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

Abstract

The present invention relates to a method for synthesizing two hydrated crystalline forms and one anhydrous crystalline form of 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-1H-1,2,4-triazole-3-amine. The present invention also relates to (Z)-4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)-N-cyanopiperidine-1-thiocarbamidyl ester, which is an intermediate of the method.

Description

Field of the Invention

[0001] The present invention relates to a method for synthesizing 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-1H-1,2,4-triazol-3-amine in two hydrated crystalline forms and one anhydrous crystalline form. The present invention also relates to (Z)-4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)-N-cyanopiperidine-1-thiocarbamidyl ester, which is an intermediate of the method. Background of the Invention

[0003] 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-1H-1,2,4-triazol-3-amine of structural formula 1 was first described in international patent application WO2017 / 037670.

[0004]

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

[0006] Patent application WO2017 / 037670 describes the synthesis of compounds of formula 1 from (2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholine of formula 2. This synthesis is outlined in the following scheme.

[0007]

[0008] The compound of formula 2 is reacted with N-(tert-butyloxycarbonyl)-4-piperidone of formula 3, sodium triacetoxyborohydride as a reducing agent and glacial acetic acid in 1,2-dichloroethane. After one night, crude tert-butyl 4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidine-1-carboxylate of formula 4 is separated by extraction and purified by column chromatography. The pure compound of formula 4 is subjected to a deprotection reaction of the tert-butyloxycarbonyl moiety using a solution of hydrogen chloride in ethyl acetate to obtain (2S,5S)-5-(4-chlorobenzyl)-2-methyl-4-(piperidin-4-yl)morpholine of formula 5 as a dihydrochloride. In the next step, the compound of formula 5 is reacted with dimethyl N-cyanodithioimidocarbonate 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 further refluxed for several hours. When the suspension reaches ambient temperature, the solid material is filtered off and the crude product obtained by concentrating the filtrate is purified by silica gel column chromatography 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 series of two reactions. In the first step, the compound of formula 5 is converted to an intermediate, which is most likely (Z)-4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)-N-cyanopiperidine-1-thiocarbamidate of formula 6.

[0010]

[0011] The synthesis of the compound of formula 1 described in patent application WO2017 / 037670 requires two chromatographic purifications, which is not cost-effective and time-consuming. The method involving chromatographic purification is considered to be less suitable for industrial mass production. And there is no information showing that the material obtained by this method is a crystalline form that may be considered stable. In addition, particle size distribution is an important parameter of the raw material drug, which has a great impact on the preparation of drugs in tablet form. The patent does not teach that the final product can be simply precipitated so that a material with a strictly defined particle size can be produced in a reproducible manner. Since the last step of the synthesis described in WO2017 / 037670 requires the use of hydrazine, which is known to be carcinogenic, in addition to the overall purity of the material, the residual hydrazine content of the raw material drug must be strictly controlled, which is a key factor in each method when synthesizing the raw material drug. In view of the above, there is still a need for a method for synthesizing 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-1H-1,2,4-triazole-3-amine of formula 1 that can be scaled up and effectively, which is suitable for preparing drugs. DETAILED DESCRIPTION OF THE INVENTION

[0013] The present invention provides an effective and scalable method for synthesizing (2S,5S)-5-(4-chlorobenzyl)-2-methyl-4-(piperidin-4-yl)morpholine of formula 5. Compared with the original method described in the "background of the invention", various changes are introduced into the procedure to improve the yield and simplify the synthesis, so that it can be prepared in a large amount. The compound of formula 2 and N-(tert-butyloxycarbonyl)-4-piperidone of formula 3 are reacted in a solvent (preferably an alcohol, more preferably methanol) in the presence of a sodium cyanoborohydride reducing agent and an additive (preferably zinc chloride) at 0°C to reflux temperature, preferably ambient temperature. When the starting material is completely converted, tert-butyl 4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidine-1-carboxylate of formula 4 is separated 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. When the starting material is completely converted, the solvent is replaced with a polar solvent, preferably methanol. A solvent, preferably acetone, is added to the solution and the solution is cooled to ambient temperature. The product crystallizes upon cooling and the crystals are filtered out. The filter cake is rinsed with a solvent, preferably acetone, and dried in air to obtain (2S,5S)-5-(4-chlorobenzyl)-2-methyl-4-(piperidin-4-yl)morpholine of formula 5 as white crystals. A careful analysis of the resulting material shows that the resulting product is a dihydrochloride hydrate.

[0014]

[0015] The key step in synthesizing the compound of formula 2 is to react the mixture of compounds of formula 7 and formula 8 with potassium tert-butoxide to produce the amide of formula 9. Only the compound of formula 8 is cyclized to the compound of formula 9. Under the reaction conditions, the compound of formula 7 is epimerized to the compound of formula 8, which is cyclized to the compound of formula 9. Accordingly, the reaction of potassium tert-butoxide with the mixture of compounds of formula 7 and formula 8 only provides the compound of formula 9. The compound of formula 9 is epimerized to the compound of formula 10 under the reaction conditions, which is a by-product of the reaction. The crude product of formula 9 is then crystallized, but it is cumbersome to completely remove the unwanted compound of formula 10 and will result in a large loss of product. The compound of formula 9 is reduced to obtain the compound of formula 2, but when the compound of formula 9 is contaminated by the compound of formula 10, the compound of formula 2 will contain the compound of formula 11 obtained as the reduction product of the compound of formula 10.

