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Synthetic method of 6-oxo-2-azaspiro[3,3]heptane-2-t-butyl carboxylate

A compound, potassium carbonate technology, applied in the direction of organic chemistry, etc., can solve the problems of low yield of tert-butyl heptane-2-carboxylate, impossibility of large-scale production, difficult purification of intermediates, etc., and achieve high yield and reaction The effect of reasonable process design and mild conditions

Inactive Publication Date: 2012-05-09
PHARMABLOCK SCIENCES (NANJING) INC
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  • Application Information

AI Technical Summary

Problems solved by technology

It mainly solves the existing technical problems of low yield of tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate, difficult purification of intermediates, and inability to mass-produce

Method used

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  • Synthetic method of 6-oxo-2-azaspiro[3,3]heptane-2-t-butyl carboxylate
  • Synthetic method of 6-oxo-2-azaspiro[3,3]heptane-2-t-butyl carboxylate
  • Synthetic method of 6-oxo-2-azaspiro[3,3]heptane-2-t-butyl carboxylate

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Embodiment 1

[0038] Synthesis of compound (15)

[0039]

[0040] Suspend 105g (2.749mol, 1.5eq) lithium aluminum hydride in 4000mL THF, lower the temperature to 0°C, add dropwise 528g compound (14) (1.931mol, 1.0eq) / 1000mL THF, control the temperature not to exceed 20°C, and stir at room temperature after dropping 30min, TLC no starting material. Carefully add 105 mL of water, 105 mL of 15% sodium hydroxide solution, and 105 mL of water to the reaction solution dropwise, filter, wash the filter cake twice with THF, and evaporate the solvent to obtain 310 g of yellow liquid, which is put into the next reaction. Yield 96.2%. 1 H NMR (400 MHz, CDCl3) δ (ppm) 3.69 (s, 4H), 3.32 (s, 2H), 3.13 (s, 6H), 1.94 (s, 4H).

[0041] Synthesis of Compound 18

[0042]

[0043] Compound (15) 500g (2.838mol, 1.0eq) was dissolved in 2500mL pyridine, 1623g TsCl (8.513mol, 3.0eq) was added in batches, the temperature was controlled not to exceed 20°C during the addition, and the mixture was stirred ov...

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Abstract

The invention relates to the chemical synthesis field, and concretely relates to a synthetic method of 6-oxo-2-azaspiro[3,3]heptane-2-t-butyl carboxylate. The synthetic method is characterized in that the synthetic method comprises the following steps: 1, reducing a raw material compound (14) with lithium aluminum hydride; 2, selecting Ts (toluene sulfonyl) protection; 3, carrying out ring closure on the substance obtained in step 2 and o-nitrobenzenesulfonamide under the action of potash to obtain a compound (19); 4, reacting the compound (19) with thiophenol in a solvent DMF (dimethylformamide) under the action of potash to obtain a compound (20); and 5, generating a ketone under acidic conditions, and reacting the ketone with BOC2O (di-tert-butyl dicarbonate) under alkaline conditions to obtain 6-oxo-2-azaspiro[3,3]heptane-2-t-butyl carboxylate. The preparation method of the invention, which allows the yield to be high, the whole yield to reach 41% and conditions to be mild, is a synthetic method with large scale preparation values.

Description

technical field [0001] The invention relates to the field of chemical synthesis, in particular to a synthesis method of tert-butyl 6-oxo-2-azaspiro[3,3]heptane-2-carboxylate. Background technique [0002] Recent drug-like chemical structure analyzes have shown that relatively few structural frameworks occupy most of the so-called chemical diversity space. The lack of structural diversity of molecules in compound libraries limits the possibility of discovering novel leads in drug development. Therefore, it is necessary to find novel and easy-to-synthesize structural modules for novel pharmacodynamic functional groups. Among the 1350 or so small molecule drugs approved by the FDA, 137 have piperidine rings and 73 have piperazine rings. The discovery of structurally similar alternatives to piperidine and piperazine opens up the possibility of expanding the drug-like chemical space and diversity. In fact, 2,6-diazaspiro[3.3]heptane has attracted intense interest in the pharma...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D205/12
Inventor 郭路刘迅刘贵华吴希罕杨民民
Owner PHARMABLOCK SCIENCES (NANJING) INC
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