CN106632301A - Method for synthesizing pyridine bithiazole carboxylic acid derivative - Google Patents
Method for synthesizing pyridine bithiazole carboxylic acid derivative Download PDFInfo
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- HYUPDIZNKUEZLD-UHFFFAOYSA-N OC(C1N=C(C2=CC=CNC2)SC1)=O Chemical compound OC(C1N=C(C2=CC=CNC2)SC1)=O HYUPDIZNKUEZLD-UHFFFAOYSA-N 0.000 description 1
- LJGAQGZEJDQDAU-UHFFFAOYSA-N OC(C1N=C(c2cccnc2)SC1)=O Chemical compound OC(C1N=C(c2cccnc2)SC1)=O LJGAQGZEJDQDAU-UHFFFAOYSA-N 0.000 description 1
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- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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Abstract
The invention discloses a method for synthesizing a pyridine bithiazole carboxylic acid derivative. First pyridine bithiazole carboxylic acid is synthesized, a derivative of pyridine bithiazole carboxylic acid is synthesized by replacement, pyridine dihydro thiazole carboxylic acid is generated mainly by reaction between cyanopridine and L-cysteine hydrochloride, and after pyridine dihydro thiazole carboxylic acid forms acyl chloride, amidation or esterification is formed. The synthesis method is simple in the operation process, thiazole can be synthesized without thiazoline, the yield is high, synthesized pyridine bithiazole amide and pyridine bithiazole ester have good bacteriostatic activity and antitumor activity and can be applied well to the fields of medicines and pesticides, and the method provides a new thoughts for creation of novel pesticides.
Description
Technical field
The present invention relates to a kind of pyridine joins the synthetic method of thiazoless carboxylic acid derivates, belong to chemosynthesis technical field.
Background technology
The compound of nitrogen heterocyclic ring structure plays more and more important in the initiative application of current medical drugs and agricultural medicine
Role, wherein thiazole, pyridine compounds and their become the emphasis of new medicine and pesticide research because of its extensive biological activity
And focus.At present in the research and development and initiative of new medical drugs and agricultural medicine, pyridine, thiazoless application it is more and more extensive, in people
Play an increasingly important role during body health treatment and disease of agricultural plants preventing and treating.Pyridine, thiazole compound are current
The focus and key areas of medicine and pesticide research.
Document about pyridine di- hydrogen thiazole carboxylic acid preparation, the report such as Oleg V.Maltsev (Synthesis, 2013,
2763-2767) nicotinonitrile, cysteine hydrochloride are solvent room temperature in sodium bicarbonate and sodium hydroxide mixed base, methanol
It is prepared by reaction;, report (Chemiker-Zeitung, 1987,111,357-61) the 3- cyano group pyrroles such as Hans PeterKrimmer
Pyridine, cysteine hydrochloride potassium carbonate be alkali, methanol-water be solvent reaction synthesis.Document report pyridine joins thiazole carboxylic acid (WO
2012007500) react to prepare in sodium hydroxid aqueous solution with 3-BrPA ethyl ester by Thionicotinamide;Patent WO
2003027085 prepare Thionicotinamide with 4- methyl-nicotinonitrile, then pyridine connection thiazole is synthesized with 3-BrPA
Carboxylic acid.And manganese dioxide method (Mark is typically used by pyridine connection thiazoline derivatives pyridine synthesis connection thiazole
C.Bagley,Journal ofOrganic Chemistry,2005,70,1389-1399)。
The content of the invention
In view of the shortcomings of the prior art, the invention provides a kind of pyridine joins the synthesis side of thiazoless carboxylic acid derivates
Method.
To achieve these goals, the present invention is by the following technical solutions realizing:
A kind of pyridine joins the synthetic method of thiazoless carboxylic acid derivates, first pyridine synthesis di- hydrogen thiazoless carboxylic acid, then acyl
Chlorination, acyl chlorides is synthesized its derivant with aminated compoundss or alcohol.
A kind of described pyridine joins the synthetic method of thiazole derivative, the concrete conjunction of the pyridine di- hydrogen thiazole carboxylic acid
It is into method:3- cyano group-R- pyridines, L-cysteine hydrochloride, sodium bicarbonate are placed in reaction vessel, anhydrous second is added
Alcohol, heats 12 hours at 90 DEG C, until raw material reaction is complete, is cooled to room temperature, and rotation is gone dehydrated alcohol to obtain Off-white solid, uses water
Dissolving, under condition of ice bath, is slowly added to hydrochloric acid solution, to pH value of solution=3-4 is determined, separates out white solid, sucking filtration, then uses ice
Water washing 2-3 time, after being dried pyridine di- hydrogen thiazole carboxylic acid is obtained.
