Process for the production of 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-1H-1,2,4-triazol-3-amine

Abstract

The present invention relates to a process for the synthesis of two hydrate crystalline forms of 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-1H-1,2,4-triazol-3-amine and the anhydrous crystalline form of 1. The present invention also relates to an intermediate in this process, methyl-(Z)-4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)-N-cyanopiperidine-1-carbimidothioate.

Description

Technical Field

[0001] (Field of the Invention) The present invention relates to a synthetic process of two hydrate crystal forms and one anhydrous crystal form of 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-1H-1,2,4-triazole-3-amine. The present invention further relates to methyl-(Z)-4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)-N-cyanopiperidine-1-carbimidothioate, an intermediate in this process.

Background Art

[0002] (Background of the Invention) 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-1H-1,2,4-triazole-3-amine of Structural Formula 1 was first described in International Patent Application Publication No. WO2017 / 037670.

Chemical Formula

[0003] The compound of Formula 1 is a dual inhibitor of acidic mammalian chitinase (AMCase) and chitotriosidase 1 (CHIT-1). Such compounds can be used in the treatment of disorders associated with the overexpression of these enzymes. Those disorders are asthma and allergic reactions, or idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD).

[0004] Patent Application Publication No. WO2017 / 037670 describes the synthesis of the compound of Formula 1 from (2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholine of Formula 2. The outline of this synthesis is shown in the following scheme.

[0005]

Chemical Formula

[0006] The compound of formula 2 is reacted with N-(tert-butoxycarbonyl)-4-piperidone of formula 3, sodium triacetoxyborohydride as a reducing agent, and glacial acetic acid in 1,2-dichloroethane. After one night, the crude tert-butyl 4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidine-1-carboxylate of formula 4 is extracted and isolated and purified by column chromatography. The pure compound of formula 4 is subjected to a deprotection reaction of the tert-butoxycarbonyl moiety with an ethyl acetate solution of hydrogen chloride to obtain (2S,5S)-5-(4-chlorobenzyl)-2-methyl-4-(piperidin-4-yl)morpholine of formula 5 as the dihydrochloride. In the next step, the compound of formula 5 is reacted with dimethyl N-cyanodithioiminocarbonate in acetonitrile in the presence of potassium carbonate as a base. After heating for several hours, hydrazine monohydrate is added and the reaction mixture is refluxed for a further several hours. When the suspension reaches ambient temperature, the solid material is filtered off and the crude product is obtained by concentration of the filtrate and purified by silica gel column chromatography and then precipitated to obtain the compound of formula 1.

[0007] The conversion of the compound of formula 5 to the compound of formula 1 consists of two consecutive reactions. In the first step, the compound of formula 5 is converted to an intermediate, which is most likely to be (Z)-4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)-N-cyanopiperidine-1-carbimidothioate of formula 6.

Chemical formula

[0008] The synthesis of the compound of formula 1 described in Patent Application Publication WO2017 / 037670 requires two chromatographic purifications, which are costly and time-consuming. It is hardly conceivable that a process including chromatographic purification is industrially scalable. There is no information on whether the material obtained by this process can be obtained in a crystalline form that would be considered stable. Furthermore, the particle size distribution is an important parameter of the active pharmaceutical ingredient and can have a great impact on the manufacture of tablet-form pharmaceutical products. This patent does not teach whether the simple precipitation as described for the final product leads to a material having a precisely defined particle size in a reproducible manner. In the final step of the synthesis presented in WO2017 / 037670, it is necessary to use hydrazine, which is known to be carcinogenic, so it is necessary to strictly control the residual hydrazine level in the active pharmaceutical ingredient, which is required separately from the control of the total purity of the material, which is an important factor in all processes during the synthesis of the active pharmaceutical ingredient. According to the main points outlined above, the requirements for a synthesis process of 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-1H-1,2,4-triazole-3-amine of formula 1 that is suitable for the manufacture of pharmaceutical products, scalable, and efficient remain unresolved.

Mode for Carrying Out the Invention

[0009] (Detailed Description of the Invention) The present invention provides a synthetic process for (2S,5S)-5-(4-chlorobenzyl)-2-methyl-4-(piperidin-4-yl)morpholine of formula 5 that is efficient and scalable. Compared to the description of the original approach outlined in (Background of the Invention), various changes have been introduced into the procedure to improve the yield, simplify the synthesis, and make it scalable. The compound of formula 2 is reacted with N-(tert-butoxycarbonyl)-4-piperidone of formula 3, in the presence of sodium cyanoborohydride as a reducing agent and an additive, preferably zinc chloride, in a solvent, preferably an alcohol, more preferably methanol, at a temperature from 0 °C to reflux, preferably at ambient temperature. Once 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, and the crude product is dissolved in a solvent, preferably ethyl acetate, and a hydrochloric acid solution, preferably concentrated hydrochloric acid, is added. Once complete conversion of the starting material is obtained, the solvent is exchanged to a polar solvent, preferably methanol. To that solution, a solvent, preferably acetone, is added, and the solution is allowed to cool to ambient temperature. Upon cooling, the product crystallizes, and the crystals are filtered off. The filter cake is washed with a solvent, preferably acetone, and air-dried to obtain (2S,5S)-5-(4-chlorobenzyl)-2-methyl-4-(piperidin-4-yl)morpholine of formula 5 as white crystals. Elaborate analysis of the material obtained showed that the product was obtained as the dihydrochloride hydrate.

[0010]

Chemical formula

[0011] An important step in the synthesis of the compound of formula 2 is the reaction of a mixture of the compound of formula 7 and the compound of formula 8 with potassium tert-butoxide, which affords the amide of formula 9. Only the compound of formula 8 cyclizes to form the compound of formula 9. Under these reaction conditions, the compound of formula 7 epimerizes to form the compound of formula 8, and the compound of formula 8 cyclizes to form the compound of formula 9. Due to this fact, from the reaction of potassium tert-butoxide with the mixture of the compound of formula 7 and the compound of formula 8, almost only the compound of formula 9 is obtained. During these reaction conditions, the compound of formula 9 epimerizes to form the compound of formula 10, which is a by-product of this reaction. Next, the crude product of formula 9 is crystallized, but the procedure for complete removal of the unwanted compound of formula 10 is cumbersome and results in a significant loss of the product. Reduction of the compound of formula 9 gives the compound of formula 2, but when the compound of formula 10 is mixed in the compound of formula 9, the compound of formula 2 contains the compound of formula 11 obtained as a product by reduction of the compound of formula 10.

