of the compound of formula 2, the concentration of amine in isopropanol is about 6 molal, and the compound of formula 2 is reacted with the amine for at least about 24 hours at a temperature of from about 50° C. to about 55° C.
Another embodiment of the processes described herein further comprises crystallizing the free base form of the compound of formula 1. In an embodiment, the free base form of the compound of formula 1 is crystallized from an aqueous solvent mixture. In a preferred embodiment thereof, the aqueous solvent mixture comprises water and a non-aqueous solvent selected from the group consisting of methanol, ethanol, isopropanol and acetone. In another embodiment the free base form of the compound of formula 1 is crystallized from an organic (C
6
-C
10
)alkane solvent or mixture of such organic alkane solvents. In a preferred embodiment thereof, the compound of formula 1 is crystallized by heating the compound together with the alkane solvent followed by cooling to effect crystallization. In a preferred embodiment thereof, the organic (C
6
-C
10
)alkane solvent is selected from heptane or octane, most preferably heptane. In another embodiment, as described below, the free base is prepared from an acid addition salt of the compound of formula 1. It is to be understood that “alkane” as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbons having straight, cyclic or branched moieties, or mixtures thereof.
In a further embodiment of

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