CN114195694A - Preparation method of pyrrole compound - Google Patents
Preparation method of pyrrole compound Download PDFInfo
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- CN114195694A CN114195694A CN202010977128.9A CN202010977128A CN114195694A CN 114195694 A CN114195694 A CN 114195694A CN 202010977128 A CN202010977128 A CN 202010977128A CN 114195694 A CN114195694 A CN 114195694A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 title abstract description 4
- -1 pyrrole compound Chemical class 0.000 title abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 187
- 238000000034 method Methods 0.000 claims abstract description 24
- 238000006482 condensation reaction Methods 0.000 claims abstract description 17
- 238000006467 substitution reaction Methods 0.000 claims abstract description 16
- 238000005694 sulfonylation reaction Methods 0.000 claims abstract description 16
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 15
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 12
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000003513 alkali Substances 0.000 claims abstract description 8
- 239000003444 phase transfer catalyst Substances 0.000 claims abstract description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 93
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 75
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 66
- 238000006243 chemical reaction Methods 0.000 claims description 64
- 238000001816 cooling Methods 0.000 claims description 61
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 56
- 239000012074 organic phase Substances 0.000 claims description 52
- 239000003960 organic solvent Substances 0.000 claims description 49
- 238000001914 filtration Methods 0.000 claims description 46
- 238000001035 drying Methods 0.000 claims description 43
- 239000007787 solid Substances 0.000 claims description 40
- 238000004537 pulping Methods 0.000 claims description 35
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 34
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 33
- 239000002904 solvent Substances 0.000 claims description 30
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 27
- 239000012295 chemical reaction liquid Substances 0.000 claims description 25
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 24
- 238000004519 manufacturing process Methods 0.000 claims description 24
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 24
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 22
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 20
- 230000009471 action Effects 0.000 claims description 19
- 239000007788 liquid Substances 0.000 claims description 19
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 18
- 238000010438 heat treatment Methods 0.000 claims description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 17
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 claims description 16
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 16
- 238000002156 mixing Methods 0.000 claims description 16
- 239000000047 product Substances 0.000 claims description 16
- 238000003756 stirring Methods 0.000 claims description 14
- 239000003054 catalyst Substances 0.000 claims description 12
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 12
- 239000007810 chemical reaction solvent Substances 0.000 claims description 11
- 238000000605 extraction Methods 0.000 claims description 11
- 239000000706 filtrate Substances 0.000 claims description 11
- 238000006053 organic reaction Methods 0.000 claims description 11
- 229910052763 palladium Inorganic materials 0.000 claims description 11
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 10
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 10
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 9
- 239000012071 phase Substances 0.000 claims description 9
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 8
- 230000008569 process Effects 0.000 claims description 8
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 8
- 239000008096 xylene Substances 0.000 claims description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 7
- 150000007530 organic bases Chemical class 0.000 claims description 7
- IAUBZYYUBMBVPI-UHFFFAOYSA-N pyridine;sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O.C1=CC=NC=C1 IAUBZYYUBMBVPI-UHFFFAOYSA-N 0.000 claims description 7
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 claims description 2
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 claims description 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 238000010626 work up procedure Methods 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 7
- 238000009776 industrial production Methods 0.000 abstract 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- 238000012805 post-processing Methods 0.000 description 15
- 238000004128 high performance liquid chromatography Methods 0.000 description 13
- 238000000967 suction filtration Methods 0.000 description 7
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 5
- 230000005311 nuclear magnetism Effects 0.000 description 5
- 238000005070 sampling Methods 0.000 description 5
- 239000012265 solid product Substances 0.000 description 5
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 4
- 230000027119 gastric acid secretion Effects 0.000 description 3
- NQMRYBIKMRVZLB-UHFFFAOYSA-N methylamine hydrochloride Chemical compound [Cl-].[NH3+]C NQMRYBIKMRVZLB-UHFFFAOYSA-N 0.000 description 3
- 238000001291 vacuum drying Methods 0.000 description 3
- 239000002585 base Substances 0.000 description 2
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- XKBGEWXEAPTVCK-UHFFFAOYSA-M methyltrioctylammonium chloride Chemical compound [Cl-].CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC XKBGEWXEAPTVCK-UHFFFAOYSA-M 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- CDRNYKLYADJTMN-UHFFFAOYSA-N pyridine-3-sulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CN=C1 CDRNYKLYADJTMN-UHFFFAOYSA-N 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the field of pharmaceutical chemistry, and in particular relates to a preparation method of a pyrrole compound. The method comprises the steps of reacting raw materials with propionitrile under the conditions of a phase transfer catalyst and an alkali reagent, and then carrying out ring closing reaction, substitution reaction, sulfonylation reaction and condensation reaction to obtain the target compound. The method has relatively short route, is simple and easy to implement, and can be used for industrial production.
Description
Technical Field
The invention relates to a preparation method of a pyrrole compound, belonging to the technical field of medicinal chemistry.
Background
Vonolanide, the structural formula of which is shown in formula 06 below, is a gastric acid secretion inhibitor, has quick-acting, strong and lasting gastric acid secretion inhibition effect, and also has early termination effect on gastric acid secretion.
In the prior art, the synthesis route of Vonopalafenacin has many reaction steps and low yield, and is not beneficial to scale-up production. In the existing route for synthesizing vorexant, the compound represented by formula 03 is a crucial intermediate for synthesizing vorexant.
Therefore, the invention provides a new synthetic route which can efficiently synthesize the compound shown as the intermediate formula 03 of Vonoporan.
