A new crystal form of tetrahydrobenzyl isoquinoline compound and a preparation method and use thereof

Abstract

A new crystal form of a tetrahydrobenzyl isoquinoline compound, a preparation method and uses thereof, the new crystal form of the tetrahydrobenzyl isoquinoline compound is a crystal form of a compound of formula (I), characterized in that, using Cu-K alpha radiation, the X-ray powder diffraction of the crystal form A has characteristic peaks at diffraction angles 2 theta of 13.4+0.2, 14.1+0.2, 18.0+0.2, 21.0+0.2, 26.8+0.2 degrees. The crystal form of the application has high chemical purity and optical purity, good stability, is easy to store, is suitable for industrial production, in addition, can be used for preparing mivacurium, and is favorable for improving the purity of mivacurium.

Description

TECHNICAL FIELD

[0001] The present application relates to a new crystal form of tetrahydrobenzyl isoquinoline compound and its preparation method and use, belonging to the field of pharmaceutical chemistry. BACKGROUND

[0002] Mivacurium is a benzylisoquinoline short-acting non-depolarizing neuromuscular blocking drug, which is a new type of short-acting non-depolarizing muscle relaxant that meets the ideal muscle relaxant concept since 1975. Its structural formula is as follows:

[0003]

[0004] Mivacurium was developed by Abbott lab and first marketed in the United States in 1992, and is currently the shortest-acting muscle relaxant ever discovered, only 1 / 3-1 / 2 of cisatracurium and vecuronium. Mivacurium is often used for tracheal intubation and maintenance of muscle relaxation in surgery due to its unique advantages such as rapid onset and short duration of action. Its effect is similar to that of tubocurarine, and there is no significant accumulation under clinical dosage, and the effect of promoting histamine release is small, and there is no adverse effect on intracranial pressure and intraocular pressure, and it is easy to control muscle relaxation concentration and range, and the postoperative recovery is fast. Mivacurium can be used not only in general patients, but also in patients with neuromuscular diseases and elevated blood potassium; in particular, it has little effect on the cardiovascular system of children in pediatric surgery, and is considered a good substitute for succinylcholine. Due to its excellent pharmacological activity and wide market prospect, the synthesis method of mivacurium has also attracted more and more attention.

[0005] There are two chiral carbon centers and two quaternary ammonium salt nitrogen atom centers in the molecular structure of mivacurium, and each chiral center can have R or S configuration. Clinical studies have shown that when the chiral carbon atom of mivacurium is R configuration, there is no side effect under normal dosage; and when the carbon atom is S configuration, it is very likely to cause cardiovascular system damage and cause adverse reactions such as histamine release. Therefore, in the synthesis process of mivacurium, in order to ensure the safety of the drug, the two chiral carbon atoms must be R configuration. However, how to controllably prepare mivacurium with single R configuration of chiral carbon atom has also become a big difficulty in the synthesis process.

[0006] As a new type of multi-chiral center drug, the synthesis of mivacurium is very difficult. In the synthesis process of mivacurium, the synthesis of intermediate 6,7-dimethoxy-1-(R)-3,4,5-trimethoxybenzyl-1,2,3,4-tetrahydroisoquinoline (structure see formula I) is the key step to form the R configuration of the chiral carbon atom of the mivacurium parent structure, and is also an important control point for forming single R configuration. Therefore, formula I as a key intermediate for forming the chiral center of the mivacurium parent structure, its purity and stability will affect the quality of the finished drug mivacurium, and further affect the safety and effectiveness of the drug.

[0007]

[0008] The compound of formula I prepared by the prior method contains many impurities, is difficult to purify, and has no effective purification method; in addition, the prior art cannot obtain the compound of formula I in a crystalline form and in high purity, thereby causing many difficulties in the storage of the compound of formula I and the use of the compound of formula I for subsequent reactions to obtain high-purity migalbalcf. SUMMARY

[0009] In order to overcome the above problems existing in the prior art, the present application provides a new crystal form of the compound of formula (I), which has high chemical purity, good stability, is easy to handle and store, and is beneficial to industrialized production; in addition, the crystal form provided by the present application has high optical purity, and the preparation method of the crystal form can effectively control the content of optical isomer impurities to be less than 0.05%, thereby providing a strong technical guarantee for the subsequent preparation of high-purity migalbalcf.

[0010] The present application provides a crystal form of the compound of formula (I), characterized in that the X-ray powder diffraction of the crystal form A has characteristic peaks at diffraction angles 2 theta of 13.4±0.2, 14.1±0.2, 18.0±0.2, 21.0±0.2, and 26.8±0.2°

[0011]

[0012] Alternatively, the crystal form described above is characterized in that the X-ray powder diffraction of the crystal form further has characteristic peaks at diffraction angles 2 theta of 19.1±0.2 and 23.5±0.2°.

[0013] Alternatively, the crystal form described above is characterized in that the X-ray powder diffraction of the crystal form further has characteristic peaks at diffraction angles 2 theta of 24.2±0.2, 26.2±0.2, and 29.2±0.2°.

[0014] Alternatively, the crystal form described above is characterized in that the X-ray powder diffraction of the crystal form has characteristic peaks at the following diffraction angles 2 theta and relative intensities (I / I0):

[0015]

[0016] wherein the measurement error of the relative intensity is ±5%; optionally, the measurement error of the relative intensity is ±20%.

[0017] The present application also provides a method for preparing the crystal form as described above, characterized in that the method comprises the following steps: adding a chiral organic acid into a mixture containing the compound of formula (I) to form a salt and recrystallizing.

