Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Reexamination Certificate
2000-07-26
2002-05-14
Ford, John M. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
Reexamination Certificate
active
06388073
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to 6,7-dichloro-1,5-dihydroimidazo[2,1-b]quinazolin-2(3H)-one (compound III), more commonly known as Anagrelide base and, more particularly, to a method for the manufacture of Anagrelide base.
2. Description of Related Art
Anagrelide (6,7-dichloro-1,5-dihydroimidazo[2,1-b]quinazolin-2(3H)-one, (compound III) is a potent blood platelet reducing agent. A number of U.S. Patents have issued on Anagrelide and its method of making including U.S. Pat. Nos. 3,932,407; 4,146,718; 4,208,521; 4,357,330; Re 31,617; and 5,801,245. These patents are incorporated herein by reference.
Commercially, as discussed in U.S. Pat. No. 5,801,245 and as shown in FIG. 1, Anagrelide has been prepared as the hydrochloride monohydrate (compound IV) from the intermediate, ethyl N-(6-amino-2,3-dichlorobenzyl)glycine (compound I) by reaction with cyanogen bromide in hot alcohol solution, or, preferentially, by reaction with cyanogen bromide in an aprotic solvent to give the iminoquinazoline intermediate (compound II) which is isolated and then reacted with a base in a hot solution of alcohol to form Anagrelide base (compound III).
FIG. 1
The hydrochloride monohydrate Anagrelide salt (compound IV) is prepared by adding hydrochloric acid to a methanol slurry of Anagrelide base (compound III) and heating to reflux. The hydrochloride salt is then hydrated in a high humidity chamber. These two steps are time-consuming however, and the yield of hydrochloride salt can be poor due to competing acid hydrolysis of the lactam ring and methyl ester formation. After 15 minutes at reflux, the isolated yield is 62% and this decreases to 40% after 2 hours.
Normally, salts are prepared when the free base has undesirable properties such as poor solubility or a non-solid physical state. In this case, both Anagrelide base (compound III) and the hydrochloride salt (compound IV) are solids with low aqueous solubility. In addition, the water of crystallization can accelerate decomposition of the parent molecule through hydrolysis of the lactam ring and this presents long-term stability problems for pharmaceutical Anagrelide formulations.
Radiolabeled Anagrelide base has been used in pharmacokinetic studies in humans and monkeys and results show complete absorption into blood plasma demonstrating that the base is bioavailable. The free-base is converted into the hydrochloride salt in the stomach to enhance absorption. Both the salt and the base exhibit equivalent pharmacological effects, and there is no inherent advantage to using the hydrochloride monohydrate salt as the active pharmaceutical agent.
As an important intermediate in the synthesis of Anagrelide, ethyl N-(6-amino-2,3-dichlorobenzyl)glycine (compound I) has been prepared from 2,3-dichloro-6-nitrobenzylamine (compound V) as shown in FIG. 2. This material is no longer commercially readily available, however, as the precursor 2,3-dichloro-6-nitrobenzonitrile has extreme toxic and skin-irritant properties.
FIG. 2
The conventional process for the formation of ethyl N-(6-amino-2,3-dichlorobenzyl)glycine (compound 1) from 1,2,3-trichlorobenzene is shown in U.S. Pat. No. 4,146,718.
An improved process for the formation of ethyl-N-(6-amino-2,3-dichlorobenzyl)glycine (compound 1) involving the intermediate 2,3-dichloro-6-nitrobenzyl halide (compound VIII), where halide is iodide, chloride or bromide, has been developed as an environmentally acceptable alternative (FIG. 3). The route of preparation from 2,3-dichloro-6-nitro-toluene (compound VII) is claimed in U.S. Pat. No. 5,801,245, and involves a radical halogenation of the toluene group. Radical conditions can be nonselective, however, and could be difficult to effectively implement in large-scale commercial manufacture.
