[go: up one dir, main page]
More Web Proxy on the site http://driver.im/

CN101307029A - 2,4,6-tri-substituted-1,3,5-triazine derivates library and preparation method - Google Patents

2,4,6-tri-substituted-1,3,5-triazine derivates library and preparation method Download PDF

Info

Publication number
CN101307029A
CN101307029A CNA2008100630513A CN200810063051A CN101307029A CN 101307029 A CN101307029 A CN 101307029A CN A2008100630513 A CNA2008100630513 A CN A2008100630513A CN 200810063051 A CN200810063051 A CN 200810063051A CN 101307029 A CN101307029 A CN 101307029A
Authority
CN
China
Prior art keywords
solvent
reaction
resin
preparation
class
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CNA2008100630513A
Other languages
Chinese (zh)
Other versions
CN101307029B (en
Inventor
胡章
叶苇
吴旭伶
章国林
俞永平
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Zhejiang University ZJU
Original Assignee
Zhejiang University ZJU
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Zhejiang University ZJU filed Critical Zhejiang University ZJU
Priority to CN2008100630513A priority Critical patent/CN101307029B/en
Publication of CN101307029A publication Critical patent/CN101307029A/en
Application granted granted Critical
Publication of CN101307029B publication Critical patent/CN101307029B/en
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Landscapes

  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention provides a solid phase synthesis method for a 2, 4, 6-trisubstituted-1, 3, 5-triazine derivative library. The method comprises the following steps that: aldehyde group resin reacts with primary amine in organic solvent; resin containing a secondary amine structure is obtained through reductive amination; the resin reacts with 2, 4, 6-trisubstituted-1, 3, 5-triazine so as to obtain resin connected with a triazine mother ring, and then the resin reacts with primary amine or secondary amine so as to have 6-chlorine replaced; finally a formed product is cut from the resin through a cutting agent, so as to obtain a 2, 4, 6-trisubstituted-1, 3, 5-triazine derivative with molecular diversity. The 2, 4, 6-trisubstituted-1, 3, 5-triazine derivative provided by the invention is moderate in synthesis condition, easy to get raw materials, high in yield and beneficial to high-throughput screening and the discovery of anti-cancer anticancer drug lead compounds.

