Method for synthesizing 1-methyl-3-nitro-4-phenyl-2, 6-dipiperidone

A technology of dipiperidone and methylnitroacetamide, applied in the direction of organic chemistry, can solve the problems of high cost of raw materials, cumbersome operation of synthesis methods, and high cost of synthesis, and achieve good diastereoselectivity and synthesis The effect of low cost and simple operation

Inactive Publication Date: 2017-08-29
XIAN MODERN CHEM RES INST
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The above two methods have the following disadvantages: First, the synthesis method is cumbersome to operate and easily generates by-products. For example, in the first method, when the chiral addition intermediate is closed with formaldehyde and amine compounds, not only the nitro α The - position can react, and the α-position of the malonate structure of the substrate can also react, and it is easy to form a bicyclic by-product; the second is that the cost of raw materials is relatively high, such as nitroalkene, β-nitroethylamine and other raw materials, which lack commercialization The source, the cost required for synthesis is relatively high, and a catalyst is required for catalytic ring closure in the reaction; the third is that the diastereoisomer ratio of the products obtained by the above two methods, that is, the dr value, is generally between 2:1 and 25:1 , not very ideal, there is still a lot of room for improvement, too low dr value is not good for the chiral resolution of the compound

Method used

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  • Method for synthesizing 1-methyl-3-nitro-4-phenyl-2, 6-dipiperidone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] Add 59mg (0.5mmol) of N-methylnitroacetamide, 89mg (0.65mmol) of cinnamaldehyde and 25mg (0.25mmol) of triethylamine solution into 4mL of methanol, stir at room temperature for 2 days; spin off the solvent and then react Add 10 mL of dichloromethane solution and 215 mg (1 mmol) of pyridinium chlorochromate to the system, and react for 16 hours. Post-processing: filter out the residue of pyridinium chlorochromate with a small amount of silica gel, and rinse 100 mL with petroleum ether: ethyl acetate = 2:1 After the solvent was spin-dried, it was directly separated by column chromatography to obtain 99 mg of racemic 1-methyl-3-nitro-4-phenyl-2,6-dipiperidone with a yield of 80%. The dr value is 70:1, the product is confirmed by NMR analysis, 1 H NMR(500MHz, CDCl 3 )δ7.42–7.32(m,3H), 7.25–7.20(m,2H), 5.62(d,J=12.0Hz,1H), 4.03(td,J=12.5,4.8Hz,1H), 3.27(s ,3H),3.17-2.91(m,2H). 13 C NMR(125MHz, CDCl 3 )δ168.68,163.59,135.25,129.63,129.10,126.70,90.53,40.13,37.27,27.57.

Embodiment 2

[0020] Add 59mg (0.5mmol) of N-methylnitroacetamide, 89mg (0.65mmol) of cinnamaldehyde and 43mg (0.65mmol) of lithium acetate into 4mL of methanol and stir at room temperature for 3 days; spin off the solvent and add to the reaction system Add 10 mL of dichloromethane solution and 215 mg (1 mmol) of pyridinium chlorochromate, and react for 16 hours. Post-processing: filter out the reaction residue of pyridinium chlorochromate with a small amount of silica gel, rinse 100 mL with petroleum ether: ethyl acetate = 2:1, and spin. After drying the solvent, it was directly separated by column chromatography to obtain 93 mg of racemic 1-methyl-3-nitro-4-phenyl-2,6-dipiperidone with a yield of 75%. The dr value is 50:1.

Embodiment 3

[0022] 120mg (1mmol) of N-methylnitroacetamide, 132mg (1mmol) of cinnamaldehyde and 30mg (0.3mmol) of triethylamine were added to 8mL of ethyl acetate and stirred at room temperature for 2 days; the solvent was spun off to the reaction system Add 20mL of dichloromethane solution and 430mg (2mmol) of pyridinium chlorochromate, and react for 16h. Post-processing: filter off the residue of the pyridinium chlorochromate with a small amount of silica gel, rinse 150mL with petroleum ether: ethyl acetate = 2:1, After the solvent was spin-dried, it was directly separated by column chromatography to obtain 175 mg of racemic 1-methyl-3-nitro-4-phenyl-2,6-dipiperidone with a yield of 70%. The dr value is 70:1.

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Abstract

The invention discloses a method for synthesizing 1-methyl-3-nitro-4-phenyl-2, 6-dipiperidone. The method comprises adding N-methylnitroacetamide, cinnamaldehyde and additives into an organic solvent, carrying out a reaction process at 10-30 DEG C for 24-72h, then distilling to remove the organic solvent, adding dichloromethane and pyridinium chlorochromate into the reaction system, and carrying out a reaction process for 16h to obtain 1-methyl-3-nitro-4-phenyl-2, 6-dipiperidone. The method has the advantages of mild reaction conditions, simple operation and easy availability of raw materials. The 1-methyl-3-nitro-4-phenyl-2, 6-dipiperidone has good diastereoselectivity. The method has a good potential application value in preparation of piperidine drugs or piperidine intermediates.

Description

Technical field [0001] The invention belongs to the field of organic and pharmaceutical intermediate synthesis, and specifically relates to a method for synthesizing 1-methyl-3-nitro-4-phenyl-2,6-dipiperidone. Background technique [0002] Piperidine is an important molecular structure. Many drugs and natural products contain piperidine units. At present, although there have been many studies on the synthesis of piperidine structures with 3-position and 4-position substituents, they often require More synthetic steps, for example: the synthesis of many piperidine compounds is achieved by hydrogenation of pyridine (Org. Synth. 1964, 44, 86). The method of pyridine hydrogenation to synthesize piperidine is conducive to industrial scale-up, but the difficulty lies in the high cost of polysubstituted pyridine raw materials and requires more synthesis steps; Dieckman ester condensation ring closure is another common method for synthesizing polysubstituted piperidine rings ( WO2009010...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/88
CPCC07D211/88
Inventor 王伦王月梅张媛媛宁斌科卫天琪杨翠凤陈涛毛明珍徐泽刚
Owner XIAN MODERN CHEM RES INST
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