Patent Application
20220235030
The present invention relates to physically and chemically stable salts of the selective histamine H3 receptor antagonist compound of 1-[4-(4-{3-[(2R)-2-methyl-pyrrolidin-1-yl]-propoxy}-phenoxy)-piperidin-1-yl]-ethanone of formula (1)
and/or polymorphs thereof and/or hydrates/solvates thereof, the process for the preparation thereof, pharmaceutical compositions comprising them, and for use in the treatment and/or prevention of conditions requiring the modulation of histamine H3 receptors (e.g. Alzheimer's disease, obesity, schizophrenia, myocardial ischaemia, migraine, autism spectrum disorder).
The histamine H3 receptor antagonists were extensively studied aiming to produce drugs that would enable the treatment of different diseases, such as Alzheimer's disease, obesity, schizophrenia, myocardial ischaemia, migraine, nasal congestion etc. (Leurs et al., Nat. Rev. Drug. Disc. 2005, 4(2):107-120; Berlin et al., J. Med. Chem. 2011, 54(1):26-53). Numerous compound showed promising preclinical results and entered clinical phase in diseases such as excessive daytime sleepiness (EDS) associated with Parkinson's disease, obstructive sleep apnea, epilepsy, schizophrenia, dementia, and attention deficit hyperactivity disorder (Kuhne et al., Exp. Opin. Inv. Drugs 2011, 20(12):1629-1648). It has been suggested that histamine H3 receptor antagonists/inverse agonists may also be suitable for pharmacotherapeutic treatment of sleep disorders (Barbier and Bradbury, CNS Neurol. Disord. Drug Targets 2007, 6(1):31-43), but so far, only one histamine H3 receptor antagonist, pitolisant (under the Wakix brand), has been granted marketing authorization for the treatment of narcolepsy with or without cataplexy in adults (Kollb-Sielecka et al., Sleep Med. 2017, 33:125-129).
WO 2014/136075 describes the synthesis of chemically modifiable, selective and drug-like H3 antagonists and inverse agonists. The preparation and characterization of such phenoxypiperidine-derived compounds are disclosed therein that bind to H3 receptor with high affinity and high selectivity and are drug-like.
Among the compounds disclosed in WO 2014/136075, the hydrochloride salt of 1-[4-(4-{3-[(2R)-2-methyl-pyrrolidin-1-yl]-propoxy}-phenoxy)-piperidin-1-yl]-ethanone of formula (1) is highlighted. In the preparation of the compound as described in Example 11, the starting material was 4-(4-{3-[(2R)-2-methyl-pyrrolidin-1-yl]-propoxy}-phenoxy)-piperidine dihydrochloride salt. After the base is released, the reaction mixture is treated with acetyl chloride in dichloromethane, and after the aqueous extraction work-up of the reaction mixture, the dried solution of the resulting base of formula (1) in dichloromethane was evaporated. To a solution of the crude product in dichloromethane excess hydrochloric acid in ethyl acetate was added. The precipitate was filtered off with ethyl acetate and washed with diethyl ether to give a crystalline product, the hydrochloride salt of 1-[4-(4-{3-[(2R)-2-methyl-pyrrolidin-1-yl]-propoxy}-phenoxy)-piperidin-1-yl]-ethanone.
A general requirement for active ingredients in the development of a pharmaceutical composition is that the active ingredient has the appropriate physical, physico-chemical and chemical parameters. Examples of such parameters include solubility, in particular water solubility. Another important feature that should be taken into account in industrial-scale production is the easy handling and the good isolability, which is extremely important for the economicalness of the manufacturing process. A further important aspect is that the solid form of the active ingredient has appropriate physical and chemical stability, for example, not hygroscopic, and does not degrade significantly. Furthermore, different polymorphic forms of a given salt may have different solid phase characteristics, physical and chemical stability.
From a drug development perspective, the water-binding tendency of a substance, the degree of hygroscopicity (ability of absorbency), is of paramount importance, since ambient humidity means a meaningful interaction in addition to the temperature. The degree of hygroscopicity of active ingredients affects the handling, storage, stability, formulability and many other qualities of the substance. There are several approaches and methods to characterize the hygroscopic properties of the active ingredients, and to categorize the degree of hygroscopicity, which is summarized in detail by Newman et al. (Newman et al., J. Pharm. Sci. 2007, 97(3):1047-1059). Typically, non-hygroscopic, slightly hygroscopic, moderately hygroscopic, very hygroscopic, as well as deliquescent categories are used in the literature, while in the pharmacopeia (European Pharmacopeia 9.0, 5.11 Character Section in Monographs) the less hygroscopic, hygroscopic, highly hygroscopic and deliquescent categories are used depending on the weight gain at the given temperature and relative humidity under the test conditions, in a given time. There are static and dynamic measurement methods for the investigation of hygroscopic tendency. Among the dynamic measurements Dynamic Vapor Sorption (DVS) analysis is a technique commonly used in the pharmaceutical industry, which typically measures mass change of the substance (sorption and desorption curve) as a function of relative humidity in isothermic conditions, from which the nature, mechanism and phase transitions of the sorption process can be inferred.
