Crystal form of xanthomeline tartrate and preparation method thereof

Abstract

The invention provides a preparation method of annomeline tartrate crystal form A. Cu-K alpha radiation is used, and an X-ray powder diffraction pattern of the crystal form A expressed by a 2 theta angle has characteristic peaks at 9.4 degrees + / -0.2 degrees, 20.4 degrees + / -0.2 degrees and 23.7 degrees + / -0.2 degrees. The preparation method comprises the following steps: (1) adding annomeline and L-tartaric acid into a first organic solvent, and stirring to obtain a second organic solvent; stirring and heating to obtain a clear solution; (2) adding a second organic solvent into the settled solution in the step (1), slowly cooling to 2-8 DEG C while stirring, and separating out crystals; and (3) filtering and collecting crystals, washing with a second organic solvent, and carrying out vacuum drying to obtain the Nomeline tartrate crystal form A. The first organic solvent is selected from methanol, ethanol, isopropanol, n-butanol, acetone or a combination thereof, and the second organic solvent is selected from methyl tert-butyl ether, an ester solvent, acetonitrile, an alkane solvent or a combination thereof. The preparation method of the xanthomeline tartrate is simple to operate, high in yield and high in purity.

Description

TECHNICAL FIELD

[0001] The present application relates to a crystal form of a salt of an organic compound, in particular to a crystal form of xanomeline tartrate Form A and a preparation method thereof. BACKGROUND

[0002] The chemical name of xanomeline is 3-[(4-hexyloxy)-1,2,5-thiadiazol-3-yl]-1,2,5,6-tetrahydro-1-methylpyridine, and the chemical structure is as follows:

[0003]

[0004] Xanomeline is a partial agonist of muscarinic receptors, which is jointly developed and marketed by Eli Lilly and Novo Nordisk, and is mainly used for the treatment of Alzheimer's disease.

[0005] The prior art CN1128999A (authorized publication number CN1064681C) discloses a salt of xanomeline and various acids, wherein the xanomeline tartrate has good bioavailability, good physical properties and reproducible crystal form, and discloses a preparation method of the xanomeline tartrate: dissolving the obtained xanomeline free base in 2-propanol, adding fumaric acid, heating the mixture to become a transparent solution, and then adding acetone. Stir the solution and cool to 5-10℃, filter to obtain xanomeline fumarate, then suspend in dichloromethane, add water and sodium hydroxide solution, stir the reaction mixture until a transparent solution is obtained, then separate the dichloromethane phase, and concentrate to obtain free xanomeline. Dissolve the free xanomeline in 2-propanol, add L-tartaric acid, heat the mixture until a transparent solution is formed. Slowly cool the solution to 5-10℃ under stirring, collect the precipitate by filtration, dry to obtain the desired product, and then recrystallize with 2-propanol added with activated carbon to obtain xanomeline tartrate.

[0006] The preparation method of the xanomeline tartrate is complex, and the cost of industrial production is high. SUMMARY

[0007] In view of the problems in the prior art of the preparation method of xanomeline tartrate, the present application provides a preparation method of xanomeline tartrate crystal Form A, wherein the xanomeline tartrate obtained by the preparation method is in a crystal form, has high yield and high purity.

[0008] A process for preparing crystalline Zanomeline tartrate Form A, said crystalline Zanomeline tartrate Form A having an X-ray powder diffraction pattern expressed in terms of 2 theta angle using Cu-K alpha radiation comprising characteristic peaks at 9.4°±0.2°, 20.4°±0.2°, 23.7°±0.2°, said process comprising the steps of:

[0009] (1) adding Zanomeline and L-tartaric acid into a first organic solvent, stirring and heating to obtain a clear solution;

[0010] (2) adding a second organic solvent into the clear solution of step (1), and then slowly cooling to 2-8°C under stirring to precipitate crystals;

[0011] (3) collecting the crystals by filtration, washing with the second organic solvent, and vacuum drying to obtain crystalline Zanomeline tartrate Form A,

[0012] said first organic solvent is selected from methanol, ethanol, isopropanol, n-butanol, acetone or a combination thereof.

