CN104876913B - Preparation method of 4,6-dimethyl-2-thiopyrimidine-1,2,3-triazole compound with antitumor activity - Google Patents
Preparation method of 4,6-dimethyl-2-thiopyrimidine-1,2,3-triazole compound with antitumor activity Download PDFInfo
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Abstract
The invention discloses a preparation method of a 4,6-dimethyl-2-thiopyrimidine-1,2,3-triazole compound with antitumor activity, which belongs to the field of antitumor drug synthesis technologies. The key point of the technical scheme of the invention is as follows: the method is implemented by taking a 4,6-dimethyl-2-thiopyrimidine terminal alkyne compound and a nitrine compound as raw materials, taking a copper wire as a catalyst and taking a supercutical fluid as a reaction solvent through reacting in a supercritical reaction device, so that a 4,6-dimethyl-2-thiopyrimidine-1,2,3-triazole compound is obtained. According to the invention, a supercritical fluid technology is applied to the process of synthesizing 4,6-dimethyl-2-thiopyrimidine-1,2,3-triazole compounds, so that the application of the reaction solvent is reduced, and a chemical reaction is quicker, time-saving, green and environmentally friendly, and reduces the energy consumption; and the catalyst used in a 'click' step is a fine copper wire in an electric wire, so that when the catalyst is separated, the fine copper wire can be taken out only by using tweezers, therefore, the operate is extremely simple and the fine copper wire can be repeatedly used.
Description
Technical field
The invention belongs to the synthesis technical field of anti-tumor activity medicine is and in particular to a kind of have the 4 of anti-tumor activity,
The preparation method of 6- dimethyl -2- mercaptopyrimidine -1,2,3- triazole compound.
Background technology
Pyrimidine is a class be made up of 2 nitrogen-atoms and 4 carbon atoms containing the hexa-member heterocycle gripping two keys altogether, pyrimidine ring
2,4,5,6 all can occur substitution reaction, generate corresponding substituted uracil compound.Although pyrimidine in nature not
Exist, but pyrimidines are the critically important materials of a class in vital movement, be widely present in human body and biology is internal, such as
In five kinds of bases of modal formation dna and rna in nucleic acid three kinds are the derivant of pyrimidine: cytosine, thymus pyrimidine
And uracil.In pesticide and medicine, the compound containing pyrimidine ring also occupies critically important status.Pesticide containing pyrimidine heterocyclic removes
Play an important role in parasite killing, sterilization and the big field of weeding three outer, also have extensive work at aspects such as plant growth regulations
With, and the medicine containing pyrimidine heterocyclic is concentrated mainly on antiviral and anti-tumor aspect, such as 5-fluorouracil, imatinib etc..4,
6- dimethyl -2- mercaptopyrimidine is a kind of pyrimidine cyclics containing sulfydryl, have leukemia, antithyroid enlargement,
The effects such as antifungal, antitumor and anti-tubercle bacillus growth, medically have potential application prospect, can serve as metal simultaneously
Buffer agent or electroplating additive (chemistry and biological engineering, 2007,10:77-78).In addition it has been reported that mercaptopyrimidine is permissible
Form monodentate or bidentate complex with many transition metal, and formed stable four-membered ring chelate or by n, s atom with
Three metallic atoms form cluster complexes, and these metal complexs similarly have biological activity, can produce antibacterial, convulsion and
Antitetanic effect (inorg. biochem., 1997,65 (3): 207-217).
Calendar year 2001, meldal and sharpless is independently found that copper catalysis azide end group acetylene compound
Additive reaction (cuaac), this reaction has raw material and is easy to get, and operation is simple, mild condition, product yield high, three-dimensional selection
Property good, the features such as product easy purification, post-reaction treatment and product separate simple and convenient.1,2,3- triazole group chemistry and
Field of medicaments has highly important status, and many contains the compound of 1,2,3- triazole ring structures, gives birth to well because having
Manage activity and be developed to various medicines.For example: beta-Lactam antibiotic Tazobactam Sodium, it is continue clavulanic acid, sulbactam two
The third after planting inhibitor is applied to clinical beta-lactamase inhibitor.Additionally, the azepine that " click-reaction " generates afterwards
Oxazolyl group has the stability of aromatic rings, is not easily decomposed, and can tolerate strong acid, highly basic, and can protect under multiple Redox Conditions
Keep steady fixed (j. org. chem., 2003,68:5381-5383).