For testing hygroscopicity of active substances it is particularly important to determine whether the substance is susceptible to deliquescence, i.e. what is the point at which the solid material is in dissolved state when interacting with the ambient humidity (Mauer et al., Pharm. Dev. Techn. 2010, 15(6):582-594). Deliquescence of the substance occurs when the relative humidity (RH) reaches or exceeds the critical relative humidity (CRH) when a film corresponding to a saturated solution of the substance is formed on the surface of the solid substance. By further increasing the humidity the substance continuously takes up moisture, leading to drastic weight gain due to the complete dissolution of the material and dilution of the resulting solution. Even a slight surface deliquescence of the substance might have a significant effect on the chemical stability of the compound, since typically in case of compounds with acidic or basic characteristic such microenvironment might occur that leads to the degradation of acid or alkali-sensitive compounds. Deliquescence and strong ability to absorb moisture of the crystalline drugs are typically due to their good solubility.
Determination of the critical relative humidity is feasible by gravimetric method, e.g. with DVS, where relative humidity is changed in suitably selected steps and a sufficiently long time is used to the onset of quasi-equilibrium. After reaching the critical relative humidity, the sorption curve shows a more or less sharp change in the slope, typically followed by a monotonous rise and a significant increase in mass, the extent of which and the shape of the sorption curve cannot be associated with the formation of a hydrate form.
The base form of the salts of the present invention, the 1-[4-(4-{3-[(2R)-2-methyl-pyrrolidin-1-yl]-propoxy}-phenoxy)-piperidin-1-yl]-ethanone of formula (1), cannot be isolated in crystalline form, but as oil.
The aim was to obtain a solid form (salt and/or polymorph) of 1-[4-(4-{3-[(2R)-2-methyl-pyrrolidin-1-yl]-propoxy}-phenoxy)-piperidin-1-yl]-ethanone which possesses appropriate properties with regard to the above mentioned aspects, exhibiting adequate physical and chemical stability, slightly hygroscopic, not deliquescent, thereby its isolation is facilitated, handling is better and has excellent solubility.
It has been found during the preparation of the crystalline form of the hydrochloride acid addition salts of the 1-[4-(4-{3-[(2R)-2-methyl-pyrrolidin-1-yl]-propoxy}-phenoxy)-piperidin-1-yl]-ethanone base, that two crystalline polymorphs (Form A and Form B) of the monohydrochloride stoichiometry can be produced. In addition, the crystalline dihydrochloride salt of the compound can also be produced besides the monohydrochloride.
Surprisingly, it has been found that in contrast to the 1-[4-(4-{3-[(2R)-2-methyl-pyrrolidin-1-yl]-propoxy}-phenoxy)-piperidin-1-yl]-ethanone monohydrochloride and dihydrochloride salts the novel dihydrobromide, sulfate, oxalate, monocitrate and dicitrate salts have outstanding properties, are less hygroscopic, easier to be isolated, their physical and chemical stability are more favorable, and have excellent solubility. All of these advantageous properties of the novel 1-[4-(4-{3-[(2R)-2-methyl-pyrrolidin-1-yl]-propoxy}-phenoxy)-piperidin-1-yl]-ethanone dihydrobromide, sulfate, oxalate, monocitrate, and dicitrate salts make them suitable for the development of a pharmaceutical composition for the treatment of diseases targeting the selective modulation of H3 receptor.
The present invention relates to dihydrobromide, sulfate, oxalate, monocitrate and dicitrate salts of 1-[4-(4-{3-[(2R)-2-methyl-pyrrolidin-1-yl]-propoxy}-phenoxy)-piperidin-1-yl]-ethanone, and/or polymorphs thereof and/or hydrates/solvates thereof, the process for the preparation thereof, pharmaceutical compositions comprising them, and the use thereof in the treatment and/or prevention of conditions requiring the modulation of histamine H3 receptors (e.g. Alzheimer's disease, obesity, schizophrenia, myocardial ischaemia, migraine, autism spectrum disorder).
Hiba! A hivatkozási forrás nem található. Dynamic vapor sorption curves of the salts tested (relative weight change %−relative humidity %) at 25° C. (a) deliquescent salts (b) not deliquescent salts.