[0018] Optionally, the method comprises the following steps: adding a salt-forming solvent and a chiral organic acid into a mixture containing the compound of formula (I) to form a salt, crystallizing, filtering, adding water or not to the filter cake, adjusting the pH with a lye, extracting with an extraction solvent, removing the solvent from the organic phase to obtain the compound of formula (I), mixing the compound of formula (I) with a recrystallization solvent, heating, and cooling to crystallize.

[0019] Optionally, the method for preparing as described above is characterized in that:

[0020] The chiral organic acid is selected from at least one of D-tartaric acid, D-malic acid, D-aspartic acid, D-glutamic acid, D-mandelic acid, N-acetyl-D-glutamic acid, D-pyroglutamic acid, D-quinic acid, D-camphorsulfonic acid, D-camphoric acid, diacetyl-D-tartaric acid; optionally, the chiral organic acid is selected from at least one of D-tartaric acid, D-malic acid, D-mandelic acid, D-camphoric acid, diacetyl-D-tartaric acid.

[0021] The salt-forming solvent is selected from at least one of alcohols, esters, acetonitrile, tetrahydrofuran; optionally, the salt-forming solvent is selected from at least one of methanol, ethanol, isopropanol.

[0022] The extraction solvent is selected from at least one of alcohols, ethers, ketones, esters, alkanes, halogenated alkanes, aromatic hydrocarbons, tetrahydrofuran, carbon disulfide; optionally, the extraction solvent is selected from at least one of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, diethyl ether, methyl ethyl ether, acetone, butanone, ethyl acetate, petroleum ether, hexane, cyclohexane, dichloromethane, chloroform, toluene, xylene, tetrahydrofuran, carbon disulfide; optionally, the extraction solvent is selected from at least one of ethyl acetate and dichloromethane.

[0023] The lye is selected from at least one of an aqueous solution of NaOH, KOH.

[0024] The recrystallization solvent is selected from at least one of ethers, alcohols, esters, alkanes, halogenated alkanes, aromatic hydrocarbons, ketones, tetrahydrofuran, nitriles; optionally, the recrystallization solvent is selected from at least one of petroleum ether, methanol, ethanol, isopropanol, diethyl ether, ethyl acetate, cyclohexane, n-octane, n-heptane, n-hexane, n-pentane, acetonitrile, acetone, butanone, methyl tert-butyl ether, tetrahydrofuran.

[0025] Optionally, the preparation method described above is characterized in that:

[0026] The mass ratio of the chiral organic acid to the compound of formula (I) is ≥ 1:1; optionally, the mass ratio of the chiral organic acid to the compound of formula (I) is 1:1-2:1;

[0027] The pH is ≥ 7;

[0028] The mass-volume ratio of the compound of formula (I) to the recrystallization solvent is 1:8-40 g / mL;

[0029] The heating temperature is room temperature-reflux.

[0030] Optionally, the preparation method described above is characterized in that the method comprises the following steps: adding a chiral organic acid to a mixture containing the compound of formula (I), refluxing under stirring, stirring and cooling to crystallize, filtering, dissolving the filter cake with water, adding activated carbon and stirring, filtering, adding a base to the filtrate to adjust the pH to ≥ 7, extracting with an extraction solvent, concentrating to dryness, and obtaining the compound of formula (I); mixing the compound of formula (I) with a recrystallization solvent, heating, cooling, stirring, filtering, washing, and drying

[0031] Optionally, the stirring temperature is 0°C-room temperature; and the stirring time is 1-5 hours.

[0032] The application also provides the use of the crystal form described above in the synthesis of mivacurium chloride.

[0033] The new crystal form of the compound of formula (I) has high chemical purity and optical purity, is easy to store and operate, has good stability, is suitable for the preparation of mivacurium chloride, and has a very positive significance for improving the quality of mivacurium chloride bulk drug. The preparation method of the application not only improves the yield, but also ensures the high purity of the product. The crystal form of the compound of formula (I) prepared by the method of the application has a yield of more than 94% and a chemical purity of more than 99.5%, effectively improving the yield and chemical purity of the product and greatly reducing the purification difficulty of the product; the optical purity of the obtained crystal form is more than 99.95%, ensuring the singleness of the configuration of the chiral compound and providing a strong guarantee for improving the quality of the finished drug mivacurium chloride. In addition, the preparation method of the application is simple and convenient to operate, has no special requirements for equipment, is environmentally friendly and safe, meets the needs of large-scale industrial production, greatly saves materials, and reduces the cost of industrial production. The new crystal form of the compound of formula (I) and the preparation method thereof provided by the application fill the gap in the prior art and can be better applied to the preparation of bulk drug. BRIEF DESCRIPTION OF DRAWINGS

[0034] Figure 1is an X-ray powder diffraction pattern of crystals of 6,7-dimethoxy-l-(R)-3,4,5- trimethoxybenzyl-l,2,3,4-tetrahydroisoquinoline (a compound of formula (I)) prepared in Example 1.

[0035] Figure 2 is a high performance liquid chromatogram of the test group in Test Example 2.

[0036] Figure 3 is a high performance liquid chromatogram of the control group in Test Example 2. DETAILED DESCRIPTION

[0037] The following detailed description of the application is provided for the purpose of example and explanation only and is not intended to limit the application.

[0038] The starting material 6,7-dimethoxy-l-(R)-3,4,5-trimethoxybenzyl-l,2,3,4- tetrahydroisoquinoline used in the following examples of the present application is prepared by the Preparation Example. The starting material 6,7-dimethoxy-l-(R)-3,4,5- trimethoxybenzyl-l,2,3,4-tetrahydroisoquinoline and the catalyst (S,S)-N-(p- toluenesulfonyl)-l,2-diphenylethanedi-amine (p-isopropylbenzene) chloro-ruthenium (II) used in the following Preparation Example can be obtained commercially or can be prepared according to the method reported in the literature, such as Tetrahedron: Asymmetry, 2013, 24, 50.

