阅读说明：本技术 樟脑基嘧啶类化合物的合成及其抗肿瘤活性 (Synthesis of camphoryl pyrimidine compounds and antitumor activity thereof ) 是由 王石发 张燕 徐徐 王忠龙 谷文 杨益琴 徐海军 匡红波 周新成 于 2018-05-30 设计创作，主要内容包括：本发明公开了樟脑基嘧啶类化合物及其制备方法和抗肿瘤活性研究。本发明利用樟脑为原料,在碱性催化条件下,分别与不同的芳香醛进行羟醛缩合反应得到系列α,β-不饱和酮,再经叔丁醇钾催化,与盐酸胍发生成环反应得到系列樟脑基嘧啶类化合物,并对所合成的樟脑基嘧啶类化合物进行了抗肿瘤活性的研究。实验表明,樟脑基嘧啶类化合物对人多发性骨髓瘤细胞(RPMI-8226)、人乳腺癌细胞(MDA-MB-231)和人非小细胞肺癌细胞(A549)具有较好的抑制活性,且对正常细胞人胃粘膜细胞(GES-1)毒性较小,具有潜在的抗肿瘤应用价值。(the invention discloses a camphor pyrimidine compound, a preparation method thereof and antitumor activity research. The camphor is used as a raw material, the camphor and different aromatic aldehydes are subjected to aldol condensation reaction under the alkaline catalysis condition to obtain a series of alpha, beta-unsaturated ketones, the alpha, beta-unsaturated ketones and guanidine hydrochloride are subjected to cyclization reaction under the catalysis of potassium tert-butoxide to obtain a series of camphor-based pyrimidine compounds, and the research on the anti-tumor activity of the synthesized camphor-based pyrimidine compounds is carried out. Experiments show that the camphor-based pyrimidine compounds have good inhibitory activity on human multiple myeloma cells (RPMI-8226), human breast cancer cells (MDA-MB-231) and human non-small cell lung cancer cells (A549), have low toxicity on normal cells, human gastric mucosal cells (GES-1) and have potential anti-tumor application value.)

1. The camphor-based pyrimidine compound is characterized in that the structural general formula of the compound is as follows:

4-alkyl-8, 9, 9-trimethyl-5, 6, 7, 8-tetrahydro-5, 8-methanoquinazolin-2-amines

In the formula: r is a group such as a 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 2-chlorophenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 2-bromophenyl group, 3-bromophenyl group, 4-bromophenyl group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 2-methoxyphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl group, 2-hydroxyphenyl group, 3-hydroxyphenyl group, 4-hydroxyphenyl group, 2-pyridyl group, 3-pyridyl group, 4-dimethylaminophenyl group, 4-nitrophenyl group, or phenyl group.

2. A process for the preparation of the camphorpyrimidine compounds of claim 1, comprising the process steps of:

(1) Performing aldol condensation reaction on camphor serving as a starting material and potassium tert-butoxide serving as a catalyst and an aromatic aldehyde derivative to obtain a 3-arylmethylene camphor compound;

(2) The 3-arylmethylene camphor compound and guanidine hydrochloride are subjected to cyclization reaction under the catalysis of potassium tert-butoxide to obtain the camphor pyrimidine compound.

3. The process for producing 3-arylmethylenecamphors according to claim 2, wherein the step (1) is carried out by the following steps:

1) Sequentially adding camphor (8mmol), tert-butyl alcohol (35mL) and potassium tert-butoxide (8-16 mmol) into a 50mL three-neck flask provided with a magnetic stirrer, a thermometer and a reflux condenser tube, and starting the stirrer;

2) Adding aromatic aldehyde (10mmol) after the camphor and the potassium tert-butoxide are dissolved, heating and refluxing for reaction for several hours until the camphor conversion rate reaches more than 95 percent (GC tracking detection);

3) After the reaction is finished, concentrating the reaction liquid to remove tert-butyl alcohol, adding ethyl acetate, washing the reaction liquid with distilled water and saturated saline water respectively to be neutral, drying the reaction liquid with anhydrous Na ₂ SO ₄, and filtering and concentrating the reaction liquid to obtain a crude product of the 3-arylmethylidene camphor;

4) Recrystallizing the crude product with methanol to obtain the 3-arylmethylidene camphor compound.

4. The process for preparing camphorylpyrimidines according to claim 2, wherein the specific process in the step (2) is as follows:

1) Guanidine hydrochloride (8mmol), tert-butanol (35mL) and potassium tert-butoxide (12mmol) are added in sequence to a 50mL three-necked flask equipped with a magnetic stirrer, a thermometer and a reflux condenser, and stirring is started to dissolve the guanidine hydrochloride and the potassium tert-butoxide;

2) Adding 3-arylmethylidene camphor (2mmol), heating and refluxing for reaction for several hours, and adopting TLC to track and detect;

3) After the reaction is finished, concentrating the reaction liquid to remove tert-butyl alcohol, adding ethyl acetate, washing the reaction liquid with distilled water and saturated saline water respectively to be neutral, drying the reaction liquid with anhydrous Na ₂ SO ₄, and filtering and concentrating the reaction liquid to obtain a crude camphor-based pyrimidine compound;

4) Recrystallizing the crude product by methanol to obtain the camphor-pyrimidine compounds.

5. The camphorpyrimidine compounds of claim 1 have good inhibitory activity against human multiple myeloma cells (RPMI-8226), human breast cancer cells (MDA-MB-231), and human non-small cell lung cancer cells (A549), and are potentially useful as antitumor compounds.