[0013] said second solvent is selected from methyl tert-butyl ether, ester solvent, acetonitrile, alkane solvent, or a combination thereof.

[0014] In another preferred embodiment, said ester solvent is selected from ethyl acetate, isopropyl acetate, or a combination thereof.

[0015] In another preferred embodiment, said alkane solvent is selected from n-heptane, n-hexane or a combination thereof.

[0016] In another more preferred embodiment, said first organic solvent is selected from ethanol, isopropanol, acetone or a combination thereof, and said second solvent is selected from ethyl acetate, methyl tert-butyl ether, n-heptane.

[0017] In another preferred embodiment, the weight to volume ratio of Zanomeline to the first organic solvent is 1 g / 2-8 mL, more preferably 1 g / 4-6 mL.

[0018] In another preferred embodiment, the weight to volume ratio of Zanomeline to the second organic solvent is 1 g / 2-20 mL.

[0019] In another preferred embodiment, the molar ratio of Zanomeline to L-tartaric acid is 1:1.0-1.2, more preferably 1:1.

[0020] In another preferred embodiment, in step (1), the heating temperature is 50-85°C.

[0021] In another preferred embodiment, in step (3), the temperature for vacuum drying is 35-45°C, and the time is 8-24 hours.

[0022] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form of zanamivir tartrate Form A expressed in terms of 2 theta angle using Cu-Ka radiation further has a characteristic peak at any one or more of 4.7°±0.2°, 12.0±0.2°, 12.7±0.2°, 13.7±0.2°, 15.1±0.2°, 16.8±0.2°, 17.3±0.2°, 18.1±0.2°, 18.4±0.2°, 18.9±0.2°, 19.2±0.2°, 21.9±0.2°, 24.1±0.2°, 24.4±0.2°, 25.6±0.2°, 26.5±0.2°, 29.1±0.2°, 33.2±0.2°, 37.9±0.2°.

[0023] The present application also provides a crystalline form of zanamivir tartrate Form A, which has an X-ray powder diffraction pattern expressed in terms of 2 theta angle using Cu-Ka radiation having characteristic peaks at 9.4°±0.2°, 20.4°±0.2°, 23.7°±0.2°,

[0024] The tartaric acid is L-tartaric acid.

[0025] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form of zanamivir tartrate Form A expressed in terms of 2 theta angle using Cu-Ka radiation further has a characteristic peak at any one or more of 4.7°±0.2°, 12.0±0.2°, 12.7±0.2°, 13.7±0.2°, 15.1±0.2°, 16.8±0.2°, 17.3±0.2°, 18.1±0.2°, 18.4±0.2°, 18.9±0.2°, 19.2±0.2°, 21.9±0.2°, 24.1±0.2°, 24.4±0.2°, 25.6±0.2°, 26.5±0.2°, 29.1±0.2°, 33.2±0.2°, 37.9±0.2°.

[0026] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form of zanamivir tartrate Form A is substantially as shown in Figure 1 、 4 , 7, 10 or 13.

[0027] In another preferred embodiment, the differential scanning calorimetry profile of the crystalline form of zanamivir tartrate Form A has an endothermic peak present at 97±5°C.

[0028] In another preferred embodiment, the differential scanning calorimetry profile of the crystalline form of zanamivir tartrate Form A is substantially as shown in Figure 2 、 5 , 8, 11 or 14.

[0029] In another preferred embodiment, the thermogravimetric analysis profile of the crystalline form Form A of xanomeline tartrate salt shows a weight loss of about 0.6% at 70-150°C.

[0030] In another preferred embodiment, the thermogravimetric analysis profile of the crystalline form Form A of xanomeline tartrate salt shows a weight loss of about 0.6% at 70-150°C. Figure 3 、 6 , 9, 12 or 15.