Although the rise of supercritical liquid extraction technique only tens of year, due to this technology superior function and
Good application prospect, many scientific research personnel have carried out research extensively and profoundly, tentatively realize industrialization, become supercritical
The most ripe in fluid technique, most widely used one kind.Critical fluids have the diffusibility of similar gas and the dissolving energy of liquid
Power, has low-viscosity concurrently, the characteristic of low surface tension is so that supercritical fluid can quickly penetrate into the thing of micropore simultaneously
Matter.Thus be accordingly used in extraction rate during extraction quicker and effective than liquid, especially solvability can be with temperature, pressure and polarity
Change.Supercritical fluid mainly has as reaction medium: supercritical h2O and supercritical co2Chemical reaction as solvent.Research
Supercritical fluid chemical reaction has become exploitation Green Chemistry project the most active, particularly supercritical co2.Supercritical co2
Great advantage be nontoxic, non-combustible and cheap etc..In the state of supercritical, property can change carbon dioxide, and it is close
Degree is bordering on liquid, and viscosity is bordering on gas, and diffusion coefficient is 100 times of liquid, thus has surprising solvability.Supercritical two
The critical temperature of carbonoxide is 31.26 DEG C, and critical pressure is 7.3mpa, workable, and super critical condition readily satisfies.To surpass
Critical technology is applied to chemical sending out and answers, and reaction system material not only can be made to contact more abundant, effective collision increase, also more agree with
The theme of " Green Chemistry ".
Content of the invention
Present invention solves the technical problem that there is provided a kind of process is simple, be swift in response and energy-conserving and environment-protective have anti-swollen
The preparation method of the 4,6- dimethyl -2- mercaptopyrimidine -1,2,3- triazole compound of tumor activity.
The present invention is to solve above-mentioned technical problem to adopt the following technical scheme that, have 4, the 6- dimethyl of anti-tumor activity-
2- mercaptopyrimidine -1, the preparation method of 2,3- triazole compounds it is characterised in that: with 4,6- dimethyl -2- mercaptopyrimidine
End group acetylene compoundAnd azido compoundFor raw material, with copper wire as catalyst, with
Supercritical fluid is reaction dissolvent, reacts 4,6- dimethyl -2- mercaptopyrimidine -1 is obtained in supercritical reaction apparatus, 2,3- tri-
Nitrogen azole compounds, its general structure is, wherein substituent group r is cl, ch3、no2, in br or f
One or more, substituent group r be phenyl ring on ortho position, meta or para position.
Limit further, there are 4,6- dimethyl -2- mercaptopyrimidine -1 of anti-tumor activity, 2,3- triazole compounds
Preparation method, concretely comprise the following steps: weigh 4,6- dimethyl -2- mercaptopyrimidine end group acetylene compound, azido compound and urge
Agent copper wire is placed in supercritical reaction apparatus, reacts 0.5-2h in 60-80 DEG C, after completion of the reaction with dichloromethane by reactant
System's dissolution from supercritical reaction apparatus, then takes out catalyst copper wire with tweezers, rotation removes solvent, and column chromatography purification obtains 4,6-
Dimethyl -2- mercaptopyrimidine -1,2,3- triazole compound.
Limit further, described 4,6- dimethyl -2- mercaptopyrimidine end group compound is the potassium carbonate with acetone as solvent
For acid binding agent, 4,6- dimethyl -2- mercaptopyrimidines and propargyl bromide are obtained for raw material reaction, wherein 4,6- dimethyl -2- sulfydryl
The mol ratio of pyrimidine, propargyl bromide and acid binding agent potassium carbonate is 1:2.5:2.
Limit further, described 4,6- dimethyl -2- mercaptopyrimidine -1, the preparation process of 2,3- triazole compounds
The mol ratio of middle 4,6- dimethyl -2- mercaptopyrimidine end group acetylene compound, azido compound and catalyst copper wire is 1:1-2:
0.11-2.18.
Limit further, described catalyst is the copper wire extracted out from copper cash.Described supercritical fluid is supercritical
CO 2 fluid.
