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

Preparation method of BTK inhibitor and intermediate thereof Download PDF

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CN111909152B
CN111909152B CN201910382010.9A CN201910382010A CN111909152B CN 111909152 B CN111909152 B CN 111909152B CN 201910382010 A CN201910382010 A CN 201910382010A CN 111909152 B CN111909152 B CN 111909152B
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CN111909152A (en
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刘军涛
杜争鸣
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Baiji Shenzhou Suzhou Biotechnology Co ltd
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Baiji Shenzhou Suzhou Biotechnology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Abstract

The present application relates to a process for the preparation of (S) -7- (1-propenylpiperidin-4-yl) -2- (4-phenoxyphenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidine-3-carboxamide and intermediates thereof.

Description

Preparation method of BTK inhibitor and intermediate thereof
Technical Field
The present application relates to a process for the preparation of (S) -7- (1-propenylpiperidin-4-yl) -2- (4-phenoxyphenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidine-3-carboxamide and intermediates thereof.
Background
International application WO2014173289 discloses a series of fused heterocyclic compounds which act as inhibitors of Bruton's Tyrosine Kinase (BTK). In particular, WO2014173289 discloses (S) -7- (1-propenylpiperidin-4-yl) -2- (4-phenoxyphenyl) -4,5,6, 7-tetrahydropyrazolo [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 B-cell malignancy growth. Since compound 1 shows better selectivity than ibrutinib (ibrutinib) for inhibiting BTK versus EGFR, FGR, FRK, HER, HER4, ITK, JAK3, LCK and TEC, clinically less side effects than ibrutinib are expected. Furthermore, compound 1, due to its weaker ITK inhibition, shows significantly less Yu Yilu tenib to rituximab-induced antigen-dependent cell-mediated cytotoxicity (ADCC) and thus may provide better efficacy when used in combination with rituximab or other ADCC-dependent antibodies for the treatment of B-cell malignancies.
WO2018033853 discloses a process for preparing compound 1 by resolution of BG-11A using chiral acid resolving agent D-DBTA to give intermediate BG-11B in a single stereoconfiguration. The process disclosed in WO2018033853 is suitable for industrial mass production, but the yield of intermediate BG-11A used in the key chiral resolution step is to be increased.
Disclosure of Invention
The inventors of the present application found that: by optimizing the reaction parameters, in particular by improving the reaction temperature in the step of synthesizing intermediate BG-11A from intermediate BG-10, the reaction yield and purity of the product are significantly improved.
In a first aspect, the present application relates to a process for preparing compound 1, said process comprising: intermediate BG-13 is reacted with an acryl compound in a solvent, and then seed crystals of compound 1 are added, and crystallization is performed to obtain compound 1.
In some embodiments, the acryl compound is dosed at 0.95 to 1.3 equivalents.
In some embodiments, the acryl compound is selected from the group consisting of acryl halides, acrylic acid, or acrylic anhydride. In a further embodiment, the acryl compound is an acryl halide, preferably an acryl 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 a non-polar solvent, a polar protic solvent, and a polar aprotic solvent, or mixtures thereof. Suitable polar aprotic solvents include, but are not limited to, N-methylpyrrolidone, N-methylmorpholine, methyl isobutyl ketone, methyl ethyl ketone, tetrahydrofuran, methylene chloride, ethyl acetate, acetone, 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, acetic acid, and the like. Suitable nonpolar 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 carried out at a temperature of-5 to 35 ℃.
In some embodiments, the methods of preparing compound 1 of the present application comprise: intermediate BG-13 and the acryloyl compound are reacted in a solvent, after the reaction is completed, ethyl acetate is used for extraction, ethyl acetate and methylene dichloride are used for solvent exchange, then seed crystal of the compound 1 is added, and methyl tertiary butyl ether is used for crystallization, so that the compound 1 is obtained.
In a second aspect, the present application relates to a process for preparing intermediate BG-13, comprising: hydrolyzing intermediate BG-11D in the presence of acid; or further reacting with a resolving agent to form an intermediate BG-12, wherein the intermediate BG-12 is subjected to alkali removal of the resolving agent in a solvent to obtain an 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 phosphate, 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 acids such as acetic acid and HOOC- (CH 2) n-COOH, where n is selected from 0 to 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 ℃, preferably at a temperature of 75 to 85 ℃, more preferably at a temperature of 75 to 80 ℃.