[0039] Preparation Example 1: 30 g of the catalyst (S,S)-N-(p-toluenesulfonyl)-l,2- diphenylethanedi-amine (p-isopropylbenzene) chloro-ruthenium (II) was added to a mixture of 3000 mL of dichloromethane and 4000 mL of formic acid / triethylamine (5:2) to prepare a stock solution. 1500 g of 6,7-dimethoxy-l-(3,4,5- trimethoxybenzyl)-3,4-dihydroisoquinoline was weighed and dissolved in 3000 mL of dichloromethane, and the above stock solution was added thereto, and the reaction was allowed to proceed at room temperature until completion. The reaction was quenched by adding an aqueous potassium hydroxide solution to the reaction solution, and the mixture was allowed to stand to separate into layers. The organic phase was concentrated to obtain a solid.

[0040] The solid was dissolved by adding ethanol, and 602 g of D-tartaric acid was added thereto, and the mixture was refluxed with stirring until the reaction was completed. The mixture was allowed to cool with stirring to precipitate crystals, and the crystals were filtered. The filter cake was dissolved in water, and activated carbon was added thereto with stirring, and the mixture was filtered. The filtrate was adjusted to pH 12 by adding an aqueous potassium hydroxide solution, and extracted with dichloromethane, and concentrated to dryness. This resulted in 1390 g of 6,7-dimethoxy-l-(R)-3,4,5-trimethoxybenzyl-l,2,3,4- tetrahydroisoquinoline.

[0041] Preparation Example 2: To 2500 mL of dimethylsulfoxide and 1500 mL of formic acid / triethylamine (5:2) mixture was added 26 g of catalyst (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanedi-amine (p-cymene) chlororuthenate (II) to make a stock solution. 1500 g of 6,7-dimethoxy-1-(3,4,5-trimethoxybenzyl)-3,4-dihydroisoquinoline was weighed into 2000 mL of dimethylsulfoxide and the stock solution was added. The reaction was allowed to proceed at room temperature until completion. To the reaction mixture was added an aqueous solution of sodium carbonate to quench the reaction and the reaction was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine, respectively, and the organic phase was separated and concentrated.

[0042] Ethanol was added to dissolve the solid and 900 g of diacetyl-D-tartaric acid was added. The reaction was refluxed until completion with stirring. The reaction was allowed to cool and crystals were formed. The crystals were filtered. The filter cake was dissolved in water and activated carbon was added with stirring. The mixture was filtered. To the filtrate was added an aqueous solution of potassium hydroxide to adjust the pH to 11. The mixture was extracted with dichloromethane and the organic phase was concentrated to dryness. 6,7-Dimethoxy-1-(R)-3,4,5-trimethoxybenzyl-1,2,3,4-tetrahydroisoquinoline was obtained in 1385 g.

[0043] Preparation Example 3: To 100 mL of N,N-dimethylformamide and 600 mL of formic acid / triethylamine (5:2) mixture was added 4.0 g of catalyst (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanedi-amine (p-cymene) chlororuthenate (II) to make a stock solution. 150 g of 6,7-dimethoxy-1-(3,4,5-trimethoxybenzyl)-3,4-dihydroisoquinoline was weighed into 200 mL of N,N-dimethylformamide and the stock solution was added. The reaction was allowed to proceed at room temperature until completion. To the reaction mixture was added an aqueous solution of potassium carbonate to quench the reaction and the reaction was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine, respectively, and the organic phase was separated and concentrated to dryness.

[0044] Isopropyl alcohol was added to dissolve the solid and 80 g of D-camphoric acid was added. The reaction was refluxed until completion with stirring. The reaction was allowed to cool and crystals were formed. The crystals were filtered. The filter cake was dissolved in water and activated carbon was added with stirring. The mixture was filtered. To the filtrate was added an aqueous solution of potassium hydroxide to adjust the pH to 8. The mixture was extracted with dichloromethane and the organic phase was concentrated to dryness. 6,7-Dimethoxy-1-(R)-3,4,5-trimethoxybenzyl-1,2,3,4-tetrahydroisoquinoline was obtained in 137.5 g.

[0045] Preparation Example 4: 3.0 g of a catalyst (S, S)-N-(p-toluenesulfonyl)-1,2- diphenylethanedi-amine (p-cymene) chlororuthenate (II) was added to a mixture of 200 mL of acetonitrile and 700 mL of formic acid / triethylamine (5:2) to prepare a stock solution. 150 g of 6,7-dimethoxy-1-(3,4,5-trimethoxybenzyl)-3,4-dihydroisoquinoline was weighed and dissolved in 250 mL of acetonitrile, and the stock solution was added thereto, and the reaction was allowed to proceed at room temperature until the reaction was completed. The reaction solution was concentrated, and the reaction was quenched with an aqueous sodium hydroxide solution, and extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, respectively, and separated, and the organic phase was concentrated to dryness.

[0046] D-mandelic acid was added thereto, and refluxed with stirring until the reaction was completed. The reaction solution was stirred and cooled to precipitate crystals, and filtered. The filter cake was dissolved in water, and activated carbon was added thereto with stirring, and filtered. The filtrate was adjusted to pH 10 with an aqueous sodium hydroxide solution, and extracted with ethyl acetate, and concentrated to dryness. Thus, 6,7-dimethoxy-1-(R)-3,4,5-trimethoxybenzyl-1,2,3,4-tetrahydroisoquinoline was obtained in an amount of 136.5 g.