Description

2,4,6-three replacement-1,3,5-triazines analog derivative storehouse and preparation methods
Technical field
It is synthetic to the invention belongs to compound, relates generally to 2,4,6-three replacement-1,3,5-triazines analog derivative storehouse and solid phase synthesis process thereof.
Background technology
Apoptosis is important biological phenomena, apoptosis process be unusually tumour take place and evolution in an important step.The PKB signal path transmits born of the same parents' external stimulus signals such as somatomedin, plays a significant role at the aspects such as hyperplasia, apoptosis, metabolism and tumor-blood-vessel growth of regulate tumor cell.PKB reactivation process is the key link of signal transduction pathway, and the activity of utilizing variety of way to suppress PKB can promote apoptosis process.PKB will be new, a good antitumor drug target position.
In the research of present kinases inhibitor, the Iressa of the Gleevec of Novartis company and Astrazenca company is to enter clinical application as treatment chronic leukemia and treatment lung cancer drugs.In addition, also have tens compounds carrying out preclinical test.Though the research to the PKB inhibitor obtains some progress recently, does not also enter the compound of clinical trial.Therefore, high reactivity, the specific inhibitor that further develops and optimize PKB demanded urgently being developed.
Triazine derivative receives much concern because of restraining effect, antiretroviral activity, estrogen receptor regulating effect, cytotoxic activity and the neovascularization inhibiting activity etc. of biological activity with wide scope such as anti-microbial activity, anti-trypanosome activity, integrin Vla-4-4 (VLA-4) antagonism, SODH, and particularly antitumour activity causes scholars' broad research.The hexamethyl trimeric cyanamide is a kind of effective anti-breast cancer, lung cancer and ovarian cancer medicine, but its severe side effect has limited application clinically [Cancer Treat.Rev., 1986,13,197-217] as nauseating, vomiting, abdominal colic and apositia etc.The medicine irsogladine [2 that is used for anti-gastric-ulcer in Japan, 4-diamino-6-(2, the 5-dichlorophenyl)-1,3, the 5-triazine] because of having the angiogenesis restraining effect, thus in epidermoma and gliomatous heteroplastic graft mouse model, all present stronger anti-tumor activity, and can suppress mammary cancer regrowth and pulmonary metastases [Breast Cancer Res.Treat.2004,83,195-199].Particularly Recent study is reported, the triazines structure all has significant antiproliferative effect [Bioorg.Med.Chem.2007 for JEG-3 HCT116, HT29, MALME-3M, A498, COLO205, HeLa, HCT-116, U937, A375, SR, OVCAR-4 and HOP-62,15,1815-1827; Eur.J.Med.Chem.2006,41,611-615; J.Med.Chem.2005,48,4535-4546].Armistead etc. from 1900 compound libraries, filter out two compounds to the IC50 value of PKB respectively less than 1.0 and 0.89 μ M[WO0125220].
So a large amount of synthetic 2,4 of molecular diversities that have, the compound library of 6-three replacement-1,3,5-triazines class formations are for screening and find that the lead compound of cancer therapy drug is significant.
Summary of the invention
The purpose of this invention is to provide a class 2,4,6-three replacement-1,3,5-triazines analog derivatives have following general structure:
R wherein 1Be C 1-C 10Alkyl group, C 3-C 7Cycloalkyl, C 2-C 10Unsaturated alkyl, C 5-C 10Aromatic base or assorted aromatic base;
R 2Be hydrogen, C 1-C 10Alkyl group, C 3-C 7Cycloalkyl, C 2-C 10Unsaturated alkyl, C 5-C 10Aromatic base or assorted aromatic base;
R 3Be hydrogen, C 1-C 10Alkyl group, C 3-C 7Cycloalkyl, C 2-C 10Unsaturated alkyl, C 5-C 10Aromatic base or assorted aromatic base;
R 4Be hydrogen, C 1-C 10Alkyl group, C 3-C 7Cycloalkyl, C 2-C 10Unsaturated alkyl, C 5-C 10Aromatic base or assorted aromatic base.
Another object of the present invention provides the preparation method of said structure general formula, obtains (with compound VIII: 2,4,6-three replacement-1,3,5-triazines analog derivatives are example) by following steps:
(1) formaldehyde-based resin IV and primary amine reaction form the resin V of secondary amine structure by reduction amination:
Used reduction amination reagent can be sodium cyanoborohydride, POTASSIUM BOROHYDRIDE, sodium borohydride, sodium triacetoxy borohydride, sodium borohydride-zinc chloride, hydroboration sodium-nickel chloride, zinc borohydride, borine in this step reaction, adopts sodium cyanoborohydride usually.The temperature of reaction can normally be carried out between-10～100 ℃ at ambient temperature.Used solvent can be an ether solvent, as 1, and 4-dioxane, glycol dimethyl ether, tetrahydrofuran (THF) etc.; Can be chlorinated solvent, as methylene dichloride, ethylene dichloride, chloroform etc.; Also can be aromatic solvent, as benzene,toluene,xylene etc.; Can also be amide solvent, as dimethyl formamide, N,N-DIMETHYLACETAMIDE etc.Usually adopt dimethyl formamide.