[0012] [Chemical formula]

[0013] Under the conditions described in Patent Application Publication WO2017 / 037670 (sodium triacetoxyborohydride, acetic acid, and 1,2-dichloroethane), when the compound of Formula 11 is reacted with N-Boc-4-piperidone, a by-product of Formula 12 is observed in the crude compound of Formula 3. The impurity of Formula 12 can be removed by careful purification on silica gel, but that method is not applicable on a multi-kilogram scale. The compound of Formula 11 does not react with N-Boc-4-piperidone when the conditions described in this patent application (sodium cyanoborohydride, zinc chloride, and methanol) are employed. Since the compound of Formula 11 can be easily removed by crystallization after removal of the tert-butoxycarbonyl protecting group, the present invention relates to a method for synthesizing the compound of Formula 5 without the impurity of Formula 13. Furthermore, the conditions described in this application non-trivially use the hydrochloride salt of the compound of Formula 2 as a starting material, thereby facilitating the process. The compound of Formula 2 is an oil with low stability, meaning that it needs to be stored in the form of a salt to prevent decomposition. Conversely, the reaction described in WO2017 / 037670 does not proceed when the hydrochloride salt of the compound of Formula 2 is used as a starting material, and an additional operation to first convert the salt to the free base is required.

[0014] [Chemical Formula]

[0015] The present invention further provides a method for synthesizing methyl-(Z)-4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)-N-cyanopiperidine-1-carbimidothioate of formula 6. This compound has not yet been isolated or described. The related compound can be synthesized by reacting (2S,5S)-5-(4-chlorobenzyl)-2-methyl-4-(piperidin-4-yl)morpholine of formula 5 with dimethyl N-cyanodithioiminocarbonate in the presence of a base, preferably a trialkylamine, more preferably triethylamine, in a solvent, preferably ethanol, 1-propanol or 2-propanol. This reaction is carried out at a temperature from room temperature to reflux, preferably at 50 °C. Once complete conversion of the starting material is obtained, the reaction mixture is allowed to cool to ambient temperature. The product crystallizes upon cooling. The material is filtered off, the filter cake is washed with a solvent, preferably ethanol, 1-propanol, or 2-propanol, and dried to obtain the compound of formula 6.

[0016]

Chemical formula

[0017] The present invention further provides a method for directly synthesizing a compound of formula 6 from a compound of formula 2, avoiding a three-step synthesis. This approach relates to the reaction of a compound of formula 2 with 4-oxopiperidine-methyl-N-cyanothioimidocarbonate of formula 14. The compound of formula 14 can be readily obtained by reacting commercially available 4,4-dihydroxypiperidine hydrochloride with dimethyl N-cyanodithioiminocarbonate in the presence of a base, preferably a trialkylamine, more preferably triethylamine, in a solvent, preferably a mixture of solvents, more preferably a mixture of 2-propanol and water, at a temperature from 0 °C to reflux, preferably at ambient temperature. The reaction mixture is quenched with 6 M hydrochloric acid solution and extracted with an organic solvent, preferably dichloromethane. The solution is washed with water and the solvent is exchanged to a polar solvent, preferably 2-propanol. To the hot solution, a non-polar solvent, preferably isopropyl ether, is added to crystallize the product. The solid is filtered off and the filter cake is washed with a solvent, preferably a mixture of solvents, more preferably a mixture of 2-propanol and isopropyl ether, and then dried to obtain the compound of formula 14 as an off-white solid.

[0018] [Chemical formula]

[0019] The reaction of the compound of formula 2 with the compound of formula 14 was carried out under the conditions for the synthesis of the compound of formula 4 described in WO2017 / 037670, but it did not proceed simply by changing the ketone compound of formula 3 to the ketone compound of formula 14. Furthermore, the synthesis conditions for the compound of formula 4 from the compound of formula 2, as described in the present application, resulted in a mixture of the compound of formula 6 and the by-product of formula 15 simply by changing the compound of formula 3 to the compound of formula 14. This gave rise to the unsolved problem of developing new conditions for directly synthesizing the compound of formula 6 from the compound of formula 2.

[0020] The reaction of the compound of formula 2 and the compound of formula 14 is carried out in a polar solvent, preferably ethanol, in the presence of a reducing agent, preferably sodium cyanoborohydride, and an additive, preferably zinc chloride, at a temperature from 0 °C to reflux, preferably at ambient temperature. Once complete conversion of the starting materials has taken place, the reaction mixture is quenched with 1 M sodium hydroxide solution and extracted with an organic solvent, preferably dichloromethane. This solvent is exchanged for an organic solvent, preferably ethanol. The solution is allowed to cool to ambient temperature to crystallize the product. The solid is filtered off, the filter cake is washed with a solvent, preferably ethanol, and dried to obtain the compound of formula 6 as a white solid.

[0021] The target molecule of formula 1 can be obtained from either the compound of formula 5 or the compound of formula 6. Furthermore, this patent application describes a method for preparing the anhydrous form, two hydrate forms (hydrate form I and II), and the amorphous form of the target molecule of formula 1. The method outlined in this paragraph is summarized in Figure 1.

[0022] The present invention further provides a method for synthesizing the compound of formula 1 · hydrate form I from the compound of formula 5 (Figure 1, reaction A). The compound of formula 5 is suspended in a solvent, preferably ethanol, dimethyl N-cyanodithioiminocarbonate is added, followed by a base, preferably a trialkylamine, more preferably triethylamine, at a temperature from ambient temperature to the boiling point, preferably at 40 °C. Once complete conversion of the starting materials has taken place, hydrazine monohydrate is added and the reaction is continued at a temperature from ambient temperature to the boiling point, preferably at 60 °C. Once complete conversion of the intermediate has taken place, water is added and the solution is cooled to a temperature from -20 °C to ambient temperature, preferably to 5 °C. The precipitated solid is filtered off, the filter cake is washed with a mixture of water and an organic solvent (preferably ethanol), and dried to obtain the compound of formula 1 · hydrate form I as a white solid.