Through the compound 03, the invention also provides a synthetic route of Voranolan. The Vorinogene provided by the invention has the advantages of short synthetic route, simple and convenient process, small environmental pollution, safe and stable process and contribution to amplification production.
Disclosure of Invention
The inventors have studied and developed a method for preparing compound 03. The invention also provides a method for preparing the compound 06 by using the compound 03 through reaction, and the method has fewer steps and is simple, convenient and safe to operate.
In one aspect, the present invention provides a method of preparing compound 03, comprising: in an organic solvent, the compound 02 is subjected to ring closing reaction under the action of a palladium catalyst and hydrogen, after the reaction is finished, the compound 03 is prepared by post-treatment,
in the ring closing reaction, the organic solvent comprises at least one selected from 1, 4-dioxane, DMF and tetrahydrofuran.
In a ring closure reaction, in some embodiments, the organic solvent comprises 1, 4-dioxane; in some embodiments, the organic solvent comprises DMF; in some embodiments, the organic solvent comprises tetrahydrofuran. In some embodiments, the organic solvent is 1, 4-dioxane in the ring closure reaction.
In the ring-closing reaction, the amount of the organic solvent used can be 3ml to 10ml per gram of the compound 02.
In the ring closing reaction, the reaction temperature can be 40-100 ℃.
The palladium catalyst may be palladium on carbon, palladium hydroxide, palladium chloride, or a combination thereof. In some embodiments, the palladium catalyst is palladium on carbon.
The mass ratio of the palladium catalyst to the compound 02 may be 0.05% to 10%. In some embodiments, the mass ratio of the palladium catalyst to compound 02 is 0.1% to 10%. In some embodiments, the mass ratio of the palladium catalyst to compound 02 is 1% to 10%. In some embodiments, the mass ratio of the palladium catalyst to compound 02 is 5%.
The post-treatment for preparing compound 03 from compound 02 comprises: cooling the reaction solution, filtering, mixing the filtrate with water while stirring, cooling, crystallizing, filtering and drying to obtain the compound 03. In some embodiments, the post-processing comprises: cooling the reaction liquid to-5-40 ℃, filtering, mixing the filtrate with water while stirring, crystallizing, cooling to-5-15 ℃, filtering, and drying the solid to obtain the compound 03. In some embodiments, the post-processing comprises: cooling the reaction liquid to 0-40 ℃, then carrying out suction filtration, adding water into the filtrate while stirring for crystallization, cooling to-5 ℃, then carrying out suction filtration, and drying the solid to obtain the compound 03. In some embodiments, the post-processing comprises: cooling the reaction liquid to 20-40 ℃, then carrying out suction filtration, adding water into the filtrate while stirring for crystallization, cooling to-5 ℃, then carrying out suction filtration, and drying the solid to obtain the compound 03.
In some embodiments, a method of making compound 03, comprises: in an organic solvent, under the action of a palladium catalyst and hydrogen, a compound 02 is subjected to a ring closing reaction at 40-100 ℃, after the reaction is finished, the reaction liquid is cooled to 0-40 ℃, filtered, added with water to crystallize while the filtrate is stirred, cooled to-5-15 ℃, filtered, dried in solid state, and subjected to post-treatment to prepare a compound 03.
In some embodiments, a method of making compound 03, comprises: in 1, 4-dioxane, compound 02 is subjected to ring closing reaction at 40-100 ℃ under the action of palladium carbon and hydrogen, and after the reaction is finished, compound 03 is prepared through post-treatment; the post-processing comprises: cooling the reaction liquid to 0-40 ℃, filtering, adding water into the filtrate while stirring for crystallization, cooling to-5 ℃, filtering, and drying the solid to obtain the compound 03.
A process for the preparation of compound 02 comprising: in an organic reaction solvent, under the conditions of a phase transfer catalyst and an optional alkali reagent, reacting the compound 01 with propionitrile, and after the reaction is finished, carrying out post-treatment to prepare a compound 02,
the alkali reagent comprises at least one selected from sodium carbonate, potassium carbonate and N, N-diisopropylethylamine. In some embodiments, the alkaline agent comprises sodium carbonate; in some embodiments, the base reagent comprises potassium carbonate; in some embodiments, the base reagent comprises N, N-diisopropylethylamine. In some embodiments, the alkaline agent is sodium carbonate, facilitating the reaction and handling.
The molar ratio of the basic reagent to compound 01 may be 1:1 to 2.5: 1. In some embodiments, the molar ratio of the basic reagent to compound 01 is from 1:1 to 2: 1. In some embodiments, the molar ratio of the basic reagent to compound 01 is 1.1:1 to 1.5: 1.
The phase transfer catalyst comprises tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium hydrogen sulfate, trioctylmethylammonium chloride, benzyltriethylammonium chloride, or a combination thereof. In some embodiments, the catalyst is tetrabutylammonium bromide, which facilitates the reaction and the obtaining of the target product. The molar ratio of the phase transfer catalyst to compound 01 charged can be from 0.01:1 to 0.5: 1. In some embodiments, the molar ratio of the phase transfer catalyst to compound 01 charged is from 0.05:1 to 0.2: 1.
The organic reaction solvent used for preparing the compound 02 comprises at least one selected from ethyl acetate, acetonitrile and tetrahydrofuran. In some embodiments, the organic reaction solvent comprises ethyl acetate; in some embodiments, the organic reaction solvent comprises acetonitrile; in some embodiments, the organic reaction solvent comprises tetrahydrofuran. In some embodiments, the organic reaction solvent is ethyl acetate, which facilitates handling and obtaining the desired product.
