Resolution method of nitrogen heterocyclic derivative

Abstract

The invention discloses a resolution method of a nitrogen heterocyclic derivative. Specifically, the invention provides a resolution method of an isomer mixture of a compound shown as a formula I. The resolution method comprises the step of carrying out chiral resolution on the isomer mixture of the compound shown as the formula I by taking tartaric acid or a tartaric acid derivative as a resolving agent. The resolution method is low in cost, simple to operate and suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of medicinal chemistry, and particularly relates to a method for splitting nitrogen heterocyclic derivatives. Background Art

[0002] Chirality means that two molecules are mirror-symmetrical to each other. Chiral molecules with different configurations may have completely different physical and chemical properties. Therefore, it is necessary to separate racemic compounds with high purity. Currently, common separation methods include chemical separation, crystallization separation, enzyme separation, chromatography separation, etc.

[0003] The chemical resolution method is to react the racemate with a chiral resolution agent to generate diastereomeric salts, and separate them by using the different physical and chemical properties of the diastereomeric salts to obtain a single enantiomer. Depending on the properties of the compound to be resolved, the selection of resolution agents and resolution solvents is also different. Among them, the selection of the type of resolution agent and the different resolution solvents and the ratio of different solvents to the resolution compound have a great influence on whether the resolution can be successful, whether crystals can be precipitated, the resolution efficiency and the purity of the enantiomers. In the process of resolution, factors such as temperature, reaction time, pH also have a certain influence on the resolution results.

[0004] CN201480071438.7 discloses the use of CHIRALPAK AD column and heptane / EtOAc / MeOH 90 / 5 / 5+0.1 diethylamine to achieve the separation of the enantiomers of (±)-3-(3-hydroxyphenyl)piperazine-1-carboxylic acid tert-butyl ester by chiral HPLC. CN201780035906.9 discloses the use of OZ-H 100*4.6mm 5um column and MeOH (0.2% methanol ammonia) solvent to obtain two single enantiomers of 3-(4-bromophenyl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester by chiral-HPLC separation. The above methods are all separated by chiral HPLC columns, with low yields, and chiral chromatographic columns are expensive and costly; and the injection volume is small, which is limited to small-scale preparation and is not suitable for industrial production.

[0005] Therefore, it is necessary to develop new separation methods to obtain high-purity enantiomers. Summary of the invention

[0006] In one aspect, the present invention provides a method for resolving an isomeric mixture of a compound of formula I.

[0007]

[0008] Wherein, R1 is H, halogen, OH, C1-C6 alkyl, C1-C6 alkoxy, cyano, -C(=O)-R3 or -CH2C(=O)-R3,

[0009] X is CH or N,

[0010] R2 is a protecting group or a C1-C6 alkoxy group,

[0011] R3 is H, OH, cyano, C1-C6 alkyl or C1-C6 alkoxy,

[0012] The splitting method comprises the following steps:

[0013] The isomeric mixture of the compound of formula I is chirally resolved using tartaric acid or a tartaric acid derivative as a resolving agent.

[0014] In some embodiments, X is N.

[0015] In some embodiments, said R2 is a protecting group.

[0016] In some embodiments, the protecting group is selected from benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (BOC), benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethylcarbonyl (Fmoc), or trityl (Trt).

[0017] In some embodiments, the tartaric acid derivative refers to dibenzoyltartaric acid, p-methyldibenzoyltartaric acid or di-O,O'-p-toluoyltartaric acid. Preferably, the tartaric acid is one of the D-type or L-type.

[0018] In some embodiments, the resolving agent is selected from one of D-tartaric acid, L-tartaric acid, di-O,O'-p-toluoyl-D-tartaric acid, di-O,O'-p-toluoyl-L-tartaric acid, dibenzoyl-D-tartaric acid, dibenzoyl-L-tartaric acid, p-methoxydibenzoyl-D-tartaric acid or p-methoxydibenzoyl-L-tartaric acid.

[0019] In some embodiments, the isomeric mixture of the compound of formula I is a mixture including any diastereomers of the compound of formula I, preferably a racemate.