[0016]

[0017] 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-piperidone to produce a byproduct of formula 12, which can be seen in the crude compound of formula 3. The impurities of formula 12 can be removed by careful purification on silica gel, but this approach is not suitable for kilo-scale. When the conditions described in this patent application are used (sodium cyanoborohydride, zinc chloride and methanol), the compound of formula 11 does not react with N-Boc-4-piperidone. Since it is easy to remove the compound of formula 11 by crystallization after removing the tert-butyloxycarbonyl protecting group, the present invention relates to a method for synthesizing a compound of formula 5 without the impurity of formula 13. In addition, it is not obvious that the conditions described in the present application can use the hydrochloride salt of the compound of formula 2 as a starting material, which is beneficial to the method. The compound of formula 2 is an oil with limited stability, which means that it needs to be kept in salt form to prevent decomposition. On the contrary, 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 the salt must first be converted into a free base, which is an additional operation.

[0018]

[0019] The present invention further provides a method for synthesizing (Z)-4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)-N-cyanopiperidin-1-thiocarbamidyl ester of formula 6. This compound has not 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-cyanodithioimidocarbonate in a solvent (preferably ethanol, 1-propanol or 2-propanol) in the presence of a base (preferably a trialkylamine, more preferably triethylamine). The reaction is carried out at room temperature to reflux temperature, preferably 50°C. When the starting material is completely converted, the reaction mixture is cooled to ambient temperature. The product crystallizes upon cooling. The material is filtered, the filter cake is washed with a solvent, preferably ethanol, 1-propanol or 2-propanol, and then dried to obtain the compound of formula 6.

[0020]

[0021] The present invention also provides a method for synthesizing a compound of formula 6 directly from a compound of formula 2 to avoid a three-step synthesis. This method involves reacting a compound of formula 2 with methyl 4-oxopiperidinyl N-cyanothioimidocarbamate of formula 14. The compound of formula 14 is easily obtained by reacting commercially available 4,4-dihydroxypiperidine hydrochloride with dimethyl N-cyanodithioimidocarbonate at 0°C to reflux temperature, preferably ambient temperature, in a solvent (preferably a solvent mixture, more preferably a mixture of 2-propanol and water) in the presence of a base (preferably a trialkylamine, more preferably triethylamine). The reaction mixture is quenched with a 6M hydrochloric acid solution and extracted with an organic solvent, preferably dichloromethane. The solution is washed with water and the solvent is replaced with a polar solvent, preferably 2-propanol. A non-polar solvent, preferably isopropyl ether, is added to the hot solution to crystallize the product. The solid is filtered out, the filter cake is rinsed with a solvent, preferably a solvent mixture, more preferably a mixture of 2-propanol and isopropyl ether, and then dried to obtain a compound of formula 14 as an off-white solid.

[0022]

[0023] After simply replacing the keto compound of Formula 3 with the keto compound of Formula 14, the reaction of the compound of Formula 2 with the compound of Formula 14 under the conditions described in WO2017 / 037670 for synthesizing the compound of Formula 4 will not proceed. In addition, after simply replacing the compound of Formula 3 with the compound of Formula 14, the conditions for synthesizing the compound of Formula 4 from the compound of Formula 2 as described in the present application will produce a mixture of the compound of Formula 6 and the byproduct of Formula 15. Therefore, it is necessary to develop new conditions for directly synthesizing the compound of Formula 6 from the compound of Formula 2.

[0024] The reaction of the compound of formula 2 with the compound of formula 14 is carried out in the presence of a reducing agent (preferably sodium cyanoborohydride) and an additive (preferably zinc chloride) in a polar solvent (preferably ethanol) at 0°C to reflux temperature, preferably ambient temperature. After the starting material is completely converted, the reaction mixture is quenched with a 1M sodium hydroxide solution and extracted with an organic solvent, preferably dichloromethane. The solvent is replaced with an organic solvent, preferably ethanol. The solution is cooled to ambient temperature, thereby crystallizing the product. The solid is filtered out, the filter cake is rinsed with a solvent, preferably ethanol, and then dried to obtain a compound of formula 6 as a white solid.

[0025] The target molecule of formula 1 can be obtained from the compound of formula 5 or the compound of formula 6. In addition, this patent application describes a method for preparing anhydrous form, two hydrated forms (hydrated forms I and II) and an amorphous form of the target molecule of formula 1. The method outlined in this paragraph is summarized in Figure 1.

[0026] The present invention also provides a method for synthesizing the hydrated form I of the compound of formula 1 from the compound of formula 5 (reaction A in Figure 1). The compound of formula 5 is suspended in a solvent, preferably ethanol, at ambient temperature to boiling temperature, preferably 40°C, and dimethyl N-cyanodithioimidocarbonate is added, followed by a base, preferably a trialkylamine, more preferably triethylamine. When the starting material is completely converted, hydrazine monohydrate is added and the reaction is continued at ambient temperature to boiling temperature, preferably 60°C. When the intermediate is completely converted, water is added and the solution is cooled to -20°C to ambient temperature, preferably to 5°C. The precipitated solid is filtered out, the filter cake is rinsed with a mixture of water and an organic solvent (preferably ethanol), and then dried to obtain the hydrated form I of the compound of formula 1 as a white solid.

[0027] The present invention also provides a method for synthesizing the hydrated form I of the compound of formula 1 from the compound of formula 6 (reaction B in Figure 1). The compound of formula 6 is suspended in a solvent, preferably ethanol, at ambient temperature to boiling temperature, preferably 60°C, and hydrazine monohydrate is added. When the starting material is completely converted, water is added and the solution is cooled to -20°C to ambient temperature, preferably to 5°C. The precipitated solid is filtered out, the filter cake is washed with a mixture of water and an organic solvent (preferably ethanol), and then dried to obtain the hydrated form I of the compound of formula 1 as a white solid.

[0028] 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 of the compound of formula 6 with hydrazine monohydrate is carried out in an organic solvent (preferably acetonitrile) at ambient temperature to boiling temperature (preferably 60° C.). After the starting material is completely converted, the solution is cooled to ambient temperature, and the product precipitates upon cooling. The solid is filtered out, the filter cake is rinsed with a solvent, preferably acetonitrile, and dried to obtain an anhydrous form of the compound of formula 1 as a white solid.