The organic reaction solvent may be used in an amount of 3ml to 15ml or 5ml to 10ml per gram of compound 01.
The compound 01 reacts with propionitrile, and can be carried out at the temperature of 20-60 ℃. In some embodiments, compound 01 is reacted with propionitrile at 30 ℃ to 50 ℃.
The preparation of compound 02 from compound 01 is post-treated, including: cooling, adding water, extracting to obtain an organic phase, concentrating, adding toluene, xylene or a combined solvent thereof, heating, pulping, cooling, filtering, and drying to obtain the compound 02.
In some embodiments, the post-processing comprises: cooling the reaction liquid to-5-40 ℃, adding water, extracting and separating liquid to obtain an organic phase, concentrating the organic phase, adding toluene, xylene or a combined solvent thereof, heating to 40-100 ℃, pulping for 0.5-4 h, cooling to-5-25 ℃, filtering, and drying the solid to obtain the compound 02. In some embodiments, the post-processing comprises: cooling to 20-40 ℃, adding water, extracting and separating to obtain an organic phase, then carrying out reduced pressure concentration, adding toluene, xylene or a combined solvent thereof, heating to 70-90 ℃, pulping for 1-3 h, then cooling to-5-15 ℃, filtering, and drying the solid to obtain the compound 02. In some embodiments, the temperature is reduced to 0 ℃ to 10 ℃, filtered, and the solid is dried to give compound 02.
In some embodiments, a method of making compound 02 comprises: reacting the compound 01 with propionitrile at 0-60 ℃ in an organic reaction solvent under the conditions of a phase transfer catalyst and an alkali reagent, cooling the reaction solution to 0-40 ℃ after the reaction is finished, adding water, extracting and separating liquid to obtain an organic phase, concentrating the organic phase, adding toluene or xylene or a combined solvent thereof, heating to 40-100 ℃, pulping for 0.5-4 h, cooling to-5-25 ℃, filtering, and drying the solid to obtain the compound 02.
In some embodiments, a method of making compound 02 comprises: reacting the compound 01 with propionitrile at 20-50 ℃ in ethyl acetate under the conditions of tetrabutylammonium bromide and sodium carbonate, and after the reaction is finished, performing post-treatment to prepare a compound 02; the post-processing comprises: cooling the reaction liquid to 0-40 ℃, adding water, extracting and separating to obtain an organic phase, concentrating the organic phase under reduced pressure until the organic phase is dry, adding toluene or xylene or a combined solvent thereof, heating to 40-100 ℃, pulping for 0.5-4 h, then cooling to-5-15 ℃, filtering, and drying the solid to obtain the compound 02.
In some embodiments, a method of making compound 03, comprises: reacting the compound 01 with propionitrile at 20-50 ℃ in ethyl acetate under the conditions of tetrabutylammonium bromide and sodium carbonate, and after the reaction is finished, performing post-treatment to prepare a compound 02; the post-processing comprises: cooling the reaction solution to 0-40 ℃, adding water, extracting and separating to obtain an organic phase, concentrating the organic phase, adding toluene or xylene or a combination thereof, heating to 40-100 ℃, pulping for 0.5-4 h, cooling to-5-15 ℃, filtering, and drying the solid to obtain a compound 02; in an organic solvent, carrying out a ring closing reaction on a compound 02 at 40-100 ℃ under the action of palladium carbon and hydrogen, and after the reaction is finished, carrying out post-treatment to prepare a compound 03; the post-processing comprises: cooling the reaction liquid to 20-40 ℃, filtering, adding water into the filtrate while stirring for crystallization, cooling to-5 ℃, filtering, and drying the solid to obtain the compound 03.
In another aspect, the invention provides a method of making compound 06. A method of making compound 06 comprising: the compound 03 is subjected to substitution reaction to prepare a compound 04, the compound 04 is subjected to sulfonylation reaction to prepare a compound 05, the compound 05 is subjected to condensation reaction to prepare a compound 06,
in some embodiments, a method of making compound 06, comprising: the compound 03 is prepared according to the method for preparing the compound 03, the compound 03 is subjected to substitution reaction to prepare a compound 04, the compound 04 is subjected to sulfonylation reaction to prepare a compound 05, and the compound 05 is subjected to condensation reaction to prepare a compound 06.
The preparation method of the compound 04 can comprise the following steps: in an organic solvent, under the action of azobisisobutyronitrile, the compound 03 and N-bromosuccinimide undergo substitution reaction and post-treatment to prepare the compound 04.
In the substitution reaction, the organic solvent includes at least one selected from acetonitrile and dichloroethane. In some embodiments, the organic solvent comprises acetonitrile; in some embodiments, the organic solvent comprises ethylene dichloride. In some embodiments, the organic solvent is acetonitrile.
The amount of the organic solvent used in the substitution reaction may be 3ml to 20ml, or 5ml to 15ml, per gram of the compound 03.
The feeding molar ratio of the azobisisobutyronitrile to the compound 03 can be 0.9:1-1.1: 1.
The feeding molar ratio of the N-bromosuccinimide to the compound 03 can be 1:1-2.5: 1. In some embodiments, the molar charge ratio of N-bromosuccinimide to compound 03 is from 1.2:1 to 2: 1.
The reaction temperature of the substitution reaction can be controlled to be 20-80 ℃, or 40-80 ℃ or 20-40 ℃.
