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5-methyl-7-amino-5H,7H-dibenzo[b,d]azepin-6-ketone preparation method

A technology of azepane and ethoxycarbonylaminobiphenyl, which is applied in the field of synthesis of pharmaceutical intermediates, can solve the problems of difficult purification, complex products, and low yield, and achieve cheap and easy-to-obtain raw materials, simple preparation process, and low production cost low effect

Inactive Publication Date: 2013-12-11
HUIFEICHEM WUXI PHARMATECH CO LTD
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  • Abstract
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  • Claims
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AI Technical Summary

Problems solved by technology

[0012] In the above method one, the starting material 2-aminobiphenyl is derived from a small amount of by-products in the production of 4-aminobiphenyl, and tests have proved that the product is complex, the yield is low, and the purification is difficult after the Friedel-Crafts cycloalkylation reaction. Unable to meet the needs of industrialization
[0013] In the second method, although the yield can be increased by performing the Friedel-Crafts reaction after methylation, there is also the problem of limited sources of raw material 2-aminobiphenyl, and the metal reducing agent red aluminum or hydrogen needs to be used during methylation. Lithium oxide is expensive and has potential safety hazards (spontaneous combustion in air, explosion in water)
[0014] The raw materials o-bromoboric acid, o-iodoaniline and o-iodophenylacetic acid in method three and method four are expensive and difficult to obtain, and have no industrial production value

Method used

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  • 5-methyl-7-amino-5H,7H-dibenzo[b,d]azepin-6-ketone preparation method

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Experimental program
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Effect test

Embodiment 1

[0040] Such as figure 1 As shown, the whole synthesis reaction of the present embodiment is divided into the following six steps:

[0041] The first step: Suzuki coupling reaction to synthesize 2-aminobiphenyl

[0042] Add o-bromoaniline (321.6g, 1.87mol) and phenylboronic acid (269.5g, 2.21mol) into a 10L reaction flask, add 3L of ethanol, 1L of deionized water, and then add potassium carbonate (703.8g, 5.1mol), and stir well , evacuate and use nitrogen to break the air; heat to reflux under the protection of nitrogen, add ditriphenylphosphine palladium dichloride (2.63g, 3.7mmol), reflux reaction for 0.5h, and perform thin layer chromatography (TLC) to detect whether there is any remaining raw material , if the reaction is not complete, add a small amount of ditriphenylphosphine palladium dichloride until the reaction is complete; distill the alcohol off under reduced pressure, add ethyl acetate to the residue, extract the water phase, wash the organic phase with saturated ...

Embodiment 2

[0054] The first step: Suzuki coupling reaction to synthesize 2-aminobiphenyl

[0055] Add o-bromoaniline (100g, 0.58mol) and phenylboronic acid (91.9g, 0.754mol) into a 3L reaction flask, add 1L of ethanol, 0.35L of deionized water, and then add potassium carbonate (240g, 1.74mol), stir well, Vacuumize and use nitrogen to break the air; heat to reflux under the protection of nitrogen, add tetrakistriphenylphosphopalladium (0.67g, 0.58mmol), reflux for 0.5h, and then conduct thin-layer chromatography (TLC) to detect whether there are any remaining raw materials. For the rest, add a small amount of tetrakistriphenylphosphopalladium until the reaction is complete; distill off the alcohol under reduced pressure, add ethyl acetate to the residue, extract the water phase, wash the organic phase with saturated brine, and then concentrate the solvent to dryness under reduced pressure. Obtain 106 g of oily substance, yield 108%. The product was directly used in the next reaction with...

Embodiment 3

[0066] Embodiment 3 The whole synthesis reaction of this embodiment is divided into the following six steps:

[0067] The first step: Suzuki coupling reaction to synthesize 2-aminobiphenyl

[0068] Add 38.6kg of o-bromoaniline and 32.4kg of phenylboronic acid into the reaction kettle, add 325kg of ethanol, 120kg of deionized water, and 84.5kg of potassium carbonate, stir evenly, vacuumize and break the air with nitrogen, repeat the operation three times; start under nitrogen protection Heating, after reflux, add 300g of ditriphenylphosphine palladium dichloride, then add 50g of catalyst every 20min until the reaction is complete; distill under reduced pressure to remove alcohol, add ethyl acetate to the residue, extract the water phase, and saturate it with 10kg The organic phase was washed with brine, and the solvent was concentrated to dryness under reduced pressure to obtain an oily substance without releasing the product, which was directly used in the reaction kettle for ...

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Abstract

The invention relates to a 5-methyl-7-amino-5H,7H-dibenzo[b,d]azepin-6-ketone preparation method, wherein the method takes bromoaniline and phenylboronic acid as raw materials, a Suzuki coupling reaction is conducted to get 2-aminobphenyl, amino is protected with ethyl chloroformate, then potassium tert-butoxide is used as an acid-binding agent, the 2-aminobphenyl is subjected to N-methylation with methyl iodide, deprotected with amino, reacted with chloracetyl, and subjected to a Friedel Craft cyclizing hydrocarbylation to get the target product. The 5-methyl-7-amino-5H,7H-dibenzo[b,d]azepin-6-ketone preparation method has the advantages of simple process, high overall yield and low production cost, and is applicable to industrial mass production.

Description

technical field [0001] The present invention relates to the technical field of synthesis of pharmaceutical intermediates, in particular to 5-methyl-7-amino-5H,7H-dibenzo[b,d]azepane-6-a potential drug intermediate for Alzheimer's disease Process for the industrial preparation of ketones. Background technique [0002] Alzheimer's disease (Alzheimer's disease, AD) is one of the three major diseases that seriously threaten the life of the elderly, manifested as memory loss and cognitive impairment, etc., and gradually aggravates with age. The generally accepted view in medicine is that Aβ Peptides and their oligomers play an important role in the pathology of AD. Studies have found that by inhibiting γ-secretase and reducing the cleavage of β-amyloid precursor protein to reduce the generation of Aβ peptide, AD can be effectively prevented and treated . A large number of studies have proved that inhibition of γ-secretase is an ideal drug target. The first γ-secretase inhibitor...

Claims

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Application Information

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IPC IPC(8): C07D223/18
Inventor 陈雪松吴君
Owner HUIFEICHEM WUXI PHARMATECH CO LTD
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