Method for producing 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidine-1-yl)-1H-1,2,4-triazole-3-amine

Abstract

The present invention relates to a method for synthesizing 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidine-1-yl)-1H-1,2,4-triazole-3-amine in two hydrated crystalline forms and one anhydrous crystalline form. The present invention also relates to methyl (Z)-4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)-N-cyanopiperydin-1-carbimidothioate, which is an intermediate in this method.

Description

Technology Field

[0001] The present invention relates to a method for synthesizing 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidine-1-yl)-1H-1,2,4-triazole-3-amine in two hydrated crystalline forms and one anhydrous crystalline form. The present invention also relates to methyl (Z)-4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)-N-cyanopiperydin-1-carbimidothioate, which is an intermediate in this method. Background Technology

[0002] The 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidine-1-yl)-1H-1,2,4-triazole-3-amine of the following chemical formula 1 was first described in international patent application WO2017 / 037670.

[0003] [Chemical Formula 1]

[0004]

[0005] The compound of Chemical Formula 1 is a dual inhibitor of acidic mammalian chitinase (AMCase) and chitotriosidase 1 (CHIT-1). Such a compound can be used to treat disorders associated with the overexpression of said enzymes. Such disorders include asthma and allergic reactions or idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD).

[0006] Patent application WO2017 / 037670 describes the synthesis of a compound of Formula 1 from (2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholine of Formula 2. This synthesis is outlined by the following reaction scheme.

[0007]

[0008] The compound of Formula 2 is reacted in 1,2-dichloroethane with N-(tert-butoxycarbonyl)-4-piperidone of Formula 3, sodium triacetoxyborohydride as a reducing agent, and glacial acetic acid. After one night, crude tert-butyl 4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)-piperidine-1-carboxylate of Formula 4 is isolated by extraction and purified by column chromatography. To the pure compound of Formula 4, a deprotection reaction of the tert-butoxycarbonyl moiety is applied using a hydrogen chloride solution in ethyl acetate to produce (2S,5S)-5-(4-chlorobenzyl)-2-methyl-4-(piperidine-4-yl)morpholino as a dihydrochloride. In the next step, the compound of Formula 5 is reacted with dimethyl N-cyanodithiomiminocarbonate in the presence of potassium carbonate as a base in acetonitrile. After heating for several hours, hydrazine monohydrate is added, and the reaction mixture is refluxed for several more hours. When the suspension reaches ambient temperature, the solid material is filtered, and the crude product obtained by concentrating the filtrate is purified by column chromatography on silica gel and then precipitated to produce the compound of Formula 1.

[0009] The conversion of the compound of Formula 5 to the compound of Formula 1 is a sequence of two reactions. In the first step, the compound of Formula 5 is converted to an intermediate, which is likely methyl (Z)-4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)-N-cyanopiperidine-1-carbimidothioate of Formula 6 below.

[0010] [Chemical Formula 6]

[0011]

[0012] The synthesis of the compound of Formula 1 as described in patent application WO2017 / 037670 requires two chromatographic purifications that are not cost-effective and are time-consuming. A process involving chromatographic purification may rather be considered unsuitable for industrial scale-up. There is no information on whether the material obtained from such a process is obtained in a crystalline form that can be considered stable. Furthermore, particle size distribution is an important parameter of the drug substance that can have a significant impact on the production of the drug in tablet form. This patent does not teach that the simple precipitation of the final product as described leads to a material having strictly limited particle sizes in a repeatable manner. Since the final step of the synthesis provided in WO2017 / 037670 requires the use of hydrazine, which is known to be carcinogenic, the level of residual hydrazine in the drug substance must be strictly controlled in addition to the overall purity of the material, which is a key factor in all processes of drug substance synthesis. The problem to be solved

[0013] According to the features outlined above, there is an unmet need for a scale-controllable and efficient synthesis process for 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidine-1-yl)-1H-1,2,4-triazole-3-amine of Formula 1 suitable for the production of drugs. means of solving the problem

[0014] The present invention provides an efficient and scalable method for the synthesis of (2S,5S)-5-(4-chlorobenzyl)-2-methyl-4-(piperidine-4-yl)morpholine of Formula 5. Compared to the description of the original approach outlined in the "Background of the Invention," various modifications have been introduced to the process to enable scalability by improving yield and simplifying the synthesis. A compound of Formula 2 is reacted with N-(tert-butoxycarbonyl)-4-piperidone of Formula 3 at 0°C to a reflux temperature, preferably ambient temperature, in a solvent, preferably an alcohol, more preferably methanol, in the presence of a reducing agent, sodium cyanoborohydride, and an additive, preferably zinc chloride. When complete conversion of the starting material is obtained, tert-butyl 4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidine-1-carboxylate of Formula 4 is isolated by extraction, the crude product is dissolved in a solvent, preferably ethyl acetate, and hydrochloric acid, preferably a concentrated hydrochloric acid solution, is added. When complete conversion of the starting material is obtained, the solvent is replaced with a polar solvent, preferably methanol. A solvent, preferably acetone, is added to the solution, and the solution is allowed to cool to ambient temperature. The product crystallizes upon cooling, and the crystals are filtered. The filter cake is washed with a solvent, preferably acetone, and dried in air to yield (2S,5S)-5-(4-chlorobenzyl)-2-methyl-4-(piperidine-4-yl)morpholline of Formula 5 as white crystals. Careful analysis of the obtained material showed that the product is obtained as a dihydrochloride hydrate.

[0015]

[0016] An important step in the synthesis of the compound of Formula 2 is the reaction between the mixture of compounds of Formulas 7 and 8 and potassium tertiary-butoxide, which leads to the compound of Formula 9. Only the compound of Formula 8 is cyclized into the compound of Formula 9. Under reaction conditions, the compound of Formula 7 is epimerized into the compound of Formula 8, which is then cyclized into the compound of Formula 9. Due to this fact, the reaction between potassium tertiary-butoxide and the mixture of compounds of Formulas 7 and 8 yields only the compound of Formula 9. Under reaction conditions, the compound of Formula 9 is epimerized into the compound of Formula 10, which is a reaction byproduct. Subsequently, the crude product of Formula 9 is crystallized, but the complete removal of the unwanted compound of Formula 10 is lengthy and leads to a significant loss of product. The reduction of the compound of formula 9 leads to the compound of formula 2, but when the compound of formula 9 is contaminated with the compound of formula 10, the compound of formula 2 contains the compound of formula 11, which is obtained as the reduction product of the compound of formula 10.

[0017]

[0018] Under the conditions described in patent application WO2017 / 037670 (sodium triacetoxyborohydride, acetic acid, and 1,2-dichloroethane), the compound of Formula 11 reacts with N-Boc-4-piperidinone to lead to a byproduct of Formula 12, which is observed in the crude compound of Formula 4. Although the impurity of Formula 12 can be removed by careful purification on silica gel, such an approach is not permissible on a kilo-scale. The compound of Formula 11 does not react with N-Boc-4-piperidinone when the conditions described in this patent application (sodium cyanoborohydride, zinc chloride, and methanol) are used. Since the compound of Formula 11 can be easily removed by crystallization after the removal of the tertiary-butoxycarbonyl protecting group, the present invention relates to a method for synthesizing the impurity-free compound of Formula 5 of Formula 13. Furthermore, it is unclear whether the conditions described in this application allow the use of a hydrochloride salt of the compound of Formula 2 as a starting material to accelerate the process. The compound of Formula 2 is an oil with limited stability, which means that the compound must be maintained in salt form to prevent decomposition. Conversely, the reaction described in WO2017 / 037670 does not proceed when the hydrochloride of the compound of Formula 2 is used as a starting material, and the salt must first be converted into a free base, which is an additional operation.