[0023] The present invention further provides a method for synthesizing the compound of formula 1, hydrate form I, from the compound of formula 6 (Figure 1, reaction B). The compound of formula 6 is suspended in a solvent, preferably ethanol, at a temperature from ambient temperature to the boiling point, preferably at 60 °C, and hydrazine monohydrate is added. When complete conversion of the starting material has occurred, water is added and the solution is cooled to a temperature from -20 °C to ambient temperature, preferably to 5 °C. The precipitated solid is filtered off, the filter cake is rinsed with a mixture of water and an organic solvent (preferably ethanol), and dried to obtain the compound of formula 1, hydrate form I as a white solid.

[0024] The present invention further provides a method for synthesizing the compound of formula 1, anhydrous form, from the compound of formula 6 (Figure 1, reaction C). The reaction of the compound of formula 6 with hydrazine monohydrate is carried out in an organic solvent, preferably acetonitrile, at a temperature from ambient temperature to the boiling point, preferably at 60 °C. When complete conversion of the starting material has occurred, the solution is allowed to cool to ambient temperature and the product precipitates upon cooling. The solid is filtered off, the filter cake is rinsed with a solvent, preferably acetonitrile, and dried to obtain the compound of formula 1, anhydrous form as a white solid.

[0025] Compared with WO2017 / 037670, when obtaining the compound of formula 1 by a one-pot procedure, the process of separating the compound of formula 6 non-obviously enables the compound of formula 1, anhydrous form, to be obtained in a higher yield (72% for WO2017 / 037670 compared to 86% in the present application). An important factor in the second step involving the reaction of the compound of formula 6 is acetonitrile used as the solvent. In a more polar solvent (i.e., methanol, ethanol or 2-propanol), the reaction yield is lower. On the other hand, when a less polar solvent (i.e., dichloromethane, methyl-tert-butyl ether or toluene) is employed, the residual hydrazine reaches an unacceptable level.

[0026] The present invention further provides a method for preparing the anhydrous form of the compound of formula 1 from its hydrate form I (Figure 1, Method D). The compound of formula 1 in hydrate form I is suspended in an organic solvent, preferably ethyl acetate, and the suspension is heated to the reflux temperature. The suspension becomes a clear solution upon heating. The solution is distilled until the evaporation temperature reaches 76 °C. The product precipitates during distillation. The solid is filtered off at ambient temperature. The filter cake is washed with an organic solvent, preferably ethyl acetate, and dried to obtain the anhydrous form of the compound of formula 1 as white crystals.

[0027] The synthesis of the compound of formula 1 in hydrate form I and the subsequent synthesis of the compound of formula 1 in anhydrous form have significant advantages compared to the synthesis of the compound of formula 1 described in WO2017 / 037670. Under the new conditions, the precipitate of the compound of formula 1 in hydrate form I is non-trivially considered a genotoxic impurity and enables control of the amount of residual hydrazine that needs to be controlled at the ppm level. Using the method outlined in the previous paragraph, the synthesis of the compound of formula 1 in anhydrous form was carried out in 3 batches. This material was carefully analyzed for purity, residual hydrazine level, and particle size distribution.

[0028]

Table 1

[0029] The present invention further provides a method for preparing the hydrate form II of the compound of formula 1 from its anhydrous form (Figure 1, Method E). The anhydrous form of the compound of formula 1 is dissolved by refluxing in methanol. Water is added to the solution and the product precipitates. The suspension is cooled to a temperature from -20 °C to ambient temperature, preferably 5 °C. The aged solid is filtered off. The filter cake is washed with a mixture of water and methanol and dried to obtain the hydrate form II of the compound of formula 1 as a white solid.

[0030] Due to the fact that the compound of Formula 6 is unstable in methanol, the hydrate II form cannot be directly obtained from Compound 6 as in the case of the compound of Formula 1·hydrate I form. Both the hydrate I form and the hydrate II form of the compound of Formula 1 are unstable and become amorphous upon drying. The XPRD data of the dried material is different from the data calculated from the X-ray structure. Furthermore, analysis of the dried single crystal from the structure determination using the compound of Formula 1·hydrate I form shows the absence of a crystal structure, leading to the conclusion that the crystal structure collapses upon drying. The amorphous form of the compound of Formula 1 can be prepared by a more convenient method, which involves melting the anhydrous form or the hydrate I form or the hydrate II form of the compound of Formula 1 and then cooling the material to ambient temperature. After grinding this glassy solid, the compound of Formula 1·anhydrous form is an off-white solid. Summary of the Invention

[0031] (Summary of the Invention) The present invention provides a process for synthesizing the (2S,5S)-5-(4-chlorobenzyl)-2-methyl-4-(piperidin-4-yl)morpholine dihydrochloride hydrate of Formula 5 in a solid crystalline state.

[0032] The present invention (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° 2θ; (ii) IR bands at 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 -1; (iii) DSC starting at 156.26 °C and having a peak at 157.51 °C, Relating to methyl-(Z)-4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)-N-cyanopiperidine-1-carbimidothioate of formula 6 in solid crystalline state, characterized by at least one of the following. The aforementioned features substantially coincide with FIGS. 2 to 4.

[0033] The present invention provides a synthesis process of methyl-(Z)-4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)-N-cyanopiperidine-1-carbimidothioate of formula 6 in solid crystalline state.

[0034] The present invention further provides (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° 2θ; (ii) IR bands at 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 ; (iii) DSC starting at 80.60 °C and having a peak at 91.32 °C, Relating to Form I of 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-1H-1,2,4-triazole-3-amine monohydrate of formula 1 in solid crystalline state, characterized by at least one of the following. The aforementioned features substantially coincide with FIGS. 7 to 9.

[0035] The present invention provides a synthetic process for the solid crystalline state of 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-1H-1,2,4-triazole-3-amine monohydrate Form I of formula 1.