After the substitution reaction is finished, the post-treatment comprises the following steps: adding water and dichloromethane into the reaction solution, extracting and separating to obtain an organic phase, concentrating the organic phase, mixing the obtained product with acetonitrile, ethyl acetate, acetone, methanol or a combined solvent thereof, pulping for 0.5 to 4 hours, controlling the temperature to be between 5 ℃ below zero and 30 ℃, filtering, and drying the solid to obtain the compound 04. In some embodiments, the post-processing comprises: cooling the reaction solution to below 40 ℃, adding water and dichloromethane, extracting and separating to obtain an organic phase, concentrating the organic phase under reduced pressure, mixing the obtained product with acetonitrile, ethyl acetate, acetone, methanol or a combined solvent thereof, pulping at 40-80 ℃ for 0.5-4 hours, cooling to-5-20 ℃, filtering, and drying the solid to obtain the compound 04.
In some embodiments, a method of making compound 04, comprises: in an organic solvent, under the action of azobisisobutyronitrile, performing substitution reaction on a compound 03 and N-bromosuccinimide at 0-80 ℃, after the reaction is finished, controlling the temperature of reaction liquid to 0-40 ℃, adding water and an extraction solvent, extracting and separating liquid to obtain an organic phase, concentrating the organic phase, mixing the obtained product with acetonitrile, ethyl acetate, acetone, methanol or a combination thereof, pulping for 0.5-4 hours, controlling the temperature to-5-20 ℃, filtering, and drying the solid to obtain a compound 04.
In some embodiments, a method of making compound 04, comprises: in acetonitrile, under the action of azobisisobutyronitrile, the compound 03 undergoes substitution reaction through N-bromosuccinimide at 0-80 ℃, after the reaction is finished, the temperature of reaction liquid is controlled to be 0-40 ℃, water and dichloromethane are added, organic phase is obtained by extraction and liquid separation, reduced pressure concentration is carried out, the obtained product is mixed with acetonitrile, pulping is carried out for 0.5-4 hours, the temperature is controlled to be-5-15 ℃, filtering is carried out, and solid drying is carried out, thus obtaining the compound 04.
The preparation method of the compound 05 comprises the following steps: in an organic solvent, under the conditions of organic base and 4-dimethylamino pyridine, the compound 04 and pyridine sulfonyl chloride undergo sulfonylation reaction to prepare the compound 05.
In the sulfonylation reaction, the organic solvent includes at least one selected from dichloromethane and tetrahydrofuran. In some embodiments, the organic solvent comprises dichloromethane; in some embodiments, the organic solvent comprises tetrahydrofuran. In some embodiments, the organic solvent is dichloromethane.
The amount of the organic solvent may be 3ml to 20ml or 5ml to 15ml per gram of compound 04.
The feeding molar ratio of the compound 04 to the pyridine sulfonyl chloride can be 1:1-1:1.5, or 1:1-1: 1.3.
The organic base is triethylamine, N, N-diisopropylethylamine, pyridine, isopropylamine or a combination thereof. The charging molar ratio of the organic base to the compound 04 can be 1:1-3:1 or 1.2:1-2: 1.
The reaction temperature of the sulfonylation reaction may be 0 ℃ to 60 ℃, or 20 ℃ to 40 ℃, or 20 ℃ to 60 ℃, or 30 ℃ to 60 ℃.
After the sulfonylation reaction is finished, post-treatment can be carried out to obtain a compound 05; the post-processing comprises: adding water into the reaction liquid, separating to obtain an organic phase, concentrating, mixing the obtained product with acetonitrile, ethyl acetate, acetone, methanol or a combined solvent thereof, pulping for 0.1-2 hours, cooling to-5-15 ℃, filtering, and drying the solid to obtain the compound 05. In some embodiments, after completion of the sulfonylation reaction, a post-treatment is performed, the post-treatment comprising: adding water into the reaction liquid, separating to obtain an organic phase, concentrating, mixing the obtained product with acetonitrile, ethyl acetate, acetone, methanol or a combined solvent thereof, pulping at 40-80 ℃ for 0.1-2 hours, cooling to-5 ℃, filtering, and drying the solid to obtain the compound 05.
In some embodiments, a method of making compound 05, comprises: in an organic solvent, under the conditions of organic base and 4-dimethylamino pyridine, the compound 04 and pyridine sulfonyl chloride undergo sulfonylation reaction at 0-60 ℃, and the reaction is finished; adding water into the reaction liquid, separating to obtain an organic phase, concentrating, mixing the obtained product with acetonitrile, ethyl acetate, acetone, methanol or a combined solvent thereof, pulping for 0.1-2 hours, cooling to-5 ℃, filtering, and drying the solid to obtain the compound 05.
In some embodiments, a method of making compound 05, comprises: in an organic solvent, under the conditions of triethylamine and 4-dimethylaminopyridine, carrying out sulfonylation reaction on a compound 04 and pyridine sulfonyl chloride at 0-60 ℃, and after the reaction is finished, carrying out post-treatment to prepare a compound 05; the post-processing comprises: adding water into the reaction liquid, separating to obtain an organic phase, concentrating, mixing the obtained product with acetonitrile, pulping for 0.1-2 hours, cooling to-5 ℃, filtering, and drying the solid to obtain the compound 05.
The preparation method of the compound 06 comprises the following steps: in an organic solvent, under the action of potassium carbonate and potassium iodide, the compound 05 and methylamine or hydrochloride thereof undergo a condensation reaction to prepare a compound 06.
