CN111909152A - Preparation method of BTK inhibitor and intermediate thereof - Google Patents
Preparation method of BTK inhibitor and intermediate thereof Download PDFInfo
- Publication number
- CN111909152A CN111909152A CN201910382010.9A CN201910382010A CN111909152A CN 111909152 A CN111909152 A CN 111909152A CN 201910382010 A CN201910382010 A CN 201910382010A CN 111909152 A CN111909152 A CN 111909152A
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- acid
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- ethanol
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Links
- 238000002360 preparation method Methods 0.000 title abstract description 5
- 229940124291 BTK inhibitor Drugs 0.000 title description 3
- 238000000034 method Methods 0.000 claims abstract description 29
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- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 54
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 49
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 45
- 239000000203 mixture Substances 0.000 claims description 37
- 239000002904 solvent Substances 0.000 claims description 32
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- 229940125904 compound 1 Drugs 0.000 claims description 21
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 20
- 239000013078 crystal Substances 0.000 claims description 19
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Classifications
-
- 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 invention relates to processes for the preparation of (S) -7- (1-acryloylpiperidin-4-yl) -2- (4-phenoxyphenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidine-3-carboxamide and intermediates thereof.
Description
Technical Field
The present invention relates to processes for the preparation of (S) -7- (1-acryloylpiperidin-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 that are inhibitors of Bruton's Tyrosine Kinase (BTK). Specifically, WO2014173289 discloses (S) -7- (1-acryloylpiperidin-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 showed better selectivity than ibrutinib (ibrutinib) for inhibiting BTK against EGFR, FGR, FRK, HER2, HER4, ITK, JAK3, LCK and TEC, less side effects are expected clinically than ibrutinib. Furthermore, compound 1, due to its weak ITK inhibition, showed significantly less antigen-dependent cell-mediated cytotoxicity (ADCC) induced by rituximab than ibrutinib, 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 method for preparing compound 1, which 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.
Disclosure of Invention
The inventors of the present invention found that: by optimizing the reaction parameters, particularly by improving the reaction temperature in the step of synthesizing the intermediate BG-11A from the intermediate BG-10, the reaction yield and the purity of the product are remarkably improved.
In a first aspect, the present invention relates to a process for preparing compound 1, said process comprising: reacting the intermediate BG-13 with an acryloyl compound in a solvent, adding a seed crystal of the compound 1, and crystallizing to obtain the compound 1.
In some embodiments, the acryloyl compound is dosed in an equivalent amount of 0.95 to 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 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 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, dichloromethane, ethyl acetate, acetone, 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, 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 some embodiments, the reaction is carried out at a temperature of-5 to 35 ℃.
In some embodiments, the methods of the invention for preparing compound 1 comprise: and (2) reacting the intermediate BG-13 with an acryloyl compound in a solvent, extracting with ethyl acetate after the reaction is finished, carrying out solvent exchange on the ethyl acetate and dichloromethane, adding seed crystals of the compound 1, and crystallizing methyl tert-butyl ether to obtain the compound 1.
In a second aspect, the present invention relates to a step of preparing intermediate BG-13, comprising: hydrolyzing the intermediate BG-11D in the presence of an 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. Such inorganic acids as hydrochloric acid, phosphoric acid, dihydrogenphosphoric 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, 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, after hydrolysis of 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 a non-polar solvent, a polar protic solvent, and a polar aprotic solvent, 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-dimethylformamide, isopropyl acetate, acetonitrile and dimethyl sulfoxide, or a mixture of two or more thereof. In a still further embodiment, 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 a specific embodiment, a method of making BG-13 comprises:
in a third aspect, the invention relates to a process for preparing BG-11D comprising: splitting the intermediate BG-11A by using a resolving agent to obtain an intermediate salt BG-11B,
then reacting the intermediate salt BG-11B with alkali, removing 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- (+) -dibenzoyltartaric acid (D-DBTA) and the like. 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 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 performance. 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 reform the salt. In a further embodiment, the amount of resolving agent used to re-form the salt is 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, which 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, and the like.