(2) resin V and above-mentioned synthetic compound III reaction obtains being connected with the female resin VI that encircles of triazine:
In this step reaction, can add alkali as a catalyst, also can not add.The alkali that is added can be organic bases, as triethylamine, diisopropyl ethyl amine, pyridine etc.; Also can be mineral alkali, as sodium bicarbonate, saleratus, yellow soda ash, salt of wormwood, cesium carbonate, sodium hydroxide, potassium hydroxide etc.The temperature of reaction can normally be carried out between 0～100 ℃ at ambient temperature.Used solvent can be an amide solvent, as dimethyl formamide, N,N-DIMETHYLACETAMIDE etc.; Can be chlorinated solvent, as methylene dichloride, ethylene dichloride, chloroform etc.; Also can be aromatic solvent, as benzene,toluene,xylene etc.; Can also be ether solvent, as 1,4-dioxane, glycol dimethyl ether, tetrahydrofuran (THF) etc.Usually adopt tetrahydrofuran (THF).
(3) resin VI and replacement primary amine or secondary amine reaction obtain resin VII:
In this step reaction, can add alkali as a catalyst, also can not add.The alkali that is added can be organic bases, as triethylamine, diisopropyl ethyl amine, pyridine etc.; Also can be mineral alkali, as sodium bicarbonate, saleratus, yellow soda ash, salt of wormwood, cesium carbonate, sodium hydroxide, potassium hydroxide etc.The temperature of reaction can normally be carried out under 100 ℃ of conditions between 0～150 ℃.Used solvent can be an amide solvent, as dimethyl formamide, N,N-DIMETHYLACETAMIDE etc.; Can be chlorinated solvent, as methylene dichloride, ethylene dichloride, chloroform etc.; Also can be aromatic solvent, as benzene,toluene,xylene etc.; Can also be ether solvent, as 1,4-dioxane, glycol dimethyl ether, tetrahydrofuran (THF) etc.Usually adopt dimethyl formamide.
(4) last, resin VII cuts with cutting agent, obtains target product---the crude product of compound VIII, and the purified pure products VIII that obtains of gained crude product:
Used cutting agent can be a trifluoroacetic acid in step in this reaction, also can be trifluoroacetic acid and the mixture of organic solvent arbitrary volume ratio.Usually the cutting agent that adopts is a trifluoroacetic acid and the methylene chloride volume ratio is 1: 1 a mixture.The temperature of reaction can normally be carried out between 0～100 ℃ at ambient temperature.
Figure A20081006305100071
Above-mentioned reaction formula is the reaction expression (according to above-mentioned reaction formula, reaction intermediate III is synthetic according to document) of preparation compound VIII (2,4,6-three replacement-1,3,5-triazines analog derivatives).
Usefulness of the present invention is: the present invention transforms the structure of existing cyanuric chloride, and three chlorine atoms on the triazine ring are carried out nucleophilic substitution respectively three times.Simultaneously, we use the method for combinatorial chemistry, make that the substituting group on 2,4 and 6 can have multiple variation in the improved structure, help synthesizing fast and in large quantities and have 2,4 of molecular diversity, 6-three replacements-1,3, the compound library of 5-triazines structure.Provided by the invention 2,4, the synthesis condition gentleness of 6-three replacement-1,3,5-triazines analog derivatives, raw material is easy to get, and purity and productive rate are all higher.And can synthesize in a large number and have 2,4 of molecular diversity, 6-three replacement-1,3,5-triazines analog derivative storehouses help high flux screening and find the cancer therapy drug lead compound.
Embodiment
The present invention is further illustrated below by embodiment.
Embodiment 1:2, the preparation of 4-two chloro-6-phenyl-1,3,5-triazines III
Add 0.78g (33mmol) magnesium rod and 20mL anhydrous tetrahydro furan (THF) in the 50mL there-necked flask, add several iodo activations, slowly drip 4.7g (30mmol) bromobenzene in system, the maintenance system is in slight boiling condition.Wait to dropwise the back in 65 ℃ of insulations 2 hours, (2.8g is in THF 15mmol) (30mL) solution after the cooling room temperature grignard reagent slowly to be added drop-wise to the cyanuric chloride that is cooled to 0 ℃ in advance, temperature is 0～10 ℃ in keeping, dropwise the back in 20 ℃ of reactions 3 hours, mixture dilution with toluene, 10% salt acid elution, washing, decompression steams solvent, obtains yellow solid 2,4-two chloro-6-phenyl-1,3, the crude product of 5-triazine III.Productive rate 66%, m.p.110 ℃.
Embodiment 2:2, the preparation of 4-two chloro-6-(4-methoxyphenyl)-1,3,5-triazines III