A kind of described pyridine joins the synthetic method of thiazole derivative, and the cyanopyridines are 3- cyano group pyrroles
Pyridine, 4- methyl-nicotinonitrile, the chloro- nicotinonitriles of 2-.
A kind of described pyridine joins the synthetic method of thiazole derivative, the 3- cyano group-R- pyridines and L-Cysteine
The mol ratio of hydrochlorate is 1:1.5-1:2.5.
A kind of described pyridine joins the synthetic method of thiazole derivative, takes compound pyridine di- hydrogen thiazole carboxylic acid in anti-
In answering container, add dichloromethane to make solvent, thionyl chloride is slowly instilled under condition of ice bath, remove ice bath, react under room temperature
18 hours, steaming vibrating dichloromethane after reacting completely obtained intermediate product A, added 15mL dichloromethane dissolving intermediate product A,
Under zero degrees celsius, triethylamine is added dropwise in reactant liquor, aminated compoundss are then added dropwise over again, ice bath is removed, under room temperature
Reaction 16h, until raw material is wholly absent;Saturation NaHCO is added in reaction system3Aqueous solution uses dichloromethane reaction is quenched
Alkane is extracted, the washing of saturation NaCl solution, anhydrous Na2SO4It is dried, filters, steaming vibrating dichloromethane uses DCM:MeOH=40:1~10:
1 or PE:EA=5:1~3:1, obtain pyridine connection thiazoless amide.
A kind of described pyridine joins the synthetic method of thiazole derivative, takes compound pyridine di- hydrogen thiazole carboxylic acid in anti-
In answering container, alcohol compound is added, thionyl chloride is slowly instilled under condition of ice bath, remove ice bath, be heated to 80 DEG C, backflow
4h, reaction is complete, is spin-dried for solvent, adds saturation NaHCO3Solution, is extracted three times with DCM, then is washed with saturation NaCl, anhydrous
Na2SO4It is dried, is spin-dried for solvent, column chromatography PE:EA=2:1, obtain pyridine connection thiazoless ester.
Beneficial effects of the present invention:
The synthetic method operating process of the present invention is simple, needs not move through synthetizing thiazolium by thiazoline, high income, synthesis
Pyridine di- hydrogen thiazole carboxylic acid there is good bacteriostatic activity, while pyridine di- hydrogen thiazole carboxylic acid can further pyridine synthesis
Connection thiazoless amide and pyridine connection thiazoless ester, can well be applied in medical and agricultural medicine field, be novel pesticide with
The creation of medicine provides new thinking, with good development prospect.
Specific embodiment
Technological means, creation characteristic, reached purpose and effect to make present invention realization is easy to understand, with reference to
Specific embodiment, is expanded on further the present invention.
Embodiment 1
Pyridine di- hydrogen thiazole carboxylic acid's synthetic reaction formula is:
The structural formula of the pyridine di- hydrogen thiazole carboxylic acid is as follows:
Weigh nicotinonitrile (10mmol, 1.04g), L-cysteine hydrochloride (15mmol), sodium bicarbonate
(60mmol) in 100mL round-bottomed flasks, add dehydrated alcohol 30mL, at 90 DEG C heat 12 hours, until raw material reaction it is complete,
Room temperature is cooled to, rotation goes dehydrated alcohol to obtain Off-white solid.With water dissolution, under condition of ice bath, hydrochloric acid solution is slowly added to (dense
Spend for 2mol/L), to pH value of solution=3-4 is determined, substantial amounts of white solid, sucking filtration are separated out in reaction system, then washed with frozen water
2-3 time, compound pyridine di- hydrogen thiazole carboxylic acid A1 is obtained after being dried, white solid, yield is 87%.
Its chemical characterization is:1H-NMR(300MHz,CDCl3),δ(ppm):8.95 (1H, d, J=1.8Hz), 8.75 (1H,
Dd, J=1.2Hz, J=4.8Hz), 8.17 (1H, d, J=7.8Hz), 7.55 (1H, dd, J=1.8Hz, J=4.8Hz), 5.35
(1H, t, J=9.0Hz), 3.81~3.64 (2H, m).
13C-NMR(75MHz,CDCl3),δ(ppm):171.5,166.2,152.4,148.5,135.6,128.1,124.0,
78.2,35.2.