[0036] The present invention further (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° 2θ; (ii) IR bands at 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 ; (iii) DSC starting at 175.83 °C and having a peak at 177.59 °C, relates to the solid crystalline state of 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-1H-1,2,4-triazole-3-amine anhydrate Form of formula 1, characterized by at least one of the above. The aforementioned features substantially coincide with FIGS. 10-12.

[0037] The present invention further provides a preparation of the solid crystalline state of 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-1H-1,2,4-triazole-3-amine anhydrate Form of formula 1.

[0038] The present invention further (i) XRPD peaks at 2θ of 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°; (ii) IR bands at 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 -1; (iii) Two DSC peaks, a first peak of 70.29 °C starting at 60.12 °C and a second peak of 90.87 °C starting at 82.83 °C, characterizing the solid crystalline form of 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-1H-1,2,4-triazole-3-amine hydrate Form II of formula 1; The foregoing characteristics substantially coincide with FIGS. 15 - 17.

[0039] The present invention provides a process for synthesizing the solid crystalline form of 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-1H-1,2,4-triazole-3-amine hydrate Form II of formula 1.

[0040] The present invention further provides (i) IR bands at 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 -1, Relates to an amorphous form of 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-1H-1,2,4-triazole-3-amine of formula 1 in solid state. The foregoing features substantially coincide with FIG. 18.

[0041] The present invention provides a method for preparing an amorphous form of 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-1H-1,2,4-triazole-3-amine of formula 1 in solid state.

[0042] The present invention provides a method for synthesizing a compound of formula 1 that is industrially scalable. This method avoids chromatographic purification, which was the most time-consuming part of the process. The final product is obtained in a reproducible manner with respect to particle size distribution, purity, and residual hydrazine level, meeting the high standards for drug substances.

Brief Description of the Drawings

[0043] (Brief Description of the Drawings)

Figure 1

Figure 2

Figure 3

[0044]

Figure 4

Figure 5

Figure 6

[0045]

Figure 7

Figure 8

Figure 9

[0046]

Figure 10

Figure 11

Figure 12

[0047]

Figure 13

Figure 14

Figure 15

[0048]

Figure 16

Figure 17

Figure 18

Example

[0049] The present invention will be described by the following examples. (Example) The following examples are provided for illustrative purposes only and are not intended to limit the scope of the present invention in any way.

[0050] All commercially available solvents, substrates and reagents were used without further purification. NMR spectra were recorded on an Agilent Mercury 400 MHz spectrometer and a Bruker Avance 500, as well as a 700 MHz spectrometer (DXR500 and DXR700 respectively). NMR spectra were recorded in commercially available deuterated solvents as indicated.

[0051] Nuclear magnetic resonance was 1 In 1H NMR, tetramethylsilane (δ 0.00 ppm in CD3Cl) or residual solvent (δ 4.87 ppm in CD3OD, or δ 7.61 ppm in C6D6), or 13 In 13C NMR, with respect to the solvent (δ 49.00 ppm in CD3OD, δ 77.26 ppm in CDCl3, or δ 128.06 ppm in C6D6), it is obtained in parts per million (ppm). The data is recorded as follows: chemical shift (δ), multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet, bs = broad singlet), coupling constant (J, unit is Hz) and integral value.

[0052] The FT-IR spectrum was recorded in ATR mode (zinc selenide crystal) using a Shimadzu IR Tracer-100. The X-ray diffraction experiment was carried out at T = 100(2) K on high-quality single crystals. The crystals were mounted in a MiTeGen micromount using Paratone-N oil. Diffraction data were obtained with CuKα radiation (λ = 1.54184 Å) using a SuperNova Dual Source from Agilent Technologies. The lattice parameters were obtained by least-squares refinement against the optimized setting angles of the reflections collected using CrysAlis CCD software. The data were processed and reduced using the CrysAlis RED program. Empirical absorption correction using a multi-scan method with spherical harmonics implemented in the SCALE3 ABSPACK scaling algorithm was applied. The structure determination procedure was carried out using the SHELX package.

[0053] The XPRD diffractograms of the compounds obtained in Examples 3 and 8 were recorded on a Bruker D8 Discover powder X-ray diffractometer equipped with Cu CuKα radiation (1.54 Å) and a Vantec detector. The samples were analyzed in continuous mode between 3 and 50° 2θ (theta) with a step size of 0.01222276° and a step time of 0.9 s. The XPRD diffractograms of the compounds obtained in Examples 6 and 10 were calculated from single crystal X-ray data using Mercury software.

[0054] The DSC thermogram was recorded with a temperature gradient of 5 °C / min using a Mettler Toledo DSC 3. PSD data were recorded (recoded) in Isopar G using a Malvern Mastersizer 2000.

[0055] The purity was measured by HPLC-UV method. The analysis was carried out on a phenyl-hexyl analytical column (Kinetex phenyl-hexyl, 2.1 mm × 100 mm; 2.6 μm) at 20 °C with a mobile phase flow rate of 0.3 mL / min. The mobile phase is a mixture of solvent A (900 mL of water, 100 mL of methanol, 1 g of ammonium formate) and solvent B (100 mL of water, 900 mL of methanol, 1 g of ammonium formate). The elution is performed by gradient elution (60% of solvent B from 0.0 to 2.0 minutes, then 60% - 85% of solvent B from 2.0 to 2.5 minutes, then 85% of solvent B from 2.5 to 5.5 minutes, then 85% - 100% of solvent B from 5.5 to 6.0 minutes, then 100% of solvent B from 6.0 to 8.0 minutes, then 100% - 60% of solvent B from 8.0 to 8.2 minutes, then 60% of solvent B from 8.2 to 13.0 minutes). The peaks are recorded using UV detection at 225 nm.

