CN111909152B - Preparation method of BTK inhibitor and intermediate thereof - Google Patents

Abstract

The invention relates to (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1, Preparation method of 5-a]pyrimidine-3-carboxamide and its intermediates.

Description

Preparation methods of BTK inhibitors and intermediates thereof

Technical field

The present invention relates to (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1, Preparation method of 5-a]pyrimidine-3-carboxamide and its intermediates.

Background technique

International application WO2014173289 discloses a series of fused heterocyclic compounds that can serve as inhibitors of Bruton's tyrosine kinase (BTK). Specifically, WO2014173289 discloses (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazole And[1,5-a]pyrimidine-3-carboxamide (hereinafter also referred to as compound 1)

Compound 1 is a potent, specific and irreversible BTK inhibitor. Preclinical study data indicate that Compound 1 may have a significant effect on inhibiting the growth of B-cell malignant tumors. Since compound 1 shows better selectivity than ibrutinib for inhibiting BTK against EGFR, FGR, FRK, HER2, HER4, ITK, JAK3, LCK and TEC, it is expected to be more clinically effective than ibrutinib. Minor side effects. Furthermore, compound 1 showed that its antigen-dependent cell-mediated cytotoxicity (ADCC) induced by rituximab was significantly less than that of ibrutinib due to its weaker ITK inhibition, and thus could be used in combination with rituximab Monoclonal antibodies or other ADCC-dependent antibody combinations provide better efficacy when used to treat B-cell malignancies.

WO2018033853 discloses a method for preparing compound 1, which uses a chiral acid resolving agent D-DBTA to resolve BG-11A to obtain a single stereoconfiguration intermediate BG-11B. The method disclosed in WO2018033853 is suitable for industrial large-scale production, but the yield of intermediate BG-11A used in the key chiral resolution step needs to be improved.

Contents of the invention

The inventor of the present invention found that by optimizing the reaction parameters, especially by improving the reaction temperature in the step of synthesizing intermediate BG-11A from intermediate BG-10, the reaction yield and the purity of the product can be significantly improved.

In a first aspect, the present invention relates to a method for preparing compound 1. The method includes: reacting intermediate BG-13 with an acryl compound in a solvent, then adding seed crystals of compound 1, and crystallizing to obtain compound 1.

In some embodiments, the acryloyl compound feed equivalent is 0.95-1.3.

In some embodiments, the acryloyl compound is selected from acrylic halide, acrylic acid, or acrylic anhydride. In a further embodiment, the acryloyl compound is an acryloyl halide, preferably acryloyl chloride.

In some embodiments, the reaction is further performed in the presence of L-(+)-tartaric acid and sodium bicarbonate.

In some embodiments, the solvent is selected from the group consisting of non-polar solvents, polar protic solvents, and polar aprotic solvents, or mixtures thereof. Suitable polar aprotic solvents include, but are not limited to, N-methylpyrrolidone, N-methylmorpholine, methyl isobutyl ketone, methyl ethyl ketone, tetrahydrofuran, dichloromethane, ethyl acetate, acetone , N,N-dimethylformamide, acetonitrile and dimethyl sulfoxide. Suitable polar protic solvents include, but are not limited to, water, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, formic acid or acetic acid, etc. Suitable non-polar solvents include, but are not limited to, dioxane, toluene, hexane, cyclohexane and diethyl ether. In a further embodiment, the solvent is a mixed solvent of a polar aprotic solvent and a polar protic solvent. Preferably, the solvent is a mixed solvent of acetonitrile and water.

In some embodiments, the reaction is performed at a temperature of -5 to 35°C.

In some embodiments, the method for preparing compound 1 of the present invention includes: reacting intermediate BG-13 with an acryloyl compound in a solvent, and after the reaction is completed, extracting with ethyl acetate, ethyl acetate and dichloromethane The solvent was exchanged, and then the seed crystal of compound 1 was added, and methyl tert-butyl ether was crystallized to obtain compound 1.

