Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
  • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D495/04—Ortho-condensed systems

Definitions

• the present invention relates to a method of making olanzapine including olanzapine salts, and intermediates therefor.
• Olanzapine or 2-methyl-4-[4-methyl-l-piperazinyl]-10H-thieno[2,3b][l,5]- benzodiazepine is a pharmaceutically active compound that can be represented by the formula (1).
• Olanzapine acts as a serotonin (5-HT2) and dopamine (D1/D2) receptor antagonist with anticholinergic activity.
• the active substance is marketed as a free base, which is a white to yellow crystalline solid that is insoluble in water.
• One synthetic route for making olanzapine starts from "des-methylpiperazine olanzapine precursor" of formula (3), which reacts with piperazine to form a " des-methyl olanzapine precursor” of formula (2) (see Jun-Da Cen , Chinese Journal of Pharmaceuticals 2001, 32(9),391-393).
• the compound (2) can be methylated to form olanzapine (see US 4,115,568 for such suggestion).
• the methylation reaction can be carried out using formaldehyde under conditions of Eschweiler-Clarke reaction (see Jun-Da Cen) or by classical methylation agents such as methyl iodide (see WO 04-000847).
• a first aspect of the present invention relates to a process, which comprises reacting a des-piperazine olanzapine of formula (3) or a salt thereof (3) with an N- formyl piperazine of formula (5) CHO N (5) H to form an N- formyl olanzapine of formula (4) or a salt thereof
• the reaction can be carried out in an inert solvent, generally a dipolar aprotic solvent, and is typically accomplished by heating.
• the N-formyl olanzapine can be converted to olanzapine.
• Another aspect of the invention relates to a process for making an olanzapine salt, which comprises: reducing an N-formyl olanzapine of formula (4) or a salt thereof
• a further aspect of the present invention relates to purifying the N-formyl olanzapine, which process comprises: (1) dissolving and/or slurrying an N-formyl olanzapine of formula (4)
• steps (l)-(3) can be repeated if necessary until the desired purity is reached. Generally, such a process can achieve purity of greater than 95% and preferably greater than 98%.
• the present invention relates to the discovery that the intermediate N-formyl olanzapine can be provided in relatively high purity and converted to olanzapine in high purity. Because N-formyl olanzapine does not suffer from the ready formation of polymorphs, in contrast to olanzapine base, it may be isolated and purified in a reliable process, easily applicable to an industrial scale. Preferred embodiments of the invention can achieve solid state olanzapine base or salt thereof in a purity of at least 98%, preferably more than 99% and more preferably more than 99.5% (calculated on an anhydrous and/or" ⁇ solvent- free basis). Such a pharmaceutical grade olanzapine product is suitable for being formulated into pharmaceutical compositions.
• An overall synthetic scheme for making olanzapine, which combines various aspects of the present invention, is set forth below:
• the first step reacts des-piperazine olanzapine of formula (3), shown as the HCI sart thereof in this scheme, with N-formyl piperazine (5) to produce N-formyl olanzapine (4).
• the starting compounds (3) and (5) are commercially available and/or readily obtained by methods known in the art. In comparison with the prior art suggestion discussed above, this represents a simplified way to obtain (4).
• the acid addition salt e.g. hydrochloride
• N-formyl piperazine (5) react together by heating in an inert solvent for a time sufficient for conversion. The conversion can be complete.
• the progress of the reaction may be monitored by a suitable method including HPLC, etc.
• a suitable inert solvent is generally a dipolar aprotic solvent especially a mixture of dimethyl sulfoxide and toluene.
• the reaction is normally carried out at elevated temperatures such as 40°C to reflux of the solvent, and typically within 10°C of the reflux temperature; i.e. a temperatufe at, or near, the reflux temperature.
• the reaction typically runs for 1 to 24 hours, generally 4- 12 hours depending upon the scale, the temperature, the concentrations, the conversion level desired, etc.
• the product may be isolated in a solid state by diluting the reaction mixture with water.
• the isolated product comprises approximately 90% of the compound (4), i.e. the product is obtainable in approx. 90% quality.
• the next step shown in the overall reaction scheme involves purifying the compound (4).
• the crude N-formyl-olanzapine (4) is purified by crystallization from a solvent selected from the group consisting of a lower aliphatic alcohol, e.g., a C1-C4 alcohol such as methanol, or an aromatic hydrocarbon, e.g., a benzene substituted by 0-2 methyl groups such as toluene. It is not strictly required that the N-formyl olanzapine is fully dissolved in the solvent system within the crystallization.
• the purity of the solid N-formyl olanzapine improves.
• the heating is generally above 35°C and typically in the range of 40°C to 65°C.
• the time of the treatment in the crystallization treatment medium depends upon how much, if any, of the N-formyl olanzapine remains undissolved. Once fully dissolved, the cooling can begin immediately if desired. If a slurry is made without ever reaching complete dissolution, the treatment time is generally at least one hour and typically one to four hours, but is not limited thereto. After cooling the purified solid (4) is isolated generally by filtration or centrifugation.
• a compound with purity of at least 95% may be obtained with a single crystallization as described above. If not, the process of (1) dissolving and/or slurrying in the heated solvent; (2) cooling; and (3) isolating the solid N-formyl olanzapine (4) may be repeated, using the same or different conditions. Similarly, if a higher purity is desired, such as at least 98% pure, the steps can be repeated as often as necessary, using the same or different conditions. While shown in the context of the overall scheme, it should be understood that the purification procedure can be applied to N-formyl olanzapine (4) regardless of how it was made.
• the above-described purification technique can be applied to the N- formyl olanzapine process suggested in WO 2004/000847.
