CN117229202B - Preparation method of intermediate of BRD9 targeted degradation compound - Google Patents
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- CN117229202B CN117229202B CN202311516649.4A CN202311516649A CN117229202B CN 117229202 B CN117229202 B CN 117229202B CN 202311516649 A CN202311516649 A CN 202311516649A CN 117229202 B CN117229202 B CN 117229202B
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Abstract
The invention provides a preparation method of an intermediate of a BRD9 targeted degradation compound, belonging to the field of biological medicine; the preparation method comprises the following steps: 2-chloro-4-methylpyridine is taken as a raw material to be combined with an organic solvent, an extractant, a catalyst and reactants to synthesize 2-methoxy-4-methylpyridine, 3, 5-dibromo-2-methoxy-4-methylpyridine, 5-bromo-2-methoxy-3, 4-dimethylpyridine, 5-bromo-3, 4-dimethylpyridine-2-ol and 5-bromo-1, 3, 4-trimethylpyridin-2 (1H) -one in sequence; compared with the prior art, the reaction yield of the invention in the 5 steps reaches 64%; the preparation process is simple, the reaction condition is controllable, and the large-scale production is convenient.
Description
Technical Field
The invention belongs to the field of biological medicine, and relates to a preparation method of an intermediate of a BRD9 targeted degradation compound.
Background
Bromodomain-containing proteins (BRDs) such as BRD9 are proteins that recognize acetylated lysine residues, such as on the N-terminus of histone proteins; has many functions related to transcription mediation and coactivation. Studies show that the deletion of BRD9 causes gene expression changes related to apoptosis regulation, translation and development regulation, and is of great importance for the proliferation of SMARCB 1-deficient cancer cell lines, so that BRD9 is mainly used for cancers carrying SMARCB1 gene abnormalities and plays an important role in various types of tumors such as malignant rhabdoid tumors, acute myeloid leukemia, synovial sarcoma and the like, and is a treatment target point of the cancers. The 5-bromo-1, 3, 4-trimethylpyridin-2 (1H) -one can be used to prepare targeted degradation compounds of BRD9 protein for the treatment of cancer.
WO2015058160 discloses a series of substituted heterocyclic derivative compounds, and compositions comprising the compounds, and the use of the compounds and compositions for the treatment of cancer and neoplastic diseases by inhibiting bromodomain-mediated epigenetic modulation of the recognition of the acetolysine region of the protein (e.g., histone). Therefore, how to provide a preparation method or a synthetic raw material of a bromodomain-containing protein is one of the key problems of technical studies in the art, and has important significance for treating cancer.
Meanwhile, the patent also discloses 5-bromo-1, 3, 4-trimethylpyridin-2 (1H) -one, a preparation method thereof and application in preparing BRD related substances, wherein the preparation method specifically comprises the following steps: to a mixture of 5-bromo-3, 4-dimethylpyridin-2-amine and concentrated sulfuric acid was added dropwise an aqueous solution of sodium nitrite. Then, the resulting mixture was stirred for 30 minutes and filtered to obtain an intermediate. The intermediate was dissolved in a solution of anhydrous tetrahydrofuran, sodium hydride was added, stirring was continued at 0 ℃, methyl iodide was added for reaction, and a saturated aqueous ammonium chloride solution was further added and extracted with ethyl acetate. The combined organic layers were washed with brine, dried, filtered and concentrated, and purified by column chromatography on silica gel to give 5-bromo-1, 3, 4-trimethylpyridin-2 (1H) -one as a white solid in 80% yield.
Therefore, how to provide a preparation method of 5-bromo-1, 3, 4-trimethylpyridin-2 (1H) -one to obtain higher yield, higher safety and lower cost is one of the problems studied by the skilled in the art, and has important significance for preparing the targeted degradation compound of BRD 9.
