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Synthetic method for anti-sleeplessness medicine MK-4305 intermediate

A technology of MK-4305 and a synthetic method, applied in the field of organic and pharmaceutical synthesis, can solve the problems of high preparation cost, harsh separation conditions, complicated operation and the like

Inactive Publication Date: 2013-04-03
TONGJI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The preparation cost of the reaction substrate iodide is also high, and the separation conditions are harsh, requiring repeated acidification, alkalization and recrystallization, the cost is high and the operation is cumbersome, so this route is difficult to apply to industrial production

Method used

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  • Synthetic method for anti-sleeplessness medicine MK-4305 intermediate
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  • Synthetic method for anti-sleeplessness medicine MK-4305 intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] (1) Synthesis of Compound 1

[0024]

[0025] Add 4-methyl-2-carboxyphenylhydrazine hydrochloride (2.0g, 0.0115mol) dissolved in acetic acid (70ml) into a 500mL two-necked flask, dilute glyoxal (2.1g, 0.0362mol) with 50mL of water, Slowly add this solution dropwise into the two-necked flask under ice bath; after the dropwise addition, continue to stir for half an hour; filter, 50 o C was dried in vacuo to obtain 2.35 g of compound 1. The yield was 99.0%. It can be directly used in the next reaction without purification.

[0026] (2) Synthesis of Compound 2

[0027]

[0028] Add compound 1 (2.35 g, 0.0114mol) and 30mL ethanol into a 100mL two-necked bottle, stir until dissolved, add hydroxylamine hydrochloride (3.26g, 0.0472mol) under ice cooling; then add 2M sodium hydroxide aqueous solution (2.5ml) dropwise, Continue to stir for 1h after dripping, filter, 50 o C was dried in vacuo to obtain 2.4 g of compound 2 with a yield of 95.2%. It can be directly used ...

Embodiment 2

[0036] (1) Synthesis of Compound 1

[0037]

[0038] Add 4-methyl-2-carboxyphenylhydrazine hydrochloride (2.0g, 0.0115mol) dissolved in 6M hydrochloric acid (70ml) into a 500mL two-necked bottle, take glyoxal (2.1g, 0.0362mol) and add 50mL of water to dilute , slowly drop this solution into the two-necked bottle at room temperature; after the dropwise addition, continue to stir for half an hour; filter, 50 o C was dried in vacuo to obtain 2.25 g of compound 1. The yield was 94.5%. It can be directly used in the next reaction without purification.

[0039] (2) Synthesis of Compound 2

[0040]

[0041] Add compound 1 (2.25 g, 0.0109 mol) and 30 mL of methanol into a 100 mL two-necked flask, stir until dissolved, add hydroxylamine hydrochloride (3.26 g, 0.0472 mol) under ice cooling; then add 2M potassium hydroxide aqueous solution (2.5 mL) dropwise, Continue to stir for 1h after dripping, filter, 50 o C was dried in vacuo to obtain 2.2 g of compound 2 with a yield of ...

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Abstract

The invention belongs to the field of organic synthesis and in particular relates to a synthesis method for an anti-sleeplessness medicine MK-4305 (suvorexant) intermediate. According to the synthesis method provided by the invention, 4-methyl-2-carboxyl phenylhydrazine hydrochloride is taken as substrate, hydrazone formation, oxime formation, loop closing and deoxidization are carried out, and 2-(4-methyl-2-carboxyl phenyl)-1,2,3-triazole can be conveniently and effectively synthesized. Compared with the existing method, the synthesis method provided by the invention has the advantages that raw materials are low in price, operation is easy, industrial production is easy to realize and no isomer is formed, so that the synthesis method provided by the invention has important application value. The compound synthesized by adopting the invention is a key intermediate for synthesizing anti-sleeplessness medicine MK-4305 (suvorexant) medicinal molecules.

Description

technical field [0001] The invention belongs to the technical field of organic and drug synthesis, and in particular relates to a preparation method of an anti-insomnia drug MK-4305 (Suvorexant) intermediate. Background technique [0002] MK-4305 (Suvorexant) is an anti-insomnia drug newly developed by Merk Pharmaceuticals in the United States. Merk Pharmaceuticals of the United States previously announced the late clinical trial data of MK-4305. According to the data of the clinical trial, the drug can significantly shorten the time for the test patients to fall asleep compared with other drugs, and the drug can also improve the sleep quality of the patients. The difference between MK-4305 and other sleep medicines is that general sleep medicines are taken on demand (that is to say, they are taken only when needed, not the root cause), while the MK-4305 medicine of Merk Pharmaceuticals needs to be taken for a long time to eradicate the disease. Treatment of insomnia. MK-4...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D249/06
Inventor 匡春香刘伟王悦石鹏皓袁钰
Owner TONGJI UNIV
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