In the condensation reaction, the organic solvent comprises at least one selected from dichloromethane, DMF, DMAC, acetonitrile, tetrahydrofuran and ethyl acetate. In some embodiments, the organic solvent comprises dichloromethane; in some embodiments, the organic solvent comprises DMF; in some embodiments, the organic solvent comprises DMAC; in some embodiments, the organic solvent comprises acetonitrile; in some embodiments, the organic solvent comprises tetrahydrofuran; in some embodiments, the organic solvent comprises ethyl acetate. In some embodiments, the organic solvent is dichloromethane.
The amount of organic solvent used in the condensation reaction may be from 5ml to 25ml, alternatively from 10ml to 20ml, alternatively from 8ml to 15ml, per gram of compound 05.
The feed molar ratio of compound 05 to methylamine or its hydrochloride salt may be 1:1-1:2.5 or 1:1-1:2.
The feed molar ratio of compound 05 to potassium carbonate may be from 1:1 to 1: 2.5. In some embodiments, the feed molar ratio of compound 05 to potassium carbonate may be from 1:1 to 1:2.
The molar ratio of potassium iodide to compound 05 can be 1:1 to 2: 1. In some embodiments, the molar ratio of potassium iodide to compound 05 charged is from 1:1.1 to 1.6: 1.
The reaction temperature of the condensation reaction may be 30 ℃ to 100 ℃. In some embodiments, the condensation reaction is at a reaction temperature of 40 ℃ to 60 ℃, or 50 ℃ to 80 ℃, or 60 ℃ to 100 ℃.
After the condensation reaction is completed, the compound 06 can be obtained by post-treatment, which includes: adding water into the reaction solution, extracting and separating liquid from the water phase by using an extraction solvent, combining organic phases, concentrating, adding n-hexane, cyclohexane, isopropanol or a combination solvent thereof, pulping, cooling to-5-30 ℃, filtering, and drying the solid to obtain the compound 06. In some embodiments, the post-processing comprises: controlling the temperature of the reaction liquid to be 0-30 ℃, adding water, extracting and separating liquid by using an extraction solvent for a water phase, combining organic phases, concentrating, adding n-hexane, cyclohexane, isopropanol or a combination solvent thereof, pulping at 30-70 ℃ for 0.5-4 hours, cooling to-5-20 ℃, filtering, and drying the solid to obtain the compound 06. In some embodiments, the post-processing comprises: controlling the temperature of the reaction liquid to be 0-30 ℃, adding water, extracting and separating liquid by using dichloromethane for a water phase, combining organic phases, concentrating, adding n-hexane, pulping at 30-70 ℃ for 0.5-4 hours, cooling to-5-10 ℃, filtering, and drying solid to obtain the compound 06.
In some embodiments, a method of making compound 06 comprises: in an organic solvent, under the action of potassium carbonate and potassium iodide, carrying out condensation reaction on the compound 05 and methylamine or hydrochloride thereof at the temperature of 30-100 ℃, and finishing the reaction; adding water into the reaction solution, extracting and separating liquid from the water phase by using an extraction solvent, combining organic phases, concentrating, adding n-hexane, cyclohexane, isopropanol or a combination solvent thereof, pulping at the temperature of 30-70 ℃ for 0.5-4 hours, cooling to-5-30 ℃, filtering, and drying the solid to obtain the compound 06.
In some embodiments, a method of making compound 06 comprises: in an organic solvent, under the action of potassium carbonate and potassium iodide, carrying out condensation reaction on the compound 05 and methylamine hydrochloride at the temperature of 30-100 ℃, and after the reaction is finished, carrying out post-treatment to prepare a compound 06; the post-processing comprises: controlling the temperature of the reaction liquid to be-5-30 ℃, adding water, extracting and separating liquid of a water phase by using an extraction solvent, combining organic phases, concentrating, adding n-hexane for pulping, cooling to-5-10 ℃, filtering, and drying solid to obtain the compound 06.
In some embodiments, a method of making compound 06 comprises:
(1) in an organic reaction solvent, under the conditions of a phase transfer catalyst and an alkali reagent, reacting the compound 01 with propionitrile at 0-60 ℃, and finishing the reaction; cooling the reaction solution to-5-40 ℃, adding water, extracting and separating to obtain an organic phase, concentrating the organic phase, adding toluene or xylene or a combined solvent thereof, heating to 40-100 ℃, pulping for 0.5-4 h, cooling to-5-25 ℃, filtering, and drying the solid to prepare a compound 02;
(2) in an organic solvent, under the action of a palladium catalyst and hydrogen, carrying out a ring closing reaction on a compound 02 at 40-100 ℃, and finishing the reaction; cooling the reaction solution to-5-40 ℃, filtering, adding water into the filtrate while stirring for crystallization, cooling to-5-15 ℃, filtering, drying the solid, and performing post-treatment to prepare a compound 03;
(3) in an organic solvent, under the action of azobisisobutyronitrile, the compound 03 and N-bromosuccinimide carry out substitution reaction at 0-80 ℃, and the reaction is finished; controlling the temperature of the reaction liquid to be-5-40 ℃, adding water and an extraction solvent, extracting and separating liquid to obtain an organic phase, concentrating the organic phase, mixing the obtained product with acetonitrile, ethyl acetate, acetone or a combined solvent thereof, pulping for 0.5-4 hours, controlling the temperature to be-5-30 ℃, filtering, and drying the solid to obtain a compound 04;
(4) in an organic solvent, under the conditions of organic base and 4-dimethylamino pyridine, the compound 04 and pyridine sulfonyl chloride undergo sulfonylation reaction at 0-60 ℃, and the reaction is finished; adding water into the reaction liquid, separating the liquid to obtain an organic phase, concentrating the organic phase, mixing the obtained product with acetonitrile, ethyl acetate, acetone or a combined solvent of the acetonitrile, the ethyl acetate and the acetone, pulping for 0.1 to 2 hours, cooling to-5 to 15 ℃, filtering, and drying the solid to obtain a compound 05;
(5) in an organic solvent, under the action of potassium carbonate and potassium iodide, carrying out condensation reaction on the compound 05 and methylamine or hydrochloride thereof at the temperature of 30-100 ℃, and finishing the reaction; controlling the temperature of the reaction liquid to be-5-30 ℃, adding water, extracting and separating liquid by using an extraction solvent for a water phase, combining organic phases, concentrating, adding n-hexane, cyclohexane, isopropanol or a combination solvent thereof, pulping at 30-70 ℃ for 0.5-4 hours, cooling to-5-30 ℃, filtering, and drying a solid to obtain the compound 06.