Add 4.2g (176mmol) magnesium rod and the anhydrous THF of 60mL in the 100mL there-necked flask, add several iodo activations, slowly drip 24.3g (130mmol) para-bromoanisole in system, the maintenance system is in slight boiling condition.Wait to dropwise the back in 65 ℃ of insulations 0.5 hour, (12g is in THF 65mmol) (60mL) solution after the cooling room temperature grignard reagent slowly to be added drop-wise to the cyanuric chloride that is cooled to 0 ℃ in advance, temperature is 0～10 ℃ in keeping, dropwise the back in 20 ℃ of reactions 3 hours, mixture dilution with toluene, 10% salt acid elution, washing, decompression steams solvent, obtains white-yellowish solid 2,4-two chloro-6-(4-methoxyphenyl)-1,3, the crude product of 5-triazine III.Productive rate 61%, m.p.122-124 ℃.
Embodiment 3:2, the preparation of 4-two chloro-6-(3-chloro-phenyl-)-1,3,5-triazines III
Add 3.0g (125mmol) magnesium rod and the anhydrous THF of 50mL in the 100mL there-necked flask, add several iodo activations, drip slowly that chloro-bromobenzene is in system between 22.8g (119mmol), the maintenance system is in slight boiling condition.Wait to dropwise the back in 65 ℃ of insulations 2 hours, (11.1g is in THF 60mmol) (60mL) solution after the cooling room temperature grignard reagent slowly to be added drop-wise to the cyanuric chloride that is cooled to 0 ℃ in advance, temperature is 0～10 ℃ in keeping, dropwise the back in 20 ℃ of reactions 3 hours, mixture dilution with toluene, 10% salt acid elution, washing, decompression steams solvent, obtains yellow solid 2,4-two chloro-6-(3-chloro-phenyl-)-1,3, the crude product of 5-triazine III.Productive rate 58%, m.p.92-95 ℃.
The preparation of embodiment 4:2-phenyl-4-para-totuidine base-6-N-piperidyl-1,3,5-triazines
With 100mg (0.1mmol, volume containing the sample 1mmol/g) formaldehyde-based resin IV is (available from Nova Biochem production code member: NO:01-64-0331, degree of crosslinking 1%) encloses resin pocket, to monomethylaniline 0.107g (1mmol), N, dinethylformamide 10ml, Glacial acetic acid 0.1ml, sodium cyanoborohydride 0.063g (1mmol) joins in the reaction flask of 15ml, put shaking table after the sealing, the room temperature vibration was rocked 24 hours, and the liquid of falling the dereaction is used N successively with resin pocket then, dinethylformamide, ethanol and methylene dichloride respectively wash three times, dry in air.Obtain the resin V (R of secondary amine structure this moment 2=p-methylphenyl).
Get according to 2 of example 1 described preparation 4-two chloro-6-phenyl-1,3,5-triazine III 0.226g (1mmol), tetrahydrofuran (THF) 10ml, last step reaction back air dried resin pocket V (100mg, 0.1mmol), triethylamine 0.1g joins the 15ml reaction flask, puts shaking table after the sealing, and the room temperature vibration was rocked 24 hours, the liquid of falling the dereaction then, resin pocket is used N successively, and dinethylformamide, ethanol and methylene dichloride respectively wash three times, dry in air.Obtain being connected with the resin VI (R of the female ring of triazine this moment 1=phenyl, R 2=p-methylphenyl).
Get step reaction back air dried resin pocket VI (100mg, 0.1mmol), N, dinethylformamide 10ml, piperidines 0.085g (1mmol) and triethylamine 0.1g (1mmol) join the 15ml reaction tubes, system is heated to 100 ℃, reacted 48 hours, the liquid of falling the dereaction is used N successively with resin pocket then, dinethylformamide, ethanol and methylene dichloride respectively wash three times, dry in air.Obtain resin VII (R this moment 1=phenyl, R 2=p-methylphenyl, R 3, R 4=N-piperidyl).
Get step reaction back air dried resin pocket VII (100mg, 0.1mmol), put into the test tube of 8ml, add trifluoroacetic acid and methylene chloride volume ratio again and be 1: 1 mixing solutions 5ml, test tube is sealed, 1 resin pocket of back taking-up as a child behind the solution normal pressure evaporate to dryness in the test tube, obtains yellow solid.This solid washs with saturated sodium bicarbonate, and with ethyl acetate extraction 3 times.Collected organic layer is also used anhydrous sodium sulfate drying, filters then.The ethyl acetate solution that obtains is concentrated, and product obtains white solid (productive rate 66.9%) after column chromatography.m.p.103-105℃。
1HNMR(400MHz，DMSO-d6)δ9.49(1H，s)，8.35(2H，d，J＝7.2Hz)，7.65(2H，d，J＝8.0Hz)，7.49-7.55(3H，m)，7.13(2H，d，J＝8.0Hz)，3.82-3.89(4H，m)，2.26(3H，s)，1.56-1.65(6H，m)
13CNMR(100MHz，DMSO-d6)δ169.7，164.2，137.2，136.9，131.4，130.9，128.8，128.2，127.8，119.9，43.7，25.3，24.2，20.3
The preparation of embodiment 5:2-(4-methoxyphenyl)-4-para-totuidine base-6-N-piperidyl-1,3,5-triazines
Operating process is with embodiment 4, just with embodiment 2 obtain 2,4-two chloro-6-(4-methoxyphenyl)-1,3,5-triazines replacement 2,4-two chloro-6-phenyl-1,3,5-triazines obtain white solid (productive rate 61.5%).m.p.137-139℃。