The base form of the salts of the present invention, the 1-[4-(4-{3-[(2R)-2-methyl-pyrrolidin-1-yl]-propoxy}-phenoxy)-piperidin-1-yl]-ethanone of formula (1), cannot be isolated in crystalline form, but as oil. The base according to the procedure described in Example 11 of WO 2014/136075 can be obtained by evaporating the dichloromethane solution of the resulting product or, after isolation of the hydrochloride salt—in a manner obvious to the skilled person—by base releasing.
The hydrochloride acid addition salts of 1-[4-(4-{3-[(2R)-2-methyl-pyrrolidin-1-yl]-propoxy}-phenoxy)-piperidin-1-yl]-ethanone base (Example 1) are prepared in crystalline form (Example 2 to Example 8). It has been found that two crystalline polymorphs (Form A and Form B) of the salt characterized by monohydrochloride stoichiometry can be produced (Example 4 to Example 8), of which X-ray powder diffraction (XRPD) patterns, infrared (IR) and Raman spectra, and dynamic vapor sorption (DVS) isotherm plot are shown in
In further experiments, it was found that crystalline dihydrochloride salt (diHCl) of the compound can also be produced (Example 2 and Example 3) in addition to the monohydrochloride, of which X-ray powder diffraction (XRPD) pattern, termogravimetric (TG) curve, differential scanning calorimetry (DSC) thermogram, infrared (IR) and Raman spectra, and dynamic vapor sorption (DVS) isotherm plot are shown in
A further disadvantage of the dihydrochloride form is that, it is highly hygroscopic, according to the DVS (dynamic vapor sorption) analysis at 25° C., a significant monotonic weight increase is observed on the sorption curve above 60% relative humidity, showing the deliquescence of the substance (
The hygroscopic nature of the mono- and dihydrochloride salts of 1-[4-(4-{3-[(2R)-2-methyl-pyrrolidin-1-yl]-propoxy}-phenoxy)-piperidin-1-yl]-ethanone poses many issues in terms of the pharmaceutical development, handling, storing, stability and formulability of the compound. It has been observed that hydrochloride salts are already susceptible to deliquescence under the conditions of isolation, their filtering and handling are thus problematic. The degradation tendency of the substance is also clearly related to its hygroscopic nature, as the deacetylation of the compound may occur due to exposure to acid in the presence of moisture.
It is therefore necessary to produce salts of 1-[4-(4-{3-[(2R)-2-methyl-pyrrolidin-1-yl]-propoxy}-phenoxy)-piperidin-1-yl]-ethanone that are less hygroscopic, easier to handle, physically and chemically more stable than mono- and dihydrochloride salts.
In our experiments, dihydrobromide salt (Example 9), sulfate salt (Example 10 to Example 12), oxalate salt (Example 13 and Example 14), monocitrate salt (Example 15 to Example 18) and dicitrate salt (Example 19 to Example 22) of 1-[4-(4-{3-[(2R)-2-methyl-pyrrolidin-1-yl]-propoxy}-phenoxy)-piperidin-1-yl]-ethanone was prepared in crystalline form, which are more preferred than the mono- and dihydrochloride salts, as these are less hygroscopic (Table 1), thus easier to isolate and handle, and their stability is much more favorable (Table 2). X-ray powder diffraction, IR and Raman data suitable to characterize polymorphs of crystalline salts of 1-[4-(4-{3-[(2R)-2-methyl-pyrrolidin-1-yl]-propoxy}-phenoxy)-piperidin-1-yl]-ethanone are shown in Table 3 to Table 5.
Thus, the present invention relates to pharmaceutically acceptable, less hygroscopic, acid addition salts of 1-[4-(4-{3-[(2R)-2-methyl-pyrrolidin-1-yl]-propoxy}-phenoxy)-piperidin-1-yl]-ethanone that can be formed with organic or inorganic acids and/or polymorphs thereof and/or hydrates/solvates thereof. Examples of acid addition salts that can be formed with such organic or inorganic acids include salts derived from hydrogen bromide, sulfuric acid, oxalic acid, or citric acid.
Preferably, the present invention relates to 1-[4-(4-{3-[(2R)-2-methyl-pyrrolidin-1-yl]-propoxy}-phenoxy)-piperidin-1-yl]-ethanone dihydrobromide, sulfate, oxalate, monocitrate and dicitrate salts and/or polymorphs thereof and/or hydrates/solvates thereof.
The present invention also relates to the preparation of pharmaceutically acceptable, less hygroscopic, acid addition salts of 1-[4-(4-{3-[(2R)-2-methyl-pyrrolidin-1-yl]-propoxy}-phenoxy)-piperidin-1-yl]-ethanone that can be formed with organic or inorganic acids, preferably dihydrobromide, sulfate, oxalate, monocitrate and dicitrate salts thereof, and/or polymorphs thereof and/or hydrates/solvates thereof.