In some embodiments, a method of making compound 06 comprises:
(1) reacting the compound 01 with propionitrile at 20-50 ℃ in ethyl acetate under the conditions of tetrabutylammonium bromide and sodium carbonate, cooling the reaction solution to 0-40 ℃ after the reaction is finished, adding water, extracting and separating liquid to obtain an organic phase, concentrating the organic phase, adding toluene, heating to 40-100 ℃, pulping for 0.5-4 h, cooling to-5-25 ℃, filtering, and drying the solid to obtain a compound 02;
(2) in 1, 4-dioxane, compound 02 is subjected to ring closing reaction at 40-100 ℃ under the action of palladium carbon and hydrogen, after the reaction is finished, the reaction liquid is cooled to 0-40 ℃, filtered, added with water to crystallize while the filtrate is stirred, cooled to-5-15 ℃, filtered, dried, and subjected to post-treatment to prepare compound 03;
(3) in acetonitrile, under the action of azobisisobutyronitrile, performing substitution reaction on a compound 03 and N-bromosuccinimide at 0-80 ℃, after the reaction is finished, controlling the temperature of reaction liquid to be 0-40 ℃, adding water and dichloromethane, extracting and separating liquid to obtain an organic phase, concentrating the organic phase, mixing the obtained product with acetonitrile, pulping for 0.5-4 hours, controlling the temperature to be-5-20 ℃, filtering, and drying the solid to obtain a compound 04;
(4) in dichloromethane, under the conditions of triethylamine and 4-dimethylaminopyridine, carrying out sulfonylation reaction on the compound 04 and pyridine sulfonyl chloride at 0-60 ℃, and finishing the reaction; adding water into the reaction liquid, separating to obtain an organic phase, concentrating, mixing the obtained product with acetonitrile, pulping for 0.1-2 hours, cooling to-5 ℃, filtering, and drying the solid to obtain a compound 05;
(5) in dichloromethane, under the action of potassium carbonate and potassium iodide, the compound 05 and methylamine hydrochloride undergo a condensation reaction at 30-100 ℃, and the reaction is finished; controlling the temperature of the reaction liquid to be 0-30 ℃, adding water, extracting and separating liquid by using dichloromethane for a water phase, combining organic phases, concentrating, adding n-hexane, pulping at 30-70 ℃ for 0.5-4 hours, cooling to-5-10 ℃, filtering, and drying solid to obtain the compound 06.
In the above-mentioned method, when extraction is concerned, the extraction solvent which can be used may be an organic solvent which can be separated from water such as methylene chloride, toluene, ethyl acetate, etc.
In the above method, when drying is involved, the solid is dried to a constant weight or the weight change before and after drying is not more than ± 1%; when concentration is involved, distillation can be carried out under reduced pressure or other conditions until no significant fraction is distilled off.
The preparation method of the compound 06 provided by the invention is relatively simple, has a short process route, is easy to operate and implement, and is suitable for large-scale production.
Detailed Description
In order to make the technical solutions of the present invention better understood by those skilled in the art, the following further discloses some non-limiting examples to further explain the present invention in detail.
The reagents used in the present invention are either commercially available or can be prepared by the methods described herein.
In the invention, the reaction is finished, namely the residual amount of the raw materials is not more than 5% or not more than 3% or not more than 1% or not more than 0.5%; the confirmation can be judged by HPLC (high performance liquid chromatography) or TLC (thin layer chromatography).
In the invention, the room temperature refers to the ambient temperature and is 15-35 ℃, or 20-30 ℃, or 23-28 ℃ or 25 ℃.
In the invention, g: g; mL: ml; DEG C: c, centigrade degree; h: hours; min: the method comprises the following steps of (1) taking minutes; MS means mass spectrum; HPLC means high performance liquid chromatography. DMF means N, N-dimethylformamide; DMAC represents N, N-dimethylacetamide; TABA stands for tetrabutylammonium bromide; NBS represents N-bromosuccinimide; TEA represents triethylamine; DMAP stands for 4-dimethylaminopyridine.
Example 1
Preparation of Compound 02
Adding 100.00g of compound 01, 33.00g of propionitrile, 121.89g of sodium carbonate, 16.12g of tetrabutylammonium bromide and 600ml of ethyl acetate into a reaction bottle at room temperature, heating to 40 ℃ after the addition of the ethyl acetate, reacting for 4 hours under the stirring condition, sampling and detecting, and stopping the reaction when HPLC (high performance liquid chromatography) results show that the raw materials are completely reacted; cooling to 30 ℃, adding 250ml of water, extracting and separating to obtain an organic phase, reducing the pressure to 35 ℃ and concentrating to dryness, adding 100ml of toluene, heating to 80 ℃, pulping for 2h, cooling to 20 ℃, performing suction filtration, and performing vacuum drying on a filter cake at 80 ℃ for 12h to obtain 76.11g of a compound 01 yellow solid product, wherein the yield is 86.40%, and the purity is 96.31%.