[0020] In some embodiments, the method for resolving the isomeric mixture of the compound of formula I prepares a single-configuration compound of formula I or its tartrate salt.

[0021] In some embodiments, the compound of formula I is a compound of formula II (tert-butyl 3-(4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate).

[0022]

[0023] In some embodiments, the compound of formula I is a compound of formula III.

[0024]

[0025] In some embodiments, the isomeric mixture of the compound of Formula II includes a mixture of a compound of Formula II-1 and a compound of Formula II-2.

[0026]

[0027] In some embodiments, the isomeric mixture of the compound of formula II includes a mixture of the compound II-1 ((R)-3-(4-(methoxycarbonyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester) and the compound of formula II-2 ((S)-3-(4-(methoxycarbonyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester) in a molar ratio of 2:5 to 5:2, preferably 1:1.

[0028] In some embodiments, the chiral resolution of the isomeric mixture of the compound of formula I specifically comprises the following steps:

[0029] (1) a mixture of isomers of the compound of formula I is subjected to a salt-forming reaction with tartaric acid or a tartaric acid derivative in a solvent;

[0030] (2) crystallizing to obtain a tartrate salt of the compound of formula I with a single configuration;

[0031] Optionally, (3) adding an alkaline agent to free the tartrate obtained in step (2), thereby obtaining a compound of formula I with a single configuration.

[0032] In some embodiments, the molar ratio of the isomeric mixture of the compound of formula I to tartaric acid or a tartaric acid derivative in step (1) is 1 to 4:1, preferably 1.5 to 3.5:1, more preferably 2 to 2.5:1, and further preferably 2:1.

[0033] In some embodiments, the solvent in step (1) is one or more of water, methanol, ethanol, acetonitrile, acetone, dichloromethane, chloroform, ethyl acetate, tetrahydrofuran, dioxane, DMF, and DMSO; preferably methanol, ethanol, or acetonitrile; more preferably methanol.

[0034] In some embodiments, the mass volume ratio of the isomer mixture of the compound of formula I to the solvent in step (1) is 1:8-50, preferably 1:10-40, more preferably 1:15-30; further preferably 1:20-30.

[0035] In some embodiments, the temperature of the salt-forming reaction in step (1) is 20°C to 50°C, preferably 30°C.

[0036] ~40°C, more preferably 45°C.

[0037] In some embodiments, the crystallization temperature in step (2) is 15°C to 30°C, preferably 20°C to 30°C.

[0038] In some embodiments, the alkaline agent is selected from one or more of NaOH, KOH, Na2CO3, NaHCO3, K2CO3, triethylamine, diethylamine, pyridine, DIPEA, sodium ethoxide, or sodium methoxide.

[0039] Specifically, the step (3) is to add an alkaline reagent to the tartrate of the single-configuration compound of formula I, add an organic solvent for extraction, wash, dry, filter, and concentrate to obtain the product.

[0040] In some embodiments, the organic solvent used for extraction in step (3) is selected from one or more of ethyl acetate, tetrahydrofuran, n-butanol, methyl tert-butyl ether or dimethylformamide.

[0041] In another aspect, the present invention provides a method for preparing a compound of formula II-1:

[0042] (a) reacting an isomer mixture of a compound of formula II with L-tartaric acid or an L-tartaric acid derivative in a solvent to form a salt;

[0043] (b) crystallizing and filtering to obtain solid tartrate of compound II-1;

[0044] Optionally, (c) adding an alkaline agent to the tartrate of the II-1 compound obtained in step (b), adding an organic solvent for extraction, washing, drying, filtering and concentrating to obtain the II-1 compound.

[0045] In some embodiments, the L-tartaric acid derivative is one of di-O,O'-p-toluoyl-L-tartaric acid, dibenzoyl-L-tartaric acid, or p-methoxydibenzoyl-L-tartaric acid.

[0046] In some embodiments, in step (a), the molar ratio of the isomeric mixture of the compound of formula II to tartaric acid or a tartaric acid derivative is 1 to 4:1, preferably 1.5 to 3.5:1, more preferably 2 to 2.5:1, and further preferably 2:1.

