Intermediates useful in the preparation of blarcamesine, the methods for obtaining same, and use thereof in obtaining blarcamesine

Abstract

The present invention discloses compounds useful in obtaining blarcamesine, as well as the methods for preparing and obtaining blarcamesine from same.

Description

[0001] INTERMEDIATES USEFUL IN THE PREPARATION OF BLARCAMESINE, THE METHODS FOR OBTAINING SAME, AND USE THEREOF IN OBTAINING BLARCAMESINE

[0002] Field of the Invention

[0003] The present invention is encompassed in the field of active ingredient synthesis. More specifically, the present invention belongs to the technical field of blarcamesine synthesis.

[0004] Background of the Invention

[0005] Blarcamesine, also known as tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride or ANAVEX2-73, is an agonist compound of the intracellular sigma-1 chaperone protein. Blarcamesine can be administered orally, and has anticonvulsant, anti-amnesic, neuroprotective, and antidepressant properties.

[0006] \

[0007]

[0008] (Blarcamesine)

[0009] Blarcamesine was described for the first time in patent document WO97 / 30983 A, which discloses the synthesis of this active ingredient:

[0010]

[0011] 4 3

[0012] However, the synthesis described therein occurs by means of reducing compound 2 to 3, which requires the use of lithium aluminium hydride, which has the drawback of being hazardous due to its high flammability and risk of explosion. These risks are even more undesirable in the industrial scaling of the method. In the final step of the method described therein, blarcamesine is obtained in the form of a free base, which is isolated as a crude product, which must then be purified by means of column chromatography, which is a technique that can be very cumbersome.

[0013] Therefore, in view of the promising applications of blarcamesine, it is highly desirable to find a synthesis route that allows the possibility of dispensing with the use of hard-to-handle and highly hazardous reducing agents, as well as obtaining the product such that the purification thereof by means of column chromatography is not necessary.

[0014] Brief Description of the Invention

[0015] The inventors have developed a method of obtaining blarcamesine in which there is used a derivative of formula (II):

[0016]

[0017] Furthermore, all the steps of the method occur with high yields, all exceeding 75%, whereas the need to use highly flammable reducing agents with a risk of explosion is dispensed with. Additionally, the purification of blarcamesine obtained in the final step by means of column chromatography is not necessary, given that, after simple steps of liquid-liquid extraction that are common in the technical field, it is obtained as a solid with a high purity that exceeds 98.9%.

[0018] Therefore, in a first aspect, the invention relates to a compound of formula (II):

[0019]

[0020] In a second aspect, the invention relates to a method for preparing the compound of formula (II):

[0021]

[0022] characterized in that it comprises contacting a compound of formula (I)

[0023]

[0024] with dimethylamine in an organic solvent.

[0025] In a third aspect, the invention relates to a method for obtaining the compound of formula

[0026]

[0027] characterized in that it comprises contacting the compound of formula (II)

[0028]

[0029] with a reducing agent in an organic solvent.

[0030] A fourth aspect of the invention relates to a method for obtaining blarcamesine:

[0031] \

[0032] N—

[0033]

[0034] (Blarcamesine)

[0035] or a pharmaceutically acceptable salt thereof, characterized in that it comprises:

[0036] a) contacting the compound of formula (II)

[0037]

[0038] with a reducing agent in an organic solvent to obtain the compound of formula (III)

[0039]

[0040] and

[0041] b) reacting the compound of formula (III) with an acid in an organic solvent to obtain blarcamesine.

[0042] The compound of formula (II) is an intermediate useful in the synthesis of blarcamesine. Therefore, a fifth aspect of the invention relates to the use of a compound of formula (II) in the preparation of blarcamesine or a pharmaceutically acceptable salt thereof.

[0043] Additionally, in a sixth inventive aspect the invention relates to a method of preparing a compound of formula (IV):

[0044]

[0045] (IV)

[0046] which comprises contacting a compound of formula (I):

[0047]

[0048] with a reducing agent in an organic solvent.

[0049] A seventh inventive aspect of the invention relates to a method for obtaining blarcamesine or a pharmaceutically acceptable salt thereof, characterized in that it comprises:

[0050] a) contacting the compound of formula (IV)

[0051]

[0052] with p-toluenesulfonic acid in an organic solvent to obtain the compound of formula (V):

[0053]

[0054] and

[0055] b) contacting the compound of formula (V) with triethylamine and methanesulfonyl chloride in an organic solvent.

[0056] An eighth inventive aspect relates to the use of a compound of formula (IV) in the preparation of blarcamesine or a pharmaceutically acceptable salt thereof, wherein blarcamesine is obtained as a mixture comprising the (+)-blarcamesine and (-)-blarcamesine enantiomers.

[0057] Finally, a last aspect of the invention relates to the use of a compound of formula (V) in the preparation of blarcamesine or a pharmaceutically acceptable salt thereof, wherein blarcamesine is obtained as a mixture comprising the (+)-blarcamesine and (-)-blarcamesine enantiomers.

[0058] Description of the Figures

[0059] Figure 1. X-ray powder diffraction pattern of the compound of formula (II).

[0060] Detailed Description of the Invention

[0061] Compound of formula (II)

[0062] As mentioned above, a first aspect of the invention relates to a compound of formula (II):

[0063]

[0064] (II)

[0065] In a particular embodiment, the compound of formula (II) is characterized by being in solid form.

[0066] In a particular embodiment, the compound of formula (II) is characterized by having a crystalline structure.