1HNMR(400MHz，DMSO-d6)δ9.40(1H，s)，8.30(2H，d，J＝8.8Hz)，7.65(2H，d，J＝8.0Hz)，7.12(2H，d，J＝8.2Hz)，7.04(2H，d，J＝8.8Hz)，3.83(7H，s)，2.26(3H，s)，1.56-1.65(6H，m)
13CNMR(100MHz，DMSO-d6)δ169.3，164.2，161.9，137.3，130.8，129.6，129.2，128.8，119.9，113.6，55.3，43.7，25.4，24.2，20.3
The preparation of embodiment 6:2-(3-chloro-phenyl-)-4-para-totuidine base-6-N-piperidyl-1,3,5-triazines
Operating process is with embodiment 4, just with embodiment 3 obtain 2,4-two chloro-6-(3-chloro-phenyl-)-1,3,5-triazines replacement 2,4-two chloro-6-phenyl-1,3,5-triazines obtain white solid (productive rate 58.6%).m.p.141-143℃。
1HNMR(400MHz，DMSO-d6)δ9.56(1H，s)，8.27-8.31(2H，m)，7.52-7.64(4H，m)，7.12(2H，d，J＝8.0Hz)，3.80-3.89(4H，m)，2.26(3H，s)，1.56-1.64(6H，m)
13CNMR(100MHz，DMSO-d6)δ168.3，164.2，164.1，139.1，137.0，133.2，131.1，130.2，128.8，127.4，126.3，120.0，43.8，25.3，24.2，20.3
The preparation of embodiment 7:2-phenyl-4-anilino-6-(4-methylpiperazine base)-1,3,5-triazines
Operating process just changes para-totuidine into aniline with embodiment 4, and piperidines changes N methyl piperazine into, obtains white solid (productive rate 62.6%).m.p.161-163℃。
1HNMR(400MHz，DMSO-d6)δ9.64(1H，s)，8.36(2H，d，J＝6.8Hz)，7.79(2H，d，J＝8.0Hz)，7.49-7.56(3H，m)，7.33(2H，t，J 1＝7.6Hz，J 2＝8.0Hz)，7.01(1H，t，J 1＝7.2Hz，J 2＝7.2Hz)，3.92(4H，t)，2.40(4H，t)，2.23(3H，s)
13CNMR(100MHz，DMSO-d6)δ169.8，164.4，164.2，139.7，136.6，131.5，128.4，128.3，127.9，122.1，119.9，54.3，45.7，42.8
The preparation of embodiment 8:2-(4-methoxyphenyl)-4-anilino-6-(4-methylpiperazine base)-1,3,5-triazines
Operating process is with embodiment 4, just with embodiment 2 obtain 2,4-two chloro-6-(4-methoxyphenyl)-1,3, the 5-triazine replaces 2,4-two chloro-6-phenyl-1,3,5-triazines, para-totuidine changes aniline into, and piperidines changes N methyl piperazine into, obtains white solid (productive rate 58.7%).m.p.225-228℃。
1HNMR(400MHz，DMSO-d6)δ9.56(1H，s)，8.32(2H，d，J＝8.8Hz)，7.77(2H，d，J＝7.6Hz)，7.32(2H，t，J 1＝8.0Hz，J 2＝8.0Hz)，7.05(2H，d，J＝8.8Hz)，6.99(1H，t，J 1＝7.2Hz，J 2＝7.6Hz)，3.84(7H，s)，2.39(4H，t)，2.23(3H，s)
13CNMR(100MHz，DMSO-d6)δ164.4，164.1，162.1，139.8，129.7，128.9，128.4，122.0，119.8，113.6，55.3，54.3，45.7，42.8
The preparation of embodiment 9:2-(3-chloro-phenyl-)-anilino-6-(4-methylpiperazine base)-1,3,5-triazines
Operating process is with embodiment 4, just with embodiment 3 obtain 2,4-two chloro-6-(3-chloro-phenyl-)-1,3, the 5-triazine replaces 2,4-two chloro-6-phenyl-1,3,5-triazines, para-totuidine changes aniline into, and piperidines changes N methyl piperazine into, obtains white solid (productive rate 52.8%).m.p.175-177℃。
1HNMR(400MHz，DMSO-d6)δ9.71(1H，s)，8.31(2H，t，J 1＝7.2Hz，J 2＝8.0Hz)，7.75(2H，d，J＝8.0Hz)，7.62-7.64(1H，m)，7.55(1H，t，J 1＝7.6Hz，J 2＝8.0Hz)，7.33(2H，t，J 1＝7.6Hz，J 2＝8.0Hz)，7.01(1H，t，J 1＝7.2Hz，J 2＝7.2Hz)，3.82-3.92(4H，t)，2.40(4H，t)，2.23(3H，s)
13CNMR(100MHz，DMSO-d6)δ168.5，164.4，164.1，139.5，138.8，133.2，131.3，130.3，128.5，127.4，126.4，122.3，120.0，54.3，45.7，42.8
The preparation of embodiment 10:2-(4-methoxyphenyl)-4-anilino-6-N-piperidyl-1,3,5-triazines
Operating process is with embodiment 4, just with embodiment 2 obtain 2,4-two chloro-6-(4-methoxyphenyl)-1,3,5-triazines replacement 2,4-two chloro-6-phenyl-1,3,5-triazines, para-totuidine changes aniline into, obtains white solid (productive rate 68.1%).m.p.148-151℃。
1HNMR(400MHz，DMSO-d6)δ9.50(1H，s)，8.32(2H，d，J＝8.8Hz)，7.79(2H，d，J＝8.0Hz)，7.32(2H，t，J 1＝8.0Hz，J 2＝8.0Hz)，7.05(2H，d，J＝8.8Hz)，6.99(1H，t，J 1＝7.2Hz，J 2＝7.2Hz)，3.83(7H，s)，1.56-1.66(6H，m)
13CNMR(100MHz，DMSO-d6)δ169.4，164.2，164.1，162.0，139.9，129.6，129.1，128.4，121.9，119.8，113.6，55.3，43.7，25.3，24.2
The preparation of embodiment 11:2-(4-methoxyphenyl)-4-p-Chlorobenzoic acid amide base-6-N-piperidyl-1,3,5-triazines
Operating process is with embodiment 4, just with embodiment 2 obtain 2,4-two chloro-6-(4-methoxyphenyl)-1,3,5-triazines replacement 2,4-two chloro-6-phenyl-1,3,5-triazines, para-totuidine changes p-Chlorobenzoic acid amide into, obtains white solid (productive rate 61.5%).m.p.182-185℃。
1HNMR(400MHz，DMSO-d6)δ9.65(1H，s)，8.30(2H，d，J＝8.8Hz)，7.80(2H，d，J＝8.8Hz)，7.36(2H，d，J＝8.8Hz)，7.05(2H，d，J＝8.8Hz)，3.83(7H，s)，1.56-1.66(6H，m)
13CNMR(100MHz，DMSO-d6)δ169.4，164.1，164.0，162.1，138.9，129.7，128.9，128.3，125.4，121.2，113.6，55.3，43.7，25.3，24.2
The preparation of embodiment 12:2-(4-methoxyphenyl)-4-para-totuidine base-6-morpholinyl-1,3,5-triazines
Operating process is with embodiment 4, just with embodiment 2 obtain 2,4-two chloro-6-(4-methoxyphenyl)-1,3,5-triazines replacement 2,4-two chloro-6-phenyl-1,3,5-triazines, piperidines changes morpholine into, obtains white solid (productive rate 66.8%).m.p.222-224℃。
1HNMR(400MHz，DMSO-d6)δ9.49(1H，s)，8.31(2H，d，J＝8.8Hz)，7.64(2H，d，J＝8.0Hz)，7.12(2H，d，J＝8.0Hz)，7.05(2H，d，J＝8.8Hz)，3.83(7H，s)，3.68(4H，t)，2.26(3H，s)
13CNMR(100MHz，DMSO-d6)δ169.4，164.6，164.1，162.1，137.1，130.9，129.7，128.9，128.8，120.1，113.6，65.9，55.3，43.3，20.3
