Crystal form of piperidine compound and preparation method thereof

Abstract

The invention discloses a piperidine compound crystal form and a preparation method thereof. The invention provides a crystal form A of compounds 1-13, which uses Cu-K alpha radiation, and an X-ray powder diffraction pattern represented by a 2 theta angle has diffraction peaks at 6.42 degrees + / -0.20 degrees, 11.80 degrees + / -0.20 degrees, 17.46 degrees + / -0.20 degrees, 18.18 degrees + / -0.20 degrees, 18.58 degrees + / -0.20 degrees and 19.34 degrees + / -0.20 degrees. According to the preparation method of the compound 1-13, the compound 1-13 with the single stereo configuration is obtained, and then the compound 1 with the single stereo configuration is obtained. The chemical purity and optical purity of the compound 1 are improved, the production cost is greatly reduced, and the production scale is greatly enlarged, so that the method is more suitable for industrial production. # imgabs0 #

Description

Technical Field

[0001] The present application relates to a crystalline form of a piperidine compound and a preparation method thereof. Background Art

[0002] Patent WO2022022559 proposes a new antiplatelet drug that can produce active metabolites in vivo through the action of hydrolases, thereby further irreversibly inhibiting platelet coagulation activity. The patent discloses a compound described by the following formula:

[0003]

[0004] And discloses the following preparation method:

[0005]

[0006]

[0007] In the above preparation process, how to obtain compound 1 with a specific configuration is one of the core issues that need to be solved in the preparation process.

[0008]

[0009] In the existing preparation method, after obtaining the product 1b, since 1b is a racemate, the product still needs to be subjected to chiral separation to obtain the final product compound 1. The chiral separation is difficult, and the separation process requires the use of chiral columns and other equipment, which is very expensive; and the production scale of the product is only at the gram level, which is difficult to scale up, and is not conducive to industrial production. Summary of the invention

[0010] The technical problem to be solved by the present invention is to overcome the defect of the racemate being difficult to separate in the prior art, thereby providing a crystalline form of a piperidine compound and a preparation method thereof. By the preparation method of the compound 1-13 of the present invention, 1-13 with a single stereo configuration is obtained, and then compound 1 with a single stereo configuration is obtained. The present invention improves the yield and purity of 1-13, and then improves the chemical purity and optical purity of compound 1, greatly reduces the production cost, and greatly increases the production scale, so that it is more suitable for industrial production.

[0011] The present invention provides a crystalline form A of a compound 1-13, which has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles at 6.42°±0.20°, 11.80°±0.20°, 17.46°±0.20°, 18.18°±0.20°, 18.58°±0.20° and 19.34°±0.20°;

[0012]

[0013] In a certain embodiment, the crystalline form A of the compound 1-13 has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles at 6.42°±0.20°, 11.80°±0.20°, 17.46°±0.20°, 17.60°±0.20°, 18.18°±0.20°, 18.58°±0.20°, 19.34°±0.20° and 23.02°±0.20°.

[0014] In a certain embodiment, the crystalline form A of the compound 1-13 has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles at 6.42°±0.20°, 11.80°±0.20°, 12.86°±0.20°, 14.44°±0.20°, 17.46°±0.20°, 17.6°±0.20°, 18.18°±0.20°, 18.58°±0.20°, 19.34°±0.20°, 23.02°±0.20°, 24.22°±0.20° and 24.70°±0.20°.

[0015] In a certain embodiment, the crystal form A of the compound 1-13 has characteristic peaks and relative intensities of an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles as shown in Table 1;

[0016] Table 1

[0017]

[0018]

[0019] The crystalline form A of the compound 1-13 may have an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles as follows: Figure 2 shown.

[0020] In a preferred embodiment, the thermogravimetric analysis (TGA) of the crystalline form A of the compound 1-13 shows no obvious weight loss before being heated to 150°C.

[0021] In a preferred embodiment, the differential scanning calorimetry (DSC) of the crystalline form A of the compound 1-13 has a main endothermic peak at 143.85°C±3°C.

[0022] In a preferred embodiment, the DSC graph of the crystalline form A of the compound 1-13 is substantially as follows: Figure 3 shown.

[0023] In a preferred embodiment, the TGA diagram of the crystalline form A of the compound 1-13 is substantially as follows: Figure 4 shown.

[0024] The present application also provides a method for preparing compound 1-13, which comprises the following steps: slurrying a crude product of compound 1-13 in isopropanol to separate the compound 1-13;

[0025] Wherein, the crude product of compound 1-13 is With compound 1-12-B mixture.