[0067] In another particular embodiment, the compound of formula (II) is characterized in that it has an X-ray powder diffraction pattern measured with CuK* radiation comprising peaks at one or more of the following angles (2* ) ± 0.2: 5.6°, 11.2°, 11.3°, 11.5°, 15.0°, 15.5°, 21 .7°, 22.2°, and 25.2°. In a more particular embodiment, the X-ray powder diffraction pattern of the compound of formula (II) additionally has peaks at one or more of the following angles (2«) ± 0.2: of 8.5°, 12.2°, 12.7°, 16.1°, 16.5°, 17.8°, 18.1 , 19.1°, 20.4°, and 22.8°. In an even more particular embodiment, the compound of formula (II) is characterized in that it has, in an X-ray powder diffraction pattern measured with CuK* radiation, peaks at the following angles (2» ) ± 0.2: 5.6°, 8.5°, 11.2°, 11.3°, 11.5°, 12.2°, 12.7°, 15.0°, 15.5°, 16.1°, 16.5°, 17.8°, 18.1°, 19.1°, 20.4°, 21.7°, 22.2°, 22.8°, and 25.2°.

[0068] This compound has an X-ray diffraction pattern that is substantially such as shown in Figure 1. One skilled in the art will understand that the X-ray diffraction pattern peak intensity ratio may vary based on the crystallinity of the analyzed sample corresponding to the product in question.

[0069] In another particular embodiment, the compound of formula (II) is characterized in that it has a purity determined by HPLC of at least 85%, preferably of at least 90%, more preferably of at least 95%; even more preferably of at least 99%.In the context of the present invention, the term “HPLC” refers to high performance liquid chromatography.

[0070] In another particular embodiment, the compound of formula (II) is characterized in that it is the stereoisomer of formula (Ila):

[0071]

[0072] In another particular embodiment, the compound of formula (II) is characterized by being a racemic mixture of the stereoisomers of formula (Ila) and (lib):

[0073]

[0074] (Ha) (Hb)

[0075] In a particular embodiment, the present invention relates to the compound of the first aspect, characterized in that it has a differential scanning calorimetry (DSC) plot comprising an endothermic peak having a threshold temperature of about 102.4°C ± 2°C.

[0076] Method of obtaining the compound of formula (II)

[0077] The second aspect of the present invention relates to a method for preparing the compound of formula (II)

[0078]

[0079] characterized in that it comprises contacting a compound of formula (I)

[0080]

[0081] (I)

[0082] with dimethylamine in an organic solvent.

[0083] In a particular embodiment, the method of the second aspect of the invention is characterized in that it is performed at a pressure comprised between 1 and 5 bar, preferably between 2 and 4 bar, more preferably at a pressure of about 3 bar.

[0084] In the context of the present invention, the terms “approximate” and “about” in reference a certain value refer to a value that is ±5% of said value.

[0085] In a particular embodiment, the organic solvent used in the method of the second aspect of the invention is selected from the group consisting of tetrahydrofuran, methyltetrahydrofuran, diethyl ether, dioxane, methanol, ethanol, isopropanol, or mixtures thereof. In a preferred embodiment, the organic solvent used is selected from the group consisting of tetrahydrofuran, methyl-tetrahydrofuran, ethanol, and methanol, or mixtures thereof, more preferably tetrahydrofuran and methyl-tetrahydrofuran or mixtures thereof, even more preferably tetrahydrofuran.In a particular embodiment, the method of the second aspect of the invention is characterized in that the compound of formula (I) is obtained from the reaction of gammabutyrolactone and benzophenone in an organic solvent. In a more particular embodiment, the method of the second aspect of the invention further comprises adding lithium diisopropylamide to the mixture of gamma-butyrolactone and benzophenone in an organic solvent. In a more particular embodiment, this organic solvent is selected from the group consisting of tetrahydrofuran, methyl-tetrahydrofuran, diethyl ether, dioxane, or a mixture thereof, more preferably tetrahydrofuran.

[0086] In another particular embodiment, the method of the second aspect of the invention is characterized in that it is carried out at a temperature comprised between 60°C and 100°C, preferably between 70°C and 90°C, more preferably between 75°C and 85°C.

[0087] In another particular embodiment, the method is carried out under stirring. In another more particular embodiment, the method is carried out under stirring for a time interval comprised between 1 and 24 hours, preferably between 10 and 20 hours, even more preferably for about 16 hours.

[0088] In a particular embodiment, the method further comprises removing the organic solvent by means of vacuum distillation once the stirring time has ended.

[0089] In a particular embodiment, the method of the second aspect of the invention further comprises adding a second organic solvent selected from the group consisting of methyl-tert-butyl-ether, dichloromethane, C1-C4 alkyl acetates or mixtures thereof, or mixtures thereof, preferably methyl- tert-butyl-ether.

[0090] Non-limiting examples of C1-C4 alkyl acetates are: methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, or butyl acetate, preferably isopropyl acetate.

[0091] In another particular embodiment, the resulting solution after adding the second organic solvent is cooled until reaching a temperature comprised between 0°C and 10°C, preferably between 0 and 5°C, for the purpose of forming a precipitate. One skilled in the art will know the optimal cooling temperature according to the freezing point of the second organic solvent added. Furthermore, one skilled in the art may use any techniqueknown in the prior art to reach this temperature.

