Synthesis method of tert-butyl 4,7-diazaspiro[2.5]octyl-7-formate

A technology of 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 achieve low risk factor for feeding, mild reaction conditions, easy to control effects

Inactive Publication Date: 2015-12-02
WUHAN INSTITUTE OF TECHNOLOGY
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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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  • Synthesis method of tert-butyl 4,7-diazaspiro[2.5]octyl-7-formate
  • Synthesis method of tert-butyl 4,7-diazaspiro[2.5]octyl-7-formate
  • Synthesis method of tert-butyl 4,7-diazaspiro[2.5]octyl-7-formate

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Embodiment 1

[0034] A kind of synthetic method of 4,7-diazaspiro[2.5]octane-7-carboxylic acid tert-butyl ester, comprises the steps:

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

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

[0037] (2) Synthesis of monoethyl 1,1-cyclopropanedicarboxylate:

[0038] In a 100mL three-necked reaction flask, add 19.6g of 1,1-cyclopropanedicarboxylate diethyl ester, 65mL EtOH, cool it down to 0°C in an ice bath, slowly add 5.9g of KOH, ...

Embodiment 2

[0052] A kind of synthetic method of 4,7-diazaspiro[2.5]octane-7-carboxylic acid tert-butyl ester, comprises the steps:

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

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

[0055] (2) Synthesis of monoethyl 1,1-cyclopropanedicarboxylate:

[0056] In a 2L three-necked reaction flask, add 255.3g of 1,1-diethyl cyclopropanedicarboxylate, 840mL EtOH, cool it down to 0°C ...

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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 chemically synthesizing N-containing heterocyclic drug intermediates, in particular to a synthesis method of 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 synthetic raw material for 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, protein kinase inhibitors and their preparation pharmaceutical ingredients can treat heart failure and cancer, tyrosine kinases, especially JAK kinase inhibitors , and the preparation of some antiviral drugs and antihypertensive drugs are all applied to tert-butyl 4,7-diazaspiro[2.5]octane-7-carboxylate. In recent years, a series of pharmaceutically active groups synthesized from tert-butyl 4,7-diazaspiro[2.5]octane-7-carb...

Claims

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Application Information

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