4,6- dimethyl -2- mercaptopyrimidine -1,2,3- triazole the chemical combination with anti-tumor activity of the present invention
Concrete reaction equation in the preparation method of thing is:
.
The invention has the advantages that (1) is according to medicine principle of hybridization, will have leukemia, anti-antifungal, antitumor
4,6- dimethyl -2- mercaptopyrimidine and the 1,2,3- triazole ring link with anti-hiv virus, antitumor isoreactivity Deng effect
Get up, play the effect such as good antitumor；(2) supercritical fluid technology is applied to synthesis 4,6- dimethyl -2- sulfydryl phonetic
Pyridine -1, during 2,3- triazole compounds, not only reduces the use of reaction dissolvent, and makes chemical reaction more fast
Speed, saving time, reducing energy consumption, environmental protection；(3) present invention catalyst used in " click " step is in electric wire
Thin copper wire, only need to be taken out with tweezers in separating catalyst, and operation is extremely simple and capable of circulation is used for multiple times.
Specific embodiment
By the following examples the above of the present invention is described in further details, but this should not be interpreted as this
The scope inventing above-mentioned theme is only limitted to below example, all belongs to this based on the technology that the above of the present invention is realized
Bright scope.
Reaction equation in preparation process is:
Embodiment 1
By 178.25mg (1mmol) compound (), 154.51mg (1mmol) neighbour's azido chlorobenzene and be coiled into spring-like
7.0mg thin copper wire sequentially adds in supercritical reaction apparatus, sets t=60 DEG C, and carbon dioxide is charged to 5.0mpa and (after stable is
9.0mpa), react 2h, use the dissolution from reaction unit by reaction system of 5ml dichloromethane after completion of the reaction, then taken with tweezers
Go out catalyst thin copper wire, rotation removes solvent, and chromatography over CC obtains compound 1 328.2mg, yield 98.91%.1h nmr (400
mhz, cdcl3):δ= 7.93 (s, 1h), 7.47 (m, 1h), 7.42 (m, 1h), 7.32 (m, 2h), 6.63
(s, 1h), 4.47 (s, 2h), 2.29 (s, 6h).
Embodiment 2
By azido chlorobenzene between 178.25mg (1mmol) compound (), 184.28mg (1.2mmol) and be coiled into spring-like
22.7mg thin copper wire sequentially add in supercritical reaction apparatus, set t=70 DEG C, carbon dioxide is charged to 4.5mpa (after stable
For 8.9mpa), react 1.5h, use the dissolution from reaction unit by reaction system of 5ml dichloromethane after completion of the reaction, then use tweezer
Son takes out catalyst thin copper wire, and rotation removes solvent, and chromatography over CC obtains compound 2 329.5mg, yield 99.30%.1h nmr
(400 mhz, cdcl3):δ= 7.97 (s, 1h), 7.74 (s, 1h), 7.60 (d, 1h), 7.44 (t, 1h),
7.39 (d, 1h), 6.75 (s, 1h), 4.58 (s, 2h), 2.43 (s, 6h).
Embodiment 3
178.25mg (1mmol) compound (), 266.01mg (2mmol) to azido toluene and are coiled into spring-like
110.8mg thin copper wire sequentially adds in supercritical reaction apparatus, sets t=80 DEG C, and carbon dioxide is charged to 4.0mpa and (after stable is
11.9mpa), react 1.5h, use the dissolution from reaction unit by reaction system of 5ml dichloromethane after completion of the reaction, then use tweezer
Son takes out catalyst thin copper wire, and rotation removes solvent, and chromatography over CC obtains compound 3 309.2mg, yield 99.42%.1h nmr
(400 mhz, cdcl3):δ= 7.93 (s, 1h), 7.56 (d, 2h), 7.29 (d, 2h), 6.74 (s, 1h),
4.59 (s, 2h), 2.44 (d, 9h).
Embodiment 4
By 178.25mg (1mmol) compound (), 266.01mg (2mmol) neighbour's azido toluene and be coiled into spring-like
67.8mg thin copper wire sequentially adds in supercritical reaction apparatus, sets t=70 DEG C, and carbon dioxide is charged to 5.0mpa and (after stable is
8.5mpa), react 0.5h, use the dissolution from reaction unit by reaction system of 5ml dichloromethane after completion of the reaction, then use tweezers
Take out catalyst thin copper wire, rotation removes solvent, and chromatography over CC obtains compound 4 308.3mg, yield 99.13%.1h nmr (400
mhz, cdcl3):δ=7.67 (s, 1h), 7.27 (t, 1h), 7.23 (d, 1h), 7.19 (d, 2h), 6.64
(s, 1h), 4.49 (s, 2h), 2.30 (s, 6h), 2.07 (s, 3h).