[0019]

[0020] The present invention further provides a method for synthesizing methyl (Z)-4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)-N-cyanopipiridin-1-carbimidothioate of Formula 6. This compound has never been isolated or described before. The related compound can be synthesized by reacting (2S,5S)-5-(4-chlorobenzyl)-2-methyl-4-(piperidin-4-yl)morpholino of Formula 5 with dimethyl N-cyanodithiomiminocarbonate in the presence of a base, preferably a trialkylamine, more preferably a triethylamine, in a solvent, preferably ethanol, 1-propanol, or 2-propanol. The reaction is carried out at room temperature to a reflux temperature, preferably 50°C. Once complete conversion of the starting materials is obtained, the reaction mixture is cooled to ambient temperature. Upon cooling, the product crystallizes. Filter the material and wash the filter cake with a solvent, preferably ethanol, 1-propanol, or 2-propanol, and dry it to provide a compound of Formula 6.

[0021]

[0022] The present invention further provides a method to avoid a three-step synthesis by directly synthesizing the compound of Formula 6 from the compound of Formula 2. This approach relates to the reaction of the compound of Formula 2 with the 4-oxopiperidine methyl N-cyanothioimidocarbamate of Formula 14. The compound of Formula 14 can be readily obtained from commercially available 4,4-dihydroxypiperidine hydrochloride by reacting it with dimethyl N-cyanodithiomiminocarbonate in the presence of a base, preferably a trialkylamine, more preferably a triethylamine, in a solvent, preferably a mixture of solvents, and more preferably a mixture of 2-propanol and water at a reflux temperature of 0°C to ambient temperature, preferably ambient temperature. The reaction mixture is quenched with a 6 M hydrochloric acid solution and extracted with an organic solvent, preferably dichloromethane. The solution is washed with water, and the solvent is exchanged with a polar solvent, preferably 2-propanol. A non-polar solvent, preferably isopropyl ether, is added to a hot solution to induce crystallization of the product. The solid is filtered, and the filter cake is washed with a solvent, preferably a mixture of solvents, and more preferably a mixture of 2-propanol and isopropyl ether, and then dried to provide the compound of Formula 14 as a gray solid.

[0023]

[0024] The reaction between the compound of Formula 2 and the compound of Formula 14, reacted under the conditions described in WO217 / 037670 to synthesize the compound of Formula 4, did not proceed after simply replacing the ketone compound of Formula 3 with the ketone compound of Formula 14. Furthermore, as described in this application, the conditions for synthesizing the compound of Formula 4 from the compound of Formula 2 resulted in a mixture of the compound of Formula 6 and the byproduct of Formula 15 after simply replacing the compound of Formula 3 with the compound of Formula 14. This created an unmet need for the development of new conditions to directly synthesize the compound of Formula 6 from the compound of Formula 2.

[0025] The reaction between the compound of Formula 2 and the compound of Formula 14 is carried out at 0°C to a reflux temperature, preferably ambient temperature, in a polar solvent, preferably ethanol, in the presence of a reducing agent, preferably sodium cyanoborohydride, and an additive, preferably zinc chloride. After complete conversion of the starting materials is obtained, the reaction mixture is quenched with a 1 M sodium hydroxide solution and extracted with an organic solvent, preferably dichloromethane. The solvent is exchanged with an organic solvent, preferably ethanol. The solution is allowed to cool to ambient temperature to induce crystallization of the product. The solid is filtered, the filter cake is washed with a solvent, preferably ethanol, and dried to provide the compound of Formula 6 as a white solid.

[0026] The target molecule of Formula 1 can be obtained from a compound of Formula 5 or a compound of Formula 6. Furthermore, this patent application describes a method for preparing the anhydrous form, two hydrated forms (hydrated forms I and II), and amorphous form of the target molecule of Formula 1. The method outlined in this paragraph is summarized in FIG. 1.

[0027] The present invention further provides a method for synthesizing a compound of Formula 1 in its hydrated form I from a compound of Formula 5 (Reaction A in FIG. 1). A compound of Formula 5 is suspended in a solvent, preferably ethanol, dimethyl N-cyanodithiomiminocarbonate is added, and then a base, preferably a trialkylamine, more preferably a triethylamine, is added at ambient temperature to the boiling point, preferably 40°C. Once complete conversion of the starting material is achieved, hydrazine monohydrate is added, and the reaction is continued at ambient temperature to the boiling point, preferably 60°C. Once complete conversion of the intermediate is achieved, water is added, and the solution is cooled to -20°C to ambient temperature, preferably 5°C. The precipitated solid is filtered, and the filter cake is washed with a mixture of water and an organic solvent, preferably ethanol, and dried to provide a compound of Formula 1 in its hydrated form I as a white solid.

[0028] The present invention further provides a method for synthesizing a compound of Formula 1 in its hydrated form I from a compound of Formula 6 (Reaction B in FIG. 1). A compound of Formula 6 is suspended in a solvent, preferably ethanol, at ambient temperature to a boiling point temperature, preferably 60°C, and hydrazine monohydrate is added. Once complete conversion of the starting material is achieved, water is added, and the solution is cooled to a temperature of -20°C to ambient temperature, preferably 5°C. The precipitated solid is filtered, and the filter cake is washed with a mixture of water and an organic solvent, preferably ethanol, and dried to provide a compound of Formula 1 in its hydrated form I as a white solid.

[0029] The present invention further provides a method for synthesizing an anhydrous form of a compound of Formula 1 from a compound of Formula 6 (Reaction C in FIG. 1). The reaction between the compound of Formula 6 and hydrazine monohydrate is carried out in an organic solvent, preferably acetonitrile, at ambient temperature to a boiling point temperature, preferably 60°C. Once complete conversion of the starting materials is achieved, the solution is cooled to ambient temperature, and the product precipitates upon cooling. The solid is filtered, the filter cake is washed with a solvent, preferably acetonitrile, and dried to provide an anhydrous form of the compound of Formula 1 as a white solid.

[0030] Compared to WO2017 / 037670, when the compound of Formula 1 is obtained by a single-vessel approach, it is unclear whether a process using the separation of the compound of Formula 6 results in obtaining the anhydrous form of the compound of Formula 1 in a higher yield (86% in this application versus 72% in WO2017 / 037670). A critical factor in the second step involving the reaction of the compound of Formula 6 is the acetonitrile used as a solvent. Among more polar solvents (i.e., methanol, ethanol, or 2-propanol), the reaction yield is significantly lower. On the other hand, when less polar solvents (i.e., dichloromethane, methyl tert-butyl ether, or toluene) are applied, the levels of residual hydrazine become unacceptable.

[0031] The present invention further provides a method for preparing the anhydrous form of a compound of Formula 1 from its hydrated form I (Method D in FIG. 1). The compound of Formula 1 in its hydrated form I is suspended in an organic solvent, preferably ethyl acetate, and the suspension is heated and refluxed. Upon heating, the suspension turns into a clear solution. The solution is distilled until the temperature of the volatile substance reaches 76°C. During distillation, the product precipitates. The solid is filtered at ambient temperature. The filter cake is washed with an organic solvent, preferably ethyl acetate, and dried to provide the anhydrous form of the compound of Formula 1 as white crystals.

[0032] The synthesis of the anhydrous form of the compound of Formula 1 following the synthesis of the hydrated form I of Formula 1 has significant advantages compared to the synthesis of the compound of Formula 1 described in WO2017 / 037670. Under new conditions, it is unclear whether the precipitation of the hydrated form I of the compound of Formula 1 can control the amount of residual hydrazine, which is considered a genotoxic impurity and must be controlled to the ppm level. The method outlined in the preceding paragraph was used to synthesize three batches of the anhydrous form of the compound of Formula 1. These materials were analyzed in detail for purity, residual hydrazine levels, and particle size distribution.

