CN112194637B - Aromatic methylamine substituted nitrogen heterocyclic compound and preparation method and application thereof - Google Patents
Aromatic methylamine substituted nitrogen heterocyclic compound and preparation method and application thereof Download PDFInfo
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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
- C07D251/18—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 with nitrogen atoms directly attached to the two other ring carbon atoms, e.g. guanamines
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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
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The invention aims to solve the technical problem of providing an aromatic methylamine substituted nitrogen heterocyclic compound shown as a formula (III), a synthetic method thereof and application thereof in preparing anti-tumor drugs. Mixing a triazine compound shown in a formula (I) and arylcarbinol shown in a formula (II), adding the mixture into a solvent, stirring and reacting for 8-14 hours at the temperature of 100-140 ℃ under the action of a ruthenium catalyst and an alkaline substance, and after the reaction is finished, carrying out post-treatment on the obtained reaction liquid to obtain an arylmethylamino-substituted triazine compound shown in a formula (III); the method has high application value, and provides a practical, efficient and green method for high-throughput screening of the arylmethylamino-substituted triazine skeleton small molecule drug and synthesis of a complex natural product.
Description
(I) technical field
The invention relates to an aromatic methylamine substituted nitrogen heterocyclic compound and a preparation method and application thereof.
(II) background of the invention
The nitrogen heterocyclic compounds are common compounds, wherein triazine compounds are one of important nitrogen heterocyclic compounds and have important application value. Triazine skeleton contained in some natural products, bioactive molecules and drug molecules is one of the hot spots of research of pharmaceutical chemists at present. The traditional amino-substituted triazine derivative is mainly prepared from trichlorotriazine and an amine compound, but the application of the method is limited due to a plurality of byproducts, so that the development of a novel synthetic method of the amino-triazine derivative has practical application value.
Disclosure of the invention
The invention aims to solve the technical problem of providing an aromatic methylamine substituted nitrogen heterocyclic compound and a synthesis method and application thereof.
In order to solve the technical problem, the invention adopts the following technical scheme:
the invention provides an aromatic methylamine substituted nitrogen heterocyclic compound shown in a formula (III),
in the formula (III), Ar is phenyl, substituted phenyl or aromatic heterocycle; wherein the substituent in the substituted phenyl is methyl, methoxy, trifluoromethyl, fluorine or chlorine, and the aromatic heterocycle is thiophene, furan or pyridine.
Preferably, the aromatic methylamine-substituted nitrogen heterocyclic compound shown in the formula (III) is one of the following compounds:
the invention also provides a preparation method of the aromatic methylamine substituted nitrogen heterocyclic compound, which comprises the following steps:
mixing a triazine compound shown in a formula (I) and arylcarbinol shown in a formula (II), adding into a solvent, stirring and reacting at the temperature of 100-140 ℃ for 8-14 hours under the action of a ruthenium catalyst and an alkaline substance, and after the reaction is finished, carrying out post-treatment on the obtained reaction liquid to obtain an arylmethylamino-substituted triazine compound shown in a formula (III);
in the formula (I), Ar is phenyl, substituted phenyl or aromatic heterocycle; wherein the substituent in the substituted phenyl is methyl, methoxy, trifluoromethyl, fluorine or chlorine, and the aromatic heterocycle is thiophene, furan or pyridine;
the mol ratio of the triazine compound shown in the formula (I), the arylcarbinol shown in the formula (II), the ruthenium catalyst and the alkali is 1: 2-3.42: 0.015-0.027: 1.6-2; the solvent is an ether compound; the ruthenium catalyst is RuCl 2 (PPh 3 ) 3 ，Ru 3 (CO) 12 ，RuO 2 ，RuCl 3 ，RuCl 2 (COD),C 5 H 5 Ru(PPh 3 ) 2 Cl or C 20 H 28 Cl 4 Ru 2 (ii) a The alkaline substance is organic alkali or inorganic alkali.
Preferably, the reaction conditions are 120 ℃, 10 hours; the volume usage amount of the solvent is 4mL/mmol based on the amount of the triazine compound represented by formula (I).