Disclosure of Invention
Aiming at the problems of lower yield, higher raw material preparation cost and poor safety of 5-bromo-1, 3, 4-trimethylpyridin-2 (1H) -one in the prior art, the invention provides a preparation method of an intermediate of a BRD9 targeted degradation compound.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
a method for preparing an intermediate of a BRD9 targeted degradation compound, comprising the following steps:
(1) Dissolving 2-chloro-4-methylpyridine in a solvent 1, stirring, adding alkali for reaction, extracting in the solvent 2, and drying to obtain 2-methoxy-4-methylpyridine;
(2) Adding alkali and solvent 3 into the 2-methoxy-4-methylpyridine obtained in the step (1) for dissolution, and stirring and adding Br 2 Reacting and quenching to obtain 3, 5-dibromo-2-methoxy-4-methylpyridine;
(3) Adding a solvent 4 into the 3, 5-dibromo-2-methoxy-4-methylpyridine obtained in the step (2), then sequentially adding alkali and methyl iodide for reaction, quenching, extracting by the solvent 5, spin-drying an organic phase, pulping, filtering and drying to obtain 5-bromo-2-methoxy-3, 4-dimethylpyridine;
(4) Adding the 5-bromo-2-methoxy-3, 4-lutidine obtained in the step (3) into hydrochloric acid for reaction, cooling, filtering, leaching with a solvent 6, filtering and drying to obtain 5-bromo-3, 4-lutidine-2-alcohol;
(5) Adding the 5-bromo-3, 4-dimethylpyridine-2-ol obtained in the step (4) into a solvent 7, adding sodium hydride, then adding methyl iodide for reaction, quenching, adding a solvent 8 for extraction, and obtaining the 5-bromo-1, 3, 4-trimethylpyridin-2 (1H) -one.
Preferably, the invention also provides a reaction flow of the preparation method:
preferably, the solvent 1 in the step (1) is one or more selected from methanol, ethanol, isopropanol, n-butanol, tert-butanol, acetonitrile, acetone and other organic solvents which do not affect the reaction.
Preferably, the alkali in the step (1) is selected from one or more of sodium hydroxide, potassium tert-butoxide, sodium tert-butoxide, potassium carbonate and sodium carbonate.
Preferably, the temperature of the reaction in step (1) is 80-100 ℃ and the time of the reaction is 20-30h.
It is further preferred that the temperature of the reaction in step (1) is 90-100 ℃ and the time of the reaction is 24 hours.
Preferably, the solvent 2 in step (1) is methyl tert-butyl ether.
Preferably, the dosage ratio of the 2-chloro-4-methylpyridine, the solvent 1, the alkali and the solvent 2 in the step (1) is as follows: 1g:2.7-3.2mL, 0.9-1g:2.9-3.2mL.
Preferably, the base in step (2) is at least one selected from sodium acetate, sodium carbonate and potassium carbonate.
Preferably, the solvent 3 in the step (2) is one or more selected from acetic acid, isopropanol, n-butanol, tert-butanol, acetonitrile, acetone and other organic solvents which do not affect the reaction.
Preferably, the Br in step (2) 2 The ambient temperature of the addition of (2) is 15-30 ℃.
Preferably, the temperature of the reaction in step (2) is 80-100 ℃.
Preferably, the quenching in step (2) is: adding saturated Na 2 SO 3 Quenching with water solution.
Further preferably, the reaction starting material is confirmed to be completely involved in the reaction by using a spot plate before the quenching.
Preferably, in step (2), the 2-methoxy-4-methylpyridine, solvent 3, base and Br 2 The dosage ratio of (2) is as follows: 1g:5.8-6.3mL:1.8-2.2g:3.8-4.0g.
Preferably, the base in step (3) is selected from one of n-butyllithium, t-butyllithium, isobutyllithium, isopropyl-formatted reagent
Preferably, the quenching in step (3) is: quenched by addition of saturated ammonium chloride solution.
Preferably, the solvent 4 in the step (3) is selected from one of tetrahydrofuran, dioxane and diethyl ether.
Preferably, the solvent 5 in step (3) is selected from one or both of petroleum ether and ethyl acetate.
Preferably, the solvent used in the beating in the step (3) is petroleum ether.
Preferably, the beating time in step (3) is 8-24 hours.
Further preferably, the beating time is 10-16 hours.
Preferably, the dosage ratio of 3, 5-dibromo-2-methoxy-4-methylpyridine, alkali, methyl iodide, solvent 4 and solvent 5 in the step (3) is as follows: 1g:1.3-1.5mL:0.4-0.6g:5-6mL:7-8mL.