[0033] Purity by HPLC Residual hydrazine levels Particle size distribution 99.92% 0.3 ppm D10 152 ㎛, D50 255 ㎛, D90 403 ㎛ ≥9.95% 0.1 ppm D10 202 ㎛, D50 357 ㎛, D90 577 ㎛ ≥9.95% 0.2 ppm D10 154 ㎛, D50 284 ㎛, D90 485 ㎛

[0034] The present invention further provides a method for preparing a compound of Formula 1 in its hydrated form II from its anhydrous form (Method E in FIG. 1). The anhydrous form of the compound of Formula 1 is dissolved in methanol under reflux. Water is added to the solution and the product is precipitated. The suspension is cooled to a temperature of -20°C to ambient temperature, preferably 5°C. The solid is aged and filtered. The filter cake is washed with a mixture of water and methanol and dried to provide the compound of Formula 1 in its hydrated form II as a white solid.

[0035] Due to the fact that the compound of Formula 6 is not stable in methanol, it is not possible to obtain hydrated form II directly from Compound 6 as in the case of hydrated form I of Compound 1. Both hydrated forms I and II of Compound 1 are unstable, leading to an amorphous form upon drying. XPRD data and data derived from X-ray structures for the dried material differ. Furthermore, analysis of the dried single crystal of Compound 1 in hydrated form I used for structural measurements revealed a lack of crystalline structure, leading to the conclusion that the crystalline structure collapses upon drying. The amorphous form of Compound 1 can be prepared more conveniently by melting Compound 1 in its anhydrous form or in hydrated forms I or II, and then cooling the material to ambient temperature. After grinding the glassy solid, the anhydrous form of Compound 1 is a gray solid. Brief explanation of the drawing

[0036] Fig. 1. Synthesis reaction scheme of various forms of 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidine-1-yl)-1H-1,2,4-triazole-3-amine. Fig. 2. XPRD diffractogram of methyl (Z)-4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)-N-cyanopiperidine-1-carbimidothioate obtained in Example 3. Fig. 3. FT-IR (ATR) spectrum of methyl (Z)-4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)-N-cyanopiperidine-1-carbimidothioate obtained in Example 3. Fig. 4. DSC thermogram of methyl (Z)-4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)-N-cyanopiperidine-1-carbimidothioate obtained in Example 3. Fig. 5. Methyl (Z)-4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)-N-cyanopiperidine-1-carbimidothioate obtained in Example 3 1 H NMR spectrum (CDCl3 at 400 MHz). Fig. 6. Methyl (Z)-4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)-N-cyanopiperidine-1-carbimidothioate obtained in Example 3 13 C NMR spectrum (CDCl3 at 100 MHz). Fig. 7. XPRD dipractogram of 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidine-1-yl)-1H-1,2,4-triazole-3-amine hydrated form I calculated from X-ray analysis of a single crystal obtained from a mixture of water and ethanol. Fig. 8. FT-IR (ATR) spectrum of 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidine-1-yl)-1H-1,2,4-triazole-3-amine hydrated form I obtained in Example 6. Fig. 9. DSC thermogram of 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidine-1-yl)-1H-1,2,4-triazole-3-amine hydrated form I obtained in Example 6. Fig. 10. XPRD dipractogram of the 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidine-1-yl)-1H-1,2,4-triazole-3-amine anhydrous form obtained in Example 8. Fig. 11. FT-IR (ATR) spectrum of the 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidine-1-yl)-1H-1,2,4-triazole-3-amine anhydrous form obtained in Example 8. Fig. 12. DSC thermogram of the 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidine-1-yl)-1H-1,2,4-triazole-3-amine anhydrous form obtained in Example 8. FIG. 13. 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidine-1-yl)-1H-1,2,4-triazole-3-amine anhydrous form obtained in Example 8 1 1H NMR (C6D6 at 700 MHz) spectrum. FIG. 14. 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidine-1-yl)-1H-1,2,4-triazole-3-amine anhydrous form obtained in Example 8 13 1C NMR (C6D6 at 176 MHz) spectrum. Fig. 15. XPRD dipractogram of 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidine-1-yl)-1H-1,2,4-triazole-3-amine hydrated form II calculated from X-ray analysis of a single crystal obtained from a mixture of water and methanol. Fig. 16. FT-IR (ATR) spectrum of 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidine-1-yl)-1H-1,2,4-triazole-3-amine hydrated form II obtained in Example 10. Fig. 17. DSC thermogram of 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidine-1-yl)-1H-1,2,4-triazole-3-amine hydrated form II obtained in Example 10. FIG. 18. FT-IR (ATR) spectrum of the 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidine-1-yl)-1H-1,2,4-triazole-3-amine anhydrous form obtained in Example 11. Specific details for implementing the invention

[0037] Summary of the Invention

[0038] The present invention provides a method for synthesizing (2S,5S)-5-(4-chlorobenzyl)-2-methyl-4-(piperidine-4-yl)morpholine dihydrochloride hydrate of formula 5 in a solid crystalline state.

[0039] The present invention relates to methyl (Z)-4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)-N-cyanopiperidine-1-carbimidothioate of Formula 6 in a solid crystalline state, and is characterized by at least one of the following:

[0040] (i) XRPD peaks at 10.13, 10.98, 12.03, 13.54, 13.98, 14.40, 14.88, 16.84, 18.67, 20.21, 20.85, 21.71, 22.56, 22.98, 24.10, 24.56, 25.27, 27.48, 29.80, 30.43, and 33.36° 2-theta.

[0041] (ii) 2959, 2926, 2866, 2820, 2795, 2167, 1541, 1491, 1450, 1431, 1383, 1358, 1273, 1215, 1151, 1117, 1096, 1070, 1043, 1013, 988, 930, 862, 833, 806, 714, 665, and 638 cm -1 IR band.

[0042] (iii) DSC of the onset at 156.26℃ and the peak at 157.51℃.

[0043] The above-mentioned features substantially correspond to FIGS. 2 to 4.

[0044] The present invention provides a method for synthesizing methyl (Z)-4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)-N-cyanopiperidine-1-carbimidothioate of formula 6 in a solid crystalline state.

[0045] The present invention further relates to a hydrated form I of Formula 1 of Formula 1 in a solid crystalline state, 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidine-1-yl)-1H-1,2,4-triazole-3-amine, characterized by at least one of the following:

[0046] (i) XRPD peaks at 6.70, 9.96, 10.68, 12.74, 13.42, 14.20, 14.82, 15.40, 15.58, 16.44, 17.00, 17.46, 18.02, 18.30, 18.64, 19.52, 20.16, 20.66, 21.40, 21.64, 21.86, 22.16, 22.58, 23.22, 23.68, 24.64, 27.00, 27.26, 27.88, and 28.84° 2-theta.

[0047] (ii) 3318, 3206, 2963, 2934, 2859, 2833, 1636, 1589, 1553, 1489, 1462, 1404, 1346, 1314, 1277, 1250, 1151, 117, 1092, 1069, 1013, 917, 868, 829, 800, 764, 725, and 673 cm -1 IR band.

[0048] (iii) DSC of the onset at 80.60°C and the peak at 91.32°C.

[0049] The above-mentioned features substantially follow FIGS. 7 to 9.

[0050] The present invention provides a method for synthesizing the hydrated form I of the formula 1 of 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidine-1-yl)-1H-1,2,4-triazole-3-amine in a solid crystalline state.

