Brakamethacin hydrochloride and preparation method of intermediate thereof

Abstract

The invention provides a preparation method of buracametacin hydrochloride and an intermediate compound shown as a formula II thereof. The preparation method of the compound as shown in the formula II comprises the following steps: in the presence of a reducing agent, a compound as shown in the formula I is subjected to a reduction reaction to generate the compound as shown in the formula II. The reducing agent is selected from sodium borohydride and / or lithium borohydride, lewis acid also exists in the reaction system, and the lewis acid is also selected from zinc bromide, zinc chloride, boron trifluoride, aluminum chloride, ferric chloride or a combination thereof. The preparation method disclosed by the invention is low in reducing agent price, mild in reaction, relatively high in product yield and purity, and suitable for industrial large-scale production. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the technical field of organic compound synthesis, and in particular relates to a preparation method of bracametacin hydrochloride and an intermediate thereof. Background Art

[0002] The chemical name of Blarcamesine Hydrochloride is 1-(2,2-diphenyltetrahydrofuran-3-yl)-N,N-dimethylmethanamine hydrochloride, and its English name is Blarcamesine Hydrochloride. The structural formula is:

[0003]

[0004] Bracamathiacin hydrochloride is an oral small molecule agonist targeting Sigma-1. It effectively improves mitochondrial activation and neuroinflammation in neurons, exhibiting anticonvulsant, anti-amnesic, neuroprotective, and antidepressant properties. It is used to treat early-stage Alzheimer's disease (AD) in adults. Anavex Life Sciences Corp. filed its first application for marketing authorization with the European Medicines Agency (EMA) on November 20, 2023.

[0005] Prior art WO1997030983A1 discloses a method for synthesizing bracamethin hydrochloride, as described in the following Scheme 1:

[0006]

[0007] Route 1

[0008] In Route 1, lithium aluminum hydride is used as a reducing agent in the preparation of the compound of Formula II from the compound of Formula I. The inventors of the present application repeated this step disclosed in the prior art and found that using lithium aluminum hydride as a reducing agent resulted in a relatively high number of byproducts, particularly impurities that are difficult to remove. Furthermore, slight variations in the amount of lithium aluminum hydride used and the reaction temperature resulted in significant variations in product yield, making the scale-up process difficult to control. Furthermore, lithium aluminum hydride is expensive and highly flammable, both in solid and solution form, posing significant safety risks in its handling, storage, and transportation.

[0009] Furthermore, in Route 1 of prior art WO1997030983A1, during the preparation of compound III, compound II is refluxed in a class of solvents (benzene). According to ICH guidelines, such solvents should be avoided. Furthermore, the inventors of the present application repeated the method of this reference document, and the HPLC spectrum of the resulting reaction solution showed that the purity of compound III was low, with an impurity content as high as 3.86%, making purification difficult. Furthermore, this prior art utilizes a chromatographic column to purify the resulting compound III, making this method unsuitable for industrial scale-up production.

[0010] Therefore, a method for preparing bracamethin hydrochloride and its intermediates suitable for industrial scale-up production is needed. Summary of the Invention

[0011] In view of the defects in the preparation methods of bracamethin hydrochloride and its intermediates in the prior art, the present invention aims to provide a preparation method of a compound of formula II, which comprises the following steps:

[0012] In the presence of a reducing agent, the compound of formula I undergoes a reduction reaction to generate a compound of formula II, as shown in the following reaction formula:

[0013]

[0014] The reducing agent is selected from sodium borohydride and / or lithium borohydride, and

[0015] A Lewis acid is also present in the reaction system, and the Lewis acid is further selected from zinc bromide, zinc chloride, boron trifluoride, aluminum chloride, ferric chloride, or a combination thereof.

[0016] In another preferred embodiment, the reducing agent is selected from sodium borohydride, and the Lewis acid is further selected from aluminum chloride.