In some embodiments, intermediate BG-11D is further pH adjusted to 11-12 with a base after hydrolysis in the presence of an acid.
In some embodiments, the resolving agent is an acidic resolving agent, such as (+) -tartaric acid, (+) -camphoric acid-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 a non-polar solvent, a polar protic solvent, and a polar aprotic solvent, or a mixture thereof. In further embodiments, the solvent is a polar aprotic solvent selected from the group consisting of N-methylpyrrolidone, N-methylmorpholine, methyl isobutyl ketone, methyl ethyl ketone, tetrahydrofuran, dichloromethane, ethyl acetate, acetone, N-dimethylformamide, isopropyl acetate, acetonitrile and dimethyl sulfoxide, or a mixture of two or more thereof. 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 or alkaline earth metal bicarbonate, preferably sodium hydroxide, potassium hydroxide or sodium bicarbonate, and the like.
In one embodiment, a method for preparing BG-13 comprises:
in a third aspect, the present application relates to a process for preparing BG-11D comprising: resolving intermediate BG-11A with resolving agent to obtain intermediate salt BG-11B,
then the intermediate salt BG-11B reacts with alkali to remove the combined resolving agent, thus obtaining the enantiomer intermediate BG-11D,
in some embodiments, the resolving agent is an acidic resolving agent. The acid resolving agent is selected from (+) -tartaric acid, (+) -camphoric acid-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 ratio of acetic acid to the acetic acid/water/ethanol mixed solvent is 13 to 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 ℃.
In some embodiments, a solution of the intermediate BG-11A in the mixed solvent is reacted with the resolving agent at a temperature of 30-65 ℃, preferably at a temperature of 50 to 55 ℃.
In some embodiments, the BG-11A is added sequentially or simultaneously with the resolving agent (preferably D-DBTA). In a further embodiment, the BG-11A is added simultaneously with the resolving agent (preferably D-DBTA) to obtain stable chemical resolution properties. In some embodiments, the resolving agent (preferably D-DBTA) is present in an amount of 0.5 to 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 reformulate the salt. In a further embodiment, the amount of resolving agent used to reformulate the salt is from 0.2 to 0.6 equivalents (relative to 1.0 equivalent of BG-11B).
In some embodiments, the intermediate salt BG-11B is reacted with a base that is an alkali metal hydroxide, an alkaline earth metal hydroxide, an alkali metal carbonate, an alkali metal bicarbonate, or an alkaline earth metal bicarbonate, preferably sodium hydroxide, potassium hydroxide, or sodium bicarbonate, or the like.
In some embodiments, the solvent is selected from the group consisting of a non-polar solvent, a polar protic solvent, and 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, methylene chloride, ethyl acetate, acetone, 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, 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 a polar aprotic solvent and a polar protic solvent. Preferably, the solvent is a mixed solvent of acetonitrile and water.
In one embodiment, a method for preparing BG-11D comprises:
in a fourth aspect, the present application relates to a process for preparing intermediate BG-11A, comprising: treating intermediate BG-11A with an acid at an elevated temperature in a solvent to remove the Boc group to give intermediate BG-11A,
in some embodiments, the acid is an inorganic acid, such as hydrochloric acid, phosphoric acid, dihydrogen phosphate, hydrobromic acid, sulfuric acid, sulfurous acid, and nitric acid, or an organic 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 acids (such as acetic acid and HOOC- (CH 2) n-COOH, where n is selected from 0 to 4) and the like. Preferably, the acid is hydrochloric acid.
In some embodiments, the elevated temperature is a temperature above room temperature, below 65 ℃. In a further embodiment, the elevated temperature is in the temperature range of 40 to 60 ℃.
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, methylene chloride, ethyl acetate, acetone, 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 nonpolar 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 to 8.0X by mass.
In some embodiments, the deprotection reaction is performed for no more than 72 hours.
