CN113149917B - Preparation method of triazine compound - Google Patents
Preparation method of triazine compound Download PDFInfo
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- CN113149917B CN113149917B CN202110479051.7A CN202110479051A CN113149917B CN 113149917 B CN113149917 B CN 113149917B CN 202110479051 A CN202110479051 A CN 202110479051A CN 113149917 B CN113149917 B CN 113149917B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
- C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
- C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D251/14—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom
- C07D251/16—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The invention provides a preparation method of a 4-methyl-6-anilino-2-mercapto-1, 3,5-triazine compound shown in formula (I), which comprises the steps of adding sodium into methanol, adding a phenylamidyl thiourea intermediate shown in formula (III) after the sodium is completely dissolved, adding ethyl acetate after reacting for 1-5h at room temperature, continuing to react for 22-40 h at 25-50 ℃, and after the reaction is finished, carrying out aftertreatment treatment on the reaction liquid C to obtain the 4-methyl-6-anilino-2-mercapto-1, 3,5-triazine compound shown in formula (I); the invention develops a preparation method of a 4-methyl-6-anilino 2-mercapto-1, 3,5-triazine compound, and the preparation method has the advantages of mild reaction conditions, easily obtained raw materials, convenient operation and wide industrial application prospect.
Description
(I) technical field
The invention relates to a preparation method of a 4-methyl-6-anilino 2-mercapto-1, 3,5-triazine compound.
(II) background of the invention
Triazine compounds are widely applied to the aspects of insect killing, weeding, sterilization, antivirus and the like due to good biological activity, wherein the mercapto-s-triazine compounds are also widely applied to the fields of materials, medicines and the like, but the reports on the synthesis method of the compounds are less. Among them, 4-methyl-6-anilino-2-mercapto-1, 3,5-triazine compounds are mainly prepared by reacting phenylcyanoguanidine with benzylthionamide, but the yields are low, but only 18%, which limits the application (Journal C P, rajan V P, journal C P, et al, interaction of biochemical with thioamides: formation of 6-alkyl-4-amino-1, 3,5-triazine-2-thiols and amidino (arylamidino) thioureas [ J ] Australian Journal of Chemistry,1974,27 (12): 2627-2634.). Therefore, the development of a novel preparation method of the 4-methyl-6-anilino-2-mercapto-1, 3,5-triazine compound has important practical application value.
Disclosure of the invention
The invention aims to develop a novel preparation method of 4-methyl-6-anilino 2-mercapto-1, 3,5-triazine compound with mild reaction conditions, easily obtained raw materials and convenient operation.
In order to achieve the purpose, the invention adopts the following technical scheme:
the invention provides a preparation method of a 4-methyl-6-anilino-2-mercapto-1, 3,5-triazine compound shown in formula (I),
the technical route is as follows:
the technical route is as follows:
reacting sodium dicyandiamide with aniline to obtain phenyl cyanoguanidine shown in a formula (II); then reacting with sodium thiosulfate to obtain phenylamidyl thiourea shown in the formula (III); finally, condensing the mixture with ethyl acetate under the action of sodium methoxide to obtain the 4-methyl-6-anilino-2-mercapto-1, 3,5-triazine shown in the formula (I).
The method comprises the following steps:
adding sodium into methanol, adding the phenylamidyl thiosemicarbazide intermediate shown in the formula (III) after the sodium is completely dissolved, reacting for 1-5h (preferably 2-5 h, particularly preferably 2 h) at room temperature, adding ethyl acetate, continuing to react for 22-40 h (preferably 25 ℃, 30-40 h, particularly preferably 30 h) at the temperature of 25-50 ℃, and after the reaction is finished, carrying out aftertreatment C on the obtained reaction liquid C to obtain the 4-methyl-6-anilino-2-mercapto-1, 3,5-triazine compound shown in the formula (I); the mass ratio of the phenylamidinothiourea intermediate shown in the formula (III) to the sodium-ethyl acetate is 1:1 to 3:2 to 4 (preferably 1;
preferably, the volume of methanol is 2 to 5mL/mmol (preferably 2 mL/mmol) based on the amount of the substance of the phenylamidylthiourea intermediate represented by the formula (III).
Further, the post-treatment C is as follows: the resulting reaction solution C was concentrated, water was added, extraction was performed 3 times with dichloromethane, organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a petroleum ether: and (3) performing column chromatography separation by using the ethyl acetate mixed solution as an eluent, collecting the eluent containing the target compound, concentrating and drying to obtain the 4-methyl-6-anilino-2-mercapto-1, 3,5-triazine compound shown in the formula (I).