[0029] Compared to WO2017 / 037670, when the compound of formula 1 is obtained in a one-pot approach, it is not obvious that the method of separating the compound of formula 6 can obtain the anhydrous form of the compound of formula 1 in a higher yield (86% in the present application and 72% in WO2017 / 037670). The key factor in the second step of the reaction of the compound of formula 6 is acetonitrile used as a solvent. In a more polar solvent (i.e., methanol, ethanol or 2-propanol), the reaction yield is much lower. On the other hand, when a less polar solvent (i.e., dichloromethane, methyl tert-butyl ether or toluene) is used, the amount of residual hydrazine is unacceptable.

[0030] The present invention further provides a method for preparing an anhydrous form of a compound of formula 1 from its hydrated form I (method D of Figure 1). The hydrated form I of the compound of formula 1 is suspended in an organic solvent, preferably ethyl acetate, and the suspension is heated to reflux. After heating, the suspension becomes a clear liquid. The solution is distilled until the volatile temperature reaches 76°C. During the distillation, the product precipitates. The solid is filtered out at ambient temperature. The filter cake is rinsed with an organic solvent, preferably ethyl acetate, and then dried to obtain an anhydrous form of the compound of formula 1 as white crystals.

[0031] The synthesis of the hydrated form I of the compound of formula 1 followed by the anhydrous form of the compound of formula 1 has significant advantages over the synthesis of the compound of formula 1 described in WO2017 / 037670. Under the new conditions, it is not obvious that 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 at the ppm (parts per million) level. The method outlined in the previous paragraph was used to synthesize three batches of the anhydrous form of the compound of formula 1. The purity, residual hydrazine content and particle size distribution of the material were carefully analyzed.

[0032]

[0033] The present invention also provides a method for preparing a hydrated form II of a compound of formula 1 from its anhydrous form (method E of Figure 1). The anhydrous form of the compound of formula 1 is dissolved in methanol under reflux. Water is added to the solution to precipitate the product. The suspension is cooled to -20°C to ambient temperature, preferably to 5°C. The solid is aged and filtered out. The filter cake is rinsed with a mixture of water and methanol and then dried to obtain a hydrated form II of the compound of formula 1 as a white solid.

[0034] Since the compound of formula 6 is unstable in methanol, it is not possible to obtain hydrated form II directly from compound 6, as in the case of hydrated form I of the compound of formula 1. Both hydrated forms I and II of the compound of formula 1 are unstable and will become amorphous after drying. The XPRD data of the dried material is different from the data calculated from the X-ray structure. In addition, the analysis of the dried single crystal of hydrated form I of the compound of formula 1 used for structure determination shows a lack of crystalline structure, so it can be inferred that the crystalline structure will collapse after drying. The amorphous form of the compound of formula 1 can be prepared in a more convenient way: melt the anhydrous form or hydrated form I or II of the compound of formula 1, and then cool the material to ambient temperature. After grinding the glassy solid, the anhydrous form of the compound of formula 1 is an off-white solid. SUMMARY OF THE INVENTION

[0036] The present invention provides a method for synthesizing a solid crystalline (2S,5S)-5-(4-chlorobenzyl)-2-methyl-4-(piperidin-4-yl)morpholine dihydrochloride hydrate of formula 5.

[0037] The present invention relates to a solid crystalline (Z)-4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)-N-cyanopiperidine-1-thiocarbamidyl ester of formula 6, characterized by at least one of the following:

[0038] (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 degrees 2θ;

[0039] (ii) 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 IR band;

[0040] (iii) DSC with an onset at 156.26°C and a peak at 157.51°C.

[0041] The above features are substantially consistent with those of FIGS. 2 to 4 .

[0042] The present invention provides a method for synthesizing solid crystalline (Z)-4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)-N-cyanopiperidine-1-thiocarbamidyl methyl ester of formula 6.

[0043] The present invention also relates to a solid crystalline 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-1H-1,2,4-triazol-3-amine hydrated form I of formula 1, characterized by at least one of the following:

[0044] (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 degrees 2θ;

[0045] (ii) at 3318, 3206, 2963, 2934, 2859, 2833, 1636, 1589, 1553, 1489, 1462, 1404, 1346, 1314, 1277, 1250, 1151, 1117, 1092, 1069, 1013, 917, 868, 829, 800, 764, 725 and 673 cm -1 IR band;

[0046] (iii) DSC with an onset at 80.60 °C and a peak at 91.32 °C.

[0047] The above features are substantially consistent with those of FIGS. 7 to 9 .

[0048] The present invention provides a method for synthesizing a solid crystalline hydrated Form I of 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-1H-1,2,4-triazol-3-amine of Formula 1.

[0049] The present invention further relates to a solid crystalline anhydrous form of 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-1H-1,2,4-triazol-3-amine of formula 1, characterized by at least one of the following:

[0050] (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 degrees 2θ;

[0051] (ii) 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 IR band;

[0052] (iii) DSC with an onset at 175.83°C and a peak at 177.59°C.

[0053] The above features are substantially consistent with those of FIGS. 10 to 12 .

[0054] The present invention further provides the preparation of a solid crystalline anhydrous form of 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-1H-1,2,4-triazol-3-amine of Formula 1.

[0055] The present invention further relates to a solid crystalline 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-1H-1,2,4-triazol-3-amine hydrate Form II of Formula 1, characterized by at least one of the following:

[0056] (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 degrees 2θ;

[0057] (ii) 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 IR band;

[0058] (iii) Two DSC peaks: the first one starts at 60.12°C and peaks at 70.29°C. The second one starts at 82.83°C and peaks at 90.87°C.

[0059] The above features are substantially consistent with those of FIGS. 15 to 17 .