In some embodiments, the method of preparing intermediate BG-11A further comprises: after the deprotection reaction, the pH is adjusted at a temperature of 20 to 75℃and preferably at a temperature of 50 to 65 ℃. In a further embodiment, the pH is not lower than 11.5, preferably in the range of 12.5-13.5. In a further embodiment, the pH is adjusted by adding an alkaline solution, for example by adding aqueous sodium hydroxide.
In a specific embodiment, a method for preparing BG-11A comprises:
examples
The following reaction scheme details the scheme for preparing compound 1 starting from intermediate BG-10.
Reaction scheme
The process of the present application is particularly suitable for the reproducible production of compound 1 on a commercial scale in high quality and high yield; and by optimizing or improving the synthesis process, the method of the application can further increase the reaction yield or purity of each step, and generate the final target compound in a more economical or environment-friendly way.
For example, from the step of synthesizing BG-11A from intermediate BG-10, more environmentally friendly ethanol is used as solvent to replace the original methylene chloride; the deprotection reaction is carried out at an elevated temperature, which further improves the purity and/or yield of the reaction product by a significant increase (e.g., up to 97.6%); furthermore, 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%. Meanwhile, an intermediate BG-11A and a resolving agent D-DBTA are added to obtain consistent chemical resolution performance; and stable chemical resolution performance and high chiral purity are realized; and the whole manufacturing cycle time is reduced, thereby improving the manufacturing efficiency.
For another example, in the step of synthesizing BG-13 from intermediate BG-11D, the post-treatment step is optimized by directly performing phase separation by adding acetonitrile as a solvent; and BG-13 is isolated directly as the free base form, rather than as the L-DBTA salt form. And the added methanesulfonic acid can be removed by simple work-up. This step also reduces the formation of some impurities.
For another example, in the step of synthesizing compound 1 from intermediate BG-13, the crystallization process is optimized by adding seed crystals, particularly in the post-treatment, to avoid agglomeration during the crystallization process, thereby improving the quality of the final product.
The following examples are illustrative of the application and are not intended to limit the scope of the application.
Example 1 Synthesis of BG-11A
Example 1A
Compound BG-10 (20 g, 1.0X) was suspended in ethanol (8.0X) and then approximately 20% ethanol solution of hydrochloric acid was added. The reaction mixture was heated to 40 ℃ and then stirred for 5 hours until the reaction was complete. The reaction mixture was concentrated and then additional ethanol and water were added. The pH was adjusted to 13.2 with aqueous sodium hydroxide at a temperature of 20℃over a period of 1 hour. The mixture was cooled and centrifuged. The wet cake obtained was washed with a mixed solvent of ethanol/water and then dried in vacuo to give 15.6g of compound BG-11A (purity: 99.05%, yield: 96.6%).
Example 1B
Compound BG-10 (20 g, 1.0X) was suspended in ethanol (6.5X) and then approximately 20% ethanol solution of hydrochloric acid was added. The reaction mixture was heated to 60 ℃ and then stirred for 72 hours until the reaction was complete. The reaction mixture was concentrated and then additional ethanol and water were added. The pH was adjusted to 13.0 with aqueous sodium hydroxide at a temperature of 50℃over a period of 24 hours. The mixture was cooled and centrifuged, and then beaten in ethanol and water. The obtained wet cake was washed with a mixed solvent of ethanol/water, and then dried in vacuo to give 16.5g of Compound BG-11A (purity: 99.13%, yield: 95.2%).
Example 2 Synthesis of BG-11B
Example 2A
BG-11A (30 g,1.0X,1.0 eq.) was dissolved in a mixture of ethanol/water/acetic acid (14.7X, acetic acid: 23%). The obtained solution was partially transferred to a reaction vessel. Additional ethanol/water/acetic acid mixed solvent (3.6X, acetic acid: 24%) was then added to the reaction vessel. The reaction solution was heated to 55 ℃. D-DBTA (1.0 eq.) was then dissolved in a mixture of ethanol/water/acetic acid (4.8X, acetic acid: 23%) and then the resulting D-DBTA solution was partially added to the reaction vessel followed by seeding with BG-11B. The remaining BG-11A solution and D-DBTA solution were added together. The reaction mixture was stirred at 55℃for 4 hours. The mixture is then cooled to be crystallized. The solid was collected by centrifugation, washed successively with a mixture of ethanol/water/acetic acid, ethanol, and then dried in vacuo to give 28.31g of BG-11B (purity: 99.81%, chiral purity: 90.8%, yield: 49.2%).
