CN103012440A - Method for synthesizing thiazolo [3,2-a] pyrimidine derivative by one pot process - Google Patents
Method for synthesizing thiazolo [3,2-a] pyrimidine derivative by one pot process Download PDFInfo
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Abstract
The invention relates to a method for synthesizing thiazolo pyrimidine compounds, and aims at providing a method for synthesizing thiazolo [3,2-a] pyrimidine derivative by a one pot process. The method comprises the following steps of: adding 2-aminothiazole, benzaldehyde or substituted benzaldehyde, acetoacetate alkyl ester and ionic liquid into an organic solvent, reacting for 2-12hours in an interval from 35 DEG C to a solvent boiling point; and distilling at reduced pressure to obtain a solvent, and re-crystallizing a crude product to prepare the thiazolo [3,2-a] pyrimidine derivative. The method is easily available raw materials, simple to operate, mild in conditions, easy to separate, high in yield, environment-friendly, and suitable for industrialized production.
Description
Technical field
The present invention relates to a kind of synthetic method of Thiazolopyrimidine derivative, particularly the one kettle way synthetizing thiazolium synthetic method of [3,2-a] pyridine derivatives also.
Background technology
Chinese patent CN 101613362A has reported the three-step synthesis method of carbonyl-6-ethoxycarbonyl thiazolopyrimidine, and namely the first step methyl aceto acetate, thiocarbamide and aromatic aldehyde obtain white crystal under catalyst action; Second step obtains yellow crystals behind the white crystal that the first step is obtained and Mono Chloro Acetic Acid, the acetic acid sodium reaction, treated, recrystallization; In the 3rd step, the yellow crystals that second step is obtained and aromatic aldehyde back flow reaction under catalyst action of replacement are after column chromatography for separation, more respectively with obtaining target product after alkali, the sour neutralization.In addition, the patent such as Chinese patent CN 102002044A, CN 101932587A, CN101899058 has all been reported the synthetic method of the thiazolopyrimidine of different structure.The shortcoming of these synthetic methods is, raw material is complicated, be not easy to obtain, and synthesis step is many, synthetic in the catalyzer that use more, relate in the building-up process separating for several times and, the use of purifying and multiple organic solvent.Such reaction process is so that whole operation is complicated, and productive rate descends, and reaction time is longer; The catalyzer that uses in the reaction process and organic solvent and have caused bad impact to environment so that synthetic cost increases, and its application prospect is subject to certain restrictions.
Shortcoming and defect in view of above these synthetic methods, and the advantage of thiazolopyrimidine on biological activity, a kind of raw material of design and development is easy to get, low price, method is simple, yield is high, and eco-friendly synthetizing thiazolium miazines compound had both had theory significance and also had important practical significance.
Summary of the invention
The technical problem to be solved in the present invention provides a kind of by thiazolamine, aromatic aldehyde and the Acetacetic acid alkyl ester one kettle way synthetizing thiazolium synthetic method of [3,2-a] pyridine derivatives also under the ionic liquid effect.The method is simple to operate, and aftertreatment is easy, and productive rate is high, is easy to suitability for industrialized production.
For solving the problems of the technologies described above, the present invention is achieved by the following technical solutions.
The invention provides a kind of one kettle way synthetizing thiazolium also [3,2-a] method of pyridine derivatives, may further comprise the steps: phenyl aldehyde, Acetacetic acid alkyl ester and the ionic liquid of thiazolamine, phenyl aldehyde or replacement are joined in the reaction solvent, at 35 ℃ to the interval internal reaction of solvent boiling point after 2 ~ 12 hours, decompression steams solvent, behind recrystallization, make also [3,2-a] pyridine derivatives of thiazole.