[0056] The residual level of hydrazine was measured by HPLC-UV method. The sample was prepared by dissolving 75 mg in 1 mL of methanol. 1 mL of 1M HCl solution was added, followed by 1 mL of benzaldehyde solution (0.6 g / mL in methanol / water 1 / 1 (v / v)), and the solution was vortexed. 1 mL of n-heptane was added, the two-phase liquid was vortexed and centrifuged at high speed. The upper phase (5 μL) was injected for analysis. The chromatographic (HPLC-UV) analysis was performed using a C18 analytical column (LumiSep C18, 2.1 mm × 50 mm; 3 μm) maintained at 40 °C with a mobile phase flow rate of 0.5 mL / min. The mobile phase consists of a mixture of solvent A (900 mL of water, 100 mL of acetonitrile, 1 g of ammonium formate) and solvent B (100 mL of water, 900 mL of acetonitrile, 1 g of ammonium formate). The elution is carried out under isocratic conditions (55% of solvent B for 6 minutes until the trial is completed). The peaks are recorded using UV detection at 305 nm. The retention time of benzaldehyde hydrazone is about 2.43 minutes.

[0057] Boc represents a tert-butoxycarbonyl protecting group. The reaction yield is expressed in mol%. The HPLC purity is expressed as the area percentage under the curve. The water content and loss on drying by the Karl Fischer method are expressed as weight percentage.

[0058] (Example 1) (2S,5S)-5-(4-Chlorobenzyl)-2-methyl-4-(piperidin-4-yl)morpholine dihydrochloride hydrate (4) (dihydrochloride hydrate) was prepared from (2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholine (2). (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 portionwise and the reaction mixture was stirred overnight. The reaction mixture was separated between ethyl acetate (240 mL) and 1 M sodium hydroxide solution (240 mL). The aqueous layer was extracted with ethyl acetate (240 mL), and the combined extracts were washed with half-saturated aqueous 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, water was distilled off using a Dean-Stark trap. Ethyl acetate was exchanged with methanol and concentrated to a volume of about 100 mL. Acetone (300 mL) was gradually added to this solution to precipitate the product. The suspension was allowed to cool to ambient temperature and aged for 1 hour. The solid was filtered off, and the filter cake was rinsed with acetone (2 × 100 mL) and air-dried to obtain (2S,5S)-5-(4-chlorobenzyl)-2-methyl-4-(piperidin-4-yl)morpholine dihydrochloride hydrate (4) (dihydrochloride hydrate, 20.92 g, yield 90% in two steps, HPLC purity 99.5%) as a white solid. [Chemical formula]

[0059] (Example 2) (2S,5S)-5-(4-Chlorobenzyl)-2-methyl-4-(piperidin-4-yl)morpholine dihydrochloride hydrate (4) (dihydrochloride hydrate), Preparation from (2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholine hydrochloride (2) (hydrochloride) (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 portionwise and the reaction mixture was stirred overnight. The reaction mixture was partitioned between ethyl acetate (240 mL) and 1 M sodium hydroxide solution (240 mL). The aqueous layer was extracted with ethyl acetate (240 mL), and the combined extracts were washed with semi-saturated aqueous sodium chloride solution (240 mL) and dried. The solution was concentrated to dryness and the residue was dissolved in 3 M hydrochloric acid solution in ethyl acetate. After 1 hour, the solution was concentrated to dryness and refluxed in MeOH (30 mL). Acetone (30 mL) was added to this clear solution and the mixture was allowed to cool to ambient temperature to precipitate the product. A second portion of acetone (20 mL) was added to this suspension and the suspension was aged for 1 hour. The solid was filtered off, the filter cake was rinsed with acetone (2 × 30 mL) and air dried to give (2S,5S)-5-(4-chlorobenzyl)-2-methyl-4-(piperidin-4-yl)morpholine dihydrochloride hydrate (4) (dihydrochloride hydrate, 12.51 g, 86% yield in two steps, 98.9% HPLC purity) as a white solid. [Chemical formula]

[0060] (Example 3) Methyl-(Z)-4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)-N-cyanopiperidine-1-carbimidothioate (6), Preparation from (2S,5S)-5-(4-chlorobenzyl)-2-methyl-4-(piperidin-4-yl)morpholine dihydrochloride hydrate (4) (dihydrochloride hydrate) (2S,5S)-5-(4-Chlorobenzyl)-2-methyl-4-(piperidin-4-yl)morpholine dihydrochloride hydrate (4) (dihydrochloride hydrate, 5.82 g) and dimethyl N-cyanodithioiminocarbonate (2.34 g) were suspended in ethanol (60 mL). Triethylamine (6.1 mL) was added to this suspension, and the reaction mixture was heated to 40 °C. The suspension became a clear solution upon heating. After 3 hours, when the solution was allowed to cool to ambient temperature, the product precipitated. This suspension was aged, and the solid was filtered off. The filter cake was washed with ethanol (5 mL) and dried to give methyl-(Z)-4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)-N-cyanopiperidine-1-carbimidothioate (6) (5.48 g, yield 92%, 99.2% HPLC purity) as a fluffy white solid.

Chemical formula

[0061] (Example 4) Preparation of 4-oxopiperidine-methyl-N-cyanothioimidocarbamate (14) Dimethyl N-cyanodithioiminocarbonate (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 this solution. After 2 hours, the reaction mixture was quenched with 6 M hydrochloric acid solution (30 mL) and extracted with CH2Cl2 (4 × 75 mL). The combined organic layers were washed with water (75 mL) and 2-propanol (90 mL) was added. The solution was concentrated under atmospheric pressure until the volume reached 90 mL, and then isopropyl ether (90 mL) was added dropwise to the boiling solution while maintaining reflux. The product precipitated and the suspension was allowed to cool to ambient temperature. The suspension was aged and the solid was filtered off. The filter cake was washed with a mixture of 2-propanol (20 mL) and isopropyl ether (20 mL) and dried to give 4-oxopiperidine-methyl-N-cyanothioimidocarbamate (14) (17.94 g, 88% yield) as an off-white solid.