Example 2B:
BG-11A (30 g,1.0X,1.0 eq.) was dissolved in a mixture of ethanol/water/acetic acid (17.2X, acetic acid: 23%). The obtained solution was partially transferred to a reaction vessel. Additional ethanol/water/acetic acid mixed solvent (4.2X, acetic acid: 24%) was then added to the reaction vessel. The reaction solution was heated to 65 ℃. D-DBTA (1.0 eq.) was then dissolved in a mixture of ethanol/water/acetic acid (5.7X, acetic acid: 23%) and then the resulting D-DBTA solution was partially added to the reaction vessel followed by the addition of BG-11B crystals. The remaining BG-11A solution and D-DBTA solution were added together. The reaction mixture was stirred at 65℃for 6 hours. The mixture is then cooled to be crystallized. The solid was collected by centrifugation, washed successively with a mixture of ethanol/water/acetic acid, ethanol, and then dried in vacuo to obtain 22.5g of BG-11B (purity: 99.23%, chiral purity: 94.1%, yield: 39.1%).
Example 2C
BG-11A (30 g,1.0X,1.0 eq.) was dissolved in a mixture of ethanol/water/acetic acid (17.2X, acetic acid: 23%). The obtained solution was partially transferred to a 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 ℃. D-DBTA (1.45 eq.) was dissolved in a mixed solution of ethanol/water/acetic acid (5.7X, acetic acid: 23%) and then the resulting D-DBTA solution was partially added to the reaction vessel followed by the addition of BG-11B crystals. The remaining BG-11A solution and D-DBTA solution were added together. The reaction mixture was stirred at 55℃for 4 hours. The mixture is then cooled to be crystallized. The solid was collected by centrifugation, washed successively with a mixture of ethanol/water/acetic acid, ethanol, and then dried in vacuo to give 28.9g of BG-11B (purity: 99.79%, chiral purity: 91.3%, yield: 50.8%).
Example 3 Synthesis of BG-11D
Example 3A-1, first split:BG-11A (30.0 g,1.0X,1.0 eq.) was dissolved in a mixture of ethanol/water/acetic acid (17.0X, acetic acid: 23.6%). The obtained solution was partially transferred to a reaction vessel. Additional ethanol/water/acetic acid mixed solvent (4.2X, acetic acid: 24.0%) was added to the reaction vessel. The solution in the reactor was heated to 55 ℃. D-DBTA (1.0 eq.) was then dissolved in a mixture of ethanol/water/acetic acid (5.6X, acetic acid: 23.4%) and then the resulting D-DBTA solution was partially added to the reaction vessel followed by seeding with BG-11B. The remaining D-DBTA solution and BG-11A solution were added to the reaction vessel and the mixture was stirred at 55deg.C for 4 hours. The mixture was then cooled to allow the crystals to completely precipitate. The solid was collected by centrifugation, washed successively with a mixture of ethanol/water/acetic acid, ethanol each 1.6X, and then dried in vacuo to give 27.3g of BG-11B (chiral purity: 91.7%, yield: 48.0%).
Example 3B-1, second split:BG-11B (20.0 g,1.0X,1.0 eq.) was suspended in ethanol and water followed by the addition of aqueous potassium hydroxide (1.7 eq.). The mixture was heated and then seeded with acetic acid and BG-11B to precipitate crystals. Additional acetic acid (1.65X) was added to dissolve the crystals. D-DBTA (0.4 eq.) ethanol/water/acetic acid mixed solvent (3.2X, ethyl)Acid: 11.0%) solution, followed by cooling crystallization. The solid was collected by centrifugation, washed successively with a mixture of ethanol/water/acetic acid, ethanol, and then dried in vacuo to give 16.4g of BG-11B (chiral purity: 97.4%, yield: 81.3%).