In a second aspect, the present invention relates to a step for preparing intermediate BG-13, which includes: hydrolyzing intermediate BG-11D in the presence of acid; or further reacting with a resolving agent to form intermediate BG-12, Wherein, the intermediate BG-12 is used to remove the resolving agent with an alkali in a solvent to obtain the intermediate BG-13,

The acid used in hydrolysis is not particularly limited and may be a common organic acid or inorganic acid. The inorganic acid is, for example, hydrochloric acid, phosphoric acid, dihydrogen phosphoric acid, hydrobromic acid, sulfuric acid, sulfurous acid and nitric acid; and the organic acid is, for example, malic acid, maleic acid, fumaric acid, tartaric acid, succinic acid , citric acid, lactic acid, methanesulfonic acid, p-toluenesulfonic acid, 2-hydroxyethanesulfonic acid, benzoic acid, salicylic acid, stearic acid, alkanoic acid (such as acetic acid and HOOC-(CH2)n-COOH, Where n is selected from 0-4) etc. In some embodiments, the acid is an organic acid, such as methanesulfonic acid. In some embodiments, the hydrolysis reaction is carried out at a temperature of 75 to 100°C, preferably at a temperature of 75 to 85°C, more preferably at a temperature of 75 to 80°C.

In some embodiments, after the intermediate BG-11D is hydrolyzed in the presence of acid, the pH value is further adjusted to 11-12 with a base.

In some embodiments, the resolving agent is an acidic resolving agent, such as (+)-tartaric acid, (+)-camphoric acid, (+)-camphor-10-sulfonic acid, L-(+)-glycine, L-(+)-dibenzoyltartaric acid (L-DBTA) and the like, preferably L-DBTA.

In some embodiments, the solvent is selected from the group consisting of non-polar solvents, polar protic solvents, and polar aprotic solvents, or mixtures thereof. In a further embodiment, the solvent is a polar aprotic solvent selected from N-methylpyrrolidone, N-methylmorpholine, methyl isobutyl ketone, methyl ethyl ketone, tetrahydrofuran, dichloromethane , ethyl acetate, acetone, N,N-dimethylformamide, isopropyl acetate, acetonitrile and dimethyl sulfoxide, or a mixture of two or more of the above. In a further embodiment, the solvent is acetonitrile.

In some embodiments, the base is an alkali metal hydroxide, an alkaline earth metal hydroxide, an alkali metal carbonate, an alkali metal bicarbonate, an alkali metal bicarbonate, or an alkaline earth metal bicarbonate, preferably hydroxide Sodium, potassium hydroxide or sodium bicarbonate, etc.

In a specific embodiment, a method of preparing BG-13 includes:

In a third aspect, the present invention relates to steps for preparing BG-11D, which includes: using a resolving agent to resolve intermediate BG-11A to obtain intermediate salt BG-11B,

Then the intermediate salt BG-11B is reacted with a base to remove the bound resolving agent and obtain the enantiomeric intermediate BG-11D.

In some embodiments, the resolving agent is an acidic resolving agent. The acidic resolving agent is selected from (+)-tartaric acid, (+)-camphoric acid, (+)-camphor-10-sulfonic acid, D-(+)-glycine, D-(+)-dibenzoyl Tartaric acid (D-DBTA), etc. Preferably, the resolving agent is D-DBTA.

In some embodiments, the mixed solvent used in the resolution reaction is acetic acid/water/ethanol. In a further embodiment, the proportion of acetic acid in the acetic acid/water/ethanol mixed solvent is 13-29% mass ratio. In some embodiments, the amount of mixed solvent is not less than 23.1 volumes.

In some embodiments, the intermediate BG-11A is stirred in the mixed solvent at a temperature of 30 to 65°C.

In some embodiments, the solution of the intermediate BG-11A in the mixed solvent reacts with the resolving agent at a temperature of 30-65°C, preferably at a temperature of 50 to 55°C.

In some embodiments, the BG-11A and the resolving agent (preferably D-DBTA) are added sequentially or simultaneously. In a further embodiment, the BG-11A and the resolving agent (preferably D-DBTA) are added simultaneously to obtain stable chemical resolving performance. In some embodiments, the amount of resolving agent (preferably D-DBTA) is 0.5-1.45 equivalents.

In some embodiments, the intermediate salt BG-11B is reacted with a base, and the step of removing the bound resolving agent further includes adding an additional amount of resolving agent to reform the salt. In a further embodiment, the amount of resolving agent used to reform the salt is 0.2-0.6 equivalents (relative to 1.0 equivalents of BG-11B).