[0047] In some embodiments, the solvent in step (a) is one or more of water, methanol, ethanol, acetonitrile, acetone, dichloromethane, chloroform, ethyl acetate, tetrahydrofuran, dioxane, DMF, DMSO; preferably methanol, ethanol or acetonitrile; more preferably methanol.

[0048] In some embodiments, the mass volume ratio of the isomer mixture of the compound of formula II to the solvent in step (a) is 1:8-50, preferably 1:10-40, more preferably 1:15-30; further preferably 1:20-30.

[0049] In some embodiments, the temperature of the salt-forming reaction in step (a) is 20°C to 50°C, preferably 30°C to 40°C, and more preferably 45°C;

[0050] In some embodiments, the crystallization temperature in step (b) is 15°C to 30°C, preferably 20°C to 30°C;

[0051] In some embodiments, the alkaline reagent is selected from one or more of NaOH, KOH, Na2CO3, NaHCO3, K2CO3, triethylamine, diethylamine, pyridine, DIPEA, sodium ethoxide or sodium methoxide; the organic solvent is selected from one or more of ethyl acetate, tetrahydrofuran, n-butanol, methyl tert-butyl ether or dimethylformamide.

[0052] In some embodiments, the salt-forming reaction in step (a) obtains a solution of (R, S)-diastereoisomer tartrate.

[0053] In some embodiments, the chemical purity of the II-1 compound or its tartrate salt is ≥90%; preferably ≥93%; more preferably ≥95%.

[0054] In some embodiments, the optical purity of the II-1 compound or its tartrate salt is ≥85%; preferably ≥90%; more preferably ≥93%.

[0055] Optionally, the filtrate obtained in step (b) is dried and then subjected to step (c) to obtain an isomeric mixture of the compound of formula II, and steps (a), (b) and (c) are repeated to obtain the compound of formula II-1.

[0056] The present invention is to react the isomeric mixture of the compound of formula I with a resolving agent under a specific solvent and a resolving agent, so that one enantiomer is crystallized in the form of a salt, and the other enantiomer is retained in the solution in the form of a salt. The free base of each enantiomer is obtained by extraction with an alkaline aqueous solution or a solvent.

[0057] The compound of formula I of the present invention is a key intermediate for preparing active drugs. The enantiomers of the compound of formula I can be prepared by splitting, and then the active drugs can be prepared, thereby improving the utilization rate of raw materials and reducing costs, and is suitable for industrial production.

[0058] The invention increases the resolution efficiency by introducing a protecting group into the piperazine 4-position of the compound of formula I.

[0059] The single-configuration salt of the compound of formula I obtained by separation after salt formation in the present invention, after adding an alkaline reagent to remove the resolving agent to obtain the single-configuration compound of formula I, has substantially unchanged chemical purity.

[0060] Technical Effects

[0061] The invention provides a method for separating an isomer mixture with high optical purity which has low cost, simple operation and is suitable for industrial production.

[0062] 1) The single-configuration compound of formula I obtained by the resolution method of the present invention has a relatively high yield, high chemical purity and high optical purity, and achieves a very good resolution effect.

[0063] 2) Compared with chiral HPLC column separation, the separation method of the present invention is simple and feasible.

[0064] 3) The separation method of the present invention has little impact on the yield and purity after being scaled up, and the process is controllable, highly operable, suitable for large-scale industrial production, and low cost.

[0065] 4) The splitting method of the present invention uses a small amount of splitting agent, which saves costs and has a high splitting yield.

[0066] definition

[0067] The term "diastereomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror images of one another. The stereochemistry at each chiral carbon can be specified as R or S.

[0068] The term "racemic" refers to a composition obtained by mixing a pair of enantiomers in equal amounts.

[0069] The term "isomer mixture" refers to a mixture formed by mixing two or more isomers. Each isomer in the isomer mixture can exist in any proportion. In some embodiments, the isomer mixture is a mixture in which the molar ratio of R-isomer to S-isomer is 1:1, i.e., a racemic mixture.