MS：[M+1]＝192.11；
Nuclear magnetism1H NMR(400MHz,DMSO)δ7.89-7.96(m，2H)，7.25-7.36(m，2H)，3.21(m,J＝14.3Hz,1H)，2.66-3.03(dd，2H)，1.51(t，3H)。
Example 2
Preparation of Compound 03
Adding 70.00g of compound 02, 3.50g of 10% palladium carbon and 250ml of 1, 4-dioxane into a reaction bottle at room temperature, adding replacement hydrogen, heating to 80 ℃, reacting for 16 hours under the condition of stirring, sampling and detecting, and stopping the reaction when HPLC (high performance liquid chromatography) results show that the raw materials completely react; cooling to 30 ℃, filtering, adding 250ml of water into the filtrate while stirring, crystallizing, cooling to 10 ℃ after adding, filtering, and drying the filter cake in vacuum for 12 hours at 80 ℃ to obtain 46.30g of a compound 03 yellow solid product, wherein the yield is 72.18%, and the purity is 97.22%.
MS：[M+1]＝176.11；
Nuclear magnetism1H NMR(400MHz,DMSO)δ9.79(s，1H)，7.69-7.81(m，2H)，7.52(m，1H)，7.33(m，1H)，6.71(s，1H)，6.35(s，1H)，2.12(s，3H)。
Example 3
Preparation of Compound 04
Adding 50.00g of compound 03, 103.23g of NBS, 47.62g of azobisisobutyronitrile and 500ml of acetonitrile into a reaction bottle at room temperature, heating to 80 ℃ after the addition, reacting for 16 hours under stirring, sampling and detecting, wherein HPLC results show that the raw materials completely react, and stopping the reaction; cooling to 30 ℃, adding 500ml of water and 500ml of dichloromethane, extracting and separating to obtain an organic phase, reducing the pressure to 35 ℃, concentrating to dryness, adding 200ml of acetonitrile, heating to 60 ℃, pulping for 2h, cooling to 20 ℃, performing suction filtration, and performing vacuum drying on a filter cake at 60 ℃ for 12h to obtain 45.55g of a compound 04 yellow solid product, wherein the yield is 62.81%, and the purity is 95.44%.
MS：[M+1]＝254.05；
Nuclear magnetism1H NMR(400MHz,DMSO)δ10.20(s，1H)，7.69-7.81(m，2H)，7.52(m，1H)，7.33(m，1H)，6.71(s，1H)，6.35(s，1H)，4.52(s，2H)。
Example 4
Preparation of Compound 05
Adding 50.00g of compound 04, 46.18g of pyridine-3-sulfonyl chloride, 40.48g of triethylamine, 2.44g of 4-dimethylaminopyridine and 500ml of dichloromethane into a reaction bottle at room temperature, heating to 40 ℃ after the addition, reacting for 8 hours under the stirring condition, sampling and detecting, and stopping the reaction when HPLC (high performance liquid chromatography) results show that the raw materials are completely reacted; cooling to 30 ℃, adding 500ml of water, extracting and separating to obtain an organic phase, reducing the pressure to 35 ℃, concentrating to dryness, adding 200ml of acetonitrile, heating to 50 ℃, pulping for 1h, cooling to 0 ℃, performing suction filtration, and performing vacuum drying on a filter cake at 60 ℃ for 12h to obtain 64.32g of a compound 05 yellow solid product, wherein the yield is 83.36%, and the purity is 96.43%.
MS：[M+1]＝395.00；
Nuclear magnetism1H NMR(400MHz,DMSO)δ8.89(d，1H)，8.64(s，1H)，7.85(dd，1H)，7.76(s，1H)，7.55-7.64(m，1H)，7.49-7.54(m，1H)，7.29-7.38(m，2H)，7.17-7.25(m，2H)，7.00-7.05(m，1H)，6.41-6.46(d，1H)，4.57-4.65(s，2H)。
Example 5
Preparation of Compound 06
Adding 50.00g of compound 05, 17.56g of methylamine hydrochloride, 35.93g of potassium carbonate, 33.20g of potassium iodide and 600ml of dichloromethane into a reaction bottle at room temperature, completely heating to 40 ℃, reacting for 8 hours under the condition of stirring, sampling and detecting, and stopping the reaction when HPLC (high performance liquid chromatography) results show that the raw materials are completely reacted; cooling to 30 ℃, adding 500ml of water, extracting and separating liquid, adding 500ml of dichloromethane into the water phase, extracting and separating liquid, combining organic phases, reducing the pressure to 35 ℃, concentrating until the organic phases are dry, adding 250ml of n-hexane, heating to 60 ℃, pulping for 2h, cooling to 20 ℃, filtering, and drying the filter cake in vacuum for 12h at 80 ℃ to obtain 35.96g of compound 06 yellow solid product, wherein the yield is 82.31%, and the purity is 98.34%.