Example 3B-2, free: will beBG-11B (30.0 g,1.0X,1.0 eq.) was dissolved in acetonitrile (4.2X) and water (9.0X), followed by addition of sodium hydroxide (30% aqueous solution, 5.0 eq.) solution to precipitate a solid. The precipitated solid was collected by centrifugation, washed with water, and then dried in vacuo to give 15.5g 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 eq) was added to methanesulfonic acid (19.3 eq) and water (1.7 eq). The reaction mixture was heated to 80 ℃ and stirred until the reaction was complete. The mixture was then cooled, followed by additional water and acetonitrile (4.0X). An aqueous sodium hydroxide solution was added dropwise at 20℃followed by heating to 50 ℃. The pH was adjusted to 12 with additional aqueous sodium hydroxide. The organic layer was collected, followed by addition of isopropyl acetate (2.6X) followed by washing with brine. Seed crystals were added to the obtained organic layer, and isopropyl acetate was then added for solvent exchange. Methyl tert-butyl ether was added and then cooled to crystallize. The solid was collected by centrifugation, washed with methyl tert-butyl ether and then dried in vacuo to give 18.29g of crude BG-13 (purity: 98.73%, yield: 87.2%).
Example 4B:
compound BG-11D (20 g,1.0x,1.0 eq) was added to methanesulfonic acid (18.0 eq) and water (1.0 eq). The reaction mixture was heated to 80 ℃ and stirred until the reaction was complete. The mixture was then cooled, followed by additional water and acetonitrile (4.0X). An aqueous sodium hydroxide solution was added dropwise at 20℃followed by heating to 50 ℃. The pH was adjusted to 11-12 with additional aqueous sodium hydroxide. The organic layer was collected, followed by addition of isopropyl acetate (2.6X) followed by washing with brine. Seed crystals were added to the obtained organic layer, and isopropyl acetate was then added for solvent exchange. Methyl tert-butyl ether was added and then cooled to crystallize. The solid was collected by centrifugation, washed with methyl tert-butyl ether and then dried in vacuo to give 18.7g of crude BG-13 (purity: 98.69%, yield: 87.8%).
Example 4C:
compound BG-11D (20 g,1.0x,1.0 eq) was added to methanesulfonic acid (18.0 eq) and water (1.7 eq). The reaction mixture was heated to 75 ℃ and stirred until the reaction was complete. The mixture was then cooled, followed by additional water and acetonitrile (3.7X). The pH is adjusted to 11-12 with additional aqueous sodium hydroxide at a temperature of less than 50 ℃. The temperature of the mixture was adjusted to 50 ℃. The organic layer was collected, followed by addition of isopropyl acetate (2.6X) and washing with brine. Seed crystals were added to the obtained organic layer, and isopropyl acetate was then added for solvent exchange. Methyl tert-butyl ether was added and then cooled to crystallize. The solid was collected by centrifugation, washed with methyl tert-butyl ether and then dried in vacuo to give 17.63g 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 ℃ and stirred until the reaction was complete. The reaction solution was portioned and 107.5g (x=20g, 1 eq based on 20g BG-11 d) was sampled for the following step. Additional water and acetonitrile (3.0X) were added. The pH was adjusted to 12 with additional aqueous sodium hydroxide at a temperature of 35 ℃. The temperature of the mixture was adjusted to 50 ℃. The organic layer was collected, followed by addition of isopropyl acetate (3.2X) and washing with brine. Seed crystals were added to the obtained organic layer, and isopropyl acetate was then added for solvent exchange. Methyl tert-butyl ether was added and then cooled to crystallize. The solid was collected by centrifugation, washed with methyl tert-butyl ether and then dried in vacuo to give 19g of crude BG-13 (purity: 98.95%, yield: 89.5%).
Example 4E:
example 4E-1:compound BG-11D (20 g,1.0x,1.0 eq) was added to methanesulfonic acid (16.6 eq) and water (1.7 eq). The reaction mixture was heated to 80 ℃ and stirred until the reaction was complete. The mixture was then cooled, followed by acetonitrile (5.0X volume). At 2Aqueous sodium hydroxide (20%) was added dropwise at 0deg.C followed by heating to 50deg.C. The pH was adjusted to 11-12 with additional aqueous sodium hydroxide (20%). The organic layer was collected, followed by addition of isopropyl acetate (2.6X) followed by washing with brine. Seed crystals were added to the obtained organic layer, and isopropyl acetate was then added for solvent exchange. Methyl tert-butyl ether was added and then cooled to crystallize. The solid was collected by centrifugation, washed with methyl tert-butyl ether and then dried in vacuo to give 18.8g of crude BG-13 (yield: 89%).