Chemical formula

[0062] (Example 5) Direct preparation of methyl-(Z)-4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)-N-cyanopiperidine-1-carbylimidothioate (6) from (2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholine (2) (2S,5S)-5-(4-Chlorobenzyl)-2-methylmorpholine (2) (5.23 g), 4-oxopiperidine-methyl-N-cyanothioimidocarbonate (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 portionwise. The suspension was stirred at ambient temperature for 24 h. The reaction mixture was quenched by the addition of 1 M sodium hydroxide solution (60 mL) and extracted with dichloromethane (60 mL, then 2 × 30 mL). The combined organic layers were washed with water (30 mL) and the solvent was exchanged to ethanol. The product precipitated during this exchange. The suspension was allowed to cool to ambient temperature and the solid was filtered off. The filter cake was washed with ethanol (18 mL) and dried to give methyl-(Z)-4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)-N-cyanopiperidine-1-carbimidothioate (6) (7.80 g, 83% yield, 99.5% HPLC purity) as an off-white solid. [Chemical Structure]

[0063] (Example 6) Preparation of 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-4H-1,2,4-triazol-3-amine monohydrate Form I (1) (Monohydrate Form I) from (2S,5S)-5-(4-chlorobenzyl)-2-methyl-4-(piperidin-4-yl)morpholine dihydrochloride monohydrate (4) (Dihydrochloride Monohydrate) (2S,5S)-5-(4-Chlorobenzyl)-2-methyl-4-(piperidin-4-yl)morpholine dihydrochloride hydrate (4) (dihydrochloride hydrate, 9.03 g) and dimethyl N-cyanodithioiminocarbonate (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 additionally at 60 °C for 2 hours. Water (144 mL) was added to this hot solution, and it was allowed to cool to ambient temperature, seeded with crystalline material, and placed in the refrigerator for 24 hours. The precipitate was filtered off, the filter cake was washed with water (2 × 40 mL), air-dried, and crude product (14.3 g) of 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-4H-1,2,4-triazol-3-amine monohydrate Form I (1) (monohydrate Form I, 7.06 g, loss on drying 25%, yield 80% on dry basis, 99.4% HPLC purity) was obtained as a white solid.

[0064] The seed crystal material used was obtained from the crude reaction mixture. The reaction mixture was concentrated to dryness under reduced pressure and the residue was purified on silica for chromatography (EtOAc:MeOH 1:0 → 200:1 → 100:1 → 50:1 → 20:1 → 10:1). The fractions containing the product were combined and concentrated to dryness under reduced pressure. The residue was dissolved by refluxing in acetonitrile (10 mL / product 1 g). This solution was allowed to cool to ambient temperature to precipitate the product. The solid was filtered off, washed with acetonitrile, and the seed was obtained. [Chemical formula]

[0065] (Example 7) Preparation of 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-4H-1,2,4-triazol-3-amine monohydrate Form I (1) (monohydrate Form I) from methyl-(Z)-4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)-N-cyanopiperidine-1-carbimidothioate (6) 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 60 °C to obtain a clear solution. After 2 hours, water (113 mL) was added, and when cooled to ambient temperature, the product precipitated. The solid was filtered off, the filter cake was washed with water (37 mL), and dried to obtain 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-4H-1,2,4-triazol-3-amine monohydrate Form I (1) (monohydrate Form I, 15.82 g, loss on drying 36%, yield 133%, HPLC purity 99.7%) as a white solid. [Chemical formula]

[0066] (Example 8) Preparation of 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-4H-1,2,4-triazol-3-amine anhydrate Form I (1) (anhydrate Form I) from 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-4H-1,2,4-triazol-3-amine monohydrate Form I (1) (monohydrate Form I) 5-(4-((2S,5S)-5-(4-Chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-4H-1,2,4-triazol-3-amine monohydrate Form I (1) (6.62 g on anhydrous basis) was suspended in ethyl acetate (66 mL), and the suspension was heated until refluxing. The suspension became a clear solution upon heating. Water was distilled off using a Dean-Stark trap until the boiling point reached 76 °C. The product precipitated during the distillation. The suspension was allowed to cool to ambient temperature, and the solid was filtered off. The filter cake was washed with ethyl acetate (13 mL) and dried to obtain 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-4H-1,2,4-triazol-3-amine anhydrous Form I (1) (anhydrous form, 6.38 g, yield 83%, HPLC purity >99.9%) as white crystals.

Chemical formula

[0067] (Example 9) Preparation of 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-4H-1,2,4-triazol-3-amine anhydrous Form I (1) (anhydrous form) from methyl-(Z)-4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)-N-cyanopiperidine-1-carbimidothioate (6) 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 60 °C to obtain a clear solution. After 2 hours, when the solution was allowed to cool to ambient temperature, the product precipitated. The solid was filtered off, and the filter cake was washed with acetonitrile (12.5 mL) to obtain 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-4H-1,2,4-triazol-3-amine·anhydrous form (1) (anhydrous form, 4.39 g, yield 90%, 98.7% HPLC purity) as white crystals. [Chemical formula]

[0068] (Example 10) Preparation of 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-4H-1,2,4-triazol-3-amine·hydrate form II (1) (hydrate form II) from 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-4H-1,2,4-triazol-3-amine·anhydrous form (1) (anhydrous form) 5-(4-((2S,5S)-5-(4-Chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-4H-1,2,4-triazol-3-amine anhydrous form (1) (anhydrous form, 5.03 g) was dissolved by refluxing in methanol (20 mL). Water (30 mL) was gradually added while maintaining reflux. The product precipitated upon this addition. The suspension was allowed to cool to ambient temperature and aged for 1 hour. The solid was filtered off, and the filter cake was washed with a mixture of methanol and water (25 mL, 2:3 v / v) and air-dried overnight to obtain 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-4H-1,2,4-triazol-3-amine hydrate form II (1) (hydrate form II, 5.44 g, 8.2% moisture by Karl Fischer measurement, 99% yield on a dry basis, HPLC purity >99.9%) as a white solid.