Further, the phenylamidinothiourea intermediate shown in the formula (III) is prepared according to the following method:
(1) Adding aniline into water, adding hydrochloric acid A and dicyandiamide sodium, heating to 70-100 ℃, reacting for 5-12 h (preferably 90 ℃ for 8 h), after the reaction is finished, cooling the obtained reaction liquid A to room temperature, filtering, and drying to obtain a crude product of the phenylcyanoguanidine intermediate shown in the formula (II); the mass ratio of aniline to sodium dicyandiamide to HCl in the hydrochloric acid is 1:1 to 2:0.5 to 2 (preferably 1;
(2) Adding the crude product of the phenylcyanoguanidine intermediate shown in the formula (II) obtained in the step (1) into acetone, adding hydrochloric acid B and sodium thiosulfate, reacting at 15-35 ℃ for 1-5h (preferably at 25 ℃ for 3 h), and carrying out aftertreatment treatment on the obtained reaction liquid B to obtain a phenylamidinothiourea intermediate shown in the formula (III); the mass ratio of the aniline to the hydrochloric acid to the sodium thiosulfate is 1:1 to 3:0.5 to 1.5 (preferably 1;
further, the volume of the water in the step (1) is 0.5 to 2mL/mmol (preferably 1 mL/mmol) based on the amount of the substance of aniline.
Further, the volume of the acetone in the step (2) is 1 to 3mL/mmol (preferably 1.3 mL/mmol) based on the amount of the substance of the aniline in the step (1);
further, the post-treatment B in the step (2) is as follows: the obtained reaction solution B was adjusted to PH =9 with aqueous ammonia, concentrated, and concentrated in a volume ratio of petroleum ether: and (3) performing column chromatography separation by taking the ethyl acetate mixed solution as an eluent, collecting the eluent containing the target compound, concentrating and drying to obtain the phenylguanyl thiourea intermediate shown in the formula (III).
Compared with the prior art, the invention has the beneficial effects that: the invention develops a preparation method of a 4-methyl-6-anilino 2-mercapto-1, 3,5-triazine compound, and the preparation method has the advantages of mild reaction conditions, easily obtained raw materials, convenient operation and wide industrial application prospect. The compound provided by the invention shows certain activity of resisting human breast cancer cells or human non-small cell lung cancer cells, lays a foundation for screening and developing new drugs, and has good practical value.
(IV) detailed description of the preferred embodiments
The invention will now be further illustrated by the following examples, without limiting the scope of the invention thereto.
Example 1: preparation of Compound (I)
(1) Aniline (5.00g, 53.65mmol) was added to water (50 mL), hydrochloric acid (1 mol/L,54mL, 54mmol) and sodium dicyandiamide (4.8g, 53.91mmol) were added, respectively, and the mixture was heated to 90 ℃ for reaction for 8 hours. And cooling the reaction liquid to room temperature, filtering, washing a filter cake with water, and drying to obtain a compound (II).
(2) Adding the compound (II) into acetone (70 mL), adding concentrated hydrochloric acid (8mL, 96mmol) and sodium thiosulfate pentahydrate (11.3g, 45.53mmol) respectively, reacting at room temperature for 3h, adding 10% ammonia water to adjust the pH to be =9 after the reaction is finished, concentrating, separating by column chromatography (eluent is petroleum ether: ethyl acetate =2, volume ratio is 1), collecting eluent containing the target compound, concentrating and drying to obtain a compound (III) (5.00 g).
(3) Sodium (1.06g, 46.09mmol) was added to methanol (30 mL), the compound (III) (3.00g, 15.44mmol) was added after sodium was completely dissolved, ethyl acetate (6.0ml, 61.77mmol) was added after reaction for 2 hours at room temperature, reaction was carried out for 30 hours at room temperature, after completion of the reaction, the reaction solution was concentrated, water was added, extraction was carried out 3 times with dichloromethane, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, separated by column chromatography (eluent: petroleum ether: ethyl acetate =2, volume ratio), the eluent containing the objective compound was collected, concentrated and dried to obtain a 4-methyl-6-anilino 2-mercapto-1, 3,5-triazine compound represented by formula (I) (2.80g, 83%). 1 HNMR(500MHz,DMSO-d6)δ13.17(s,1H),10.34(s,1H),7.82-7.60(m,2H),7.38-7.29(m,2H),7.15-7.06(m,1H),2.28(s,3H)。
Example 2:
the same operation as in example 1 was performed, except that the amount of sodium (1.06g, 46.09mmol) in step (3) was changed to (0.36g, 15.44mmol), to obtain Compound (I) (0.74g, 22% yield)
Example 3:
the operation was as in example 1 except that the amount of ethyl acetate (6.0mL, 61.77mmol) in the step (3) was changed to (3.0mL, 30.88mmol), to obtain Compound (I) (1.28g, 38% yield)
Example 4:
the operation is as in example 1, except that in step (3), after addition of ethyl acetate the reaction temperature is changed from room temperature to 50 ℃ to obtain compound (I) (2.7g, 80% yield)
Example 5:
the procedure of example 1 was repeated except that the reaction time after the addition of ethyl acetate in step (3) was changed from 30 hours to 22 hours to obtain Compound (I) (2.1g, 61% yield)
Example 6:
the same procedure as in example 1 was repeated, except that in the step (3), the reaction time after the addition of the compound (III) was changed from 2 hours to 1 hour, to obtain the compound (I) (1.01g, 30% yield).
