A kind of method of synthesizing milrinone

A technology for synthesizing rice and compounds, applied in the field of medicine, can solve problems such as serious pollution, poor operating environment, and non-synthetic routes

Active Publication Date: 2017-11-24
HUNAN SAILONG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] Synthetic route 2 uses a large amount of acetic anhydride, resulting in relatively poor operating environment and serious pollution. It is not an environmentally friendly synthetic route

Method used

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  • A kind of method of synthesizing milrinone
  • A kind of method of synthesizing milrinone
  • A kind of method of synthesizing milrinone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Synthesis of Compound 2

[0049] Add 46.5g of sodium methoxide in 950ml of tetrahydrofuran (THF) solution to the reaction vessel, cool in an ice bath to an internal temperature of 0-5°C, add a solution of 46.5g of acetone and 59.6g of ethyl formate dropwise within 1 hour, and remove the ice after the addition is complete. bath, slowly rose to room temperature within 1h, and concentrated under reduced pressure (not exceeding 50°C). Transfer the concentrate to a reaction vessel, add 400ml aqueous solution of 67g cyanoacetamide and piperidine acetic acid (condensation reaction catalyst), reflux for 2h, cool to room temperature, adjust pH=5 with acetic acid, stand at room temperature overnight, and cool in an ice bath After 45 minutes, it was filtered with suction, washed with ice water three times, and dried in vacuum at 80° C. overnight to obtain 65.5 g of compound 2 as a yellow solid (yield 61.0%).

[0050] 1 H NMR (DMSO-d 6 )δ 12.50 (br s, 1H), 8.03 (d, 1H), 6.21 (d,...

Embodiment 2

[0052] Add 26.2g of compound 2 and 36.5g of NBS in 250ml of dichloroethane solution to the reaction vessel, heat to reflux for 18h, cool to room temperature, filter, the solid is slurried with 500ml of water for 2h, filter, wash with water, and dry in vacuo to obtain 38.4g of compound as a white solid 3 (92.3% yield).

[0053] 1H NMR (DMSO-d 6 )δ12.92(br s,1H), 8.30(s,1H), 2.35(s,3H).

Embodiment 3

[0055] Add 21.3g of compound 3, 12.9g of 4-pyridineboronic acid, 50ml of toluene, 50ml of 2M aqueous sodium hydroxide solution, 2.3g of tetrakis(triphenylphosphine)palladium to the reaction vessel, reflux for 18h under nitrogen atmosphere, cool to room temperature, and add 10ml 50% sodium hydroxide aqueous solution was stirred for 15 minutes, and the water layer was separated. The pH of the water layer was adjusted to about 6 with acetic acid, and a solid was precipitated. The yield was 15.3 g of milrinone (yield 72.5%) as a white solid.

[0056] 1 H NMR (DMSO-d 6 )δ 12.86 (br s, 1H), 8.62 (d, 2H), 8.20 (s, 1H), 7.40 (d, 2H), 2.31 (d, 3H).

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Abstract

The invention discloses a new method for synthesizing milrinone. The method is characterized in that a compound of formula 3 and 4-pyridineboronic acid undergo a Suzuki coupling reaction to synthesize milrinone. The method has the advantages of easily available raw materials, high yield and simple post-treatment.

Description

technical field [0001] The invention belongs to the field of medicine. More specifically, the present invention relates to a novel process for the preparation of 1,6-dihydro-2-methyl-6-oxo-[3,4'dipyridine]-5-carbonitrile (milrinone). Background technique [0002] Milirinone is the general name of 1,6-dihydro-2-methyl-6-oxo-[3,4'dipyridine]-5-carbonitrile, and its structural formula is [0003] [0004] Milrinone is a phosphodiesterase III (PDEIII) inhibitor, a second-generation bispyridine cardiotonic drug that was launched in the United States in 1987. It is a homologue of amrinone and has the same mechanism of action. The cardiotonic activity is 10-30 times that of amrinone, with few adverse reactions, and both oral and intravenous injection are effective. Since its listing, many companies have synthesized milrinone through multiple routes, but there are generally disadvantages such as complicated routes, high starting prices, unobtainable prices, and low yields. [...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D213/85
CPCC07D213/85
Inventor 龙治湘李剑峰朱克明吴彪周文谢雪娟
Owner HUNAN SAILONG PHARMA
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