[0031] The present application also provides the use of the crystalline form Form A of xanomeline tartrate salt in the preparation of a medicament containing xanomeline. BRIEF DESCRIPTION OF DRAWINGS

[0032] Figure 1 XRPD pattern of the crystalline form Form A of xanomeline tartrate salt obtained in Example 2;

[0033] Figure 2 DSC pattern of the crystalline form Form A of xanomeline tartrate salt obtained in Example 2;

[0034] Figure 3 TGA pattern of the crystalline form Form A of xanomeline tartrate salt obtained in Example 2;

[0035] Figure 4 XRPD pattern of the crystalline form Form A of xanomeline tartrate salt obtained in Example 3;

[0036] Figure 5 DSC pattern of the crystalline form Form A of xanomeline tartrate salt obtained in Example 3;

[0037] Figure 6 TGA pattern of the crystalline form Form A of xanomeline tartrate salt obtained in Example 3;

[0038] Figure 7 XRPD pattern of the crystalline form Form A of xanomeline tartrate salt obtained in Example 4;

[0039] Figure 8 DSC pattern of the crystalline form Form A of xanomeline tartrate salt obtained in Example 4;

[0040] Figure 9 TGA pattern of the crystalline form Form A of xanomeline tartrate salt obtained in Example 4;

[0041] Figure 10 XRPD pattern of the crystalline form Form A of xanomeline tartrate salt obtained in Example 5;

[0042] Figure 11DSC pattern of crystalline form Form A of zanamivir tartrate salt obtained in Example 5;

[0043] Figure 12 TGA pattern of crystalline form Form A of zanamivir tartrate salt obtained in Example 5;

[0044] Figure 13 XRPD pattern of crystalline form Form A of zanamivir tartrate salt obtained in Example 6;

[0045] Figure 14 DSC pattern of crystalline form Form A of zanamivir tartrate salt obtained in Example 6;

[0046] Figure 15 TGA pattern of crystalline form Form A of zanamivir tartrate salt obtained in Example 6;

[0047] Figure 16 HNMR pattern of zanamivir obtained in Example 1;

[0048] Figure 17 HNMR pattern of crystalline form Form A of zanamivir tartrate salt obtained in Example 2. DETAILED DESCRIPTION

[0049] In view of the problems existing in the preparation method of zanamivir tartrate salt disclosed in the prior art, the present inventors have found, through in-depth research, that the present application can obtain zanamivir tartrate salt with high purity at a high yield by adding zanamivir and L-tartrate salt into a first solvent, dissolving after heating, then adding a second solvent into the solution, and cooling. The salt is a crystal, which is named as "crystalline form Form A". The present application first characterizes the crystalline form Form A. Moreover, the preparation method of the crystalline form Form A of zanamivir tartrate salt of the present application is relatively simple, and the product has a high yield and good purity, which is suitable for industrial large-scale production.

[0050] Process for preparing crystalline zanomeline tartrate Form A

[0051] In a preferred embodiment of the present application, the preparation method of the crystalline form Form A comprises the following steps:

[0052] (1) adding zanamivir and L-tartrate salt into a first organic solvent, stirring and heating to obtain a clear solution;

[0053] (2) adding a second organic solvent into the clear solution of step (1), and then slowly cooling to 2-8°C under stirring to precipitate crystals;

[0054] (3) collecting the crystals, washing with a second organic solvent, and vacuum drying to obtain crystalline form A of onanontin tartrate,

[0055] Further, the first organic solvent is selected from ethanol, isopropanol, acetone or a combination thereof, and the second solvent is selected from ethyl acetate, methyl tert-butyl ether, n-heptane or a combination thereof; the amount of the first organic solvent is such that the raw material can be completely dissolved therein, and in a specific embodiment, the weight / volume ratio of onanontin to the first organic solvent is 1 g / 4-6 mL; the amount of the first organic solvent is such that the onanontin tartrate crystalline form A dissolved in the first organic solvent can be substantially completely precipitated.

[0056] Further, the molar ratio of onanontin to L-tartaric acid is 1:1.0-1.2, more preferably 1:1.

[0057] Further, in step (1), the heating temperature is 50-85°C.

[0058] Further, in step (3), the temperature for vacuum drying is 35-45°C, and the time is 8-24 hours.