Weigh 4- methyl-nicotinonitrile (10mmol, 1.04g), L-cysteine hydrochloride (20mmol), sodium bicarbonate
(60mmol) in 100mL round-bottomed flasks, add dehydrated alcohol 30mL, at 90 DEG C heat 12 hours, until raw material reaction it is complete,
Room temperature is cooled to, rotation goes dehydrated alcohol to obtain Off-white solid.With water dissolution, under condition of ice bath, hydrochloric acid solution is slowly added to (dense
Spend for 2mol/L), to pH value of solution=3-4 is determined, substantial amounts of white solid, sucking filtration are separated out in reaction system, then washed with frozen water
2-3 time, compound pyridine di- hydrogen thiazole carboxylic acid A2 is obtained after being dried, white solid, yield is 91%.
Its chemical characterization is:1H-NMR(300MHz,CDCl3),δ(ppm):8.66 (1H, s), 8.54 (1H, d, J=
4.8Hz), 7.40 (1H, d, J=4.8Hz), 5.45~5.39 (1H, m), 3.80~3.65 (2H, m), 2.51 (3H, s).
13C-NMR(75MHz,CDCl3),δ(ppm):171.6,165.8,150.8,149.4,146.2,128.7,126.1,
78.8,35.4,19.9
Weigh the chloro- nicotinonitriles of 2- (10mmol, 1.04g), L-cysteine hydrochloride (25mmol), sodium bicarbonate
(60mmol) in 100mL round-bottomed flasks, add dehydrated alcohol 30mL, at 90 DEG C heat 12 hours, until raw material reaction it is complete,
Room temperature is cooled to, rotation goes dehydrated alcohol to obtain Off-white solid.With water dissolution, under condition of ice bath, hydrochloric acid solution is slowly added to (dense
Spend for 2mol/L), to pH value of solution=3-4 is determined, substantial amounts of white solid, sucking filtration are separated out in reaction system, then washed with frozen water
2-3 time, after being dried compound pyridine di- hydrogen thiazole carboxylic acid A3 is obtained, shallow crocus pulverulent solids, yield is 88%.
Its chemical characterization is:1H-NMR(300MHz,CDCl3),δ(ppm):8.54 (1H, d, J=2.4Hz), 8.11 (1H,
D, J=6.9Hz), 7.56~7.52 (1H, m), 5.32 (1H, t, J=9.0Hz), 3.82~3.68 (2H, m).
13C-NMR(75MHz,CDCl3),δ(ppm):171.3,165.0,151.3,147.4,139.9,128.7,123.3,
78.1,36.3.
The pyridine of embodiment 2 joins thiazoless amide synthetic reaction formula:
The structural formula of the pyridine connection thiazole carboxylic acid amides is as follows:
Weigh Compound pyridine di- hydrogen thiazole carboxylic acid A (0.2mmol) adds dichloromethane in 25mL round-bottomed flasks
(8mL) make solvent, 0.14mL thionyl chlorides are slowly instilled under condition of ice bath, remove ice bath, react 18 hours under room temperature, decompression
It is evaporated, adds the dissolving of 15mL dichloromethane, under zero degrees celsius, triethylamine (2.5eq), Ran Houyong is added dropwise in reactant liquor
Syringe is added dropwise over again amine (1.1eq), to remove and react 16h under ice bath, room temperature, until raw material is wholly absent.To reaction system
Middle addition 20mL saturations NaHCO3Aqueous solution is quenched reaction, is extracted with the dichloromethane of 3 × 15mL, and 25mL saturation NaCl solutions are washed
Wash, anhydrous Na2SO4It is dried, filters, steaming vibrating dichloromethane uses DCM:MeOH=40:1~10:1 or PE:EA=5:1~3:1, obtain
To target product B.
The chemical characterization of target product pyridine connection thiazole carboxylic acid amides B1 is as follows:Yellow oily liquid, yield is 78%;1H-
NMR(300MHz,CDCl3),δ(ppm):9.20 (1H, d, J=2.1Hz), 8.72~8.68 (2H, m), 8.23~8.20 (1H,
M), 8.15 (1H, s), 7.42 (1H, dd, J=3.4Hz, J=8.1Hz), 3.60 (2H, q, J=6.0Hz), 2.63~2.55
(6H, m), 1.84~1.75 (2H, m), 1.08 (6H, t, J=7.2Hz).13C-NMR(75MHz,CDCl3),δ(ppm):164.5,
160.8,151.9,151.2,147.7,133.7,129.1,123.8,123.3,52.0,47.1,39.5,26.0,11.7.