Embodiment 5
By 178.25mg (1mmol) compound (), 164.01mg (1mmol) neighbour's azido Nitrobenzol and be coiled into spring-like
10.8mg thin copper wire sequentially add in supercritical reaction apparatus, set t=70 DEG C, carbon dioxide is charged to 5.0mpa (after stable
For 8.8mpa), react 0.5h, use the dissolution from reaction unit by reaction system of 5ml dichloromethane after completion of the reaction, then use tweezer
Son takes out catalyst thin copper wire, and rotation removes solvent, and chromatography over CC obtains compound 5 336.7mg, yield 98.34%.1h nmr
(400 mhz, cdcl3):δ= 8.05 (t, 1h), 7.84 (s, 1h), 7.80 (m, 1h), 7.78 (m, 2h),
6.75 (s, 1h), 4.59 (s, 2h), 2.44 (s, 6h).
Embodiment 6
178.25mg (1mmol) compound (), 164.01mg (1mmol) to azido Nitrobenzol and are coiled into spring-like
75.6mg thin copper wire sequentially add in supercritical reaction apparatus, set t=70 DEG C, carbon dioxide is charged to 5.0mpa (after stable
For 8.3mpa), react 0.5h, use the dissolution from reaction unit by reaction system of 5ml dichloromethane after completion of the reaction, then use tweezer
Son takes out catalyst thin copper wire, and rotation removes solvent, and chromatography over CC obtains compound 6 338.3mg, yield 98.81%.1h nmr
(400 mhz, cdcl3):δ= 8.39 (d, 2h), 8.10 (s, 1h), 7.94 (d, 2h), 6.76 (s, 2h),
4.59 (s, 2h), 2.43 (s, 6h).
Embodiment 7
By azido Nitrobenzol between 178.25mg (1mmol) compound (), 164.01mg (1mmol) and be coiled into spring-like
8.3mg thin copper wire sequentially add in supercritical reaction apparatus, set t=70 DEG C, carbon dioxide is charged to 5.0mpa and (after stable is
9.8mpa), react 0.5h, use the dissolution from reaction unit by reaction system of 5ml dichloromethane after completion of the reaction, then use tweezers
Take out catalyst thin copper wire, rotation removes solvent, and chromatography over CC obtains compound 7 335.8mg, yield 98.08%.1h nmr (400
mhz, cdcl3):δ= 8.54 (s, 1h), 8.28 (d, 1h), 8.15 (d, 1h), 8.10 (s, 1h), 7.74
(t, 1h), 6.76 (s, 1h), 4.60 (s, 2h), 2.44 (s, 6h).
Embodiment 8
178.25mg (1mmol) compound (), 237.60mg (1.2mmol) to azido bromobenzene and are coiled into spring-like
140.0mg thin copper wire sequentially add in supercritical reaction apparatus, set t=70 DEG C, carbon dioxide is charged to 5.0mpa (after stable
For 10.3mpa), react 0.5h, after completion of the reaction use 5ml dichloromethane by reaction system dissolution from reaction unit, Ran Houyong
Tweezers take out catalyst thin copper wire, and rotation removes solvent, and chromatography over CC obtains compound 8 374.8mg, yield 99.61%.1h nmr
(400 mhz, cdcl3):δ= 7.59 (s, 1h), 7.58 (t, 4h), 6.72 (s, 1h), 4.55 (s, 2h),
2.40 (s, 6h).
