CN113896683A - Preparation method of pazopanib key intermediate - Google Patents
Preparation method of pazopanib key intermediate Download PDFInfo
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- CN113896683A CN113896683A CN202111290680.1A CN202111290680A CN113896683A CN 113896683 A CN113896683 A CN 113896683A CN 202111290680 A CN202111290680 A CN 202111290680A CN 113896683 A CN113896683 A CN 113896683A
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- CUIHSIWYWATEQL-UHFFFAOYSA-N pazopanib Chemical compound C1=CC2=C(C)N(C)N=C2C=C1N(C)C(N=1)=CC=NC=1NC1=CC=C(C)C(S(N)(=O)=O)=C1 CUIHSIWYWATEQL-UHFFFAOYSA-N 0.000 title claims abstract description 18
- 239000003798 L01XE11 - Pazopanib Substances 0.000 title claims abstract description 17
- 229960000639 pazopanib Drugs 0.000 title claims abstract description 17
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 229940125898 compound 5 Drugs 0.000 claims abstract description 28
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 22
- 238000000034 method Methods 0.000 claims abstract description 19
- 150000001875 compounds Chemical class 0.000 claims abstract description 18
- 239000002253 acid Substances 0.000 claims abstract description 16
- 230000008569 process Effects 0.000 claims abstract description 13
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 claims abstract description 11
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims abstract description 10
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000012022 methylating agents Substances 0.000 claims abstract description 8
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 claims abstract description 6
- 150000003839 salts Chemical class 0.000 claims abstract description 6
- 230000001035 methylating effect Effects 0.000 claims abstract description 4
- 238000006386 neutralization reaction Methods 0.000 claims abstract description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 24
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 14
- 238000006243 chemical reaction Methods 0.000 claims description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 8
- 239000002798 polar solvent Substances 0.000 claims description 8
- 239000000725 suspension Substances 0.000 claims description 8
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 7
- 238000003756 stirring Methods 0.000 claims description 7
- 238000005406 washing Methods 0.000 claims description 7
- 239000003054 catalyst Substances 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- 239000007868 Raney catalyst Substances 0.000 claims description 5
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical group [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 5
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 5
- 239000003638 chemical reducing agent Substances 0.000 claims description 5
- 229940125904 compound 1 Drugs 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 5
- 229910017604 nitric acid Inorganic materials 0.000 claims description 5
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 4
- 238000003786 synthesis reaction Methods 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 3
- 238000000967 suction filtration Methods 0.000 claims description 3
- 230000009471 action Effects 0.000 claims description 2
- 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 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 5
- 239000000463 material Substances 0.000 abstract description 4
- 239000000126 substance Substances 0.000 abstract description 4
- 238000002474 experimental method Methods 0.000 abstract description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 230000011987 methylation Effects 0.000 description 6
- 238000007069 methylation reaction Methods 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- FUNWSYKLFDLUIZ-UHFFFAOYSA-N 3-methyl-6-nitro-2h-indazole Chemical compound C1=C([N+]([O-])=O)C=CC2=C(C)NN=C21 FUNWSYKLFDLUIZ-UHFFFAOYSA-N 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 229940126214 compound 3 Drugs 0.000 description 5
- MLPVBIWIRCKMJV-UHFFFAOYSA-N 2-ethylaniline Chemical compound CCC1=CC=CC=C1N MLPVBIWIRCKMJV-UHFFFAOYSA-N 0.000 description 4
- JHGRUPGVUMAQQU-UHFFFAOYSA-N 2,3-dimethyl-6-nitroindazole Chemical compound C1=C([N+]([O-])=O)C=CC2=C(C)N(C)N=C21 JHGRUPGVUMAQQU-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000006193 diazotization reaction Methods 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- RUTULKJFQZYUDG-UHFFFAOYSA-N 1,3-dimethyl-6-nitroindazole Chemical compound [O-][N+](=O)C1=CC=C2C(C)=NN(C)C2=C1 RUTULKJFQZYUDG-UHFFFAOYSA-N 0.000 description 2
- PVNVSSNARYHLRF-UHFFFAOYSA-N 2,3-dimethylindazol-6-amine Chemical compound C1=C(N)C=CC2=C(C)N(C)N=C21 PVNVSSNARYHLRF-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 206010029113 Neovascularisation Diseases 0.000 description 2
- 206010039491 Sarcoma Diseases 0.000 description 2
- 208000021712 Soft tissue sarcoma Diseases 0.000 description 2
- 108091008605 VEGF receptors Proteins 0.000 description 2
- 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000002274 desiccant Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- IOGXOCVLYRDXLW-UHFFFAOYSA-N tert-butyl nitrite Chemical compound CC(C)(C)ON=O IOGXOCVLYRDXLW-UHFFFAOYSA-N 0.000 description 2
- 239000012414 tert-butyl nitrite Substances 0.000 description 2
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 2
- 229940124676 vascular endothelial growth factor receptor Drugs 0.000 description 2
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 description 1
- VEEGZPWAAPPXRB-BJMVGYQFSA-N (3e)-3-(1h-imidazol-5-ylmethylidene)-1h-indol-2-one Chemical compound O=C1NC2=CC=CC=C2\C1=C/C1=CN=CN1 VEEGZPWAAPPXRB-BJMVGYQFSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- 208000007571 Ovarian Epithelial Carcinoma Diseases 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229940121369 angiogenesis inhibitor Drugs 0.000 description 1
- 239000004037 angiogenesis inhibitor Substances 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000036770 blood supply Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000012024 dehydrating agents Substances 0.000 description 1
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- OWFXIOWLTKNBAP-UHFFFAOYSA-N isoamyl nitrite Chemical compound CC(C)CCON=O OWFXIOWLTKNBAP-UHFFFAOYSA-N 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- -1 occupying 1-site N Chemical class 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000011112 process operation Methods 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000004537 pulping Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 239000001119 stannous chloride Substances 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
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- 210000005239 tubule Anatomy 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
- C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a preparation method of a pazopanib key intermediate, which comprises the following specific synthetic processes: occupying 1-site N with strong acid to obtain an acid salt corresponding to the compound 4, methylating 2-site N with a methylating agent in an aprotic polar solution, carrying out alkalization neutralization treatment to obtain a compound 5, reducing the compound 5 and purifying to obtain the compound 1. The invention obtains more ideal yield through repeated experiments by using auxiliary materials such as hydrochloric acid, dimethyl sulfate, hydrazine hydrate and the like which are conventional cheap chemicals, effectively reduces the cost of raw materials for preparing the key intermediate, and the provided process is simple to operate and can be popularized and applied.
Description
Technical Field
The invention relates to a preparation method of a pazopanib key intermediate.
Background
Pazopanib, chemical name 5- [ [4- [2, 3-dimethyl-2H-indol-6-yl) methylamino]-2-pyrimidinyl]Amino group]-2-methyl-benzenesulfonamide of the formula C21H23N7O2S, CAS: 444731-52-6. Is a novel oral angiogenesis inhibitor developed by Kurarin Schker that interferes with neovascularization required for the survival and growth of refractory tumors. Targeting at Vascular Endothelial Growth Factor Receptor (VEGFR) acts by inhibiting neovascularization of the blood supply to the tumor. Is suitable for treating advanced renal cell carcinoma (a type of renal cancer in which cancer cells are found in renal tubules), Soft Tissue Sarcoma (STS), epithelial ovarian cancer, and non-small cell lung cancer (NSCLC). 2, 3-dimethyl-6-amino-2H-indazole is a key intermediate for preparing pazopanib, and the molecular formula is C9H11N3CAS: 444731-72-0, hereinafter referred to as Compound 1.
Patents CN103373989, CN109384724, CN103910716 and CN103739550 all report the synthesis method of compound 1. The synthetic route can be illustrated as follows.
According to the material property and reaction mechanism, the methylation of 3-methyl-6-nitro-1H-indazole (compound 4) can obtain 2, 3-dimethyl-6-nitro-2H-indazole (compound 5), wherein the protection or occupation of N at position 1 is needed, and then the methylation of N at position 2 can obtain the required 2, 3-dimethyl product. If not protected or occupied, methylation proceeds directly to give the 1-methylated product, i.e., 1, 3-dimethyl-6-nitro-1H-indazole, structure:
in the process described in patent CN103373989, compound 4 is suspended in toluene and directly added dropwise with dimethyl sulfate for methylation to obtain 1, 3-dimethyl-6-nitro-1H-indazole instead of 2, 3-dimethyl-6-nitro-2H-indazole.
In the process description of patent CN103910716, strong base NaH is used to occupy the 1-position N first, and then dimethyl carbonate is added dropwise for methylation. The yield is 33 percent, which is not ideal, and in addition, a large amount of stannous chloride with high price reagent is used for nitro reduction in the process from the compound 5 to the compound 1, which causes high raw material cost.
In the process of patent CN103739550, the N in the 1-position is occupied by metallic sodium, and then methyl iodide is added dropwise for methylation. However, sodium metal is too active and is troublesome to store and use. And the price of the methyl iodide is high, and the cost of the raw materials is high.
Patent CN109384724 mainly studies the microchannel hydrogenation reduction of compound 5 to compound 1. The reaction equipment is special and has no popularization and application.
Disclosure of Invention
The invention aims to overcome the defects in the prior art, provides a preparation method of a pazopanib key intermediate, is simple in process operation, and can be popularized and applied.
In order to solve the technical problems, the invention adopts the technical scheme that: a preparation method of a pazopanib key intermediate comprises the following synthetic route:
the synthesis process is as follows: occupying 1-site N with strong acid to obtain an acid salt corresponding to the compound 4, methylating 2-site N with a methylating agent in an aprotic polar solution, carrying out alkalization neutralization treatment to obtain a compound 5, reducing the compound 5 and purifying to obtain the compound 1.
Further, compound 4 is dissolved in a mixture of a strong acid including nitric acid, hydrochloric acid, and sulfuric acid and ethanol.
Further, the resulting mixture was stirred for 1 hour to sufficiently produce a hydrochloride, and water and ethanol were distilled off under a vacuum atmosphere.
Further, the acid salt was placed in an aprotic polar solvent at room temperature, stirred and then heated to 60 ℃ to obtain a suspension.
Further, the aprotic polar solvent includes acetonitrile, DMF and DMSO, and the volume amount of the aprotic polar solvent is 3 to 4 times (g-ml) the weight of the compound 4.
Further, a methylating agent is dropwise added into the suspension, and the mixture is stirred and purified to obtain a compound 5, wherein the methylating agent is dimethyl sulfate.
Further, in the suspension, the molar weight ratio of the compound 4, the strong acid and the dimethyl sulfate is 1:1.5-2.0: 1.
Further, after the reaction is finished, distilling out acetonitrile in vacuum, adjusting the pH value to 8-9, precipitating a solid, and obtaining a compound 5 after suction filtration, water washing and drying.
Further, compound 5 is dissolved in an organic solvent, and compound 1 is obtained under the action of a catalyst and a reducing agent.
Further, the organic solvent is methanol or ethanol, and the volume usage amount of the organic solvent is 10 times (g-ml) of the weight of the compound 5; the catalyst is Raney nickel, and the weight and the use amount of the catalyst are 15-20% of the weight of the compound 5; the reducing agent is hydrazine hydrate, and the molar amount of the hydrazine hydrate is 7-8 times of that of the compound 5.
Compared with the prior art, the invention has the beneficial effects that: by using auxiliary materials such as hydrochloric acid, dimethyl sulfate, hydrazine hydrate and the like which are conventional cheap chemicals, the process obtains more ideal yield through repeated tests, effectively reduces the cost of raw materials for preparing the key intermediate, and the provided process is simple to operate and can be popularized and applied.
Drawings
The disclosure of the present invention is illustrated with reference to the accompanying drawings. It is to be understood that the drawings are designed solely for the purposes of illustration and not as a definition of the limits of the invention. In the drawings, like reference numerals are used to refer to like parts. Wherein:
figure 1 schematically shows the hydrogen nuclear magnetic spectrum of compound 4.
Detailed Description
It is easily understood that according to the technical solution of the present invention, a person skilled in the art can propose various alternative structures and implementation ways without changing the spirit of the present invention. Therefore, the following detailed description and the accompanying drawings are merely illustrative of the technical aspects of the present invention, and should not be construed as all of the present invention or as limitations or limitations on the technical aspects of the present invention.
A preparation method of a pazopanib key intermediate comprises the following synthetic route:
the synthesis process comprises the following steps of firstly using strong acid (comprising hydrochloric acid, nitric acid and sulfuric acid) and a compound 4 to form corresponding acid salt, namely occupying 1-site N, then using a cheap and easily-obtained methylating reagent dimethyl sulfate to methylate 2-site N in an aprotic polar solvent (acetonitrile, DMF, DMSO and the like), and then carrying out alkalization neutralization treatment to obtain the 2, 3-dimethyl-6-nitro-2H-indazole (compound 5).