In some embodiments, the solvent is selected from 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, dichloromethane, ethyl acetate, acetone, 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, 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 of making BG-11D comprises:
in a fourth aspect, the present invention relates to a step of preparing intermediate BG-11A, comprising: treating the intermediate BG-11A with an acid in a solvent at an elevated temperature to remove the Boc group to provide an intermediate BG-11A,
in some embodiments, the acid is an inorganic or organic acid, such as hydrochloric acid, phosphoric acid, dihydrogen phosphate, hydrobromic acid, sulfuric acid, sulfurous acid, and nitric acid; and organic acids 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 acids 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, 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, 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, dichloromethane, ethyl acetate, acetone, 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 to 8.0X (by mass).
In some embodiments, the deprotection reaction is carried out 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 ℃, 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 to 13.5. In a still further embodiment, the pH is adjusted by adding an alkaline solution, for example, an aqueous sodium hydroxide solution.
In one embodiment, a method of making BG-11A comprises:
examples
The following reaction scheme describes in detail the scheme for the preparation of compound 1 starting from intermediate BG-10.
Reaction scheme
The process of the present invention is particularly suitable for preparing compound 1 reproducibly on a commercial scale, in high quality and in high yield; moreover, by optimizing or improving the synthesis process, the method of the invention can further improve the reaction yield or purity of each step, and generate the final target compound in a more economic or more environment-friendly manner.
For example, from the step of synthesizing BG-11A from the intermediate BG-10, more environmentally friendly ethanol is used as a solvent to replace the original dichloromethane; the deprotection reaction is carried out at elevated temperatures, further improving the purity and/or yield of the reaction product significantly (e.g. 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 the intermediate BG-11A, the amount of solvent used is reduced to about 50%. Simultaneously adding an intermediate BG-11A and a resolving agent D-DBTA to obtain consistent chemical resolution performance; and stable chemical resolution performance and high chiral purity are realized; and the whole manufacturing cycle time is also reduced, thereby improving the manufacturing efficiency.
For another example, in the step of synthesizing BG-13 from the 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, not as a salt of L-DBTA. Furthermore, the added methanesulfonic acid can be removed by a simple aftertreatment. This step also reduces the formation of some impurities.
For another example, in the step of synthesizing the compound 1 from the intermediate BG-13, the crystallization process is optimized by adding seed crystals, particularly in the post-treatment, so that the agglomeration in the crystallization process is avoided, and the quality of the final product is improved.
The following examples are intended to illustrate the invention, but not to limit the scope of the 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% ethanol hcl solution 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, 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 obtained wet cake was washed with a mixed solvent of ethanol/water, and then dried in vacuum to obtain 15.6g of 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% ethanol hcl solution 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, 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, then slurried in ethanol and water. The obtained wet cake was washed with a mixed solvent of ethanol/water, and then dried in vacuum to obtain 16.5g of 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 obtained solution was partially transferred to a reaction vessel. Further, another 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 ℃. D-DBTA (1.0 equiv.) was then dissolved in a mixture of ethanol/water/acetic acid (4.8X, acetic acid: 23%) and the resulting solution of D-DBTA was added in part to the reaction vessel, followed by seed crystals of 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 obtain 28.31g of 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 obtained solution was partially transferred to a reaction vessel. Further, another 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 ℃. D-DBTA (1.0 equiv.) was then dissolved in a mixture of ethanol/water/acetic acid (5.7X, acetic acid: 23%) and the resulting solution of D-DBTA was added in part 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 (30g,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 a 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 ℃. D-DBTA (1.45 equiv.) was dissolved in a mixed solution of ethanol/water/acetic acid (5.7X, acetic acid: 23%), and then the obtained D-DBTA solution was partially added to the reaction vessel, followed by 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 obtain 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 resolution:BG-11A (30.0g,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 a reaction vessel. Will be further anotherThe 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 ℃. 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 solution of D-DBTA was then added in portions to the reaction vessel, followed by seed crystals of BG-11B. The remaining D-DBTA solution and BG-11A solution were added to the reaction vessel and the mixture was stirred at 55 deg.C for 4 hours. The mixture was then cooled until crystals completely precipitated. 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 obtain 27.3g of BG-11B (chiral purity: 91.7%, yield: 48.0%).