MS：[M+1]＝346.15；
Nuclear magnetism1H NMR(400MHz,DMSO)δ8.79(d，1H)，8.62(s，1H)，7.89(dd，1H)，7.78(s，1H)，7.60-7.64(m，1H)，7.49-7.54(m，1H)，7.28-7.38(m，2H)，7.15-7.25(m，2H)，7.02-7.07(m，1H)，6.40-6.46(d，1H)，3.77-3.85(s，2H)，2.51-3.60(s，3H)。
While the methods of the present invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications of the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of the present invention within the context, spirit and scope of the invention. Those skilled in the art can modify the process parameters appropriately to achieve the desired results with reference to the disclosure herein. It is expressly intended that all such similar substitutes and modifications which would be obvious to those skilled in the art are deemed to be included within the invention.
Claims (10)
1. A method of preparing compound 03 comprising: in an organic solvent, the compound 02 is subjected to ring closing reaction under the action of a palladium catalyst and hydrogen, after the reaction is finished, the compound 03 is prepared by post-treatment,
wherein the organic solvent comprises at least one selected from 1, 4-dioxane, DMF and tetrahydrofuran; the palladium catalyst is palladium on carbon, palladium hydroxide, palladium chloride, or a combination thereof.
2. The method of manufacturing according to claim 1, further comprising: reacting the compound 01 with propionitrile in an organic reaction solvent under the conditions of a phase transfer catalyst and an alkali reagent, and after the reaction is finished, carrying out post-treatment to prepare a compound 02; wherein the organic reaction solvent comprises at least one selected from ethyl acetate, acetonitrile and tetrahydrofuran;
3. the production method according to claim 2, the alkali agent comprising at least one selected from sodium carbonate, potassium carbonate, N-diisopropylethylamine; and/or the molar ratio of the alkali agent to the compound 01 is 1:1-2.5: 1.
4. The preparation method according to claim 2 or 3, wherein the reaction temperature of the ring closing reaction is 40-100 ℃; and/or compound 01 is reacted with propionitrile at 20 ℃ to 60 ℃.
5. The production process according to any one of claims 1 to 4, wherein the post-treatment comprises, after completion of the ring-closing reaction: cooling the reaction solution to-5-40 ℃, filtering, mixing the filtrate with water while stirring, crystallizing, cooling to-5-15 ℃, filtering, and drying the solid to obtain a compound 03; and/or the work-up of the process for the preparation of compound 02 comprises: cooling the reaction liquid to-5-40 ℃, adding water, extracting and separating liquid to obtain an organic phase, concentrating the organic phase, adding toluene, xylene or a combined solvent thereof, heating to 40-100 ℃, pulping for 0.5-4 h, cooling to-5-25 ℃, filtering, and drying the solid to obtain the compound 02.
6. A method of preparing compound 06, comprising: in an organic solvent, under the action of azobisisobutyronitrile, performing substitution reaction on a compound 03 and N-bromosuccinimide, and performing post-treatment to obtain a compound 04; in an organic solvent, under the conditions of organic base and 4-dimethylaminopyridine, carrying out sulfonylation reaction on a compound 04 and pyridine sulfonyl chloride, and carrying out post-treatment to prepare a compound 05; in an organic solvent, under the action of potassium carbonate and potassium iodide, carrying out condensation reaction on the compound 05 and methylamine or hydrochloride thereof, and carrying out post-treatment to prepare a compound 06; wherein the organic base is triethylamine, N, N-diisopropylethylamine, pyridine, isopropylamine or a combination thereof;
7. the production method according to claim 6, wherein, in the substitution reaction, the organic solvent includes at least one selected from acetonitrile, dichloroethane; and/or in the sulfonylation reaction, the organic solvent comprises at least one selected from dichloromethane and tetrahydrofuran; and/or in the condensation reaction, the organic solvent comprises at least one selected from dichloromethane, DMF, DMAC, acetonitrile, tetrahydrofuran and ethyl acetate.
8. The production method according to claim 6 or 7, wherein the reaction temperature of the substitution reaction is 20 ℃ to 80 ℃; and/or the reaction temperature of the sulfonylation reaction is 0-60 ℃; and/or the reaction temperature of the condensation reaction is 30 ℃ to 100 ℃.
9. The production process according to any one of claims 6 to 8, wherein the post-treatment comprises, after completion of the substitution reaction: adding water and dichloromethane into the reaction solution, extracting and separating to obtain an organic phase, concentrating the organic phase, mixing the obtained product with acetonitrile, ethyl acetate, acetone, methanol or a combined solvent thereof, pulping for 0.5 to 4 hours, controlling the temperature to be between 5 ℃ below zero and 30 ℃, filtering, and drying the solid to obtain a compound 04; and/or after the sulfonylation reaction is finished, the post-treatment comprises the following steps: adding water into the reaction solution, separating the solution to obtain an organic phase, concentrating the organic phase, mixing the obtained product with acetonitrile, ethyl acetate, acetone, methanol or a combined solvent of the acetonitrile, the ethyl acetate, the acetone and the methanol, pulping for 0.1 to 2 hours, cooling to the temperature of between 5 ℃ below zero and 15 ℃, filtering, and drying the solid to obtain a compound 05; and/or after the condensation reaction is finished, the post-treatment comprises the following steps: adding water into the reaction solution, extracting and separating liquid from the water phase by using an extraction solvent, combining organic phases, concentrating, adding n-hexane, cyclohexane, isopropanol or a combination solvent thereof, pulping, cooling to-5-30 ℃, filtering, and drying the solid to obtain the compound 06.
10. The process according to any one of claims 6 to 9, wherein compound 03 is prepared according to the process of any one of claims 1 to 5.
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