[0070] The term "single configuration" refers to a compound represented by a specified structural formula (such as R configuration or S configuration) and having a specific configuration. Generally, the optical purity of a compound of a single configuration is ≥85%; preferably ≥90%; more preferably ≥93%.

[0071] The term "room temperature" refers to a temperature of 15°C to 30°C.

[0072] The term "protecting group" refers to those groups that protect a given atom or functional group from undesired reactions during synthetic procedures and have stereospecific effects due to their large steric hindrance, including but not limited to benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (BOC), benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethylcarbonyl (Fmoc) or trityl (Trt).

[0073] ee refers to optical purity, which is the difference in the amount of each enantiomer present in a mixture. Those skilled in the art can measure or calculate the ee value according to conventional technical means in the art (such as HPLC method). For example, if a racemate contains two optical isomers A and B, then the ee value = A%-B%.

[0074] The term "mass to volume ratio" refers to the ratio of the mass of a solid in grams to the volume of a solution in milliliters. DETAILED DESCRIPTION

[0075] The present invention is described in more detail below by way of examples, but these specific descriptions are only used to illustrate the technical solution of the present invention and do not constitute any limitation to the present invention.

[0076] The reagents and raw materials used in the present invention are all commercially available. Experimental methods without specific conditions are usually carried out under conventional conditions.

[0077] Example 1 Preparation of tert-butyl 3-(4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate

[0078]

[0079] a) Preparation of methyl 4-(pyrazin-2-yl)benzoate

[0080] Add (4-(Methoxycarbonyl)phenyl)boric acid (2 g), 1,4-dioxane (100 mL), and water (20 mL) into a (250 mL) two-necked bottle, then add sodium carbonate (3.53 g) and tetrakis(triphenylphosphine palladium) (1.28 g), replace with nitrogen for protection, add 2-chloropyrazine (1.91 g), stir at 100°C for 4.5 hours, cool the reaction solution to room temperature, filter, and concentrate the filtrate under reduced pressure to make sand. Purify by column chromatography (mobile phase: dichloromethane / methanol = 10 / 1 (V / V)) to obtain 2.04 g of the title compound.

[0081] b) Preparation of (±) 4-(piperazin-2-yl)benzoic acid methyl ester

[0082] Dissolve methyl 4-(pyrazin-2-yl)benzoate (1 g) in a mixed solvent of acetic acid / methanol (28 mL / 14 mL), add palladium acetate (105 mg) and palladium / carbon (350 mg), replace with hydrogen, stir overnight at room temperature, filter with celite, and evaporate the filtrate to dryness to obtain 0.9 g of the title compound.

[0083] c) Preparation of (±) tert-butyl 3-(4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate

[0084] (±) 4-(piperazine-2-yl) benzoic acid methyl ester (480 mg) was added to a 50 mL two-necked bottle, and dichloromethane (30 mL) and triethylamine (661.54 mg) were added. After nitrogen replacement protection, di-tert-butyl dicarbonate (475.59 mg) was added, and the mixture was stirred at room temperature for 1 hour. After quenching with water, the mixture was extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to make sand, and purified by column chromatography (mobile phase: dichloromethane / methanol=20 / 1 (V / V)) to obtain 300 mg of (±) 3-(4-(methoxycarbonyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester. LC-MS: m / z=312.1[M+H] + .

[0085] Example 2 Resolution of Formula II Compound 3-(4-(methoxycarbonyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester

[0086] Example 2-1

[0087]

[0088] (1) Methanol (1.5 mL) was added to the racemic compound II (R, S)-3-(4-(methoxycarbonyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester) (50 mg) prepared in Example 1, and the mixture was heated to 45° C. to dissolve. A resolving agent D-tartaric acid (12 mg, 0.5 eq) was added to carry out a resolving reaction, and the mixture was stirred at 45° C. until the mixture was completely dissolved.