[0026] In one embodiment, in the crude product of the compound 1-13, the molar ratio of the compound 1-13 to the compound 1-12-B is 1:0.9-1.1, for example, 1:1.

[0027] In a certain embodiment, in the crude product of the compound 1-13, the chemical purity of the compound 1-13 is 60%-99.9%, for example 99.5%.

[0028] In one embodiment, the crude product of compound 1-13 is With compounds 1-12 mixture.

[0029] In one embodiment, the compound 1-13 is the crystalline form A of the compound 1-13 as described in any of the previous embodiments.

[0030] In a certain embodiment of the present invention, the mass volume ratio of the crude product of compound 1-13 to isopropanol can be 1:(1-10) g / ml, for example 1:3 g / ml.

[0031] In a certain embodiment of the present invention, the beating temperature is conventional in the art, preferably 0-50°C, more preferably 20-30°C, and more preferably 25°C.

[0032] In a certain embodiment of the present invention, the beating time is conventional in the art, preferably 0.5-8 hours, more preferably 1-4 hours, and more preferably 4 hours.

[0033] In one embodiment of the present invention, the crude product of the compound 1-13 is prepared by the following method: Compound 1-12 and L-mandelic acid are subjected to a salt-forming reaction as shown below in an ether solvent to obtain a crude product of the compound 1-13;

[0034]

[0035] The salt-forming reaction may be a conventional reaction of this type in the art, and the present invention particularly prefers the following conditions and operations:

[0036] In the salt-forming reaction, the molar ratio of the compound 1-12 to the L-mandelic acid is preferably 1:(0.5-2), such as 0.75:1.

[0037] In the salt-forming reaction, the ether solvent is preferably methyl tert-butyl ether.

[0038] In the salt-forming reaction, the mass volume ratio of the compound 1-12 to the solvent may be 1:(1-10) g / ml, for example 1:3 g / ml.

[0039] In the salt-forming reaction, the reaction temperature is conventional in the art, preferably 0-50°C, more preferably 20-30°C, and more preferably 25°C.

[0040] The salt-forming reaction further comprises the following steps: in a solvent, in the presence of an acid, compound 1-11 undergoes a deprotection reaction to obtain compound 1-12,

[0041]

[0042] The deprotection reaction can be a conventional reaction of this type in the art. The present invention particularly prefers the following conditions and operations:

[0043] In the deprotection reaction, the acid may be selected from one or more of acetic acid, trifluoroacetic acid and p-toluenesulfonic acid, preferably p-toluenesulfonic acid; more preferably p-toluenesulfonic acid monohydrate.

[0044] In the deprotection reaction, the solvent is a halogenated alkane solvent and / or an ester solvent, preferably dichloromethane.

[0045] In the deprotection reaction, the amount of the solvent is not limited as long as it does not affect the reaction; for example, the mass volume ratio of the compound 1-11 to the solvent is 1:(1-10) g / ml, and another example is 1:3 g / ml.

[0046] In the deprotection reaction, the mass ratio of the compound 1-11 to the acid is preferably 1:(0.5-1.5), more preferably 1:0.79; or the molar ratio of the compound 1-11 to the acid is preferably 1:(1-5), more preferably 1:2.

[0047] The deprotection reaction may further include post-treatment, and the post-treatment operation may be a conventional post-treatment operation in this type of preparation method in the art, which includes the following steps: after the reaction is completed, extraction, neutralization, washing, concentration, and purification.

[0048] The extraction may be a conventional extraction method in this type of reaction in the art, for example, the extractant of the extraction is methyl tert-butyl ether. The neutralization may be a conventional neutralization method in this type of reaction in the art, for example, using saturated sodium bicarbonate for neutralization. The washing may be a conventional washing method in this type of reaction in the art, for example, using saturated sodium bicarbonate and / or saturated sodium chloride for washing. The purification may be a conventional purification method in this type of reaction in the art, for example, column chromatography purification.

[0049] The present invention also provides a method for using L-mandelic acid as a resolving agent in the resolving of compound 1-12-A. and compound 1-12-B Application in.

[0050] The present invention also provides a method for preparing compound 1-14, comprising the following steps: in a solvent, subjecting compound 1-13 to a free reaction with a base to obtain compound 1-14;

[0051]

[0052] The free reaction can be a conventional reaction of this type in the art, and the present invention particularly prefers the following conditions and operations:

[0053] In the free reaction, the solvent is preferably an ether solvent, preferably methyl tert-butyl ether.