Preferably, the concentration of the hydrochloric acid in the step (4) is 6mol/L.
Preferably, the reaction conditions in step (4) are: and heating and refluxing, wherein the heating temperature is 80-120 ℃, and the refluxing time is 8-16h.
Preferably, in the step (4), the solvent 6 is petroleum ether and ethyl acetate according to a volume ratio of 1: 0.8-1.2.
Preferably, the beating time in step (4) is 8-24 hours.
Further preferably, the beating time is 10-16 hours.
Preferably, the dosage ratio of the 5-bromo-2-methoxy-3, 4-lutidine, the hydrochloric acid and the solvent 6 in the step (4) is 1g:9-11mL:0.6-8mL.
Preferably, the solvent 7 in step (5) is selected from one or both of Tetrahydrofuran (THF) and Dimethylformamide (DMF).
Preferably, the sodium hydride is added in step (5) immediately followed by stirring at 0 ℃ for 0.5-1h.
Preferably, the quenching in step (5) is: saturated ammonium chloride solution was added.
Preferably, in the step (5), the temperature is raised to 20-50 ℃ immediately after the methyl iodide is added, and the mixture is stirred for 2-4 hours.
Further preferably, the stirring time is 3 hours.
Preferably, the solvent 8 in the step (5) is selected from one or more of ethyl acetate, chloroform, dichloromethane, diethyl ether and other 5-bromo-1, 3, 4-trimethylpyridin-2 (1H) -one extractants which do not affect the chemical nature of the product.
Preferably, the extraction in step (5) is followed by column chromatography purification.
Further preferably, the eluting solvent used for column chromatography purification is petroleum ether/ethyl acetate (10/1-2/1).
Preferably, the dosage ratio of the 5-bromo-3, 4-dimethylpyridine-2-ol, the solvent 7, the sodium hydride, the methyl iodide and the solvent 8 in the step (5) is as follows: 1g 9-11mL:0.12-0.15g, 1.3-1.5g:13-16mL.
Compared with the prior art, the invention has the following beneficial effects:
the invention provides a new synthesis path for preparing 5-bromo-1, 3, 4-trimethylpyridine-2 (1H) -ketone by taking 2-chloro-4-methylpyridine as a reaction raw material, and provides a new choice for synthesizing 5-bromo-1, 3, 4-trimethylpyridine-2 (1H) -ketone;
the novel method for preparing 5-bromo-1, 3, 4-trimethylpyridin-2 (1H) -one by using 2-chloro-4-methylpyridine as a reaction raw material has the advantage of high yield, and the yield of 5 steps can reach 64%;
the novel method for preparing 5-bromo-1, 3, 4-trimethylpyridin-2 (1H) -one by using 2-chloro-4-methylpyridine as a reaction raw material has the advantages of low raw material cost, simple preparation process, mild and controllable reaction conditions and convenience for large-scale production.
Drawings
FIG. 1 is a liquid chromatogram of 2-methoxy-4-methylpyridine;
FIG. 2 is a mass spectrum of 2-methoxy-4-methylpyridine;
FIG. 3 is a liquid chromatogram of 3, 5-dibromo-2-methoxy-4-methylpyridine;
FIG. 4 is a mass spectrum of 3, 5-dibromo-2-methoxy-4-methylpyridine;
FIG. 5 is a liquid chromatogram of 5-bromo-2-methoxy-3, 4-lutidine;
FIG. 6 is a mass spectrum of 5-bromo-2-methoxy-3, 4-dimethylpyridine;
FIG. 7 is a liquid chromatogram of 5-bromo-3, 4-dimethylpyridin-2-ol;
FIG. 8 is a mass spectrum of 5-bromo-3, 4-dimethylpyridin-2-ol;
FIG. 9 is a liquid chromatogram of 5-bromo-1, 3, 4-trimethylpyridin-2 (1H) -one;
FIG. 10 is a mass spectrum of 5-bromo-1, 3, 4-trimethylpyridin-2 (1H) -one;
FIG. 11 is a nuclear magnetic resonance hydrogen spectrum of 5-bromo-1, 3, 4-trimethylpyridin-2 (1H) -one.