[0092] In a particular embodiment, the method of the second aspect of the invention further comprises filtering the precipitate formed after adding the second organic solvent. In a preferred embodiment, this filtering is carried out by means of filtration with a porous plate.

[0093] In another particular embodiment, the method of the second aspect of the invention further comprises drying the product obtained after filtering the precipitate. In a more particular embodiment, the drying of the precipitate is carried out at a temperature comprised between 40°C and 60°C, preferably between 40°C and 50°C, even more preferably at a temperature of about 45°C.

[0094] In a more particular embodiment, the method of the second aspect of the invention comprises:

[0095] a) contacting the compound of formula (I) with dimethylamine in an organic solvent, preferably selected from the group consisting of tetrahydrofuran, diethyl ether, dioxane, methanol, ethanol, isopropanol, or mixtures thereof;

[0096] b) heating the mixture resulting from step a) at a temperature comprised between 60°C and 100°C, preferably between 70°C and 90°C, more preferably between 75°C and 85°C, in a closed container with the subsequent increase in pressure of the mixture, preferably at a pressure comprised between 1 and 5 bar, preferably between 2 and 4 bar, more preferably at a pressure of about 3 bar;

[0097] c) keeping the mixture resulting from step b) under stirring for a time interval comprised between 1 and 24 hours, preferably between 10 and 20 hours, even more preferably for about 16 hours;

[0098] d) removing the organic solvent by means of vacuum distillation once the stirring time of step c) has ended;

[0099] e) adding a second organic solvent, preferably selected from the group consisting of methyl-tert-butyl-ether, dichloromethane, C1-C4 alkyl acetates, or mixturesthereof, preferably methyl-tert-butyl-ether;

[0100] f) cooling the mixture obtained in step e) until reaching a temperature comprised between 0°C and 10°C, preferably between 0 and 5°C, to form a precipitate;

[0101] g) isolating by means of filtration the precipitate formed in step f); and

[0102] h) optionally, drying the precipitate obtained in step g) at a temperature comprised between 40°C and 60°C, preferably between 40°C and 50°C, even more preferably at a temperature of about 45°C.

[0103] Method of obtaining the compound of formula (III)

[0104] The third aspect of the invention relates to a method for obtaining the compound of formula (III):

[0105]

[0106] (HI)

[0107] characterized in that it comprises contacting the compound of formula (II)

[0108]

[0109] with a reducing agent in an organic solvent.

[0110] In a particular embodiment, the reducing agent is selected from the group consisting of sodium bis(2-methoxyethoxy)aluminium hydride, BH3-THF, lithium borohydride, lithium aluminium hydride, and diisobutylaluminium hydride, preferably sodium bis(2-methoxyethoxy)aluminium hydride.

[0111] In a particular embodiment, the organic solvent is selected from the group consisting of tetrahydrofuran, methyl-tetrahydrofuran, diethyl ether, dioxane, or mixtures thereof, preferably tetrahydrofuran.

[0112] In another particular embodiment, the method of the third aspect of the invention is characterized in that it is carried out under an inert gas atmosphere, preferably under a nitrogen atmosphere.

[0113] In the context of the present invention, the term “inert atmosphere” refers to a gas the composition of which, at the temperature and during the period provided for contact with the substances that are part of a chemical process, does not give rise to noticeable phenomena of degradation or oxidation.

[0114] In a particular embodiment of the third aspect of the invention, the reducing agent is added at a temperature comprised between 0°C and 5°C. In a more particular embodiment, the reducing agent is added at a temperature of about 0°C. One skilled in the art may use any technique known in the prior art to reach this temperature.

[0115] In a particular embodiment, the method of the third aspect of the invention is carried out under stirring. In another more particular embodiment, the method is carried out under stirring for a time interval comprised between 0.5 and 2 hours, preferably between 0.5 and 1 .5 hours, even more preferably for about 1 hour.

[0116] In a particular embodiment, the method of the third aspect of the invention further comprises adding water to the reaction medium once the stirring period has ended, for the purpose of removing the reducing agent. After adding water, a suspension is formed.In a particular embodiment, the method of the third aspect of the invention further comprises filtering the suspension formed after adding water, to remove the insoluble fraction from the suspension. In a preferred embodiment, this filtering is carried out by means of filtration with diatomaceous earth.

[0117] Method for obtaining blarcamesine using the compound of formula (II)

[0118] A fourth aspect of the invention relates to a method for obtaining blarcamesine:

[0119]

[0120] (Blarcamesine)

[0121] or a pharmaceutically acceptable salt of blarcamesine, characterized in that it comprises:

[0122] a) contacting the compound of formula (II)

[0123]

[0124] with a reducing agent in an organic solvent to obtain the compound of formula (III)

[0125]

[0126] and

[0127] b) reacting the compound of formula (III) with an acid in an organic solvent to obtain blarcamesine:

[0128] N

[0129]

[0130] (Blarcamesine).

[0131] In the context of the present invention, the term “pharmaceutically acceptable salt” as used herein refers to any organic or inorganic addition salt of blarcamesine, the concentration of which is relatively non-toxic and harmless for a patient, is effectively activated, and the side effects of which do not degrade the beneficial efficacy of blarcamesine.

[0132] In a particular embodiment of the fourth aspect of the invention, the method of step a) is as described in the different embodiments of the third aspect of the invention.