The synthesis process of the present invention is specifically described below with reference to examples.
Preparation of Compound 3
The reaction route is as follows:
adding 300ml of sulfuric acid serving as a dehydrating agent into a 500ml reaction bottle, slowly adding 75g of o-ethylaniline after stirring, cooling to 0 ℃ in an ice salt bath after complete salification, and dropwise adding 43g of fuming nitric acid, wherein the addition amount of the fuming nitric acid needs to be 10-20% in excess. The mol ratio of the o-ethylaniline, the nitric acid and the sulfuric acid is 1:1.1-1.2: 9-10. After the dropwise addition, stirring was continued at 0-5 ℃ for 1 hour. The reaction solution was poured into about 1 kg of crushed ice (the amount of crushed ice was 2 to 2.5 times the weight of sulfuric acid) and stirred to precipitate yellow powder, which was then filtered under suction to obtain 157g of wet product, i.e., compound 2.
Putting 157g of wet product into a beaker, adding water which is 2-3 times of the weight of the wet product and about 400ml of the wet product, stirring and pulping, adjusting the pH value to 9-10 with liquid alkali, filtering at room temperature, washing with water, and drying to obtain 85g of compound 3 with the yield of 82.6%.
Preparation of Compound 4
The reaction route is as follows:
85g of the compound 3 prepared above is added into a 1000ml reaction bottle and stirred and dissolved in 600ml of acetic acid, and the volume of the acetic acid is 7-8 times of the weight of the compound 3 and is used as a solvent. 60g of diazotization reagent tert-butyl nitrite is dripped at the temperature of 20-25 ℃, the diazotization reagent comprises sodium nitrite, isoamyl nitrite and tert-butyl nitrite, the addition amount of the diazotization reagent needs to be excessive by 10-20%, and after the dripping is finished, the stirring is continued for 1 hour. Vacuum distilling to recover acetic acid 550ml, dissolving the residue with 500ml ethyl acetate 5-6 times of the compound 3, washing with saturated sodium bicarbonate solution 200ml, washing with water, washing with saturated saline solution, and drying with neutral desiccant such as anhydrous sodium sulfate and magnesium sulfate overnight. The next day, the drying agent was filtered, about 300ml ethyl acetate was recovered by vacuum distillation, the remaining solution was cooled for crystallization, frozen to-5-0 deg.C, filtered, and dried to give 83g of compound 4 (yellow powder) with a yield of 91.5%, and the hydrogen nuclear magnetic spectrum is shown in FIG. 1.
Preparation of Compound 5
The reaction route is as follows:
83g of compound 4 is added to a solution of 71ml of hydrochloric acid (strong acid includes nitric acid, hydrochloric acid, sulfuric acid) and 71ml of ethanol (equal volume to the hydrochloric acid), and the mixture is stirred for 1 hour to form hydrochloride sufficiently. The water and ethanol were distilled off in vacuo. After room temperature 300ml acetonitrile (aprotic polar solvent including acetonitrile, DMF, DMSO, volume amount is 3-4 times of compound 4 weight), after stirring, heating to 60 deg.C to form suspension. 60g of dimethyl sulfate (methylating agent), compound 4: hydrochloric acid: dimethyl sulfate 1:1.5-2.0:1, and stirring was continued for 1 hour after the addition. As the reaction proceeded, the suspension gradually turned into a homogeneous liquid. Most of acetonitrile is distilled out in vacuum, the rest solution is poured into ice water to be stirred, and solid is separated out by adjusting the pH value to 8-9 with liquid alkali. Suction filtration, water washing and drying were carried out to obtain 72.6g of compound 5 with a yield of 81%.
Preparation of Compound 1
The reaction route is as follows:
72.6g of the compound 5 prepared above are put into 726ml of ethanol, and stirred, the ethanol is used as a solvent, and the volume dosage of the methanol is 10 times of the weight of the compound 5, and the temperature is raised to 60-65 ℃, and the substrate is basically dissolved. 15g of Raney nickel is added, the dosage of the Raney nickel is 15% -20% of the compound 5, 182ml of 80% hydrazine hydrate is added dropwise, the hydrazine hydrate is used as a reducing agent, and the molar dosage of the hydrazine hydrate is 7-8 times of the compound 5. After the addition was completed, the TLC was continued to be stirred until the starting material spot disappeared (about 2-3 hours). And (4) filtering to remove Raney nickel, and vacuum distilling to recover ethanol until the ethanol is dry. Cooling the residual liquid and solidifying, adding a certain amount of methanol, heating, refluxing and dissolving, adding 5g of activated carbon, and refluxing for 1 hour. The hot solution is filtered to remove the active carbon, and the filtrate is cooled, frozen, filtered and dried to obtain 58.4g of compound 1, white-like crystal powder at m.p.149-151 ℃. The yield thereof was found to be 95.6%.
