阅读说明：本技术 一种异喹啉衍生物的制备方法及应用 (Preparation method and application of isoquinoline derivative ) 是由 金晴昊 龚戬芳 孙昕皓 于 2019-10-10 设计创作，主要内容包括：本发明涉及药物合成领域,针对现有技术的发明物分子活性不足及合成路线较长的问题,公开了一种异喹啉衍生物的制备方法及应用,包括以下步骤：(<I>S</I>)-<I>N,N</I>,1-三苯基-3,4-二氢异喹啉-2(1<I>H</I>)-甲酰胺的合成,以(<I>S</I>)-1-苯基-1,2,3,4-四氢异喹啉羧酸乙酯和二苯胺为原料,通过上述一步制得(<I>S</I>)-<I>N,N</I>,1-三苯基-3,4-二氢异喹啉-2(1<I>H</I>)-甲酰胺。本发明既引入了异喹啉母核,到抗炎和镇痛活性强,副作用低的化合物(<I>S</I>)-<I>N,N</I>,1-三苯基-3,4-二氢异喹啉-2(1<I>H</I>)-甲酰胺；该药物的合成路线短,且成本较低,并且该工艺的可控性好,易于实际大规模工业化量产,制得的产品收率高,纯度高。(The invention relates to the field of drug synthesis, and discloses a preparation method and application of an isoquinoline derivative aiming at the problems of insufficient molecular activity and long synthetic route of an invention in the prior art, wherein the preparation method comprises the following steps: ( S )‑ N,N 1-triphenyl-3, 4-dihydroisoquinoline-2 (1) H ) -synthesis of formamide by S ) (1-phenyl-1, 2,3, 4-tetrahydroisoquinoline carboxylic acid ethyl ester and diphenylamine are used as raw materials to prepare (I) through the one-step process S )‑ N,N 1-triphenyl-3, 4-dihydroisoquinoline-2 (1) H ) -formamide. The invention not only introduces isoquinoline mother nucleus, but also is a compound (I) with strong anti-inflammatory and analgesic activity and low side effect S )‑ N,N 1-triphenyl-3, 4-dihydroisoquinoline-2 (1) H ) -a formamide; the medicine has the advantages of short synthetic route, low cost, good controllability of the process, easy actual large-scale industrial mass production, high yield of the prepared product and high purity.)

1. A preparation method of isoquinoline derivatives is characterized in that the isoquinoline derivatives are (S) -N, N, 1-triphenyl-3, 4-dihydroisoquinoline-2 (1H) -formamide, and comprises the following steps:

2. the method for preparing isoquinoline derivatives according to claim 1, wherein, based on 1.0mmol of (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline carboxylic acid ethyl ester, the raw materials are fed in the following ratios: (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinolinecarboxylic acid ethyl ester, 1.0 mmol; toluene, 28-32 mL; 5.8-5.9mL of diphenylamine; NaH 0.41-0.43 g; saturated NaCl solution, 30-32 mL; 55-65mL of ethyl acetate; 28-32mL of distilled water; 20-22% HCI, 10-12 mL; 1.9-2.1mol/L sodium hydroxide solution; anhydrous sodium sulfate; ethanol;

the preparation process comprises the following steps:

mixing 1.0mmol of (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline carboxylic acid ethyl ester with 28-32mL of toluene, heating and stirring in an oil bath for 1.8-2h, and evaporating the toluene; adding 5.8-5.9mL of diphenylamine and 0.41-0.43g of NaH into the reaction system, heating to 130-140 ℃ for reaction for 2-2.5h, evaporating ethanol generated in the reaction, evaporating to dryness, and reacting for 10-15 min; cooling to room temperature after the reaction is finished, adding 30-32mL of saturated NaCl solution, extracting with ethyl acetate, combining organic extraction layers, washing the organic extraction layer with 28-32mL of distilled water, extracting with 10-12mL of 20-22% HCI again, and adjusting the pH value to 9.5-10 with 1.9-2.1mol/L sodium hydroxide solution; drying with anhydrous sodium sulfate, and recrystallizing with 94-96% ethanol to obtain the final product.

