CN111909152A - The preparation method of BTK inhibitor and its intermediate - Google Patents

Abstract

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

Description

The preparation method of BTK inhibitor and its intermediate

technical field

The present invention relates to (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1, The 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 act as Bruton's tyrosine kinase (BTK) inhibitors. Specifically, WO2014173289 discloses (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazole Iso[1,5-a]pyrimidine-3-carboxamide (hereinafter also referred to as compound 1)

Compound 1 is a potent, specific and irreversible BTK inhibitor. Data from preclinical studies suggest that Compound 1 may have a significant effect on inhibiting the growth of B-cell malignancies. Compound 1 shows better selectivity than ibrutinib for inhibiting BTK against EGFR, FGR, FRK, HER2, HER4, ITK, JAK3, LCK and TEC and is expected to be more clinically effective than ibrutinib Small side effects. In addition, compound 1 showed significantly less rituximab-induced antigen-dependent cell-mediated cytotoxicity (ADCC) than ibrutinib due to its weaker ITK inhibition, and is therefore comparable to 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. The method utilizes a chiral acid resolving agent D-DBTA to resolve BG-11A to obtain an intermediate BG-11B with a single stereoconfiguration. The method disclosed in WO2018033853 is suitable for industrial large-scale production, but the yield of the intermediate BG-11A used in the key chiral resolution step needs to be improved.

SUMMARY OF THE INVENTION

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

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

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

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

In some embodiments, the reaction is further carried out 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 dimethylsulfoxide. Suitable polar protic solvents include, but are not limited to, water, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, formic acid or acetic acid, and the like. 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 polar aprotic solvent and polar protic solvent. Preferably, the solvent is a mixed solvent of acetonitrile and water.

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

In some embodiments, the method for preparing compound 1 of the present invention comprises: 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 After solvent exchange, seed crystals of compound 1 were added, and methyl tert-butyl ether was crystallized to obtain compound 1.

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

The acid used in the hydrolysis is not particularly limited, and may be a common organic acid or inorganic acid. The inorganic acids are, for example, hydrochloric acid, phosphoric acid, dihydrogen phosphoric acid, hydrobromic acid, sulfuric acid, sulfurous acid and nitric acid; and, the organic acids are, 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 acids (such as acetic acid and HOOC-(CH2)n-COOH, wherein n is selected from 0-4) and the like. 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 hydrolysis of the intermediate BG-11D in the presence of an acid, the pH 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 still further embodiments, the solvent is acetonitrile.

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

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

In a third aspect, the present invention relates to a step for preparing BG-11D, which comprises: splitting intermediate BG-11A with a resolving agent to obtain intermediate salt BG-11B,

Then the intermediate salt BG-11B is reacted with a base to remove the combined resolving agent to obtain an 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% by mass. In some embodiments, the amount of the 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 is reacted with the resolving agent at a temperature of 30-65°C, preferably at a temperature of 50-55°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 is added simultaneously with the resolving agent (preferably D-DBTA) to obtain stable chemical resolution performance. In some embodiments, the amount of the 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 comprises adding an additional amount of resolving agent to reform the salt. In a further embodiment, the amount of resolving agent used to reformulate 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 that is an alkali metal hydroxide, alkaline earth metal hydroxide, alkali metal carbonate, alkali metal bicarbonate, alkali metal carbonate The hydrogen salt or alkaline earth metal hydrogen carbonate is preferably sodium hydroxide, potassium hydroxide or sodium hydrogen carbonate or the like.

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 dimethylsulfoxide. Suitable polar protic solvents include, but are not limited to, water, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, formic acid or acetic acid, and the like. 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 polar aprotic solvent and polar protic solvent. Preferably, the solvent is a mixed solvent of acetonitrile and water.

In a specific embodiment, the method of making BG-11D comprises:

In a fourth aspect, the present invention relates to a step for preparing intermediate BG-11A, comprising: treating intermediate BG-11A in a solvent with an acid 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 such as 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) and the like. Preferably, the acid is hydrochloric acid.

