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Method for preparing key intermediate of PKB/Akt inhibitor

A technology of solvent and reagent, which is applied in the field of preparation of N-substituted-1-cyclobutylamine, can solve problems such as danger, low reaction yield, unsuitability for industrial production, etc., achieves low environmental pollution, high product purity, and low cost Effect

Active Publication Date: 2016-02-10
XIAMEN MEDICAL COLLEGE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

But the reaction not only needs to use the very expensive raw material 4-(1-tert-butoxycarbonylaminocyclobutyl) benzoic acid, but also needs to use the dangerous reagent diphenylphosphoryl azide, and the reaction yield is very low, so it is not suitable for Industrial production

Method used

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  • Method for preparing key intermediate of PKB/Akt inhibitor
  • Method for preparing key intermediate of PKB/Akt inhibitor
  • Method for preparing key intermediate of PKB/Akt inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] Embodiment one: the synthesis of 1-(4-nitrophenyl) cyclobutanecarbonitrile (Ⅲ)

[0055] At room temperature, add 600mL methanesulfonic acid into the reaction flask, slowly add 326gMg(NO 3 ) 2 . 6H 2 O, stirred for 2h, slowly added 200g of 1-phenylcyclobutanecarbonitrile, then stirred at room temperature for 2h, HPLC showed that the content of the raw material was less than 1%. Poured into 2L of water, stirred for 2 hours, a large amount of solids were precipitated, filtered by suction and dried to obtain 250g of light yellow solids with a yield of 97% and a purity of more than 98%. 1 HNMR (400MHz, CDCl 3 )δ2.13-2.30(m,1H),2.50-2.61(m,1H),2.65-2.73(m,2H),2.90-3.00(m,2H),7.65(d,J=8.8Hz,2H) , 8.31 (d, J=8.8Hz, 2H).

Embodiment 2

[0056] Embodiment two: the synthesis of 1-(4-nitrophenyl) cyclobutanecarboxamide (Ⅳ)

[0057] At room temperature, 202g of 1-(4-nitrophenyl)cyclobutanecarbonitrile and 600mL of 10% sodium hydroxide aqueous solution were added to the reaction flask, 500mL of hydrogen peroxide was added, and stirred at room temperature for 24h. HPLC showed that the content of the raw material was less than 1%. Suction filtration and drying yielded 218 g of a light yellow solid with a yield of 99% and a purity greater than 98%. 1 HNMR (400MHz, CDCl 3 )δ1.90-1.96(m,1H),2.15-2.21(m,1H),2.48-2.55(m,2H),2.85-2.88(m,2H),5.18(br,1H),5.53(br, 1H), 7.49 (d, J=8.8Hz, 2H), 8.22 (d, J=8.8Hz, 2H).

Embodiment 3

[0058] Embodiment three: the synthesis of 1-(4-nitrophenyl) cyclobutanecarboxamide (Ⅳ)

[0059] At room temperature, add 202g of 1-(4-nitrophenyl)cyclobutanecarbonitrile into 1L of dimethyl sulfoxide, add 276g of potassium carbonate, add 500mL of hydrogen peroxide, stir at room temperature for 3h, HPLC shows that the content of raw materials is less than 1% . After adding 2L of water, a large amount of solid was precipitated, which was filtered by suction and dried to obtain 209 g of a light yellow solid with a yield of 95% and a purity of more than 98%. 1 HNMR (400MHz, CDCl 3 )δ1.90-1.96(m,1H),2.15-2.21(m,1H),2.48-2.55(m,2H),2.85-2.88(m,2H),5.18(br,1H),5.53(br, 1H), 7.49 (d, J=8.8Hz, 2H), 8.22 (d, J=8.8Hz, 2H).

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Abstract

The invention discloses a novel method for synthesizing a key intermediate, N-substituted-1-(4-aminophenyl) cyclobutylamine (I), of a PKB / Akt inhibitor. The method comprises the steps that 1-(4-nitrophenyl) cyclobutane formonitrile (III) is obtained through nitration of 1-phenyl cyclobutane formonitrile (II), the compound (III) is hydrolyzed into 1-(4-nitrophenyl) cyclobutane formamide (IV) under the action of an oxidizing agent, the compound (IV) is subjected to rearrangement reaction to generate 1-(4-nitrophenyl) cyclobutylamine (V), the intermediate compound (V) does not need to be purified and can further react with a corresponding reagent to generate N-substituted-1-(4-nitrophenyl) cyclobutylamine (VI), and the compound (V) or (VI) reacts under the action of a reducing agent to form the compound (I). The method has the advantages of being low in cost, environmentally friendly, high in yield and the like and is suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of N-substituted-1-(4-aminophenyl)cyclobutylamine (I), a key intermediate of a class of PKB / Akt inhibitors. Background technique [0002] Cancer has become one of the primary diseases that threaten human health in the world, and my country has become the second country with the highest incidence of cancer in the world. So far, in addition to surgical treatment and radiotherapy, chemotherapy is still the most effective method for treating cancer patients. [0003] The Akt oncogene is a serine / threonine protein kinase, also named protein kinase B (PKB). So far, three subtypes of PKB / Akt have been found in mammals: PKB α / Akt 1 、PKB β / Akt 2 、PKB γ / Akt 3 . The presence of PKB / Akt protein was found in retro-oncoviruses, and it was thought that it might be a proto-oncogene. Moreover, a substantial increase in the activity of PKB / Akt can be detected in many tumors, and the activation of PKB / Akt is one o...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C211/49C07C209/36C07C211/40C07C269/06C07C271/24
Inventor 陈欢生陈宇
Owner XIAMEN MEDICAL COLLEGE
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