Further preferably, the ruthenium catalyst is RuCl 2 (PPh 3 ) 3 。
The invention also recommends that the alkaline substance is potassium tert-butoxide, NaH, NaOH or KOH, and particularly preferably the alkaline substance is potassium tert-butoxide; the solvent is 1, 4-dioxane.
Further, the post-treatment process comprises the following steps: adding water into the obtained reaction liquid, extracting for three times by using ethyl acetate, combining organic phases, drying by using anhydrous sodium sulfate, filtering, concentrating the filtrate, and carrying out column chromatography by using the volume ratio of petroleum ether to ethyl acetate of 2:1 to obtain the arylmethylamino substituted triazine compound shown in the formula (III).
The invention also provides application of the arylmethylamino-substituted triazine compound in preparation of antitumor drugs.
Preferably, the tumor cell is human osteosarcoma cell U2OS, liver cancer cell HepG2 or human breast cancer cell MCF-7.
More preferably, the arylmethylamino-substituted triazine compound is one of the compounds shown in (III-1), (III-6) to (III-8) and (III-10), and the tumor cell is a human breast cancer cell MCF-7.
The invention also provides application of the compounds (III-2), (III-3) and (III-9) in preparing anti-human osteosarcoma medicaments, namely the compounds (III-1) to (III-3) and (III-5) to (III-10). Application in preparing anti-liver cancer medicine; the compounds (III-1), (III-4), (III-6) to (III-8) and (III-10) can be applied to the preparation of the anti-human breast cancer drugs.
Compared with the prior art, the invention develops a preparation method of the aromatic methylamino substituted nitrogen heterocyclic, namely, the target compound is synthesized by taking an easily obtained and easily preserved alcohol compound as an initial raw material and performing carbon-nitrogen coupling reaction with amino triazine under the action of a ruthenium catalyst. The process is convenient to operate, green and environment-friendly, and has the advantages of easily available raw materials, low price, easiness in storage and excellent functional group adaptability. The method has high application value, and provides a practical, efficient and green method for high-throughput screening of the arylmethylamino-substituted triazine skeleton small molecule medicine and synthesis of a complex natural product.
(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.
The raw material formula (I) compound used by the invention is prepared by reacting methyl formate with metformin at room temperature under the action of sodium methoxide; specific synthetic methods are described in the literature (Bioorganic & Medicinal Chemistry Letters,19(2009), 5644-.
The compound of the formula (I) as a raw material in the invention is specifically prepared: methanol was added to the reaction flask under ice-bath conditions, sodium wire (2.91g,126.43mmol) was added and stirred until dissolved, and metformin hydrochloride (10.47g,63.21mmol) and methyl formate (7.27g,158.03mmol) were added to the reaction solution and stirred at room temperature for 4h, and the end of the reaction was monitored by TLC. After the reaction, vacuum concentration, water, filtration, methanol recrystallization three triazine compound (I) (6.07g, 69%).
Example 1: preparation of Compound (III-1)
Adding N into a reaction vessel 2 ,N 2 -dimethyl-1, 3, 5-triazine-2, 4-diamino (70.1mg, 0.50mmol), benzyl alcohol (167.4mg, 1.49mmol), RuCl 2 (PPh 3 ) 3 (9.5mg, 9.91. mu. mol), potassium tert-butoxide (118.8mg, 1.06mmol), mixed in 1, 4-dioxane (2mL), reacted in an oil bath at 120 ℃ with stirring for 10 hours; after the reaction was completed, water was added, and extraction was performed with ethyl acetate (30mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain column chromatography (PE: EA ═ 2:1) to obtain the objective compound (III-1) and obtain 107.4mg of the product with a yield of 93%.
1 H NMR(500MHz,CDCl 3 )δ8.01(s,1H),7.34-7.31(m,4H),7.29-7.26(m,1H),6.00(br,1H),4.61(d,J＝5.2Hz,2H),3.15(s,3H),3.12(s,3H).
Example 2:
the temperature was lowered to 100 ℃ and the other operations were the same as in example 1 to give 39.2mg of the product in 34% yield.
Example 3:
the temperature was raised to 140 ℃ and the other operations were the same as in example 1 to give 79.5mg of product in 70% yield.
Example 4:
the time was extended to 14h and the other operations were the same as in example 1 to obtain 109.9mg of product in 95% yield.