[0060] The present invention provides a method for synthesizing a solid crystalline hydrated form II of 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-1H-1,2,4-triazol-3-amine of Formula 1.

[0061] The present invention also relates to a solid amorphous form of 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-1H-1,2,4-triazol-3-amine of formula 1, characterized in that:

[0062] (i) 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 IR band.

[0063] The above features are substantially consistent with FIG. 18 .

[0064] The present invention provides a method for preparing a solid-state amorphous form of 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-1H-1,2,4-triazol-3-amine of Formula 1.

[0065] The present invention provides a method for synthesizing the compound of formula 1 in industrial mass production. The method can avoid chromatographic purification, which is the most cumbersome part of the method. The final product can be obtained in a reproducible manner in terms of particle size distribution, purity and residual hydrazine level, and meets the high standards of bulk drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0067] FIG. 1 is a flow chart for synthesizing various forms of 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-1H-1,2,4-triazol-3-amine.

[0068] FIG. 2 is an XPRD diffraction pattern of (Z)-4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)-N-cyanopiperidine-1-thiocarbamidyl ester obtained in Example 3.

[0069] FIG3 is the FT-IR (ATR) spectrum of (Z)-4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)-N-cyanopiperidine-1-thiocarbamidyl ester obtained in Example 3.

[0070] FIG4 is a DSC thermogram of (Z)-4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)-N-cyanopiperidine-1-thiocarbamidyl ester obtained in Example 3.

[0071] Figure 5 is a graph showing the (Z)-4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)-N-cyanopiperidine-1-thiocarbamidyl ester obtained in Example 3 1 H NMR spectrum (CDCl 3 , 400MHz).

[0072] FIG6 is a graph showing the (Z)-4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)-N-cyanopiperidine-1-thiocarbamidyl ester obtained in Example 3. 13 C NMR spectrum (CDCl 3 , 100MHz).

[0073] Figure 7 is an XPRD diffraction pattern of 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-1H-1,2,4-triazol-3-amine, hydrated Form I, calculated from X-ray analysis of a single crystal obtained from a mixture of water and ethanol.

[0074] 8 is the FT-IR (ATR) spectrum of 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-1H-1,2,4-triazol-3-amine of hydrated form I obtained in Example 6.

[0075] Figure 9 is a DSC thermogram of hydrated form I of 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-1H-1,2,4-triazol-3-amine obtained in Example 6.

[0076] 10 is an XPRD diffraction pattern of the anhydrous form of 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-1H-1,2,4-triazol-3-amine obtained in Example 8.

[0077] 11 is the FT-IR (ATR) spectrum of the anhydrous form of 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-1H-1,2,4-triazol-3-amine obtained in Example 8.

[0078] 12 is a DSC thermogram of the anhydrous form of 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-1H-1,2,4-triazol-3-amine obtained in Example 8.

[0079] FIG. 13 is a diagram of the anhydrous form of 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-1H-1,2,4-triazol-3-amine obtained in Example 8 1 H NMR (C 6 D 6 , 700MHz) spectrum.

[0080] FIG. 14 is a diagram of the anhydrous form of 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-1H-1,2,4-triazol-3-amine obtained in Example 8 13 C NMR (C 6 D 6 , 176MHz) spectrum.

[0081] Figure 15 is an XPRD diffraction pattern of 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-1H-1,2,4-triazol-3-amine, hydrated Form II, calculated from X-ray analysis of a single crystal obtained from a mixture of water and methanol.

[0082] 16 is the FT-IR (ATR) spectrum of 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-1H-1,2,4-triazol-3-amine of hydrated form II obtained in Example 10.

[0083] 17 is a DSC thermogram of hydrated form II of 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-1H-1,2,4-triazol-3-amine obtained in Example 10.

[0084] 18 is the FT-IR (ATR) spectrum of the amorphous form of 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-1H-1,2,4-triazol-3-amine obtained in Example 11.

[0085] The invention will be illustrated by the following examples. Example

[0086] The following examples are for illustration only and are not intended to limit the scope of the present invention in any way.

[0087] All commercially available solvents, substrates, and reagents were used without further purification.

[0088] NMR spectra were recorded on an Agilent Mercury 400 MHz spectrometer and a Bruker Avance 500 and 700 MHz spectrometer (DXR500 and DXR700, respectively).

[0089] NMR spectra were all recorded in commercially available deuterated solvents as indicated.

[0090] Resonance is measured in parts per million, for 1 H NMR, relative to tetramethylsilane (δ = 0.00 ppm, CD 3 Cl) or residual solvent (CD 3 OD delta = 4.87 ppm or C 6 D 6 δ = 7.61ppm) gives, for 13 CNMR, is relative to the solvent (CD 3 ODδ=49.00ppm,CDCl 3 δ = 77.26 ppm, or C 6 D 6 Data are reported as follows: chemical shift (δ), multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet, bs = broad singlet), coupling constant (J, in Hz) and integration.

[0091] FT-IR spectra were recorded in ATR mode using a Shimadzu IRTracer-100 (ZnSe crystal).

[0092] X-ray diffraction experiments at T = 100 (2) K were performed on high-quality single crystals. The crystals were mounted on a MiTeGen micromount using Paratone-N oil. Diffraction data were collected using an Agilent Technologies SuperNova Dual Source. Lattice parameters were obtained using the least squares method to fit the best set of reflection angles collected by CrysAlis CCD software. Data reduction was performed using the CrysAlis RED program. Multi-scan empirical absorption correction was performed using spherical harmonics implemented using the SCALE3ABSPACK scaling algorithm. Structure determination procedures were performed using the SHELX software package.

[0093] The XPRD diffraction patterns of the compounds obtained in Examples 3 and 8 were obtained by irradiating with Cu CuKα radiation. The X-ray diffractograms of the compounds obtained in Examples 6 and 10 were calculated from single crystal X-ray data using Mercury software.