[0089] (2) After standing at room temperature for 3 hours, the product was crystallized and filtered to collect the solid (20 mg, yield 64.6%). The chemical purity was determined by chiral HPLC: (R)-3-(4-(methoxycarbonyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester tartrate 3.62%, (S)-3-(4-(methoxycarbonyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester tartrate 96.38%.

[0090] The resolving agent 0.5 eq means that the molar ratio of the resolving agent to the compound of formula II is 0.5.

[0091] Example 2-2

[0092] (1) Add the solvent methanol (1.5 mL) to the racemic compound (R, S)-3-(4-(methoxycarbonyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester) (50 mg), heat to 45°C to dissolve, add the resolution agent L-tartaric acid (12 mg, 0.5 eq) to perform resolution reaction, and stir at 45°C until the solution is completely dissolved;

[0093] (2) After standing at room temperature for 3 hours, the product was crystallized and filtered to collect the solid (22 mg, yield 71.0%). The chemical purity was determined by chiral HPLC: (R)-3-(4-(methoxycarbonyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester tartrate 96.90%, (S)-3-(4-(methoxycarbonyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester tartrate 3.10%.

[0094] Example 3 Effects of different factors on splitting results

[0095] Example 3 was set up with reference to Example 2, and the effects of the solvent, solvent dosage, resolving agent and resolving agent dosage in step 1 on the product yield and product chemical purity were investigated respectively. The results are shown in Table 1.

[0096] (1) Effects of different resolution agents on resolution results

[0097] Table 1 Effects of different resolving agents on the resolution results

[0098]

[0099] The results showed that different types of splitting agents achieved different splitting effects.

[0100] (2) Effects of different solvents and solvent amounts on the separation results

[0101] Table 2 Effects of different solvents and solvent amounts on the separation results

[0102]

[0103] The yield is the yield of the solid obtained by standing at room temperature after the salt-forming reaction, crystallizing and filtering.

[0104] The results showed that different types of solvent systems achieved different separation effects. The amount of different solvents had a greater impact on the separation effect. When the amount of solvent was increased, the yield of the precipitated salt decreased; while reducing the amount of solvent affected the purity of the product.

[0105] (3) Effect of different split doses on split results

[0106] Table 3 Effect of different split doses on split results

[0107]

[0108] Example 4 Scaled-up preparation of (R)-tert-butyl 3-(4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate

[0109]

[0110] (1) Compound II (25.66 g) was added with 513 mL of methanol (MeOH), heated to 45°C to dissolve, and L-tartaric acid (6.01 g, 0.5 eq) was added, and stirred at 45°C until completely dissolved.

[0111] (2) The mixture was allowed to stand at room temperature, and then a small amount of seed crystals of the compound of formula II-1 were added and allowed to stand overnight. A large amount of white crystals were precipitated, and 12 g of white solid (R)-3-(4-(methoxycarbonyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester tartrate was obtained by filtration (chemical purity 97.94%; ee 95.87%).

[0112] (3) The filtrate was dried by spin-drying, and then saturated sodium bicarbonate solution was added to dissociate it. The mixture was extracted with ethyl acetate three times. The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried by spin-drying to obtain 17 g of the compound of formula II (chemical purity 32%).

[0113] Add MeOH (340 mL) to the above 17 g of light yellow solid, heat to 45°C to dissolve, add L-tartaric acid (2.55 g). After dissolving, move to room temperature and let stand, then add a small amount of compound 1-1 seed crystals and let stand overnight. Filter to obtain 4.1 g of white solid (R)-3-(4-(methoxycarbonyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester tartrate (chemical purity 96.63%; ee 93.26%).

[0114] A total of 16.1 g of (R)-tert-butyl 3-(4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate tartrate was prepared.

[0115] Example 5 Preparation of (R)-tert-butyl 3-(4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate

[0116] 16.1 g of (R)-3-(4-(methoxycarbonyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester tartrate prepared in Example 4 was freed by adding saturated sodium bicarbonate solution, extracted three times with ethyl acetate, and the organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain 9.2 g of free base (R)-3-(4-(methoxycarbonyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester (chemical purity 97.5%; ee 95%).