[0047] Preparation Example 5: 2.6 g of a catalyst (S, S)-N-(p-toluenesulfonyl)-1,2- diphenylethanedi-amine (p-cymene) chlororuthenate (II) was added to a mixture of 300 mL of dimethyl sulfoxide and 750 mL of formic acid / triethylamine (5:2) to prepare a stock solution. 150 g of 6,7-dimethoxy-1-(3,4,5-trimethoxybenzyl)-3,4-dihydroisoquinoline was weighed and dissolved in 300 mL of dimethyl sulfoxide, and the stock solution was added thereto, and the reaction was allowed to proceed at room temperature until the reaction was completed. To the reaction solution was added an aqueous potassium carbonate solution to quench the reaction, and extracted with dichloromethane, and the organic layer was washed with water and saturated brine, respectively, and separated, and the organic phase was concentrated to dryness.

[0048] D-mandelic acid was added thereto, and refluxed with stirring until the reaction was completed. The reaction solution was stirred and cooled to precipitate crystals, and filtered. The filter cake was dissolved in water, and activated carbon was added thereto with stirring, and filtered. The filtrate was adjusted to pH 10 with an aqueous sodium hydroxide solution, and extracted with ethyl acetate, and concentrated to dryness. Thus, 6,7-dimethoxy-1-(R)-3,4,5-trimethoxybenzyl-1,2,3,4-tetrahydroisoquinoline was obtained in an amount of 136.5 g.

[0049] Example 1: 50 g of 6,7-dimethoxy-1-(R)-3,4,5-trimethoxybenzyl-1,2,3,4- tetrahydroisoquinoline was weighed, 1500 mL of petroleum ether was added, heated to reflux, and stirred until completely dissolved. The solution was allowed to cool to room temperature, and stirring was continued at room temperature for 2 hours. Filtration, washing, and drying yielded 48.4 g of 6,7-dimethoxy-1-(R)-3,4,5-trimethoxybenzyl-1,2,3,4-tetrahydroisoquinoline crystals, with a yield of 96.8%, an optical purity of 99.97%, and a chemical purity of 99.60%. Mass spectrometry showed that the ESI m / z of the compound was 374.2 [M+1] + .

[0050] The crystal phase of the sample was analyzed using a DX-2700 X-ray powder diffractometer, with Cu-Ka radiation, a tube voltage of 40 KV, and a tube current of 30 mA. The X-ray powder diffraction pattern of the 6,7-dimethoxy-1-(R)-3,4,5-trimethoxybenzyl-1,2,3,4-tetrahydroisoquinoline crystals is shown in FIG. 1, and the diffraction-related data is shown in Table 1. The measurement error of 2θ was ±0.2°, and the measurement error of relative intensity was ±5%, and sometimes even ±20%. Figure 1

[0051] Table 1. X-ray powder diffraction data of the compound of Formula I crystals

[0052]

[0053]

[0054] The X-ray powder diffraction data with a relative intensity greater than 5% is shown below.

[0055]

[0056]

[0057] Further, the crystals have the following X-ray powder diffraction characteristics:

[0058]

[0059] ​Example 2: 50 g of 6,7-dimethoxy-l-(R)-3,4,5-trimethoxybenzyl-l,2,3,4- tetrahydroisoquinoline was weighed, 500 mL of cyclohexane was added, heated to reflux, and stirred until completely dissolved. The solution was naturally cooled to room temperature and stirred for 2 hours at room temperature. Filtration, washing and drying were performed to obtain 47.8 g of 6,7-dimethoxy-l-(R)-3,4,5-trimethoxybenzyl-l,2,3,4- tetrahydroisoquinoline crystal, with a yield of 95.6%, an optical purity of 99.95%, and a chemical purity of 99.50%. The structural analysis results and X-ray powder diffraction pattern of the obtained product were not significantly different from those of Example 1.

[0060] Example 3: 50 g of 6,7-dimethoxy-l-(R)-3,4,5-trimethoxybenzyl-l,2,3,4- tetrahydroisoquinoline was weighed, 400 mL of ethyl acetate was added, heated to reflux, and stirred until completely dissolved. The solution was naturally cooled to room temperature and stirred for 2 hours at room temperature. Filtration, washing and drying were performed to obtain 47.4 g of 6,7-dimethoxy-l-(R)-3,4,5-trimethoxybenzyl-l,2,3,4- tetrahydroisoquinoline crystal, with a yield of 94.8%, an optical purity of 99.96%, and a chemical purity of 99.52%. The structural analysis results and X-ray powder diffraction pattern of the obtained product were not significantly different from those of Example 1.

[0061] Example 4: 50 g of 6,7-dimethoxy-l-(R)-3,4,5-trimethoxybenzyl-l,2,3,4- tetrahydroisoquinoline was weighed, 750 mL of ether was added, and stirred for 3 hours at reflux. The solution was naturally cooled to room temperature and stirred for 5 hours at room temperature. Filtration, washing and drying were performed to obtain 48.3 g of 6,7-dimethoxy-l-(R)-3,4,5-trimethoxybenzyl-l,2,3,4- tetrahydroisoquinoline crystal, with a yield of 96.6%, an optical purity of 99.95%, and a chemical purity of 99.55%. The structural analysis results and X-ray powder diffraction pattern of the obtained product were not significantly different from those of Example 1.

[0062] Example 5: 50 g of 6,7-dimethoxy-l-(R)-3,4,5-trimethoxybenzyl-l,2,3,4- tetrahydroisoquinoline was weighed, 1000 mL of methyl tert-butyl ether was added, and stirred for 5 hours at reflux. The solution was naturally cooled to room temperature and stirred for 4 hours at room temperature. Filtration, washing and drying were performed to obtain 48.6 g of 6,7-dimethoxy-l-(R)-3,4,5-trimethoxybenzyl-l,2,3,4- tetrahydroisoquinoline crystal, with a yield of 97.1%, an optical purity of 99.95%, and a chemical purity of 99.53%. The structural analysis results and X-ray powder diffraction pattern of the obtained product were not significantly different from those of Example 1.