Example 7:
the procedure of example 1 was followed, except that in the step (3), the reaction time was changed from 2 hours to 5 hours after the addition of the compound (III), to obtain the compound (I) (2.67g, 79% yield).
Example 8:
the procedure of example 1 was repeated except that in the step (3), the reaction time was changed from 30 hours to 40 hours after the addition of ethyl acetate to obtain Compound (I) (2.73g, 81% yield).
Example 9: biological activity test of human breast cancer cell (T47D) or human non-small cell lung cancer cell (A549)
Human breast cancer cell (T47D) or human non-small cell lung cancer cell (a 549) activity assay: MTT method
The experimental steps are as follows:
1) Preparation of samples: for soluble samples, each 1mg was dissolved in 20. Mu.L DMSO, 2. Mu.L was diluted with 1000. Mu.L of culture medium to a concentration of 100. Mu.g/mL, and then serially diluted with culture medium to the use concentration.
2) Culture of cells
2.1 Preparation of culture medium, each 1000mL of culture medium contains 80 ten thousand units of penicillin, 1.0g of streptomycin and 10% inactivated fetal bovine serum.
2.2 Culture of cells): inoculating tumor cells into cultureMedium, 37 ℃ and 5% CO 2 Culturing in an incubator, and carrying out passage for 3-5 days.
3) Determination of the inhibitory Effect of samples on tumor cell growth cells were digested with EDTA-pancreatin and diluted to 1X 10 with medium 5 mL, added to a 96-well cell culture plate at 37 ℃ with 100uL per well, 5% 2 Culturing in an incubator. 24h after inoculation, adding the medium diluted sample, 100. Mu.L per well, 3 wells per concentration, 37 ℃,5% 2 The culture was performed in an incubator, 5mg/mL MTT was added to the cell culture wells after 72h, 10. Mu.L per well, incubated at 37 ℃ for 4h, DMSO was added, 150. Mu.L per well, shaken with a shaker, and formazan was completely solubilized and colorimetric at a wavelength of 570nm using a microplate reader. The tumor cell inhibition rate of the samples was calculated by using cells cultured in the medium containing no sample and the same concentration of DMSO as a control under the same conditions, and the results are shown in Table 1. The inhibition effect of the compound (I) sample on the growth of human breast cancer cells or non-small cell lung cancer cells in vitro was determined using human breast cancer cells (T47D) or human non-small cell lung cancer cells (a 549) as a model (see table 1 for details of results).
TABLE 1 inhibition ratio (%). Of 60. Mu.M Compound (I) against human breast cancer cells (T47D) or human non-small cell lung cancer cells (A549)
| Compound (I) | T47D | A549 |
| (I) | 59.73 | 42.41 |
Claims (10)
1. A method for preparing a 4-methyl-6-anilino-2-mercapto-1, 3,5-triazine compound represented by formula (I), characterized in that the method comprises:
adding sodium into methanol, adding the phenylguanyl thiourea intermediate shown in the formula (III) after the sodium is completely dissolved, reacting at room temperature for 2-5 h, adding ethyl acetate, continuing to react at 25-50 ℃ for 22-40 h, and after the reaction is finished, carrying out aftertreatment C on the obtained reaction liquid C to obtain a 4-methyl-6-anilino-2-mercapto-1, 3,5-triazine compound shown in the formula (I); the mass ratio of the phenylamidinothiourea intermediate shown in the formula (III) to the sodium and ethyl acetate is 1:3:2 to 4;
2. the process for producing a 4-methyl-6-anilino 2-mercapto-1, 3,5-triazine compound represented by formula (I) according to claim 1, characterized in that: the mass ratio of the phenylamidinothiourea intermediate represented by the formula (III) to sodium to ethyl acetate is 1.