[0094] DSC thermograms were recorded with a Mettler Toledo DSC 3 with a gradient of 5°C / min.

[0095] PSD data were recorded using a Malvern Mastersizer 2000 with Isopar G.

[0096] Purity was measured by HPLC-UV method. The analysis was performed using a phenyl-hexyl analytical column (Kinetex Phenyl-Hexyl, 2.1 millimeters (mm) × 100 mm; 2.6 micrometers (μm)) at 20°C with a mobile phase flow rate of 0.3 milliliters per minute (mL / min). The mobile phase was 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 was performed under gradient elution (60% solvent B: 0.0-2.0 min, then 60%-85% solvent B: 2.0-2.5 min, then 85% solvent B: 2.5-5.5 min, then 85%-100% solvent B: 5.5-6.0 min, then 100% solvent B: 6.0-8.0 min, then 100%-60% solvent B: 8.0-8.2 min, then 60% solvent B: 8.2-13.0 min). Peaks were recorded using UV detection at 225 nm.

[0097] Residual hydrazine levels were determined by HPLC-UV. Samples were prepared as follows: 75 mg was dissolved in 1 mL of methanol. 1 mL of 1 M HCl solution was added followed by 1 mL of benzaldehyde solution (0.6 g / mL in 1 / 1 (v / v) methanol / water) and the solution was vortexed. 1 mL of n-heptane was added, the two-phase system was vortexed and centrifuged at high speed. The upper phase (5 μL) was injected for analysis. Chromatographic (HPLC-UV) analysis was performed using a C18 analytical column (LumiSep C18, 2.1 mm×50 mm; 3 μm) and maintained at 40°C with a mobile phase flow rate of 0.5 mL / min. The mobile phase consisted 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 was performed under isocratic conditions (55% solvent B until the completion of a 6 min run). Peaks were recorded using UV detection at 305 nm. The retention time of benzaldehyde hydrazone was about 2.43 min.

[0098] Boc represents a tert-butyloxycarbonyl protecting group.

[0099] The reaction yield is expressed in mole %.

[0100] HPLC purity is expressed as % area under the curve.

[0101] The water content and loss on drying were measured by the Karl Fischer method and are expressed in % by weight.

[0102] Example 1

[0103] Preparation of (2S,5S)-5-(4-chlorobenzyl)-2-methyl-4-(piperidin-4-yl)morpholine dihydrochloride hydrate (4, dihydrochloride hydrate) from (2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholine (2).

[0104] (2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholine (2, 13.06 g), N-Boc-4-piperidone (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 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 half-saturated sodium chloride solution (240 mL) and then dried. The solution was concentrated to about 200 mL and concentrated hydrochloric acid (40 mL) was added. After half an hour, the water was distilled off using a Dean-Stark trap. The ethyl acetate was exchanged for methanol and concentrated to a volume of about 100 mL. Acetone (300 mL) was slowly added to the solution to precipitate the product. The suspension was cooled to ambient temperature and aged for 1 hour. The solid was filtered off, the filter cake was rinsed with acetone (2×100 mL), and then dried in air to give (2S,5S)-5-(4-chlorobenzyl)-2-methyl-4-(piperidin-4-yl)morpholine dihydrochloride hydrate (4, dihydrochloride hydrate, 20.92 g, 90% yield after two steps, 99.5% HPLC purity) as a white solid.

[0105] 1 H NMR (500MHz, CD 3 OD)δ7.40–7.30(m,4H),4.08–3.98(m,1H),3.96–3.83(m,2H),3.82–3.74(m,1H),3.69(d,J=13.3Hz,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=6.2Hz,3H)ppm.

[0106] 13 C NMR (125MHz, CD 3 OD) 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.

[0107] Example 2

[0108] Preparation of (2S,5S)-5-(4-chlorobenzyl)-2-methyl-4-(piperidin-4-yl)morpholine dihydrochloride hydrate (4, dihydrochloride hydrate) from (2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholine hydrochloride (2, hydrochloride).

[0109] (2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholine (2, hydrochloride, 9.99 g), N-Boc-4-piperidone (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 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 half-saturated 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 one hour, the solution was concentrated to dryness 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 portion of acetone (20 mL) was added to the suspension and the suspension was aged for 1 hour. The solid was filtered off and the filter cake was rinsed with acetone (2×30 mL) and then dried in air 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% purity by HPLC) as a white solid.

[0110] 1 H NMR (500MHz, CD 3 OD)δ7.40–7.30(m,4H),4.08–3.98(m,1H),3.96–3.83(m,2H),3.82–3.74(m,1H),3.69(d,J=13.3Hz,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=6.2Hz,3H)ppm.

[0111] 13 C NMR (125MHz, CD 3 OD) 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.

[0112] Example 3

[0113] Preparation of (Z)-4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)-N-cyanopiperidine-1-thiocarbamidyl ester (6) from (2S,5S)-5-(4-chlorobenzyl)-2-methyl-4-(piperidin-4-yl)morpholine dihydrochloride hydrate (4, dihydrochloride hydrate).

[0114] (2S,5S)-5-(4-chlorobenzyl)-2-methyl-4-(piperidin-4-yl)morpholine dihydrochloride hydrate (4, dihydrochloride hydrate, 5.82 g) and dimethyl N-cyanodithioimidocarbonate (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 40° C. After heating, the suspension became clear. After 3 hours, the solution was cooled to ambient temperature to precipitate the product. The suspension was aged and the solid was filtered off. The filter cake was rinsed with ethanol (5 mL) and then dried to give (Z)-4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)-N-cyanopiperidine-1-thiocarbamidyl ester (6, 5.48 g, 92% yield, 99.2% HPLC purity) as a white fluffy solid.