[0051] The present invention further relates to the 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidine-1-yl)-1H-1,2,4-triazole-3-amine anhydrous form of Formula 1 in a solid crystalline state, characterized by at least one of the following:

[0052] (i) XRPD peaks at 5.81, 7.39, 9.95, 11.53, 11.97, 12.39, 13.13, 14.07, 14.60, 14.81, 15.11, 16.09, 16.45, 17.15, 17.67, 17.85, 18.21, 18.68, 19.21, 19.84, 20.75, 21.22, 22.24, 23.00, 24.22, 24.98, and 27.48° 2-theta.

[0053] (ii) 3252, 3198, 3119, 2955, 2924, 2857, 2793, 1666, 1599, 1543, 1483, 1456, 1404, 1337, 1283, 1248, 1136, 1117, 1094, 1072, 1053, 1013, 908, 858, 795, and 718 cm -1 IR band.

[0054] (iii) DSC of the onset at 175.83℃ and the peak at 177.59℃.

[0055] The above-mentioned features substantially correspond to FIGS. 10 to 12.

[0056] The present invention further provides for the preparation of the 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidine-1-yl)-1H-1,2,4-triazole-3-amine anhydrous form of Formula 1 in a solid crystalline state.

[0057] The present invention further relates to a hydrated form II of Formula 1 of 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidine-1-yl)-1H-1,2,4-triazole-3-amine in a solid crystalline state, characterized by at least one of the following:

[0058] (i) XRPD peaks at 10.14, 12.88, 13.50, 13.94, 15.30, 15.48, 16.12, 16.34, 17.60, 17.98, 18.14, 18.64, 18.72, 19.34, 19.76, 20.16, 20.36, 21.64, 22.16, 22.54, 22.86, 23.02, 23.70, 24.28, 25.92, 26.14, 26.32, 27.08, 27.34, 27.70, 30.50, and 39.24° 2-theta.

[0059] (ii) 3325, 2963, 2814, 1634, 1580, 1553, 1489, 1460, 1418, 1389, 1343, 1279, 1248, 1206, 1151, 1119, 1090, 1069, 1047, 1013, 991, 914, 866, 831, 797, 760, 665, and 600 cm -1 IR band.

[0060] (iii) Two DSC peaks: The first starts at 60.12°C and peaks at 70.29°C. The second starts at 82.83°C and peaks at 90.87°C.

[0061] The above-mentioned features substantially correspond to FIGS. 15 to 17.

[0062] The present invention provides a method for synthesizing the hydrated form II of Formula 1, 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidine-1-yl)-1H-1,2,4-triazole-3-amine, in a solid crystalline state.

[0063] The present invention further relates to a solid-state 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidine-1-yl)-1H-1,2,4-triazole-3-amine anhydrous form, characterized as follows:

[0064] (i) 3312, 3173, 2968, 2859, 2822, 1634, 1551, 1489, 1458, 1346, 1277, 1246, 1150, 1115, 1094, 1069, 1013, 920, 858, 804, 758, 719, and 665 cm -1 IR band.

[0065] The above-mentioned features substantially correspond to Fig. 18.

[0066] The present invention provides a method for preparing an amorphous form of 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidine-1-yl)-1H-1,2,4-triazole-3-amine of Formula 1 in a solid state.

[0067] The present invention provides an industrially scalable synthesis method for a compound of Formula 1. The method avoids chromatographic purification, which is the most verbose part of the process. The final product is obtained in a repeatable manner in terms of particle size distribution, purity, and residual hydrazine levels, and meets high standards for drug substances.

[0068] The invention will be illustrated by the following examples.

[0069] Examples

[0070] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the invention in any way.

[0071] All commercially available solvents, substrates, and reagents were used without further purification.

[0072] NMR spectra were recorded on an Agilent Mercury 400 MHz spectrometer and Bruker Avance 500 and 700 MHz spectrometers (DXR500 and DXR700, respectively).

[0073] NMR spectra were recorded in commercially available labeled deuterated solvents.

[0074] Gong-eun 1 For 1H NMR, tetramethylsilane (δ 0.00 ppm for CD3Cl) or residual solvent (δ 4.87 ppm for CD3OD or δ 7.61 ppm for C6D6), or 13 For 1C NMR, values ​​are provided in parts per million for the solvent (δ 49.00 ppm for CD3OD, δ 77.26 ppm for CDCl3, or δ 128.06 ppm for C6D6). Data are reported as follows: chemical shift (δ), multiplet (s = singlet, d = doublet, t = triplet, m = multiplet, bs = broad singlet), coupling constant (J(Hz)), and integration.

[0075] The FT-IR spectrum was recorded in ATR mode (zinc selenide crystal) using a Shimadzu IRTracer-100.

[0076] X-ray diffraction experiments at T = 100(2) K were performed on a high-quality single crystal. The crystal was placed on a MiTeGen micromount in Paratone-N oil. Diffraction data were collected using CuKα radiation (λ = 1.54184 Å) on an Agilent Technologies SuperNova Dual Source. Lattice parameters were obtained by least-squares fitting to the optimized set angles of the collected reflections using CrysAlis CCD software. Data reduction was performed using the CrysAlis RED program. Multi-scan empirical absorption correction using spherical harmonics executed in the SCALE3 ABSPACK scaling algorithm was applied. The structure determination process was performed using the SHELX package.

[0077] XPRD diffractograms of the compounds obtained in Examples 3 and 8 were recorded using a Bruker D8 Discover powder X-ray diffractometer equipped with Cu CuKα radiation (1.54 Å) and a Vantec detector. Samples were analyzed in continuous mode over an angular range of 3–50° 2θ with a step size of 0.01222276° and a step time of 0.9 s. XPRD diffractograms of the compounds obtained in Examples 6 and 10 were calculated from single-crystal X-ray data using Mercury software.

[0078] The DSC thermogram was recorded with a Mettler Toledo DSC at a gradient of 5°C / min.

[0079] PSD data was recorded on Isopar G with Malvern Mastersizer 2000.

[0080] Purity was measured by the HPLC-UV method. The analysis was performed at 20°C on a phenyl-hexyl analysis column (Kinetex Phenyl-Hexyl, 2.1 mm x 100 mm; 2.6 μm) at a mobile phase flow rate of 0.3 mL / min. The mobile phase is a mixture of solvent A (900 mL water, 100 mL methanol, 1 g ammonium formate) and solvent B (100 mL water, 900 mL methanol, 1 g ammonium formate). Elution is performed under gradient elution (60% solvent B 0.0 to 2.0 min, followed by 60% to 85% solvent B 2.0 to 2.5 min, followed by 85% solvent B 2.5 to 5.5 min, followed by 85% to 100% solvent B 5.5 to 60 min, followed by 100% solvent B 6.0 to 8.0 min, followed by 100% to 60% solvent B 8.0 to 8.2 min, followed by 60% solvent B 8.2 to 13.0 min). Peaks are recorded using UV detection at 225 nm.

[0081] The residual level of hydrazine was measured by the HPLC-UV method. The sample is prepared by dissolving 75 mg in 1 mL of methanol. 1 mL of 1 M HCl solution is added, followed by 1 mL of benzaldehyde solution (0.6 g / mL in methanol / aqueous 1 / 1 (v / v)) and the solution is vortexed. 1 mL of n-heptane is added, the two-phase system is vortexed, and high-speed centrifugation is performed. The upper phase (5 µL) is injected for analysis. Chromatography (HPLC-UV) analysis is performed on a C18 analytical column (LumiSep C18, 2.1 mm x 50 mm; 3 µm) maintained at 40°C at a mobile phase flow rate of 0.5 mL / min. The mobile phase consists of a mixture of solvent A (900 mL water, 100 mL acetonitrile, 1 g ammonium formate) and solvent B (100 mL water, 900 mL acetonitrile, 1 g ammonium formate). Elution is performed under isosolvent conditions (55% solvent B until the run is completed at 6 minutes). Peaks are recorded using UV detection at 305 nm. The retention time of the benzaldehyde hydrazone is approximately 2.43 minutes.

