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Preparation method and intermediate of 3-hydroxyl-5-aryl pyridine-2-formamide derivative

A technology of dimethylformamide and alkyl, which is applied in the field of medicinal chemistry, can solve the problems of unfavorable scale-up production, long synthetic route, cumbersome treatment, etc., and achieve the effects of high total yield, low cost, and shortened reaction steps

Inactive Publication Date: 2015-01-14
CHINA PHARM UNIV
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  • Abstract
  • Description
  • Claims
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AI Technical Summary

Problems solved by technology

[0010] (2) Triflate is used as the Suzuki coupling site, and its synthesis requires the use of relatively expensive N-phenyl bis(imine trifluoromethanesulfonate), which has a high cost;
[0011] (3) The total reaction steps need 7 steps, the synthetic route is long, and the post-reaction treatment is cumbersome, and the multi-step reaction needs to be separated and purified by column chromatography, which is not conducive to industrial scale-up production

Method used

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  • Preparation method and intermediate of 3-hydroxyl-5-aryl pyridine-2-formamide derivative
  • Preparation method and intermediate of 3-hydroxyl-5-aryl pyridine-2-formamide derivative
  • Preparation method and intermediate of 3-hydroxyl-5-aryl pyridine-2-formamide derivative

Examples

Experimental program
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Effect test

Embodiment 1

[0050] Preparation of 2-[3-benzyloxy-5-(4-fluorophenyl)pyridine-2-carboxamido]acetic acid (I-1)

[0051] (1) Preparation of 2-(3-benzyloxy-5-bromopyridine-2-carboxamido)methyl acetate (V-1)

[0052] Intermediate IV (49.3g, 0.16mol) was dissolved in 500mL of dichloromethane, then 60ml of trimethylamine and 1-hydroxybenzotriazole (32.6g, 0.24mol) were added, and after stirring for 10min, 1-ethyl-( 3-Dimethylaminopropyl) carbodiimide hydrochloride (45.9g, 0.24mol), glycine methyl ester hydrochloride (24g, 0.19mmol). Reaction at room temperature for 10h. , after the reaction, washed with saturated sodium bicarbonate (500mL), water (2×500mL) and saturated brine (500mL) respectively. The organic phase was dried over anhydrous sodium sulfate, and after vacuum distillation, the crude product was recrystallized with 95% ethanol to obtain 8.2 g of white solid compound V-15. Yield 96%. m.p.101.2-102.9℃. 1 H-NMR (300MHz, CDCl 3 )δ3.79(s,3H,-OC H 3 ),4.27(d,2H,-NH CH 2 -),5.26(s,...

Embodiment 2

[0058] Preparation of 2-[3-benzyloxy-5-(4-cyanophenyl)pyridine-2-carboxamido]acetic acid (I-2)

[0059] (1) Preparation of 3-benzyloxy-5-bromo-2-cyanopyridine (III)

[0060] Benzyl alcohol (59.08 mL, 0.57 mol) and 60% NaH (2.60 g) were thrown into 1 L of anhydrous THF under ice-cooling conditions, stirred until no bubbles were generated, and reacted at room temperature for 2 h. The reaction solution was added dropwise to a solution of 5-bromo-2-cyano-3-nitropyridine II (100 g, 0.46 mol) in anhydrous THF (0.5 L). After the addition was complete, the reaction was maintained at room temperature for 24 h. After the reaction was completed, water (200 mL) was added to quench the reaction, and the organic solvent in the reaction solution was distilled off under reduced pressure, then dichloromethane (1 L) was added, and water (3×500 mL) and saturated brine (500 mL) were washed successively respectively, Keep the organic phase, dry it over anhydrous sodium sulfate, and distill under ...

Embodiment 3

[0070] Preparation of 2-[3-benzyloxy-5-(3-cyanophenyl)pyridine-2-carboxamido]acetic acid (I-3)

[0071] (1) Preparation of 2-(3-benzyloxy-5-bromopyridine-2-carboxamido)butyl acetate (V-3)

[0072] Intermediate IV (49.3g, 0.16mol) was dissolved in 500mL of toluene, and then 73g of p-dimethylaminopyridine and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate were added (0.24mol), after stirring for 10min, add 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (45.9g, 0.24mol), butyric acid butyl ester hydrochloride (31.98g , 0.19 mol). Reaction at 50°C for 6h. Post-treatment was the same as step (1) of Example 1 to obtain 77 g of white solid compound V-3. Yield 96%. m.p.105.4-107.8℃. 1 H-NMR (300MHz, CDCl 3 )δ0.9(t,3H,-CH 2 CH 3 ),1.45(m,2H,- CH 2 CH 3 ),1.62(m,2H,- CH 2 CH 2 -),4.15(m,2H,-O CH 2 - ),4.25(d,2H,-NH CH 2 -),5.26(s,2H,-Ph CH 2 ),7.28-7.44(m,3H,Ar- H ),7.51-7.53(m,2H,Ar- H ),7.57(d,1H,Py- H ),8.311(s,1H,-N H CO-...

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Abstract

The invention relates to the field of drug synthesis and particularly relates to a preparation method of a 3-hydroxyl-5-aryl pyridine-2-formamide derivative (I) with effect of treating chronic renal anemia. The preparation method is characterized is that a compound (I) is prepared by virtue of three reactions (amidation, coupling reaction and deprotection reaction) by starting from 5-bromine-2-cyan-3-benzyloxy pyridine. The preparation method disclosed by the invention is short in synthesis step, mild in reaction condition, relatively low in cost, convenient in after-treatment and suitable for large-scale production.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a preparation method of 3-hydroxy-5-arylpyridine-2-carboxamide derivatives with a therapeutic effect on chronic renal anemia and a synthetic intermediate thereof. Background technique [0002] Anemia is the most common complication in patients with chronic kidney disease (CKD). Chronic renal anemia not only affects the quality of life of CKD patients, but also is an important factor leading to increased incidence and mortality of cardiovascular diseases. The main cause of chronic renal anemia is insufficient secretion of erythropoietin (EPO). At present, the clinically used drugs for the treatment of chronic renal anemia are mainly biological drugs, such as recombinant human EPO and its structural modifications. However, biological drugs cannot be taken orally, and need to be used in combination with iron, and have side effects such as high blood pressure and vomiting ( Rabino...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/81C07D401/04C07D405/04C07D409/04C07D417/04C07D413/04
CPCC07D213/81C07D401/04C07D405/04C07D409/04C07D413/04C07D417/04
Inventor 张晓进尤启冬雷永华孙昊鹏徐晓莉郭小可
Owner CHINA PHARM UNIV
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