Technical Field

The invention belongs to the technical field of organic synthesis and pharmaceutical synthesis, and relates to synthesis of camphor-based pyrimidine compounds and antitumor activity thereof.

background

Tumors are the first killers harmful to human health, so the antitumor drugs are the key points for the research and development of new drugs. Due to the diversity of natural product structures and wide physiological activity, obtaining anti-tumor drugs from natural products becomes a popular field for developing anti-tumor drugs at home and abroad. The camphor is a natural product with a high yield in China, the chemical name is 2-camphene, the camphor can be used as an ideal raw material of an optically active compound through rearrangement reaction, functional action on C and breakage of C-C bonds, the research on the camphor is more in the field of chiral catalysis, but the research on introducing the camphor into the field of medicine is relatively less.

The pyrimidine compounds are important biological endogenous substances, and three pyrimidine derivatives exist in nucleic acid: thymine (thymine), cytosine (cytosine) and uracil (uracil), wherein the pyrimidine compounds have more modifiable sites in the structure, a large number of pyrimidine compounds can be synthesized, and the compounds form antagonism with the pyrimidine in nucleic acid by utilizing the principles of biological electron isosteres and the like to interfere and inhibit the synthesis of nucleic acid in organisms such as fungi, tumor cells or insects, so that the compounds have wide research and application in the fields of pesticides and medicines. In recent years, with the intensive research of pyrimidine compounds, a large number of pyrimidine antitumor drugs are reported, but only a small number of pyrimidine antitumor drugs can enter clinical tests due to large toxic and side effects.

disclosure of Invention

The purpose of the invention is as follows: aiming at the defects in the prior art, the invention aims to search a pyrimidine compound which is prepared from natural product camphor serving as a raw material, has potential anti-tumor activity and low toxicity. The invention also aims to provide a preparation method of the camphor-based pyrimidine compound. The invention also aims to provide application of the camphor-based pyrimidine compound.

The technical scheme is as follows:

The camphor-based pyrimidine compound has a structural general formula as follows:

in the formula: r is a group such as a 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 2-chlorophenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 2-bromophenyl group, 3-bromophenyl group, 4-bromophenyl group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 2-methoxyphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl group, 2-hydroxyphenyl group, 3-hydroxyphenyl group, 4-hydroxyphenyl group, 2-pyridyl group, 3-pyridyl group, 4-dimethylaminophenyl group, 4-nitrophenyl group, or phenyl group.

The preparation method of the camphor-based pyrimidine compound comprises the following process steps:

(1) Camphor is used as a starting material, potassium tert-butoxide is used as a catalyst, and the camphor and different aromatic aldehydes are subjected to aldol condensation reaction to obtain a 3-arylmethylene camphor compound;

(2) The 3-arylmethylene camphor compound and guanidine hydrochloride are subjected to condensation cyclization reaction under the catalysis of potassium tert-butoxide to obtain the camphor pyrimidine compound.

The preparation method of the 3-arylmethylene camphor compound comprises the following specific synthetic steps:

1) Sequentially adding camphor (8mmol), tert-butyl alcohol (35mL) and potassium tert-butoxide (8-16 mmol) into a 50mL three-neck flask provided with a magnetic stirrer, a thermometer and a reflux condenser tube, and starting the stirrer;

2) Adding aromatic aldehyde (10mmol) after the camphor and the potassium tert-butoxide are dissolved, heating and refluxing for reaction for several hours until the camphor conversion rate reaches more than 95 percent (GC tracking detection);

3) After the reaction is finished, concentrating the reaction liquid to remove tert-butyl alcohol, adding ethyl acetate, washing the reaction liquid with distilled water and saturated saline water respectively to be neutral, drying the reaction liquid with anhydrous Na ₂ SO ₄, and filtering and concentrating the reaction liquid to obtain a crude product of the 3-arylmethylidene camphor;

4) recrystallizing the crude product with methanol to obtain the 3-arylmethylidene camphor compound.

The preparation method of the camphor-based pyrimidine compound comprises the following specific synthetic steps:

1) guanidine hydrochloride (8mmol), tert-butanol (35mL) and potassium tert-butoxide (12mmol) are added in sequence to a 50mL three-necked flask equipped with a magnetic stirrer, a thermometer and a reflux condenser, and stirring is started to dissolve the guanidine hydrochloride and the potassium tert-butoxide;

2) Adding 3-arylmethylidene camphor (2mmol), heating and refluxing for reaction for several hours, and adopting TLC to track and detect;

3) after the reaction is finished, concentrating the reaction liquid to remove tert-butyl alcohol, adding ethyl acetate, washing the reaction liquid with distilled water and saturated saline water respectively to be neutral, drying the reaction liquid with anhydrous Na ₂ SO ₄, and filtering and concentrating the reaction liquid to obtain a crude camphor-based pyrimidine compound;

4) recrystallizing the crude product by methanol to obtain the camphor-pyrimidine compounds.

The camphor pyrimidine compound has good inhibitory activity on human multiple myeloma cells (RPMI-8226), human breast cancer cells (MDA-MB-231) and human non-small cell lung cancer cells (A549), and can be used as an anti-tumor compound with potential.

the invention has the advantages that:

(1) The camphor raw material is cheap and easy to obtain, has rich sources and is beneficial to industrial production;

(2) The camphor pyrimidine compound has simple synthesis process, high selectivity and yield and high solvent recovery rate, and meets the requirement of sustainable development;

(3) Compared with positive control etoposide, the camphoryl pyrimidine compound has the advantages of equivalent activity and lower toxicity than the etoposide.

Detailed Description

The present invention will be further described with reference to the following specific examples.