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Synthesis method of dimethyphosphorylbenzoic acid

A technology of dimethylphosphoryl benzoic acid and dimethylphosphoryl benzoate is applied in the synthesis field of dimethylphosphoryl benzoic acid, and can solve the problems of harsh conditions, complicated operation, expensive reaction route reagents and the like, To achieve the effect of short reaction route

Active Publication Date: 2012-10-17
CHANGZHOU HEQUAN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] The purpose of the present invention is to provide a novel synthesis method of dimethylphosphorylbenzoic acid, mainly through a method of quickly and efficiently introducing dimethylphosphoryl on the aromatic ring to solve the lack of existing synthetic routes and existing reaction routes The reagents are expensive, the operation is complicated, the conditions are harsh, the applicability is not wide and other technical problems

Method used

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  • Synthesis method of dimethyphosphorylbenzoic acid
  • Synthesis method of dimethyphosphorylbenzoic acid
  • Synthesis method of dimethyphosphorylbenzoic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0016] Embodiment 1: Synthesis of p-dimethylphosphorylbenzoic acid.

[0017] first step reaction

[0018]

[0019] Add 800 mL of methylmagnesium bromide ether solution (0.8 mol, 3M in ether) into 800 mL of tetrahydrofuran. Then diethyl phosphite 1 (110g, 0.8mol) was slowly added to the reaction solution. During this period the reaction solution was kept at 20-30°C. Stirring was continued for 1 hour after the dropwise addition was complete. It was then poured slowly into 400 mL of aqueous potassium carbonate solution (331 g, 2.4 mol) under an ice bath. After complete addition, stir for 1 hour and filter. The filter cake was washed with ethanol (2Lx4). After the filtrate was collected, the solvent was removed, and the residue was dissolved in 100 mL of dichloromethane, dried over anhydrous sodium sulfate, and filtered. First remove dichloromethane, then distill under reduced pressure to obtain dimethyl phosphine 2 (39g, 62.5%).

[0020] second step reaction

[00...

Embodiment 2

[0027] Embodiment 2: Synthesis of m-dimethylphosphorylbenzoic acid: the first step reaction is the same as in Example 1.

[0028] second step reaction

[0029]

[0030] methyl m-iodobenzoate 3b (77.4g, 0.36mol), diphenylphosphine 2 (28.1g, 0.36mol), tetrakistriphenylphosphine palladium (12.5g, 0.0108mol) and triethylamine (72.7g, 0.42mol) were added to 700mL of ethanol. The reaction system was replaced with nitrogen three times, and then heated to 90-100° C. under the protection of nitrogen. After 10 hours, the reaction was filtered, concentrated and the residue was dissolved in dichloromethane, washed with water, dried and filtered. After the filtrate was concentrated, it was purified by column chromatography (the eluent was dichloromethane:methanol=30:1) to obtain methyl m-dimethylphosphorylbenzoate 4b (54g, 70%).

[0031] third step reaction

[0032]

[0033] Sodium hydroxide (10 g, 0.25 mol) was dissolved in 300 mL of water, then methyl m-dimethylphosphoryl...

Embodiment 3

[0035] Embodiment 3: Synthesis of o-dimethylphosphorylbenzoic acid: the first step reaction is the same as in Example 1.

[0036] second step reaction

[0037]

[0038] methyl o-iodobenzoate 3c (67g, 0.255mol), diphenylphosphine 2 (19.9g, 0.255mol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (19.8g, 0.025mol) and triethylamine (77g, 0.765mol) were added to 700mL ethanol middle. The reaction system was replaced with nitrogen three times, and then heated to 100° C. under the protection of nitrogen. After 12 hours, the reaction was filtered, concentrated and the residue was dissolved in dichloromethane, washed with water, dried and filtered. After the filtrate was concentrated, it was purified by column chromatography (the eluent was dichloromethane:methanol=30:1) to obtain methyl o-dimethylphosphorylbenzoate 4c (48g, 89%).

[0039] third step reaction

[0040]

[0041]Dissolve lithium hydroxide (28.8 g, 1.2 mol) into 380 mL of water, then add 300...

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Abstract

The invention relates to a synthesis method of dimethyphosphorylbenzoic acid. Mainly by rapid and efficient introduction of dimethyphosphoryl to an aromatic ring, the invention solves the problem of lack of synthetic routes, as well as the technical problems of presence of the reaction route expensive reagent, complicated operation, harsh condition, non-wide applicability and the like in existing reaction routes. The method of the invention comprises: taking inexpensive diethyl phosphite as the raw material, which reacts with methylmagnesium bromide in diethyl ether so as to obtain dimethyl phosphorous oxide; bringing the dimethyl phosphorous oxide and halogenated benzoate into a coupling reaction in the presence of a palladium catalyst so as to obtain corresponding dimethylphosphorylbenzoate; then hydrolyzing the dimethylphosphorylbenzoate to obtain corresponding dimethyphosphorylbenzoic acid. The synthetic route in the invention can quickly and conveniently prepare dimethyphosphorylbenzoic acid.

Description

technical field [0001] The present invention relates to the synthetic method of dimethyl phosphoryl benzoic acid. Background technique [0002] Dimethylphosphoryl aryl compounds are a new class of pharmaceutical intermediates. The dimethylphosphoryl group contained in them can effectively promote the water solubility of the original compounds, which has greatly improved many compounds that were originally poorly water soluble. Therefore, the scope of drug screening has been expanded. Benzoic acid and the like are very common and effective drug intermediates. After adding a dimethylphosphoryl group, the water solubility of this type of compound is obviously promoted, which effectively expands the scope of application of subsequent drug screening. At the same time, phosphorus-containing groups also have many applications in drug development: patent WO / 2008 / 010985 mentions dimethylphosphoryl compounds as histone deacetylase inhibitors, which can be used to inhibit histone deac...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/53
Inventor 柏祝陈先印刘培元刘洲亚周超吴安树贺海鹰陈曙辉
Owner CHANGZHOU HEQUAN PHARMA CO LTD