[0133] Accordingly, all the respective embodiments of the method of the third aspect of the invention are applicable to step a) of the fourth aspect of the invention.In another particular embodiment, the acid of point b) is selected from the group consisting of p-toluenesulfonic acid, camphorsulfonic acid, benzenesulfonic acid, and methylsulfonic acid, preferably p-toluenesulfonic acid.

[0134] In another particular embodiment, the organic solvent of point b) is an aromatic hydrocarbon, preferably selected from the group consisting of toluene or xylene, preferably toluene.

[0135] The term “aromatic hydrocarbon” is well known in the art and refers to a cyclically conjugated hydrocarbon with a stability due to delocalization that is significantly higher than that of the hypothetical localized structure (for example, Kekule structure).

[0136] In a particular embodiment, the reaction of point b) is performed at a temperature comprised between 80°C and 120°C, preferably between 90°C and 110°C, more preferably between 100°C and 110°C, even more preferably between 105°C and 110°C. One skilled in the art will know how to choose the temperature suitable for this process, as the temperature of the reaction must be the reflux temperature of the selected solvent.

[0137] In a particular embodiment, the reaction of point b) is performed under stirring for a period of time comprised between 2 and 6 hours, preferably between 3 and 5 hours, even more preferably for about 4 hours.

[0138] Use of a compound of formula (II) in the preparation of blarcamesine

[0139] In a fifth aspect, the invention relates to the use of a compound of formula (II)

[0140]

[0141] in the preparation of blarcamesine:

[0142]

[0143] (Blarcamesine)

[0144] or a pharmaceutically acceptable salt thereof.

[0145] Preparation of a compound of formula (IV)

[0146] In a sixth aspect, the invention relates to a method of preparing a compound of formula (IV):

[0147]

[0148] (IV)

[0149] which comprises contacting a compound of formula (I):

[0150]

[0151] (I)

[0152] with a reducing agent in an organic solvent.

[0153] In a particular embodiment, the method of the sixth aspect of the invention is characterized in that the reducing agent is selected from the group consisting of lithium borohydride, sodium borohydride, lithium aluminium hydride, and diisobutylaluminium hydride, preferably lithium borohydride.

[0154] In a particular embodiment of the sixth aspect of the invention, the organic solvent is selected from the group consisting of tetrahydrofuran, methyl-tetrahydrofuran, diethyl ether, dioxane, or mixtures thereof, preferably tetrahydrofuran.

[0155] In another particular embodiment, the method of the sixth aspect of the invention is characterized in that it is carried out at a temperature comprised between 0°C and 10°C, preferably between 0°C and 5°C. One skilled in the art may use any technique known in the prior art to reach this temperature.

[0156] In another particular embodiment, the method is carried out under stirring. In another more particular embodiment, the method is carried out under stirring for a time interval comprised between 0.2 and 2 hours, preferably between 0.5 and 1.5 hours, even more preferably for about 1 hour.

[0157] Method for obtaining blarcamesine using the compound of formula (IV)

[0158] A seventh aspect of the invention relates to a method for obtaining blarcamesine:\

[0159] N—

[0160]

[0161] (Blarcamesine)

[0162] or a pharmaceutically acceptable salt thereof, characterized in that it comprises:

[0163] a) contacting the compound of formula (IV)

[0164]

[0165] (IV)

[0166] with p-toluenesulfonic acid in an organic solvent to obtain the compound of formula (V):

[0167]

[0168] (V) and

[0169] b) contacting the compound of formula (V) with triethylamine and methanesulfonyl chloride in an organic solvent.Use of a compound of formula (IV) in the preparation of blarcamesine

[0170] An eighth aspect of the invention relates to the use of a compound of formula (IV)

[0171]

[0172] (IV)

[0173] in the preparation of blarcamesine:

[0174] \

[0175] N

[0176]

[0177] (Blarcamesine)

[0178] or a pharmaceutically acceptable salt thereof, wherein blarcamesine is obtained as a mixture comprising the (+)-blarcamesine and (-)-blarcamesine enantiomers.

[0179] It has recently been described that (+)-blarcamesine is associated with the (R) form, whereas (-)-blarcamesine is associated with the (S) form (Szokol etal. Period. Polytech. Chem. Eng., 66(4), pp. 536-540, 2022):

[0180]

[0181] (R)-(+)-blarcamesine (S)-(-)-blarcamesine

[0182] Therefore, in a preferred embodiment of the seventh aspect of the invention, blarcamesine is obtained as a mixture in which the molar ratio of both enantiomers is between 5:95 and 95:5, more preferably between 45:55 and 55:45, even more preferably as a racemic mixture of both enantiomers.

[0183] Use of a compound of formula (V) in the preparation of blarcamesine

[0184] A last aspect of the invention relates to the use of a compound of formula (V)

[0185]

[0186] (V)

[0187] in the preparation of blarcamesine:\ N

[0188]

[0189] (Blarcamesine)

[0190] or a pharmaceutically acceptable salt thereof, wherein blarcamesine is obtained as a mixture comprising the (+)-blarcamesine and (-)-blarcamesine enantiomers. (+)-Blarcamesine is associated with the (F?) form, whereas (-)-blarcamesine is associated with the (S) form, as described in detail in the eighth aspect of the invention.