Embodiment 9
By 178.25mg (1mmol) compound (), 164.53mg (1.2mmol) neighbour's azido fluorobenzene and be coiled into spring-like
126.7mg thin copper wire sequentially add in supercritical reaction apparatus, set t=70 DEG C, carbon dioxide is charged to 5.0mpa (after stable
For 10.0mpa), react 1.0h, after completion of the reaction use 5ml dichloromethane by reaction system dissolution from reaction unit, Ran Houyong
Tweezers take out catalyst thin copper wire, and rotation removes solvent, and chromatography over CC obtains compound 9 314.1mg, yield 99.60%.1h nmr
(400 mhz, cdcl3):δ= 8.12 (d, 1h), 7.97 (t, 1h), 7.41 (q, 1h), 7.28 (q, 2h),
6.73 (s, 1h), 4.58 (s, 2h), 2.43 (s, 6h).
Embodiment 10
By 178.25mg (1mmol) compound (), 161.10mg (1.2mmol) 2,6- dimethyl -4- azido toluene
Sequentially add in supercritical reaction apparatus with the 125.1mg thin copper wire being coiled into spring-like, set t=80 DEG C, carbon dioxide is charged to
5.0mpa (being 11.1mpa after stable), reacts 2.0h, uses 5ml dichloromethane by reaction system from reaction unit after completion of the reaction
Middle dissolution, then takes out catalyst thin copper wire with tweezers, rotation removes solvent, and chromatography over CC obtains compound 10 337.5mg, yield
99.56%.1h nmr (400 mhz, cdcl3):δ=7.55 (s, 1h), 6.96 (s, 2h), 6.72 (s, 1h),
4.60 (s, 2h), 2.40 (s, 6h), 2.33 (s, 3h), 1.91 (s, 6h).
Embodiment 11
By 178.25mg (1mmol) compound (), 142.80mg (1.2mmol) aziminobenzene be coiled into spring-like
110.6mg thin copper wire sequentially adds in supercritical reaction apparatus, sets t=70 DEG C, and carbon dioxide is charged to 5.0mpa and (after stable is
10.9mpa), react 2.0h, use the dissolution from reaction unit by product of 5ml dichloromethane after completion of the reaction, then taken with tweezers
Go out catalyst thin copper wire, rotation removes solvent, and chromatography over CC obtains compound 11 296.1mg, yield 99.57%.1h nmr (400
mhz, cdcl3):δ= 7.97 (s, 1h), 7.67 (d, 2h), 7.48 (t, 2h), 7.41 (t, 1h), 6.73
(s, 1h), 4.58 (s, 2h), 2.41 (s, 6h).
Embodiment 12
By 178.25mg (1mmol) compound (), 213.78mg (1.2mmol) 2- nitro -6- azido toluene and around
The 40.3mg thin copper wire becoming spring-like sequentially adds in supercritical reaction apparatus, sets t=70 DEG C, carbon dioxide is charged to 5.0mpa
(being 9.0mpa after stable), reacts 1.5h, uses the dissolution from reaction unit by product of 5ml dichloromethane after completion of the reaction, then
Take out catalyst thin copper wire with tweezers, rotation removes solvent, and chromatography over CC obtains compound 12 350.7mg, yield 98.40%.1h
nmr (400 mhz, cdcl3):δ= 8.02 (d, 1h), 7.76 (s, 1h), 7.61 (d, 1h), 7.51 (t,
1h), 6.75 (s, 1h), 4.60 (s, 2h), 2.42 (s, 6h), 2.25 (s, 3h).