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

In some embodiments, the solvent is a non-polar solvent, polar protic solvent, 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, t-butanol, formic acid or acetic acid, and the like. 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 the solvent (preferably ethanol) is 5.0-8.0X (mass).

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

In some embodiments, the method of preparing the intermediate BG-11A further comprises: after the deprotection reaction, adjusting the pH 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 lower than 11.5, preferably in the range of 12.5-13.5. In still further embodiments, the pH is adjusted by adding an alkaline solution, such as the addition of aqueous sodium hydroxide.

In a specific embodiment, the method of making BG-11A comprises:

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 the reproducible preparation of 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, so as to improve the An economical or more environmentally friendly way to generate the final target compound.

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

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

For another example, in the step of synthesizing BG-13 from the intermediate BG-11D, the phase separation is directly carried out by adding the solvent acetonitrile, thereby optimizing the post-processing steps; and BG-13 is directly separated into the free base form, rather than L-DBTA salt form. Furthermore, the added methanesulfonic acid can be removed by a simple post-treatment. This step can also reduce the generation of some impurities.

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

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

Example 1: Synthesis of BG-11A

Example 1A

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

Example 1B

Compound BG-10 (20 g, 1.0X) was suspended in ethanol (6.5X), then about 20% hydrochloric acid in ethanol 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, then additional ethanol and water were added. At a temperature of 50°C, the pH was adjusted to 13.0 with an aqueous sodium hydroxide solution over a period of 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 vacuum-dried to obtain compound 16.5 g of BG-11A (purity: 99.13%, yield: 95.2%).

Example 2: Synthesis of BG-11B

Example 2A

BG-11A (30 g, 1.0X, 1.0 equiv) was dissolved in a mixture of ethanol/water/acetic acid (14.7X, acetic acid: 23%). The obtained solution was partially transferred to the reaction vessel. Additional mixed solvent of ethanol/water/acetic acid (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 resulting D-DBTA solution was partially added to the reaction vessel followed by BG-11B 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 was then cooled to allow crystallization. The solid was collected by centrifugation, washed successively with a mixture of ethanol/water/acetic acid, ethanol, and then vacuum dried to obtain 28.31 g of BG-11B (purity: 99.81%, chiral purity: 90.8%, yield: 49.2%).

Example 2B:

BG-11A (30 g, 1.0X, 1.0 equiv) was dissolved in a mixture of ethanol/water/acetic acid (17.2X, acetic acid: 23%). The obtained solution was partially transferred to the reaction vessel. Additional mixed solvent of ethanol/water/acetic acid (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 resulting 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 was then cooled to allow crystallization. The solid was collected by centrifugation, washed successively with a mixture of ethanol/water/acetic acid, ethanol, and then vacuum dried to obtain 22.5 g of BG-11B (purity: 99.23%, chiral purity: 94.1%, yield: 39.1%).

Example 2C

BG-11A (30 g, 1.0X, 1.0 equiv) was dissolved in a mixture of ethanol/water/acetic acid (17.2X, acetic acid: 23%). The obtained solution was partially transferred to the reaction vessel. Additional mixed solvent of ethanol/water/acetic acid (4.2X, acetic acid: 24%) was added to the reaction vessel. The reaction solution was heated to 55°C. D-DBTA (1.45 equiv) was dissolved in a mixed solution of ethanol/water/acetic acid (5.7X, acetic acid: 23%), then 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 55°C for 4 hours. The mixture was then cooled to allow crystallization. The solid was collected by centrifugation, washed successively with a mixture of ethanol/water/acetic acid, ethanol, and then vacuum dried to obtain 28.9 g of 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 (30.0 g, 1.0X, 1.0 equiv) was dissolved in a mixture of ethanol/water/acetic acid (17.0X, acetic acid: 23.6%). The obtained solution was partially transferred to the reaction vessel. Additional mixed solvent of ethanol/water/acetic acid (4.2X, acetic acid: 24.0%) was added to the reaction vessel. The solution in the reactor was heated to 55°C. D-DBTA (1.0 equiv.) was then dissolved in a mixture of ethanol/water/acetic acid (5.6X, acetic acid: 23.4%), and the resulting D-DBTA solution was partially added to the reaction vessel, followed by the addition of BG-11B seeds. The remaining D-DBTA solution and BG-11A solution were added to the reaction kettle, and the mixture was stirred at 55°C for 4 hours. The mixture was then cooled to allow complete precipitation of crystals. The solid was collected by centrifugation, washed successively with a mixture of ethanol/water/acetic acid, 1.6X each of ethanol, followed by vacuum drying to obtain 27.3 g of BG-11B (chiral purity: 91.7%, yield: 48.0%).