[0082] Boc represents a tertiary butoxycarbonyl protecting group.

[0083] The reaction yield is expressed in mol%.

[0084] HPLC purity is indicated by the percentage of the area under the curve.

[0085] Water content and loss upon drying according to the Karl Fischer method are expressed in weight%.

[0086] Example 1

[0087] Preparation of (2S,5S)-5-(4-chlorobenzyl)-2-methyl-4-(piperidine-4-yl)morpholine dihydrochloride hydrate (5, dihydrochloride hydrate) from (2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholine (2).

[0088] (2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholine (2, 13.06 g), N-Boc-4-piperidinone (3, 17.30 g), and zinc chloride (7.89 g) were dissolved in methanol (130 ml). Sodium cyanoborohydride (5.45 g) was added in portions, and the reaction mixture was stirred overnight. The reaction mixture was divided between ethyl acetate (240 ml) and a 1 M sodium hydroxide solution (240 ml). The aqueous layer was extracted with ethyl acetate (240 ml), the combined extract was washed with a half-saturated sodium chloride solution (240 ml), and dried. The solution was concentrated to about 200 ml, and concentrated hydrochloric acid (40 ml) was added. After 30 minutes, the water was distilled using a Dean-Stark trap. Ethyl acetate was exchanged with methanol and concentrated to a volume of about 100 ml. Acetone (300 ml) was slowly added to the solution to induce precipitation of the product. The suspension was cooled to ambient temperature and aged for 1 hour. The solid was filtered, the filter cake was washed with acetone (2 x 100 ml), and air-dried to yield (2S,5S)-5-(4-chlorobenzyl)-2-methyl-4-(piperidin-4-yl)morpholine dihydrochloride hydrate as a white solid (5, dihydrochloride hydrate, 20.92 g, 90% yield over two steps, 99.5% purity by HPLC).

[0089] 1 H NMR (500 MHz, CD3OD) δ 7.40-7.30 (m, 4H), 4.08-3.98 (m, 1H), 3.96-3.83 (m, 2H), 3.82-3.74 (m, 1H), 3.69 (d, J = 13.3 Hz, 1H), 3.67-3.54 (m, 3H), 3.29-3.06 (m, 5H), 2.60-2.50 (m, 2H), 2.26-2.11 (m, 2H), and 1.32 (d, J = 6.2 Hz, 3H) ppm.

[0090] 13C NMR (125 MHz, CD3OD) δ 135.2, 134.4, 132.5, 130.1, 71.7, 65.7, 58.0, 57.6, 50.4, 43.7, 43.5, 28.4, 25.2, 25.0, and 18.7 ppm.

[0091] Example 2

[0092] Preparation of (2S,5S)-5-(4-chlorobenzyl)-2-methyl-4-(piperidine-4-yl)morpholine dihydrochloride hydrate (5, dihydrochloride hydrate) from (2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholine hydrochloride (2, hydrochloride)

[0093] (2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholine (2, hydrochloride, 9.99 g), N-Boc-4-piperidinone (3, 11.39 g), and zinc chloride (5.23 g) were dissolved in methanol (80 ml). Sodium cyanoborohydride (3.71 g) was added in portions, and the reaction mixture was stirred overnight. The reaction mixture was divided between ethyl acetate (240 ml) and a 1 M sodium hydroxide solution (240 ml). The aqueous layer was extracted with ethyl acetate (240 ml), the combined extract was washed with a half-saturated sodium chloride solution (240 ml), and dried. The solution was concentrated and dried, and the residue was dissolved in a 3 M hydrochloric acid solution in ethyl acetate. After 1 hour, the solution was concentrated and dried and dissolved in MeOH (30 ml) under reflux. Acetone (30 ml) was added to the clear solution, and the mixture was cooled to ambient temperature to precipitate the product. A second aliquot of acetone (20 ml) was added to the suspension, and the suspension was aged for 1 hour. The solid was filtered, the filter cake was washed with acetone (2 x 30 ml), and air-dried to yield (2S,5S)-5-(4-chlorobenzyl)-2-methyl-4-(piperidin-4-yl)morpholine dihydrochloride hydrate as a white solid (5, dihydrochloride hydrate, 12.51 g, 86% yield over two steps, 98.9% purity by HPLC).

[0094] 1 H NMR (500 MHz, CD3OD) δ 7.40-7.30 (m, 4H), 4.08-3.98 (m, 1H), 3.96-3.83 (m, 2H), 3.82-3.74 (m, 1H), 3.69 (d, J = 13.3 Hz, 1H), 3.67-3.54 (m, 3H), 3.29-3.06 (m, 5H), 2.60-2.50 (m, 2H), 2.26-2.11 (m, 2H), and 1.32 (d, J = 6.2 Hz, 3H) ppm.

[0095] 13 C NMR (125 MHz, CD3OD) δ 135.2, 134.4, 132.5, 130.1, 71.7, 65.7, 58.0, 57.6, 50.4, 43.7, 43.5, 28.4, 25.2, 25.0, and 18.7 ppm.

[0096] Example 3

[0097] Preparation of methyl (Z)-4-((2S,5S)-5-(4-chlorobenzyl)-2-methyl-4-(piperidin-4-yl)morpholine dihydrochloride hydrate (5, dihydrochloride hydrate) of N-cyano-piperidin-1-carbimidothioate (6)

[0098] (2S,5S)-5-(4-chlorobenzyl)-2-methyl-4-(piperidin-4-yl)morpholine dihydrochloride hydrate (5, dihydrochloride hydrate, 5.82 g) and dimethyl N-cyanodithiomiminocarbonate (2.34 g) were suspended in ethanol (60 ml). Triethylamine (6.1 ml) was added to the suspension, and the reaction mixture was heated to a maximum of 40°C. The suspension turned into a clear solution upon heating. After 3 hours, the solution was cooled to ambient temperature, and the product was precipitated. The suspension was aged, and the solid was filtered. The filter cake was washed with ethanol (5 ml) and dried to yield methyl (Z)-4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)-N-cyanopiperidine-1-carbimidothioate (6, 5.48 g, 92% yield, 99.2% purity by HPLC) as a white, fluffy solid.

[0099] 1 H NMR (400 MHz, CDCl3) δ 7.28-7.22 (m, 2H), 7.13-7.08 (m, 2H), 4.45-4.34 (m, 2H), 3.68-3.54 (m, 2H), 3.46 (dd, J = 11.5, 2.7 Hz, 1H), 3.32 (dd, J= 12.1, 2.8 Hz, 2H), 3.01 (dd, J = 12.9, 10.8 Hz, 1H), 2.88-2.77 (m, 2H), 2.76 (s, 3H), 2.71-2.62 (m, 2H), 2.36 (dd, J = 11.8, 10.3 Hz, 1H), 2.07-1.94 (m, 2H), 1.68-1.47 (m, 2H), and 1.21 (d, J = 6.2 Hz, 3H) ppm.

[0100] 13 C NMR (100 MHz, CDCl3) δ 168.7, 138.3, 132.0, 130.8, 128.8, 115.4, 72.5, 67.8, 55.8, 55.4, 50.0, 46.9, 30.3, 29.8, 27.5, 19.3, and 16.4 ppm.

[0101] FT-IR (ATR): 2959, 2926, 2866, 2820, 2795, 2167, 1541, 1491, 1450, 1431, 1383, 1358, 1273, 1215, 1151, 1117, 1096, 1070, 1043, 1013, 988, 930, 862, 833, 806, 714, 665, and 638 cm -1 .