[0069] (Example 11) Preparation of 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-4H-1,2,4-triazol-3-amine amorphous form (1) (amorphous form) from 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-4H-1,2,4-triazol-3-amine anhydrous form (1) (anhydrous form) A Petri dish containing 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-4H-1,2,4-triazol-3-amine anhydrous form (1) (anhydrous form, 5.02 g) was placed on a hot plate and heated to 200 °C. Once the material had melted, the dish was allowed to cool to ambient temperature. The glassy material was ground in a mortar to obtain 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-4H-1,2,4-triazol-3-amine amorphous form (1) (amorphous form, 4.82 g, 96% yield, HPLC purity >99.9%) as a white solid. [Chemical formula]

[0070] (Example 12) Preparation of amorphous form (1) of 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-4H-1,2,4-triazol-3-amine from hydrate form I or II (1) of 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-4H-1,2,4-triazol-3-amine A Petri dish containing hydrate form I or II (1) (5.01 g) of 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-4H-1,2,4-triazol-3-amine was placed on a hot plate and heated to 125 °C. Once the material had melted, the dish was allowed to cool to ambient temperature. The glassy material was triturated in a mortar to give amorphous form (1) of 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-4H-1,2,4-triazol-3-amine (4.49 g, yield 90%, HPLC purity >99.99%) starting from hydrate form I and (4.41 g, yield 88%, HPLC purity >99.9%) starting from hydrate form II as white solids. [Chemical formula] The present application provides an invention in the following aspects. (Aspect 1) A method for preparing (2S,5S)-5-(4-chlorobenzyl)-2-methyl-4-(piperidin-4-yl)morpholine of formula 5, (Chemical formula 1) TIFF0007697933000021.tif36170 (a) Reacting (2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholine of formula 2, (Chemical formula 2) TIFF0007697933000022.tif37170 N-Boc-4-piperidinone of formula 3, (Chemical formula 3) TIFF0007697933000023.tif21170and sodium cyanoborohydride in alcohol as a solvent to obtain tert-butyl 4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidine-1-carboxylate of formula 4, (Chemical formula 4) TIFF0007697933000024.tif39170 (b) Removing the tert-butoxycarbonyl protecting group using hydrochloric acid to obtain the (2S,5S)-5-(4-chlorobenzyl)-2-methyl-4-(piperidin-4-yl)morpholine of formula 5. The above preparation method comprises the above steps. (Aspect 2) The method according to Aspect 1, wherein in step (a), the compound of formula 2 is used as its hydrochloride salt. (Aspect 3) The method according to Aspect 1, wherein in step (a), zinc chloride is an additive. (Aspect 4) The method according to Aspect 1, wherein in step (a), methanol is the solvent. (Aspect 5) The method according to Aspect 1, wherein in step (b), ethyl acetate is the solvent. (Aspect 6) (a) An XRPD pattern comprising at least the following peaks: 12.03±0.1, 20.18±0.1, 22.56±0.1, and 24.08±0.1° 2θ; (b) A characteristic infrared (IR) spectrum comprising IR bands at 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 ; (c) A DSC thermogram starting at 156.26°C ± 2.0°C and having a peak at 157.51°C ± 2.0°C, The solid crystalline form of (Z)-4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)-N-cyanopiperidine-1-carboximidothioate of formula 6, characterized thereby. (Chemical Formula 5) TIFF0007697933000025.tif39170 (Embodiment 7) (a) An XRPD pattern comprising at least the following peaks: 14.20 ± 0.1, 15.58 ± 0.1, 18.30 ± 0.1, 23.22 ± 0.1, and 23.68 ± 0.1° 2θ; (b) A characteristic infrared (IR) spectrum comprising IR bands at 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 ; The solid crystalline form of 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-1H-1,2,4-triazole-3-amine monohydrate Form I of formula 1, characterized thereby. (Chemical Formula 6) TIFF0007697933000026.tif35170 (Embodiment 8) (a) An XRPD pattern comprising at least the following peaks: 14.61 ± 0.1, 19.86 ± 0.1, and 21.22 ± 0.1° 2θ; (b) A characteristic infrared (IR) spectrum comprising IR bands at 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 ; (c) A DSC thermogram starting at 175.83 °C ± 2.0 °C and having a peak at 177.59 °C ± 2.0 °C, The solid crystalline form of 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-1H-1,2,4-triazole-3-amine anhydrate form, characterized thereby. (Embodiment 9) A method for preparing 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-1H-1,2,4-triazole-3-amine of formula 1, (a) Reacting the compound of formula 5 with dimethyl N-cyanodithioiminocarbonate in a solvent in the presence of a base to yield (Z)-4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)-N-cyanopiperidine-1-carbimidothioate of formula 6; (b) Reacting the compound of formula 6 with hydrazine monohydrate in a solvent to obtain the compound of formula 1, which comprises the preparation method. (Aspect 10) The method according to aspect 9, wherein in step (a), the compound of formula 5 is in the form of a salt. (Aspect 11) The method according to aspect 10, wherein in step (a), the salt is dihydrochloride hydrate. (Aspect 12) The method according to aspect 11, wherein in step (a), the trialkylamine is the base. (Aspect 13) The method according to aspect 12, wherein in step (a), the triethylamine is the base. (Aspect 14) The method according to aspect 11, wherein in step (a), ethanol, 1-propanol, or 2-propanol is the solvent. (Aspect 15) The method according to aspect 11, wherein in step (a), acetonitrile is the solvent. (Aspect 16) The method according to aspect 14, wherein the compound of formula 6 is isolated by precipitation upon cooling of the reaction mixture after step (a). (Aspect 17) The method according to aspect 14, wherein step (b) is carried out without isolation of the compound of formula 6. (Aspect 18) The method according to aspect 14, wherein the compound of formula 1 is isolated by precipitation upon addition of water to the reaction mixture after step (b). (Aspect 19) The method according to aspect 17, wherein the compound of formula 1 is isolated by precipitation upon addition of water to the reaction mixture after step (b). (Aspect 20) The method according to aspect 15, wherein the compound of formula 1 is isolated by precipitation upon cooling of the reaction mixture after step (b). (Aspect 21) A method for preparing 4-oxopiperidinemethyl N-cyanothioimidocarbamate of formula 14, which comprises reacting dimethyl N-cyanodithioiminocarbonate, 4,4-dihydroxypiperidine hydrochloride and a base in a solvent. (Chemical formula 7) TIFF0007697933000027.tif25170 (Aspect 22) The method according to aspect 21, wherein the trialkylamine is the base. (Aspect 23) The method according to aspect 22, wherein the triethylamine is the base. (Aspect 24) The method according to embodiment 21, wherein the solvent is a mixture of water and 2-propanol. (Embodiment 25) The method according to embodiment 21, wherein the product of formula 14 is purified by crystallization. (Embodiment 26) The method according to embodiment 25, wherein the product of formula 14 is purified by crystallization from a mixture of diisopropyl ether and 2-propanol. (Embodiment 27) A method for preparing a compound of formula 6, comprising reacting the compound of formula 2 and the compound of formula 14, and sodium cyanoborohydride and an inorganic salt in a solvent. (Embodiment 28) The method according to embodiment 27, wherein the solvent is ethanol. (Embodiment 29) The method according to embodiment 27, wherein zinc chloride is used as an additive. (Embodiment 30) The method according to embodiment 27, wherein the product of formula 6 is purified by crystallization. (Embodiment 31) The method according to embodiment 30, wherein the product of formula 6 is purified by crystallization during solvent exchange from dichloromethane to ethanol. (Embodiment 32) The method according to embodiment 27, wherein the compound of formula 2 is used in the form of a salt. (Embodiment 33) A method for preparing the anhydrous form of the compound of formula 1, comprising azeotropic distillation of a solution of the starting compound of formula 1, 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-1H-1,2,4-triazole-3-amine monohydrate form I or form II. (Embodiment 34) The method according to embodiment 33, wherein the starting compound of formula 1 is the monohydrate form I. (Embodiment 35) (a) An XRPD pattern comprising at least the following peaks: 15.48±0.1, 19.76±0.1, 22.54±0.1, and 22.86±0.1° 2θ; (b) A characteristic infrared (IR) spectrum comprising IR bands at 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 A solid crystalline form of 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-1H-1,2,4-triazole-3-amine monohydrate form II of formula 1, characterized by (Embodiment 36) A process for preparing the hydrate form II of the compound of formula 1, 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-1H-1,2,4-triazole-3-amine, which comprises crystallization of the anhydrous form of the compound of formula 1 from a mixture of methanol and water. (Aspect 37) 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 A solid amorphous form of 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-1H-1,2,4-triazole-3-amine of formula 1, characterized by a characteristic infrared (IR) spectrum including IR bands at. (Aspect 38) A process for preparing an amorphous form of 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-1H-1,2,4-triazole-3-amine of formula 1, the process by melting a starting compound of formula 1 in either the anhydrous form or the hydrate form I or II. (Aspect 39) The method according to aspect 38, wherein the starting compound of formula 1 is in the anhydrous form and the melting temperature is 200 °C. (Aspect 40) The method according to aspect 38, wherein the starting compound of formula 1 is in the hydrate form I and the melting temperature is 125 °C.

