SYNTHESIS OF QUETIAPINE AND PHARMACEUTICALLY ACCEPTABLE
SALTS THEREOF
RELATED APPLICATIONS
The present application claims the benefît of the February 22, 2003 filing date of United States Provisional Patent Application 60/448,934.
FPELD OF THE INVENTION
The prcsent invention relates to synthesis of quetiapine and pharmaceuticaHy acceptable salts thereof.
BACKGROUND OF THE INVENTION
The structure of quetiapine, 2-(2-(4-dibenzo[&t/][l,4Jthiazepm-ll-yl-l-piperazinyl)ethoxy)ethano], is shown below (I).
(Figure Removed)
Quetiapine is a psychoactive organic compound that is an antagonist for multiple neurotransmitter receptors in the brain. Merck Index, 13th Ed., 8130 (2001). Quetiapine is an anu'psychotic agent useful for treating, among other things, schizophreriia. Quetiapine can be made, for example, as taught in United States Patent 4,879,288, iiicorporated in its entirety herein by reference.
As taught ui the '288 patent, quetiapine can be made m reaction of 11-piperazinyl dibenzo[Z),/]-[l,4]tliiazepiiiehydrochloride and 2-(2-chloroethoxy)ethanol in a
solvent. Reaction times are long (e.g. 24 hours). Also, starting materials such as the 11-piperazinyl dibenzofA/j-fl^Jthiazepine are undesired in the product and can be difficult to remove from the product.
There is a need for an improved process for making quetiapine from 11-piperazinyl diben2o[Z>jQ-[l,4]thiazepine allowing shorter reaction tirnes and affording a quetiapine product that contains a lower level of impurities (such as the unreacted starting material).
SUMMARY OF THE INVENTION
In one aspect, the present method relates to a process for making quetiapine comprising the step of reacting 11-piperazinyl dibeiizo[&t/]-[l,4]thiazepine hydrochloride and 2-(2-chloroethoxy)ethanol in a solvent, especially n-butanol, toluene, or dimethyl formamide, in the presence of a base, especially an inorganic base, most especially sodium carbonate, a phase transfer catalyst, especially tetrabutylammonium bromide, and, optionally, an alkali metal halide, especially sodium iodide.
In another aspect, the present invention relates to quetiapine made by the foregoing process.
In yet another aspect, the present invention relates to a process for making quetiapine heminimarate including the steps of: reacting 11-piperazinyl dibenzo[6,/]-[l,4]thiazepine hydrochloride and 2-(2-chIoroethoxy)ethanol in a solvent, especially «-butanol, toluene, or dimethyl formamide, in the preseuce of a base, especially an inorganic base, most especially sodium carbonate, a phase transfer catalyst, especially tetrabutyammonium biomide, and, optionally, an alkali metal halide, especially sodium iodide, whereby a fîrst slurry is obtained; separating the solid from the fîrst slurry, whereby a liquid filtrate is obtained; combining the liquid filtrate with fumărie acid, whereby a second slurry is obtained; and isolating quetiapine hemifumarate from the second slurry. In this aspect, the present invention also relates to recrystallizion of the quetiapine heminimarate so obtained from a solvent, that is a lower alkanol, especially ethanol, or amixture of water and a dipolar aprotic solvent, especially dimethyl formamide.
In still a further aspect, the present invention relates to a pharmaceutical composition, and dosage forms thereof, including at least one pharmaceutically acceptable excipient and quetiapine hemijfumarate made by the foregoing described
process in any of its embodiments.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a process of making quetiapine - 11-[4-[2-(2-hydroxyethoxy)ethyl]-l-piperazin.yl]dibenzo[6,_/]-[l,4]tbiazepine - in shorter time and with lower amounts of dif5cult-to-remove residual 11-piperazinyl dibenzo[6,/|-[l,4]thiazepine than hîtherto reaHzable with the methods of the prior art. The process of the present invention is readily adapted to encompass the preparation of pharmaceutically acceptable salts of quetiapine, especially quetiapine hemifumarate.
As used herein, slurry refers to undissolved particles in a liquid.
The process of the present invention includes the step of reacting, in a suitable vessel, preferably with agitation (e.g. stirring), 11-piperazinyl dibenzo[&/)]-[l,4]thiazepiue with 2-(2-chloroethoxy)ethanol in a solvent in the presence of a base, a phase transfer catalyst, and, optionally, an alkali metal halide. The reacting is preferably at a temperature greater than about 100°C, especially at reflux. The skilled artisan understands that reference to 11-piperazinyl dibenzo[& but can be substituted with one or more linear or branched C i - Q alkyl groups; or other groups that do not interfere with the reaction. Toluene (n = 6, methyl substituent) and xylene are particularly preferred aromatic hydrocarbons for use in the practice of the present invention.