FIG. 3
In both reactions shown in FIGS. 2 and 3, ethyl N-(2,3-dichloro-6-nitrobenzyl)glycine (compound VI) is reduced to the 6-amino-2,3-dichlorobenzyl glycine (compound I) by stannous chloride reduction (SnCl
2
/HCl). A disadvantage of this route is the formation of large amounts of tin-containing waste products. In addition, the strongly acidic reaction conditions can promote chlorination of the aromatic ring, producing a mixture of tri-chloro impurities which are difficult to remove in successive steps.
Bearing in mind the problems and deficiencies of the prior art, it is therefore an object of the present invention to provide a method for the making of Anagrelide HCl (compound IV) and Anagrelide base (compound III).
It is an additional method of the present invention to make intermediate 2,3-dichloro-6-nitrobenzyl chloride (compound VIII) from readily available starting materials.
It is another object of the present invention to provide a method for making intermediate ethyl-(6-amino-2,3-dichlorobenzyl)glycine (compound I) from ethyl N-(2,3-dichloro-6-nitrobenzyl)glycine (compound VI) using either SnCl
2
or a hydrogenation catalyst as the reducing agent.
A further object of the present invention is to provide a method for the cyclization of 5,6-dichloro-3,4-dihydro-2(1H)iminoquinazoline-3-acetate HBR (compound II) to form Anagrelide base (compound III).
Still other objects and advantages of the present invention will in part be obvious and will in part be apparent from the specification.
SUMMARY OF THE INVENTION
The above and other objects, which will be apparent to those skilled in the art, are achieved by the present invention which relates in a first aspect to an environmentally acceptable method for making the intermediate 2,3-dichloro-6-nitrobenzyl chloride (compound VIII) from readily available starting materials (FIG. 4). As shown in FIG. 4, 2,3-dichlorobenzaldehyde (compound IX) is nitrated preferentially at the 6-position to form 2,3-dichloro-6-nitro benzaldehyde (compound X), separated from its isomer, and reduced to 2,3-dichloro-6-nitrobenzyl alcohol (compound XI) under standard hydride conditions. Treatment of the alcohol under standard nucleophilic displacement conditions gives 2,3-dichloro-6-nitrobenzyl chloride (compound VIII).
FIG. 4
The above compounds can also contain substituents such as F,Cl, Br and I and the like. Further, the 2,3 chlorine atoms may likewise be substituted with substituents such as F, Br and I. This will also apply to the other reaction schemes shown hereinbelow and for convenience the description will be directed to the desired unsubstituted dichloro compounds.
Ethyl N-(2,3-dichloro-6-nitrobenzyl)glycine (compound VI) is then produced by reaction of 2,3-dichloro-6-nitrobenzyl chloride (compound VIII) with ethyl glycine, compound VI reduced to form compound I which is reacted to form compound II and then cyclized to form Anagrelide base (compound III) as shown below:
Alternatively, compound VI can be made directly from 2,3-dichloro-6-nitro benzaldehyde (compound X) by reductive amination with a glycine ester as shown in FIG. 5. This is a novel approach to the known intermediate compound VI, which intermediate is reduced to compound I by either catalytic hydrogenation or by stannous chloride preferably following the method of the invention.
FIG. 5
Normally, catalytic hydrogenation of aromatic chloro compounds such as ethyl N-(2,3-dichloro-6-nitrobenzyl)glycine (compound VI) is accompanied by excessive dechlorination, however, it has been found that a specially defined poisoned catalyst (for example, sulfided platinum on a carbon support) allows the selective reduction of the nitro group without significant chlorine loss at moderate hydrogen pressures. Other catalysts include Raney nikel, rhodium or palladium on a carbon support. This is an environmentally acceptable alternative to the tin-acid reductions conventionally used in the preparation of Anagrelide since the heterogeneous poisoned catalyst can be recycled. This novel method eliminates the production of large quantities of tin-containing waste of the prior art and produces material in higher yield and purity than the conventional route. Though this selective catalytic hydrogenation is preferable, this inventi
Lang Philip C.
Roth Michael Joseph
Spencer Roxanne P.
Yeh Wen-Lung
DeLio & Peterson LLC
Ford John M.
Shire US Inc.
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