In some embodiments, the intermediate salt BG-11B is reacted with a base, the base being an alkali metal hydroxide, an alkaline earth metal hydroxide, an alkali metal carbonate, an alkali metal bicarbonate, an alkali metal carbonate The hydrogen salt or alkaline earth metal hydrogen carbonate is preferably sodium hydroxide, potassium hydroxide or sodium hydrogen carbonate.

In some embodiments, the solvent is selected from the group consisting of non-polar solvents, polar protic solvents, and polar aprotic solvents, or mixtures thereof. Suitable polar aprotic solvents include, but are not limited to, N-methylpyrrolidone, N-methylmorpholine, methyl isobutyl ketone, methyl ethyl ketone, tetrahydrofuran, dichloromethane, ethyl acetate, acetone , N,N-dimethylformamide, acetonitrile and dimethyl sulfoxide. Suitable polar protic solvents include, but are not limited to, water, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, formic acid or acetic acid, etc. Suitable non-polar solvents include, but are not limited to, dioxane, toluene, hexane, cyclohexane and diethyl ether. In a further embodiment, the solvent is a mixed solvent of a polar aprotic solvent and a polar protic solvent. Preferably, the solvent is a mixed solvent of acetonitrile and water.

In a specific embodiment, a method of preparing BG-11D includes:

In a fourth aspect, the present invention relates to a step for preparing intermediate BG-11A, which includes: treating intermediate BG-11A with an acid in a solvent at an elevated temperature to remove the Boc group to obtain intermediate BG-11A,

In some embodiments, the acid is an inorganic acid or an organic acid, such as hydrochloric acid, phosphoric acid, dihydrogen phosphoric acid, hydrobromic acid, sulfuric acid, sulfurous acid, and nitric acid; and the organic acid is, for example, malic acid. , maleic acid, fumaric acid, tartaric acid, succinic acid, citric acid, lactic acid, methanesulfonic acid, p-toluenesulfonic acid, 2-hydroxyethanesulfonic acid, benzoic acid, salicylic acid, stearic acid, alkanoic acid (Such as acetic acid and HOOC-(CH2)n-COOH, where n is selected from 0-4), etc. Preferably, the acid is hydrochloric acid.

In some embodiments, the elevated temperature is a temperature above room temperature and below 65°C. In a further embodiment, the elevated temperature is in the temperature range of 40 to 60°C.

In some embodiments, the solvent is a non-polar solvent, a polar protic solvent, a polar aprotic solvent, or a mixture thereof. Suitable polar aprotic solvents include, but are not limited to, N-methylpyrrolidone, N-methylmorpholine, methyl isobutyl ketone, methyl ethyl ketone, tetrahydrofuran, dichloromethane, ethyl acetate, acetone, N , N-dimethylformamide, acetonitrile and dimethyl sulfoxide. Suitable polar protic solvents include, but are not limited to, water, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, formic acid or acetic acid, etc. Suitable non-polar solvents include, but are not limited to, dioxane, toluene, hexane, cyclohexane and diethyl ether. Preferably, the solvent is ethanol.

In some embodiments, the amount of solvent (preferably ethanol) is 5.0-8.0X (mass).

In some embodiments, the deprotection reaction proceeds for no more than 72 hours.

In some embodiments, the method for preparing intermediate BG-11A further includes: after the deprotection reaction, adjusting the pH value at a temperature of 20 to 75°C, preferably at a temperature of 50 to 65°C. In a further embodiment, the pH value is not less than 11.5, preferably in the range of 12.5-13.5. In a further embodiment, the pH value is adjusted by adding an alkaline solution, such as aqueous sodium hydroxide solution.

In a specific embodiment, the method of preparing BG-11A includes:

Example

The following reaction scheme details the preparation of compound 1 starting from intermediate BG-10.

reaction scheme

The method of the present invention is particularly suitable for reproducibly preparing compound 1 on a commercial scale with high quality and high yield; and by optimizing or improving the synthesis process, the method of the present invention can further improve the reaction yield or purity of each step to better Generate the final target compound in an economical or more environmentally friendly way.

For example, in the step of synthesizing BG-11A from intermediate BG-10, a more environmentally friendly ethanol is used as the solvent to replace the original methylene chloride; the deprotection reaction is performed at an elevated temperature, further improving the purity and purity of the reaction product. /or the yield is significantly improved (for example, as high as 97.6%); moreover, the process complexity of downstream steps is further reduced.