Example 5:
the time was shortened to 8h and the other operations were the same as in example 1 to give 73.1mg of product in 64% yield.
Example 6:
the amount of benzyl alcohol was changed to (139.3mg, 1.24mmol), and the same operation as in example 1 was carried out to obtain 104.2mg of a product in 92% yield.
Example 7:
the same operation as in example 1 was carried out except for changing the amount of benzyl alcohol to (109.2mg, 1.00mmol), so as to obtain 76.5mg of a product with a yield of 68%.
Example 8:
adding RuCl 2 (PPh 3 ) 3 The same operation as in example 1 was carried out except that the amount of (1) was changed to (7.4mg, 7.72. mu. mol), to obtain 81.8mg of a product with a yield of 71%.
Example 9:
adding RuCl 2 (PPh 3 ) 3 To C 5 H 5 Ru(PPh 3 ) 2 Cl (7.4mg, 10.19. mu. mol), the same operations as in example 1 were carried out to give the product 62.9mg in 55% yield.
Example 10:
adding RuCl 2 (PPh 3 ) 3 Conversion to RuCl 2 (COD) (2.4mg, 11.88. mu. mol), the same operation as in example 1 was carried out to obtain 85.5mg of a product in a yield of 74%.
Example 11:
adding RuCl 2 (PPh 3 ) 3 Modified to RuO 2 (1.7mg, 12.77. mu. mol), the same procedures as in example 1 were carried out to give 56.7mg of a product in a yield of 49%。
Example 12:
adding RuCl 2 (PPh 3 ) 3 Modified to Ru 3 (CO) 12 (6.6mg, 10.32. mu. mol), the same procedures as in example 1 were repeated to give 103.1mg of a product in a yield of 89%.
Example 13:
adding RuCl 2 (PPh 3 ) 3 To C 20 H 28 Cl 4 Ru 2 (6.0mg, 9.80. mu. mol), the same operations as in example 1 were carried out to give 101.5mg of a product in 88% yield.
Example 14:
adding RuCl 2 (PPh 3 ) 3 Modified to RuCl 3 (2.8mg, 13.50. mu. mol), the same operations as in example 1 were carried out to give 62.4mg of a product in a yield of 54%.
Example 15:
the operation was otherwise the same as in example 1 except that the amount of potassium t-butoxide was changed to KOH (46.00mg, 0.82mmol), to give 105.0mg of a product with a yield of 91%.
Example 16:
the operation was otherwise the same as in example 1 except that the amount of potassium t-butoxide was changed to NaOH (40.5mg, 1.01mmol), to give 97.9mg of a product with a yield of 84%.
Example 17:
the operation was otherwise the same as in example 1 except that potassium tert-butoxide was changed to NaH (24.2mg, 1.01mmol), to give 102.6mg of a product in 90% yield.
Example 18: preparation of Compound (III-2)
The same operation as in example 1 was repeated, except that the benzyl alcohol was changed to 4-methylbenzyl alcohol (185.9mg,1.52mmol), and the other operation was performed as in example 1 to obtain 122.0mg of a product in 99% yield.
1 H NMR(500MHz,CDCl 3 )δ7.96(s,1H),7.25(d,J＝7.8Hz,2H),7.14(d,J＝7.8Hz,2H),6.31(br,1H),4.55(d,J＝5.6Hz,2H),3.14(s,3H),3.07(s,3H),2.34(s,3H)；
Example 19: preparation of Compound (III-3)
The same procedure as in example 1 was repeated, except that the benzyl alcohol was changed to 3-trifluoromethylbenzyl alcohol (271.2mg,1.54mmol), and the other operation was carried out the same as in example 1 to obtain 136.5mg of a product with a yield of 91%. 1 H NMR(500MHz,CDCl 3 )δ7.98(s,1H),7.61(s,1H),7.52(d,J＝7.6Hz,2H),7.47-7.41(m,1H),6.63(br,1H),4.60-4.79(m,2H),3.14(s,3H),3.08(s,3H).