The present invention also relates to 1-[4-(4-{3-[(2R)-2-methyl-pyrrolidin-1-yl]-propoxy}-phenoxy)-piperidin-1-yl]-ethanone dihydrobromide, sulfate, oxalate, monocitrate and dicitrate salts for use in the treatment and/or prevention of conditions requiring the modulation of histamine H3 receptors.
The present invention relates to the use of 1-[4-(4-{3-[(2R)-2-methyl-pyrrolidin-1-yl]-propoxy}-phenoxy)-piperidin-1-yl]-ethanone salts in the manufacture of a pharmaceutical composition.
The present invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of 1-[4-(4-{3-[(2R)-2-methyl-pyrrolidin-1-yl]-propoxy}-phenoxy)-piperidin-1-yl]-ethanone dihydrobromide, sulfate, oxalate, monocitrate and dicitrate salts together with pharmaceutically acceptable excipients.
The present invention also relates to the use of the pharmaceutical composition of the previous paragraph in the treatment and/or prevention of conditions requiring the modulation of histamine H3 receptors, preferably in the treatment and/or prevention of autism spectrum disorder.
For example, the preparation of salts from the base can be carried out as follows: the 1-[4-(4-{3-[(2R)-2-methyl-pyrrolidin-1-yl]-propoxy}-phenoxy)-piperidin-1-yl]-ethanone base is dissolved in a suitable solvent or mixture of solvents, followed by the addition of the acid or a salt thereof—formed by a base weaker than 1-[4-(4-{3-[(2R)-2-methyl-pyrrolidin-1-yl]-propoxy}-phenoxy)-piperidin-1-yl]-ethanone—or a solution thereof, to the mixture. In addition, the 1-[4-(4-{3-[(2R)-2-methyl-pyrrolidin-1-yl]-propoxy}-phenoxy)-piperidin-1-yl]-ethanone base can be prepared from a salt thereof, and after releasing the base, after the appropriate separation and/or solvent exchange, the desired salt is formed by addition of the acid, without isolation of the base. If necessary, the reaction mixture is concentrated, the precipitated product is isolated by filtration at room temperature or after cooling, then dried, if necessary, at an appropriate temperature. If necessary, the resulting salt is crystallized by addition of a suitable antisolvent from its solution at room temperature or after reflux, and the precipitated product is isolated by filtration, then dried, if necessary, at an appropriate temperature.
The salts of the present invention can be well isolated and as a result of the process obtainable in high purity, which makes them particularly valuable for pharmaceutical use. In terms of implementation of the present invention, the monocitrate and dicitrate salts are particularly preferred for the preparation of a pharmaceutical composition, in which case the best quality and most stable product is obtained in excellent yields. Monocitrate and dicitrate salts are poorly hygroscopic, do not show deliquescence, their physical and chemical stability, as well as solubility are excellent.
Both citrate salts have a higher melting point than the dihydrochloride salt. It the case of monocitrate, approx. a 15° C., while in the case of dicitrate, approx. a 30° C. of melting point increase can be observed which indicates greater stability and is more advantageous for the preparation of a pharmaceutical composition. The monocitrate salt is stable under normal laboratory conditions in the form of monohydrate (monocitrate Form A), but by increasing the temperature from room temperature to approx. 70 to 90° C. it loses weakly bound structural water and converts to anhydrate form (monocitrate Form B). The dried sample also takes up its stoichiometric water content relatively quickly when interacting with ambient humidity. The dicitrate salt is stable in the form of anhydrate, does not convert to hydrate form, and has in a development view a favorable, sufficiently high melting point.
Comparison of the dynamic vapor sorption curves measured at 25° C. of the investigated salts of 1-[4-(4-{3-[(2R)-2-methyl-pyrrolidin-1-yl]-propoxy}-phenoxy)-piperidin-1-yl]-ethanone is depicted on Hiba! A hivatkozási forrás nem található. that shows the relative weight change (˜percentage change in weight relative to a weight at 0% relative humidity) as a function of relative humidity (RH %).
On the sorption curve of monohydrochloride salt Form A (
On the sorption curve of monohydrochloride salt Form B (
On the sorption curve of the dihydrochloride salt (
On the sorption curve of the dihydrobromide salt (
On the sorption curve of the sulfate salt (
On the sorption curve of the oxalate salt (
On the DVS curves of the monocitrate salt (
On the sorption curve of the dicitrate salt (
The generally observed hygroscopic nature of the 1-[4-(4-{3-[(2R)-2-methyl-pyrrolidin-1-yl]-propoxy}-phenoxy)-piperidin-1-yl]-ethanone salts is inter alia related to the good solubility thereof. In simulated gastric fluid (SGF without pepsin, pH=1.3), the dihydrochloride salt has a solubility of greater than 59 mM, the solubility of the monocitrate salt is greater than 44 mM, and the solubility of the dicitrate salt is 469 mM.