[0059] Crystalline zanomeline tartrate Form A

[0060] In a preferred specific embodiment of the present application, using Cu-Ka radiation, the X-ray powder diffraction pattern of the crystalline form A of onanontin tartrate has characteristic peaks at 9.4°±0.2°, 20.4°±0.2°, 23.7°±0.2° in terms of 2θ angle;

[0061] Further, the X-ray powder diffraction pattern of the crystalline form A of onanontin tartrate has characteristic peaks at any one or more of 4.7°±0.2°, 12.0±0.2°, 12.7±0.2°, 13.7±0.2°, 15.1±0.2°, 16.8±0.2°, 17.3±0.2°, 18.1±0.2°, 18.4±0.2°, 18.9±0.2°, 19.2±0.2°, 21.9±0.2°, 24.1±0.2°, 24.4±0.2°, 25.6±0.2°, 26.5±0.2°, 29.1±0.2°, 33.2±0.2°, 37.9±0.2° in terms of 2θ angle; further, the X-ray powder diffraction pattern of the crystalline form A of onanontin tartrate is substantially as shown in Figure 1 、 4 , 7, 10 or 13.

[0062] Further, the differential scanning calorimetry pattern of the crystalline form of zanomeline tartrate Form A has an endothermic peak at 97±5℃; further, the differential scanning calorimetry pattern of the crystalline form of zanomeline tartrate Form A is substantially as shown in Figure 2 , 5 , 8, 11 or 14.

[0063] Further, the thermogravimetric analysis pattern of the crystalline form of zanomeline tartrate Form A has a weight loss of about 0.6% at 70-150℃; further, the thermogravimetric analysis pattern of the crystalline form of zanomeline tartrate Form A is substantially as shown in Figure 3 , 6 , 9, 12 or 15.

[0064] Compared with the prior art, the present application has the following beneficial effects:

[0065] 1) The present application first discloses and characterizes the crystalline form of zanomeline tartrate Form A;

[0066] 2) The preparation method of the zanomeline tartrate of the present application is simple in operation, high in yield, and good in purity of the obtained product, and is suitable for industrial large-scale production.

[0067] The compounds of the present application, the preparation method and application thereof will be further described in detail below in conjunction with specific examples. It should be understood that the following examples are only illustratively and explainatively described and should not be interpreted as limiting the scope of protection of the present application. Any technology realized based on the above description of the present application is encompassed in the scope of protection intended by the present application.

[0068] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0069] Example 1

[0070] Under nitrogen protection, 3-(4-hexyloxy-1,2,5-thiadiazol-3-yl)-1-methylpyridine iodide (10.0 g, 24.67 mmol.) and methanol (100 mL, 10 vol.) were added into a 100 mL flask, cooled to 0-5℃, and a 0.1 N sodium hydroxide solution (5 mL, 0.5 vol.) of sodium borohydride (1.13 g, 29.85 mmol.) was added dropwise, the dropwise time was about 3 hours, and the temperature was controlled at 0-5℃ and stirred for 0.5 hours. The pH was adjusted to 7-8 by adding 4N hydrochloric acid. Water (80 mL, 8 vol.) was added, and the mixture was extracted twice with dichloromethane (50 mL, 5 vol.*2), and the combined organic phase was concentrated to obtain 6.5 g of zanomeline free base with a HPLC purity of 94.59%. The mass spectrum and nuclear magnetic hydrogen spectrum data of the product are as follows:

[0071] (EI-MS m / z 282.4 [M+1] + ,

[0072] HNMR (300 MHz, CD3OD) δ (ppm): 7.3 (1H, t), 4.5 (2H, t), 3.4 (2H, t), 2.6 (2H, s), 2.5 (5H, q), 1.9 (2H, m), 1.3-1.5 (6H, m), 0.9 (3H, t) Cl 3) δ (ppm): 7.3 (1H, t), 4.5 (2H, t), 3.4 (2H, t), 2.6 (2H, s), 2.5 (5H, q), 1.9 (2H, m), 1.3-1.5 (6H, m), 0.9 (3H, t)

[0073] The HNMR spectrum of the free base of Zanomeline is shown in Figure 16 .