The chemical characterization of target product pyridine connection thiazole carboxylic acid amides B2 is as follows:Orange red color oily liquids, yield is 74%
;1H-NMR(300MHz,CDCl3),δ(ppm):8.88 (1H, s), 8.54 (1H, d, J=2.1Hz), 8.44 (1H, s), 8.23
(1H, s), 7.71 (1H, d, J=7.8Hz), 7.36 (1H, d, J=7.8Hz), 7.10~7.26 (4H, m), 4.65 (2H, t, J=
7.2Hz), 3.27 (2H, t, J=7.2Hz), 2.61 (3H, s).
13C-NMR(75MHz,CDCl3),δ(ppm):164.7,161.4,150.4,150.0,148.0,146.2,136.3,
128.98.128.3,127.5,126.1,122.4,122.1,119.4,118.8,111.6,111.3,65.7,24.8,20.8.
The chemical characterization of target product pyridine connection thiazole carboxylic acid amides B3 is as follows:Yellow oily liquid, yield is 73%, is melted
Journey:91.5~93.1 DEG C,1H-NMR(300MHz,CDCl3),δ(ppm):8.58 (1H, dd, J=1.8Hz, J=7.8Hz), 8.44
(1H, dd, J=1.8Hz, J=4.5Hz), 8.32 (1H, s), 7.83 (1H, s), 7.39~7.25 (6H, m), 4.69 (2H, d, J
=6.0Hz).
13C-NMR(75MHz,CDCl3),δ(ppm):161.5,160.8,150.3,149.9,148.3,139.2,138.1,
128.8,128.1,127.9,127.6,125.6,122.8,43.4.
The pyridine of embodiment 3 joins thiazoless ester synthesis reaction formula:
The structural formula of the pyridine connection thiazole carboxylic ester is as follows:
Weigh Compound A (0.5mmoL), in 25mL round-bottomed flasks, adds the dissolving of 10eq alcohol, slowly drips under zero degrees celsius
Plus 0.145mL thionyl chlorides, 80 DEG C are heated to, flow back 4h, and reaction is complete, is spin-dried for solvent, adds 10mL saturations NaHCO3Solution
Solution, is extracted three times with 3 × 10Ml DCM, then is washed with 15mL saturations NaCl, anhydrous Na2SO4It is dried, is spin-dried for solvent, column chromatography
PE:EA=2:1, obtain target compound C.
Target product C1's is characterized as below:White solid, yield is 75%, melting range:114.4~115.9 DEG C;1H-NMR
(300MHz,CDCl3),δ(ppm):9.19 (1H, d, J=1.8Hz), 8.70 (1H, dd, J=0.9Hz, J=4.5Hz), 8.35
(1H, dd, J=1.8Hz, J=8.1Hz), 8.21 (1H, s), 7.44~7.38 (3H, m), 6.93~6.90 (2H, d, J=
8.4Hz),5.37(2H,s),3.82(3H,s).
13C-NMR(75MHz,CDCl3),δ(ppm):165.4,161.1,159.9,151.5,148.3,148.0,134.2,
130.51,128.9,127.9,127.7,123.8,114.0,67.1,55.3
Target product C2's is characterized as below:White powdery solids, yield is 70%, melting range:76.3~76.8 DEG C;1H-
NMR(300MHz,CDCl3),δ(ppm):8.78 (1H, s), 8.43 (1H, d, J=4.8Hz), 8.21 (1H, s), 7.15 (1H, d,
), J=4.5Hz 4.36 (2H, q, J=6.9Hz), 2.51 (3H, s), 1.33 (3H, t, J=7.2Hz).
13C-NMR(75MHz,CDCl3),δ(ppm):164.6,161.2,150.4,145.0,1478.0,145.9,
128.8,128.1,125.9,61.5,20.6,14.3.
Target product C3's is characterized as below:White powdery solids, yield is 82%, melting range:98.8~99.5 DEG C,1H-
NMR(300MHz,CDCl3),δ(ppm):8.76 (1H, dd, J=1.8Hz, J=7.8Hz), 8.47 (1H, dd, J=1.8Hz, J
=4.5Hz), 8.34 (1H, s), 7.46 (1H, t, J=1.8Hz), 7.41 (1H, dd, J=4.8Hz, J=8.1Hz), 6.54
(1H, d, J=3.3Hz), 6.40 (1H, t, J=1.8Hz), 5.38 (2H, s).