[0054] In the free reaction, the amount of the solvent is not limited as long as it does not affect the reaction; for example, the mass volume ratio of the compound 1-13 to the solvent is 1:(1-10) g / ml, and for example 1:5 g / ml.

[0055] In the free reaction, the base is preferably an inorganic base, more preferably one or more of a carbonate inorganic base, a bicarbonate inorganic base and a hydroxide inorganic base, more preferably a bicarbonate inorganic base, such as sodium bicarbonate.

[0056] In the free reaction, the mass volume ratio of the compound 1-13 to the base is 1:(1-10) g / ml, for example 1:5 g / ml.

[0057] In one embodiment, the compound 1-13 is the crystalline form A of the compound 1-13 as described in any of the previous embodiments.

[0058] In one embodiment, the method for preparing compound 1-14 also includes the method for preparing compound 1-13 as described in any of the previous embodiments.

[0059] The present invention also provides a compound 1-13;

[0060]

[0061] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0062] In the present invention, the compounds 1-12 Compound 1-12-A and compound 1-12-B Mass ratio = 1:1 mixture.

[0063] In the present invention, the compound 1-11 is a racemate, that is, compound 1-11 Compound 1-11-A and compound 1-11-B Mass ratio = 1:1 mixture.

[0064] The term “substantially” means that the positions of the peaks in the graph may vary slightly with slight variations in measuring equipment, measuring conditions, and batches of products to be measured, and are not to be regarded as absolute values.

[0065] The reagents and raw materials used in the present invention are commercially available.

[0066] The positive and progressive effect of the present invention is that: through the preparation method of the present invention, 1-13 with a single stereo configuration is obtained, and then the single stereo configuration of compound 1 is obtained. The present invention improves the chemical purity and optical purity of compound 1, greatly reduces the production cost, and greatly increases the production scale, so that it is more suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0067] Figure 1 This is a single crystal structure diagram of Form A of Compound 1-13 in Example 2.

[0068] Figure 2 This is the XRPD pattern of Form A of Compound 1-13 in Example 2.

[0069] Figure 3 This is the DSC graph of Form A of Compound 1-13 in Example 2.

[0070] Figure 4 This is the TGA chart of Form A of Compound 1-13 in Example 2. DETAILED DESCRIPTION

[0071] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0072] The test methods involved in the following embodiments are as follows:

[0073] X-ray powder diffractometer (XRPD) method

[0074] Instrument model: PANalytical, Empyrean powder X-ray diffractometer

[0075] Test method: About 10-20 mg of sample was used for XRPD detection.

[0076] The detailed XRPD parameters are as follows:

[0077]

[0078] Differential Scanning Calorimeter (DSC) method

[0079] Instrument model: American TA differential scanning calorimeter Discovery DSC 250

[0080] Test method: Take a sample (2-6 mg) and place it in an aluminum crucible for testing. Heat the sample from 25°C to 300°C at a heating rate of 10°C / min.

[0081] The detailed DSC parameters are as follows:

[0082] Sample pot Aluminum crucible with holes Temperature range 25–300℃ Heating rate 10℃ / min Purge gas <![CDATA[N2]]> Flow rate 50mL / min

[0083] Thermogravimetric analysis (TGA) method

[0084] Instrument model: TATGA55 thermogravimetric analyzer

[0085] Test method: Take a sample (2-10 mg) and place it in an aluminum crucible, and then place it in a platinum hanging basket for testing. Under nitrogen (N2) conditions, at a gas flow rate of 40 mL / min and a heating rate of 10°C / min, heat the sample from room temperature to 300°C.

[0086] The detailed TGA parameters are as follows:

[0087]

[0088]

[0089] 1 H-NMR method

[0090] Instrument model: Bruker 400MHz instrument

[0091] Detailed 1 The H-NMR parameters are as follows:

[0092] frequency 400MHz Scan times 4 temperature 295K Relaxation time 1s

[0093] Example 1-1 Synthesis of Compound 1-12

[0094]

[0095] To a solution of 1-11 (5.3 kg, M=445.57, 11.89 mol) in DCM (15.9 L) was added TsOH·H2O (4.52 kg, 23.78 mol) at 15-20°C. After addition, the mixture was stirred at 15-20°C for 8 hours. After the reaction was complete, MTBE (53 L) was added to the mixture, and then saturated sodium bicarbonate was added at 15-20°C. After stirring and standing, the mixture was separated into two layers, and the upper organic phase was collected. The organic phase was washed 3 times with saturated sodium bicarbonate and then dried over anhydrous sodium sulfate. The organic phase was filtered and the filter cake was rinsed with MTBE. The filtrate was concentrated to obtain a concentrated solution containing 1-12.