For another example, in the step of synthesizing BG-11D from intermediate BG-11A, the amount of solvent used is reduced to about 50%. By adding intermediate BG-11A and resolving agent D-DBTA at the same time, consistent chemical resolution performance was obtained; stable chemical resolution performance and high chiral purity were achieved; and the entire manufacturing cycle time was also reduced, This further improves manufacturing efficiency.

For another example, in the step of synthesizing BG-13 from intermediate BG-11D, the post-processing steps are optimized by adding the solvent acetonitrile to directly perform phase separation; and BG-13 is directly separated into the free base form instead of L-DBTA salt form. Moreover, the added methanesulfonic acid can be removed through simple post-treatment. This step can also reduce the formation of some impurities.

For another example, in the step of synthesizing compound 1 from intermediate BG-13, especially in the post-processing, the crystallization process was optimized by adding seed crystals to avoid agglomeration during the crystallization process, thus improving the quality of the final product.

The following examples are used to illustrate the present invention but are not intended to limit the scope of the present invention.

Example 1: Synthesis of BG-11A

Example 1A

Compound BG-10 (20g, 1.0X) was suspended in ethanol (8.0X), and then about 20% hydrochloric acid ethanol solution was added. The reaction mixture was heated to 40°C and then stirred for 5 hours until the reaction was complete. The reaction mixture was concentrated and additional ethanol and water were added. At a temperature of 20°C, adjust the pH value to 13.2 with sodium hydroxide aqueous solution within 1 hour. The mixture was cooled and centrifuged. The obtained wet cake was washed with a mixed solvent of ethanol/water, and then dried under vacuum to obtain 15.6 g of compound BG-11A (purity: 99.05%, yield: 96.6%).

Example 1B

Compound BG-10 (20g, 1.0X) was suspended in ethanol (6.5X), and then about 20% hydrochloric acid ethanol solution was added. The reaction mixture was heated to 60°C and then stirred for 72 hours until the reaction was complete. The reaction mixture was concentrated and additional ethanol and water were added. At a temperature of 50°C, adjust the pH value to 13.0 with sodium hydroxide aqueous solution within 24 hours. The mixture was cooled and centrifuged, then slurried in ethanol and water. The obtained wet cake was washed with a mixed solvent of ethanol/water, and then dried under vacuum to obtain 16.5 g of compound BG-11A (purity: 99.13%, yield: 95.2%).

Example 2: Synthesis of BG-11B

Example 2A

BG-11A (30g, 1.0X, 1.0 equiv) was dissolved in a mixture of ethanol/water/acetic acid (14.7X, acetic acid: 23%). The solution obtained was partially transferred to the reaction vessel. Additional ethanol/water/acetic acid mixed solvent (3.6X, acetic acid: 24%) was added to the reaction vessel. The reaction solution was heated to 55°C. D-DBTA (1.0 equiv) was then dissolved in a mixture of ethanol/water/acetic acid (4.8X, acetic acid: 23%), and the obtained D-DBTA solution was partially added to the reaction vessel, followed by BG-11B of crystal seeds. Add the remaining BG-11A solution and D-DBTA solution together. The reaction mixture was stirred at 55°C for 4 hours. The mixture is then cooled to allow crystallization. The solid was collected by centrifugation, washed continuously with a mixture of ethanol/water/acetic acid and ethanol, and then dried under vacuum to obtain 28.31g BG-11B (purity: 99.81%, chiral purity: 90.8%, yield: 49.2%).

Example 2B:

BG-11A (30g, 1.0X, 1.0 equiv) was dissolved in a mixture of ethanol/water/acetic acid (17.2X, acetic acid: 23%). The solution obtained was partially transferred to the reaction vessel. Additional ethanol/water/acetic acid mixed solvent (4.2X, acetic acid: 24%) was added to the reaction vessel. The reaction solution was heated to 65°C. D-DBTA (1.0 equiv) was then dissolved in a mixture of ethanol/water/acetic acid (5.7X, acetic acid: 23%), and the obtained D-DBTA solution was partially added to the reaction vessel, followed by BG-11B crystal. Add the remaining BG-11A solution and D-DBTA solution together. The reaction mixture was stirred at 65°C for 6 hours. The mixture is then cooled to allow crystallization. The solid was collected by centrifugation, washed continuously with a mixture of ethanol/water/acetic acid and ethanol, and then dried under vacuum to obtain 22.5g BG-11B (purity: 99.23%, chiral purity: 94.1%, yield: 39.1%).

