CN117229202A - Preparation method of intermediate of BRD9 targeted degradation compound - Google Patents
Preparation method of intermediate of BRD9 targeted degradation compound Download PDFInfo
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- CN117229202A CN117229202A CN202311516649.4A CN202311516649A CN117229202A CN 117229202 A CN117229202 A CN 117229202A CN 202311516649 A CN202311516649 A CN 202311516649A CN 117229202 A CN117229202 A CN 117229202A
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- bromo
- methoxy
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- methylpyridine
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- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- 102100029893 Bromodomain-containing protein 9 Human genes 0.000 title claims abstract description 12
- 101000794032 Homo sapiens Bromodomain-containing protein 9 Proteins 0.000 title claims abstract description 12
- 150000001875 compounds Chemical class 0.000 title claims abstract description 12
- 230000015556 catabolic process Effects 0.000 title claims abstract description 10
- 238000006731 degradation reaction Methods 0.000 title claims abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 47
- NOTHVFNKDDEMEB-UHFFFAOYSA-N 5-bromo-1,3,4-trimethylpyridin-2-one Chemical compound Cc1c(Br)cn(C)c(=O)c1C NOTHVFNKDDEMEB-UHFFFAOYSA-N 0.000 claims abstract description 20
- HGRXBKDKSYDWLD-UHFFFAOYSA-N 2-methoxy-4-methylpyridine Chemical compound COC1=CC(C)=CC=N1 HGRXBKDKSYDWLD-UHFFFAOYSA-N 0.000 claims abstract description 14
- SYQAACONMLRXPR-UHFFFAOYSA-N 3,5-dibromo-2-methoxy-4-methylpyridine Chemical compound COC1=NC=C(Br)C(C)=C1Br SYQAACONMLRXPR-UHFFFAOYSA-N 0.000 claims abstract description 14
- -1 5-bromo-2-methoxy-3, 4-dimethylpyridine Chemical compound 0.000 claims abstract description 14
- PTIDDSJVNIIEGL-UHFFFAOYSA-N 5-bromo-3,4-dimethyl-1h-pyridin-2-one Chemical compound CC1=C(C)C(O)=NC=C1Br PTIDDSJVNIIEGL-UHFFFAOYSA-N 0.000 claims abstract description 12
- MZVSTDHRRYQFGI-UHFFFAOYSA-N 2-chloro-4-methylpyridine Chemical compound CC1=CC=NC(Cl)=C1 MZVSTDHRRYQFGI-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000003960 organic solvent Substances 0.000 claims abstract description 6
- 239000002904 solvent Substances 0.000 claims description 51
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 36
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 28
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- 238000010791 quenching Methods 0.000 claims description 16
- 230000000171 quenching effect Effects 0.000 claims description 16
- 239000003513 alkali Substances 0.000 claims description 14
- 238000003756 stirring Methods 0.000 claims description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 13
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- 239000003208 petroleum Substances 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 7
- 238000001914 filtration Methods 0.000 claims description 7
- 239000012312 sodium hydride Substances 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 6
- 238000010009 beating Methods 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 5
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 5
- 229920006395 saturated elastomer Polymers 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 239000012074 organic phase Substances 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 3
- 238000000605 extraction Methods 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 claims description 2
- 238000002386 leaching Methods 0.000 claims description 2
- CCZVEWRRAVASGL-UHFFFAOYSA-N lithium;2-methanidylpropane Chemical compound [Li+].CC(C)[CH2-] CCZVEWRRAVASGL-UHFFFAOYSA-N 0.000 claims description 2
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- 238000004537 pulping Methods 0.000 claims description 2
- 239000001632 sodium acetate Substances 0.000 claims description 2
- 235000017281 sodium acetate Nutrition 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 14
- RMOUBSOVHSONPZ-UHFFFAOYSA-N Isopropyl formate Chemical compound CC(C)OC=O RMOUBSOVHSONPZ-UHFFFAOYSA-N 0.000 claims 1
- TWJVNKMWXNTSAP-UHFFFAOYSA-N azanium;hydroxide;hydrochloride Chemical class [NH4+].O.[Cl-] TWJVNKMWXNTSAP-UHFFFAOYSA-N 0.000 claims 1
- 230000035484 reaction time Effects 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 10
- 239000003054 catalyst Substances 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 2
- 239000000376 reactant Substances 0.000 abstract description 2
- 239000007788 liquid Substances 0.000 description 10
- 238000001819 mass spectrum Methods 0.000 description 10
- 239000000243 solution Substances 0.000 description 9
- 206010028980 Neoplasm Diseases 0.000 description 7
- 239000000203 mixture Substances 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- 102000001805 Bromodomains Human genes 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 108091005575 Bromodomain-containing proteins Proteins 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000002390 rotary evaporation Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- YAVKJNIMFGZBSY-UHFFFAOYSA-N 5-bromo-3,4-dimethylpyridin-2-amine Chemical compound CC1=C(C)C(N)=NC=C1Br YAVKJNIMFGZBSY-UHFFFAOYSA-N 0.000 description 1
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 1
- 108050009021 Bromodomains Proteins 0.000 description 1
- 102100039869 Histone H2B type F-S Human genes 0.000 description 1
- 108010033040 Histones Proteins 0.000 description 1
- 101001035372 Homo sapiens Histone H2B type F-S Proteins 0.000 description 1
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 1
- 208000008938 Rhabdoid tumor Diseases 0.000 description 1
- 101150008214 SMARCB1 gene Proteins 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 239000007805 chemical reaction reactant Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000006690 co-activation Effects 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- 230000009025 developmental regulation Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000001973 epigenetic effect Effects 0.000 description 1
- 230000005861 gene abnormality Effects 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000025915 regulation of apoptotic process Effects 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 206010042863 synovial sarcoma Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
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- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
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Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Pyridine Compounds (AREA)
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 andBr 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:0.6-8 mL.