[0017] In another preferred embodiment, the solvent used in the reaction is selected from ethanol, tetrahydrofuran, ethylene glycol monomethyl ether, 1,4-dioxane, toluene, ethylene glycol dimethyl ether, isopropyl ether, isopropanol, methyl tert-butyl ether or a combination thereof, more preferably 1,4-dioxane or tetrahydrofuran.

[0018] In another preferred embodiment, the molar ratio of the compound of formula I to the reducing agent is 1:1.5-6.0, more preferably 1:2.0-4.0, most preferably 1:2.0-3.0, for example 1:2.0, 1:2.5, 1:2.8, 1:3.0.

[0019] In another preferred embodiment, the molar ratio of the compound of formula I to the Lewis acid is 1:1.0-7.0, more preferably 1:3.0-6.0, most preferably 1:4.0-6.0, for example 1:4.0, 1:4.5, 1:4.8, 1:6.0.

[0020] In another preferred embodiment, the reaction temperature is 40-70°C, more preferably 50-60°C.

[0021] In another preferred embodiment, the present invention also provides a method for preparing the compound of formula II comprising the following steps:

[0022] In tetrahydrofuran, in the presence of sodium borohydride and aluminum chloride, the compound of formula I undergoes a reduction reaction to generate a compound of formula II, as shown in the following reaction formula:

[0023]

[0024] In another preferred embodiment, the molar ratio of the compound of formula I to sodium borohydride is 1:2.0-3.0, the molar ratio of the compound of formula I to aluminum chloride is 1:4.0-6.0, and the reaction temperature is 50-60°C.

[0025] The present invention also provides a method for preparing bracametacin hydrochloride, comprising the following steps:

[0026] (1) According to the preparation method of the compound of formula II above, prepare the compound of formula II;

[0027] (2) In the presence of an acid, the compound of formula II undergoes an intramolecular condensation reaction to produce bracamethin;

[0028] (3) Bracamethin forms a salt with hydrochloric acid to generate bracamethin hydrochloride. The reaction formula is as follows

[0029]

[0030] In another preferred embodiment, in step (2), the acid is selected from p-toluenesulfonic acid, phosphoric acid, oxalic acid, boron trifluoride etherate, sulfuric acid or hydrochloric acid, preferably oxalic acid or hydrochloric acid, and / or

[0031] In step (2), the solvent is selected from toluene, ethylene glycol dimethyl ether, dichloromethane, tetrahydrofuran, 1,4-dioxane, water or a combination thereof, more preferably, water or toluene, and / or

[0032] In step (2), the molar ratio of the compound of formula II to the acid is 1:1.5 to 1:8, more preferably 1:2 to 5.

[0033] In another preferred embodiment, the preparation method of bracamethin hydrochloride further comprises the steps of:

[0034] (4) The crude product of bracametin hydrochloride obtained by treating the reaction solution of bracametin with hydrochloric acid in an organic solvent containing hydrogen chloride is slurried and filtered to obtain bracametin hydrochloride.

[0035] The organic solvent is selected from methyl tert-butyl ether, n-heptane, isopropyl ether, n-hexane, petroleum ether, ethanol, methanol, isopropanol, tetrahydrofuran, 1,4-dioxane, dichloromethane or a combination thereof, more preferably, a mixed solvent of ethanol or isopropanol and n-heptane or n-hexane.

[0036] In another preferred embodiment, the organic solvent is selected from a mixed solution of isopropyl alcohol and n-heptane, wherein the volume ratio of isopropyl alcohol to n-heptane is 1:3-7.

[0037] In another preferred embodiment, the weight-to-volume ratio of the crude bracametacin hydrochloride to the mixed solution of isopropyl alcohol and n-heptane is 1 g / 10-20 mL. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 is the HPLC spectrum of the reaction solution obtained in Comparative Example 1a.

[0039] Figure 2 Comparative Example 1 shows the H-NMR spectrum of impurity A.

[0040] Figure 3 Comparative Example 1 shows the H-NMR spectrum of impurity B.

[0041] Figure 4 This is the HPLC spectrum of the compound of formula II obtained in Example 4.

[0042] Figure 5 This is the HPLC spectrum of the crude product of the compound of formula III obtained in Example 5.