Example 2C

BG-11A (30g, 1.0X, 1.0 equiv) was dissolved in a mixture of ethanol/water/acetic acid (17.2X, acetic acid: 23%). The solution obtained was partially transferred to the reaction vessel. Additional ethanol/water/acetic acid mixed solvent (4.2X, acetic acid: 24%) was added to the reaction vessel. The reaction solution was heated to 55°C. Dissolve D-DBTA (1.45 equivalents) in a mixed solution of ethanol/water/acetic acid (5.7X, acetic acid: 23%), then add part of the obtained D-DBTA solution to the reaction vessel, and then add BG-11B crystal. Add the remaining BG-11A solution and D-DBTA solution together. The reaction mixture was stirred at 55°C for 4 hours. The mixture is then cooled to allow crystallization. The solid was collected by centrifugation, washed continuously with a mixture of ethanol/water/acetic acid and ethanol, and then dried under vacuum to obtain 28.9g BG-11B (purity: 99.79%, chiral purity: 91.3%, yield: 50.8%).

Example 3: Synthesis of BG-11D

Example 3A-1, first resolution: BG-11A (30.0g, 1.0X, 1.0 equivalent) was dissolved in a mixture of ethanol/water/acetic acid (17.0X, acetic acid: 23.6%). The solution obtained was partially transferred to the reaction vessel. Then add additional ethanol/water/acetic acid mixed solvent (4.2X, acetic acid: 24.0%) into the reaction vessel. The solution in the reactor was heated to 55°C. Then D-DBTA (1.0 equivalent) was dissolved in a mixture of ethanol/water/acetic acid (5.6X, acetic acid: 23.4%), and then part of the obtained D-DBTA solution was added to the reaction vessel, followed by addition of BG-11B seed crystal. Add the remaining D-DBTA solution and BG-11A solution to the reaction kettle, and stir the mixture at 55°C for 4 hours. The mixture was then cooled to allow complete precipitation of crystals. The solid was collected by centrifugation, washed continuously with a mixture of ethanol/water/acetic acid and ethanol 1.6X each, and then dried under vacuum to obtain 27.3g BG-11B (chiral purity: 91.7%, yield: 48.0%).

Example 3B-1, second resolution: BG-11B (20.0g, 1.0X, 1.0 equivalent) was suspended in ethanol and water, and then an aqueous solution of potassium hydroxide (1.7 equivalent) was added. The mixture was heated and then treated with acetic acid and BG-11B seed crystals to precipitate crystals. Additional acetic acid (1.65X) was added to dissolve the crystals. A solution of D-DBTA (0.4 equivalent) in ethanol/water/acetic acid mixed solvent (3.2X, acetic acid: 11.0%) was added dropwise, followed by cooling and crystallization. The solid was collected by centrifugation, washed continuously with a mixture of ethanol/water/acetic acid and ethanol, and then dried under vacuum to obtain 16.4 g of BG-11B (chiral purity: 97.4%, yield: 81.3%).

Example 3B-2, free: Dissolve BG-11B (30.0g, 1.0X, 1.0 equiv) in acetonitrile (4.2X) and water (9.0X), then add sodium hydroxide (30% aqueous solution, 5.0 equiv) solution, solid precipitated. The precipitated solid was collected by centrifugation, washed with water, and then dried under vacuum to obtain 15.5 g of compound BG-11D (chiral purity: 98.7%, HPLC purity: 99.6%, yield: 96.0%).

Example 4: Synthesis of BG-13

Example 4A:

Compound BG-11D (20 g, 1.0X, 1.0 equiv) was added to methanesulfonic acid (19.3 equiv) and water (1.7 equiv). The reaction mixture was heated to 80°C and stirred until the reaction was complete. The mixture was then cooled and additional water and acetonitrile (4.0X) were added. The sodium hydroxide aqueous solution was added dropwise at 20°C, and then heated to 50°C. Adjust pH to 12 with additional aqueous sodium hydroxide solution. The organic layer was collected and isopropyl acetate (2.6X) was added followed by washing with brine. Seed crystals were added to the obtained organic layer, and then isopropyl acetate was added for solvent exchange. Methyl tert-butyl ether was added, followed by cooling and crystallization. The solid was collected by centrifugation, washed with methyl tert-butyl ether, and then dried under vacuum to obtain 18.29 g of crude BG-13 (purity: 98.73%, yield: 87.2%).