3. The method for preparing an isoquinoline derivative according to claim 2, wherein the oil bath heating temperature is 110-120 ℃.

4. The method for preparing isoquinoline derivatives according to claim 2, wherein the toluene evaporation temperature is 100-105 ℃.

5. The method of claim 2, wherein the number of the ethyl acetate extractions is 2-3, 28-32mL is used for the first extraction, and 14-16mL is used for the subsequent extraction.

6. The method for preparing isoquinoline derivatives according to claim 2, wherein the drying time of the anhydrous sodium sulfate is 12 to 14 hours.

7. The method for preparing isoquinoline derivatives according to claim 2, wherein during the reaction, thin layer chromatography is used to track the reaction progress, and the developing agents used are: a mixture of dichloromethane and methanol, wherein the volume ratio of the dichloromethane to the methanol is 4-5: 1.

8. Use of an isoquinoline derivative according to any one of claims 1 to 7 in the preparation of a medicament having anti-inflammatory and/or analgesic activity.

9. The use according to claim 8, wherein the isoquinoline derivative- (S) -N, N, 1-triphenyl-3, 4-dihydroisoquinoline-2 (1H) -carboxamide has an inhibition rate of 86.3% and exhibits an anti-inflammatory activity; the inhibition rate of analgesic activity was 73.3%, showing analgesic activity.

10. The use of claim 8, wherein the medicament is an injectable medicament.

Technical Field

The invention relates to the field of drug synthesis, in particular to a preparation method and application of an isoquinoline derivative.

Background

Inflammation is a protection mechanism for the body to defend external infection, and is clinically manifested as red swelling and pain at the infected part on the skin surface, and pain is a self-protection mechanism of the body to external adverse stress. At present, anti-inflammatory and analgesic drugs are mainly classified into steroids and non-steroids, however, steroidal anti-inflammatory drugs have obvious side effects in the application process and easily cause dysfunction of endocrine systems of patients, and non-steroidal anti-inflammatory and analgesic drugs have the effects of relieving fever and pain besides the characteristics of high activity and low toxicity, and thus, the anti-inflammatory and analgesic drugs become the key points for research and development of scientists. Isoquinoline compounds have various biological activities, a plurality of medicaments containing isoquinoline parent nucleus are applied to clinic, and the compounds containing isoquinoline ring have anti-inflammatory and analgesic activities according to literature reports.

The patent number CN201710156455.6 discloses a synthesis method of 6-phenylindole [2,1-a ] isoquinoline compound, which comprises the steps of taking indole compound and alkyne bromide as raw materials, taking alkali as an accelerator, adding a palladium catalyst and a ligand, taking an organic solvent as a solvent, heating to 80-130 ℃ under the protection of inert gas, stirring for reaction, cooling to room temperature after the reaction is finished, carrying out reduced pressure distillation and concentration to obtain a crude product, and carrying out column chromatography purification to obtain the 6-phenylindole [2,1-a ] isoquinoline compound.

The invention has the disadvantages of insufficient molecular activity, poor anti-inflammatory and analgesic abilities, longer synthetic route, higher synthetic cost, complex reaction control conditions and more side reactions in the synthetic process.

Disclosure of Invention

The invention aims to overcome the problems of insufficient molecular activity, poor anti-inflammatory and analgesic abilities and long synthetic route of the invention in the prior art, and provides a preparation method and application of an isoquinoline derivative.

In order to achieve the purpose, the invention adopts the following technical scheme:

a preparation method of isoquinoline derivative, wherein the isoquinoline derivative is (S) -N, N, 1-triphenyl-3, 4-dihydroisoquinoline-2 (1H) -formamide, and comprises the following steps:

the amide group can well interact with the action site in the biomacromolecule in the human body.