Claims

1. A process for preparing (2S,5S)-5-(4-chlorobenzyl)-2-methyl-4-(piperidin-4-yl)morpholine of formula 5, comprising: 【Chemical 1】 (a) reacting (2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholine of formula 2 with [Chemical 2] N-Boc-4-piperidinone of formula 3 【Chemical Formula 3】 and sodium cyanoborohydride in methanol as a solvent in the presence of zinc chloride to obtain tert-butyl 4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholin-4-yl)piperidine-1-carboxylate of formula 4; [Chemical Formula 4] (b) removing the tert-butoxycarbonyl protecting group using hydrochloric acid to obtain (2S,5S)-5-(4-chlorobenzyl)-2-methyl-4-(piperidin-4-yl)morpholine of formula 5.

2. The method according to claim 1, wherein in step (a), the compound of formula 2 is used as its hydrochloride salt.

3. The method according to claim 1, wherein in step (b), ethyl acetate is the solvent.

4. A process for preparing 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholin-4-yl)piperidin-1-yl)-1H-1,2,4-triazol-3-amine of formula 1, comprising: 【Chemical Formula 5】 (a) reacting (2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholine of formula 2 with 【Chemical Formula 6】 N-Boc-4-piperidinone of formula 3 【Chemical Formula 7】 and sodium cyanoborohydride in methanol as a solvent in the presence of zinc chloride to obtain tert-butyl 4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholin-4-yl)piperidine-1-carboxylate of formula 4; 【Chemical Formula 8】 (b) removing the tert-butoxycarbonyl protecting group using hydrochloric acid to obtain (2S,5S)-5-(4-chlorobenzyl)-2-methyl-4-(piperidin-4-yl)morpholine of formula 5; 【Chemical Formula 9】 (c) reacting the compound of formula 5 with dimethyl N-cyanodithioiminocarbonate in a solvent in the presence of a base to yield methyl (Z)-4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholin-4-yl)-N-cyanopiperidine-1-carbimidothioate of formula 6; 【Chemical Formula 10】 (d) reacting the compound of formula 6 with hydrazine monohydrate in a solvent to obtain the compound of formula 1, wherein the preparation method comprises the above steps. **Claim 5** The method according to claim 4, wherein in step (c), the compound of formula 5 is in the form of a salt. **Claim 6** The method according to claim 5, wherein in step (c), the salt is dihydrochloride hydrate. **Claim 7** The method according to claim 6, wherein in step (c), the base is a trialkylamine. **Claim 8** The method according to claim 7, wherein in step (c), the base is triethylamine. **Claim 9** The method according to claim 6, wherein in step (c), the solvent is ethanol, 1-propanol, or 2-propanol. **Claim 10** The method according to claim 6, wherein in step (c), the solvent is acetonitrile. **Claim 11** The method according to claim 9, further comprising isolating the compound of formula 6 by precipitation during cooling after step (c). **Claim 12** The method according to claim 9, wherein step (d) is carried out without isolation of the compound of formula 6. **Claim 13** The method according to claim 9, further comprising isolating the compound of formula 1 by precipitation upon addition of water after step (d). **Claim 14** The method according to claim 12, further comprising isolating the compound of formula 1 by precipitation upon addition of water after step (d). **Claim 15** The method according to claim 10, further comprising isolating the compound of formula 1 by precipitation during cooling after step (d).

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