[0102] Example 4

[0103] Preparation of 4-oxopiperidine methyl N-cyanothioimidocarbamate (14)

[0104] Dimethyl N-cyanodithiomiminocarbonate (15.02 g) and 4,4-dihydroxypiperidine hydrochloride (19.72 g) were dissolved in a mixture of 2-propanol (60 ml) and water (90 ml). Triethylamine (17.3 ml) was added to the solution. After 2 hours, the reaction mixture was quenched with a 6 M hydrochloric acid solution (30 ml) and extracted with CH2Cl2 (4 x 75 ml). The combined organic layer was washed with water (75 ml) and 2-propanol (90 ml) was added. The solution was concentrated to a volume of 90 ml under atmospheric pressure, and then isopropyl ether (90 ml) was added in portions to the boiling solution while maintaining reflux. The product was allowed to precipitate and the suspension to cool to ambient temperature. The suspension was aged and the solid was filtered. The filter cake was washed with a mixture of 2-propanol (20 ml) and isopropyl ether (20 ml) and dried to provide 4-oxopiperidine methyl N-cyanothioimidocarbamate (14, 17.94 g, 88% yield) as a white solid.

[0105] 1 H NMR (400 MHz, CDCl3) δ 4.11 (t, J = 6.4 Hz, 4H), 2.85 (s, 3H), 2.60 (t, J = 6.3 Hz, 4H) ppm.

[0106] 13 C NMR (100 MHz, CDCl3) δ 204.8, 169.7, 114.5, 46.4, 40.2, 16.4 ppm.

[0107] Example 5

[0108] Preparation of methyl (Z)-4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)-N-cyanopiperidine-1-carbimidothioate (6) directly from (2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)-N-cyanopiperidine-1-carbimidothioate (6)

[0109] (2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholine (2, 5.23 g), 4-oxopiperidine methyl N-cyanothioimidocarbamate (14, 6.86 g), and zinc chloride (3.16 g) were suspended in ethanol (52 ml). The slightly turbid solution was cooled to 0°C, and sodium cyanoborohydride (2.19 g) was added in a fraction. The suspension was stirred at ambient temperature for 24 hours. The reaction mixture was quenched with 1 M sodium hydroxide solution (60 ml) and extracted with dichloromethane (60 ml, followed by 2 x 30 ml). The combined organic layer was washed with water (30 ml), and the solvent was exchanged with ethanol. During the exchange, the product precipitated. The suspension was allowed to cool to ambient temperature, and the solid was filtered. The filter cake was washed with ethanol (18 ml) and dried to yield methyl (Z)-4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)-N-cyanopiperidine-1-carbimidothioate (6, 7.80 g, 83% yield, 99.5% purity by HPLC) as a gray solid.

[0110] 1 H NMR (400 MHz, CDCl3) δ 7.28-7.22 (m, 2H), 7.13-7.08 (m, 2H), 4.45-4.34 (m, 2H), 3.68-3.54 (m, 2H), 3.46 (dd, J = 11.5, 2.7 Hz, 1H), 3.32 (dd, J = 12.1, 2.8 Hz, 2H), 3.01 (dd, J = 12.9, 10.8 Hz, 1H), 2.88-2.77 (m, 2H), 2.76 (s, 3H), 2.71-2.62 (m, 2H), 2.36 (dd, J = 11.8, 10.3 Hz, 1H), 2.07-1.94 (m, 2H), 1.68-1.47 (m, 2H), and 1.21 (d, J = 6.2 Hz, 3H) ppm.

[0111] 13C NMR (100 MHz, CDCl3) δ 168.7, 138.3, 132.0, 130.8, 128.8, 115.4, 72.5, 67.8, 55.8, 55.4, 50.0, 46.9, 30.3, 29.8, 27.5, 19.3, and 16.4 ppm.

[0112] FT-IR (ATR): 2959, 2926, 2866, 2820, 2795, 2167, 1541, 1491, 1450, 1431, 1383, 1358, 1273, 1215, 1151, 1117, 1096, 1070, 1043, 1013, 988, 930, 862, 833, 806, 714, 665, and 638 cm -1 .

[0113] Example 6

[0114] Preparation of 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methyl-4-(piperidine-4-yl)morpholin dihydrochloride hydrate (5, dihydrochloride hydrate)-4H-1,2,4-triazole-3-amine hydrated form I (1, hydrated form I) from (2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidine-1-yl)-4H-1,2,4-triazole-3-amine hydrated form I (1, hydrated form I)

[0115] (2S,5S)-5-(4-chlorobenzyl)-2-methyl-4-(piperidin-4-yl)mormoline dihydrochloride hydrate (5, dihydrochloride hydrate, 9.03 g) and dimethyl N-cyanodithiomiminocarbonate (3.80 g) were suspended in 1-propanol (72 ml). Triethylamine (9.9 ml) was added, and the clear solution was refluxed for 3 hours. Hydrazine monohydrate (3.5 ml) was added, and the reaction was carried out at 60°C for an additional 2 hours. Water (144 ml) was added to the hot solution, it was cooled to ambient temperature, the crystalline material was seeded, and the solution was placed in a refrigerator for 24 hours. The precipitate was filtered, the filter cake was washed with water (2 x 40 ml), and air-dried to provide a crude product (14.3 g) as a white solid, 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-4H-1,2,4-triazole-3-amine hydrated form I (1, hydrated form I, 7.06 g, 25% loss upon drying, 80% yield on a dry basis, 99.4% purity by HPLC).

[0116] The seed crystalline material used was obtained from the crude reaction mixture. The reaction mixture was concentrated and dried under reduced pressure, and the residue was purified by chromatography on silica gel (EtOAc:MeOH 1:0→200:1→100:1→50:1→20:1→10:1). The fractions containing the product were combined and concentrated and dried under reduced pressure. The residue was dissolved in acetonitrile (10 ml / 1 g of product) under reflux. The solution was cooled to ambient temperature to precipitate the product. The solid was filtered and washed with acetonitrile to provide a seed.

[0117] 1 H NMR (500 MHz, CD3OD) δ 7.29-7.25 (m, 2H), 7.21-7.16 (m, 2H), 3.67-3.54 (m, 2H), 3.47 (d, J= 11.5 Hz, 1H), 3.01-2.72 (m, 6H), 2.72-2.63 (m, 1H), 2.35 (dd, J = 12.0, 10.5 Hz, 1H), 2.10-1.95 (m, 2H), 1.58-1.39 (m, 2H), and 1.19 (d, J = 6.2 Hz, 3H) ppm.

[0118] 13 C NMR (125 MHz, CD3OD) δ 140.1, 132.9, 132.0, 129.6, 73.7, 68.5, 57.6, 56.7, 50.9, 46.7, 30.4, 29.9, 28.1, and 19.4 ppm.

[0119] FT-IR (ATR): 3318, 3206, 2963, 2934, 2859, 2833, 1636, 1589, 1553, 1489, 1462, 1404, 1346,1314, 1277, 1250, 1151, 117, 1092, 1069, 1013, 917, 868, 829, 800, 764, 725, and 673 cm -1 .

[0120] Example 7

[0121] Preparation of 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-4H-1,2,4-triazole-3-amine hydrated form I (1, hydrated form I) from methyl (Z)-4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-carbimidothioate (6)

[0122] Methyl (Z)-4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)-N-cyanopiperidine-1-carbimidothioate (6, 7.51 g) was suspended in ethanol (37 ml) and hydrazine hydrate (2.67 ml) was added. The suspension was heated to a maximum of 60°C and a clear solution was obtained. After 2 hours, water (113 ml) was added and the product precipitated upon cooling to ambient temperature. The solid was filtered, the filter cake was washed with water (37 ml), and dried to provide 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidine-1-yl)-4H-1,2,4-triazole-3-amine hydrated form I (1, hydrated form I, 15.82 g, 36% loss upon drying, 133% yield, 99.7% purity by HPLC).