13C-NMR(75MHz,CDCl3),δ(ppm):162.2,160.8,150.4,149.1,148.2,146.6,143.5,
139.9,129.7,128.2,122.9,111.4,110.7,58.9.
Antibacterial Activity is tested
(1) making of culture medium
5 grams of Sodium Chloride, 10 grams of peptones and 5 grams of yeast extracts are weighed, is dissolved respectively in the hot water, heated and boiled
(LB solid mediums by boiling of agar), constant volume is 1L.During the culture medium for preparing is sub-packed in into triangular flask or test tube, it is placed on
Autoclave high temperature sterilizes 20 minutes.
(2) solvent is selected
Choose acetone:Water=10:The mixed solution of 1 (V/V) is configured to as the solvent of pyridine di- hydrogen thiazole carboxylic acid
The compound solution A of 500ppm;
Streptomycin sulfate solution B of 500ppm is prepared with distilled water;Use acetone:Water=10:The mixed solution of 1 (V/V) is made
For solvent control C.
(3) experimental procedure
The solution for later use that a certain amount of noval chemical compound is configured to 500ppm is dissolved with solvent, is inoculated with LB fluid mediums
Pseudomonas syringae, is placed in being cultivated 24 hours in 25 DEG C of incubators.Take about 0.3ml bacterium solutions to be spread evenly across on LB plates, dry in the air
It is dry, with filter paper adsorption solvent, streptomycin sulfate solution and noval chemical compound solution, again filter paper is placed on into three of plate respectively
On point, it is placed in cultivating 24-36 hours in 25 DEG C of incubators, the size of aseptic circle around observation filter paper, parallel three times.
Experimental result see the table below:
It can be seen that, the growth of pyridine connection thiazole carboxylic acid amides and pyridine connection thiazole carboxylic acid ester to pseudomonas syringae has significantly
Inhibitory action.
The active anticancer experiment of pyridine connection thiazole compound
(1) configuration of buffer:Buffer solution a:With hydrochloric acid solution 50mM Tris and 18mM NaCl is adjusted to the solution
PH=7.20.Buffer solution b:5 × reaction terminating liquid:0.25% bromophenol blue, 4.5%SDS and 45% glycerol.TBE running buffers
Solution:4.5g EDTA, 27.5g H3BO3 and 54g Tris are dissolved in 1000mL redistilled waters, the boric acid of SXTBE is obtained
System solution, needs for solution to dilute 5 times when using, and finally obtains the H3BO3 solution that concentration is 89mM, 89mM Tris and 2mM
EDTA (pH=8.3).
(2) agarose gel electrophoresiies experiment
The complex solution of different volumes is separately added in the solution of the DNA containing equivalent, is mixed, pipette the anti-of 20uL
Whole solution is answered, is irradiated under the long light sources of 365nm after certain hour and is added bromophenol blue solution terminating reaction.The fine jade of loading to 0.8%
In sepharose plate hole groove, with 95V electrophoresis 1.2 hours in TBE.The last record analyses under chemiluminescence Image analysis system
Electrophoresis picture.
(3) Topo II Inhibition tests
Topo II are bought in GE companies, are directly used.Reactant mixture (20uL) includes 10mM Tris-HCl (pH=
7.9), 5.0mM MgC12,50mM KCI, 50mM NaCI, 15ug/mL BSA, 1.0mM ATP, 0.1mM EDTA, 2Unit
Ru (II) coordination compound of variable concentrations in Topo II, 0.1ug pBR322DNA and certain limit.Will reaction under the conditions of 30 DEG C
Mixture is incubated after 15min, is added the reaction terminating liquid of 4uL × 5 and is made reaction terminating.Electrophoresis method and analysis mode are ibid.Will
The concentration for suppressing the noval chemical compound of 50% Topo II activity is defined as IC50.
Inhibitory action result of the noval chemical compound to TopoII
The ultimate principle and principal character and advantages of the present invention of the present invention has been shown and described above.The technology of the industry
Personnel it should be appreciated that the present invention is not restricted to the described embodiments, the simply explanation described in above-described embodiment and description this
The principle of invention, without departing from the spirit and scope of the present invention, the present invention also has various changes and modifications, these changes
Change and improvement is both fallen within scope of the claimed invention.The claimed scope of the invention by appending claims and its
Equivalent thereof.