[0191] Therefore, in a preferred embodiment of the last aspect of the invention, blarcamesine is obtained as a mixture in which the molar ratio of both enantiomers is between 5:95 and 95:5, more preferably between 45:55 and 55:45, even more preferably as a racemic mixture of both enantiomers

[0192] Examples

[0193] High performance liquid chromatography (HPLC)

[0194] The purity of the products obtained has been analyzed by means of the high performance liquid chromatography technique in a Waters Acquity apparatus provided with a UV / visible detector and temperature-controlled oven for the column. A ZORBAX SB-C18 column (250 x 4.6 mm; 5 • m) and mobile phases A (0.1% of H3PO4) and B (acetonitrile) have been used with the following analysis conditions:

[0195] Flow rate: 1 mL / min

[0196] Column temperature: 30°C

[0197] Wavelength: 210 nm

[0198] Injection volume: 20 • L

[0199] Diluent: water / acetonitrile (1 :1)Gradient:

[0200] t (min) %A %B 0 90 10 20 20 80 25 0 100 30 0 100 31 90 10

[0201]

[0202] 40 90 10

[0203] Differential scanning calorimetry (DSC)

[0204] DSC analysis was performed in a Mettler Toledo 822e apparatus with STARe SW15 software, using the following parameters: heating range of 30 to 300°C with a ramp of 10°C / min and N2 flow of 50 mL / min. The measurement was taken with a perforated closed capsule.

[0205] Nuclear magnetic resonance

[0206] Proton nuclear magnetic resonance (1H-NMR) and13C-NMR analyses were performed in a 400 MHz Brucker Avance III spectrometer. Chemical shifts were referenced to the DMSO-de signal (2.52 ppm (multiplet) for proton and 39.5 ppm (multiplet) for carbon).

[0207] X-ray crystallography (XRPD)

[0208] XRPD analysis was performed using a BRIIKER D2 PHASER X-ray powder diffractometer equipped with a copper anode. The radiation used is CuK* with a wavelength of 1.54 A. The following scanning parameters were used: 3-50 degrees 2* , continuous scanning, ratio: 5.6 degrees / minute.

[0209]

[0210] of the of formula

[0211]

[0212] (I)

[0213] 5 g (27.4 mmol) of benzophenone and 3.12 g (36.2 mmol) of • -butyrolactone were mixed with 25 mL of tetrahydrofuran under N2atmosphere, maintaining the temperature of about 20°C. The resulting solution was cooled at the temperature of between -20 and -25°C, and 25 mL (5.35 g, 49.9 mmol) of a 2 M solution of lithium diisopropylamide in THF were added slowly. The resulting solution was kept under stirring and at the temperature of about between -20 and -25°C for 1 hour.

[0214] Once stirring ended, 28 mL of a 20% NH4CI aqueous solution were added, and the obtained mixture was kept under stirring at the temperature of about 20°C for 1 hour. 50 mL of 2-methyl-tetrahydrofuran were added, and the resulting mixture was kept under stirring for 10 minutes at the temperature of about 20°C. The phases were separated, and 50 mL of water were added to the resulting organic phase. The phases were separated again, and the solvent was removed from the organic phase by means of vacuum distillation. 25 mL of isopropyl acetate were added to the resulting solid, and the obtained mixture was heated at a temperature of about 100°C and kept under stirring for 10 minutes at said temperature. The resulting solution was cooled slowly to a temperature of about 20°C, crystallizing a solid. The resulting mixture was cooled at a temperature of about 0°C, kept for 1 hour at said temperature, and the resulting solid was filtered and washed successively with three 14 mL fractions each of a 1 :1 isopropyl acetate / n-heptane mixture. Finally, the solid was dried in a vacuum oven at the temperature of 45°C to obtain 12.8 g of a white solid corresponding to 3-(hydroxy(diphenyl)methyl)tetrahydrofuran-2-one (compound of formula (I)), with a yield of 87.0%, purity of 99.80% by means of HPLC.

[0215] The differential scanning calorimetry (DSC) spectrum of the compound of formula (I) comprises an endothermic peak having a threshold temperature of about 149.7°C.Example 2: Synthesis of the compound of formula (II)

[0216]

[0217] (II)

[0218] In a flask adapted to withstand high pressures, 10 g (37.3 mmol) of 3-(hydroxy(diphenyl)methyl)tetrahydrofuran-2-one (compound of formula (I)) and 101 mL (9.7 g, 201 mmol) of a 2M solution of dimethylamine in THF were mixed together. The reaction mixture was heated at a temperature of about 80°C and kept under stirring at said temperature and at a pressure of about 3 bar for 16 hours.

[0219] Once the stirring time elapsed, the reaction mixture was depressurized and the solvent was removed by means of vacuum distillation to obtain an oily residue. 25 mL of methyl-tert-butyl-ether were added and the obtained mixture was kept under stirring at the reflux temperature for 10 minutes. The resulting solution was cooled slowly to the temperature of about 20°C, was kept for 30 minutes at said temperature and then cooled at a temperature of between 0 and 5eC, and was kept for 2 hours at said temperature. The resulting solid was filtered and washed successively with two 12 mL fractions each of a 4:1 methyl-te / 7-butyl-ether / n-heptane mixture. Finally, it was dried in a vacuum oven at a temperature of 45°C to obtain 10.4 g of a white solid corresponding to 4-hydroxy-2-(hydroxy(diphenyl)methyl)-N,N-dimethyl-butanamide (compound of formula (II)) with a yield of 89.4% and a purity of 99.66% by means of HPLC.