[0096] 1 H NMR (300 MHz, chloroform-d) δ 5.69 (s, 1H), 5.53 (s, 1H), 5.32–5.13 (dd, 2H, J1=45 Hz, J2=12 Hz), 4.99–4.75 (m, 1H), 3.28–2.81 (m, 4H), 2.20–1.92 (m, 2H), 1.48 (s, 9H), 1.30 (d, J=6.3 Hz, 6H).

[0097] Example 1-2 Synthesis of Compound 1-13

[0098]

[0099] MTBE (3V) was added to the concentrated solution obtained in Example 1-1. The resulting mixture was further concentrated, and then L-mandelic acid (0.75eq) was added at 25±5°C, and the mixture was stirred for 12 hours. The mixture was filtered, and the filter cake was rinsed with MTBE (1V) and slurried with i-PrOH (3V) for 4 hours. After filtering and drying the mixture, an off-white solid 1-13 (1053g, M=497.60, 2.12mol) was obtained. The yield was 17.8%. The chemical purity was 99.5%, and the optical purity was 97.3%. Its single crystal structure is shown in the figure below. Figure 1 shown.

[0100] LC-MS[M±1] ± =346.1

[0101] 1 H NMR (400MHz, CD3Cl-d3): δ7.32(d,J=7.1Hz,2H),7.24(t,J=7.3Hz,2H),7.20–7.16(m,1 H),5.66(s,1H),5.39(s,1H),5.22(d,J=12.1Hz,1H),5.07(d,J=12.1Hz,1H),4.86-4.8 0(m,1H),4.78(s,1H),3.55(d,J=13.9Hz,1H),3.06(d,J=13.9Hz,1H),2.97-2.91(m,2H ),1.95-1.87(m,1H),1.74(d,J=15.0Hz,1H),1.43(s,9H),1.24(dd,J=6.3,2.6Hz,6H).

[0102] The X-ray powder diffraction pattern of compound 1-13 was determined to be form A. The X-ray powder diffraction pattern thereof, expressed in 2θ angles, and its diffraction peaks and relative intensities are shown in Table 1.

[0103] Table 1

[0104]

[0105]

[0106] The XRPD of Form A of Compound 1-13 is as follows: Figure 2 shown.

[0107] Figure 3 In the DSC spectrum, the crystalline form A of compound 1-13 has a main endothermic signal at 143.85°C±3°C.

[0108] Figure 4 In the figure, the TGA spectrum shows that the crystalline form A of compound 1-13 has no obvious weight loss before being heated to 150°C.

[0109] Example 2-1 Synthesis of Compound 1-12

[0110]

[0111] TsOH·H2O (2 eq) was added to a solution of 1-11 in DCM (3 V) at 15-20°C. After addition, the mixture was stirred at 15-20°C for 8 hours. After the reaction was completed, MTBE (10 V) was added to the mixture, and then saturated sodium bicarbonate (5 V) was added at 15-20°C. After stirring and standing, the mixture was separated into two layers, and the upper organic phase was collected. The organic phase was washed 3 times with saturated sodium bicarbonate (3 V), and then washed with saturated sodium chloride solution (5 V). The organic phase was concentrated to obtain an oily substance 1-12, which was purified by silica gel column chromatography to obtain 1-12 in a yield of 73%.

[0112] Example 2-2 Synthesis of Compound 1-13

[0113]

[0114] MTBE (5V) was added to 1-12 obtained in Example 2-1. The resulting mixture was further concentrated, and then L-mandelic acid (0.75eq) was added at 25±5°C, and the mixture was stirred for 12 hours. The mixture was filtered, and the filter cake was rinsed with MTBE (1V) and slurried with i-PrOH (4V) for 4 hours. After the mixture was filtered and dried, an off-white solid 1-13 was obtained. The single-step yield was 19%, the chemical purity was 99.5%, and the optical purity was 97.5%.

[0115] With reference to the characterization data of Example 1-2, it was confirmed that Form A of Compound 1-13 was obtained.

[0116] Example 3 Synthesis of Compound 1-14

[0117]

[0118] To a solution of 1-13 (900 g) in MTBE (4.5 L) was added saturated sodium bicarbonate (4.5 L) at 20 ± 5 ° C. After stirring and standing, the mixture was separated into two layers, and the upper organic phase was collected. The organic phase was washed with saturated sodium bicarbonate and then with saturated sodium chloride. The organic phase was concentrated, and MeCN was added to concentrate the mixture. The solvent replacement was repeated again. The solution weight was 1577.8 g, of which the content of 1-14 was 39.89%, and the yield was 91.1%.