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

Example 3B-2, free: BG-11B (30.0 g, 1.0X, 1.0 equiv) was dissolved in acetonitrile (4.2X) and water (9.0X) followed by sodium hydroxide (30% aqueous solution, 5.0 equiv) solution, a solid precipitated out. The precipitated solid was collected by centrifugation, washed with water, and then dried in vacuo 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, followed by addition of additional water and acetonitrile (4.0X). Aqueous sodium hydroxide solution was added dropwise at 20°C, followed by heating to 50°C. Adjust pH to 12 with additional aqueous sodium hydroxide solution. The organic layer was collected, followed by the addition of isopropyl acetate (2.6X), followed by a brine wash. Seed crystals were added to the obtained organic layer, followed by addition of isopropyl acetate for solvent exchange. Methyl tert-butyl ether was added, followed by cooling to crystallize. The solid was collected by centrifugation, washed with methyl tert-butyl ether, and then dried in vacuo 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, followed by addition of additional water and acetonitrile (4.0X). Aqueous sodium hydroxide solution was added dropwise at 20°C, followed by heating to 50°C. Adjust pH to 11-12 with additional aqueous sodium hydroxide solution. The organic layer was collected, followed by the addition of isopropyl acetate (2.6X), followed by a brine wash. Seed crystals were added to the obtained organic layer, followed by addition of isopropyl acetate for solvent exchange. Methyl tert-butyl ether was added, followed by cooling to crystallize. The solid was collected by centrifugation, washed with methyl tert-butyl ether, and then dried in vacuo 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, followed by addition of additional water and acetonitrile (3.7X). The pH was adjusted 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, followed by the addition of isopropyl acetate (2.6X) and washed with brine. Seed crystals were added to the obtained organic layer, followed by addition of isopropyl acetate for solvent exchange. Methyl tert-butyl ether was added, followed by cooling to crystallize. The solid was collected by centrifugation, washed with methyl tert-butyl ether, and then dried in vacuo to obtain 17.63 g of crude BG-13 (purity: 98.93%, yield: 81.9%).

Example 4D:

Compound BG-11D (400 g) was added to methanesulfonic acid (1720 g) and water (30.4 g). The reaction mixture was heated to 83°C and stirred until the reaction was complete. The reaction solution was aliquoted and 107.5 g (based on 20 g BG-11D, X=20 g, 1 equiv) were sampled for the following steps. Additional water and acetonitrile (3.0X) were added. The pH was adjusted 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 layers were collected, followed by the addition of isopropyl acetate (3.2X) and washed with brine. Seed crystals were added to the obtained organic layer, followed by addition of isopropyl acetate for solvent exchange. Methyl tert-butyl ether was added, followed by cooling to crystallize. The solid was collected by centrifugation, washed with methyl tert-butyl ether, and then dried in vacuo 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 vol) was added. Aqueous sodium hydroxide solution (20%) was added dropwise at 20°C, followed by heating to 50°C. The pH was adjusted to 11-12 with additional aqueous sodium hydroxide (20%). The organic layer was collected, followed by the addition of isopropyl acetate (2.6X), followed by a brine wash. Seed crystals were added to the obtained organic layer, followed by addition of isopropyl acetate for solvent exchange. Methyl tert-butyl ether was added, followed by cooling to crystallize. The solid was collected by centrifugation, washed with methyl tert-butyl ether, and then dried in vacuo to obtain 18.8 g of crude BG-13 (yield: 89%).

Example 4E-2: Crude BG-13 (20 g) was dissolved in methanol (6 times mass) and water (4 times mass), heated to 45°C, followed by addition of L-DBTA (0.57 equiv) in methanol/water solution. The mixture was cooled to allow crystallization. The precipitated solid was collected by centrifugation, and then washed with water to obtain BG-12.

