Preparation method and application of picolinamide

A technology of pyridine amide and picolinamide group, applied in the field of preparation of pyridine amide, can solve the problems of high requirements on reaction vessel, inability to enlarge, inconvenient operation and the like

Active Publication Date: 2020-06-23
SUNSHINE LAKE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] 2. The first step of benzyl alcohol substitution reaction is harsh and cannot be scaled up (microwave reaction, 190°C). In addition, there are one-step hydrogenation reaction and one-step coupling reaction. A total of 5 column chromatography purifications are required, which is inconvenient to operate and expensive
[0013] 1. There are strong acid conditions in the route, which has high requirements on the reaction vessel, which is not conducive to the expansion of production

Method used

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  • Preparation method and application of picolinamide
  • Preparation method and application of picolinamide
  • Preparation method and application of picolinamide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] Synthesis of 3,5-dihydroxy-2-pyridinecarboylhydroxamic acid

[0050] Add methyl 3,5-dihydroxy-2-pyridinecarboxylate (6.0g), hydroxylamine hydrochloride (4.8g), KOH solid (9.9g) and MeOH (methanol, 120mL) into the reaction flask at room temperature. After the reaction was completed, the pH was adjusted to 5-6 with 20% acetic acid aqueous solution, and the organic phase was extracted and separated with 240 mL ethyl acetate, and concentrated to dryness to obtain 5.16 g of solid product, with a yield of 85.50% and a purity of 91.80%.

[0051] MS: [M+1] = 171.1;

[0052]1H NMR (400MHz, DMSO) δ7.67(d, J=2.3Hz, 1H), 6.63(d, J=2.3Hz, 1H), 13CNMR (101MHz, DMSO) δ166.18(s), 158.96(s ), 158.91(s), 130.51(s), 123.05(s), 109.75(s).

Embodiment 2

[0054] Synthesis of (3,5-dihydroxy-2-pyridinecarboxamido)methyl acetate

[0055] Add 3,5-dihydroxy-2-pyridineformylhydroxamic acid (2.0g), iodine element (6.0g), glycine methyl ester hydrochloride (3.0g), triethylamine (3.6g) into the reaction flask at room temperature ) and dimethyl sulfoxide (20.0mL), add and stir the reaction at room temperature. After completion, use 80mL of ethyl acetate to extract and separate liquids to obtain an organic phase. %.

[0056] MS: [M+1] = 227.1;

[0057] 1H NMR (400MHz, DMSO) δ12.27(s, 1H), 10.82(s, 1H), 9.11(t, J=5.9Hz, 1H), 7.77(d, J=2.2Hz, 1H), 6.69( d, J=2.2Hz, 1H), 4.05(d, J=6.1Hz, 2H), 3.66(s, 3H).

Embodiment 3

[0059] Synthesis of Methyl (3-Hydroxy-5-trifluoromethanesulfonyloxy-2-pyridinecarboxamido)acetate

[0060] Add methyl (3,5-dihydroxy-2-pyridinecarboxamido)acetate (1.8g), methanol (54.0mL) and N,N-dimethylformamide (27.0mL) into the reaction flask at room temperature, add After completion, the temperature was lowered to 0°C under the protection of nitrogen, and then N-phenylbis(trifluoromethanesulfonyl)imide (2.8g) and DIPEA (N,N'-diisopropylethylamine, 1.0g) were added, and the After the reaction was completed, 80 mL of ethyl acetate was used to extract and separate the liquid to obtain an organic phase, which was concentrated to dryness to obtain 2.19 g of solid, with a yield of 76.77% and a purity of 94.50%.

[0061] MS: [M+1] = 358.9;

[0062] 1H NMR (600MHz, DMSO) δ12.64(s, 1H), 9.61(s, 1H), 8.43(d, J=2.3Hz, 1H), 7.87(d, J=2.4Hz, 1H), 4.11( d, J=6.2Hz, 2H), 3.68(s, 3H).

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Abstract

The invention provides a preparation method of a picolinamide compound, and belongs to the field of pharmaceutical and chemical industry. According to the preparation method, 3,5-dihydroxypicolinic acid methyl ester, hydroxylamine hydrochloride, an alkali and an organic solvent are mixed, ammonolysis is performed to obtain 3,5-dihydroxyl-2-pyridine formyl hydroxamic acid; and 3,5-dihydroxyl-2-pyridine formyl hydroxamic acid and glycine methyl ester hydrochloride sequentially carry out a reaction, upper protection, coupling and hydrolysis to obtain {[5-(3-chlorphenyl)-3-hydroxypyridine-2-yl]amino} acetic acid. The product produced by the method is high in purity, and high in yield. The process cost is low, the operation is simple, and the process is stable.

Description

technical field [0001] The invention relates to the field of medicine and chemical industry, in particular to a preparation method and application of pyridine amide. Background technique [0002] Vadadustat is a novel titratable oral hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor currently being developed for the treatment of anemia. Vadadustat utilizes the same mechanism of action that the body uses to naturally adapt to low oxygen levels like those caused by increased altitude. At higher altitudes, the body's response to a hypoxic environment is an increase in HIF, which coordinates the interdependent processes of iron mobilization and erythropoietin production to increase red blood cell production and ultimately oxygen delivery. [0003] Vadadustat (Vadadustat), the structural formula is as follows: [0004] [0005] US20070299086 discloses the preparation method of Vadadustat (Vadadustat), specifically as follows: [0006] [0007] There are foll...

Claims

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Application Information

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IPC IPC(8): C07D213/81
CPCC07D213/81Y02P20/55
Inventor 肖清波丘鑫福林碧悦寇景平李英龙孙景伟王仲清罗忠华黄芳芳
Owner SUNSHINE LAKE PHARM CO LTD
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