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A kind of synthetic method of tert-butyl 4,7-diazaspiro[2.5]octane-7-carboxylate

A technology for tert-butyl formate and diazaspiro, which is applied in the field of chemical synthesis of N-containing heterocyclic drug intermediates, can solve the problems of high equipment requirements, harsh conditions and high costs, and achieves low risk factor for feeding materials, mild reaction conditions, Easy-to-control effects

Inactive Publication Date: 2018-12-14
WUHAN INSTITUTE OF TECHNOLOGY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] The above two methods all have the following disadvantages: (1) expensive raw materials and high cost; (2) complicated operation and low yield; (3) harsh conditions and high requirements for equipment; (4) under normal circumstances, the properties of raw materials are unstable , high risk

Method used

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  • A kind of synthetic method of tert-butyl 4,7-diazaspiro[2.5]octane-7-carboxylate
  • A kind of synthetic method of tert-butyl 4,7-diazaspiro[2.5]octane-7-carboxylate
  • A kind of synthetic method of tert-butyl 4,7-diazaspiro[2.5]octane-7-carboxylate

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Embodiment 1

[0034] A method for synthesizing 4,7-diazaspiro[2.5]octane-7-carboxylic acid tert-butyl ester, comprising the following steps:

[0035] (1) Synthesis of diethyl 1,1-cyclopropanedicarboxylate:

[0036] In a 250mL three-necked reaction flask, add 24g diethyl malonate, 33.8g 1,2-dibromoethane, 51.8g K 2 CO 3 , 0.24g Bu 4NBr and 120 mL of DMF were added to a drying tube, heated to 80 °C in an oil bath and refluxed for 15 h; TLC monitored the completion of the reaction, slowly lowered to room temperature, filtered to remove the resulting potassium salt, washed with 100 mL of EA, combined the filtrates, concentrated under reduced pressure to remove the solvent, 19.6 g of diethyl 1,1-cyclopropanedicarboxylate were obtained with a yield of 70.3%.

[0037] (2) Synthesis of 1,1-cyclopropanedicarboxylic acid monoethyl ester:

[0038] In a 100mL three-necked reaction flask, add 19.6g diethyl 1,1-cyclopropanedicarboxylate and 65mL EtOH, cool it down to 0°C in an ice bath, slowly add 5....

Embodiment 2

[0052] A method for synthesizing 4,7-diazaspiro[2.5]octane-7-carboxylic acid tert-butyl ester, comprising the following steps:

[0053] (1) Synthesis of diethyl 1,1-cyclopropanedicarboxylate:

[0054] In a 3L three-necked reaction flask, add 288g diethyl malonate, 405.4g 1,2-dibromoethane, 449.7g KHCO 3 , 1.67g Bu 4 NBr and 1.5L DMF were stirred and reacted at room temperature for 16 hours. TLC monitored the oil bath and heated to 100 °C and stirred for 2 hours. TLC monitored the reaction to complete, slowly lowered to room temperature, filtered to remove the generated potassium salt, washed with 200 mL of EA, combined the filtrates, reduced The solvent was removed by concentration under pressure to obtain 255.3 g of diethyl 1,1-cyclopropanedicarboxylate with a yield of 76.3%.

[0055] (2) Synthesis of 1,1-cyclopropanedicarboxylic acid monoethyl ester:

[0056] In a 2L three-necked reaction flask, add 255.3g diethyl 1,1-cyclopropanedicarboxylate, 840mL EtOH, cool it down to...

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Abstract

The invention belongs to the technical field of chemical synthesis of N-heterocycle-containing drug intermediates, and particularly relates to a synthesis method of tert-butyl 4,7-diazaspiro[2.5]octyl-7-formate. By using diethyl malonate as a raw material, cyclization reaction, Hofmann reaction, hydrolysis reaction, acylation reaction for recyclization, reduction reaction and the like are performed to conveniently synthesize the target compound product. The method has the advantages of simple synthesis technique, cheap and accessible raw materials, mild reaction conditions, high controllability, low cost and high yield, and is convenient to operate.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis of N-containing heterocyclic pharmaceutical intermediates, in particular to a method for synthesizing tert-butyl 4,7-diazaspiro[2.5]octane-7-carboxylate. Background technique [0002] Tert-butyl 4,7-diazaspiro[2.5]octane-7-carboxylate is an important pharmaceutical intermediate and an important raw material for the synthesis of many drugs and auxiliary agents. For example, the preparation of cyanoguanidine, its derivatives can be used as a protein kinase inhibitor and anti-tumor agent, the protein kinase inhibitor and its preparation pharmaceutical ingredients can treat heart failure and cancer, tyrosine kinase, especially JAK kinase inhibitor , and the preparation of some antiviral drugs and antihypertensive drugs are applied to tert-butyl 4,7-diazaspiro[2.5]octane-7-carboxylate. In recent years, a series of pharmacologically active groups synthesized from tert-butyl 4,7-diazaspiro[2....

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D241/38
CPCC07D241/38
Inventor 黄齐茂冯瑾瑾高辉
Owner WUHAN INSTITUTE OF TECHNOLOGY