[0115] 1 H NMR (400 MHz, CDCl 3 )δ7.28–7.22(m,2H),7.13–7.08(m,2H),4.45–4.34(m,2H),3.68–3.54(m,2H), 3.46(dd,J=11.5,2.7Hz,1H),3.32(dd,J=12.1,2.8Hz,2H),3.01(dd,J=12.9,10 .8Hz,1H),2.88–2.77(m,2H),2.76(s,3H),2.71–2.62(m,2H),2.36(dd,J=11.8 ,10.3Hz,1H), 2.07–1.94(m,2H), 1.68–1.47(m,2H), and 1.21(d,J=6.2Hz,3H)ppm.

[0116] 13 C NMR (100 MHz, CDCl 3 )δ168.7,138.3,132.0,130.8,128.8,115.4,72.5,67.8,55.8,55.4,50.0,46.9,30.3,29.8,27.5,19.3,and 16.4ppm.

[0117] 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 .

[0118] Example 4

[0119] Preparation of methyl 4-oxopiperidine N-cyanothioimidocarbamate (14).

[0120] Dimethyl N-cyanodithioimidocarbonate (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 was quenched with 6M hydrochloric acid solution (30 mL) and washed with CH 2 Cl 2 The product was concentrated to 4-nitropropane (14,17.94 g, 88% yield) and stirred for 24 hours at room temperature.Then the product was precipitated into 4-nitropropane (14,17.94 g, 88% yield) and the mixture was stirred for 24 hours at room temperature.Then the product was precipitated into 4-nitropropane (14,17.94 g, 88% yield) and the mixture was stirred for 24 hours at room temperature.Then the product was precipitated into 4-nitropropane (14,17.94 g, 88% yield) and the mixture was stirred for 24 hours at room temperature.The product was precipitated into 4-nitropropane (14,17.94 g, 88% yield) and the mixture was stirred for 24 hours at room temperature.The product was precipitated into 4-nitropropane (14,17.94 g, 88% yield) and the mixture was stirred for 24 hours at room temperature.The product was precipitated into 4-nitropropane (14,17.94 g, 88% yield) and the mixture was stirred for 24 hours at room temperature.

[0121] 1 H NMR (400 MHz, CDCl 3 )δ4.11(t,J=6.4Hz,4H),2.85(s,3H),2.60(t,J=6.3Hz,4H)ppm.

[0122] 13 C NMR (100 MHz, CDCl 3 )δ204.8,169.7,114.5,46.4,40.2,16.4ppm.

[0123] Example 5

[0124] (Z)-4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)-N-cyanopiperidine-1-thiocarbamidyl ester (6) was prepared directly from (2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholine (2).

[0125] (2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholine (2, 5.23 g), methyl 4-oxopiperidine 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 portions. The suspension was stirred at ambient temperature for 24 hours. 1M sodium hydroxide solution (60 mL) was added to quench the reaction 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. During the exchange, the product precipitated. The suspension was cooled to ambient temperature and the solid was filtered off. The filter cake was rinsed with ethanol (18 mL) and then dried to give (Z)-methyl 4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)-N-cyanopiperidine-1-thiocarbamidate (6, 7.80 g, 83% yield, 99.5% HPLC purity) as an off-white solid.

[0126] 1 H NMR (400 MHz, CDCl 3 )δ7.28–7.22(m,2H),7.13–7.08(m,2H),4.45–4.34(m,2H),3.68–3.54(m,2H), 3.46(dd,J=11.5,2.7Hz,1H),3.32(dd,J=12.1,2.8Hz,2H),3.01(dd,J=12.9,10 .8Hz,1H),2.88–2.77(m,2H),2.76(s,3H),2.71–2.62(m,2H),2.36(dd,J=11.8 ,10.3Hz,1H), 2.07–1.94(m,2H), 1.68–1.47(m,2H), and 1.21(d,J=6.2Hz,3H)ppm.

[0127] 13 C NMR (100 MHz, CDCl 3 )δ168.7,138.3,132.0,130.8,128.8,115.4,72.5,67.8,55.8,55.4,50.0,46.9,30.3,29.8,27.5,19.3,and 16.4ppm.

[0128] 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 .

[0129] Example 6

[0130] 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-4H-1,2,4-triazol-3-amine Hydrated Form I (1, Hydrated Form I) was prepared from (2S,5S)-5-(4-chlorobenzyl)-2-methyl-4-(piperidin-4-yl)morpholine dihydrochloride hydrate (4, dihydrochloride hydrate).

[0131] (2S,5S)-5-(4-chlorobenzyl)-2-methyl-4-(piperidin-4-yl)morpholine dihydrochloride hydrate (4, dihydrochloride hydrate, 9.03 g) and dimethyl N-cyanodithioimidocarbonate (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 allowed to proceed at 60° C. for an additional 2 hours. Water (144 mL) was added to the hot solution, allowed to cool to ambient temperature, seeded with crystalline material, and placed in a refrigerator for 24 hours. The precipitate was filtered off, the filter cake was rinsed with water (2×40 mL), and then dried in air to give a crude product (14.3 g), which is the hydrated form I of 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-4H-1,2,4-triazol-3-amine (1, hydrated form I, 7.06 g, drying loss 25%, dry basis yield 80%, HPLC purity 99.4%) as a white solid.

[0132] 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 by silica gel 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 in acetonitrile (10 mL / 1 g product) under reflux. The solution was cooled to ambient temperature to precipitate the product. The solid was filtered out and rinsed with acetonitrile to obtain seed crystals.

[0133] 1 H NMR (500MHz, CD 3OD)δ7.29–7.25(m,2H),7.21–7.16(m,2H),3.67–3.54(m,2H),3.47(d,J=11.5Hz,1H),3.01–2.72(m,6H),2.72 –2.63(m,1H), 2.35(dd,J=12.0,10.5Hz,1H), 2.10–1.95(m,2H), 1.58–1.39(m,2H), and 1.19(d,J=6.2Hz,3H)ppm.

