CN103086965A - Niacin p-acetylamino phenyl ester compound and synthesis method thereof - Google Patents

Abstract

The invention belongs to the technical field of medicine synthesis, and in particular relates to a nicotinic acid p-acetamidophenyl ester compound and a synthesis method thereof. A synthetic method for nicotinic acid p-acetaminophenyl ester compound, the method uses nicotinic acid and paracetamol as raw materials, under the presence of condensing agent DCC, under the action of organic amine catalyst in an organic solvent not containing active hydrogen at normal temperature or under heating Condensation reaction in the system. The invention has the advantages of simple method, mild reaction conditions, simple and easy operation, high yield, easy separation of by-products, relatively easy separation of substrates, good product quality, high yield and low cost, and is suitable for large-scale industrial production Methods.

Description

Nicotinic acid p-acetamidophenyl ester compound and its synthesis method

technical field

The invention belongs to the technical field of medicine synthesis, and in particular relates to a nicotinic acid p-acetamidophenyl ester compound and a synthesis method thereof. the

Background technique

Nicotinic acid p-acetamidophenyl is a synergistic prodrug designed and synthesized based on the principle of prodrug design and structure combination. After entering the human body, it can be gradually hydrolyzed by esterase in the small intestine, releasing free niacin and Paracetamol, they can not only show their respective physiological activities, but also have synergistic effects. Niacin is a B vitamin. When the dosage exceeds the dosage used as a vitamin, it can significantly regulate blood lipids. It is a blood lipid regulating drug with a certain curative effect, but because niacin requires a large amount of treatment, it is prone to facial flushing, itching, It induces side effects such as ulcer disease, aggravation of diabetes and gout, which limits its clinical application. The role of niacin in dilating small blood vessels in the skin is due to its increase in the synthesis of endogenous prostaglandins. Paracetamol is just an inhibitor of prostaglandin synthase, which can relieve skin flushing, itching and other symptoms caused by niacin; Release effect, slow decomposition in the body, long-term stable drug effect, solves the side effect problem of vasodilation that is too fast and easily causes blood vessel rupture when niacin is used alone. In summary, nicotinic acid p-acetaminophenyl can be used as a new type of blood lipid-lowering drug. the

With the advent of the aging of the social population, the proportion of hypertension and other diseases caused by hyperlipidemia in the cardiovascular diseases of the elderly is increasing year by year, which seriously threatens people's life safety. Therefore, seeking effective, safe and reliable hypolipidemic drugs has always been one of the long-term and popular research topics in the medical field. the

Regarding the synthesis method of nicotinic acid p-acetamidophenyl ester, what is currently reported in the literature is to adopt a chemical two-step synthesis method, and the synthesis route is as follows:

。

.

Using nicotinic acid, thionyl chloride, and p-acetaminophen as raw materials, first react nicotinic acid and thionyl chloride under the catalysis of DMF to prepare nicotinic acid chloride hydrochloride, and then under the condition of ice-salt bath, the organic amine As a catalyst, react with paracetamol in acetone solvent to obtain the crude product, and obtain the product after ethanol recrystallization with a yield of 26.7%. This route has the problems of low esterification rate, harsh operating conditions of ice-salt bath, and high production cost. At the same time, thionyl chloride is a light yellow or light red liquid with a pungent odor and is toxic. Its vapor will irritate the eyes and mucous membranes, and damage the bronchial mucous membranes. The operating environment will be very harsh and will hinder industrial production. the

Contents of the invention

In order to solve the above-mentioned technical problems, the object of the present invention is to provide a kind of method for preparing nicotinic acid p-acetamidophenyl ester, and this method is simple, and reaction condition is mild, easy and simple to handle, simultaneously, product quality is good, yield is high, The cost is low, and it is suitable for large-scale industrial production. the

In order to achieve the above object, the present invention adopts the following technical solutions:

A synthetic method for nicotinic acid p-acetaminophenyl ester compound, the method uses nicotinic acid and paracetamol as raw materials, under the presence of condensing agent DCC, under the action of an organic amine catalyst, in an organic solvent not containing active hydrogen at normal temperature or under heating It is prepared by condensation reaction, and its chemical reaction equation is as follows:

.

Preferably, the substance ratio of the aforementioned niacin to acetaminophen and DCC is 1˜1.4:1:1. the

Preferably, the above-mentioned organic solvent is a mixture of one or more of DMF, acetone, dichloromethane, triethylamine, pyridine and DMSO. the

Preferably, the amount of the above-mentioned organic solvent is 2-10 times the mass of paracetamol. the

Preferably, the above-mentioned organic amine catalyst is a mixture of one or more of 4-N.N-dimethylaminopyridine, triethylamine, N,N-dimethylaniline and p-toluamide. the

Preferably, the above-mentioned catalyst is 4-N.N-dimethylaminopyridine or N,N-dimethylaniline. the

As a preference, the above-mentioned method also includes a refining process, and the said refining adopts the method of ethanol recrystallization. the