Example 20: preparation of Compound (III-4)
The same operation as in example 1 was repeated, except that benzyl alcohol was changed to 4-methoxymethanol (209.3mg,1.51mmol), and the other operation was performed as in example 1 to obtain 121.7mg of a product with a yield of 94%.
1 H NMR(500MHz,CDCl 3 )δ7.97(s,1H),7.26(d,J＝8.65Hz,2H),6.86(d,J＝8.65Hz,2H),6.16(br,1H),4.52(d,J＝5.4Hz,2H),3.80(s,3H),3.10(s,6H).
Example 21: preparation of Compound (III-5)
The same operation as in example 1 except for changing benzyl alcohol to p-fluorobenzyl alcohol (191.9mg,1.52mmol) and the other operations as in example 1 gave 67.6mg of a product with a yield of 54%.
1 H NMR(500MHz,CDCl 3 )δ7.93(s,1H),7.33-7.28(m,2H),7.02-6.98(m,2H),6.55(br,1H),4.55(d,J＝5.3Hz,2H),3.14(s,3H),3.11(s,3H).
Example 22: preparation of Compound (III-6)
The same procedure as in example 1 was conducted except that benzyl alcohol was changed to p-chlorobenzyl alcohol (224.1mg,1.57mmol), and the other operations were conducted as in example 1 to obtain 85.5mg of a product in a yield of 64%.
1 H NMR(500MHz,CDCl 3 )δ8.11(s,1H),7.30(d,J＝8.6Hz,2H),7.26(d,J＝8.6Hz,2H),6.37(br,1H),4.56(d,J＝5.5Hz,2H),3.14(s,3H),3.09(s,3H).
Example 23: preparation of Compound (III-7)
The same operation as in example 1 was repeated, except that benzyl alcohol was changed to 2-thiophenemethanol (171.0mg,1.50mmol), and the other operation was performed as in example 1, to obtain 86.0mg of a product with a yield of 73%.
1 H NMR(500MHz,CDCl 3 )δ7.94(s,1H),7.21(dd,J＝5.1,1.1Hz,1H),7.00(dd,J＝3.5,1.1Hz,1H),6.95(dd,J＝5.1,3.5Hz,1H),6.65(br,1H),4.75(d,J＝5.4Hz,2H),3.12(s,6H).
Example 24: preparation of Compound (III-8)
The same procedure as in example 1 was conducted except that the benzyl alcohol was changed to 2-furanmethanol (146.9mg,1.49mmol), and the other operations were conducted as in example 1 to obtain 49.3mg of a product in a yield of 45%.
1 H NMR(500MHz,CDCl 3 )δ8.00(s,1H),7.36(d,J＝1.9Hz,1H),6.53(br,1H),6.32(dd,J＝3.0,1.9Hz,1H),6.24(d,J＝3.0Hz,1H),4.59(d,J＝5.0Hz,2H),3.15(s,6H).
Example 25: preparation of Compound (III-9)
The same procedure as in example 1 was repeated, except that benzyl alcohol was changed to 3-pyridinemethanol (164.8mg,1.51mmol), and the other operation was performed as in example 1 to obtain 89.7mg of a product with a yield of 77%.
1 H NMR(500MHz,CDCl 3 )δ8.60(s,1H),8.50(d,J＝4.8Hz,1H),7.95(s,1H),7.65(d,J＝7.8Hz,1H),7.24(dd,J＝7.8,4.8Hz,1H),6.76(br,1H),4.59(d,J＝5.1Hz,2H),3.13(s,3H),3.07(s,3H).
Example 26: preparation of Compound (III-10)
The same operation as in example 1 was repeated, except that benzyl alcohol was changed to 3-methylbenzyl alcohol (209.06mg,1.71mmol), and the other operation was performed as in example 1 to obtain 122.7mg of a product with a yield of 99%.
1 H NMR(500MHz,CDCl 3 )δ7.97(s,1H),7.23(t,J＝7.5Hz,1H),7.13-7.15(m,2H),7.09(s,1H),6.21(br,1H),4.57(d,J＝5.2Hz,2H),3.15(s,6H),2.35(s,3H).