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 80 ℃, stirring for 14 and h, and displaying that the reaction is completely free of raw materials by a dot plate. 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 (15)
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 the 5-bromo-1, 3, 4-trimethylpyridin-2 (1H) -one.
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 Br as described in step (2) 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 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.
9. 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.
10. 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.
11. 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; the solvent 6 is petroleum ether and ethyl acetate according to the volume ratio of 1: 0.8-1.2.
12. 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.
13. 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.
14. 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.
15. 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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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20120252777A1 (en) * | 2011-03-28 | 2012-10-04 | Johannes Cornelius Hermann | Thiazolopyrimidine compounds |
| CN105828820A (en) * | 2013-10-18 | 2016-08-03 | 赛尔基因昆蒂赛尔研究公司 | Bromodomain inhibitors |
| US20180044335A1 (en) * | 2015-03-05 | 2018-02-15 | Boehringer Ingelheim International Gmbh | New Pyridinones and Isoquinolinones as Inhibitors of the Bromodomain BRD9 |
| CN112601584A (en) * | 2018-07-24 | 2021-04-02 | 豪夫迈·罗氏有限公司 | Isoquinoline compounds and uses thereof |
| CN113166062A (en) * | 2018-10-03 | 2021-07-23 | 豪夫迈·罗氏有限公司 | 8-aminoisoquinoline compounds and uses thereof |
| CN114641473A (en) * | 2019-09-16 | 2022-06-17 | 诺华股份有限公司 | BRD9 bifunctional degradation agent and use method thereof |
| TW202328101A (en) * | 2021-09-09 | 2023-07-16 | 美商Ｃ４醫藥公司 | Selected compounds for targeted degradation of brd9 |
-
2023
- 2023-11-15 CN CN202311516649.4A patent/CN117229202B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20120252777A1 (en) * | 2011-03-28 | 2012-10-04 | Johannes Cornelius Hermann | Thiazolopyrimidine compounds |
| CN105828820A (en) * | 2013-10-18 | 2016-08-03 | 赛尔基因昆蒂赛尔研究公司 | Bromodomain inhibitors |
| US20180044335A1 (en) * | 2015-03-05 | 2018-02-15 | Boehringer Ingelheim International Gmbh | New Pyridinones and Isoquinolinones as Inhibitors of the Bromodomain BRD9 |
| CN112601584A (en) * | 2018-07-24 | 2021-04-02 | 豪夫迈·罗氏有限公司 | Isoquinoline compounds and uses thereof |
| CN113166062A (en) * | 2018-10-03 | 2021-07-23 | 豪夫迈·罗氏有限公司 | 8-aminoisoquinoline compounds and uses thereof |
| CN114641473A (en) * | 2019-09-16 | 2022-06-17 | 诺华股份有限公司 | BRD9 bifunctional degradation agent and use method thereof |
| TW202328101A (en) * | 2021-09-09 | 2023-07-16 | 美商Ｃ４醫藥公司 | Selected compounds for targeted degradation of brd9 |
Non-Patent Citations (2)
| Title |
|---|
| BRIAN M.ADGER等: "Synthesis of 2-substituted 4-pyridylpropionates. Part 2. Alkylation approach", 《J. CHEM. SOC., PERKIN TRANS. 1》, pages 2791 * |
| MAGNUS SELLSTEDT 等: "A Three-Component Reaction Forming Naphthyridones – Synthesis of Lophocladine Analogs", 《ORG. LETT.》, vol. 13, no. 19, pages 5280 * |
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