Detailed Description
It is to be noted that the raw materials used in the present invention are all common commercial products, and the sources thereof are not particularly limited.
Example preparation method of intermediate of BRD9 Targeted degradation Compound
(1) Preparation of 2-methoxy-4-methylpyridine
500 mL of MeOH was added to a single-necked flask, 166 g of 2-chloro-4-methylpyridine was added thereto, stirring was performed to dissolve the MeOH, 156.8 g of NaOH was added thereto, stirring was continued, the temperature was raised to 90℃and the reaction was performed for 24 hours until the reaction of the starting materials was completed by a dot plate. After the reaction system was cooled to room temperature, meOH was removed by rotary evaporation, and water (200, 200 mL) and methyl tert-butyl ether (500, 500 mL) were added to the residue to extract, separate, and dry by rotary evaporation.
Obtaining 2-methoxy-4-methylpyridine, weight: 146 g, yield: 91%.
The liquid chromatogram of the 2-methoxy-4-methylpyridine prepared in this example is shown in FIG. 1, and the mass spectrum is shown in FIG. 2.
(2) Preparation of 3, 5-dibromo-2-methoxy-4-methylpyridine
1500 mL of AcOH was added to a three-necked flask, 500 g of NaOAc and 250 g of 2-methoxy-4-methylpyridine were added, and the mixture was dissolved by stirring at 25℃while adding 975.6 g of Br 2 Heating to 80deg.C, stirring 14, h, and displaying on a dot boardThe reaction is completely free of raw materials. 500 g of Na is added 2 SO 3 Quenching the reaction with aqueous solution (2L), extracting with ethyl acetate (1 l×3), drying, and spin drying to obtain 3, 5-dibromo-2-methoxy-4-methylpyridine, mass: 521.6g, yield: 92%.
The liquid chromatogram of 3, 5-dibromo-2-methoxy-4-methylpyridine prepared in this example is shown in FIG. 3, and the mass spectrum is shown in FIG. 4.
(3) Preparation of 5-bromo-2-methoxy-3, 4-dimethylpyridine
202.0 g of 3, 5-dibromo-2-methoxy-4-methylpyridine is dissolved in anhydrous THF (1L), and the reaction system is cooled to-78 under the protection of nitrogen o C, gradually dropwise adding n-butyllithium (2.5M, 288 mL) for about 45min. The reaction system continues at-78 after the completion of the dripping o Stirred for 1h at C, then 102g of methyl iodide were added. After the reaction was continued for 1 hour, the spot plate showed that the reaction was complete. 200 mL saturated NH was added 4 The reaction was quenched with Cl solution and extracted with ethyl acetate (500 ml x 3). The organic phases are combined, dried and spin-dried to obtain crude products. Adding 400 mL petroleum ether to pulp 12 h, filtering and drying to obtain 5-bromo-2-methoxy-3, 4-lutidine, and the mass: 144.2g, yield: 93%.
The liquid chromatogram of 5-bromo-2-methoxy-3, 4-lutidine prepared in this example is shown in FIG. 5, and the mass spectrum is shown in FIG. 6.
(4) Preparation of 5-bromo-3, 4-dimethylpyridine-2-ol
300 g of 5-bromo-2-methoxy-3, 4-dimethylpyridine and 3L of 6M HCl were added to the reaction flask at room temperature. The reaction was carried out at an elevated temperature of 100℃for 6 hours. A large amount of solids precipitated and TLC plates were free of starting material, the reaction was stopped, cooled to 30 ℃, filtered, and the filter cake rinsed with ethyl acetate/petroleum ether (100 mL: 100 mL). Drying the filter cake to obtain a product 5-bromo-3, 4-dimethylpyridine-2-ol, wherein the product is prepared by the following components in mass: 258.0g, yield: 92%.
The liquid chromatogram of 5-bromo-3, 4-dimethylpyridine-2-ol prepared in this example is shown in FIG. 7, and the mass spectrum is shown in FIG. 8.