3. A process for the preparation of 4-methyl-6-anilino 2-mercapto-1, 3,5-triazine compounds of formula (I) according to claim 1, wherein: the reaction time after addition of the phenylamidinothiourea intermediate of formula (III) was 2h.
4. A process for the preparation of 4-methyl-6-anilino 2-mercapto-1, 3,5-triazine compounds of formula (I) according to claim 1, wherein: the reaction time after adding the ethyl acetate is 30 to 40 hours.
5. A process for the preparation of 4-methyl-6-anilino 2-mercapto-1, 3,5-triazine compounds of formula (I) according to claim 1, wherein: the volume of methanol is 2-5 mL/mmol based on the amount of the substance of the phenylamidyl thiourea intermediate represented by the formula (III).
6. The process for preparing 4-methyl-6-anilino 2-mercapto-1, 3,5-triazine compounds of formula (I) according to claim 1, wherein said post-treatment C is: the resulting reaction solution C was concentrated, water was added, extraction was performed 3 times with dichloromethane, organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a mixture of petroleum ether: and (3) performing column chromatography separation by using the ethyl acetate mixed solution as an eluent, collecting the eluent containing the target compound, concentrating and drying to obtain the 4-methyl-6-anilino-2-mercapto-1, 3,5-triazine compound shown in the formula (I).
7. The process for preparing 4-methyl-6-anilino 2-mercapto-1, 3,5-triazine compounds of formula (I) according to claim 1, wherein the phenylamidinothiourea intermediate of formula (III) is prepared as follows:
(1) Adding aniline into water, adding hydrochloric acid A and dicyandiamide sodium, heating to 70-100 ℃, reacting for 5-12 h, cooling the obtained reaction liquid A to room temperature after the reaction is finished, filtering, and drying to obtain a crude product of the phenylcyanoguanidine intermediate shown in the formula (II); the mass ratio of aniline to sodium dicyandiamide to HCl in hydrochloric acid is 1:1 to 2:0.5 to 2;
(2) Adding the crude product of the phenylcyanoguanidine intermediate shown in the formula (II) obtained in the step (1) into acetone, then adding hydrochloric acid B and sodium thiosulfate, reacting for 1-5h at 15-35 ℃, and carrying out aftertreatment treatment on the obtained reaction liquid B to obtain a phenylamidinothiourea intermediate shown in the formula (III); the mass ratio of the aniline to the hydrochloric acid to the sodium thiosulfate is 1:1 to 3:0.5 to 1.5;
8. the process for producing 4-methyl-6-anilino 2-mercapto-1, 3,5-triazine compounds represented by formula (I) according to claim 7, wherein: the volume of the water in the step (1) is 0.5-2 mL/mmol based on the mass of the aniline.
9. The process for producing a 4-methyl-6-anilino 2-mercapto-1, 3,5-triazine compound represented by formula (I) according to claim 7, wherein: the volume of the acetone in the step (2) is 1-3 mL/mmol based on the mass of the aniline in the step (1).
10. The process for producing a 4-methyl-6-anilino 2-mercapto-1, 3,5-triazine compound represented by formula (I) according to claim 7, wherein: the post-treatment B in the step (2) comprises the following steps: the obtained reaction solution B was adjusted to PH =9 with aqueous ammonia, concentrated, and concentrated in a volume ratio of petroleum ether: and (3) performing column chromatography separation by using the ethyl acetate mixed solution as an eluent, collecting the eluent containing the target compound, and concentrating and drying to obtain the phenylamidyl thiourea intermediate shown in the formula (III).
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| DE19531084A1 (en) * | 1995-08-24 | 1997-02-27 | Hoechst Schering Agrevo Gmbh | 2,4-diamino-1,3,5-triazines, process for their preparation and their use as herbicides and plant growth regulators |
| CN105837525B (en) * | 2016-03-25 | 2019-05-28 | 浙江工业大学 | 2,4- diamines -1,3,5- compound in triazine class and the preparation method and application thereof |
| CN105753801B (en) * | 2016-03-25 | 2018-06-01 | 浙江工业大学 | A kind of preparation method of s-triazine compound |
| CN108840829A (en) * | 2018-05-02 | 2018-11-20 | 浙江工业大学 | A kind of preparation method of 4- aryl -1,3,5- triazine -2- ketone compounds |
| CN112159360B (en) * | 2020-09-15 | 2022-01-25 | 浙江工业大学 | Preparation method of 2-dimethylamino-6-benzylamino substituted triazine compound |
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