The preparation of embodiment 13:2-(4-methoxyphenyl)-4-anilino-6-morpholinyl-1,3,5-triazines
Operating process is with embodiment 4, just with embodiment 2 obtain 2,4-two chloro-6-(4-methoxyphenyl)-1,3, the 5-triazine replaces 2,4-two chloro-6-phenyl-1,3,5-triazines, para-totuidine changes aniline into, and piperidines changes morpholine into, obtains white solid (productive rate 57.4%).m.p.197-199℃。
1HNMR(400MHz，DMSO-d6)δ9.59(1H，s)，8.33(2H，d，J＝8.8Hz)，7.78(2H，d，J＝8.0Hz)，7.32(2H，t，J 1＝8.0Hz，J 2＝8.0Hz)，7.05(2H，d，J＝8.8Hz)，7.00(1H，t，J 1＝7.2Hz，J 2＝7.2Hz)，3.84(7H，s)，3.69(4H，t)
13CNMR(100MHz，DMSO-d6)δ169.4，164.6，164.1，162.1，139.7，129.7，128.9，128.4，122.0，119.9，113.6，65.9，55.3，43.4
The preparation of embodiment 14:2-(4-methoxyphenyl)-4-p-Chlorobenzoic acid amide base-6-morpholinyl-1,3,5-triazines
Operating process is with embodiment 4, just with embodiment 2 obtain 2,4-two chloro-6-(4-methoxyphenyl)-1,3, the 5-triazine replaces 2,4-two chloro-6-phenyl-1,3,5-triazines, para-totuidine changes p-Chlorobenzoic acid amide into, and piperidines changes morpholine into, obtains white solid (productive rate 43.8%).m.p.231-233℃。
1HNMR(400MHz，DMSO-d6)δ9.74(1H，s)，8.32(2H，d，J＝8.8Hz)，7.80(2H，d，J＝8.8Hz)，7.37(2H，d，J＝8.8Hz)，7.05(2H，d，J＝8.8Hz)，3.84(7H，s)，3.69(4H，t)
13CNMR(100MHz，DMSO-d6)δ169.5，164.5，164.1，162.2，138.8，129.8，128.7，128.3，125.6，121.4，113.6，65.9，55.3，43.4
The preparation of embodiment 15:2-phenyl-4-para-totuidine base-6-(4-methylpiperazine base)-1,3,5-triazines
Operating process just changes piperidines into morpholine with embodiment 4, obtains white solid (productive rate 65.3%).m.p.211-213℃。
1HNMR(400MHz，DMSO-d6)δ9.55(1H，s)，8.35(2H，d，J＝7.2Hz)，7.64(2H，d，J＝8.0Hz)，7.49-7.57(3H，m)，7.13(2H，d，J＝8.0Hz)，3.83-3.92(4H，m)，2.39(4H，t)，2.27(3H，s)，2.23(3H，s)
13CNMR(100MHz，DMSO-d6)δ169.7，164.5，164.2，137.1，136.7，131.5，131.1，128.8，128.2，127.9，120.1，54.3，45.7，42.8，20.3
The preparation of embodiment 16:2-phenyl-4-para-totuidine base-6-para-totuidine base-1,3,5-triazines
Operating process just changes piperidines into para-totuidine with embodiment 4, obtains white solid (productive rate 43.5%).m.p.128-131℃。
1HNMR(400MHz，DMSO-d6)δ9.67(2H，s)，8.38(2H，d，J＝6.8Hz)，7.54-7.71(7H，m)，7.15(2H，d，J＝6.8Hz)，2.29(6H，s)，
13CNMR(100MHz，DMSO-d6)δ170.1，164.2，136.8，136.6，131.6，131.4，128.8，128.3，127.9，120.5，120.4，20.4
Embodiment 17:2-phenyl-4-para-totuidine base-6-[3-(trifluoromethyl)-5,6,7,8-tetrahydrochysene-1,2,4-triazolo [4,3-a] pyrazine-7-yl]-preparation of 1,3,5-triazines
Operating process just changes piperidines into 3-(trifluoromethyl)-5,6,7 with embodiment 4,8-tetrahydrochysene-1,2, and 4-triazolo [4,3-a] pyrazine obtains white solid (productive rate 61.9%).m.p.234-236℃。
1HNMR(400MHz，DMSO-d6)δ9.78(1H，s)，8.40(2H，d，J＝7.2Hz)，7.65(2H，d，J＝7.2Hz)，7.52-7.59(3H，m)，7.17(2H，d，J＝8.0Hz)，5.35(2H，t)，4.43(2H，t)，4.32(2H，s)，2.29(3H，s)
13CNMR(100MHz，DMSO-d6)δ164.9，164.2，151.1，142.7，136.7，136.2，131.8，131.6，131.5，128.9，128.4，128.0，120.4，119.8，43.0，42.9，28.9，20.4
Embodiment 18:2-phenyl-4-n-butylamine-based-6-[3-(trifluoromethyl)-5,6,7,8-tetrahydrochysene-1,2,4-triazolo [4,3-a] pyrazine-7-yl]-preparation of 1,3,5-triazines
Operating process just changes para-totuidine into n-Butyl Amine 99 with embodiment 4, and piperidines changes 3-(trifluoromethyl)-5,6,7 into, 8-tetrahydrochysene-1,2, and 4-triazolo [4,3-a] pyrazine obtains white solid (productive rate 41.2%).m.p.172-173℃。
1HNMR(400MHz，DMSO-d6)δ8.38(2H，d，J＝7.2Hz)，8.34(2H，d，J＝7.2Hz)，7.69(1H，t，J 1＝5.6Hz，J 2＝5.6Hz)，7.49-7.54(3H，m)，5.24(2H，t)，4.35(2H，t)，4.28(2H，s)，3.33-3.45(2H，m)，1.52-1.57(2H，m)，1.33-1.38(2H，m)，0.90-0.94(3H，m)
13CNMR(100MHz，DMSO-d6)δ165.8，165.7，151.2，136.5，131.5，131.4，128.2，127.9，127.8，119.8，43.0，42.9，31.3，30.9，19.6，19.5，13.6
The preparation of embodiment 19:2-phenyl-4-p-Chlorobenzoic acid amide base-6-(4-methylpiperazine base)-1,3,5-triazines
Operating process just changes para-totuidine into p-Chlorobenzoic acid amide with embodiment 4, and piperidines changes N methyl piperazine into, obtains white solid (productive rate 58.1%).m.p.186-188℃。
1HNMR(400MHz，DMSO-d6)δ9.79(1H，s)，8.35(2H，d，J＝8.0Hz)，7.80(2H，d，J＝8.0Hz)，7.49-7.56(3H，m)，7.37(2H，d，J＝8.0Hz)，3.92(4H，t)，2.39(4H，t)，2.22(3H，s)
13CNMR(100MHz，DMSO-d6)δ169.8，164.4，164.1，138.7，136.5，131.6，128.3，128.2，127.9，125.7，121.4，54.3，45.7，42.8
The preparation of embodiment 20:2-phenyl-4-para-totuidine base-6-n-butylamine-based-1,3,5-triazines
Operating process just changes piperidines into n-Butyl Amine 99 with embodiment 4, obtains white solid (productive rate 58.4%).m.p.95-97℃。
1HNMR(400MHz，DMSO-d6)δ9.48(1H，s)，8.35(2H，d，J＝7.2Hz)，8.30(2H，d，J＝7.2Hz)，7.72(2H，d，J＝8.4Hz)，7.65(1H，s)，7.49-7.52(3H，m)，7.10(2H，d，J＝8.0Hz)，3.34-3.44(2H，m)，2.26(3H，s)，1.54-1.61(2H，m)，1.35-1.40(2H，m)，0.92(3H，t)
13CNMR(100MHz，DMSO-d6)δ169.5，165.8，165.7，137.4，136.8，131.2，130.8，128.8，128.2，127.8，127.6，30.9，20.3，19.6，19.5，13.7