Example 28: biological activity test of anti-human osteosarcoma cell (U2OS), liver cancer cell (HepG2) and human breast cancer cell (MCF-7)
In vitro activity test methods of anti-human osteosarcoma cells (U2OS), liver cancer cells (HepG2) and human breast cancer cells (MCF-7): 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, wherein each 1000mL of culture medium contains 80 million units of penicillin, 1.0g of streptomycin and 10% of inactivated fetal calf serum.
2.2) culture of cells: inoculating tumor cells into culture medium, placing at 37 deg.C and 5% CO 2 Culturing in an incubator, and carrying out passage for 3-5 days.
3) Determination of the inhibition of tumor cell growth by samples
The cells were digested with EDTA-trypsin digest and diluted to 1X 10 with medium 5 Perml, 100 uL/well in 96-well cell culture plates, 37 ℃ 5% CO 2 Culturing in an incubator. After 24h of inoculation, samples diluted with medium were added, 100. mu.L per well, 3 wells per concentration, and placed at 37 ℃ in 5% CO 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 inhibition rate of the sample on the growth of tumor cells was calculated by using cells cultured in the medium without the sample and with the same concentration of DMSO as a control under the same conditions, and the results are shown in Table 1.
The inhibition effect of 10 samples of the compounds (III-1) to (III-10) prepared in the examples on the growth of human osteosarcoma cells, liver cancer cells and human breast cancer cells in vitro was determined by using human osteosarcoma cells U2OS, liver cancer cells (HepG2) and human breast cancer cells (MCF-7) as models.
TABLE 1 inhibition ratio (%), of each compound on human osteosarcoma cell (U2OS), liver cancer cell (HepG2), and human breast cancer cell (MCF-7)
Claims (8)
1. An aromatic methylamine substituted nitrogen heterocyclic compound shown in a formula (III),
the aromatic methylamine-substituted nitrogen heterocyclic ring compound shown in the formula (III) is one of the following compounds:
2. a process for the preparation of an aromatic methylamine substituted azaheterocyclic compound as claimed in claim 1, characterised in that the process comprises:
mixing a triazine compound shown in a formula (I) and arylcarbinol shown in a formula (II), adding into a solvent, stirring and reacting for 8-14 hours at 120-140 ℃ under the action of a ruthenium catalyst and an alkaline substance, and after the reaction is finished, carrying out post-treatment on the obtained reaction liquid to obtain an aromatic methylamine-substituted nitrogen heterocyclic compound shown in a formula (III);
the aromatic methylamine substituted nitrogen heterocyclic ring compound shown in the formula (III) is one of the following compounds:
the mol ratio of the triazine compound shown in the formula (I), the arylcarbinol shown in the formula (II), the ruthenium catalyst and the alkaline substance is 1: 2-3.4: 0.015 to 0.027: 1.6-2; the solvent is an ether compound; the ruthenium catalyst is RuCl 2 (PPh 3 ) 3 ，Ru 3 (CO) 12 ，RuCl 2 (COD) or C 20 H 28 Cl 4 Ru 2 (ii) a The alkaline substance is organic alkali or inorganic alkali.
3. The method of claim 2, wherein: the reaction condition is 120 ℃ and 10 hours; the volume usage amount of the solvent is 4mL/mmol based on the amount of the triazine compound shown in the formula (I); the solvent is 1, 4-dioxane.
4. The method of claim 2, wherein: the ruthenium catalyst is RuCl 2 (PPh 3 ) 3 。
5. The method of claim 2, wherein: the alkaline substance is potassium tert-butoxide, NaH, NaOH or KOH.
6. The method of claim 2, wherein the post-processing procedure is: adding water into the obtained reaction liquid, extracting for three times by using ethyl acetate, combining organic phases, drying by using anhydrous sodium sulfate, filtering, concentrating the filtrate, and carrying out column chromatography on the concentrated filtrate by using the volume ratio of petroleum ether to ethyl acetate of 2:1 to obtain the aromatic methylamine substituted nitrogen heterocyclic compound shown in the formula (III).
7. The use of an arylmethylamine substituted azaheterocyclic compound of claim 1 in the preparation of an anti-neoplastic drug;
the tumor is human breast cancer cell MCF-7.
8. The use of claim 7, wherein: the aromatic methylamine substituted nitrogen heterocyclic ring compound is a compound shown in (III-8).
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