[0063] Example 6: 50 g of 6,7-dimethoxy-l-(R)-3,4,5-trimethoxybenzyl-l,2,3,4- tetrahydroisoquinoline was weighed, 150 mL of methanol was added, and stirred at room temperature until completely dissolved. 500 mL of ether was added, and cooled to 0°C, and stirred at 0°C for 3 hours. Filtration, washing, and drying were performed to obtain 48.2 g of 6,7-dimethoxy-l-(R)-3,4,5-trimethoxybenzyl-l,2,3,4-tetrahydroisoquinoline crystal, with a yield of 96.4%, an optical purity of 99.98%, and a chemical purity of 99.59%. The structural analysis result and X-ray powder diffraction pattern of the obtained product were not significantly different from those of Example 1.

[0064] Example 7: 50 g of 6,7-dimethoxy-l-(R)-3,4,5-trimethoxybenzyl-l,2,3,4- tetrahydroisoquinoline was weighed, 150 mL of ethanol was added, and stirred at 40°C until completely dissolved. 500 mL of ether was added, and cooled to 5°C, and stirred at 5°C for 2 hours. Filtration, washing, and drying were performed to obtain 48.0 g of 6,7-dimethoxy-l-(R)-3,4,5-trimethoxybenzyl-l,2,3,4-tetrahydroisoquinoline crystal, with a yield of 96.0%, an optical purity of 99.97%, and a chemical purity of 99.61%. The structural analysis result and X-ray powder diffraction pattern of the obtained product were not significantly different from those of Example 1.

[0065] Example 8: 50 g of 6,7-dimethoxy-l-(R)-3,4,5-trimethoxybenzyl-l,2,3,4- tetrahydroisoquinoline was weighed, 150 mL of isopropanol was added, and stirred at 50°C until completely dissolved. 500 mL of ether was added, and cooled to room temperature, and stirred at room temperature for 2 hours. Filtration, washing, and drying were performed to obtain 47.6 g of 6,7-dimethoxy-l-(R)-3,4,5-trimethoxybenzyl-l,2,3,4-tetrahydroisoquinoline crystal, with a yield of 95.2%, an optical purity of 99.96%, and a chemical purity of 99.60%. The structural analysis result and X-ray powder diffraction pattern of the obtained product were not significantly different from those of Example 1.

[0066] Example 9: 50 g of 6,7-dimethoxy-l-(R)-3,4,5-trimethoxybenzyl-l,2,3,4- tetrahydroisoquinoline was weighed, 250 mL of dichloromethane was added, and stirred at room temperature until completely dissolved. 1750 mL of petroleum ether was added, and cooled to 10°C, and stirred at 10°C for 2 hours. Filtration, washing, and drying were performed to obtain 47.9 g of 6,7-dimethoxy-l-(R)-3,4,5-trimethoxybenzyl-l,2,3,4-tetrahydroisoquinoline crystal, with a yield of 95.8%, an optical purity of 99.97%, and a chemical purity of 99.55%. The structural analysis result and X-ray powder diffraction pattern of the obtained product were not significantly different from those of Example 1.

[0067] Example 10: 50 g of 6,7-dimethoxy-l-(R)-3,4,5-trimethoxybenzyl-l,2,3,4- tetrahydroisoquinoline was weighed, 100 mL of acetone was added, heated to 30°C, and stirred until completely dissolved. 500 mL of ether was added, quickly cooled to 15°C, and stirred at 15°C for 2 hours. Filtration, washing, and drying yielded 47.5 g of 6,7-dimethoxy-l-(R)-3,4,5-trimethoxybenzyl-l,2,3,4-tetrahydroisoquinoline crystals, with a yield of 95.0%, an optical purity of 99.95%, and a chemical purity of 99.57%. The structural analysis results and X-ray powder diffraction pattern of the product were not significantly different from those of Example 1.

[0068] Example 11: 50 g of 6,7-dimethoxy-l-(R)-3,4,5-trimethoxybenzyl-l,2,3,4- tetrahydroisoquinoline was weighed, 400 mL of ethyl acetate was added, heated to reflux, and stirred until completely dissolved. 1500 mL of petroleum ether was added, cooled to 0°C, and stirred at 0°C for 2 hours. Filtration, washing, and drying yielded 47.3 g of 6,7-dimethoxy-l-(R)-3,4,5-trimethoxybenzyl-l,2,3,4-tetrahydroisoquinoline crystals, with a yield of 94.6%, an optical purity of 99.99%, and a chemical purity of 99.52%. The structural analysis results and X-ray powder diffraction pattern of the product were not significantly different from those of Example 1.

[0069] Example 12: 50 g of 6,7-dimethoxy-l-(R)-3,4,5-trimethoxybenzyl-l,2,3,4- tetrahydroisoquinoline was weighed, 900 mL of tetrahydrofuran was added, heated to reflux, and stirred for 3 hours. The solution was quickly cooled to room temperature and stirred at room temperature for 2 hours. Filtration, washing, and drying yielded 48.6 g of 6,7-dimethoxy-l-(R)-3,4,5-trimethoxybenzyl-l,2,3,4-tetrahydroisoquinoline crystals, with a yield of 97.2%, an optical purity of 99.97%, and a chemical purity of 99.51%. The structural analysis results and X-ray powder diffraction pattern of the product were not significantly different from those of Example 1.