[0117] Examples 1 to 5 described in the present invention all use a chiral HPLC method to detect the chemical purity of the enantiomers, specifically, the mobile phase is n-heptane: ethyl acetate: methanol: ethylenediamine (90: 10: 10: 0.1), the chromatographic column is AD-H, the flow rate is 1.0 mL / min, and the wavelength is 254 nm.

[0118] Example 6 Resolution of the compound of formula III

[0119]

[0120] Different solvents were added to the racemic compound III (50 mg), heated to 45°C to dissolve, and a resolving agent (0.5 eq) was added to perform a resolving reaction, and stirred at 45°C until the solution was completely dissolved; the mixture was allowed to stand at room temperature to precipitate crystals. After the crystals precipitated, the solids were collected and the chemical purity was tested by chiral HPLC.

[0121] Table 4

[0122]

[0123] In the above Example 6, the enantiomeric chemical purity was detected by chiral HPLC method, specifically, the mobile phase was n-hexane / ethanol (90:10), the chromatographic column was AD-H column, the flow rate was 1.0 mL / min, and the wavelength was 254 nm.

[0124] Example 7

[0125]

[0126] Add the solvent methanol (1.5 mL) to the racemic compound IV (50 mg), heat to 45°C to dissolve, add the resolving agent (0.5 eq) to perform the resolving reaction, stir at 45°C until the solution is completely dissolved; stand at room temperature to precipitate crystals. Filter and collect the solids, and detect the chemical purity by chiral HPLC.

[0127] Table 5

[0128]

[0129] Example 7 Chiral HPLC method was used to detect the chemical purity of the enantiomers. Specifically, the mobile phase was n-hexane / ethanol / diethylamine (90:10:0.1), the chromatographic column was AD-H, the flow rate was 1.0 mL / min, and the wavelength was 254 nm.

Claims

1. A method for resolving an isomeric mixture of a compound of formula I, in, R1 is H, halogen, OH, C1-C6 alkyl, C1-C6 alkoxy, cyano, -C(=O)-R3 or -CH2C(=O)-R3, X is CH or N, R2 is a protecting group or a C1-C6 alkoxy group, R3 is H, OH, cyano, C1-C6 alkyl or C1-C6 alkoxy, The splitting method comprises the following steps: using tartaric acid or a tartaric acid derivative as a splitting agent to perform chiral splitting on the isomer mixture of the compound of formula I.

2. The method for resolving an isomeric mixture of a compound of formula (I) according to claim 1, characterized in that: The X is N, and R2 is a protecting group.

3. The method for resolving an isomeric mixture of a compound of formula (I) according to claim 1, characterized in that: The resolving agent is selected from one of D-tartaric acid, L-tartaric acid, di-O,O'-p-toluoyl-D-tartaric acid, di-O,O'-p-toluoyl-L-tartaric acid, dibenzoyl-D-tartaric acid, dibenzoyl-L-tartaric acid, p-methoxydibenzoyl-D-tartaric acid or p-methoxydibenzoyl-L-tartaric acid.

4. The method for resolving an isomeric mixture of a compound of formula (I) according to claim 1, characterized in that: The compound of formula I is a compound of formula II or a compound of formula III, 5. A method for resolving an isomeric mixture of a compound of formula (I) according to claim 1 or 4, characterized in that: The chiral separation of the isomeric mixture of the compound of formula I comprises the following steps: (1) a mixture of isomers of the compound of formula I is subjected to a salt-forming reaction with tartaric acid or a tartaric acid derivative in a solvent; (2) crystallizing to obtain a tartrate salt of the compound of formula I with a single configuration; Optionally, (3) adding an alkaline agent to free the tartrate obtained in step (2), thereby obtaining a compound of formula I with a single configuration.