[0074] Example 2

[0075] To a 100 mL flask was added the free base of Zanomeline (1.0 g, 3.55 mmol. HPLC purity 94.59%), L-tartaric acid (0.53 g, 3.56 mmol.) and isopropyl alcohol (5 mL, 5 vol.) and the mixture was heated until complete dissolution to give a clear solution. To this was then added ethyl acetate (15 mL, 15 vol.). The solution was slowly cooled to 2-8 °C with stirring to induce crystallization and the product was collected by filtration and washed with cold ethyl acetate and dried under vacuum at 40 °C to give a white solid 1.35 g, 87.97% molar yield, HPLC purity 99.81%. The product was Form A of Zanomeline tartrate salt as determined by XRPD. The XRPD, DSC and TGA patterns of Form A are shown in Figure 1 , Figure 2 and Figure 3 respectively.

[0076] HNMR (300 MHz, CD3OD) δ (ppm): 7.24 (1H, t), 4.52 (2H, t), 4.39 (2H, s), 4.20 (2H, s), 3.34 (2H, t), 3.0 (3H, s), 2.98 (2H, q), 1.86 (2H, m), 1.3-1.5 (6H, m), 0.9 (3H, t).

[0077] The HNMR spectrum of Form A of Zanomeline tartrate salt is shown in Figure 17 .

[0078] Example 3

[0079] To a 100 mL flask, add the compound of formula I (1.0 g, 3.55 mmol., HPLC purity: 94.59%), L-tartaric acid (0.53 g, 3.55 mmol.) and acetone (5 mL, 5 vol.), and heat the mixture until it is completely dissolved to obtain a clear solution. Then add methyl tert-butyl ether (2.5 mL, 2.5 vol.). Under stirring, slowly cool the solution to 2-8 ° C for crystallization, collect the product by filtration, wash with cold methyl tert-butyl ether, and vacuum dry at 40 ° C to obtain 1.38 g of a white solid with a molar yield of 89.80% and an HPLC purity of 99.67%. The obtained product is the crystalline form of xanomeline tartrate Form A detected by XRPD. The XRPD spectrum, DSC spectrum and TGA spectrum of Form A are shown as follows, respectively. Figure 4 、 Figure 5 and Figure 6 shown.

[0080] Example 4

[0081] To a 100 mL flask, add the compound of formula I (1.0 g, 3.55 mmol, HPLC purity: 94.59%), L-tartaric acid (0.53 g, 3.55 mmol.) and ethanol (5 mL, 5 vol.), and heat the mixture until it is completely dissolved to obtain a clear solution. Then add methyl tert-butyl ether (2.5 mL, 2.5 vol.). The solution is slowly cooled to 2-8 ° C under stirring to crystallize, the product is collected by filtration, and washed with cold methyl tert-butyl ether, and dried in vacuo at 40 ° C to obtain 1.32 g of a white solid with a molar yield of 86.08% and an HPLC purity of 99.89%. The product obtained by XRPD detection is the crystalline form of xanomeline tartrate Form A. The XRPD spectrum, DSC spectrum and TGA spectrum of Form A are shown as follows, respectively. Figure 7 、 Figure 8 and Figure 9 shown.

[0082] Example 5

[0083] A 100 mL flask was added with the compound of formula I (1.0 g, 3.55 mmol, HPLC purity: 94.59%), L-tartaric acid (0.53 g, 3.55 mmol.) and isopropanol (5 mL, 5 vol.), and the mixture was heated until completely dissolved to obtain a clear solution. Then n-heptane (15 mL, 15 vol.) was added thereto. The solution was slowly cooled to 2-8 ° C under stirring for crystallization, the product was collected by filtration, washed with cold n-heptane, and dried in vacuo at 40 ° C to obtain 1.37 g of a white solid with a molar yield of 89.01% and an HPLC purity of 99.52%. The obtained product was identified as Form A of xanomeline tartrate by XRPD. The XRPD spectrum, DSC spectrum and TGA spectrum of Form A are shown as follows:Figure 10 , Figure 11 and Figure 12 .