Preferably, the raw materials are charged according to the following charge ratio of 1.0mmol of (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline carboxylic acid ethyl ester: (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinolinecarboxylic acid ethyl ester, 1.0 mmol; toluene, 28-32 mL; 5.8-5.9mL of diphenylamine; NaH 0.41-0.43 g; saturated NaCl solution, 30-32 mL; 55-65mL of ethyl acetate; 28-32mL of distilled water; 20-22% HCI, 10-12 mL; 1.9-2.1mol/L sodium hydroxide solution; anhydrous sodium sulfate; ethanol;

the preparation process comprises the following steps:

mixing 1.0mmol of (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline carboxylic acid ethyl ester with 28-32mL of toluene, heating and stirring in an oil bath for 1.8-2h, and evaporating the toluene; adding 5.8-5.9mL of diphenylamine and 0.41-0.43g of NaH into the reaction system, heating to 130-140 ℃ for reaction for 2-2.5h, evaporating ethanol generated in the reaction, evaporating to dryness, and reacting for 10-15 min; cooling to room temperature after the reaction is finished, adding 30-32mL of saturated NaCl solution, extracting with ethyl acetate, combining organic extraction layers, washing the organic extraction layer with 28-32mL of distilled water, extracting with 10-12mL of 20-22% HCI again, and adjusting the pH value to 9.5-10 with 1.9-2.1mol/L sodium hydroxide solution; drying with anhydrous sodium sulfate, and recrystallizing with 94-96% ethanol to obtain the final product.

(S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline carboxylic acid ethyl ester and diphenylamine undergo nucleophilic addition-elimination reaction under the catalysis of NaH to obtain the target compound (S) -N, N, 1-triphenyl-3, 4-dihydroisoquinoline-2 (1H) -formamide.

Preferably, the oil bath heating temperature is 110-120 ℃.

In order to ensure that the (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline carboxylic acid ethyl ester can be fully dissolved in toluene, the process is realized by adopting condensation reflux.

Preferably, the toluene evaporation temperature is 100-.

Preferably, the number of ethyl acetate extractions is 2-3, 28-32mL for the first extraction, followed by 14-16 mL.

Extracting for 2-3 times, wherein the multiple extractions are to ensure that the reaction product can be fully obtained, the first use amount of ethyl acetate is more because the first extraction product is more, and the subsequent use amount of ethyl acetate is reduced to extract the residual reaction product from the water layer without waste.

Preferably, the drying time of the anhydrous sodium sulfate is 12-14 h.

Preferably, the reaction process is tracked by using thin layer chromatography, and the developing agent is: a mixture of dichloromethane and methanol, wherein the volume ratio of the dichloromethane to the methanol is 4-5: 1.

The isoquinoline derivative is applied to the preparation of anti-inflammatory activity and/or analgesic activity medicines.

Preferably, the isoquinoline derivative- (S) -N, N, 1-triphenyl-3, 4-dihydroisoquinoline-2 (1H) -formamide has an inhibition rate of 86.3 percent and shows certain anti-inflammatory activity. The inhibition rate of analgesic activity was 73.3%, showing analgesic activity.

Preferably, the medicament is an injectable medicament.

Therefore, the invention has the following beneficial effects:

(1) the compound prepared by the reaction contains an isoquinoline parent nucleus and also has an amide group, and the compound has strong anti-inflammatory capability, obvious analgesic effect and low toxic and side effects;

(2) has excellent bioactivity, wherein the amide group contained in the molecular formula is a dominant group, and can well interact with inflammation sites in biological macromolecules

(3) The invention takes (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline carboxylic acid ethyl ester and diphenylamine which are easy to obtain and low in price as raw materials, and obtains the compound isoquinoline derivative- (S) -N, N, 1-triphenyl-3, 4-dihydroisoquinoline-2 (1H) -formamide through simple and efficient synthesis, wherein the compound has a short synthetic route;

(4) the compound has the advantages of low synthesis cost, good controllability of the synthesis process, high synthesis efficiency, easiness in actual large-scale industrial mass production and high purity of the prepared product.

Detailed Description

The invention is further described with reference to specific embodiments.