Claims (10)

1. a class 2,4,6-three replacement-1,3,5-triazines analog derivatives is characterized in that: have following general structure:
Figure A2008100630510002C1
R wherein 2, R 3And R 4Identical or different:
R 1Be C 1-C 10Alkyl group, C 3-C 7Cycloalkyl, C 2-C 10Unsaturated alkyl, C 5-C 10Aromatic base or assorted aromatic base;
R 2Be hydrogen, C 1-C 10Alkyl group, C 3-C 7Cycloalkyl, C 2-C 10Unsaturated alkyl, C 5-C 10Aromatic base or assorted aromatic base;
R 3Be hydrogen, C 1-C 10Alkyl group, C 3-C 7Cycloalkyl, C 2-C 10Unsaturated alkyl, C 5-C 10Aromatic base or assorted aromatic base;
R 4Be hydrogen, C 1-C 10Alkyl group, C 3-C 7Cycloalkyl, C 2-C 10Unsaturated alkyl, C 5-C 10Aromatic base or assorted aromatic base.
2. a class 2,4 according to claim 1,6-three replaces-1,3, the 5-triazine derivative is characterized in that: the derivative that comprises general formula, and optically active body or raceme, non-enantiomer mixture, or its pharmacy acceptable salt, hydrate or solvate.
3. a class 2,4, the preparation method of 6-three replacement-1,3,5-triazines analog derivatives is characterized in that realizing by following steps:
(1) formaldehyde-based resin IV and primary amine reaction, form the resin V of secondary amine structure by reduction amination: the temperature of reaction is between-10～100 ℃, and used solvent is selected ether solvent, chlorinated solvent, aromatic solvent or amide solvent for use;
(2) resin V and above-mentioned synthetic compound III reaction, obtain being connected with the resin VI of the female ring of triazine: add alkali as a catalyst in the reaction or do not add alkali, temperature of reaction is between 0～100 ℃, and used solvent is selected amide solvent, chlorinated solvent, aromatic solvent or ether solvent for use;
(3) resin VI and replacement primary amine or secondary amine reaction, obtain resin VII: add alkali as a catalyst in the reaction or do not add alkali, temperature of reaction is between 0～150 ℃, and used solvent is selected amide solvent, chlorinated solvent, aromatic solvent or ether solvent for use;
(4) resin VII cuts with cutting agent, obtain the crude product of target product-compound VIII, the purified pure products VIII that obtains: used cutting agent is selected trifluoroacetic acid for use, or the mixture of trifluoroacetic acid and organic solvent arbitrary volume ratio, and temperature of reaction is between 0～100 ℃.
4. a class 2 according to claim 3,4,6-three replaces-1,3, the preparation method of 5-triazine derivative is characterized in that: the used reduction amination reagent of step (1) is selected sodium cyanoborohydride, POTASSIUM BOROHYDRIDE, sodium borohydride, sodium triacetoxy borohydride, sodium borohydride-zinc chloride, hydroboration sodium-nickel chloride, zinc borohydride or borine for use.
5. a class 2 according to claim 3,4,6-three replaces-1,3, the preparation method of 5-triazine derivative is characterized in that: the used amide solvent of step (1) is selected dimethyl formamide or N,N-DIMETHYLACETAMIDE for use, used chlorinated solvent is selected methylene dichloride, ethylene dichloride or chloroform for use, used aromatic solvent is selected benzene, toluene or dimethylbenzene for use, and used ether solvent selects 1 for use, 4-dioxane, glycol dimethyl ether or tetrahydrofuran (THF).
6. a class 2 according to claim 3,4,6-three replaces-1,3, the preparation method of 5-triazine derivative, it is characterized in that: the alkali that step (2) is added is organic bases or mineral alkali, and organic bases is selected triethylamine, diisopropyl ethyl amine or pyridine for use, and mineral alkali is selected sodium bicarbonate, saleratus, yellow soda ash, salt of wormwood, cesium carbonate, sodium hydroxide or potassium hydroxide for use.
7. a class 2 according to claim 3,4,6-three replaces-1,3, the preparation method of 5-triazine derivative is characterized in that: the used amide solvent of step (2) is selected dimethyl formamide or N,N-DIMETHYLACETAMIDE for use, used chlorinated solvent is selected methylene dichloride, ethylene dichloride or chloroform for use, used aromatic solvent is selected benzene, toluene or dimethylbenzene for use, and used ether solvent selects 1 for use, 4-dioxane, glycol dimethyl ether or tetrahydrofuran (THF).
8. a class 2 according to claim 3,4,6-three replaces-1,3, the preparation method of 5-triazine derivative, it is characterized in that: the alkali that step (3) is added is organic bases or mineral alkali, and organic bases is selected triethylamine, diisopropyl ethyl amine or pyridine for use, and mineral alkali is selected sodium bicarbonate, saleratus, yellow soda ash, salt of wormwood, cesium carbonate, sodium hydroxide or potassium hydroxide for use.
9. a class 2 according to claim 3,4,6-three replaces-1,3, the preparation method of 5-triazine derivative is characterized in that: the used amide solvent of step (3) is selected dimethyl formamide or N,N-DIMETHYLACETAMIDE for use, used chlorinated solvent is selected methylene dichloride, ethylene dichloride or chloroform for use, used aromatic solvent is selected benzene, toluene or dimethylbenzene for use, and used ether solvent selects 1 for use, 4-dioxane, glycol dimethyl ether or tetrahydrofuran (THF).
10. a class 2,4,6-three replacement-1,3,5-triazines analog derivatives is characterized in that realizing by following steps:
(1) formaldehyde-based resin IV and primary amine reaction, form the resin V of secondary amine structure by reduction amination: reaction is at room temperature carried out, and used solvent is selected the employing dimethyl formamide for use;
(2) resin V and above-mentioned synthetic compound III reaction obtains being connected with the female resin VI that encircles of triazine: add alkali as a catalyst in the reaction or do not add alkali, reaction is at room temperature carried out, and used solvent is selected tetrahydrofuran (THF) for use;
(3) resin VI and replacement primary amine or secondary amine reaction, obtain resin VII: add alkali as a catalyst in the reaction or do not add alkali, be reflected under 100 ℃ of conditions and carry out, used solvent is selected dimethyl formamide for use;
(4) resin VII cuts with cutting agent, obtains the crude product of target product-compound VIII, the purified pure products VIII that obtains: the cutting agent of employing is a trifluoroacetic acid and the methylene chloride volume ratio is 1: 1 a mixture, and reaction is carried out at ambient temperature.
CN2008100630513A 2008-07-08 2008-07-08 2,4,6-tri-substituted-1,3,5-triazine derivates library and preparation method Expired - Fee Related CN101307029B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN2008100630513A CN101307029B (en) 2008-07-08 2008-07-08 2,4,6-tri-substituted-1,3,5-triazine derivates library and preparation method