Claims (8)
1. a kind of pyridine joins the synthetic method of thiazoless carboxylic acid derivates, first pyridine synthesis di- hydrogen thiazoless carboxylic acid, then passes through
Replace and synthesize its derivant, it is characterised in that pyrrole is generated by cyanopyridines and L-cysteine hydrochloride reaction
Pyridine di- hydrogen thiazole carboxylic acid.
2. a kind of pyridine according to claim 1 joins the synthetic method of thiazole derivative, it is characterised in that the pyridine
The concrete synthetic method of di- hydrogen thiazole carboxylic acid is:It is with cyanopyridines, L-cysteine hydrochloride, sodium bicarbonate
Raw material, dehydrated alcohol is solvent, and back flow reaction 12 hours, rotation goes dehydrated alcohol to obtain Off-white solid, with water dissolution, in ice bath bar
Under part, pH=3-4 is acidified to, sucking filtration, washing obtains pyridine di- hydrogen thiazole carboxylic acid after being dried.
3. a kind of pyridine according to claim 2 joins the synthetic method of thiazole derivative, it is characterised in that the cyano group
Pyridine compounds and their is nicotinonitrile, 4- methyl-nicotinonitrile, the chloro- nicotinonitriles of 2-.
4. a kind of pyridine according to claim 2 joins the synthetic method of thiazole derivative, it is characterised in that the cyano group
Pyridine compounds and their is 1 with the mol ratio of L-cysteine hydrochloride:1.5-1:2.5.
5. a kind of pyridine according to claim 1 joins the synthetic method of thiazole derivative, it is characterised in that with pyridine connection
Thiazoline carboxylic acid is that raw material reacts in oxygen atmosphere with thionyl chloride, and Deca aminated compoundss or alcohol compound are obtained
Pyridine joins thiazoless amide or pyridine connection thiazoless ester.
6. a kind of pyridine according to claim 5 joins the synthetic method of thiazole derivative, it is characterised in that concrete steps
For:Compound pyridine di- hydrogen thiazole carboxylic acid is taken in reaction vessel, adds dichloromethane to make solvent, under condition of ice bath slowly
Thionyl chloride is instilled, ice bath is removed, is reacted under room temperature 18 hours, steaming vibrating dichloromethane after reacting completely obtains intermediate product A,
Add 15mL dichloromethane dissolving intermediate product A, under zero degrees celsius, triethylamine be added dropwise in reactant liquor, then again by
Aminated compoundss are added dropwise to, to be removed and react 16h under ice bath, room temperature, until raw material is wholly absent;Saturation is added in reaction system
NaHCO3 aqueous solutions are extracted reaction is quenched with dichloromethane, and saturation NaCl solution washing, anhydrous Na 2SO4 is dried, and filters, and steams
Dichloromethane is removed, DCM is used:MeOH=40:1~10:1 or PE:EA=5:1~3:1, obtain pyridine connection thiazoless amide.
7. a kind of pyridine according to claim 1 joins the synthetic method of thiazole derivative, it is characterised in that with pyridine connection
Thiazoline carboxylic acid is that raw material reacts in oxygen atmosphere with thionyl chloride, Deca alcohol compound, pyridine connection thiazoless ester.
8. a kind of pyridine according to claim 7 joins the synthetic method of thiazole derivative, it is characterised in that take compound
Pyridine di- hydrogen thiazole carboxylic acid adds dichloromethane to make solvent in reaction vessel, dichloro is slowly instilled under condition of ice bath sub-
Sulfone, removes ice bath, reacts under room temperature 18 hours, and steaming vibrating dichloromethane after reacting completely obtains intermediate product A, takes intermediate product A
In reaction vessel, alcohol compound is added, under zero degrees celsius thionyl chloride is slowly added dropwise, be heated to 80 DEG C, flow back 4h, reaction
Completely, solvent is spin-dried for, saturation NaHCO is added3Solution, is extracted three times with DCM, then is washed with saturation NaCl, and anhydrous Na 2SO4 is done
It is dry, it is spin-dried for solvent, column chromatography PE:EA=2:1, obtain pyridine connection thiazoless ester.
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CN112830950A (en) * | 2019-11-22 | 2021-05-25 | 成都先导药物开发股份有限公司 | Method for synthesizing On-DNA (deoxyribonucleic acid) dihydrothiazole/thiazole compound |
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CN112830950A (en) * | 2019-11-22 | 2021-05-25 | 成都先导药物开发股份有限公司 | Method for synthesizing On-DNA (deoxyribonucleic acid) dihydrothiazole/thiazole compound |
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