[0070] Example 13: 50 g of 6,7-dimethoxy-l-(R)-3,4,5-trimethoxybenzyl-l,2,3,4- tetrahydroisoquinoline was weighed, 2000 mL of petroleum ether was added, heated to reflux, and stirred until completely dissolved. The solution was cooled to 10°C and stirred at 10°C for 3 hours. Filtration, washing, and drying yielded 48.8 g of 6,7-dimethoxy-l-(R)-3,4,5-trimethoxybenzyl-l,2,3,4-tetrahydroisoquinoline crystals, with a yield of 97.6%, an optical purity of 99.96%, and a chemical purity of 99.61%. The structural analysis results and X-ray powder diffraction pattern of the product were not significantly different from those of Example 1.

[0071] Example 14: Take 500 g of 6,7-dimethoxy-1-(R)-3,4,5-trimethoxybenzyl-1,2,3,4- tetrahydroisoquinoline, add 15 L of petroleum ether, heat to reflux, and wait until completely dissolved. Allow to cool to room temperature naturally, and continue stirring at room temperature for 3 hours. Filter, wash, and dry to obtain 485 g of 6,7-dimethoxy-1-(R)-3,4,5-trimethoxybenzyl-1,2,3,4-tetrahydroisoquinoline crystals, with a yield of 97.0%, an optical purity of 99.98%, and a chemical purity of 99.63%. The structural analysis results and X-ray powder diffraction pattern of the obtained product show no significant difference from Example 1.

[0072] Example 15: Take 50 g of 6,7-dimethoxy-1-(R)-3,4,5-trimethoxybenzyl-1,2,3,4- tetrahydroisoquinoline, add 500 mL of acetonitrile, heat to reflux, and wait until completely dissolved. Add 1000 mL of methyl tert-butyl ether, and quickly cool to room temperature. Continue stirring at room temperature for 2 hours. Filter, wash, and dry to obtain 47.7 g of 6,7-dimethoxy-1-(R)-3,4,5-trimethoxybenzyl-1,2,3,4-tetrahydroisoquinoline crystals, with a yield of 95.4%, an optical purity of 99.98%, and a chemical purity of 99.56%. The structural analysis results and X-ray powder diffraction pattern of the obtained product show no significant difference from Example 1.

[0073] Example 16: Take 1000 g of 6,7-dimethoxy-1-(R)-3,4,5-trimethoxybenzyl-1,2,3,4- tetrahydroisoquinoline, add 10 L of ethyl acetate, heat to reflux, and wait until completely dissolved. Add 20 L of n-heptane, and allow to cool to room temperature naturally. Continue stirring at room temperature for 3 hours. Filter, wash, and dry to obtain 960 g of 6,7-dimethoxy-1-(R)-3,4,5-trimethoxybenzyl-1,2,3,4-tetrahydroisoquinoline crystals, with a yield of 96.0%, an optical purity of 99.99%, and a chemical purity of 99.54%. The structural analysis results and X-ray powder diffraction pattern of the obtained product show no significant difference from Example 1.

[0074] Example 17: Take 50 g of 6,7-dimethoxy-1-(R)-3,4,5-trimethoxybenzyl-1,2,3,4- tetrahydroisoquinoline, add 500 mL of ethyl acetate, heat to reflux, and wait until completely dissolved. Add 1000 mL of n-hexane, and naturally cool to room temperature. Continue stirring at room temperature for 2 hours. Filter, wash, and dry to obtain 47.5 g of 6,7-dimethoxy-1-(R)-3,4,5-trimethoxybenzyl-1,2,3,4-tetrahydroisoquinoline crystals, with a yield of 95.0%, an optical purity of 99.95%, and a chemical purity of 99.54%. The structural analysis results and X-ray powder diffraction pattern of the obtained product are not significantly different from those of Example 1.

[0075] Example 18: Take 50 g of 6,7-dimethoxy-1-(R)-3,4,5-trimethoxybenzyl-1,2,3,4- tetrahydroisoquinoline, add 350 mL of butanone, heat to reflux, and wait until completely dissolved. Add 700 mL of diethyl ether, and quickly cool to room temperature. Continue stirring at room temperature for 3 hours. Filter, wash, and dry to obtain 47.6 g of 6,7-dimethoxy-1-(R)-3,4,5-trimethoxybenzyl-1,2,3,4-tetrahydroisoquinoline crystals, with a yield of 95.2%, an optical purity of 99.97%, and a chemical purity of 99.51%. The structural analysis results and X-ray powder diffraction pattern of the obtained product are not significantly different from those of Example 1.

[0076] Example 19: Take 50 g of 6,7-dimethoxy-1-(R)-3,4,5-trimethoxybenzyl-1,2,3,4- tetrahydroisoquinoline, add 1250 mL of n-hexane, heat to reflux, and wait until completely dissolved. Naturally cool to room temperature, and continue stirring at room temperature for 1 hour. Filter, wash, and dry to obtain 48.2 g of 6,7-dimethoxy-1-(R)-3,4,5-trimethoxybenzyl-1,2,3,4-tetrahydroisoquinoline crystals, with a yield of 96.4%, an optical purity of 99.98%, and a chemical purity of 99.52%. The structural analysis results and X-ray powder diffraction pattern of the obtained product are not significantly different from those of Example 1.

[0077] Example 20: Take 500 g of 6,7-dimethoxy-1-(R)-3,4,5-trimethoxybenzyl-1,2,3,4- tetrahydroisoquinoline, add 15 L of n-octane, heat to reflux, and wait until completely dissolved. Naturally cool to room temperature, and continue stirring at room temperature for 2 hours. Filter, wash, and dry to obtain 488 g of 6,7-dimethoxy-1-(R)-3,4,5-trimethoxybenzyl-1,2,3,4-tetrahydroisoquinoline crystals, with a yield of 97.6%, an optical purity of 99.96%, and a chemical purity of 99.54%. The structural analysis results and X-ray powder diffraction pattern of the obtained product are not significantly different from those of Example 1.