[0123] 1 H NMR (500 MHz, CD3OD) δ 7.29-7.25 (m, 2H), 7.21-7.16 (m, 2H), 3.67-3.54 (m, 2H), 3.47 (d, J = 11.5 Hz, 1H), 3.01-2.72 (m, 6H), 2.72-2.63 (m, 1H), 2.35 (dd, J = 12.0, 10.5 Hz, 1H), 2.10-1.95 (m, 2H), 1.58-1.39 (m, 2H), and 1.19 (d, J = 6.2 Hz, 3H) ppm.

[0124] 13 C NMR (125 MHz, CD3OD) δ 140.1, 132.9, 132.0, 129.6, 73.7, 68.5, 57.6, 56.7, 50.9, 46.7, 30.4, 29.9, 28.1, and 19.4 ppm.

[0125] FT-IR (ATR): 3318, 3206, 2963, 2934, 2859, 2833, 1636, 1589, 1553, 1489, 1462, 1404, 1346,1314, 1277, 1250, 1151, 117, 1092, 1069, 1013, 917, 868, 829, 800, 764, 725, and 673 cm -1 .

[0126] Example 8

[0127] Preparation of 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidine-1-yl)-4H-1,2,4-triazole-3-amine anhydrous form (1, anhydrous form) from 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidine-1-yl)-4H-1,2,4-triazole-3-amine hydrated form I (1, hydrated form I)

[0128] 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidine-1-yl)-4H-1,2,4-triazole-3-amine hydrated form I (1, hydrated form I, calculated on a dry basis 6.62 g) was suspended in ethyl acetate (66 ml) and the suspension was heated and refluxed. Upon heating, the suspension turned into a clear solution. The water was distilled using a Dean-Stark trap until it reached a boiling point of 76°C. During distillation, the product precipitated. The suspension was allowed to cool to ambient temperature and the solid was filtered. The filter cake was washed with ethyl acetate (13 ml) and dried to provide 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidine-1-yl)-4H-1,2,4-triazole-3-amine anhydrous form as white crystals (1, anhydrous form, 6.38 g, 83% yield, >99.9% purity by HPLC).

[0129] 1 H NMR (700 MHz, C6D6 / CD3OD) δ 7.13 (d, J= 8.2 Hz, 2H), 6.89 (d, J = 8.2 Hz, 2H), 3.99 (br s, 2H), 3.66 (br s, 3H), 3.56 (d, J = 11.4 Hz, 1H), 3.54-3.46 (m, 1H), 3.37 (d, J = 11.4 Hz, 1H), 2.90-2.80 (m, 3H), 2.68 (d, J = 10.4 Hz, 1H), 2.40 (d, J = 11.9 Hz, 2H), 2.32-2.25 (m, 1H), 2.05 (t, J = 11.2 Hz, 1H), 1.81 (d, J = 12.5 Hz, 1H), 1.65 (d, J = 12.5 Hz, 1H), 1.54-1.46 (m, 1H), 1.46-1.37 (m, 1H), and 1.11 (d, J = 6.2 Hz, 3H) ppm.

[0130] 13 C NMR (175 MHz, C6D6) δ 139.0, 132.1, 131.2, 129.0, 128.1, 72.6, 67.8, 56.5, 55.7, 50.1, 48.9, 45.8, 45.7, 29.7, 29.2, 27.7, and 19.3 ppm.

[0131] FT-IR (ATR): 3252, 3198, 3119, 2955, 2924, 2857, 2793, 1666, 1599, 1543, 1483, 1456, 1404, 1337, 1283, 1248, 1136, 1117, 1094, 1072, 1053, 1013, 908, 858, 795, and 718 cm -1 .

[0132] Example 9

[0133] Preparation of 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-4H-1,2,4-triazole-3-amine anhydrous form (1, anhydrous form) from methyl (Z)-4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-carbimidothioate (6)

[0134] Methyl (Z)-4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)-N-cyanopiperidine-1-carbimidothioate (6, 5.05 g) was suspended in acetonitrile (50 ml) and hydrazine hydrate (1.78 ml) was added. The suspension was heated to a maximum of 60°C to obtain a clear solution. After 2 hours, the solution was cooled to ambient temperature and the product was precipitated. The solid was filtered, and the filter cake was washed with acetonitrile (12.5 ml) to provide 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidine-1-yl)-4H-1,2,4-triazole-3-amine anhydrous form as white crystals (1, anhydrous form, 4.39 g, 90% yield, 98.7% purity by HPLC).

[0135] 1 H NMR (700 MHz, C6D6 / CD3OD) δ 7.13 (d, J = 8.2 Hz, 2H), 6.89 (d, J = 8.2 Hz, 2H), 3.99 (br s, 2H), 3.66 (br s, 3H), 3.56 (d, J = 11.4 Hz, 1H), 3.54-3.46 (m, 1H), 3.37 (d, J = 11.4 Hz, 1H), 2.90-2.80 (m, 3H), 2.68 (d, J = 10.4 Hz, 1H), 2.40 (d, J = 11.9 Hz, 2H), 2.32-2.25 (m, 1H), 2.05 (t, J = 11.2 Hz, 1H), 1.81 (d, J= 12.5 Hz, 1H), 1.65 (d, J = 12.5 Hz, 1H), 1.54-1.46 (m, 1H), 1.46-1.37 (m, 1H), and 1.11 (d, J = 6.2 Hz, 3H) ppm.

[0136] 13 C NMR (175 MHz, C6D6) δ 139.0, 132.1, 131.2, 129.0, 128.1, 72.6, 67.8, 56.5, 55.7, 50.1, 48.9, 45.8, 45.7, 29.7, 29.2, 27.7, and 19.3 ppm.

[0137] FT-IR (ATR): 3252, 3198, 3119, 2955, 2924, 2857, 2793, 1666, 1599, 1543, 1483, 1456, 1404, 1337, 1283, 1248, 1136, 1117, 1094, 1072, 1053, 1013, 908, 858, 795, and 718 cm -1 .

[0138] Example 10

[0139] Preparation of 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidine-1-yl)-4H-1,2,4-triazole-3-amine hydrated form II (1, hydrated form II) from 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidine-1-yl)-4H-1,2,4-triazole-3-amine anhydrous form (1, anhydrous form)

[0140] 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidine-1-yl)-4H-1,2,4-triazole-3-amine anhydrous form (1, anhydrous form, 5.03 g) was dissolved in methanol (20 ml) under reflux. Water (30 ml) was slowly added while maintaining reflux. The product precipitated upon addition. The suspension was cooled to ambient temperature and aged for 1 hour. The solid was filtered, the filter cake was washed with a mixture of methanol and water (25 ml, 2:3 vol. / vol.) and dried overnight in air to provide 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidine-1-yl)-4H-1,2,4-triazole-3-amine hydrated form II as a white solid (1, hydrated form II, 5.44 g, 8.2% water by Karl-Fishcer, 99% yield on a dry basis, >99.9% purity by HPLC).

[0141] Example 11

[0142] Preparation of the amorphous form (1, anhydrous form) of 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidine-1-yl)-4H-1,2,4-triazole-3-amine from the anhydrous form (1, anhydrous form)

[0143] A Petri dish covered with the anhydrous form of 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-4H-1,2,4-triazole-3-amine (1, anhydrous form, 5.02 g) was placed on a hot plate heated to a maximum of 200°C. Once the material melted, the dish was allowed to cool to ambient temperature. The glassy material was ground in a mortar to yield the amorphous form of 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-4H-1,2,4-triazole-3-amine as a white solid (1, amorphous form, 4.82 g, 96% yield, >99.9% purity by HPLC).

