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Synthesis method of 6, 6-dimethyl-3-azabicyclo [3.1. 0] hexane

An azabicyclo and a synthesis method technology, which is applied in the field of synthesis of 6,6-dimethyl-3-azabicyclo[3.1.0]hexane, can solve the problem of fewer carronic anhydride manufacturers, high energy consumption, The problem of high price, to achieve the effect of less pollution of three wastes, simple post-processing, and low environmental cost

Active Publication Date: 2022-03-01
NANJING CHEMPION BIOTECHNOLOGY CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] This route uses caronic anhydride as the starting material, which is obtained by reducing the carbonyl group after ammonolysis and cyclization. There are few manufacturers of caronic anhydride, the product monopoly is serious, and the price is high
In addition, caronic anhydride is cis-trans caron diacid obtained by oxidizing the double bond of methyl chrysanthemum acid. When preparing caron acid anhydride, a high temperature of 190~200 degrees is required to isomerize the trans diacid to cis diacid and then It can be dehydrated into acid anhydride, high temperature reaction requires special equipment, takes a long time and consumes a lot of energy

Method used

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  • Synthesis method of 6, 6-dimethyl-3-azabicyclo [3.1. 0] hexane
  • Synthesis method of 6, 6-dimethyl-3-azabicyclo [3.1. 0] hexane
  • Synthesis method of 6, 6-dimethyl-3-azabicyclo [3.1. 0] hexane

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] Example 1: Compound Synthesis

[0050]

[0051] Add the compound to the three-neck flask (50.00 g, 396mmol), water (100ml, 2V), sodium hydroxide (31.7g, 793mmol, 2.0eq) was dissolved in 100ml of water (2V) at room temperature and added dropwise to the substrate, stirred at room temperature for 2 h, added Sodium bromide (2.04g, 19.8mmol, 0.05eq), lower the temperature to 0-10 degrees, add sodium hypochlorite (available chlorine concentration 10%, 422g, 1.19mol, 3.0eq) dropwise, after the addition is completed, the temperature is naturally raised at room temperature for 5 hours, Adjust the pH to 2~3 with concentrated hydrochloric acid, concentrate until solids are precipitated, cool down to 0~10°C, stir and crystallize for 2 hours, filter with suction, soak and wash the filter cake with water (50ml), drain and dry to obtain the compound (51.99g, 82.76%).

Embodiment 2

[0052] Example 2: Compounds Synthesis

[0053]

[0054] Add the compound to the three-neck flask (30.00 g, 238mmol), water (90ml, 3V), potassium carbonate (131.6g, 952mmol, 4.0eq) dissolved in water (400ml, 13V) and added dropwise to the substrate, stirred at room temperature for 4h, cooled to 0 ~10°C, add potassium permanganate (56.4, 357mmol, 1.5eq) in batches, react at room temperature for 7 hours, filter, wash the filter cake with water, adjust the pH of the combined filtrate to 2~3 with concentrated hydrochloric acid, and concentrate until there is a solid Precipitate, lower the temperature to 0-10 degrees, stir and crystallize for 2h, filter with suction, soak and wash the filter cake with water (50ml), drain and dry to obtain the compound (30.21g, 80.33%).

Embodiment 3

[0055] Example 3: Compounds Synthesis

[0056]

[0057] Add the compound to the three-neck flask (45.50g, 360mmol), methanol (90ml, 2V), lithium hydroxide (25.9g, 1.08mol, 3.0eq) dissolved in methanol (220ml, 5V) and added dropwise to the substrate, stirring at 30~40 degrees React for 3 hours, cool down to 0-10°C, add sodium bromide (1.85g, 18mmol, 0.05eq), cool down to 0-10°C, add dropwise sodium hypochlorite (available chlorine concentration 10%, 383g, 1.08mol, 3.0eq) , after the addition, react at room temperature for 8 hours, adjust the pH to 2~3 with concentrated hydrochloric acid, filter, evaporate the solvent from the filtrate, add water (45ml) to cool down to 0~10 degrees, stir and crystallize for 2 hours, wash with suction, drain, and dry dry compound (44.5g, 78%).

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Abstract

The invention relates to the technical field of drug intermediates, in particular to a synthesis method of 6, 6-dimethyl-3-azabicyclo [3.1. 0] hexane, 6, 6-dimethyl-3-oxazolo [3.1. 0] hexane-2-ketone is used as a raw material, the 6, 6-dimethyl-3-azabicyclo [3.1. 0] hexane is prepared through hydrolysis, oxidation, dehydration, ammonolysis cyclization and reduction, the 6, 6-dimethyl-3-azabicyclo [3.1. 0] hexane is used as a raw material, and the 6, 6-dimethyl-3-azabicyclo [3.1. 0] hexane is used as a raw material for preparing the 6, 6-dimethyl-3-azabicyclo [3.1. 0] hexane. The synthesis method comprises the following steps of: synthesizing 6, 6-dimethyl-3-oxazole ring [3.1. 0] hexane-2-ketone as a compound as shown in a formula, and 6, 6-dimethyl-3-azabicyclo [3.1. 0] hexane as a compound as shown in a formula in the specification according to a specific synthesis route as follows: synthesizing 6, 6-dimethyl-3-oxazole ring [3.1. 0] hexane-2-ketone as shown in a formula in the specification; the method has the advantages that starting materials are cheap and easy to obtain, the obtained key intermediate is cis-form and can be subjected to ring closing at room temperature, 200-DEG C high-temperature conditions are avoided, post-treatment of the intermediate is simple, pollution of three wastes is less, energy consumption is low, environment cost is low, and the method is suitable for industrial production.

Description

technical field [0001] The present invention relates to a kind of synthetic method of 6,6-dimethyl-3-azabicyclo[3.1.0]hexane, specifically relates to a kind of 6,6-dimethyl-3-oxazole ring A method for synthesizing 6,6-dimethyl-3-azabicyclo[3.1.0]hexane with [3.1.0]hexane-2-one as the starting material. 6,6-Dimethyl-3-azabicyclo[3.1.0]hexane is an important intermediate in the synthesis of Nirmatrelvir (PF-07321332), the main component of the new oral antiviral drug Paxlovid. Background technique [0002] The novel coronavirus pneumonia COVID-19 caused by SARS-Cov-2 has become a worldwide epidemic disease, causing millions of deaths, and the global public health defense and medical system are facing severe challenges. [0003] After layers of transformation, scientists finally obtained the compound Nirmatrelvir (PF-07321332) with better antiviral activity and higher bioavailability. Nirmatrelvir (PF-07321332) inhibits the activity of SARS-CoV-2-3CL protease, can efficiently...

Claims

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Application Information

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IPC IPC(8): C07D209/52C07K5/083
CPCC07D209/52C07K5/0808
Inventor 陈剑余长泉顾榕周文业邱亚涛祝俊李丹李斌
Owner NANJING CHEMPION BIOTECHNOLOGY CO LTD
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