[0078] Example 21: 50 g of 6,7-dimethoxy-l-(R)-3,4,5-trimethoxybenzyl-l,2,3,4- tetrahydroisoquinoline was weighed, 1500 mL of n-pentane was added, heated to reflux, and stirred until completely dissolved. The solution was allowed to cool to room temperature, and stirring was continued at room temperature for 2 hours. Filtration, washing, and drying yielded 48.5 g of 6,7-dimethoxy-l-(R)-3,4,5-trimethoxybenzyl-l,2,3,4- tetrahydroisoquinoline crystals, with a yield of 97.0%, an optical purity of 99.96%, and a chemical purity of 99.54%. The structural analysis results and X-ray powder diffraction pattern of the product were not significantly different from those of Example 1.

[0079] Example 22: 50 g of 6,7-dimethoxy-l-(R)-3,4,5-trimethoxybenzyl-l,2,3,4- tetrahydroisoquinoline was weighed, 1500 mL of n-heptane was added, heated to reflux, and stirred until completely dissolved. The solution was allowed to cool to room temperature, and stirring was continued at room temperature for 2.5 hours. Filtration, washing, and drying yielded 47.75 g of 6,7-dimethoxy-l-(R)-3,4,5-trimethoxybenzyl-l,2,3,4- tetrahydroisoquinoline crystals, with a yield of 95.5%, an optical purity of 99.95%, and a chemical purity of 99.53%. The structural analysis results and X-ray powder diffraction pattern of the product were not significantly different from those of Example 1.

[0080] Example 23: 50 g of 6,7-dimethoxy-l-(R)-3,4,5-trimethoxybenzyl-l,2,3,4- tetrahydroisoquinoline was weighed, 500 mL of n-pentane and 1000 mL of n-hexane were added, heated to reflux, and stirred until completely dissolved. The solution was allowed to cool to room temperature, and stirring was continued at room temperature for 2 hours. Filtration, washing, and drying yielded 48.0 g of 6,7-dimethoxy-l-(R)-3,4,5-trimethoxybenzyl-l,2,3,4- tetrahydroisoquinoline crystals, with a yield of 96.0%, an optical purity of 99.98%, and a chemical purity of 99.56%. The structural analysis results and X-ray powder diffraction pattern of the product were not significantly different from those of Example 1.

[0081] Example 24: 50 g of 6,7-dimethoxy-l-(R)-3,4,5-trimethoxybenzyl-l,2,3,4- tetrahydroisoquinoline was weighed, 500 mL of n-octane and 1000 mL of n-heptane were added, heated to reflux, and stirred until completely dissolved. The solution was allowed to cool to room temperature, and stirring was continued at room temperature for 3 hours. Filtration, washing, and drying yielded 48.8 g of 6,7-dimethoxy-l-(R)-3,4,5-trimethoxybenzyl-l,2,3,4- tetrahydroisoquinoline crystals, with a yield of 97.6%, an optical purity of 99.97%, and a chemical purity of 99.61%. The structural analysis results and X-ray powder diffraction pattern of the product were not significantly different from those of Example 1.

[0082] Test Example 1 Stability Effect Test

[0083] Test sample: the crystal of the compound of formula I prepared in Example 1 of the present application;

[0084] The test conditions include: 1) thermal degradation: about 200 mg of the test sample is placed in a 60℃ drying oven; 2) light degradation: about 200 mg of the test sample is placed in an environment with an illumination of 4500±500 lx; 3) high humidity degradation: about 200 mg of the test sample is placed in a desiccator containing a saturated KNO3 solution at room temperature. The results of the stability test are shown in Table 2.

[0085] Table 2 Results of the stability test

[0086]

[0087] As shown by the test results in Table 2, the crystal of the compound of formula I prepared in the present application has no significant change in chemical purity and optical purity under the conditions of high temperature, high humidity and light, and the crystal form does not change, and has good stability. It can be seen that the crystal of the compound of formula I provided in the present application has stable and controllable quality.

[0088] Test Example 2 Detection of the content of optical isomer impurities

[0089] Chromatographic conditions: instrument: Shimadzu high performance liquid chromatograph

[0090] Chromatographic column: Chiralcel AD

[0091] Mobile phase: n-heptane: isopropyl alcohol: diethylamine (70:30:0.1)

[0092] Column temperature: 30℃

[0093] Flow rate: 0.8 mL / min,

[0094] Wavelength: 280 nm

[0095] 1. Test sample:

[0096] (1) Test group: the crystal of 6,7-dimethoxy-1-(R)-3,4,5-trimethoxybenzyl-1,2,3,4-tetrahydroisoquinoline prepared in Example 1 of the present application;

[0097] (2) Control group: the oily substance of 6,7-dimethoxy-1-(R)-3,4,5-trimethoxybenzyl-1,2,3,4-tetrahydroisoquinoline prepared according to the existing literature Tetrahedron: Asymmetry, 2013, 24, 50.

[0098] 2. Optical isomer impurity content detection results:

[0099] The optical isomer impurity content of the test group and the control group was detected by high performance liquid chromatography, and was calculated by area normalization method, the liquid chromatogram of the test group is shown in Figure 2 , the liquid chromatogram of the control group is shown in Figure 3 , and the analysis results are shown in Table 3.