Example 4E-2:the crude BG-13 (20 g) was dissolved in methanol (6 times mass) and water (4 times mass), heated to 45℃and then L-DBTA (0.57 eq.) in methanol/water was added. The mixture was cooled to be crystallized. The precipitated solid was collected by centrifugation and then washed with water to give BG-12.
Example 4E-3:BG-12 (65.7 g) was dissolved in acetonitrile and water, followed by addition of aqueous sodium hydroxide solution and isopropyl acetate. The organic layer was collected, then washed with brine, and concentrated. BG-13 was seeded 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 dried in vacuo to give BG-13 pure (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 the addition of L-tartaric acid and sodium bicarbonate. The mixture was cooled, followed by addition of acryloyl chloride (6.84 g). The solution was stirred at-5 ℃ until the reaction was complete, followed by the addition of ethyl acetate and isolation. The organic layer was collected and the aqueous layer was extracted again with ethyl acetate. The organic layers were combined, washed with brine, and then dibutyl hydroxytoluene (1%) was added. Ethyl acetate and methylene chloride were continuously added for solvent exchange, followed by addition of dibutylhydroxytoluene (2%).
The solution was divided into portions and 72.2g (16.94 g of Compound 1) was taken for 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, followed by addition of ethyl acetate, and concentrated, seeded with compound 1, and crystallized at an incubation temperature. Concentration was continued and then methyl tert-butyl ether was added to precipitate further crystals. The solid was collected by centrifugation, washed with methyl tert-butyl ether and then dried in vacuo to give 14.31g 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, followed by addition of acryloyl chloride (6.63 g). The solution was stirred at 5 ℃ until the reaction was complete, followed by the addition of ethyl acetate and isolation. The organic layer was collected and the aqueous layer was extracted again with ethyl acetate. The organic layers were combined and washed with brine.
The organic solution was divided equally into two parts and half of the organic phase (expressed below as based on 15g BG-13, x=15 g) was taken for the following steps. Ethyl acetate and methylene chloride were continuously added for solvent exchange, followed by addition of 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, followed by addition of ethyl acetate, and concentration, addition of compound 1 seed crystal, stirring with heat preservation to effect crystallization. The solid was collected by centrifugation, washed with methyl tert-butyl ether and then dried in vacuo to give 14.20g of crude compound 1 (purity: 99.75%, yield: 83.7%).
The foregoing examples and description of certain embodiments should be considered illustrative and not to be construed as limiting the application as defined by the claims. It will be readily appreciated that numerous variations and combinations of the features described above may be utilized without departing from the present application as set forth in the claims. All such variations are intended to be included within the scope of the present application. All references cited are incorporated herein by reference 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:
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Citations (3)

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Publication number Priority date Publication date Assignee Title
CN104884458A (en) * 2013-04-25 2015-09-02 百济神州有限公司 Fused heterocyclic compounds as protein kinase inhibitors
WO2018033135A1 (en) * 2016-08-19 2018-02-22 Beigene, Ltd. Use of a combination comprising a btk inhibitor for treating cancers
CN109563099A (en) * 2016-08-16 2019-04-02 百济神州有限公司 (S) -7- (1- acryloylpiperidine -4- base) -2- (4- Phenoxyphenyl) -4,5,6,7- tetrahydro-pyrazole simultaneously crystal form of [1,5-A] pyrimidine -3- formamide, its preparation and use

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104884458A (en) * 2013-04-25 2015-09-02 百济神州有限公司 Fused heterocyclic compounds as protein kinase inhibitors
CN109563099A (en) * 2016-08-16 2019-04-02 百济神州有限公司 (S) -7- (1- acryloylpiperidine -4- base) -2- (4- Phenoxyphenyl) -4,5,6,7- tetrahydro-pyrazole simultaneously crystal form of [1,5-A] pyrimidine -3- formamide, its preparation and use
WO2018033135A1 (en) * 2016-08-19 2018-02-22 Beigene, Ltd. Use of a combination comprising a btk inhibitor for treating cancers

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