[0220] XRPD: 5.6°, 8.5°, 11.2°, 11.3°, 11.5°, 12.2°, 12.7°, 15.0°, 15.5°, 16.1°, 16.5°, 17.8°, 18.1e, 19.1°, 20.4°, 21.7°, 22.2°, 22.8° and 25.2°, all with a margin of error of ± 0.2° 2* . The X-ray powder diffraction pattern of the compound is shown in Figure 1. One skilled in the art will understand that the X-ray diffraction pattern peak intensity ratio may vary based on the texture, with more or less crystallinity, of the analyzed sample corresponding to the product in question.The differential scanning calorimetry (DSC) spectrum of the compound of formula (II) comprises an endothermic peak having a threshold temperature of about 102.4°C.

[0221] 1H-NMR (CDCI3, 400 MHz) • (ppm): 1.54-1 .59 (m, 1 H), 1 .77-1.86 (m, 1 H), 2.61 (s, 3H), 3.13 (s, 3H), 3.19-3.26 (m, 1 H), 3.30-3.36 (m, 1 H), 4.18-4.21 (dd, 1 H), 4.58 (broad, s, 1H), 6.86 (s, 1 H), 7.10-7.18 (m, 2H), 7.22-7.32 (m, 4H), 7.51-7.54 (d, 2H), 7.62-7.66 (d, 2H).

[0222] 13C-NMR (CDCI3, 100 MHz) * (ppm): 31.82, 34.85, 37.65, 42.81, 58.48, 78.56, 124.98 (2C), 125.40 (2C), 126.19, 126.24, 127.76 (2C), 127.90 (2C), 145.42, 148.27, 175.80.

[0223] is of the of formula

[0224]

[0225] 12 g (38.3 mmol) of 4-hydroxy-2-(hydroxy(diphenyl)methyl)-N,N-dimethyl-butanamide (compound of formula (II)) were mixed with 60 mL of tetrahydrofuran under N2 atmosphere at the temperature of about 20°C. The obtained solution was cooled at a temperature of about 0°C, and 43.6 mL (45.2 g, 134 mmol) of a 60% by weight sodium bis(2-methoxyethoxy)aluminium hydride solution (commercially known as Red-AI®) in toluene were added slowly. The solution was kept under stirring at a temperature of between 0 and 5°C for 1 hour and then at the temperature of about 20°C for 1 hour.

[0226] Once the stirring time has ended, the reaction mixture was cooled at a temperature of about 5°C, and 30 mL of water were added slowly. The temperature of the obtained mixture was adjusted between 20 and 25°C, and an additional 60 mL of water were added, obtaining a suspension of a white solid. The obtained suspension was filtered through a diatomaceous earth filter, and the filter was washed with four 25 mL fractionseach of 2-methyl-tetrahydrofuran. The obtained solution was left to stand, and the organic phase was separated from the aqueous phase. A mixture of 60 mL of water and 10 mL of a 20% by weight NaCI solution was added to the organic phase. The organic phase was separated and washed with two 25 mL fractions each of a 2N HCI aqueous solution. 35 mL of water were added to the organic phase, and the obtained aqueous phase was separated. 35 mL of water were added to the organic phase, and the aqueous phase was separated and pooled with the previously obtained aqueous phase. 60 mL of 2-methyl-tetrahydrofuran, 35 mL of water, and 25 mL of a 2N NaOH aqueous solution were added to the aqueous phase thus obtained in the previous step. The obtained mixture was stirred for 30 minutes, and the resulting organic phase was separated from the aqueous phase. 30 mL of 2-methyl-tetrahydrofuran were added to the aqueous phase, and the new organic phase was separated and pooled with the previously obtained organic phase. The solvent was removed from the organic phase by means of vacuum distillation, and 35 mL of toluene were added to the obtained solid residue to obtain a mixture that was heated at the temperature of between 95 and 100°C. The colorless solution obtained was cooled slowly at the temperature of about 20°C and kept under stirring for 1 hour at said temperature. The resulting solid was filtered upon cooling the initial solution and washed successively with two 12 mL fractions each of toluene. The obtained solid was dried in a vacuum oven at the temperature of 50°C to obtain 9.6 g of a white solid corresponding to 2-((dimethylamino)methyl)-1 ,1-diphenyl-butane-1,4-diol, the compound of formula (III) (yield of 83.5%, purity of 99.95% by means of HPLC).

[0227] The differential scanning calorimetry (DSC) spectrum of the compound of formula (III) comprises an endothermic peak having a threshold temperature of about 139.1 °C.

[0228] Example 4: Synthesis of blarcamesine using the compound of formula (II)

[0229]

[0230] 6 g (20 mmol) of 2-((dimethylamino)methyl)-1,1-diphenyl-butane-1,4-diol (compound of formula (III)) were mixed with 60 mL of toluene. The obtained mixture was heated until complete dissolution of the compound of formula (II) was observed, and 6.15 mL (7.62 g, 40.1 mmol) of p-toluenesulfonic acid monohydrate were added. The reaction mixture was heated at the reflux temperature (about 107°C) and kept under stirring at said temperature for 4 hours.