[0100] Table 3 Optical isomer impurity content detection results

[0101] Sample Relative retention time Test group Control group Main peak area (%) 1.000 99.97％ 95.54％ Optical isomer impurity (%) 0.864 0.03％ 4.46％

[0102] From Figure 2 and Figure 3 , Table 3 can be known that, compared with the prior art, the optical isomer impurity content in the 6,7-dimethoxy-1-(R)-3,4,5-trimethoxybenzyl-1,2,3,4-tetrahydroisoquinoline crystal prepared by the present application is significantly reduced, which indicates that the present application can effectively reduce the optical isomer impurity content in the existing product, and provides a strong guarantee for improving the safety and effectiveness of the finished drug.

[0103] In summary, the crystal of the compound of formula I provided by the present application has stable properties and high purity, which provides a strong guarantee for preparing effective and safe drugs; in addition, the preparation process of the crystal of the present application is simple, convenient to operate, and has high yield, and is suitable for industrial production.

Claims

1. A method for preparing the crystal form of a compound of formula (I), characterized in that, Formic acid / triethylamine (5:2) was mixed with at least one of dimethyl sulfoxide, acetonitrile, N,N-dimethylformamide, and dichloromethane to prepare a backup solution. Under the condition that (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium(II) chloride was used as a catalyst, the above backup solution was added to 6,7-dimethoxy-1-(3,4,5-trimethoxybenzyl)-3,4-dihydroisoquinoline for asymmetric reduction. Then, a salt-forming solvent and a chiral organic solvent were added to the asymmetric reduction product. The acid is converted into a salt, and then recrystallized to obtain the crystal form of compound (I); the chiral organic acid is selected from at least one of D-tartaric acid, D-malic acid, D-mandelic acid, D-camphoric acid, and diacetyl-D-tartaric acid; the salt-forming solvent is selected from at least one of methanol, ethanol, and isopropanol; the recrystallization solvent is selected from at least one of petroleum ether, methanol, ethanol, isopropanol, diethyl ether, ethyl acetate, cyclohexane, n-octane, n-heptane, n-hexane, n-pentane, acetonitrile, acetone, butanone, methyl tert-butyl ether, and tetrahydrofuran; Using Cu-Kα radiation, X-ray powder diffraction of the crystal form of the compound of formula (I) showed characteristic peaks at diffraction angles 2θ of 13.4±0.2°, 14.1±0.2°, 18.0±0.2°, 19.1±0.2°, 21.0±0.2°, 23.5±0.2°, 24.2±0.2°, 26.2±0.2°, 26.8±0.2°, and 29.2±0.2°.

2. The method for preparing the crystal form of the compound of formula (I) according to claim 1, characterized in that, The X-ray powder diffraction of the crystal form of the compound of formula (I) shows characteristic peaks and their relative intensities (I / I0) at the following diffraction angle 2θ: The measurement error of the relative intensity is ±5%.

3. The method for preparing the crystal form of the compound of formula (I) according to claim 2, characterized in that, The measurement error of the relative strength is ±20%.

4. The method for preparing the crystal form of the compound of formula (I) according to claim 1, characterized in that, The steps of adding a salt-forming solvent and a chiral organic acid to the product obtained from the asymmetric reduction step to form a salt, and recrystallization include: adding a salt-forming solvent and a chiral organic acid to form a salt, crystallizing, filtering, adding water or not to the filter cake, adjusting the pH with an alkaline solution, extracting with an extraction solvent, removing the solvent from the organic phase, obtaining compound (I), mixing compound (I) with a recrystallization solvent, heating, and cooling to crystallize.

5. The method for preparing the crystal form of the compound of formula (I) according to claim 4, characterized in that: The extraction solvent is selected from at least one of alcohols, ethers, ketones, esters, alkanes, haloalkanes, aromatic hydrocarbons, tetrahydrofuran, and carbon disulfide; The alkaline solution is selected from at least one aqueous solution of NaOH and KOH.

6. The method for preparing the crystal form of the compound of formula (I) according to claim 5, characterized in that: The extraction solvent is selected from at least one of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, diethyl ether, methyl ethyl ether, acetone, butanone, ethyl acetate, petroleum ether, hexane, cyclohexane, dichloromethane, chloroform, toluene, xylene, tetrahydrofuran, and carbon disulfide.

7. The method for preparing the crystal form of the compound of formula (I) according to claim 5, characterized in that: The extraction solvent is selected from at least one of ethyl acetate and dichloromethane.

8. The method for preparing the crystal form of the compound of formula (I) according to any one of claims 1-7, characterized in that: The molar ratio of the chiral organic acid to the asymmetric reduction product is ≥1:1; The pH is ≥10; The mass-to-volume ratio of the compound of formula (I) to the recrystallization solvent is 1:8 to 40 g / mL; The heating temperature is from room temperature to reflux.

9. The method for preparing the crystal form of the compound of formula (I) according to claim 8, characterized in that: The molar ratio of the chiral organic acid to the asymmetric reduction product is 1:1 to 2:

1.

10. The method for preparing the crystal form of the compound of formula (I) according to claim 4, characterized in that, The steps of adding a salt-forming solvent and a chiral organic acid to the product obtained from the asymmetric reduction step, and recrystallization include: adding a chiral organic acid, refluxing with stirring, stirring and cooling to precipitate crystals, filtering, dissolving the filter cake in water, adding activated carbon and stirring, filtering, adding alkali to the filtrate to adjust the pH to ≥10, extracting with an extraction solvent, concentrating to dryness to obtain compound (I), mixing compound (I) with a recrystallization solvent, heating, cooling, stirring, filtering, washing, and drying.

11. The method for preparing the crystal form of the compound of formula (I) according to claim 10, characterized in that, The stirring temperature is 0℃ to room temperature; the stirring time is 1 to 5 hours.

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