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Synthesis method of (3R, 4R)-N-PG-4-methyl-3-methylaminopiperidine

A technology of -N-PG-4-, N-PG-2-, applied in the field of organic synthesis, can solve the problems of high price, expensive raw materials, high safety risk, etc., and achieve control of production cost, simple synthesis route and good reaction conditions mild effect

Inactive Publication Date: 2013-08-21
LUOYANG NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the total yield of this method has increased (49%), the reaction route is longer (8 steps), and the raw materials used are expensive, and the products in each step need to be separated by column chromatography. The body excess (de) is only 71%, all products are liquid, difficult to purify
[0016] It can be seen that the existing methods or raw materials are expensive, or the yield is low, or the safety risk is high, or the reaction route is long, and there are always defects of one kind or another, and no method is suitable for large-scale production

Method used

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  • Synthesis method of (3R, 4R)-N-PG-4-methyl-3-methylaminopiperidine
  • Synthesis method of (3R, 4R)-N-PG-4-methyl-3-methylaminopiperidine
  • Synthesis method of (3R, 4R)-N-PG-4-methyl-3-methylaminopiperidine

Examples

Experimental program
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Effect test

Embodiment 1

[0037] The synthetic method of (3R, 4R)-N-Boc-4-methyl-3-methylaminopiperidine comprises the following steps:

[0038]1) Ring closure: 7.0g 2-butenal (0.1mol), 19.0g N-Boc-2-nitroethylamine (0.1mol), 0.0041g catalyst (0.00001mol, the molar amount is equivalent to 2-butenal 0.01%) and 0.0024g of benzoic acid (0.00002mol) were added to 50mL of water, reacted at 5°C for 0.5 hours, and then raised to room temperature (25°C) for 4 hours; after the reaction, add 0.1mL of trifluoroacetic acid to the system for dehydration, Continue to react for 3 hours at room temperature;

[0039] After the reaction is complete, add saturated sodium carbonate solution to the system to neutralize to a pH value of 6.0, extract with ethyl acetate, combine the extracts, dry over magnesium sulfate and remove the extraction solvent ethyl acetate to obtain (3R,4R)-N - Crude Boc-4-methyl-3-nitro-3,4-dihydropyridine. The crude product does not need to be further separated, and can be directly subjected to ...

Embodiment 2

[0045] The synthetic method of (3R, 4R)-N-Cbz-4-methyl-3-methylaminopiperidine comprises the following steps:

[0046] 1) Ring closure: take 7.0g 2-butenal (0.1mol), 22.4g N-Cbz-2-nitroethylamine (0.1mol), 0.41g catalyst (0.001mol), 0.24g o-chlorobenzoic acid (0.002mol ) into 50mL methanol, react at 0°C for 1 hour, then rise to room temperature (25°C) and react for 5 hours; after the reaction, add 0.1mL trifluoromethanesulfonic acid to the system for dehydration, and continue to react at room temperature for 3 hours;

[0047] After the reaction is completed, add saturated sodium bicarbonate solution to the system to neutralize to a pH value of 6.4, remove methanol and extract with ethyl acetate, combine the extracts, dry with magnesium sulfate, and remove the extraction solvent ethyl acetate to obtain (3R,4R)-N-Cbz--4-Methyl-3-nitro-3,4-dihydropyridine crude product.

[0048] 2) Hydrogenation reduction: Add the crude product obtained in step 1) and 0.5g catalyst (10%Pd / C) int...

Embodiment 3

[0052] The synthetic method of (3R, 4R)-N-Cbz-4-methyl-3-methylaminopiperidine comprises the following steps:

[0053] 1) Ring closure: 7.0g 2-butenal (0.1mol), 33.6g N-Cbz-2-nitroethylamine (0.15mol), 4.1g catalyst (0.01mol), 2.4g m-chlorobenzoic acid (0.02mol ) into ethanol, react at -10°C for 1 hour, then rise to 0°C for 5 hours; after the reaction, add 0.1mL trichloroacetic acid to the system for dehydration, and continue to react at 10°C for 3 hours;

[0054] After the reaction is complete, add saturated sodium phosphate solution to the system to neutralize to a pH value of 6.7, remove ethanol and extract with dichloromethane, combine the extracts, dry with sodium sulfate and remove the extraction solvent dichloromethane to obtain cis- (3R,4R)-N-Cbz--4-Methyl-3-nitro-3,4-dihydropyridine crude product.

[0055] 2) Hydrogenation reduction: dissolve the crude product obtained in step 1) in N,N-dimethylformamide, add 0.1g catalyst (10%Pt / C), hydrogen pressure 0.2MPa, and rea...

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Abstract

The invention relates to a synthesis method of (3R, 4R)-N-PG-4-methyl-3-methylaminopiperidine, the structural formula of which is as the following, wherein PG is an amino protecting group. The synthesis steps comprise: 1) cyclization: putting 2-butenal, N-PG-2-nitroethylamine, a catalyst and an organic acid into a reaction medium to react at a temperature ranging from -10 to 50DEG C for 0.5-8h; at the end of the reaction, adding an acid into the system to undergo dehydration, and letting the substances further react for 1-5h at 10-50DEG C so as to obtain (3R, 4R)-N-PG-4-methyl-3-nitro-3, 4-dihydropyridine, with the structure of the catalyst shown as the following; 2) subjecting (3R, 4R)-N-PG-4-methyl-3-nitro-3, 4-dihydropyridine to catalytic hydrogenation reduction so as to obtain (3R, 4R)-N-PG-3-amino-4-methylpiperidine; and 3) subjecting the (3R, 4R)-N-PG-3-amino-4-methylpiperidine to a methylation reaction so as to generate the target product.

Description

technical field [0001] The invention belongs to the field of organic synthesis, and in particular relates to a method for synthesizing a chemical intermediate—(3R,4R)-N-PG-4-methyl-3-methylaminopiperidine. Background technique [0002] (3R,4R)-N-substituted-4-methyl-3-methylaminopiperidine is an important organic chemical intermediate in the synthesis of some optically active chiral drugs (such as CP-690550) It plays a very important role, and its structural formula is: Among them, PG is an amino protecting group, which can be tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) and other groups. [0003] At present, the main synthetic methods of this compound are: [0004] 1) The literature Organic Process Research & Development, 2003, 7(1), p115-120, adopted the following synthetic route: [0005] [0006] 4-picoline was protected by benzyl group, selective reduction, oxidation, amination and other steps to obtain cis-(3R,4R)-N-benzyl-4-methyl-3-methylaminopiperidine....

Claims

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Application Information

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IPC IPC(8): C07D211/56C07D211/02
CPCY02P20/55
Inventor 刘金强吉保明
Owner LUOYANG NORMAL UNIV
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