The so-called dipolar aprotic solvent are well known as such in the art. Such solvents have a permanent dipole, but no readily removeable hydrogen atoms. Examples of well-known dipolar aprotic solvents include dimethyl formamide (DMF), dimethyl acetamide (DMAC), dimethy sulfoxide (DMSO), N-methyl pyrrolidone (NMP) and the like. Dimethyl formamide is a preferred dipolar aprotic solvent for use in the practice of the present invention in its several embodiments.
The solvent used can also be a mixture of one or more of the same or different classes (types) of solvent described above.
The base used in the practice of the present invention can be an inorganic base. Inorganic bases are inorganic compounds that are capable of reacting with and neutralizing an acid, especially a Brenstead acid. Examples of inorganic bases include alkali metal and alkalme earth metal oxides, hydroxides, bicarbonates, and carbonates. Alkali metal carbonates, especially sodium carbonate, are preferred inorganic bases for use in the practice of the present invention.
When an opţional alkali metal halide is used, sodium iodide is the preferred alkali metal halide.
11-Piperazinyl dibenzo[b,fj-[l,4]tliia2:epmehydrochloride , 2-(2-chloroethoxy)ethanol, solvent, base, alkali metal halide, and phase transfer catalyst are
combined, in any order, in a suitable reaction vessel that is preferably equipped with an agitator.
The relative molar amounts of the materials combined are not criticai. Typicaily, the mo Iar amount of chloroethoxy ethanol will be l to 2 times the molar amount of the thiazepine hydrochloride; the molar amount of base will be 4 to 8 times the molar amount of the thiazepine hydrochloride; and the amount of alkali metal iodide will be a fraction of the molar amount of thiazepine hydrochloride. The phase transfer catalyst is used in an amount of about 0.1% to about 0.7% on a weight basis. Typically, the reaction mixture will initially be about 0.5M to 1.5M in the thiazepine hydrochloride, but higher or lower concentrations can be used whilst realizing the benefits of the present invention.
The contents of the reaction vessel are preferably protected from excessive atmospheric water by providing a pad of dry inert gas over the reaction mixture, or by isolating the interior of the reaction vessel from the environment through a desiccant (e.g. molecular sieves, CaCla, or the like). The contents of the reaction vessel are heated to a reaction temperature of from about 80°C to about 100°C or higher, preferably to the reflux temperature. The reaction mixture is held at .the reaction temperature for a reaction time of about 12 to about 24 hours. Typically, a reaction time of about 17 hours is sufficient. At the end of the reaction time, the reaction is a soh'd/liquid slurry.
The two-phase (s/l) reaction mixture is cooled and the solid phase separated by a suitable means whereby a liquid filtrate containing the product (quetiapine base) is obtamed. The separation can be by any means known in the art, for example filtration (gravity or suction) or centrifugation - decanting, to mention just two.
The product quetiapine base can be isolated from the filtrate by any means known in the art, for example distillation / evaporation of the solvent, preferably at reduced pressure (< 100 mm Hg).
Pharmacutically acceptable acid addition salts are salts obtainable from quetiapine base by qutemarization of at least one amine functionality in the product; can be readily processed to the desired dosage form; and are nontoxic at the dosages used. The isolated quetiapine can be converted to apharmaceutically acceptable acid addition salt by dissolving it in a salinization solvent and combining the solution so obtained with the desired acid, for example fumărie acid. Typically, the acid addition salt will precipitate from the solvent upon cooling (if not before) and can be isolated by any means known in
the art, for example fîltration (gravity or suction) or centrifugation - decanting, to mention just two. Salinization solvents useful in the practice of the present invention include water, alcohols (e.g. methanol, butanol), esters (e.g. ethyl or butyl acetate), ketones (e.g. acetone), DMF, DMSO, or mixtures of solvents like DMSO/chlorofonn, DMF/water, or NMP/acetonitrile.
hi another and preferred embodiment, the quetiapine product is converted to a pharmaceutically acceptable acid addition salt, preferably the hemifumarate, without being isolated from the fîrst filtrate, hi this erabodiment, fîrst liquid filtrate is obtained as above and combined with the desired axnount of acid, e.g. fumărie acid. The resulting combination is optionally heated to about 100° C and thereafter cooled, whereby a second slurry, containing solid acid addition salt, is obtained. The pharmaceutically acceptable acid addition salt is isolated from the second slurry by any means known in the art, for example filtration (gravity or suction) or centrifugation - decanting, to mention just two. Jf desired, the pharmaceutically acceptable acid addition salt can be recrystallized using, for example, any of the salinization solvents mentioned above. hi particular, the crude quetiapine hemifumarate can be advantageously recrystallized from a solvent that is a lower alkanol, preferabiy ethanol, or a mixture of water and a dipolar aprotic solvent, preferably dimethyl formamide.