The deliquescence tendency of each salt is characterized by the critical relative humidity (CRH) value (Table 1), which was determined based on the sorption curves measured according to the measurement parameter settings below, with DVS analysis at 25° C. isotherm conditions, according to the following.
Derivative of the sorption curve was formed on the sorption curve between 10 to 90% RH by determining the differences in relative weight changes relative to 10% RH change:
Δm=m2−m1
where m1 and m2 are the quasi-equilibrium relative mass changes (˜percentage change in weight relative to a weight at 0% relative humidity) for the given percentage of the relative humidity of the sorption curve RH1 and RH2, and
ΔRH=RH2−RH1=10.
If the given sorption step is Δm/ΔRH≥0.5, then RH1 is considered to be the critical relative humidity (CRH) value indicating the end point of the physical stability of the substance. The value thus determined is a good match with the onset of a significant monotonic weight gain observed visually on the sorption curve. Above the critical relative humidity value, it is the process of deliquescence of the substance that determines the weight gain observed on the sorption curve.
Compared to monohydrochloride salts, it can be established that diHBr, sulfate salts begin to show deliquescence at significantly higher critical relative humidity, which indicates a reduced hygroscopic tendency associated with their greater physical stability. Surprisingly, the oxalate, monocitrate, and dicitrate salts are not deliquescent under the conditions of the DVS analysis, and are the physically most stable ones.
Increased stability to ambient humidity is beneficial for longer-term physical and chemical stability of the active ingredient. The relationship between the reduced hygroscopic nature and the increased chemical stability associated with it is shown in the most preferred citrate salts in comparison to the dihydrochloride salt.
Table 2 shows the HPLC purity test results of a 10-day solid stress stability study of dihydrochloride, monocitrate and dicitrate salts. It is clear from the results that the dihydrochloride salt is slightly degraded by heat while it degrades significantly under the combined effect of heat and humidity. In contrast, the monocitrate and dicitrate salts are stable under these conditions and are significantly more advantageous.
For solid phase analytical studies, the following experimental conditions were used:
The salts of the present invention may be administered in any pharmaceutically acceptable manner, for example, orally, parenterally, buccally, sublingually, nasally, rectally or transdermally, appropriately to the formulation of the pharmaceutical composition. The therapeutically effective dose is between 0.01 and 40 mg/day.
The following formulation examples illustrate the pharmaceutical compositions of the present invention.
However, the present invention is not limited to these compositions.
Tablet
Intravenous Injection
Suppository
The invention is illustrated by the following Reference and working Examples without limiting the scope of the present invention.
40 g of 1-[4-(4-{3-[(2R)-2-methyl-pyrrolidin-1-yl]-propoxy}-phenoxy)-piperidin-1-yl]-ethanone hydrochloride salt prepared according to Example 11 of WO 2014/136075 was dissolved in 480 mL of dichloromethane at 0 to 5° C., and then 168 mL of 1M aqueous NaOH was added. After stirring for 10 minutes, the aqueous and organic phases were separated and the organic phase was washed twice with 120 mL of deionized water, dried over 25 g of natrium sulfate and filtered. The solution was concentrated in vacuo to an oil. Evaporation residue: 32.8 g of an oil.
2.0 g (5.55 mmol) of 1-[4-(4-{3-[(2R)-2-methyl-pyrrolidin-1-yl]-propoxy}-phenoxy)-piperidin-1-yl]-ethanone was dissolved in 20 mL of acetone at room temperature. The mixture was cooled to 0 to 5° C. and 0.8 mL of ≥37% hydrochloric acid solution was added dropwise. After stirring for 30 minutes at 0 to 5° C., the crystals were filtered, covered with 1.5 mL of cold acetone, and dried at room temperature.
White crystalline material. Yield: 1.7 g.
0.548 g of 1-[4-(4-{3-[(2R)-2-methyl-pyrrolidin-1-yl]-propoxy}-phenoxy)-piperidin-1-yl]-ethanone was dissolved in 1.1 mL of isopropanol at room temperature. To the solution of the base, 0.391 g of 30% hydrochloric acid isopropanol was added dropwise at room temperature. The precipitated slurry was filtered, and then dried for 2 hours under vacuum under nitrogen at 40° C. Yield: 0.42 g.