[0134] 13 C NMR (125MHz, CD 3 OD) 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.

[0135] 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 .

[0136] Example 7

[0137] 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-4H-1,2,4-triazol-3-amine Hydrated Form I (1, Hydrated Form I) was prepared from (Z)-4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)-N-cyanopiperidine-1-thiocarbamidyl ester (6).

[0138] (Z)-4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)-N-cyanopiperidine-1-thiocarbamidyl ester (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 the product precipitated after cooling to ambient temperature. The solid was filtered off and the filter cake was rinsed with water (37 mL) and then dried to obtain 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-4H-1,2,4-triazol-3-amine (1, hydrated form I, 15.82 g, 36% weight loss on drying, 133% yield, 99.7% HPLC purity) as a white solid.

[0139] 1 H NMR (500MHz, CD 3 OD)δ7.29–7.25(m,2H),7.21–7.16(m,2H),3.67–3.54(m,2H),3.47(d,J=11.5Hz,1H),3.01–2.72(m,6H),2.72 –2.63(m,1H), 2.35(dd,J=12.0,10.5Hz,1H), 2.10–1.95(m,2H), 1.58–1.39(m,2H), and 1.19(d,J=6.2Hz,3H)ppm.

[0140] 13 C NMR (125MHz, CD 3 OD) 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.

[0141] 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 .

[0142] Example 8

[0143] 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-4H-1,2,4-triazol-3-amine anhydrous form (1, anhydrous form) was prepared from 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-4H-1,2,4-triazol-3-amine hydrate form I (1, hydrate form I).

[0144] 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, 6.62 g on a dry basis) was suspended in ethyl acetate (66 mL) and the suspension was heated to reflux. After heating, the suspension became clear. Water was distilled off using a Dean-Stark dehydrator until a boiling point of 76° C. was reached. During the distillation, the product precipitated. The suspension was cooled to ambient temperature and the solid was filtered off. The filter cake was rinsed with ethyl acetate (13 mL) and then dried to give the anhydrous form of 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-4H-1,2,4-triazol-3-amine (1, anhydrous form, 6.38 g, 83% yield, HPLC purity >99.9%) as white crystals.

[0145] 1 H NMR (700 MHz, C 6 D 6 / CD 3 OD)δ7.13(d,J=8.2Hz,2H),6.89(d,J=8.2Hz,2H),3.99(br s,2H),3.66(br s,3H),3.56(d,J=11.4Hz,1H),3.54–3.46(m,1H),3.37(d,J=11.4Hz,1H), 2.90–2.80(m,3H),2.68(d,J=10.4Hz,1H),2.40(d,J=11.9Hz,2H),2.32–2 .25(m,1H),2.05(t,J=11.2Hz,1H),1.81(d,J=12.5Hz,1H),1.65(d,J=12. 5Hz,1H), 1.54–1.46(m,1H), 1.46–1.37(m,1H), and 1.11(d,J=6.2Hz,3H)ppm.

[0146] 13 C NMR (175MHz, C 6 D 6 )δ139.0,132.1,131.2,129.0,128.1,72.6,67.8,56.5,55.7,50.1,48.9,45.8,45.7,29.7,29.2,27.7,and 19.3ppm.

[0147] 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 .

[0148] Example 9

[0149] 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-4H-1,2,4-triazol-3-amine anhydrous form (1, anhydrous form) was prepared from (Z)-4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)-N-cyanopiperidine-1-thiocarbamidyl ester (6).

[0150] (Z)-4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)-N-cyanopiperidine-1-thiocarbamidyl ester (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 give a clear solution. After 2 hours, the solution was cooled to ambient temperature and the product precipitated. The solid was filtered off and the filter cake was rinsed with acetonitrile (12.5 mL) to give the anhydrous form of 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-4H-1,2,4-triazol-3-amine (1, anhydrous form, 4.39 g, 90% yield, 98.7% HPLC purity) as white crystals.

[0151] 1 H NMR (700 MHz, C 6 D 6 / CD 3OD)δ7.13(d,J=8.2Hz,2H),6.89(d,J=8.2Hz,2H),3.99(br s,2H),3.66(br s,3H),3.56(d,J=11.4Hz,1H),3.54–3.46(m,1H),3.37(d,J=11.4Hz,1H), 2.90–2.80(m,3H),2.68(d,J=10.4Hz,1H),2.40(d,J=11.9Hz,2H),2.32–2 .25(m,1H),2.05(t,J=11.2Hz,1H),1.81(d,J=12.5Hz,1H),1.65(d,J=12. 5Hz,1H), 1.54–1.46(m,1H), 1.46–1.37(m,1H), and 1.11(d,J=6.2Hz,3H)ppm.

[0152] 13 C NMR (175MHz, C 6 D 6 )δ139.0, 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.

[0153] 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 .

[0154] Example 10

[0155] 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-4H-1,2,4-triazol-3-amine hydrated form II (1, hydrated form II) was prepared 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).

[0156] 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 in methanol (20 mL) under reflux. Water (30 mL) was added slowly, maintaining reflux. After addition, the product precipitated. The suspension was cooled to ambient temperature and aged for 1 hour. The solid was filtered off and the filter cake was rinsed with a mixture of methanol and water (25 mL, 2:3 v / v), then dried in air overnight to give hydrated form II of 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-4H-1,2,4-triazole-3-amine (1, hydrated form II, 5.44 g, Karl-Fischer measured water content of 8.2%, dry basis yield of 99%, HPLC purity>99.9%) as a white solid.

[0157] Embodiment 11

[0158] 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-4H-1,2,4-triazol-3-amine amorphous form (1, amorphous form) was prepared 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).