[0231] Once the stirring time ended, 45 mL of a 2N NaOH aqueous solution and 10 mL of water were added, and the obtained mixture was kept under stirring for 1 hour to obtain two completely transparent phases. The organic phase was separated, and 50 mL of water and 50 mL of 2-methyl-tetrahydrofuran were added to the organic phase, and the obtained mixture was kept under stirring for 15 minutes. The organic phase was then separated, washed with 50 mL of a 5% by weight NaCI aqueous solution, and 0.39 g of 4S carbon were added to the resulting organic phase. The obtained mixture was kept under stirring for 1 hour at the temperature of between 40 and 45°C. The mixture was filtered through a diatomaceous earth filter, and the filter was washed with three 15 mL fractions each of toluene. The solvent was removed from the organic phase by means of vacuum distillation to obtain 5.52 g of a slightly beige-colored solid corresponding to 1 -(2,2-diphenyltetrahydrofuran-3-yl)-N,N-dimethyl-methanamine (blarcamesine) (yield of 97.9%, purity of 99.05% by means of HPLC).

[0232] XRPD: The X-ray powder diffraction pattern of the compound coincides with that disclosed in patent application WO 2019 / 200345 A1 corresponding to the crystalline form identified as Form I of free base blarcamesine (Figure 16 of the mentioned patent application).

[0233] The differential scanning calorimetry (DSC) spectrum of blarcamesine comprises an endothermic peak having a threshold temperature of about 89.8°C.

[0234] Example 5: Synthesis of the compound of formula (IV)

[0235]

[0236] 2 g (7.46 mmol) of 3-(hydroxy(diphenyl)methyl)tetrahydrofuran-2-one (compound of formula (I)) were dissolved in 10 mL of tetrahydrofuran at the temperature of about 20°C. The resulting solution was cooled at the temperature of between 0 and 5°C, and 5.96 mL (260 mg, 11.9 mmol) of a 2M solution of lithium borohydride in THF were added slowly. The reaction mixture was kept under stirring at the indicated temperature for 1 h.

[0237] Once the stirring time elapsed, 10 mL of an NH4CI saturated aqueous solution and 10 mL of ethyl acetate were added. The organic phase was separated, and 10 mL of ethyl acetate were added to the aqueous phase. The organic phase was separated and pooled with the previously obtained organic phase, and the solvent was removed by means of vacuum distillation to obtain 1.6 g of a solid corresponding to 2-(hydroxymethyl)-1,1- diphenyl-butane-1,4-diol (yield of 78.8%, purity of 98.75% by means of HPLC).

[0238]

[0239] 6: of blarcamesine using the of formula

[0240] Example 6a: Preparation of the compound of formula (V)

[0241]

[0242] 3.38 g (12.4 mmol) of 2-(hydroxymethyl)-1 ,1-diphenyl-butane-1,4-diol (compound of formula (IV)) were mixed with 140 mL of chloroform, and 0.4 g (2.1 mmol) ofp-toluenesulfonic acid monohydrate were then added. The reaction mixture was heated at the reflux temperature and kept under stirring for 5 hours.

[0243] Once the stirring time elapsed, the reaction mixture was cooled at the temperature of about 20°C, and 5 g of Na2SO4 and 3 g of NaHCOs were added. The obtained mixture was kept for 30 minutes at the temperature of about 20°C, and the solid was filtered through a diatomaceous earth filter. The filter was washed with three 10 mL fractions each of chloroform. The solvent was removed by means of vacuum distillation, and 30 mL of n-heptane were added to the obtained solid residue. The resulting mixture was heated at the temperature of about 70°C and kept under stirring for 15 minutes at the indicated temperature. The mixture was cooled slowly at the temperature of about 0°C and kept under stirring for 1 hour at said temperature. The resulting solid was filtered and washed successively with three 10 mL fractions each of n-heptane. The obtained solid was dried in a vacuum oven at the temperature of 40°C to obtain 2.55 g of a white solid corresponding to (2,2-diphenyltetrahydrofuran-3-yl)methanol (compound of formula (V)), with a yield of 81.0% and a purity of 99.05% determined by means of HPLC.

[0244] Example 6b: Preparation of blarcamesine

[0245] 1.88 g (7.41 mmol) of (2,2-diphenyltetrahydrofuran-3-yl)methanol (compound of formula (V)) were dissolved in 25 mL of chloroform at the temperature of between 0 and 5°C.

[0246] 1.25 mL (0.91 g, 8.96 mmol) of triethylamine and 0.6 mL (0.89 g, 7.75 mmol) of methanesulfonyl chloride were added to the solution at the indicated temperature. The reaction mixture was kept under stirring for 6 hours at the indicated temperature.

[0247] Once the stirring time elapsed, the temperature of the reaction mixture was left to develop to the temperature of about 20°C, and 25 mL of a 1 N HCI aqueous solution were added. The phases were separated, and 25 mL of chloroform were added to the resulting aqueous phase. The phases were separated, and the resulting organic phase was separated and pooled with the initially obtained organic phase. The solvent was removed from the organic phase by means of vacuum distillation to obtain a solid residue comprising the mesylate derivative of the compound (2,2-diphenyltetrahydrofuran-3-yl)methanol.

[0248] 30 mL of tetrahydrofuran and 16.7 mL (3.34 g, 74.1 mmol) of a 40% by weightdimethylamine aqueous solution were added to the previously obtained residue, the reaction mixture was heated at the temperature of between 50 and 55°C and kept under stirring at said temperature for 24 hours.

[0249] Thereafter, the organic solvent was removed from the mixture by means of vacuum distillation, and 20 mL of methyl-tert-butyl-ether were added at the temperature of about 20°C. The organic phase was separated, and 10 mL of methyl-tert-butyl-ether were added to the aqueous phase. The organic phase was separated again and pooled with the first previously obtained organic phase. 20 mL of an NaHCOs saturated aqueous solution were added, and the organic phase was separated. The organic solvent was removed by means of vacuum distillation to obtain 1.45 g (yield of 75.0%, purity of 98.96% by means of HPLC) of a slightly beige-colored solid corresponding to 1-(2,2-diphenyltetrahydrofuran-3-yl)-N,N-dimethyl-methanamine (blarcamesine).