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN2008100630513A CN101307029B (en) 2008-07-08 2008-07-08 2,4,6-tri-substituted-1,3,5-triazine derivates library and preparation method

Publications (2)

Publication Number Publication Date
CN101307029A true CN101307029A (en) 2008-11-19
CN101307029B CN101307029B (en) 2011-04-13

Family

ID=40123735

Family Applications (1)

Application Number Title Priority Date Filing Date
CN2008100630513A Expired - Fee Related CN101307029B (en) 2008-07-08 2008-07-08 2,4,6-tri-substituted-1,3,5-triazine derivates library and preparation method

Country Status (1)

Country Link
CN (1) CN101307029B (en)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105384702A (en) * 2015-12-11 2016-03-09 浙江大学 Tri-substituted sym-triazine compound and preparation method thereof
CN105399695A (en) * 2015-12-11 2016-03-16 浙江大学 Triazine-kind compounds, preparation method and applications
CN105503754A (en) * 2015-12-11 2016-04-20 浙江大学 2-amino-4-benzyl-6-morpholine-1,3,5-triazine and preparing and application thereof
US10946023B2 (en) 2013-07-11 2021-03-16 Agios Pharmaceuticals, Inc. Therapeutically active compounds and their methods of use
AU2019201179B2 (en) * 2013-07-11 2021-03-25 Les Laboratoires Servier Therapeutically active compounds and their methods of use
CN113004246A (en) * 2021-02-22 2021-06-22 广西医科大学 1,3, 5-triazine-2-amine-4, 6 substituted derivative or pharmaceutically acceptable salt and application thereof
CN115160242A (en) * 2022-06-14 2022-10-11 江苏鑫露化工新材料有限公司 Preparation method of organic intermediate N, N, N-tri (3' -aminopropyl) -1,3,5-triazine

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10946023B2 (en) 2013-07-11 2021-03-16 Agios Pharmaceuticals, Inc. Therapeutically active compounds and their methods of use
AU2019201179B2 (en) * 2013-07-11 2021-03-25 Les Laboratoires Servier Therapeutically active compounds and their methods of use
US11844758B2 (en) 2013-07-11 2023-12-19 Servier Pharmaceuticals Llc Therapeutically active compounds and their methods of use
CN105384702A (en) * 2015-12-11 2016-03-09 浙江大学 Tri-substituted sym-triazine compound and preparation method thereof
CN105399695A (en) * 2015-12-11 2016-03-16 浙江大学 Triazine-kind compounds, preparation method and applications
CN105503754A (en) * 2015-12-11 2016-04-20 浙江大学 2-amino-4-benzyl-6-morpholine-1,3,5-triazine and preparing and application thereof
CN113004246A (en) * 2021-02-22 2021-06-22 广西医科大学 1,3, 5-triazine-2-amine-4, 6 substituted derivative or pharmaceutically acceptable salt and application thereof
CN113004246B (en) * 2021-02-22 2022-02-01 广西医科大学 1,3, 5-triazine-2-amine-4, 6 substituted derivative or pharmaceutically acceptable salt and application thereof
CN115160242A (en) * 2022-06-14 2022-10-11 江苏鑫露化工新材料有限公司 Preparation method of organic intermediate N, N, N-tri (3' -aminopropyl) -1,3,5-triazine
CN115160242B (en) * 2022-06-14 2024-02-06 江苏鑫露化工新材料有限公司 Preparation method of organic intermediate N, N, N-tri (3' -aminopropyl) -1,3, 5-triazine

Also Published As

Publication number Publication date
CN101307029B (en) 2011-04-13

Similar Documents

Publication Publication Date Title
CN101307029B (en) 2,4,6-tri-substituted-1,3,5-triazine derivates library and preparation method
KR101174201B1 (en) 2-biphenylamino-4-aminopyrimidine derivatives as kinase inhibitors
CA3007990C (en) Polycyclic compounds as inhibitors of bruton's tyrosine kinase
EP4240362A1 (en) Diaminopyrimidine carboxamide inhibitors of hpk1
CN106188062A (en) Replace the preparation method of Buddhist nun according to Shandong, replace intermediate and the preparation method of intermediate of Buddhist nun according to Shandong
CN110078708B (en) Smo/Bcr-Abl dual-targeting inhibitor and synthetic method and application thereof
AU2022289869A1 (en) Anticancer compounds
CN101735198A (en) Novel method for preparing c-Met inhibitor PF22341066
CN103396386A (en) Di-substituted dinaphtho-[2,1-b:1',2'-d] furan derivative as well as preparation method and application thereof
CN103980282A (en) Method for synthesizing 3-oxo-pyrrol[2,3-b]indole compounds
JP6617106B2 (en) Imidazolin-5-one derivatives useful as FASN inhibitors for the treatment of cancer
CN105949196B (en) A kind of preparation method of MER/FLT3 double inhibitors intermediate
Mibu et al. Synthesis and Biological Evaluation of Symmetrical 2, 4, 6-Trisubstituted 1, 3, 5-Triazine Derivatives
CN101544636A (en) Polyhalogenated isoquinoline class derivate and synthetic method thereof
CN101245070B (en) Novel technique for synthesizing toroid quinazoline protein tyrosine kinase restrainer
CN114920684B (en) Selenium-containing benzamide compound and synthetic method and application thereof
CN105111175B (en) Synthetic method of 3-hydroxy-6-nitroflavone prepared through adopting one-step method
CN111233843A (en) Gamma-butenolide derivative and preparation method and application thereof
JPS61140568A (en) Quinazoline derivative, and hypotensor containing said derivative as active component
KR102662394B1 (en) Spiro[indoline-3,2'-piperidin] derivatives and method for producing the same
CN109180657A (en) The preparation method of STAT3 inhibitor
CN114560845B (en) Crystal form alpha of quinoline compound, and preparation method and application thereof
CN111533700B (en) 5-substituted uracil derivative and preparation method and application thereof
CN109180702A (en) A kind of Thienopyrimidine ketone compound and application thereof
KR102731401B1 (en) Compounds used as kinase inhibitors and their applications

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
C17 Cessation of patent right
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20110413

Termination date: 20110708