(5) Preparation of 5-bromo-1, 3, 4-trimethylpyridin-2 (1H) -one
402.0 g of 5-bromo-3, 4-dimethylpyridin-2-ol was added to anhydrous tetrahydrofuran (4L) at room temperature, and 96.0 g of NaH (60% content) (2.4 mo 1) was added thereto, and stirring was continued at 0℃for 0.5h. 568.0 g methyl iodide (4.0 mol) was added and the reaction was stirred continuously at 30℃for 3: 3 h; dot panels showed complete reaction. Adding 4L saturated NH into the reaction system 4 The reaction was quenched with aqueous Cl and extracted with ethyl acetate (2 l 3). The organic phases were combined, dried, filtered, spin-dried and the residue was purified by column chromatography on a silica gel column (PE: ea=10:1 to 2:1) to give 5-bromo-1, 3, 4-trimethylpyridin-2 (1H) -one as a white solid, mass: 386 g, yield: 90%.
The liquid chromatogram of the 5-bromo-1, 3, 4-trimethylpyridin-2 (1H) -one prepared in this example is shown in FIG. 9, the mass spectrum is shown in FIG. 10, and the nuclear magnetic resonance hydrogen spectrum is shown in FIG. 11.
According to fig. 1-11, 2-chloro-4-methylpyridine is taken as a raw material, and a series of organic solvents, extracting agents, catalysts and reactants are combined to synthesize 2-methoxy-4-methylpyridine, 3, 5-dibromo-2-methoxy-4-methylpyridine, 5-bromo-2-methoxy-3, 4-dimethylpyridine, 5-bromo-3, 4-dimethylpyridine-2-ol and 5-bromo-1, 3, 4-trimethylpyridin-2 (1H) -one in sequence; the yield of 5-bromo-1, 3, 4-trimethylpyridin-2 (1H) -one prepared in the embodiment of the invention reaches 64% in 5 steps, which fully demonstrates the high efficiency of the preparation method provided by the invention.
Finally, it should be noted that the above description is only for illustrating the technical solution of the present invention, and not for limiting the scope of the present invention, and that the simple modification and equivalent substitution of the technical solution of the present invention can be made by those skilled in the art without departing from the spirit and scope of the technical solution of the present invention.
Claims (14)
1. A preparation method of an intermediate of a BRD9 targeted degradation compound, which is characterized by comprising the following steps: the method comprises the following steps:
(1) Dissolving 2-chloro-4-methylpyridine in a solvent 1, stirring, adding alkali for reaction, extracting in the solvent 2, and drying to obtain 2-methoxy-4-methylpyridine;
(2) Adding alkali and solvent 3 into the 2-methoxy-4-methylpyridine obtained in the step (1) for dissolution, and stirring and adding Br 2 Reacting and quenching to obtain 3, 5-dibromo-2-methoxy-4-methylpyridine;
(3) Adding a solvent 4 into the 3, 5-dibromo-2-methoxy-4-methylpyridine obtained in the step (2), then sequentially adding alkali and methyl iodide for reaction, quenching, extracting by the solvent 5, spin-drying an organic phase, pulping, filtering and drying to obtain 5-bromo-2-methoxy-3, 4-dimethylpyridine;
(4) Adding the 5-bromo-2-methoxy-3, 4-lutidine obtained in the step (3) into hydrochloric acid for reaction, cooling, filtering, leaching with a solvent 6, filtering and drying to obtain 5-bromo-3, 4-lutidine-2-alcohol;
(5) Adding the 5-bromo-3, 4-dimethylpyridine-2-ol obtained in the step (4) into a solvent 7, adding sodium hydride, then adding methyl iodide for reaction, quenching, adding a solvent 8 for extraction, and obtaining 5-bromo-1, 3, 4-trimethylpyridin-2 (1H) -one;
the alkali in the step (3) is selected from one of n-butyllithium, tert-butyllithium, isobutyllithium and isopropyl format reagent;
the solvent 4 in the step (3) is selected from tetrahydrofuran, dioxane, diethyl ether and other solvents which do not influence the chemical properties of the product;
the solvent 5 in the step (3) is one or two selected from petroleum ether and ethyl acetate;
in the step (4), the solvent 6 is petroleum ether and ethyl acetate according to the volume ratio of 1: 0.8-1.2.