Example 4B:

Compound BG-11D (20 g, 1.0X, 1.0 equiv) was added to methanesulfonic acid (18.0 equiv) and water (1.0 equiv). The reaction mixture was heated to 80°C and stirred until the reaction was complete. The mixture was then cooled and additional water and acetonitrile (4.0X) were added. The sodium hydroxide aqueous solution was added dropwise at 20°C, and then heated to 50°C. Adjust the pH to 11-12 with additional aqueous sodium hydroxide solution. The organic layer was collected and isopropyl acetate (2.6X) was added followed by washing with brine. Seed crystals were added to the obtained organic layer, and then isopropyl acetate was added for solvent exchange. Methyl tert-butyl ether was added, followed by cooling and crystallization. The solid was collected by centrifugation, washed with methyl tert-butyl ether, and then dried under vacuum to obtain 18.7 g of crude BG-13 (purity: 98.69%, yield: 87.8%).

Example 4C:

Compound BG-11D (20 g, 1.0X, 1.0 equiv) was added to methanesulfonic acid (18.0 equiv) and water (1.7 equiv). The reaction mixture was heated to 75°C and stirred until the reaction was complete. The mixture was then cooled and additional water and acetonitrile (3.7X) were added. Adjust the pH to 11-12 with additional aqueous sodium hydroxide solution at a temperature below 50°C. The temperature of the mixture was adjusted to 50°C. The organic layer was collected, then isopropyl acetate (2.6X) was added and washed with brine. Seed crystals were added to the obtained organic layer, and then isopropyl acetate was added for solvent exchange. Methyl tert-butyl ether was added, followed by cooling and crystallization. The solid was collected by centrifugation, washed with methyl tert-butyl ether, and then dried under vacuum to obtain 17.63 g of crude BG-13 (purity: 98.93%, yield: 81.9%).

Example 4D:

Compound BG-11D (400g) was added to methanesulfonic acid (1720g) and water (30.4g). The reaction mixture was heated to 83°C and stirred until the reaction was complete. The reaction solution was divided into portions, and 107.5g (based on 20g BG-11D, X=20g, 1 equivalent) was sampled for use in the following steps. Add additional water and acetonitrile (3.0X). Adjust the pH to 12 with additional aqueous sodium hydroxide solution at a temperature of 35°C. The temperature of the mixture was adjusted to 50°C. The organic layer was collected, then isopropyl acetate (3.2X) was added and washed with brine. Seed crystals were added to the obtained organic layer, and then isopropyl acetate was added for solvent exchange. Methyl tert-butyl ether was added, followed by cooling and crystallization. The solid was collected by centrifugation, washed with methyl tert-butyl ether, and then dried under vacuum to obtain 19 g of crude BG-13 (purity: 98.95%, yield: 89.5%).

Example 4E:

Example 4E-1: Compound BG-11D (20 g, 1.0X, 1.0 equiv) was added to methanesulfonic acid (16.6 equiv) and water (1.7 equiv). The reaction mixture was heated to 80°C and stirred until the reaction was complete. The mixture was then cooled and acetonitrile (5.0X volume) was added. Aqueous sodium hydroxide solution (20%) was added dropwise at 20°C, followed by heating to 50°C. Adjust the pH to 11-12 with additional aqueous sodium hydroxide solution (20%). The organic layer was collected and isopropyl acetate (2.6X) was added followed by washing with brine. Seed crystals were added to the obtained organic layer, and then isopropyl acetate was added for solvent exchange. Methyl tert-butyl ether was added, followed by cooling and crystallization. The solid was collected by centrifugation, washed with methyl tert-butyl ether, and then dried under vacuum to obtain 18.8 g of crude BG-13 (yield: 89%).

Example 4E-2: Dissolve crude BG-13 (20g) in methanol (6 times the mass) and water (4 times the mass), heat to 45°C, and then add the methanol/water solution of L-DBTA (0.57 equivalents). The mixture was cooled to allow crystallization. The precipitated solid is collected by centrifugation and then washed with water to obtain BG-12.