[0250] XRPD: The X-ray powder diffraction pattern of the compound coincides with that disclosed in patent application WO 2019 / 200345 A1 corresponding to the crystalline form identified as Form I of free base blarcamesine (Figure 16 of the mentioned patent application).

[0251] The differential scanning calorimetry (DSC) spectrum of blarcamesine obtained according to Example 6b comprises an endothermic peak having a threshold temperature of about 89.0°C.

Claims

1. CLAIMS1. A compound of formula (II):(II).

2. The compound according to claim 1 , characterized by being in solid form.

3. The compound according to claim 2, characterized by having a crystalline structure.

4. The compound according to any of claims 2 to 3, characterized in that it has, in an X-ray powder diffraction pattern comprising peaks at one or more of the following angles (2«) ± 0.2: 5.6°, 11.2°, 11.3°, 11.5°, 15.0°, 15.5°, 21.7°, 22.2°, and 25.2°.

5. The compound according to claim 4, characterized in that the X-ray powder diffraction pattern of the compound of formula (II) additionally comprises peaks at one or more of the following angles (2») ± 0.2: 8.5°, 12.2°, 12.7°, 16.1°, 16.5°, 17.8°, 18.1, 19.1°, 20.4°, and 22.8°.

6. The compound according to any of claims 1 to 5, characterized in that it is the stereoisomer of formula (Ila):

7. The compound according to any of claims 1 to 6, characterized in that it has a differential scanning calorimetry (DSC) plot comprising an endothermic peak having a threshold temperature of about 102.4 ± 2°C.

8. A method for preparing the compound of formula (II):(II)characterized in that it comprises contacting a compound of formula (I)(I)with dimethylamine in an organic solvent.

9. The method according to claim 8, characterized in that it is performed at a pressure comprised between 1 and 5 bar, preferably between 2 and 4 bar.

10. The method according to any of claims 8 or 9, characterized in that it is performed at a temperature comprised between 60 and 100°C, preferably between 70 and 90°C, even more preferably between 75 and 85°C.

11. The method according to any of claims 8 to 10, characterized in that the compound of formula (I) is obtained from the reaction of gamma-butyrolactone and benzophenone in an organic solvent.

12. A method for obtaining the compound of formula (III):characterized in that it comprises contacting the compound of formula (II)(II)with a reducing agent in an organic solvent.

13. The method according to claim 12, characterized in that the reducing agent is selected from the group consisting of sodium bis(2-methoxyethoxy)aluminium hydride, BH3-THF, lithium borohydride, lithium aluminium hydride, and diisobutylaluminium hydride, preferably sodium bis(2-methoxyethoxy)aluminium hydride.

14. The method according to any of claims 12 or 13, characterized in that it is performed under an inert gas atmosphere, preferably nitrogen atmosphere.

15. A method for obtaining blarcamesine:\N(Blarcamesine)or a pharmaceutically acceptable salt thereof, characterized in that it comprises:a) contacting the compound of formula (II)with a reducing agent in an organic solvent to obtain the compound of formula (III)andb) reacting the compound of formula (III) with an acid in an organic solvent to obtain blarcamesine:\ N(Blarcamesine).

16. The method according to claim 15, wherein the acid is selected from the group consisting of p-toluenesulfonic acid, camphorsulfonic acid, benzenesulfonic acid, and methylsulfonic acid, preferably p-toluenesulfonic acid.

17. Use of a compound of formula (II)in the preparation of blarcamesine:(Blarcamesine)or a pharmaceutically acceptable salt thereof.

18. A method of preparing a compound of formula (IV):which comprises contacting a compound of formula (I):(I)with a reducing agent in an organic solvent.

19. The method according to claim 18, characterized in that the reductor is selected from the group consisting of lithium borohydride, sodium borohydride, lithium aluminium hydride, and diisobutylaluminium hydride, preferably lithium borohydride.

20. A method for obtaining blarcamesine:\ N(Blarcamesine)or a pharmaceutically acceptable salt thereof, characterized in that it comprises:c) contacting the compound of formula (IV)(IV)with p-toluenesulfonic acid in an organic solvent to obtain the compound of formula (V):(V)andd) contacting the compound of formula (V) with triethylamine and methanesulfonyl chloride in an organic solvent.

21. Use of a compound of formula (IV)in the preparation of blarcamesine:(Blarcamesine)or a pharmaceutically acceptable salt thereof, wherein blarcamesine is obtained as a mixture comprising the (+)-blarcamesine and (-)-blarcamesine enantiomers, preferably as a mixture in which the molar ratio of both enantiomers is between 5:95 and 95:5, more preferably between 45:55 and 55:45, even more preferably as a racemic mixture of both enantiomers.

22. Use of a compound of formula (V)in the preparation of blarcamesine:\ N(Blarcamesine)or a pharmaceutically acceptable salt thereof, wherein blarcamesine is obtained as a mixture comprising the (+)-blarcamesine and (-)-blarcamesine enantiomers, preferably as a mixture in which the molar ratio of both enantiomers is between 5:95 and 95:5, more preferably between 45:55 and 55:45, even more preferably as a racemic mixture of both enantiomers.

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