11.831 mg of 1-[4-(4-{3-[(2R)-2-methyl-pyrrolidin-1-yl]-propoxy}-phenoxy)-piperidin-1-yl]-ethanone dihydrochloride salt was weighed in platinum jar and heat treated in TA Instruments TGA Q50 device until elimination of 1 mol of HCl, according to the following program:
0.4 mL of aqueous sodium bicarbonate solution (97.5 mg NaHCO3/1 mL H2O) was added to 0.2 g of 1-[4-(4-{3-[(2R)-2-methyl-pyrrolidin-1-yl]-propoxy}-phenoxy)-piperidin-1-yl]-ethanone dihydrochloride salt. With the equimolar base used, 1 mol of HCl was liberated during the effervescence of the solution. 1 mL of 1,4-dioxane was added to the solution and an oil was obtained after evaporation. 20 to 30 mg of oil were mixed with 0.5 mL of methyl ethyl ketone, filtered and precipitated with 0.5 mL of diisopropyl ether to give an oil. It was seeded with the 1-[4-(4-{3-[(2R)-2-methyl-pyrrolidin-1-yl]-propoxy}-phenoxy)-piperidin-1-yl]-ethanone monohydrochloride salt obtained by thermal treatment in Example 4. After crystallization, the product was filtered and dried at room temperature. Yield: 27 mg.
0.1 g of 1-[4-(4-{3-[(2R)-2-methyl-pyrrolidin-1-yl]-propoxy}-phenoxy)-piperidin-1-yl]-ethanone dihydrochloride salt was dissolved in 0.2 mL of deionized water and 0.2 mL of aqueous sodium bicarbonate solution (97.5 mg of NaHCO3/1 mL of H2O) was added. The resulting solution was concentrated at 50° C. and at 70 mbar, then dissolved in 5 mL of methyl ethyl ketone, filtered and washed with 1 mL of methyl ethyl ketone. To the solution 11.5 mL of diisopropyl ether was added and seeded with the product of Example 4, an oily precipitation was observed. The solution was concentrated to dryness, the “residue” was dissolved in 1 mL of dimethylformamide and 15 mL of methyl tert-butyl ether was added and then seeded with the product of Example 5. The next day, the precipitated crystalline product was isolated by filtration. Yield: 25 mg.
2.0 g of 1-[4-(4-{3-[(2R)-2-methyl-pyrrolidin-1-yl]-propoxy}-phenoxy)-piperidin-1-yl]-ethanone base was dissolved in 20 mL of acetone at room temperature. The mixture was cooled to 0 to 5° C. and 0.4 mL of ≥37% hydrochloric acid solution was added dropwise. After 30 minutes of stirring at 0 to 5° C. it was concentrated to constant weight in a water bath at 40° C. under vacuum. Then, twice 30 mL of toluene was evaporated. White crystalline material. Yield: 1.5 g.
0.548 g of 1-[4-(4-{3-[(2R)-2-methyl-pyrrolidin-1-yl]-propoxy}-phenoxy)-piperidin-1-yl]-ethanone base was dissolved in 0.55 mL of methyl tert-butyl ether at room temperature. Slowly, 0.18 g of 30% hydrochloric acid isopropanol was added dropwise at room temperature to the solution of the base. The initially biphasic mixture became miscible with stirring and then converted to a thick crystalline suspension. The precipitated suspension was filtered and dried for 2 hours under vacuum under nitrogen at 40° C. Yield: 0.33 g.
0.53 g of 1-[4-(4-{3-[(2R)-2-methyl-pyrrolidin-1-yl]-propoxy}-phenoxy)-piperidin-1-yl]-ethanone base was dissolved in 5 mL of ethyl acetate at room temperature, followed by the addition of a solution of acetic acid saturated with 0.8 mL of hydrobromic acid the salt was formed. After filtration it was washed twice with 1 mL of acetic acid saturated with hydrobromic acid. The dried product weighed 0.65 g.
0.1 g of 1-[4-(4-{3-[(2R)-2-methyl-pyrrolidin-1-yl]-propoxy}-phenoxy)-piperidin-1-yl]-ethanone base oil was dissolved in 9 mL of acetone at room temperature and then 0.125 mL of 20.4% H2SO4 solution was slowly added dropwise. The resulting solution first became opalescent, then a crystalline suspension was obtained which was stirred at room temperature for 2 hours. The product was filtered and washed twice with 0.5 mL of acetone. It was dried under vacuum at 40° C. for 2 hours under nitrogen. Yield: 0.08 g.