[0159] A petri dish covered with 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. When the material melted, the petri dish was allowed to cool to ambient temperature. The glassy material was ground in a mortar to give 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.

[0160] 1 H NMR (700 MHz, C 6 D 6 / CD 3OD)δ7.13(d,J=8.2Hz,2H),6.89(d,J=8.2Hz,2H),3.99(br s,2H),3.66(br s,3H),3.56(d,J=11.4Hz,1H),3.54–3.46(m,1H),3.37(d,J=11.4Hz,1H), 2.90–2.80(m,3H),2.68(d,J=10.4Hz,1H),2.40(d,J=11.9Hz,2H),2.32–2 .25(m,1H),2.05(t,J=11.2Hz,1H),1.81(d,J=12.5Hz,1H),1.65(d,J=12. 5Hz,1H), 1.54–1.46(m,1H), 1.46–1.37(m,1H), and 1.11(d,J=6.2Hz,3H)ppm.

[0161] 13 C NMR (175MHz, C 6 D 6 )δ139.0,132.1,131.2,129.0,128.1,72.6,67.8,56.5,55.7,50.1,48.9,45.8,45.7,29.7,29.2,27.7,and 19.3ppm.

[0162] 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 .

[0163] Example 12

[0164] 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-4H-1,2,4-triazol-3-amine amorphous form (1, amorphous form) is prepared from 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-4H-1,2,4-triazol-3-amine hydrate form I or II (1, hydrate form I or II).

[0165] A petri dish covered with 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-4H-1,2,4-triazol-3-amine hydrated form I or II (1, hydrated form I or II, 5.01 g) was placed on a hot plate and heated to 125° C. When the material melted, the dish was allowed to cool to ambient temperature. The glassy material was ground in a mortar to give 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-4H-1,2,4-triazol-3-amine amorphous form (starting from hydrated Form I: 1, amorphous form, 4.49 g, yield 90%, HPLC purity >99.99%; starting from hydrated Form II: 1, amorphous form, 4.41 g, yield 88%, HPLC purity >99.9%) as a white solid.

[0166] 1 H NMR (700 MHz, C 6 D 6 / CD 3 OD)δ7.13(d,J=8.2Hz,2H),6.89(d,J=8.2Hz,2H),3.99(br s,2H),3.66(br s,3H),3.56(d,J=11.4Hz,1H),3.54–3.46(m,1H),3.37(d,J=11.4Hz,1H), 2.90–2.80(m,3H),2.68(d,J=10.4Hz,1H),2.40(d,J=11.9Hz,2H),2.32–2 .25(m,1H),2.05(t,J=11.2Hz,1H),1.81(d,J=12.5Hz,1H),1.65(d,J=12. 5Hz,1H), 1.54–1.46(m,1H), 1.46–1.37(m,1H), and 1.11(d,J=6.2Hz,3H)ppm.

[0167] 13 C NMR (175MHz, C 6 D 6 )δ139.0,132.1,131.2,129.0,128.1,72.6,67.8,56.5,55.7,50.1,48.9,45.8,45.7,29.7,29.2,27.7,and 19.3ppm.

[0168] 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

1. A method for preparing (2S,5S)-5-(4-chlorobenzyl)-2-methyl-4-(piperidin-4-yl)morpholine of formula 5, The method includes: (a) (2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholine of formula 2 With N-Boc-4-piperidone of formula 3 and sodium cyanoborohydride in a methanol solvent in the presence of zinc chloride to provide tert-butyl 4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidine-1-carboxylate of formula 4, (b) Removal of the tert-butyloxycarbonyl protecting group using hydrochloric acid provides (2S,5S)-5-(4-chlorobenzyl)-2-methyl-4-(piperidin-4-yl)morpholine of Formula 5.

2. The process of claim 1, wherein in step (a), the compound of formula 2 is used in the form of its hydrochloride salt.

3. The process of claim 1, wherein in step (b), ethyl acetate is the solvent.

4. 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, The method includes: (a) (2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholine of formula 2 With N-Boc-4-piperidone of formula 3 and sodium cyanoborohydride in a methanol solvent in the presence of zinc chloride to provide tert-butyl 4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidine-1-carboxylate of formula 4, (b) Removal of the tert-butyloxycarbonyl protecting group using hydrochloric acid provides (2S,5S)-5-(4-chlorobenzyl)-2-methyl-4-(piperidin-4-yl)morpholine of Formula 5 (c) reacting the compound of formula 5 with dimethyl N-cyanodithioimidocarbonate in a solvent in the presence of a base to produce (Z)-4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)-N-cyanopiperidine-1-thiocarbamidate of formula 6 (d) reacting the compound of formula 6 with hydrazine monohydrate in a solvent to provide a compound of formula 1.

5. The method of claim 4, wherein in step (c), the compound of formula 5 is in the form of a salt.

6. The process of claim 5, wherein in step (c), dihydrochloride hydrate is the salt.

7. The process of claim 6, wherein in step (c), a trialkylamine is the base.

8. The process of claim 7, wherein in step (c), triethylamine is the base.

9. The method of claim 6, wherein in step (c), ethanol, 1-propanol or 2-propanol is the solvent.

10. The process of claim 6, wherein in step (c), acetonitrile is the solvent.

11. The process of claim 9, wherein after step (c), the compound of formula 6 is isolated by precipitation after cooling the reaction mixture.

12. The process of claim 9, wherein step (d) is carried out without isolating the compound of formula 6.

13. The process of claim 9, wherein after step (d), the compound of formula 1 is isolated by precipitation after adding water to the reaction mixture.

14. The process of claim 12, wherein after step (d), the compound of formula 1 is isolated by precipitation after adding water to the reaction mixture.

15. The process of claim 10, wherein after step (d), the compound of formula 1 is isolated by precipitation after cooling the reaction mixture.

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