6. The method for resolving an isomeric mixture of a compound of formula (I) according to claim 5, characterized in that: In the step (1), the molar ratio of the isomer mixture of the compound of formula I to tartaric acid or a tartaric acid derivative is 1 to 4:1, preferably 1.5 to 3.5:1, more preferably 2 to 2.5:1, and further preferably 2:1; and / or, in step (1), the solvent is one or more of water, methanol, ethanol, acetonitrile, acetone, dichloromethane, chloroform, ethyl acetate, tetrahydrofuran, dioxane, DMF or DMSO; preferably methanol, ethanol or acetonitrile; more preferably methanol; And / or, in step (1), the mass volume ratio of the isomer mixture of the compound of formula I to the solvent is 1:8-50, preferably 1:10-40, more preferably 1:15-30; further preferably 1:20-30; And / or, the temperature of the salt-forming reaction in step (1) is 20°C to 50°C, preferably 30°C to 40°C, more preferably 45°C; And / or, the crystallization temperature in step (2) is 15°C to 30°C, preferably 20°C to 30°C; And / or, the alkaline agent is selected from one or more of NaOH, KOH, Na2CO3, NaHCO3, K2CO3, triethylamine, diethylamine, pyridine, DIPEA, sodium ethoxide or sodium methoxide.

7. The method for resolving an isomeric mixture of a compound of formula (I) according to claim 5, characterized in that: In step (3), a tartrate salt of the compound of formula I with a single configuration is added with an alkaline reagent, extracted with an organic solvent, washed, dried, filtered, and concentrated to obtain; Preferably, the organic solvent is selected from one or more of ethyl acetate, tetrahydrofuran, n-butanol, methyl tert-butyl ether or dimethylformamide.

8. The method for resolving an isomeric mixture of a compound of formula (I) according to claim 4, characterized in that: The compound of formula I is a compound of formula II, and the isomeric mixture of the compound of formula II includes a mixture of a compound of formula II-1 and a compound of formula II-2; preferably, the molar ratio of the compound of formula II-1 to the compound of formula II-2 is 2:5 to 5:2, and more preferably 1:

1.

9. A method for resolving an isomeric mixture of a compound of formula (I) according to claim 4 or 8, characterized in that: The compound of formula I is a compound of formula II, and the separation method comprises the following steps: (a) reacting an isomer mixture of a compound of formula II with L-tartaric acid or an L-tartaric acid derivative in a solvent to form a salt; (b) crystallizing and filtering to obtain tartrate of compound II-1; Optionally, (c) adding an alkaline agent to the tartrate of the II-1 compound obtained in step (b), adding an organic solvent for extraction, washing, drying, filtering and concentrating to obtain the II-1 compound.

10. The method for resolving an isomeric mixture of a compound of formula (I) according to claim 9, characterized in that: The L-tartaric acid derivative is one of di-O,O'-p-toluoyl-L-tartaric acid, dibenzoyl-L-tartaric acid or p-methoxydibenzoyl-L-tartaric acid; and / or, in the step (a), the molar ratio of the isomer mixture of the compound of formula II to L-tartaric acid or an L-tartaric acid derivative is 1 to 4:1, preferably 1.5 to 3.5:1, more preferably 2 to 2.5:1, and further preferably 2:1; and / or, the solvent is one or more of water, methanol, ethanol, acetonitrile, acetone, dichloromethane, chloroform, ethyl acetate, tetrahydrofuran, dioxane, DMF, and DMSO; preferably methanol, ethanol or acetonitrile; more preferably methanol; And / or, the mass volume ratio of the isomer mixture of the compound of formula II to the solvent is 1:8-50, preferably 1:10-40, more preferably 1:15-30; further preferably 1:20-30; And / or, the temperature of the salt-forming reaction in step (a) is 20°C to 50°C, preferably 30°C to 40°C, more preferably 45°C; And / or, the crystallization temperature in step (b) is 15°C to 30°C, preferably 20°C to 30°C; And / or, the alkaline reagent is selected from one or more of NaOH, KOH, Na2CO3, NaHCO3, K2CO3, triethylamine, diethylamine, pyridine, DIPEA, sodium ethoxide or sodium methoxide; the organic solvent is selected from one or more of ethyl acetate, tetrahydrofuran, n-butanol, methyl tert-butyl ether or dimethylformamide.

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