[0144] 1 H NMR (700 MHz, C6D6 / CD3OD) δ 7.13 (d, J = 8.2 Hz, 2H), 6.89 (d, J = 8.2 Hz, 2H), 3.99 (br s, 2H), 3.66 (br s, 3H), 3.56 (d, J = 11.4 Hz, 1H), 3.54-3.46 (m, 1H), 3.37 (d, J = 11.4 Hz, 1H), 2.90-2.80 (m, 3H), 2.68 (d, J = 10.4 Hz, 1H), 2.40 (d, J = 11.9 Hz, 2H), 2.32-2.25 (m, 1H), 2.05 (t, J = 11.2 Hz, 1H), 1.81 (d, J = 12.5 Hz, 1H), 1.65 (d, J = 12.5 Hz, 1H), 1.54-1.46 (m, 1H), 1.46-1.37 (m, 1H), and 1.11 (d, J = 6.2 Hz, 3H) ppm.

[0145] 13C NMR (175 MHz, C6D6) δ 139.0, 132.1, 131.2, 129.0, 128.1, 72.6, 67.8, 56.5, 55.7, 50.1, 48.9, 45.8, 45.7, 29.7, 29.2, 27.7, and 19.3 ppm.

[0146] FT-IR (ATR): 3312, 3173, 2968, 2859, 2822, 1634, 1551, 1489, 1458, 1346, 1277, 1246, 1150, 1115, 1094, 1069, 1013, 920, 858, 804, 758, 719, and 665 cm -1 .

[0147] Example 12

[0148] Preparation of the amorphous form (1, amorphous form) of 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidine-1-yl)-4H-1,2,4-triazole-3-amine from the hydrated form I or II (1, hydrated form I or II).

[0149] A Petri dish covered with 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidine-1-yl)-4H-1,2,4-triazole-3-amine hydrated form I or II (1, hydrated form I or II, 5.01 g) was placed on a hot plate heated to a maximum of 125°C. When the material melted, the dish was allowed to cool to ambient temperature. Glassy material was ground in a mortar to provide 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidine-1-yl)-4H-1,2,4-triazole-3-amine amorphous forms as white solids (1, amorphous form, 4.49 g, 90% yield, starting from hydrated form I and with >99.99% purity by HPLC, and 1, amorphous form, 4.41 g, 88% yield, starting from hydrated form II and with >99.9% purity by HPLC).

[0150] 1 H NMR (700 MHz, C6D6 / CD3OD) δ 7.13 (d, J = 8.2 Hz, 2H), 6.89 (d, J = 8.2 Hz, 2H), 3.99 (br s, 2H), 3.66 (br s, 3H), 3.56 (d, J = 11.4 Hz, 1H), 3.54-3.46 (m, 1H), 3.37 (d, J = 11.4 Hz, 1H), 2.90-2.80 (m, 3H), 2.68 (d, J = 10.4 Hz, 1H), 2.40 (d, J = 11.9 Hz, 2H), 2.32-2.25 (m, 1H), 2.05 (t, J = 11.2 Hz, 1H), 1.81 (d, J = 12.5 Hz, 1H), 1.65 (d, J = 12.5 Hz, 1H), 1.54-1.46 (m, 1H), 1.46-1.37 (m, 1H), and 1.11 (d, J = 6.2 Hz, 3H) ppm.

[0151] 13 C NMR (175 MHz, C6D6) δ 139.0, 132.1, 131.2, 129.0, 128.1, 72.6, 67.8, 56.5, 55.7, 50.1, 48.9, 45.8, 45.7, 29.7, 29.2, 27.7, and 19.3 ppm.

[0152] FT-IR (ATR): 3312, 3173, 2968, 2859, 2822, 1634, 1551, 1489, 1458, 1346, 1277, 1246, 1150, 1115, 1094, 1069, 1013, 920, 858, 804, 758, 719, and 665 cm -1 .

Claims

Claim 1 A method for preparing (2S,5S)-5-(4-chlorobenzyl)-2-methyl-4-(piperidine-4-yl)morpholine of the following chemical formula 5, [Chemical Formula 5] a) (2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholine of Formula 2 below is reacted with N-Boc-4-piperidinone of Formula 3 and sodium cyanoborohydride in alcohol as a solvent to provide tertiary-butyl 4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorphollino)piperidine-1-carboxylate of Formula 4 below [Formula 2] [Chemical Formula 3] [Chemical Formula 4] b) a method comprising removing a tertiary-butoxycarbonyl protecting group using hydrochloric acid to provide (2S,5S)-5-(4-chlorobenzyl)-2-methyl-4-(piperidine-4-yl)morpholine of Formula 5. Claim 2 A method according to claim 1, wherein in step (a), the compound of formula 2 is used as its hydrochloride salt. Claim 3 A method according to claim 1 in which zinc chloride is an additive in step (a). Claim 4 A method according to claim 1 in which methanol is the solvent in step (a). Claim 5 A method according to claim 1, wherein ethyl acetate is the solvent in step (b). Claim 6 A method for preparing 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidine-1-yl)-1H-1,2,4-triazole-3-amine of the following chemical formula 1, wherein chemical formula 1 a) (2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholine of Formula 2 below is reacted with N-Boc-4-piperidinone of Formula 3 and sodium cyanoborohydride in alcohol as a solvent to provide tertiary-butyl 4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorphollino)piperidine-1-carboxylate of Formula 4 below [Formula 2] [Chemical Formula 3] [Chemical Formula 4] b) removing the tertiary-butoxycarbonyl protecting group using hydrochloric acid to provide (2S,5S)-5-(4-chlorobenzyl)-2-methyl-4-(piperidine-4-yl)morpholine of Formula 5 [Formula 5] c) The compound of Formula 5 is reacted with dimethyl N-cyanodithiomiminocarbonate in a solvent in the presence of a base to yield methyl (Z)-4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)-N-cyanopiperidine-1-carbimidothioate of Formula 6, [Formula 6] d) A method comprising reacting a compound of Formula 6 with hydrazine monohydrate in a solvent to provide a compound of Formula 1. Claim 7 In claim 6, the method in which the compound of formula 5 is in the salt form at step (c). Claim 8 In claim 7, the method in which the dihydrochloride hydrate in step (c) is a salt. Claim 9 In claim 8, the method in which the trialkylamine is a base in step (c). Claim 10 In claim 9, the method in which triethylamine is a base in step (c). Claim 11 In claim 8, a method in which ethanol, 1-propanol, or 2-propanol is the solvent in step (c). Claim 12 In claim 8, a method in which acetonitrile is the solvent in step (c). Claim 13 In claim 11, a method of isolating the compound of chemical formula 6 by precipitation upon cooling of the reaction mixture after step (c). Claim 14 In claim 11, a method of performing step (d) without isolating the compound of formula 6. Claim 15 In claim 11, a method of isolating the compound of Chemical Formula 1 by precipitation when water is added to the reaction mixture after step (d). Claim 16 In claim 14, a method of isolating the compound of Chemical Formula 1 by precipitation when water is added to the reaction mixture after step (d). Claim 17 In claim 12, a method of isolating the compound of Chemical Formula 1 by precipitation upon cooling of the reaction mixture after step (d). Claim 18 delete Claim 19 delete Claim 20 delete Claim 21 delete Claim 22 delete Claim 23 delete Claim 24 delete Claim 25 delete Claim 26 delete Claim 27 delete Claim 28 delete Claim 29 delete Claim 30 delete Claim 31 delete Claim 32 delete Claim 33 delete Claim 34 delete Claim 35 delete Claim 36 delete Claim 37 delete Claim 38 delete Claim 39 delete Claim 40 delete

Images