Example 3B-1, second resolution:BG-11B (20.0g,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. 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 for crystallization. The solid was collected by centrifugation, washed successively with a mixture of ethanol/water/acetic acid, ethanol, and then dried in vacuo to obtain 16.4g of BG-11B (chiral purity: 97.4%, yield: 81.3%).
Example 3B-2, free: will be provided withBG-11B (30.0g,1.0X,1.0 equiv.) was dissolved in acetonitrile (4.2X) and water (9.0X), followed by the addition of sodium hydroxide (30% aqueous, 5.0 equiv.) solution to precipitate a solid. The precipitated solid was collected by centrifugation, washed with water, and then dried in vacuo to obtain 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 (20g,1.0X,1.0 equiv.) is added to methanesulfonic acid (19.3 equiv.) and water (1.7 equiv.). The reaction mixture was heated to 80 ℃ and stirred until the reaction was complete. The mixture was then cooled, followed by addition of additional water and acetonitrile (4.0 ×). Aqueous sodium hydroxide solution was added dropwise at 20 ℃ and then heated to 50 ℃. The pH was adjusted to 12 with additional aqueous sodium hydroxide. The organic layer was collected, followed by the addition of isopropyl acetate (2.6X), followed by washing with brine. Seed crystals were added to the obtained organic layer, followed by the addition of isopropyl acetate for solvent exchange. Adding methyl tert-butyl ether, and cooling for crystallization. The solid was collected by centrifugation, washed with methyl t-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 (20g,1.0X,1.0 equiv.) is added to methanesulfonic acid (18.0 equiv.) and water (1.0 equiv.). The reaction mixture was heated to 80 ℃ and stirred until the reaction was complete. The mixture was then cooled, followed by addition of additional water and acetonitrile (4.0 ×). Aqueous sodium hydroxide solution was added dropwise at 20 ℃ and then heated to 50 ℃. The pH was adjusted to 11-12 with additional aqueous sodium hydroxide. The organic layer was collected, followed by the addition of isopropyl acetate (2.6X), followed by washing with brine. Seed crystals were added to the obtained organic layer, followed by the addition of isopropyl acetate for solvent exchange. Adding methyl tert-butyl ether, and cooling for crystallization. The solid was collected by centrifugation, washed with methyl t-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 (20g,1.0X,1.0 equiv.) is added to methanesulfonic acid (18.0 equiv.) and water (1.7 equiv.). The reaction mixture was heated to 75 ℃ and stirred until the reaction was complete. The mixture was then cooled, followed by addition of additional water and acetonitrile (3.7 ×). The pH was adjusted to 11-12 with additional aqueous sodium hydroxide at a temperature below 50 ℃. The temperature of the mixture was adjusted to 50 ℃. The organic layer was collected, followed by the addition of isopropyl acetate (2.6X) and washing with brine. Seed crystals were added to the obtained organic layer, followed by the addition of isopropyl acetate for solvent exchange. Adding methyl tert-butyl ether, and cooling for crystallization. The solid was collected by centrifugation, washed with methyl t-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 (400g) was added to methanesulfonic acid (1720g) and water (30.4 g). The reaction mixture was heated to 83 ℃ 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 eq) was sampled for the following procedure. 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 ℃. The temperature of the mixture was adjusted to 50 ℃. The organic layer was collected, followed by the addition of isopropyl acetate (3.2X) and washing with brine. Seed crystals were added to the obtained organic layer, followed by the addition of isopropyl acetate for solvent exchange. Adding methyl tert-butyl ether, and cooling for crystallization. The solid was collected by centrifugation, washed with methyl t-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 (20g,1.0X,1.0 equiv.) is added to methanesulfonic acid (16.6 equiv.) and water (1.7 equiv.). The reaction mixture was heated to 80 ℃ and stirred until the reaction was complete. The mixture was then cooled, followed by addition of acetonitrile (5.0X volume). Aqueous sodium hydroxide (20%) was added dropwise at 20 ℃ and then heated to 50 ℃. 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 washing with brine. Seed crystals were added to the obtained organic layer, followed by the addition of isopropyl acetate for solvent exchange. Adding methyl tert-butyl ether, and cooling for crystallization. The solid was collected by centrifugation, washed with methyl t-butyl ether, and then dried in vacuo to give 18.8g of crude BG-13 (yield: 89%).