[0119] Example 4 Synthesis of Compound 1

[0120]

[0121] At 20 ± 5 ° C, 1-14 (563.5g) was dissolved in MeCN (4.5L) solution. 1-15 (599.2g) and sodium bicarbonate (411g) were added. After addition, the mixture was stirred at 40 ± 5 ° C for 16 hours. The mixture was cooled to 20 ± 5 ° C, filtered, and then the filter cake was rinsed with MeCN. DCM (9V) was added to the filter cake. The mixture was cooled to 0-5 ° C, and TFA (20eq) was added to the mixture at 0-5 ° C. After addition, the mixture was stirred at 0-5 ° C for 16 hours. At 0 ± 5 ° C, the reaction mixture was added to an aqueous sodium bicarbonate solution (2.64kg in 5.6L water). The mixture was filtered, the filter cake was rinsed with DCM (1.2L), and then MTBE (8.4L) was added to the filtrate. After stirring and standing, the mixture was divided into two layers, and the upper organic phase was collected. The organic phase was washed with water. The aqueous phase was combined and extracted with DCM (2.8L). The two organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated, then purified with silica gel, and the eluent was concentrated to obtain a crude product containing compound 1. MeCN was added to the crude product and concentrated again. The solvent replacement was repeated again. Water (0.56 L) was added to the mixture and the mixture was freeze-dried. Amorphous solid compound 1 (300 g) was obtained with a yield of 39.0%, chemical purity 95%, and optical purity 97.5%. LC-MS [M ± 1] ± =472.1.

[0122] Comparative Example 1 Results of separation of 1-12 using different chiral separation reagents

[0123] MTBE was added to the concentrated solution obtained in Example 1-1. The resulting mixture was further concentrated, and then 0.75 eq of chiral resolution agent was added at 25 ± 5 ° C. The mixture was stirred for 12 hours. The mixture was filtered, and the filter cake was rinsed with MTBE (1V) and slurried with solvent (4V) for 4 hours. After the mixture was filtered and dried, it was found that no crystallization or off-white solid was obtained. The optical purity of the desired configuration in the product was measured by HPLC and is listed in Tables 2 and 3 below:

[0124] Table 2 Optical purity of target products when using different resolution agents

[0125]

[0126] Table 3 Optical purity of target product when using different slurry solvents

[0127]

[0128] Note: “-” in the table means no crystallization.

Claims

1. A crystalline form A of compound 1-13, characterized in that: Its X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles has diffraction peaks at 6.42°±0.20°, 11.80°±0.20°, 17.46°±0.20°, 18.18°±0.20°, 18.58°±0.20° and 19.34°±0.20°; 2. The crystalline form A of compound 1-13 according to claim 1, characterized in that: It meets one or more of the following conditions: (1) Form A of the compound 1-13, which has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles at 6.42°±0.20°, 11.80°±0.20°, 17.46°±0.20°, 17.60°±0.20°, 18.18°±0.20°, 18.58°±0.20°, 19.34°±0.20° and 23.02°±0.20°; Further, the crystalline form A of the compound 1-13 has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles at 6.42°±0.20°, 11.80°±0.20°, 12.86°±0.20°, 14.44°±0.20°, 17.46°±0.20°, 17.6°±0.20°, 18.18°±0.20°, 18.58°±0.20°, 19.34°±0.20°, 23.02°±0.20°, 24.22°±0.20° and 24.70°±0.20°; Furthermore, the characteristic peaks and relative intensities of the X-ray powder diffraction pattern of the crystalline form A of the compound 1-13 using Cu-Kα radiation and expressed in 2θ angles are shown in Table 1; Table 1 (2) The thermogravimetric analysis of Form A of Compound 1-13 shows no obvious weight loss before heating to 150° C.; and (3) The differential scanning calorimetry of the crystalline form A of the compound 1-13 showed a major endothermic peak at 143.85°C±3°C.

3. The crystalline form A of compound 1-13 according to claim 2, characterized in that: It meets one or more of the following conditions: (1) Form A of the compound 1-13, whose X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles is substantially as shown in FIG2 ; (2) The DSC graph of Form A of the compound 1-13 is substantially as shown in FIG3 ; and (3) The TGA chart of Form A of the compound 1-13 is basically as shown in FIG4 .