Quetiapine or, preferably, an acid addition salt thereof, most preferably quetapine hemiftimarate, obtained by the process of the present invention can be formulated into pharmaceutical compositions, preferably in a dosage form suitable for oral or parenteral adrninistration by methods known hi the art.
The pharmaceutical compositions of the present invention can be m the form of a dosage form and prepared using diluents or phannaceuticaU acceptable excipients such as carriers, fillers, bulking agents, binders, wetting agents, disintegrating agents, surface active ageuts, lubricants, and the like. For the pharmaceutical compositions, various types of adrninistration unit forms can be selected depending on the therapeutic purpose, for example tablets, pills, powders, h'quids, suspensions, emulsions, granules, capsules, suppositories, injectkm preparations (solutions and suspensions), and the like. Any excipient commonly known and used widely in the art and that is pharmaceutically acceptable (e.g. nontoxic at the levels consumed with tlie quetiapine hemiftimarate) can be used in the pharmaceutical composition. Carriers include, but are not limited to, lactose, white sugar, sodium chloride, glucose, urea, starch, calcium
carbonate, kaolin, crystalline cellulose, and silicic acid. Binders include, but are not limited to, water, ethanol, propanol, simple syrup, glucose solutions, starch Solutions, gelatin solutions, carboxymethyl cellulose, shelac, methyl cellulose, potassium phosphate, and polyvinylpyrrolidone. Disintegrating agents include, but are not limited to, dried starch, sodium alginate, agar powder, laminalia powder, sodium hydrogen cai-bonate, calcium carbonate, fatty acid esters of polyoxyethylene sorbitan, sodium laurylsulfate, monoglyceride of stearic acid, starch, and lactose. Disintegration inhibitors include, but are not limited to, white sugar, stearin, coconut butter, and hydrogenated oils. Absorption accelerators include, but are not limited to, quaternary ammonium base and sodium laurylsulfate. Wetting agents include, but are not limited to, glycerin and starch. Adsorbing agents include, but are not limited to, starch, lactose, kaolin, bentonite, and colloidal silicic acid. Lubricants include, but are not limited to, purified talc, stearates, boric acid powder, and polyethylene glycol. Tablets can be further coated with commonly known coating materials such as sugar coated tablete, gelatin film coated tablets, tablets coated with enteric coatings, tablets coated with fîkns, double layered tablets, and multi-layered tablets.
When shaping the pharmaceutical composition into an oral solid dosage form, any commonly known excipient used ui the art can be used. For example, carriers include, but are not limited to, lactose, starch, coconut butter, hardened vegetable oils, kaolin, and talc. Binders include, but are not limited to, gum arabic powder, tragacanth gum powder, gelatin, and ethanol. Disintegrating agents include, but are not limited to, agar, and laminalia.
For the purpose of shaping the phannaceutical composition in the form of suppositories, any commonly known excipient used in the art can be used. For example, excipients include, but are not limited to, polyethylene glycols, coconut butter, higher alcohols, esters of higher alcohols, gelatin, and semisynthesized glycerides.
When preparing injectable (parenteral) pharmaceutical compositions, solutions and suspensions are sterilized and are preferably made isotonic to blood. Injection preparations may use carriers commonly kno\vn in the art. For example, carriers for injectable preparations include, but are not limited to, water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and fatty acid esters of polyoxyethylene sorbitan. One of ordinary ski U in the art can easily determine with little or no experimentation the amount of sodium chloride, glucose, or glycerin
necessary to make the injectable preparation isotonic. Additional ingredients, such as dissolving agents, buffer agents, and analgesic agents raay be added. If necessary, coloring agents, preservatives, perfumes, seasoning agents, sweetening agents, and other medicines may also be added to the desired preparations.
The amotint of queriapine hemifumarate contained in a pharmaceurical composition is not specifically restricted, however, the dose should be sufficient to treat, ameliorate, or reduce the symptoms associated with the psycological disease or disturbance being treated.
Methods of administration of a pharmaceutical composition of the present invention are not specifically restricted, and can be administered in various preparations depending on the age, sex, and symptoms of the patient. For example, tablets, pills, solutions, suspensions, eraulsions, granules and capsules may be orally administered. Injection preparations may be administered individually or mixed with injection transfusions such as glucose solutions and amino acid solutions intravenously. If necessary, the injection preparations are administered singly intramuscularly, intracutaneously, subcutaneously or intraperitoneally. Suppositories may be administered into the rectura.
The dosage of a pharmaceutical composition according to the present invention will depend on the method of.use, the age, sex, and condition of the patient
The present invention is certain of its embodiments is illustrated by the following nonlimiting working and comparative examples.
Example l
Reagents:
11-piperazinyl dibenzo[£