The present invention adopts above-mentioned technical scheme, adopts one-step method to simplify synthetic route, and method is simple, and reaction condition is gentle, and easy to operate, reactant and condensing agent equimolar reaction, productive rate is high, even if there is a small amount of water in the system It does not affect the generation of acylated products, and the by-product dicyclohexylurea is neither soluble in water nor in organic solvents, and is easy to separate; at the same time, the product nicotinic acid p-acetamidophenyl is insoluble in water, while the separation of the substrate is relatively easy, and the product quality Good, high yield, low cost, suitable for large-scale industrial production method. the

Description of drawings

Fig. 1 is the H NMR spectrum of nicotinic acid p-acetamidophenyl ester prepared in the present invention. the

Fig. 2 is the infrared spectrogram (KBr) of the p-acetamidophenyl nicotinate prepared in the present invention. the

Detailed ways

The technical solutions of the present invention are described below with specific examples, but the protection scope of the present invention is not limited thereto. the

The feeding molar ratio is niacin:paracetamol:DCC=1.1:1:1. the

Under anhydrous conditions, add 2.25g niacin, 3.42gDCC, 1gDMAP, and 2.5g paracetamol into a three-necked flask, add an appropriate amount of anhydrous acetone to dissolve at room temperature, stir for 3 hours, filter, and pour the filtrate Pour into an appropriate amount of ice water to precipitate white crystals, filter and dry to obtain 3.48 g of nicotinic acid p-acetamidophenyl ester (II), with a yield of 82.08% and a melting point of 145-146°C. the

Please refer to Figure 1 for the H NMR spectrum of p-acetamidophenyl nicotinate. According to the spectrum, the chemical shift and related parameters are listed in the following table 1:

Table 1 ¹ HNMR (CDCl ₃ ) parameters of nicotinic acid p-acetamidophenyl absorption peak δ (ppm) number of small peaks number of hydrogen atoms 1* 1.40 m 6 2 2.18 the s 3 3 7.18 d 2 4 7.49 t 1 5 7.59 t 2 6 7.77 the s 1 7 8.46 d 1 8 8.86 d 1 9 9.38 the s 1

*: This group of hydrogens is the recrystallization solvent peak.

It can be seen from Table 1 that the positions of the absorption peaks are as follows:

HNMR: δ2.1856 (s, 3H, -CH3), 7.1818 (d, 2 H, ArH), 7.5930 (d, 2 H, ArH), 7.4939 (t, 1H, PyC ₅ -H), 7.7681 (s, H, -NHCOCH ₃ ), 8.4605(d, 1H, PyC ₄ -H), 8.8644(d, 1H, PyC ₆ -H), 9.3846(s, 1H, PyC ₂ -H), it is deduced that, with the target product The structure matches.

For the infrared spectrum (KBr) of nicotinic acid p-acetamidophenyl ester, please refer to Figure 2, the unsaturated carbon CH stretching vibration absorption peak at 3303 cm ^-1 , and a group of peaks at 1667, 1555, 1505, 1471 cm ^-1 are benzene rings 1728 cm ^-1 is the stretching vibration absorption peak of the ester carbonyl group, and a group of peaks at 1285 and 1076 cm ^-1 are the stretching vibration absorption peaks of the ester carbon-oxygen bond; 3443 , 1667, 1610 , 1422 cm ^-1 are the stretching vibration absorption peaks of NH, C=O, NH, and CN of acetamide, respectively.

Claims (8)

1. nicotinic acid acetylaminobenzene ester cpds, it is characterized in that: this compound is take nicotinic acid, paracetamol as raw material, under condensing agent DCC exists, under the organic amine catalyst action in the organic solvent that does not contain reactive hydrogen normal temperature or the heating under condensation reaction make, its chemical equation is as follows:

。

2. the synthetic method of nicotinic acid acetylaminobenzene ester cpds, it is characterized in that: the method is take nicotinic acid, paracetamol as raw material, under condensing agent DCC exists, under the organic amine catalyst action in the organic solvent that does not contain reactive hydrogen normal temperature or the heating under condensation reaction make, its chemical equation is as follows:

。

3. the synthetic method of nicotinic acid acetylaminobenzene ester cpds according to claim 2, it is characterized in that: the molar ratio of nicotinic acid and paracetamol, DCC is 1～1.4:1:1.

4. the synthetic method of nicotinic acid acetylaminobenzene ester cpds according to claim 2, it is characterized in that: organic solvent is one or more mixing in DMF, acetone, methylene dichloride, triethylamine, pyridine and DMSO.

5. the synthetic method of according to claim 2 or 4 described nicotinic acid acetylaminobenzene ester cpds is characterized in that: the consumption of organic solvent be the paracetamol quality 2-10 doubly.

6. the synthetic method of nicotinic acid acetylaminobenzene ester cpds according to claim 2, it is characterized in that: the organic amine catalyzer is one or more mixing in 4-N.N-dimethylamino pyridine, triethylamine, DMA, toluoyl amine.

7. the synthetic method of nicotinic acid acetylaminobenzene ester cpds according to claim 2, it is characterized in that: catalyzer is 4-N.N-dimethylamino pyridine or DMA.

8. the synthetic method of nicotinic acid acetylaminobenzene ester cpds according to claim 2, it is characterized in that: the method also comprises treating process, the method for described refining employing ethyl alcohol recrystallization.