[0043] Figure 6 This is the HPLC spectrum of the crude compound of formula III prepared according to the method disclosed in WO1997030983A1 in Example 7. DETAILED DESCRIPTION

[0044] To address the problems existing in the prior art methods for preparing braumatacin hydrochloride and its intermediates, the inventors of the present application, through in-depth research, screened various reducing agents for preparing the compound of Formula II. They unexpectedly discovered that using sodium borohydride and / or lithium borohydride and a Lewis acid as a reduction system, particularly sodium borohydride and aluminum chloride, as a reduction system, can simultaneously reduce the ester group and the carbonyl group in the acyl group of the compound of Formula I, resulting in a high yield of the target product with low impurities. The post-processing and reaction procedures of this method are also relatively simple, and the results of multiple batch reactions are stable, making it suitable for industrial scale-up production. Furthermore, the inventors of the present application discovered that during the purification of crude braumatacin hydrochloride, high-purity braumatacin hydrochloride can be obtained by using ethanol or isopropanol and n-heptane as solvents, followed by slurrying and filtration, making it very suitable for industrial large-scale production. The present invention was completed on this basis.

[0045] Preparation method of compound of formula II

[0046]

[0047] In the present invention, the method for preparing the compound of Formula II from the compound of Formula I utilizes sodium borohydride and / or lithium borohydride and a Lewis acid as a reducing system, particularly sodium borohydride and aluminum chloride, to simultaneously reduce the two carbonyl groups of the compound of Formula I to form the compound of Formula II. The solvent used in the reaction is a conventional solvent for such reactions in the art, including but not limited to ethanol, tetrahydrofuran, ethylene glycol monomethyl ether, 1,4-dioxane, toluene, ethylene glycol dimethyl ether, isopropyl ether, isopropyl alcohol, and methyl tert-butyl ether. The reaction temperature is a conventional temperature for such reactions in the art, preferably 40 to 70°C.

[0048] In some specific embodiments of the present invention, the post-treatment of the reaction solution in this step is very simple. The reaction is quenched with an aqueous ammonium chloride solution, and the pH of the system is adjusted to 7-8. After extraction and concentration with an organic solvent, the obtained residue is slurried with dichloromethane and n-heptane to obtain a high-purity compound of formula II.

[0049] Preparation method of bracametacin hydrochloride

[0050] In the present invention, the preparation method of bracamethin hydrochloride comprises the steps of subjecting the compound of formula II to an intramolecular condensation reaction in the presence of an acid to generate bracamethin, and then reacting the compound with hydrochloric acid to generate bracamethin hydrochloride.

[0051] In the intramolecular condensation reaction system of the compound of formula II, the acid used includes but is not limited to toluenesulfonic acid, phosphoric acid, oxalic acid, boron trifluoride etherate, sulfuric acid or hydrochloric acid. The solvent used includes but is not limited to toluene, ethylene glycol dimethyl ether, dichloromethane, tetrahydrofuran, 1,4-dioxane and water.

[0052] In some specific embodiments of the present invention, after the compound of formula II undergoes an intramolecular condensation reaction to produce bracamethin, the reaction solution is cooled to 0-30° C., the pH is adjusted to 9-10, the liquids are separated, the organic phase is washed with water, and hydrochloric acid (e.g., a mixture of hydrochloric acid and alcohol) is added. After stirring, a solid is precipitated, filtered, and dried to obtain a crude bracamethin hydrochloride.

[0053] In some specific embodiments of the present invention, the crude bracamethin hydrochloride is slurried and stirred in a mixture of ethanol or isopropanol and n-heptane (to which HCl is added in ethanol or isopropanol solution) to obtain a high-purity compound of formula III.

[0054] Compared with the prior art, the present invention has the following beneficial effects:

[0055] 1) The method for preparing the compound of formula II of the present invention uses sodium borohydride and / or lithium borohydride and a Lewis acid as a reducing agent. The reducing agent is inexpensive, the reaction is mild, and the product yield and purity are high, making it suitable for industrial large-scale production.