0.99 g of 1-[4-(4-{3-[(2R)-2-methyl-pyrrolidin-1-yl]-propoxy}-phenoxy)-piperidin-1-yl]-ethanone base oil was dissolved in 20 mL of acetone, then 1.3 mL of 18.4% H2SO4 solution was added. The mixture was seeded with the product of Example 10 (with the addition of 0.05 mL of water). The product was precipitated with 20 mL of acetone, stirred for half an hour, filtered, washed and dried at 40° C. under nitrogen. Yield: 0.814 g. Melting point of the product (based on DSC peak): 79.5° C.
1.008 g of 1-[4-(4-{3-[(2R)-2-methyl-pyrrolidin-1-yl]-propoxy}-phenoxy)-piperidin-1-yl]-ethanone base oil was mixed with 0.935 mL of 3M H2SO4 and stirred for 15 minutes. 20 mL of acetone was added and seeded with the product of Example 11 and then stirred at room temperature overnight. Filtered, dried under nitrogen at 40° C. to constant weight. Yield: 0.895 g. Melting point of the product (based on DSC peak): 79.3° C.
0.1 g of 1-[4-(4-{3-[(2R)-2-methyl-pyrrolidin-1-yl]-propoxy}-phenoxy)-piperidin-1-yl]-ethanone base oil was dissolved in 0.1 mL of acetone at room temperature and a solution of 0.055 g of oxalic acid in 0.5 mL of acetone was added. The product was precipitated with 0.3 mL of ethyl acetate. Filtered and then dried under nitrogen to constant weight. Yield: 128 mg. Melting point of the product (based on DSC peak): 54.2° C.
0.5 g of 1-[4-(4-{3-[(2R)-2-methyl-pyrrolidin-1-yl]-propoxy}-phenoxy)-piperidin-1-yl]-ethanone base oil was dissolved 0.5 mL of acetone, and then a solution of 0.275 g of oxalic acid in 1.5 mL of acetone and 0.05 mL of water was added. The precipitated material was filtered and then stirred in a mixture of 0.05 mL of water and 2.75 mL of acetone in the presence of 0.1755 g of oxalic acid. The product obtained was filtered and dried. Yield: 392 mg.
To 0.13 g of 1-[4-(4-{3-[(2R)-2-methyl-pyrrolidin-1-yl]-propoxy}-phenoxy)-piperidin-1-yl]-ethanone base oil 0.081 g of citric acid monohydrate was added at room temperature with stirring. 0.5 mL of acetone was added and stirred overnight. After the addition of further 1 mL of acetone on the following day, the mixture was stirred for an additional 30 minutes, then filtered and washed with 0.5 mL of acetone. The resulting sample was dried under vacuum under nitrogen at 25° C. Yield: 0.163 g.
To 0.513 g of 1-[4-(4-{3-[(2R)-2-methyl-pyrrolidin-1-yl]-propoxy}-phenoxy)-piperidin-1-yl]-ethanone base oil a solution of 0.315 g citric acid monohydrate in 5 mL of acetone was added at room temperature with stirring. The solution was seeded with the product of Example 15. After stirring for two hours, another 2 mL of acetone was added and stirred for a weekend. The mixture was filtered and washed with 5 mL of acetone. The resulting crystalline material was dried under vacuum under nitrogen at 25° C. Yield 0.63 g. Karl-Fischer water content: 3.1%.
1.020 g of 1-[4-(4-{3-[(2R)-2-methyl-pyrrolidin-1-yl]-propoxy}-phenoxy)-piperidin-1-yl]-ethanonebase oil was weighted to a 100 mL reactor and stirred with 15 mL of acetone at room temperature. To this solution 15 mL of a solution of citric acid monohydrate (0.872 g of citric acid monohydrate dissolved in 20 mL of acetone) was added at room temperature. In the meantime, it was seeded with a suspension of the monocitrate salt prepared in Example 16 (0.0767 g suspended in 0.5 mL of acetone). The resulting suspension was stirred at room temperature for 1 hour, then the precipitated salt was filtered and washed with 10 mL of acetone. The resulting crystalline material was dried at 25° C. under nitrogen.
Yield: 1.385 g. Melting point of the product (DSC onset): 114.3° C. Karl-Fischer water content: 3.5%.
The monocitrate salt Form A of Example 17 was dried at 70 to 90° C. under nitrogen to constant weight.
0.5 g of 1-[4-(4-{3-[(2R)-2-methyl-pyrrolidin-1-yl]-propoxy}-phenoxy)-piperidin-1-yl]-ethanone base oil was dissolved in 1 mL of acetone, to which a solution of 0.962 g of citric acid monohydrate in 4 mL of acetone was added. After stirring for 1 h 15 min at reflux temperature, it was cooled to room temperature, then filtered and washed with 10 mL of acetone. The resulting sample was dried overnight at 25° C. under vacuum under nitrogen. Yield: 0.832 mg.