[0084] Example 6

[0085] To a 100 mL flask was added the compound of Formula I (1.0 g, 3.55 mmol, HPLC purity: 94.59%), L-tartaric acid (0.53 g, 3.55 mmol.) and ethanol (5 mL, 5 vol.), the mixture was heated until completely dissolved to give a clear solution. Then to it was added n-heptane (15 mL, 15 vol.). The solution was slowly cooled to 2-8 °C with stirring to crystallize, the product was collected by filtration and washed with cold n-heptane, dried under vacuum at 40 °C to give a white solid 1.35 g, molar yield 87.98%, its HPLC purity was 99.83%. The product was tested to be Zanomeline tartrate Form A. The XRPD pattern, DSC pattern and TGA pattern of Form A are shown in Figure 13 , Figure 14 and Figure 15 .

[0086] Comparative Example 1

[0087] Zanomeline tartrate was prepared according to prior art CN1128999A

[0088] To a 100 mL flask was added 3-(4-hexyloxy-l,2,5-thiadiazol-3-yl)-l- methylpyridine iodide (10.0 g, 24.67 mmol) and methanol (100 mL, 10 vol.) under nitrogen protection, the temperature was lowered to 0-5 °C, a solution of sodium borohydride (1.13 g, 29.85 mmol.) in 0.1 N sodium hydroxide (5 mL, 0.5 vol.) was added dropwise, the dropwise time was about 3 hours, the temperature was controlled at 0-5 °C and stirred for 0.5 hours. The pH was adjusted to 7-8 by adding 4 N hydrochloric acid, and water (80 mL, 8 vol.) was added, the mixture was extracted twice with dichloromethane (50 mL, 5 vol.*2), the organic phases were combined and concentrated to give a residue (free base of the compound of Formula I). Isopropyl alcohol (25 mL, 2.5 vol.) and fumaric acid (2.86 g, 24.67 mmol.) were added to the residue, heated to dissolve clear, and acetone (25 mL, 2.5 vol.) was added. Stirring and cooling to 5-10 °C, filtration to give the fumarate salt of the compound of Formula I.

[0089] To a 100 mL flask was added the fumarate salt of the compound of Formula I (10.0 g, 25.16 mmol.) and dichloromethane (40 mL, 4.0 vol.), water (20 mL, 2.0 vol.) and aqueous sodium hydroxide (5.6 mL, 50.32 mmol.) under nitrogen protection. The mixture was stirred until the system was clear and transparent, and then was separated. The organic phase was washed twice with water (20 mL, 1.0 vol.*2), and then was filtered. The filtrate was concentrated to obtain an oil (the compound of Formula I). To the oil was added isopropyl alcohol (50 mL, 5 vol.) and L-tartaric acid (4.15 g, 27.68 mmol.). The mixture was heated until it was completely dissolved to obtain a clear solution. The solution was slowly cooled to 5-10 °C under stirring until crystals were precipitated. The product was collected by filtration and dried to obtain the crude tartaric acid salt of the compound of Formula I.

[0090] The crude tartaric acid salt of the compound of Formula I was added to a reaction bottle, activated carbon (0.01 g, 0.01 wt.) and isopropyl alcohol (50 mL, 5 vol.) were added, and the mixture was heated to 80 °C. The mixture was filtered while hot. The filtrate was cooled to 5-10 °C, and then solid was precipitated. The product was collected by filtration to obtain 9.18 g of the tartaric acid salt of the compound of Formula I, with a yield of 84.33%, and a HPLC purity of 99.73%.

[0091] As can be seen from the comparison between the above Examples 1-6 and Comparative Example 1, the method for preparing the crystalline Form A of the tartaric acid salt of montelukast according to the present application is simpler than the prior art, and is more suitable for industrial production.

[0092] All the documents mentioned in the present application are incorporated herein by reference. In addition, it should be understood that various modifications and changes can be made to the present application by those skilled in the art upon reading the above description of the present application, and such equivalent forms are also within the scope of the appended claims.