4. A method for preparing compound 1-13, characterized in that: The method comprises the following steps: slurrying the crude product of compound 1-13 in isopropanol to separate the compound 1-13; Wherein, the crude product of compound 1-13 is With compound 1-12-B mixture.

5. The preparation method according to claim 4, characterized in that: It meets one or more of the following conditions: (1) In the crude product of the compound 1-13, the molar ratio of the compound 1-13 to the compound 1-12-B is 1:0.9-1.1, for example 1:1; (2) In the crude product of the compound 1-13, the chemical purity of the compound 1-13 is 60%-99.9%, for example 99.5%; (3) The mass volume ratio of the crude product of compound 1-13 to isopropanol is 1:(1-10) g / ml, for example 1:3 g / ml; (4) The beating temperature is 0-50°C, preferably 20-30°C, more preferably 25°C; (5) The beating time is 0.5-8 hours, preferably 1-4 hours, more preferably 4 hours; (6) The crude product of compound 1-13 is With compounds 1-12 mixture of; and (7) The compound 1-13 is the crystalline form A of the compound 1-13 according to any one of claims 1-3.

6. The preparation method according to claim 4, characterized in that: The crude product of the compound 1-13 is prepared by the following method: Compound 1-12 and L-mandelic acid are subjected to a salt-forming reaction as shown below in an ether solvent to obtain a crude product of the compound 1-13; 7. The preparation method according to claim 6, characterized in that: It meets one or more of the following conditions: (1) In the salt-forming reaction, the molar ratio of the compound 1-12 to the L-mandelic acid is 1:(0.5-2), for example 0.75:1; (2) In the salt-forming reaction, the ether solvent is methyl tert-butyl ether; (3) In the salt-forming reaction, the mass volume ratio of the compound 1-12 to the solvent is 1:(1-10) g / ml, for example 1:3 g / ml; and (4) In the salt-forming reaction, the reaction temperature is 0-50°C, preferably 20-30°C, and more preferably 25°C.

8. The preparation method according to claim 6, characterized in that: The salt-forming reaction further comprises the following steps: in a solvent, in the presence of an acid, compound 1-11 undergoes a deprotection reaction to obtain compound 1-12, 9. The preparation method according to claim 8, characterized in that: It meets one or more of the following conditions: (1) In the deprotection reaction, the acid is selected from one or more of acetic acid, trifluoroacetic acid and p-toluenesulfonic acid, preferably p-toluenesulfonic acid; more preferably p-toluenesulfonic acid monohydrate; (2) In the deprotection reaction, the solvent is a halogenated alkane solvent and / or an ester solvent, preferably dichloromethane; (3) In the deprotection reaction, the mass volume ratio of the compound 1-11 to the solvent is 1:(1-10) g / ml, for example 1:3 g / ml; (4) In the deprotection reaction, the mass ratio of the compound 1-11 to the acid is 1:(0.5-1.5), preferably 1:0.79; (5) In the deprotection reaction, the molar ratio of the compound 1-11 to the acid is preferably 1:(1-5), preferably 1:2; and (6) The deprotection reaction further includes post-treatment, and the post-treatment operation includes the following steps: extraction, neutralization, washing, concentration, and purification after the reaction is completed.

10. A method for preparing compound 1-14, characterized in that: The method comprises the following steps: in a solvent, reacting compound 1-13 with a base to obtain compound 1-14; 11. The preparation method according to claim 10, characterized in that: It meets one or more of the following conditions: (1) In the free reaction, the solvent is an ether solvent, preferably methyl tert-butyl ether; (2) In the freeing reaction, the mass volume ratio of the compound 1-13 to the solvent is 1:(1-10) g / ml, for example 1:5 g / ml; (3) In the free reaction, the base is an inorganic base, preferably one or more of a carbonate inorganic base, a bicarbonate inorganic base and a hydroxide inorganic base, more preferably a bicarbonate inorganic base, such as sodium bicarbonate; and (4) In the freeing reaction, the mass volume ratio of the compound 1-13 to the base is 1:(1-10) g / ml, for example 1:5 g / ml; (5) the compound 1-13 is the crystalline form A of the compound 1-13 according to any one of claims 1-3; and (6) The method for preparing compound 1-14 also includes the method for preparing compound 1-13 as described in any one of claims 4-9.

12. L-mandelic acid as a resolving agent in the resolving of compound 1-12-A and compound 1-12-B Application in.

13. A compound 1-13;

Images