Example 4E-3: BG-12 (65.7g) was dissolved in acetonitrile and water, and then sodium hydroxide aqueous solution and isopropyl acetate were added. The organic layer was collected, washed with brine, and concentrated. Seed crystals of BG-13 were added and concentrated, then isopropyl acetate was added and distilled again. Methyl tert-butyl ether was added to the residue, followed by cooling and crystallization. The solid was collected by centrifugation, washed with methyl tert-butyl ether, and then dried under vacuum to obtain pure BG-13 (chiral purity: 99.6%, HPLC purity 99.7%, yield: 93.4%).

Example 5: Synthesis of Compound 1

Example 5A:

Compound BG-13 (30 g) was dissolved in a mixture of acetonitrile and water, followed by addition of L-tartaric acid and sodium bicarbonate. The mixture was cooled and acryloyl chloride (6.84g) was added. The solution was stirred at -5°C until the reaction was complete, then ethyl acetate was added and separated. The organic layer was collected, and the aqueous layer was extracted with ethyl acetate again. The organic layers were combined, washed with brine, then dibutylated hydroxytoluene (1%) was added. Ethyl acetate and dichloromethane were added successively for solvent exchange, followed by dibutylated hydroxytoluene (2%).

The solution was aliquoted and 72.2g (16.94g of compound 1) was used in the following step. The solution obtained was filtered through silica gel (0.67X, X based on the amount of BG-13). The solution was concentrated, and then ethyl acetate was added and concentrated. Compound 1 seed crystals were added and the mixture was kept warm for crystallization. Continue to concentrate, and then add methyl tert-butyl ether to further precipitate crystals. The solid was collected by centrifugation, washed with methyl tert-butyl ether, and then dried under vacuum to obtain 14.31 g of crude compound 1 (purity: 99.84%, yield: 83.7%).

Example 5B:

Compound BG-13 (30 g) was dissolved in a mixture of acetonitrile and water, followed by addition of L-(+)-tartaric acid and sodium bicarbonate. The mixture was cooled and acryloyl chloride (6.63g) was added. The solution was stirred at 5°C until the reaction was complete, then ethyl acetate was added and separated. The organic layer was collected, and the aqueous layer was extracted with ethyl acetate again. Combine the organic layers and wash with brine.

Divide the organic solution into two equal parts, and take half of the organic phase (the following expression is based on 15g BG-13, X=15g) for the following steps. Ethyl acetate and dichloromethane were added successively for solvent exchange, followed by dibutylated hydroxytoluene (1%). The resulting solution was filtered through silica gel (1.33X) and concentrated before being transferred to a clean container through a pad of diatomaceous earth. The solution was concentrated, and then ethyl acetate was added and concentrated. Compound 1 seed crystals were added, and the mixture was kept warm and stirred for crystallization. The solid was collected by centrifugation, washed with methyl tert-butyl ether, and then dried under vacuum to obtain 14.20 g of crude compound 1 (purity: 99.75%, yield: 83.7%).

The foregoing examples and descriptions of certain embodiments are to be considered illustrative and should not be construed as limiting the invention as defined by the claims. It will be readily understood that various variations and combinations of the above-described features may be utilized without departing from the invention as claimed. All such variations are intended to be included within the scope of this invention. All references cited are incorporated by reference into this application in their entirety.

Claims (9)

1. A method of preparing compound BG-11A, the method comprising: treating compound BG-10 with an acid in a solvent at an elevated temperature to remove Boc groups to obtain compound BG-11A, wherein the elevated temperature is above 40 ℃ and below 65 ℃, wherein the acid is hydrochloric acid, the solvent is ethanol,

2. the method of claim 1, wherein the elevated temperature is in the temperature range of 40 to 60 ℃.

3. The process of any one of claims 1 or 2, wherein the amount of solvent is 5.0 to 8.0 equivalents by weight relative to reactant BG-10.

4. The method of claim 1, wherein the deprotection reaction is conducted for no more than 72 hours.

5. The method of claim 1, wherein the method of compound BG-11A further comprises: after the deprotection reaction, the pH was adjusted at a temperature of 20 to 75 ℃.

6. The process of claim 5, wherein the pH is adjusted at a temperature of 50 to 65℃after the deprotection reaction.

7. The method of claim 5 or 6, wherein the pH is not less than 11.5.

8. The method of claim 5 or 6, wherein the pH is in the range of 12.5-13.5.

9. The method of claim 1, comprising: