Synthesis method of (poly)fluorophenylpyridine compounds

A technology of polyfluorophenylpyridine and synthesis method, which is applied in the direction of organic chemistry, can solve the problems of expensive catalysts, expensive heavy metals, and high comprehensive costs, and is conducive to the promotion of large-scale industrial production, the value of large-scale industrial production, and the reduction of post-processing effect of difficulty

Inactive Publication Date: 2016-12-21
SHAANXI NORMAL UNIV
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Problems solved by technology

[0009] Although 2-(2',6'-difluorophenyl)-3-fluoro-6-methylpyridine has achieved a good yield in this synthetic method, there are the following problems: 1) the raw material 2,6- Difluorophenylboronic acid is expensive and difficult to obtain; 2) Catalyst tris (dibenzylidene acetone) dipalladium is very expensive and can cause heavy metal residue; 3) Dibenzylidene acetone in catalyst tris (dibenzylidene acetone) dipalladium It is very similar to the product in polarity and is difficult to remove. It must be reduced with sodium borohydride and then subjected to silica gel column chromatography to separate it from the product
It can be seen that the raw materials and catalysts used in this method are expensive, and the product after coupling needs additional steps to be purified. These factors make the overall cost of the method very high, which is not conducive to industrialization.

Method used

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  • Synthesis method of (poly)fluorophenylpyridine compounds
  • Synthesis method of (poly)fluorophenylpyridine compounds
  • Synthesis method of (poly)fluorophenylpyridine compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Synthesis of 2-(2′,6′-difluorophenyl)-3-fluoro-6-methylpyridine with the following structural formula

[0039]

[0040] 1. Under anhydrous and oxygen-free conditions, dissolve 3.42g (30mmol) 1,3-difluorobenzene in 10mL tetrahydrofuran, then slowly add 6mL 2.5mol / L n-butyllithium hexane solution, and stir at -20°C After 4 hours, slowly add 22 mL of 1 mol / L zinc chloride solution in tetrahydrofuran, slowly raise to room temperature, and continue stirring for 2 hours.

[0041] 2. Under anhydrous and oxygen-free conditions, add 200 mg (0.8 mmol) bis(1,5-cyclooctadiene) nickel, 770 mg (1 mmol) bis(2-bis(3′,5′-bis Methyl-4'-methoxyphenyl)phosphine)phenyl ether, stirred at room temperature for 30 minutes.

[0042] 3. Under anhydrous and oxygen-free conditions, mix the reaction solutions obtained in step 1 and step 2, and add 1.90 g (10 mmol) of 2-bromo-3-fluoro-6-methylpyridine, stir at 50 ° C for 10 hours, and detect by TLC Reaction was complete, after methanol was added...

Embodiment 2

[0044] Synthesis of 2-(2',4',6'-trifluorophenyl)-3-fluoro-6-methylpyridine with the following structural formula

[0045]

[0046] 1. Under anhydrous and oxygen-free conditions, dissolve 3.17g (24mmol) 1,3,5-trifluorobenzene in 10mL tetrahydrofuran, then add 10mL 2mol / L tetrahydrofuran solution of ethylmagnesium chloride, and stir at 50°C for 18 hours , and then add 22 mL of 1 mol / L zinc chloride solution in tetrahydrofuran, and continue stirring at room temperature for 2 hours.

[0047] 2. Under anhydrous and oxygen-free conditions, add 220 mg (0.8 mmol) bis(1,5-cyclooctadiene) nickel, 801 mg (1 mmol) bis(2-bis(3′,4′-bis Methoxyphenyl)phosphine)phenyl ether, stirred at room temperature for 30 minutes.

[0048] 3. Under anhydrous and oxygen-free conditions, mix the reaction solutions obtained in step 1 and step 2, and add 1.90 g (10 mmol) of 2-bromo-3-fluoro-6-methylpyridine, stir at 50 ° C for 10 hours, and detect by TLC Reaction was complete, after methanol was added to...

Embodiment 3

[0050] Synthesis of 2-(2′,3′,5′,6′-tetrafluorophenyl)-3-fluoro-6-methylpyridine with the following structural formula

[0051]

[0052] In step 1 of Example 2, 1,3,5-trifluorobenzene was replaced with 1,2,4,5-tetrafluorobenzene whose molar weight was 0.8 times that of 1,2,4,5-tetrafluorobenzene, and ethylmagnesium chloride was replaced with an equimolar amount of isopropyl Magnesium chloride was replaced and the reaction temperature was changed to room temperature. In step 3 of Example 2, bis(2-bis(3',4'-dimethoxyphenyl)phosphine)phenyl ether was mixed with equimolar bis(2-bis(3',5'-bis Methyl-4'-methoxyphenyl) phosphine) phenyl ether replacement, other steps are the same as in Example 2, to obtain 2-(2',3',5',6'-tetrafluorophenyl)-3- Fluoro-6-picoline, its yield is 87%, and the structural characterization data is: 1 H NMR (600MHz, CDCl 3 ): δ7.46 (t, J = 8.6H, 1H), 7.22 (dd, J = 8.6, 3.8Hz, 1H), 7.19-7.13 (m, 2H), 2.61 (s, 3H).

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Abstract

The invention discloses a synthesis method of (poly)fluorophenylpyridine compounds. The method is characterized by under anhydrous and oxygen-free conditions, using tetrahydrofuran as a solvent, an alkyl Grignard reagent or lithium alkylide as an activating agent and equivalent zinc halide as an assistant agent and adopting a compound formed by a nickel source and a diphosphine ligand as a catalyst to achieve cross-coupling of polyfluorobenzene and halogenated pyridine, thus synthesizing a series of (poly)fluorophenylpyridine compounds with yield of about 90% and purify not less than 99%. The synthesis method has the beneficial effects that use of expensive (poly)fluorophenylboronic acid and palladium catalysts is avoided by adopting cheaper (poly)fluorophenyl and nickel compound as the raw material and the catalyst, so the synthesis method has obvious economic advantages; the synthesis method has the advantages of simple reaction system, mild conditions, simplicity in operation, easiness in aftertreatment, low pollution, easiness in industrialization, and the like and shows higher social value and industrial popularization prospect.

Description

technical field [0001] The invention belongs to the technical field of synthesizing polyfluorobiaryl compounds, and in particular relates to a method for synthesizing polyfluorophenylpyridine compounds under nickel-catalyzed mild conditions. Background technique [0002] PIM 447 is an effective drug for the treatment of malignant tumors and hematologic malignancies (Burger, Matthew et al.ACSMed.Chem.Lett.2013, 4, 1193-1197; Burger, Matthew et al. 8373-8386). At present, the drug has entered the phase III clinical trial stage, and the effect is remarkable. It is a new drug with extremely high social value and market value. [0003] [0004] 2-(2′,6′-difluorophenyl)-3-fluoro-6-methylpyridine (CAS: 1210419-18-3) and its derivatives are important intermediates for the synthesis of PIM447 related drugs. Therefore, it is very important to develop a technical route for the efficient and convenient synthesis of such intermediates. [0005] [0006] 2-(2,6-Difluorophenyl)-3-...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/61C07D213/803C07D213/84
CPCC07D213/61C07D213/803C07D213/84
Inventor 黄治炎王俊亚
Owner SHAANXI NORMAL UNIV
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