Example 4E-3: BG-12 (65.7 g) was dissolved in acetonitrile and water, followed by the addition of aqueous sodium hydroxide and isopropyl acetate. The organic layer was collected, then 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, which was then crystallized by cooling. 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 (6.84 g) 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, followed by the addition of dibutylhydroxytoluene (1%). Ethyl acetate and dichloromethane were added successively for solvent exchange, followed by dibutylhydroxytoluene (2%).

The solution was portioned and 72.2 g (16.94 g of Compound 1) were used in the following steps. The resulting solution was filtered through silica gel (0.67X, X based on the amount of BG-13). The solution was concentrated, followed by the addition of ethyl acetate, followed by concentration, seed crystals of compound 1 were added, and crystallization was maintained. Concentration was continued, and then methyl tert-butyl ether was added to further precipitate crystals. The solid was collected by centrifugation, washed with methyl tert-butyl ether, and then dried in vacuo 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 the addition of L-(+)-tartaric acid and sodium bicarbonate. The mixture was cooled and acryloyl chloride (6.63 g) 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 and washed with brine.

The organic solution was equally divided into two parts, and half of the organic phase (the following expression was based on 15 g BG-13, X=15 g) was used in the following steps. Ethyl acetate and dichloromethane were added successively for solvent exchange, followed by dibutylhydroxytoluene (1%). The resulting solution was filtered through silica gel (1.33X) and concentrated, then transferred to a clean vessel through a pad of celite. The solution was concentrated, then ethyl acetate was added, and concentrated, compound 1 seed crystals were added, and the mixture was kept stirring for crystallization. The solid was collected by centrifugation, washed with methyl tert-butyl ether, and then dried in vacuo to obtain 14.20 g of crude compound 1 (purity: 99.75%, yield: 83.7%).

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

Claims (11)

1. A method for preparing compound BG-11A, the method comprising: treating compound BG-10 in a solvent with an acid at an elevated temperature to remove the Boc group to obtain compound BG-11A,

2. The method of claim 1, wherein the acid is an inorganic acid or an organic acid selected from the group consisting of hydrochloric acid, phosphoric acid, dihydrogen phosphoric acid, hydrobromic acid, sulfuric acid, sulfurous acid, and nitric acid; and, the organic acid Selected from 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; preferably, the acid is hydrochloric acid. 3. The method of claim 1, wherein the elevated temperature is a temperature above room temperature and below 65°C, preferably the elevated temperature is in the temperature range of 40 to 60°C. 4. The method of claim 1, wherein the solvent is an apolar solvent, a polar protic solvent, a polar aprotic solvent, or a mixture thereof. 5. The method of claim 4, wherein the polar aprotic solvent is selected from the group consisting of N-methylpyrrolidone, N-methylmorpholine, methyl isobutyl ketone, methyl ethyl ketone, tetrahydrofuran, dichloromethane , ethyl acetate, acetone, N,N-dimethylformamide, isopropyl acetate, acetonitrile or dimethyl sulfoxide, the polar protic solvent is selected from water, methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, isobutanol, tert-butanol, formic acid or acetic acid, the non-polar solvent is selected from dioxane, toluene, hexane, cyclohexane or diethyl ether; preferably, the solvent is Ethanol. 6. The method of any one of claims 1 to 5, wherein the amount of the solvent is 5.0-8.0 X (weight). 7. The method of claim 1, wherein the deprotection reaction is carried out for no more than 72 hours. 8. The method of claim 1, wherein the method of compound BG-11A further comprises: after the deprotection reaction, adjusting the pH at a temperature of 20 to 75°C, preferably at a temperature of 50 to 65°C. 9. The method of claim 10, wherein the pH value is not lower than 11.5, preferably in the range of 12.5-13.5. 10. The method of claim 1, the method comprising:

11. A method for preparing compound 1, the method comprising: reacting intermediate BG-13 with an acryloyl compound in a solvent, and then adding a seed crystal of compound 1,