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A kind of catalytic synthesis method of pharmaceutical intermediate diaryl compounds

A synthesis method and compound technology are applied to the catalytic coupling of aryl hydrazine and aryl boronic acid to prepare diaryl compounds, and the field of catalytic synthesis of pharmaceutical intermediate diaryl compounds, which can solve the problem of low reaction yield and suitable substrates. narrow range, harsh reaction conditions and other problems, to overcome the effect of low yield

Active Publication Date: 2016-03-02
SHANGHAI LINKCHEM TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] Although the prior art has many reports on palladium-catalyzed coupling reactions, the reports on its application to C-N bond splitting to construct diaryl compounds are rare; in addition, the coupling of diaryl compounds in the prior art The preparation process also has the disadvantages of narrow substrate application range, harsh reaction conditions, and low reaction yield.

Method used

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  • A kind of catalytic synthesis method of pharmaceutical intermediate diaryl compounds
  • A kind of catalytic synthesis method of pharmaceutical intermediate diaryl compounds
  • A kind of catalytic synthesis method of pharmaceutical intermediate diaryl compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034]

[0035] In the reactor, add 1mmol formula (I) compound and 2.5mmol formula (II) compound successively, then add 0.06mmolPd(acac) 2 , 0.35mmol triphenylphosphine and 1.5mmol acetic acid, then add 4.2ml solvent toluene, add 55mg mass ratio of 0.3:1 porphyrin and 1-benzyl-3-methylimidazolium bromide additive mixture under stirring , warming up to 70°C and insulated for 2.5 hours, TLC monitors the end point of the reaction, after the reaction is completed, the mixture is concentrated in vacuo, and the residue is purified by silica gel column chromatography to obtain the compound of formula (III), with a yield of 97.5% and a purity of 99.3 % (HPLC).

[0036] 1 HNMR (400MHz, CDCl 3 ) δ 7.65-7.62 (m, 2H), 7.52-7.47 (m, 4H), 7.43-7.38 (m, 2H), 7.25 (d, J=7.40Hz, 1H), 2.46 (s, 3H).

Embodiment 2

[0038]

[0039] In the reactor, add 1mmol formula (I) compound and 3mmol formula (II) compound successively, then add 0.07mmolPd(acac) 2, 0.4mmol triphenylphosphine and 2mmol acetic acid, then add 4.6ml solvent toluene, add 52mg mass ratio under stirring and be the auxiliary agent mixture of the porphyrin of 0.3:1 and 1-benzyl-3-methylimidazolium bromide, The temperature was raised to 75° C. and kept for reaction for 2 hours. The end point of the reaction was monitored by TLC. After the reaction was completed, the mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography to obtain the compound of formula (III), with a yield of 98.3% and a purity of 99.1% ( HPLC).

[0040] 1 HNMR (400MHz, CDCl 3 )δ7.62-7.58 (m, 4H), 7.52-7.48 (m, 2H), 7.43-7.38 (m, 1H), 7.17-7.12 (m, 2H).

Embodiment 3

[0042]

[0043] In the reactor, add 1mmol formula (I) compound and 2mmol formula (II) compound successively, then add 0.04mmolPd(acac) 2 , 0.3mmol triphenylphosphine and 1.8mmol acetic acid, then add 5ml solvent toluene, add 60mg mass ratio under stirring and be the auxiliary agent mixture of the porphyrin of 0.3:1 and 1-benzyl-3-methylimidazolium bromide, Raise the temperature to 80°C and keep it warm for 1.5h. The end point of the reaction was monitored by TLC. After the reaction was completed, the mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography to obtain the compound of formula (III), with a yield of 98.5% and a purity of 99.0%. (HPLC).

[0044] 1 HNMR (400MHz, CDCl 3 )δ8.43(t,J=1.96Hz,1H),8.22-8.18(m,1H),7.95-7.93(m,1H),7.65-7.61(m,3H),7.53-7.49(m,2H) ,7.44-7.41(m,1H).

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Abstract

The invention relates to a catalyzed synthesis method for drug intermediate diaryl-class compounds. According to the method, arylhydrazine and arylboronic acid are taken as raw materials, and under the catalysis of Pd(acac)<2> / triphenylphosphine / acetic acid, the diaryl-class compounds are successfully prepared. Due to adding of auxiliaries, catalysis is effectively concerted, and smooth conducting of the reaction is promoted. The optimum solvent type adapting to a catalytic system is studied, and the method has the advantages of being high in yield coefficient, and moderate in reaction, and has the quite wide large-scale application value and market potentials.

Description

technical field [0001] The invention relates to a catalytic synthesis method of a pharmaceutical intermediate diaryl compound, more specifically to a method for preparing a diaryl compound by catalytic coupling of arylhydrazine and arylboronic acid, which belongs to the field of chemical synthesis. Background technique [0002] Diaryl compound is a special structural unit, which widely exists in natural products and pharmaceutical active molecules. Therefore, the development of new, effective and mild reaction diaryl compound preparation technology has been highly sought by the fields of medicine, chemical industry and so on. big concern. [0003] Palladium-catalyzed coupling reactions are an efficient method for the synthesis of diaryls, but reactions involving inactive C–N bond cleavage are rare. [0004] There are many synthetic techniques of diaryl compounds in the prior art, such as: [0005] ("Crosscoupling of thioethers with arylboroxines to construct biaryls via Rh...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07B37/00C07C1/32C07C15/14C07C17/263C07C25/18C07C201/12C07C205/06C07C41/30C07C43/205
Inventor 魏建华
Owner SHANGHAI LINKCHEM TECH CO LTD
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