[0056] 2) The purification method of the crude brakametacin hydrochloride obtained by the preparation method of brakametacin hydrochloride of the present invention is simple and does not require column chromatography purification. In particular, by beating and stirring in a mixture of ethanol and n-heptane (with the addition of HCl) or a mixture of isopropanol and n-heptane (with the addition of HCl), a high-purity product can be obtained with a yield of more than 95%, and no unknown impurities greater than 0.10% are present, meeting the impurity requirements of ICH Q3A.

[0057] The present invention will be further described below with reference to specific embodiments, but should not be limited to the following examples in practical applications.

[0058] The present invention will be further described in detail in conjunction with the following specific implementations. The protection content of the present invention is not limited to the following examples. Without departing from the spirit and scope of the inventive concept, changes and advantages that can be thought of by those skilled in the art are included in the present invention and are protected by the scope of the appended claims. The process, conditions, reagents, experimental methods, etc. for implementing the present invention, except for the contents specifically mentioned below, are all common knowledge and common common sense in the art, and the present invention does not particularly limit the content.

[0059] The starting compound of formula I can be prepared by the method disclosed in WO1997030983A1.

[0060] Comparative Example 1 Preparation of compound II according to prior art WO1997030983A1

[0061] At room temperature, 30 mL of tetrahydrofuran and 5.0 g (16.2 mmol) of the compound of Formula I were added sequentially to the reaction flask. A solution of lithium aluminum tetrahydride in tetrahydrofuran (concentration: 6.2 g / 100 mL) was then added dropwise. The mixture was stirred at a constant temperature until the starting material was essentially gone (approximately 10 hours). The reaction solution was analyzed by HPLC. After completion of the reaction, the mixture was cooled to room temperature and quenched with approximately 5 mL of a 10% aqueous sodium hydroxide solution. 5 mL of water was added, the mixture was filtered, and the filtrate was concentrated. To the resulting residue, approximately 30 mL of a mixture of ethyl acetate and n-heptane (volume ratio: 1:5) was added, the mixture was slurried, filtered, and dried to obtain the compound of Formula II.

[0062] The reaction conditions and products are shown in Table 1.

[0063] Table 1

[0064]

[0065] Note: The contents mentioned in Table 1 are those determined by HPLC, and “ / ” indicates that no content determination was performed.

[0066] The HPLC spectrum of the reaction solution of Comparative Example 1a (according to the method disclosed in WO1997030983A1) is shown in Figure 1 .

[0067] It can be seen from Table 1 that the change in temperature has a great influence on the reaction conversion rate and the generation of by-products, and the addition process (especially the reducing agent) is usually accompanied by a violent exotherm, which is difficult to control in the scale-up production and is very unfavorable for scale-up production.

[0068] It can also be seen from Table 1 that the product obtained by using lithium aluminum tetrahydride as a reducing agent contains two relatively obvious impurities. The applicant has characterized these impurities. The nuclear magnetic hydrogen spectrum of impurity A is shown in Figure 2 The H NMR spectrum of impurity B is shown in Figure 3 (Impurity A and impurity B correspond to Figure 1 RT = 11.062 and RT = 12.045), the structural formulas are as follows:

[0069] Impurity A: Impurity B:

[0070] Wherein, impurity A is an intermediate of the synthetic formula II; impurity B is a by-product of the reverse condensation reaction of impurity A in the presence of Lewis acid.

[0071] Example 1 Preparation of Compound of Formula II

[0072] The inventors of the present application reduced the compound of formula I using the following reducing agents respectively. Under the conventional use conditions of these catalysts, the yield and purity of the obtained products are shown in Table 2 below:

[0073] The experimental process of Examples 1a to 1e is as follows:

[0074] At room temperature, tetrahydrofuran (30 mL) and 5 g (16.2 mmol) of the compound of Formula I were added to the reaction flask in sequence. 2.5 eq of the reducing agent was added in batches. The mixture was stirred at a constant temperature for 10 hours. The consumption of the starting materials was monitored by HPLC. If there was a significant amount of starting materials remaining, the reaction solution was stirred and retested. The reaction was stopped when the starting materials were essentially gone or no longer reduced after 2 to 3 retests. After the reaction was completed, the reaction solution was tested by HPLC, as shown in Table 2 below.

[0075] When NaBH4 is used as the reducing agent, the Lewis acid is directly added to the solvent before adding the compound of formula I, and the amount of the Lewis acid used is 4 eq (relative to the compound of formula I).

[0076] Table 2

[0077]

[0078]

[0079] It can be seen from Table 2 that the reaction of sodium borohydride and Lewis acid is the best condition.

[0080] Example 2

[0081] Based on Example 1, the inventors further studied the conditions under which sodium borohydride was used as a reducing agent. The products and impurities obtained with different Lewis acids were studied, as shown in Table 3 below.

[0082] The experimental process of Examples 2a to 2e is as follows:

[0083] At room temperature, tetrahydrofuran (60 mL) and Lewis acid (4 eq) were added to the reaction flask in sequence, followed by 5.0 g (16.2 mmol) of the compound of formula I, and 1.5 g (40.5 mmol) of sodium borohydride in three batches. The mixture was heated to a certain temperature with temperature control and stirring. The reaction was stopped when the conversion of the compound of formula I was substantially complete (approximately 8 to 9 hours) as monitored by HPLC. When the reaction was complete, the reaction solution was detected by HPLC, as shown in Table 3 below.

[0084] Table 3

[0085]

[0086] Note: “ND” means not available.

[0087] As can be seen from Table 3, NaBH4+AlCl3 is the best reduction condition.

[0088] Example 3a-3e: Preparation of Compound II Using NaBH4+AlCl3 as Reduction Conditions

[0089] Based on Example 2, the inventors further studied the dosage of sodium borohydride as the reducing agent and AlCl3 as the Lewis acid. The dosage of AlCl3, the product, and the impurities are shown in Table 4 below.

[0090] The experimental process of Examples 3a to 3d is as follows:

[0091] At room temperature, tetrahydrofuran (30 mL) and aluminum chloride (2.2 g, 6.5 g, 8.6 g, 10.8 g, and 13.0 g, respectively (16.2 mmol, 48.6 mmol, 64.8 mmol, 81.0 mmol, and 97.2 mmol)) were added to the reaction flask. Then, 5.0 g (16.2 mmol) of the compound of Formula I was added. Then, 1.5 g (40.5 mmol) of sodium borohydride was added in three batches. The mixture was heated to 55°C and stirred under controlled temperature for 8-9 hours. After HPLC monitoring of the substantial conversion of the compound of Formula I, saturated aqueous ammonium chloride was added to the reaction solution to quench the reaction. The pH of the system was adjusted to 7-8. Dichloromethane was added, the mixture was separated, and the organic phase was concentrated to obtain a crude compound of Formula II. The crude compound of Formula II was added to approximately 45 mL of a mixture of dichloromethane and n-heptane (volume ratio of dichloromethane to n-heptane: 1:8), slurried, and stirred for 1 hour. The solid was filtered and dried under vacuum to obtain the compound of formula II.

[0092] Table 4

[0093]

[0094] Note: “ND” means not available.

[0095] As can be seen from Table 4, the amount of aluminum chloride added plays a key role in the content of impurity B in the reaction solution. Different amounts of aluminum chloride added have a significant effect on the purity of the compound of formula II. The optimal amount of AlCl3 is 5.0 eq.

[0096] Examples 3f-3g

[0097] Based on Example 3d, the inventors further studied the amount of sodium borohydride used. The amount of sodium borohydride used and the impurities of the product are shown in Table 5 below.

[0098] The experimental process of Examples 3f to 3g is as follows:

[0099] At room temperature, tetrahydrofuran (60 mL) and 10.8 g (81.0 mmol) of aluminum chloride were added to the reaction flask, followed by 5.0 g (16.2 mmol) of the compound of Formula I. Sodium borohydride (0.92 g (24.3 mmol), 1.5 g (40.5), 2.1 g (56.7 mmol), 2.8 g (72.9 mmol), and 3.4 g (89.1 mmol) were then added in three batches. The mixture was heated to 55°C and stirred under controlled temperature for 8-9 hours. After HPLC monitoring indicated near-complete conversion of the compound of Formula I or after two retests indicated minimal reduction in the starting material, the reaction mixture was removed from the heat and cooled to ambient temperature. Saturated aqueous ammonium chloride was added to quench the reaction. The pH was adjusted to 7-8. Dichloromethane was added, the mixture was separated, and the organic phase was concentrated to yield the crude compound of Formula II. The crude compound of Formula II was slurried in approximately 45 mL of a mixture of dichloromethane and n-heptane (volume ratio 1:8), and stirring was continued for 1 hour. The solid was filtered and dried under vacuum to obtain the compound of formula II.

[0100] Table 5

[0101]

[0102] Note: “ND” means not available.

[0103] As can be seen from Table 5, the amount of NaBH4 added has an impact on the yield of the target product, and the optimal amount of NaBH4 is 2.5eq.

[0104] Examples 3h to 3j

[0105] Based on Example 3g, the inventors further studied the reaction temperature. The reaction temperature and impurity conditions of the product are shown in Table 6 below.

[0106] The experimental procedures of Examples 3h to 3j are as follows:

[0107] At room temperature, tetrahydrofuran (60 mL) and 10.8 g (81.0 mmol) of aluminum chloride were added to three reaction flasks in sequence, 5.0 g (16.2 mmol) of the compound of formula I was added, and 1.5 g (40.5) of sodium borohydride was added in three batches. The three reaction flasks were heated to 45° C., 55° C., and 65° C., respectively, with temperature control and stirring. The reaction was monitored by HPLC. The HPLC test results of the reaction solution after 9 hours of reaction are shown in Table 6 below.

[0108] Table 6

[0109]

[0110] As can be seen from Table 6, temperature has an impact on the yield of the target product. The reaction temperature is low at 45°C, the reaction rate is slow, and the impurities produced at 45°C increase significantly, resulting in a low content of the target product. The optimal reaction temperature is 55°C.

[0111] Example 4 Preparation of Compound II Using Sodium Borohydride as Reducing Agent

[0112] Tetrahydrofuran (600 mL), aluminum chloride (215 g), and the compound of formula I (100 g, 323 mmol) were added to the reaction flask in sequence at room temperature. Sodium borohydride (31 g) was added in three batches, heated to 55°C, and stirred at the temperature for 8 to 9 hours. HPLC monitored the complete conversion of the compound of formula I, and saturated aqueous ammonium chloride solution (200 mL) was added to the reaction solution to quench the reaction. The pH of the system was adjusted to 7 to 8. 400 mL of dichloromethane was added, the liquids were separated, and the organic phase was concentrated to obtain a crude compound of formula II. The crude compound of formula II was added to a mixture of about 900 mL of dichloromethane and n-heptane (volume ratio 1:8) and continued to stir for 1 hour. Filter and vacuum dry the obtained solid to obtain 87 g of compound of formula II with a molar yield of 89.9% and an HPLC purity of 99.91%. The HPLC spectrum is shown in FIG. Figure 4 .

[0113] Example 5 Preparation of Formula III Compound

[0114]

[0115] Purified water (25 mL) and 7.6 g (about 75 mmol) of concentrated hydrochloric acid and 5 g (16.7 mmol) of the compound of formula II prepared in Example 4 were added to the reaction flask in sequence. Heat to 30-40°C and stir for 9 hours. HPLC monitoring showed that the compound of formula II was completely converted, the temperature was lowered, n-heptane (75 mL) was added, the pH was adjusted to 7-8, the liquid was separated, 2M hydrochloric acid / isopropanol (15 mL) was added and stirred for 2 hours, filtered, and dried for 8 hours to obtain 5.1 g of the compound of formula III with a molar yield of 96.0% and an HPLC purity of 99.95% (for the details of the compound of formula III, see Table 7). Figure 5 .

[0116] Table 7

[0117]

[0118] Example 6 Preparation of Formula III Compound

[0119] Toluene (30 mL), 60 g (66.8 mmol) of oxalic acid, and 10 g (33.4 mmol) of the compound of Formula II prepared in Example 4 were added to the reaction flask in sequence and stirred for 10 minutes. The mixture was heated to reflux and stirred for 6 hours. HPLC analysis confirmed the complete conversion of the compound of Formula I. The temperature was then lowered to 25°C, the pH was adjusted to 9-10, and the mixture was separated. The organic phase was washed twice with water (20 mL). 2M hydrochloric acid / ethanol (30 mL) was added and stirred for 2 hours, resulting in the precipitation of a large amount of white solid. Filtering and drying afforded 8.7 g of the compound of Formula III in a molar yield of 77.9% and an HPLC purity of 95.00%.

[0120] Example 7 Preparation of the compound of formula III (according to the method disclosed in WO1997030983A1)

[0121] Benzene (70 mL) and 2.0 g (6.7 mmol) of the compound of formula II prepared in Example 4, and 2.5 g (13.4 mmol) of p-toluenesulfonic acid were added to the reaction flask in sequence, heated to reflux, and stirred for 5 hours. HPLC monitoring of the complete conversion of the compound of formula I was performed, the temperature was lowered to 25°C, the pH was adjusted to 9-10 with 10% sodium hydroxide, the liquid was separated, the organic phase was washed twice with water (20 mL), concentrated hydrochloric acid (0.8 g) was added and stirred for 0.5 hours, and a large amount of white solid was precipitated. Filter and dry to obtain 1.8 g of compound of formula III, with a molar yield of 81.3%, a HPLC purity of 96.13%, and an impurity ratio of 3.86%. Figure 6 .

[0122] Example 8 Purification of the compound of formula III

[0123] Solvent A (15 mL), solvent B (75 mL) (see Table 8 for details), and HPLC-purified 95.0% compound III (5 g) were added to the reaction flask in sequence. 1 M HCl in isopropanol (1.5 eq. HCl) was added and stirred for 1 hour. The mixture was filtered and dried to obtain the highly pure compound III.

[0124] Table 8

[0125] Example No. Solvent A Solvent B purity Yield 8a / Ethyl acetate 98.25％ 85％ 8b / Toluene 96.34％ 96％ 8c Isopropyl alcohol n-heptane 99.96％ 97％ 8d Isopropyl alcohol / 99.95％ 76％ 8e ethanol / 99.96％ 60％ 8f ethanol n-heptane 99.96％ 94％ 8g / n-heptane 95.86％ 98％ 8h / Isopropyl acetate 98.18％ 89％ 8i / Methyl tert-butyl ether 96.69％ 94％ 8g dichloromethane n-heptane 98.79％ 66％ 8k dichloromethane Methyl tert-butyl ether 99.12％ 60％ 8l Ethyl acetate n-heptane 97.75％ 97％

[0126] As can be seen from Table 8, the mixture of ethanol and n-heptane or the mixture of isopropanol and n-heptane has the best purification effect on the compound of formula III.

[0127] Example 9 Purification of the compound of formula III

[0128] Based on Example 8, the inventors further studied the volume ratio of isopropyl alcohol and n-heptane in a mixture of the two. The results are shown in Table 9 below.

[0129] Isopropanol (15 mL), n-heptane (45 mL, 60 mL, 75 mL, 90 mL) (see Table 9 for details) and 95.0% HPLC purity compound III (5 g) were added to the reaction flask in sequence. 1 M HCl isopropanol solution (HCl dosage: 1.5 eq.) was added, stirred for 1 hour, filtered, and dried to obtain a high-purity compound of formula III.

[0130] Table 9

[0131] Example No. Isopropyl alcohol n-heptane purity Yield 9a 15mL 45mL 99.97％ 84％ 9b 15mL 60mL 99.95％ 88％ 9c 15mL 75mL 99.96％ 97％ 9d 15mL 90mL 99.61％ 96％

[0132] As can be seen from Table 9, when the volume ratio of isopropanol to n-heptane in the mixture is 1:5, the purification effect of the compound of formula III is the best.

[0133] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A method for preparing a compound of formula II, characterized in that: The preparation method comprises the following steps: in the presence of a reducing agent, the compound of formula I undergoes a reduction reaction to generate a compound of formula II, and the reaction formula is as follows: The reducing agent is selected from sodium borohydride and / or lithium borohydride, and A Lewis acid is also present in the reaction system, and the Lewis acid is further selected from zinc bromide, zinc chloride, boron trifluoride, aluminum chloride, ferric chloride, or a combination thereof.

2. The preparation method according to claim 1, characterized in that The reducing agent is selected from sodium borohydride, and the Lewis acid is selected from aluminum chloride.

3. The preparation method according to claim 1 or 2, characterized in that The solvent used in the reaction is selected from ethanol, tetrahydrofuran, ethylene glycol monomethyl ether, 1,4-dioxane, toluene, ethylene glycol dimethyl ether, isopropyl ether, isopropyl alcohol, methyl tert-butyl ether or a combination thereof, more preferably 1,4-dioxane or tetrahydrofuran.

4. The preparation method according to claim 1 or 2, characterized in that The molar ratio of the compound of formula I to the reducing agent is 1:1.5-6.0, more preferably 1:2.0-4.0, and The molar ratio of the compound of formula I to the Lewis acid is 1:1.0-7.0, more preferably 1:3.0-6.

0.

5. The preparation method according to claim 1, characterized in that The reaction temperature is 40-70°C, more preferably 50-60°C.

6. A method for preparing a compound of formula II, characterized in that: The preparation method comprises the following steps: In tetrahydrofuran, in the presence of sodium borohydride and aluminum chloride, the compound of formula I undergoes a reduction reaction to generate a compound of formula II. The reaction formula is as follows:

7. A method for preparing bracametacin hydrochloride, characterized in that: The preparation method comprises the following steps: (1) The preparation method according to any one of claims 1 to 6, to prepare the compound of formula II; (2) In the presence of an acid, the compound of formula II undergoes an intramolecular condensation reaction to produce bracamethin; (3) Bracametacin forms a salt with hydrochloric acid to generate bracametacin hydrochloride. The reaction formula is as follows:

8. The preparation method according to claim 1, characterized in that In step (2), the acid is selected from p-toluenesulfonic acid, phosphoric acid, oxalic acid, boron trifluoride etherate, sulfuric acid or hydrochloric acid, more preferably oxalic acid or hydrochloric acid, and / or In step (2), the solvent is selected from toluene, ethylene glycol dimethyl ether, dichloromethane, tetrahydrofuran, 1,4-dioxane, water or a combination thereof, more preferably, water or toluene, and / or In step (2), the molar ratio of the compound of formula II to the acid is 1:1.5 to 1:8, more preferably 1:2 to 5.

9. The preparation method according to claim 7 or 8, characterized in that The method further comprises the steps of: (4) The crude product of bracametin hydrochloride obtained by treating the reaction solution of bracametin with hydrochloric acid in an organic solvent containing hydrogen chloride is slurried and filtered to obtain bracametin hydrochloride. The organic solvent is selected from methyl tert-butyl ether, n-heptane, isopropyl ether, n-hexane, petroleum ether, ethanol, methanol, isopropanol, tetrahydrofuran, 1,4-dioxane, dichloromethane or a combination thereof, more preferably, a mixed solvent of ethanol or isopropanol and n-heptane or n-hexane.

10. The preparation method according to claim 9, characterized in that The organic solvent is selected from a mixed solution of isopropanol and n-heptane, wherein the volume ratio of isopropanol to n-heptane is 1:3-7, and / or The weight-to-volume ratio of the crude bracametacin hydrochloride to the mixed solution of isopropyl alcohol and n-heptane is 1 g / 10-25 mL.

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