1.928 g of citric acid monohydrate was added to a 100 mL reactor and dissolved in 15 mL of acetone at room temperature. To this solution an acetone suspension (0.1039 g/0.5 mL) of the dicitrate salt prepared in Example 19 was added. To this solution a solution of 15 mL of the base in acetone (1.695 g of 1-[4-(4-{3-[(2R)-2-methyl-pyrrolidin-1-yl]-propoxy}-phenoxy)-piperidin-1-yl]-ethanone base oil dissolved in 17.5 mL of acetone) was added. The solution was stirred at room temperature for 1 hour, then filtered off and washed with 10 mL of acetone. The resulting sample was dried for 1 day at 25° C. under nitrogen. Yield: 2.81 g. Melting point of the product (DSC onset): 133.1° C. Karl-Fischer water content: 0.4%.
17.6 kg of dichloromethane was introduced into the reactor and then inertized with nitrogen and the temperature was set to 0 to 5° C. 1.1 kg of 1-[4-(4-{3-[(2R)-2-methyl-pyrrolidin-1-yl]-propoxy}-phenoxy)-piperidin-1-yl]-ethanone dihydrochloride was added, and then a mixture of 5.7 kg of purified water and 0.19 kg of NaOH was added while maintaining the temperature at 0 to 5° C. After a reaction time of 15 to 20 minutes, the organic phase was conducted to another reactor, which was also inertized with nitrogen. 2200 mL of dichloromethane was added to the organic phase and, after stirring for 30 to 40 minutes, the organic phase was separated again. The following step was repeated twice: 3300 mL of purified water was added to the organic phase and after 30 to 40 minutes of stirring, the organic phase was separated again. A solution of 0.66 kg of NaCl in 2.6 L of purified water was added to the separated organic phase and, after stirring for 30 to 40 minutes, the organic phase was separated again. The organic phase was concentrated under 0.5 bar vacuum at max. 35° C. to the stirring limit (to 3 to 4 liters). Repeated three times, 8.8 kg acetone was added and the liberated base was concentrated under 0.7 bar vacuum at max. 45° C. to the stirring limit (to 3 to 4 liters). 1.1 kg of citric acid monohydrate was dissolved in 7.0 kg of acetone while maintaining the temperature of the solution at 20 to 25° C. To the resulting citric acid solution 5.0 g of 1-[4-(4-{3-[(2R)-2-methyl-pyrrolidin-1-yl]-propoxy}-phenoxy)-piperidin-1-yl]-ethanone dicitrate seed crystals were added. To the resulting solution the solution of the concentrated 1-[4-(4-{3-[(2R)-2-methyl-pyrrolidin-1-yl]-propoxy}-phenoxy)-piperidin-1-yl]-ethanone base in acetone was added over 110 to 130 minutes, keeping the temperature between 20 to 25° C. After addition, the mixture was heated to 55 to 60° C. and stirred at this temperature for 10 to 12 minutes and then cooled to 20 to 25° C. for an additional 10 hours. At the end of the stirring time, the material was centrifuged and dried. Yield: 1.398 kg. Melting point of the product (DSC onset): 132.7° C.
70 g of 1-[4-(4-{3-[(2R)-2-methyl-pyrrolidin-1-yl]-propoxy}-phenoxy)-piperidin-1-yl]-ethanone dihydrochloride salt was weighted and dissolved in 840 mL of dichloromethane at 0 to 5° C., followed by addition of a solution of 11.9 g of NaOH in 350 mL of deionized water. After stirring for 15 minutes, the mixture was separated and the aqueous phase was transferred to 140 mL of dichloromethane. The combined organic phase was extracted twice with 210 mL of deionized water and then with 210 mL of saturated brine. The solution was concentrated to an oil in vacuo (at max. 35° C.). The mixture was diluted three times with 700 mL of acetone and evaporated. The evaporation residue was complemented with acetone to 560 mL. The solution of 1-[4-(4-{3-[(2R)-2-methyl-pyrrolidin-1-yl]-propoxy}-phenoxy)-piperidin-1-yl]-ethanone in acetone was added to a solution of 64 g citric acid anhydrate in 560 mL of acetone and 6 mL of water (20 to 25° C.) over two hours, keeping at 20 to 25° C. After stirring for 15 minutes at reflux, the suspension was cooled back to room temperature and after further stirring for 2 hours, the precipitate was filtered off, washed twice with 60 mL of acetone and dried at 50° C. under vacuum. Yield: 101.6 g. Melting point of the product (DSC onset): 132.6° C.
| Number | Date | Country | Kind |
|---|---|---|---|
| P1900193 | May 2019 | HU | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/IB2020/055105 | 5/29/2020 | WO | 00 |