Example 4E-2:the crude BG-13 (20g) was dissolved in methanol (6 times by mass) and water (4 times by mass), heated to 45 ℃ and L-DBTA (0.57 equiv.) 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(65.7g) 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. Will be provided withMethyl tert-butyl ether was added to the residue, followed by cooling for crystallization. The solid was collected by centrifugation, washed with methyl tert-butyl ether and then dried under vacuum to give BG-13 pure product (chiral purity: 99.6%, HPLC purity 99.7%, yield: 93.4%).
Example 5 Synthesis of Compound 1
Example 5A:
compound BG-13(30g) was dissolved in a mixture of acetonitrile and water, followed by 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, then ethyl acetate was added and separated. The organic layer was collected, and the aqueous layer was extracted again by adding ethyl acetate. The organic layers were combined, washed with brine, and then dibutylhydroxytoluene (1%) was added. The solvent exchange was carried out by successively adding ethyl acetate and dichloromethane, followed by addition of dibutylhydroxytoluene (2%).
The solution was divided into portions, and 72.2g (16.94g of Compound 1) was used in the following step. The resulting solution was filtered through silica gel (0.67X, X based on the amount of BG-13). The solution is concentrated, then ethyl acetate is added, and concentrated, compound 1 seed crystals are added, and crystallization is carried out under the condition of heat preservation. Concentration was continued and then methyl tert-butyl ether was added to further precipitate crystals. The solid was collected by centrifugation, washed with methyl t-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(30g) 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, then ethyl acetate was added and separated. The organic layer was collected, and the aqueous layer was extracted again by adding ethyl acetate. The organic layers were combined and washed with brine.
The organic solution was divided equally into two portions, and half of the organic phase (expressed below based on 15g BG-13, X ═ 15g) was used in the following procedure. The solvent exchange was carried out by successively adding ethyl acetate and dichloromethane, followed by addition of dibutylhydroxytoluene (1%). The resulting solution was filtered through silica gel (1.33X) and concentrated, then transferred through a pad of celite to a clean container. The solution was concentrated, followed by addition of ethyl acetate and concentration, seeding with compound 1, and stirring with heat preservation to effect crystallization. The solid was collected by centrifugation, washed with methyl t-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 taken as illustrative, and not as limiting the invention as defined by the claims. It will be readily understood that various modifications and combinations of the above-described features may be utilized without departing from the invention as set forth in the claims. 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 of preparing compound BG-11A, the method comprising: treating compound BG-10 with an acid in a solvent at elevated temperature to remove the Boc group to give compound BG-11A,
2. the process of claim 1, wherein the acid is an inorganic acid selected from the group consisting of hydrochloric acid, phosphoric acid, dihydrogenphosphoric acid, hydrobromic acid, sulfuric acid, sulfurous acid, and nitric acid; and, the organic acid is 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 acids; 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 ℃, preferably the elevated temperature is in the temperature range of 40 to 60 ℃.
4. The process of claim 1, wherein the solvent is a non-polar solvent, a polar protic solvent, and a polar aprotic solvent, or a mixture thereof.
5. The process of claim 4, wherein the polar aprotic solvent is selected from N-methylpyrrolidone, N-methylmorpholine, methyl isobutyl ketone, methyl ethyl ketone, tetrahydrofuran, dichloromethane, ethyl acetate, acetone, N-dimethylformamide, isopropyl acetate, acetonitrile or dimethyl sulfoxide, the polar protic solvent is selected from water, methanol, ethanol, N-propanol, isopropanol, 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 process of any one of claims 1 to 5, wherein the amount of solvent is 5.0-8.0X (by weight).
7. The process 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, the pH is adjusted at a temperature of 20 to 75 ℃, preferably at a temperature of 50 to 65 ℃.
9. The process of claim 10, wherein the pH is not less than 11.5, preferably in the range of 12.5-13.5.
10. The method of claim 1, comprising:
11. a method of preparing compound 1, the method comprising: reacting the intermediate BG-13 with an acryloyl compound in a solvent, then adding seed crystals of Compound 1,
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| Publication number | Priority date | Publication date | Assignee | Title |
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| 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 |
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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 |
| 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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