The invention obtains more ideal yield through repeated experiments by using auxiliary materials such as hydrochloric acid, dimethyl sulfate, hydrazine hydrate and the like which are conventional cheap chemicals, effectively reduces the cost of raw materials for preparing the key intermediate, and the provided process is simple to operate and can be popularized and applied.
The technical scope of the present invention is not limited to the above description, and those skilled in the art can make various changes and modifications to the above-described embodiments without departing from the technical spirit of the present invention, and such changes and modifications should fall within the protective scope of the present invention.
Claims (10)
1. A preparation method of a pazopanib key intermediate is characterized in that the synthetic route comprises the following steps:
the synthesis process is as follows: occupying 1-site N with strong acid to obtain an acid salt corresponding to the compound 4, methylating 2-site N with a methylating agent in an aprotic polar solution, carrying out alkalization neutralization treatment to obtain a compound 5, reducing the compound 5 and purifying to obtain the compound 1.
2. The method of claim 1, wherein the compound 4 is dissolved in a mixture of a strong acid and ethanol, wherein the strong acid comprises nitric acid, hydrochloric acid and sulfuric acid.
3. The method of claim 2, wherein the mixture is stirred for 1 hour to form hydrochloride salt, and water and ethanol are distilled off under vacuum.
4. The method for preparing the pazopanib key intermediate according to claim 3, wherein the acid salt is placed in the aprotic polar solvent at room temperature, and the temperature is raised to 60 ℃ after stirring to obtain a suspension.
5. The method for preparing pazopanib key intermediate according to claim 4, wherein the aprotic polar solvent comprises acetonitrile, DMF and DMSO, and the volume of the aprotic polar solvent is 3-4 times (g-ml) of the compound 4 weight.
6. The preparation method of the pazopanib key intermediate as claimed in claim 4, characterized in that a methylating agent is dropped into the suspension liquid, and the mixture is stirred for reaction and purified to obtain the compound 5, wherein the methylating agent is dimethyl sulfate.
7. The method for preparing pazopanib key intermediate according to claim 6, wherein the molar ratio of compound 4, the strong acid and the dimethyl sulfate in the suspension is 1:1.5-2.0: 1.
8. The preparation method of the pazopanib key intermediate as claimed in claim 6, characterized in that after the reaction is completed, acetonitrile is distilled out in vacuum, the pH is adjusted to 8-9, a solid is precipitated, and the compound 5 is obtained after suction filtration, water washing and drying.
9. The method for preparing the pazopanib key intermediate as claimed in claim 1, wherein the compound 5 is dissolved in an organic solvent, and the compound 1 is obtained under the action of a catalyst and a reducing agent.
10. The process for preparing a pazopanib key intermediate as claimed in claim 9, wherein the organic solvent is methanol or ethanol, and the volume of the organic solvent is 10 times (g-ml) of the compound 5; the catalyst is Raney nickel, and the weight and the use amount of the catalyst are 15-20% of the weight of the compound 5; the reducing agent is hydrazine hydrate, and the molar amount of the hydrazine hydrate is 7-8 times of that of the compound 5.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2014198693A (en) * | 2013-03-29 | 2014-10-23 | 大鵬薬品工業株式会社 | Preventive and/or therapeutic agent of immune disease |
| CN104642314A (en) * | 2015-02-04 | 2015-05-27 | 宁波工程学院 | Application of N-furan phenol methyl ether-5-yl) chromene-4-amide as sterilizing agent |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2014198693A (en) * | 2013-03-29 | 2014-10-23 | 大鵬薬品工業株式会社 | Preventive and/or therapeutic agent of immune disease |
| CN104642314A (en) * | 2015-02-04 | 2015-05-27 | 宁波工程学院 | Application of N-furan phenol methyl ether-5-yl) chromene-4-amide as sterilizing agent |
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| 杨柳等: "新型吲唑类血管内皮生长因子受体抑制剂的合成", 《军事医学》 * |
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Application publication date: 20220107 |