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Preparation method of saxagliptin intermediate

An intermediate and temperature control technology, which is applied in organic chemistry and other fields, can solve problems such as complex operation, high cost, and strict temperature control requirements, and achieve the effects of reasonable process conditions, increased final yield, and simple post-treatment

Inactive Publication Date: 2014-04-16
SHANGHAI INST OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The operation of the process is complex, the temperature control requirements are relatively harsh, and diethyl zinc is expensive, which makes the cost high and the benefit low. Therefore, it is imperative to find an effective method with simple process, mild conditions, low cost and good yield. OK

Method used

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  • Preparation method of saxagliptin intermediate
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  • Preparation method of saxagliptin intermediate

Examples

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Effect test

Embodiment 1

[0033] A preparation method of saxagliptin intermediate (1S, 3S, 5S)-tert-butyl-3-carbamoyl-2-azabicyclo[3.1.0]hexane-2-carboxylate, specifically Including the following steps:

[0034] (1), Preparation of Carbene Reagent A

[0035] Under nitrogen protection, 82g (1.25mol) of zinc powder, 18g (0.125mol) of cuprous bromide, 0.14g (0.6mmol) of iodine particles were successively added to a clean and dry four-necked flask, and 125mL of diethyl ether was added dropwise while stirring. Diiodomethane 0.1g (0.37mmol), heat up to a slight reflux state to initiate the reaction, after the reaction is initiated, the system will continue to exotherm and maintain a slight reflux for 10min, then control the temperature at 28-32°C, and add it at a rate of 1ml / min 151g (0.56mol) of diiodomethane, after the dropwise addition is completed, continue to stir at 28-32°C for 30min, and cool down to 0-5°C to obtain the carbene reagent A;

[0036] The amount of used catalyst iodine, cuprous bromide,...

Embodiment 2

[0047] A preparation method of saxagliptin intermediate (1S, 3S, 5S)-tert-butyl-3-carbamoyl-2-azabicyclo[3.1.0]hexane-2-carboxylate, specifically Include steps:

[0048] (1), Preparation of Carbene Reagent A

[0049] Under the protection of nitrogen, 82 g (1.25 mol) of zinc powder, 18 g (0.125 mol) of cuprous bromide, 0.14 g (0.6 mmol) of iodine particles were successively added to a clean and dry four-necked flask, and 125 mL of tetrahydrofuran was added. Add 0.1g (0.37mmol) of diiodomethane, and raise the temperature to a slight reflux state to initiate the reaction. After the reaction is initiated, the system will continue to exotherm and keep it for 10 minutes, then control the temperature at 28-32°C, and add it at a rate of 1ml / min. 151g (0.56mol) of diiodomethane, after the dropwise addition is completed, continue to stir at 28-32°C for 30min, and cool down to 0-5°C to obtain the carbene reagent A;

[0050] The amount of used catalyst iodine, cuprous bromide, Zn powder...

Embodiment 3

[0058] A preparation method of saxagliptin intermediate (1S, 3S, 5S)-tert-butyl-3-carbamoyl-2-azabicyclo[3.1.0]hexane-2-carboxylate, specifically Include steps:

[0059] (1), Preparation of Carbene Reagent A

[0060] Under nitrogen protection, 82 g (1.25 mol) of zinc powder, 18 g (0.125 mol) of cuprous bromide, 0.14 g (0.6 mmol) of iodine particles were successively added to a clean and dry four-necked flask, and 125 mL of diethyl ether was added, and stirred First add 0.1g (0.37mmol) of diiodomethane dropwise, and raise the temperature to a slight reflux state to initiate the reaction. After the reaction is initiated, the system will continue to exotherm and maintain a slight reflux for 10 minutes, then control the temperature at 28-32°C, and the drop rate is 1ml Add 151 g (0.56 mol) of diiodomethane per minute, after the dropwise addition, continue to stir at 55-60°C for 30 minutes, and cool down to 0-5°C to obtain carbene reagent A;

[0061] The amount of used catalyst io...

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Abstract

The invention discloses a preparation method of a saxagliptin intermediate methyl (1S, 3S, 5S)-tertiary butyl-3-formamyl-2-azabicyclo[3.1.0] hexane-2-carboxylate. The preparation method comprises the following steps: firstly, with iodine as a catalyst, adding cuprous bromide, Zn powder, an organic solvent and diiodomethane, and stirring to obtain a carbene reagent A; then dissolving tert-butyl (S)-tertiary butyl-2-formamyl-2, 3-dihydro-1H-pyrrole-1-formate in an organic solvent to obtain a substrate solution B; finally, mixing the carbene reagent A and the substrate solution B to react to obtain a reaction solution, adding a saturated sodium bicarbonate water solution to the reaction solution, and then sequentially carrying out filtration, extraction, drying and spinning drying to obtain the saxagliptin intermediate methyl (1S, 3S, 5S)-tertiary butyl-3-formamyl-2-azabicyclo[3.1.0] hexane-2-carboxylate. The preparation method disclosed by the invention is simple to operate and mild in reaction conditions, and the cost is reduced while relatively high yield is achieved.

Description

technical field [0001] The present invention relates to the technical field of drug synthesis, in particular to a saxagliptin intermediate (1S,3S,5S)-tert-butyl-3-carbamoyl-2-azabicyclo[3.1.0]hexane- Preparation method of methyl 2-carboxylate. Background technique [0002] Diabetes is a common metabolic endocrine disease, which is a clinical syndrome (chronic, systemic, metabolic disease) caused by the interaction of genetic and environmental factors; it is caused by the absolute or relative lack of insulin in the human body, resulting in hyperglycemia is the main feature; is a lifelong disease. More than 90% of patients with hyperglycemia belong to type II diabetes. Type II diabetes is a heterogeneous disease caused by genetic and environmental factors. Under the influence of insufficient insulin secretion, insulin resistance and intercellular dynamics, it leads to Dysregulation of constant blood sugar levels. Saxagliptin is the third DPP-IV inhibitor developed by Brist...

Claims

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Application Information

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IPC IPC(8): C07D209/52
CPCC07D209/52
Inventor 潘仙华陈苏柯刘烽于万盛于一文徐娜闫茜
Owner SHANGHAI INST OF TECH
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