2. The method of manufacturing according to claim 1, characterized in that: the solvent 1 in the step (1) is selected from one or more of methanol, ethanol, isopropanol, n-butanol, tertiary butanol, acetonitrile, acetone and other organic solvents which do not influence the reaction; the alkali in the step (1) is selected from one or more of sodium hydroxide, potassium tert-butoxide, sodium tert-butoxide, potassium carbonate and sodium carbonate.
3. The method of manufacturing according to claim 1, characterized in that: the temperature of the reaction in the step (1) is 80-100 ℃, and the reaction time is 20-30h; the solvent 2 in the step (1) is methyl tertiary butyl ether.
4. The method of manufacturing according to claim 1, characterized in that: the dosage ratio of the 2-chloro-4-methylpyridine, the solvent 1, the alkali and the solvent 2 in the step (1) is as follows: 1g:2.7-3.2mL, 0.9-1g:2.9-3.2mL.
5. The method of manufacturing according to claim 1, characterized in that: the alkali in the step (2) is at least one selected from sodium acetate, sodium carbonate and potassium carbonate; the solvent 3 in the step (2) is one or more selected from acetic acid, isopropanol, n-butanol, tertiary butanol, acetonitrile, acetone and other organic solvents which do not influence the reaction.
6. The method of manufacturing according to claim 1, characterized in that: the Br in step (2) 2 The added ambient temperature is 15-30 ℃; the temperature of the reaction in the step (2) is 80-100 ℃; the quenching in step (2) is: adding saturated Na 2 SO 3 Quenching with water solution.
7. The method of manufacturing according to claim 1, characterized in that: 2-methoxy-4-methylpyridine, solvent 3, base and in step (2)Br 2 The dosage ratio of (2) is as follows: 1g:5.8-6.3mL:1.8-2.2g:3.8-4.0g.
8. The method of manufacturing according to claim 1, characterized in that: the quenching in step (3) is: adding saturated ammonium chloride water solution for quenching; the beating time in the step (3) is 8-24h.
9. The method of manufacturing according to claim 1, characterized in that: the dosage ratio of the 3, 5-dibromo-2-methoxy-4-methylpyridine, the alkali, the methyl iodide, the solvent 4 and the solvent 5 in the step (3) is as follows: 1g:1.3-1.5mL:0.4-0.6g:5-6mL:7-8mL.
10. The method of manufacturing according to claim 1, characterized in that: the dosage ratio of the 5-bromo-2-methoxy-3, 4-lutidine, the hydrochloric acid and the solvent 6 in the step (4) is 1g:9-11mL:0.6-8mL.
11. The method of manufacturing according to claim 1, characterized in that: the reaction conditions in step (4) are: and heating and refluxing, wherein the heating temperature is 80-120 ℃, and the refluxing time is 4-8h.
12. The method of manufacturing according to claim 1, characterized in that: the solvent 7 in the step (5) is selected from one or two of tetrahydrofuran and dimethylformamide; the solvent 8 in the step (5) is selected from one or more of ethyl acetate, chloroform, methylene dichloride, diethyl ether and other 5-bromo-1, 3, 4-trimethylpyridin-2 (1H) -one extractants which do not affect the chemical properties of the product.
13. The method of manufacturing according to claim 1, characterized in that: immediately after adding the sodium hydride in the step (5), stirring at 0 ℃ for 0.5-1h; and (3) adding the methyl iodide in the step (5), immediately heating to 20-50 ℃ and stirring for 2-4h.
14. The method of manufacturing according to claim 1, characterized in that: the dosage ratio of the 5-bromo-3, 4-dimethylpyridine-2-ol, the solvent 7, the sodium hydride, the methyl iodide and the solvent 8 in the step (5) is as follows: 1g 9-11mL:0.12-0.15g, 1.3-1.5g:13-16mL.
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| Synthesis of 2-substituted 4-pyridylpropionates. Part 2. Alkylation approach;Brian M.Adger等;《J. Chem. Soc., Perkin Trans. 1》;第2791页 * |
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