Embodiment 13
Biological activity determination
Take the centrifuge tube after 12 1.5ml sterilizings, numbering 1-12 respectively, 4, the 6- diformazan of corresponding 12 kinds of embodiments synthesis
Base -2- mercaptopyrimidine -1,2,3- triazole compounds, it is made into 10mg/ml solution with dmso, separately take the centrifuge tube after a sterilizing
Dmso is only added to make blank, it is standby that vibration is placed in 4 DEG C of refrigerators after mixing.With dmem culture fluid, ehrlich ascites cell is diluted to
3×106Individual/ml.Use 96 well culture plates, every hole adds states cell culture fluid 0.2ml.By 12 kinds of 4,6- bis- synthesized by the present invention
Methyl -2- mercaptopyrimidine -1,2,3- triazole compounds and 5-fluorouracil add to every hole 20ml in above-mentioned culture fluid respectively,
5-fluorouracil compares, and anti tumor activity in vitro test data see table:
Embodiment 14
Biological activity determination
Take the centrifuge tube after 12 1.5ml sterilizings, numbering 1-12 respectively, 4, the 6- diformazan of corresponding 12 kinds of embodiments synthesis
Base -2- mercaptopyrimidine -1,2,3- triazole compounds, it is made into 10mg/ml solution with dmso, separately take the centrifuge tube after a sterilizing
Dmso is only added to make blank, it is standby that vibration is placed in 4 DEG C of refrigerators after mixing.With rpmi-1640 culture fluid by hepatoma carcinoma cell bel-
7402 are diluted to 1 × 105Individual/ml.Use 96 well culture plates, every hole adds states cell culture fluid 0.2ml.By synthesized by the present invention
12 kinds of 4,6- dimethyl -2- mercaptopyrimidine -1,2,3- triazole compounds and 5-fluorouracil add to above-mentioned culture respectively
Every hole 20ml in liquid, 5-fluorouracil compares, and anti tumor activity in vitro test data see table:
Embodiment above describes ultimate principle, principal character and the advantage of the present invention, the technical staff of the industry should
Understand, the present invention is not restricted to the described embodiments, the simply explanation present invention's described in above-described embodiment and description is former
Reason, under the scope without departing from the principle of the invention, the present invention also has various changes and modifications, and these changes and improvements each fall within
In the scope of protection of the invention.
Claims (5)
1. there is 4,6- dimethyl -2- mercaptopyrimidine -1 of anti-tumor activity, the preparation method of 2,3- triazole compounds, its
It is characterised by: with 4,6- dimethyl -2- mercaptopyrimidine end group acetylene compoundAnd azido compoundFor raw material, with copper wire as catalyst, with supercritical carbon dioxide fluid as reaction dissolvent, in supercritical reaction
React in device and 4,6- dimethyl -2- mercaptopyrimidine -1,2,3- triazole compounds are obtained, its general structure is, wherein substituent group r is cl, ch3、no2, one or more of br or f, substituent group r is benzene
Ortho position on ring, meta or para position.
2. the 4,6- dimethyl -2- mercaptopyrimidine -1,2,3- triazole with anti-tumor activity according to claim 1
The preparation method of compound is it is characterised in that concretely comprise the following steps: weighs 4,6- dimethyl -2- mercaptopyrimidine end group acetylenic chemical combination
Thing, azido compound and catalyst copper wire are placed in supercritical reaction apparatus, react 0.5-2h in 60-80 DEG C, after completion of the reaction
With dichloromethane dissolution from supercritical reaction apparatus by reaction system, then take out catalyst copper wire with tweezers, rotation removes solvent,
Column chromatography purification obtains 4,6- dimethyl -2- mercaptopyrimidine -1,2,3- triazole compound.
3. 4,6- dimethyl -2- mercaptopyrimidine -1,2,3- three nitrogen with anti-tumor activity according to claim 1 and 2
The preparation method of azole compounds it is characterised in that: described 4,6- dimethyl -2- mercaptopyrimidine end group acetylene compound be with
Acetone is solvent, and potassium carbonate is acid binding agent, and 4,6- dimethyl -2- mercaptopyrimidines and propargyl bromide are that raw material reaction is prepared, wherein
The mol ratio of 4,6- dimethyl -2- mercaptopyrimidine, propargyl bromide and acid binding agent potassium carbonate is 1:2.5:2.
4. the 4,6- dimethyl -2- mercaptopyrimidine -1,2,3- triazole with anti-tumor activity according to claim 1
The preparation method of compound it is characterised in that: described 4,6- dimethyl -2- mercaptopyrimidine -1,2,3- triazole compounds
Preparation process in 4,6- dimethyl -2- mercaptopyrimidine end group acetylene compound, azido compound and catalyst copper wire mole
Than for 1:1-2:0.11-2.18.
5. the 4,6- dimethyl -2- mercaptopyrimidine -1,2,3- triazole with anti-tumor activity according to claim 1
The preparation method of compound it is characterised in that: described catalyst is the copper wire extracted out from copper cash.
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| Copper(II)-Promoted Regioselective Synthesis of 1,4-Disubstituted 1,2,3-Triazoles in Water;K.Rajender Reddy et al.;《Synlett》;20060221;957-959 * |
| 苯并咪唑炔丙基硫醚的绿色合成;郑文涛等;《河南师范大学学报（自然科学版）》;20130731;第41卷(第4期);106-108 * |
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