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Green synthesis method of antiviral drug intermediate

A synthesis method and compound technology, applied in organic chemistry methods, chemical instruments and methods, organic compounds/hydrides/coordination complex catalysts, etc. The effect of short, low reaction cost and easy operation

Active Publication Date: 2022-06-28
SHANGHAI HAOYUAN CHEMEXPRESS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] The existing technology has problems such as high cost, low yield, long reaction time, and the use of dangerous reagents. Therefore, it is currently necessary to find a new (1R, 2S, 5S)-6,6-dimethyl-3-nitrogen Synthetic method of heterobicyclo[3.1.0]hexane-2-carboxylate derivative or salt thereof

Method used

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  • Green synthesis method of antiviral drug intermediate
  • Green synthesis method of antiviral drug intermediate
  • Green synthesis method of antiviral drug intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Example 1 Preparation of catalyst

[0054] (1) Preparation of ligands

[0055] 2,6-diacetylpyridine and optionally substituted aniline, in an organic solvent (such as toluene), the reaction is heated to reflux for 24 hours, and concentrated under reduced pressure to obtain a solid, which can be selectively purified to obtain the ligand shown in the following formula III compound;

[0056]

[0057] Formula III

[0058] R 5 Selected from methyl, ethyl, n-propyl, isopropyl or n-butyl.

[0059] For example the preparation of the catalyst 2,6-bis[1-[2-(ethylphenyl)imino]ethyl]pyridine may include:

[0060]

[0061] 2,6-Diacetylpyridine (16.3g, 0.1mol) and 2-ethylaniline (24.3g, 0.2mol) were successively added to a three-necked flask containing 200mL of toluene, and a catalytic amount of p-toluenesulfonic acid (1.72g) was added. , 0.01mol), stirred and mixed, and the reaction solution was heated to reflux for 24h. The reaction solution was directly concentrated to...

Embodiment 2

[0067]

[0068] 1. Preparation of methyl ligand L1 with reference to Example 1, taking methyl ligand L1 and CoBr 2 The catalyst solid is prepared;

[0069] 2. Add 24.6 g of the above catalyst solid and 100 g of the substrate N-Boc-3,4-dehydro-L-proline, dissolve it in a three-necked flask with 1000 mL of anhydrous THF (tetrahydrofuran), replace it with nitrogen, and do a good job of Oxygen operation, mechanical stirring;

[0070] 3. Add 57.2 g of zinc powder into the reaction flask at room temperature, and stir mechanically;

[0071] 4. Stir at room temperature for 20 minutes, at which time the reduced cobalt catalyst in the solution shows a dark purple color;

[0072] 5. Add 235g of 2,2-dibromopropane again, and continue to stir the reaction for 3 hours at room temperature;

[0073] 6. After the reaction finishes, the reaction solution is directly concentrated under reduced pressure to obtain a crude product;

[0074] 7. the crude product is dispersed by adding 10 time...

Embodiment 3

[0076]

[0077] 1. Preparation of methyl ligand L1 with reference to Example 1, taking methyl ligand L1 and CoBr 2 The catalyst solid is prepared;

[0078] 2. Add the above catalyst solid (246 mg, 0.44 mmol), the substrate N-Boc-3,4-dehydro-L-proline (1.0 g, 4.4 mmol), and dissolve it in 25 mL of 10 mL of anhydrous THF. In the three-necked bottle, nitrogen is replaced, anaerobic operation is performed, and magnetic stirring is performed;

[0079] 3. Add zinc powder (572 mg, 8.8 mmol) to the reaction flask at room temperature and stir magnetically;

[0080] 4. Stir at room temperature for 15 minutes, at which time the reduced cobalt catalyst in the solution shows a dark purple color;

[0081] 5. Add 2,2-dibromopropane (2.4 g, 8.8 mmol) again, and continue to stir the reaction for 1 hour at room temperature;

[0082] 6. After the reaction finishes, the reaction solution is directly concentrated under reduced pressure to obtain a crude product;

[0083] 7. The crude produc...

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Abstract

The invention provides a green synthesis method of an antiviral drug intermediate, which comprises the following steps: in the presence of a catalyst, adding zinc powder into a compound as shown in a formula II and carrying out cyclization reaction with dihaloalkane to generate a compound as shown in a formula I; the cyclization reaction does not need to add zinc halide; wherein R1 is selected from H or an amino protecting group, and R2 is selected from heptyl, nonyl, decyl, fluoromethyl, trifluoromethyl, cyclopropyl methyl, C1-C6 alkyl, phenyl, p-fluorophenyl, benzyl, p-nitrobenzyl, 2-phenethyl or naphthyl methyl; r3 and R4 are independently selected from hydrogen or C1-C6 alkyl, and R3 and R4 can be connected to form an aliphatic ring containing 3-10 carbon atoms. The synthesis method has the advantages of short steps, no use of dangerous and expensive materials, high reaction conversion rate, short reaction time and simplicity and convenience in operation; the production cost and the post-treatment cost are reduced, and the cost advantage is obvious; the compound can be widely used for preparing antiviral drugs such as nemategravir, boceprevir or nalaprevir, and has a good market prospect. Formula II and formula I

Description

technical field [0001] The present application relates to the technical field of drug synthesis, in particular to a green synthesis method of an antiviral drug intermediate. Background technique [0002] (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate methyl ester or salt, a synthetic antiviral drug nirmatrelvir , an important intermediate of boceprevir and narlaprevir, its structural formula is as follows: [0003] [0004] WO2021250648A1 discloses the following preparation methods, and the synthetic route diagram is as follows: [0005] [0006] In this preparation, the reaction mixture was stirred at room temperature for 5 days, then filtered through celite and rinsed with tetrahydrofuran. Finally, through extraction, washing, drying and concentration, a yellow oily product was obtained with a yield of 75%. [0007] CN 114057627A discloses the following steps: [0008] [0009] Wherein the third step to prepare compound V uses n-butyllithium a...

Claims

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Application Information

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IPC IPC(8): C07D209/52C07D209/96C07F15/06B01J31/22
CPCC07D209/52C07D209/96C07F15/065B01J31/1815B01J2531/845B01J2531/0244B01J2231/325C07B2200/07Y02P20/55
Inventor 夏斌汪佳明张宪恕蔡伶俐王子坤曹铭杨绍波高强郑保富
Owner SHANGHAI HAOYUAN CHEMEXPRESS
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