• the compound (4), or its salt is converted to olanzapine or a salt thereof. Any technique or scheme that results in olanzapine is intended to be included within the meaning of "converting.”
• the conditions suggested in WO 2004/000847 can be used, especially if the compound (4) has been purified.
• the conversion involves reducing the compound (4) with a reducing agent. This reduction is normally carried out in a solvent.
• the olanzapine base is generally formed in the solution, i.e. it normally does not precipitate out upon formation.
• One particular embodiment comprises reducing the compound (4) in an olanzapine- soluble solvent with a reducing agent selected from an aluminum hydride or hydrogen in the presence of a hydrogenation catalyst, to form a solution of olanzapine.
• the olanzapine- soluble solvent is normally a water immiscible inert organic solvent such as an aromatic hydrocarbon, especially toluene.
• the reducing agent is typically an organic aluminum hydride reductant which is soluble in the olanzapine-soluble solvent such as sodium dihydro-bis(2-methoxyethoxy) aluminate, which is available commercially as RED-A1
• the side products may be removed by extracting the reaction mixture with water and with a water immiscible organic solvent, e.g. with water/ethylacetate mixture, whereby the product is preferentially concentrated in the organic layer.
• the so provided olanzapine solution may be further purified, if desirable, e.g. by treating with surface active material such as activated carbon.
• the solution of olanzapine e.g., the organic layer, whether extracted or not, is subsequently treated with an acid to precipitate an olanzapine salt.
• the solution of olanzapine can be formed in the presence of an acid to form the acid addition salt in essentially a single step.
• the salt of olanzapine may precipitate immediately or upon cooling or other manipulation for facilitating precipitation of a compound from a solution. Almost no loss of quality has been observed in comparison with the starting material of compound (4).
• the acid can be organic or inorganic as long as it can form an isolatable solid salt with olanzapine.
• a variety of olanzapine acid addition salts have been disclosed in U.S.
• the acid is preferably selected from malonic acid, glycolic acid, maleic acid, acetic acid, or benzoic acid.
• the olanzapine salts may be purified by an ordinary crystallization from a suitable solvent. In this way, olanzapine salts of pharmaceutical grade purity can be obtained.
• Olanzapine salts made by the process of the present invention are pharmaceutically useful products and may be formulated into pharmaceutical compositions with pharmaceutical excipients.
• the olanzapine salts produced by the process of the invention can be converted to olanzapine base and are thus suitable intermediates for making solid olanzapine base in any of its anhydrated, hydrated or solvated forms.
• an olanzapine salt as an intermediate for making solid olanzapine base can avoid the formation of the problematic technical grade olanzapine.
• a pharmaceutical grade salt of olanzapine is formed, such as by recrystallization(s), and then converted to solid olanzapine base.
• the salt is treated with a suitable alkali in a suitable solvent to liberate olanzapine base.
• Water soluble salts may be neutralized by a suitable alkali in an aqueous environment. Water insoluble salts may be converted to olanzapine in ethanol by neutralization with the alkali.
• the salt of the alkali formed during the reaction is filtered off, and the olanzapine is crystallized from the solvent.
• water hydrolysable olanzapine salts such as olanzapine glycolate, are treated just by water, without the need of the alkali.
• olanzapine acetate may be converted to olanzapine Form I by heat treatment as is described more fully in U.S. provisional application serial no. 60/562,225, filed April 15, 2004, the entire contents of which are incorporated herein by reference.
• the present invention is more particularly described and explained by the following examples.
• Example 2 Crystallization of the compound (4) 8.0 g of crude N-formyl olanzapine precursor (compound (4)) of a purity of about 89% (HPLC) was suspended in 50 ml of methanol and heated at 60°C for 3 hours. The hot suspension was allowed to cool to room temperature and was subsequently cooled to 5°C "7 under stirring. The solid material was isolated by filtration, washed with 5 ml of cold methanol and 10 ml of cold diethyl ether and dried overnight at 40°C under vacuum. Yield : 3.97 g, purity 96.7 % (HPLC)
• Example 3 Olanzapine benzoate
• N-formyl olanzapine precursor compound(4)
• compound(4) N-formyl olanzapine precursor
• 5.4 ml of Red-AlTM solution 70wt% solution of sodium dihydro-bis(2-methoxyethoxy) aluminate in toluene
• the resulting mixture was allowed to warm up to room temperature.
• next 5.0 ml of Red-AlTM solution was added dropwise at this temperature.
• reaction mixture was poured into 100 ml of water and immediately 100 ml of ethyl acetate was added.
• the mixture was filtered over a P3-f ⁇ lter to remove insoluble material.
• the biphasic filtrate was allowed to stand for separating the layers and the aqueous layer was removed and washed with 2x 50 ml of ethyl acetate.
• the combined organic layers were washed with 2x 50 ml of water, dried over anliydrous sodium sulfate and concentrated at reduced pressure to a volume of about 50-60 ml.
• 1.12 g of benzoic acid was added in one portion and the resulting mixture was stirred at 4°C for 4 hours.
• the formed solid was isolated by filtration, washed with 5 ml of cold ethyl acetate and 10 ml of cold diethyl ether, and dried overnight at 40°C under vacuum. Yield : 2.75 gram, purity (HPLC) : 94.8 %.

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• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

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• 2005
  • 2005-01-26 EP EP05707056A patent/EP1711503A1/de not_active Withdrawn
  • 2005-01-26 WO PCT/EP2005/000836 patent/WO2005070939A1/en active Application Filing
  • 2005-01-26 WO PCT/EP2005/000834 patent/WO2005070937A1/en active Application Filing
  • 2005-01-26 AR ARP050100259A patent/AR047460A1/es not_active Application Discontinuation
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