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Preparation method of 4-chloro-6,7-dimethoxyquinoline

A technology of dimethoxyquinoline and dimethoxy, applied in the preparation of 4-chloro-6,7-dimethoxyquinoline, the key to the preparation of antitumor drugs cabozantinib and tivozanib In the field of intermediates, it can solve the problems of high cost of industrial preparation, a large amount of industrial waste residue, and high cost of industrialization, and achieve the effect of simple and convenient post-processing method, simple process and convenient operation

Inactive Publication Date: 2016-10-12
SHANGHAI UNIV OF ENG SCI
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Problems solved by technology

[0009] This reaction adopts the method of strong alkali cyclization, which requires anhydrous conditions, and the cost of industrialization is high; the method of reducing nitro groups with iron powder will generate a large amount of industrial waste residue, which will bring serious environmental pollution problems, and the cost of industrialization is high.

Method used

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  • Preparation method of 4-chloro-6,7-dimethoxyquinoline
  • Preparation method of 4-chloro-6,7-dimethoxyquinoline
  • Preparation method of 4-chloro-6,7-dimethoxyquinoline

Examples

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Embodiment 1

[0039] Example 1 Preparation of 2-nitro-4,5-dimethoxyacetophenone (1)

[0040] Add 3,4-dimethoxyacetophenone (18.0g, 0.1mol) into a 500mL three-neck flask, add acetic acid (180mL) at 20°C, stir, heat to 60°C, and wait until the solids are completely dissolved , add 65wt% nitric acid (14.6mL, 0.21mol) to mix at this temperature, track the reaction with thin layer chromatography (TCL), the developer of TLC is ethyl acetate:petroleum ether=1:8, TLC detection wavelength is 254nm, After 3.5 h, TCL showed that the reaction was complete. The reaction solution was slowly poured into a stirred 400mL ice-water mixture in a beaker, and a yellow solid was generated. After stirring for half an hour, suction filtered to obtain a yellow solid, which was dried at 50°C to obtain 2-nitro-4,5-dimethoxyacetophenone (19.1 g) with a yield of 84.7% as a light yellow solid.

[0041] 1 H NMR (400MHz, DMSO-d 6 ): δ=2.52(s,3H), 3.90(s,3H), 3.93(s,3H), 7.23(s,1H), 7.64(s,1H); ESI-MS(m / z) 226.1[M +H]...

Embodiment 2

[0043] Preparation of 1-(4,5-dimethoxy-2-nitrophenyl)-3-(dimethylamino)propen-1-one (1)

[0044] Add 2-nitro-4,5-dimethoxyacetophenone (18.0g, 0.08mol) into a 250mL three-necked flask, add toluene (100mL) at 20°C, stir to dissolve, add N,N- Dimethylformamide dimethyl acetal (25.6g, 0.21mol), heated to 120°C for reaction, using TCL (the developer of TLC is dichloromethane:methanol:triethylamine=10:1:0.1, the detection wavelength is 254nm) to track the reaction, TCL detection after 4h showed that the reaction was over, the reaction solution was placed at 20°C and stirred, and after about 1h of precipitation, a yellow solid was produced, which was filtered by suction and dried to obtain a yellow solid 1-(4,5-dimethoxy -2-nitrophenyl)-3-(dimethylamino)propen-1-one (17.4 g, 77.7%).

[0045] 1 H NMR (400MHz, CDCl 3 ):δ=2.87(s,3H),3.10(s,3H),3.98(s,3H),3.99(s,3H),5.25(d,J=12.2Hz,1H),6.86(s,1H) ,7.30(brs,1H),7.60(s,1H).ESI-MS(m / z)281.2[M+H] + ,561.3[2M+H] + ,583.2[2M+Na] + .

Embodiment 3

[0047] Preparation of 4-hydroxy-6,7-dimethoxyquinoline (1)

[0048] 1-(4,5-dimethoxy-2-nitrophenyl)-3-(dimethylamino)propene-1-one (18.0g, 0.064mol) was added to a 1000mL eggplant-shaped bottle, at 20 At ℃, add 8g of Raney nickel and 600mL of tetrahydrofuran. After evacuating for 3 times, inject hydrogen gas, heat to 38℃, and track with TCL (TLC developer is dichloromethane:methanol=15:1, detection wavelength is 254nm). After 10 hours, TCL detection showed that the reaction was complete. The reaction solution was filtered with diatomaceous earth, and the diatomaceous earth was washed with tetrahydrofuran (25mL×2), and the tetrahydrofuran was evaporated to dryness to obtain a yellow solid 4-hydroxy-6,7-dimethoxy Quinoline crude product, the crude product was added to 140mL of ethyl acetate and ethanol mixed solution with a volume ratio of 1:1, and recrystallized and purified in the mixed solution to obtain off-white solid 4-hydroxyl-6,7- Dimethoxyquinoline 11.6g, yield 88.3%. ...

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Abstract

The invention relates to the technical field of organic synthesis and preparation of bulk drug intermediates, particularly a preparation method of 4-chloro-6,7-dimethoxyquinoline. The compound is used as an intermediate for preparing antineoplastic drugs cabozantinib and tivozanib. The method comprises the following steps: (1) nitrification: by using 3,4-dimethoxyacetophenone as a raw material, carrying out nitrification to obtain 2-nitro-4,5-dimethoxyacetophenone; (2) condensation: carrying out condensation on the 2-nitro-4,5-dimethoxyacetophenone and N,N-dimethylformamide dimethyl acetal to obtain 1-(4,5-dimethoxy-2-nitrophenyl)-3-(dimethylamino)propenyl-1-one; (3) reduction cyclization: carrying out hydrogenation reaction on the 1-(4,5-dimethoxy-2-nitrophenyl)-3-(dimethylamino)propenyl-1-oneto obtain 4-hydroxy-6,7-dimethoxyquinoline through reduction cyclization of the molecules; and (4) chlorination: carrying out chlorination on the 4-hydroxy-6,7-dimethoxyquinoline to obtain the 4-chloro-6,7-dimethoxyquinoline. The synthesis route has the advantages of accessible raw materials, mild reaction conditions, simple and convenient after-treatment and high yield, and is suitable for scale-up preparation.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis and the preparation of raw material drug intermediates, in particular to the preparation method of 4-chloro-6,7-dimethoxyquinoline, which is used as the preparation of anti-tumor drugs cabozantinib and tivoza Ni key intermediate. Background technique [0002] Cabozantinib (Cabozantinib, XL184) was developed by Exelixis Biopharmaceutical Company of the United States. It mainly targets MET and VEGFR2 tyrosine kinases, which are related to the growth and spread of prostate cancer, to inhibit tumor metastasis and angiogenesis. In November 2012, it was approved by the FDA for the treatment of unresectable malignant locally advanced or metastatic medullary thyroid carcinoma (MTC). Tivozanib (AV-951) is a VEGFR inhibitor with IC for VEGFR1, VEGFR2 and VEGFR3 50 30nmol / L, 6.5nmol / L and 15nmol / L respectively, can also inhibit PDGFR and c-Kit, FGFR-1, Flt3, c-Met, EGFR, developed by AVEO Oncolo...

Claims

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Application Information

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IPC IPC(8): C07D215/20
CPCC07D215/20
Inventor 朱春平茆勇军田昕乔宇王晓雨王晗
Owner SHANGHAI UNIV OF ENG SCI
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