Claims

1. A method for preparing Xanomeline tartrate crystal form A, characterized in that: Using Cu-Kα radiation, the X-ray powder diffraction pattern of the Xanomeline tartrate crystalline form Form A expressed in 2θ angles has characteristic peaks at 9.4°±0.2°, 20.4°±0.2°, and 23.7°±0.2°. The preparation method comprises the following steps: (1) adding xanomeline and L-tartaric acid to a first organic solvent, stirring and heating to obtain a clear solution; (2) adding a second organic solvent to the clarified solution of step (1), and then slowly cooling the solution to 2-8° C. under stirring to precipitate crystals; (3) collecting the crystals by filtration, washing with a second organic solvent, and vacuum drying to obtain the crystalline form of Xanax tartrate Form A. The first organic solvent is selected from methanol, ethanol, isopropanol, n-butanol, acetone or a combination thereof, The second solvent is selected from methyl tert-butyl ether, ester solvents, acetonitrile, alkane solvents, or a combination thereof.

2. The preparation method according to claim 1, characterized in that The ester solvent is selected from ethyl acetate, isopropyl acetate, or a combination thereof; and / or The alkane solvent is selected from n-heptane, n-hexane or a combination thereof.

3. The preparation method according to claim 1, wherein The first organic solvent is selected from ethanol, isopropanol, acetone or a combination thereof, and the second solvent is selected from ethyl acetate, methyl tert-butyl ether, and n-heptane.

4. The preparation method according to claim 1, characterized in that The molar ratio of Xanomeline to L-tartaric acid is 1:1.0 to 1.2, more preferably 1:1, and / or The weight-to-volume ratio of Xanomeline to the first organic solvent is 1 g / 2 to 8 mL, more preferably 1 g / 4 to 6 mL, and / or The weight-to-volume ratio of Xanomeline to the second organic solvent is 1 g / 2 to 20 mL.

5. The preparation method according to claim 1, characterized in that In step (1), the heating temperature is 50-85°C, and / or In step (3), the vacuum drying temperature is 35 to 45° C. and the time is 8 to 24 hours.

6. The preparation method according to claim 1, characterized in that Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form A of the tartrate of Xanomeline, expressed in 2θ angles, also has characteristic peaks at any one or more of 4.7°±0.2°, 12.0±0.2°, 12.7±0.2°, 13.7±0.2°, 15.1±0.2°, 16.8±0.2°, 17.3±0.2°, 18.1±0.2°, 18.4±0.2°, 18.9±0.2°, 19.2±0.2°, 21.9±0.2°, 24.1±0.2°, 24.4±0.2°, 25.6±0.2°, 26.5±0.2°, 29.1±0.2°, 33.2±0.2°, and 37.9±0.2°.

7. A crystalline form of Xanomeline tartrate Form A, characterized in that: Using Cu-Kα radiation, its X-ray powder diffraction pattern expressed in 2θ angles has characteristic peaks at 9.4°±0.2°, 20.4°±0.2°, and 23.7°±0.2°. Tartaric acid is L-tartaric acid.

8. The Xanomeline tartrate crystalline form Form A according to claim 7, characterized in that: Using Cu-Kα radiation, its X-ray powder diffraction pattern expressed in 2θ angles also has characteristic peaks at any one or more of 4.7°±0.2°, 12.0±0.2°, 12.7±0.2°, 13.7±0.2°, 15.1±0.2°, 16.8±0.2°, 17.3±0.2°, 18.1±0.2°, 18.4±0.2°, 18.9±0.2°, 19.2±0.2°, 21.9±0.2°, 24.1±0.2°, 24.4±0.2°, 25.6±0.2°, 26.5±0.2°, 29.1±0.2°, 33.2±0.2°, and 37.9±0.2°.

9. The Xanomeline tartrate crystalline form Form A according to claim 7 or 8, characterized in that: The Xanax tartrate crystalline form A also has one or more of the following characteristics: (i) having an X-ray powder diffraction pattern substantially as shown in Figures 1, 4, 7, 10 or 13, (ii) Its differential scanning calorimetry analysis chart shows an endothermic peak at 97±5℃, (iii) a differential scanning calorimetry chart substantially as shown in Figures 2, 5, 8, 11 or 14, (iv) Its thermogravimetric analysis shows a weight loss of about 0.6% at 70-150°C. (v) Its thermogravimetric analysis chart is substantially as shown in Figures 3, 6, 9, 12 or 15.

10. Use of the xanomeline tartrate crystal form A according to any one of claims 7 to 9 in the preparation of a medicament containing xanomeline.

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