The synthetic route of technical solution of the present invention is as follows:
R in the reaction formula
1Choose the phenyl of phenyl or replacement, the phenyl of replacement comprises the 2-hydroxy phenyl, 4-chloro-phenyl-, 4-p-methoxy-phenyl, 4-hydroxy 3-methoxybenzene base, R
2Choose the alkyl of C1 ~ C4;
The mol ratio of each material is in the reaction system: thiazolamine: the phenyl aldehyde of phenyl aldehyde or replacement: Acetacetic acid alkyl ester is 1.0 ~ 1.5:1.0 ~ 1.5:1.0 ~ 1.5; The ionic liquid consumption is 0.1 ~ 0.5 g.
Selected ionic liquid is 1-butyl-3-Methylimidazole villaumite ([bmim] Cl) in the reaction, 1-butyl-3-Methylimidazole bromine salt ([bmim] Br), 1-butyl-3-Methylimidazole hydrosulfate ([bmim] HSO
4), 1-butyl-3-methyl imidazolium tetrafluoroborate ([bmim] BF
4), 1-butyl-3-Methylimidazole hexafluorophosphate ([bmim] PF
6) any;
The reaction solvent for use is methyl alcohol among the present invention, ethanol, Virahol, any in the fourth alcohol and water;
The used solvent of recrystallization is ethyl acetate among the present invention, acetonitrile, tetrahydrofuran (THF), any in the ether.
The invention has the beneficial effects as follows also [3,2-a] pyridine derivatives of one kettle way synthetizing thiazolium, raw material is easy to get, and is simple to operate, and mild condition is easy to separate, and productive rate is high, is suitable for suitability for industrialized production.
Embodiment
Below by the implementation example synthetic method of the present invention is described further.
Example 1:7-methyl-6-ethoxy acyl group-5-phenyl-5H-thiazole is [3,2-a] pyrimidine also
Thiazolamine (5.0 mmol), phenyl aldehyde (5.0 mmol), methyl aceto acetate (5.0 mmol) and ionic liquid 1-butyl-3-methyl imidazolium villaumite ([bmim] Cl) (0.3 g) are joined in the ethanol (30 mL), heating, back flow reaction 8 h, decompression steams solvent, after re-crystallizing in ethyl acetate, obtain light yellow solid, productive rate 86%, 240.4-240.8 ℃ of m. p..
1H?NMR（CDCl
3）δ:?7.38-7.42?(m,?3H),?7.31-7.33?(m,?2H),?7.18(d,?J=4.0Hz,?1H),?7.01?(d,?J=4.4Hz,?1H),?6.38?(s,?1H),?4.08-4.19?(m,?2H),?2.67?(s,?3H),?1.19?(t,?J=14.4Hz,?3H);?IR?(KBr,?cm
-1):?3098,?2983,?1691,?1540,?1290;?Anal.?Calcd.?for?C
16H
16N
2O
2S:?C,?63.98;?H,?5.37,?N,?9.33;?Found:?C,?63.87;?H,?5.47?N,?9.30.
Example 2:7-methyl-6-ethoxy acyl group-5-(4-chloro-phenyl-)-5H-thiazole is [3,2-a] pyrimidine also
Thiazolamine (5.0 mmol), 4-chloro-benzaldehyde (5.2 mmol), methyl aceto acetate (5.2 mmol) and ionic liquid 1-butyl-3-methyl imidazolium bromine salt ([bmim] Br) (0.2 g) are joined in the Virahol (30 mL), heating, back flow reaction 6 h, decompression steams solvent, behind the acetonitrile recrystallization, obtain yellow solid, productive rate 80%, 138.6-139.6 ℃ of m. p..
1H?NMR（CDCl
3）?δ:?7.266-7.29(m,?4H),?6.53(d,?J=4.8Hz,?1H),?6.29?(d,?J=4.8Hz,?1H),?6.16(s,?1H),?4.04-4.11(m,?2H),?2.45(s,?3H),?1.19(t,?J=14.4Hz,?3H);?IR?(KBr,?cm
-1):?3068，2982，1693，1575，1320;?Anal.?Calcd.?for?C
16H
15ClN
2O
2S:?C,?57.40;?H,?4.52,?N,?8.37;?Found:?57.21;?H,?4.68,?N,?8.50.
Example 3:7-methyl-6-ethoxy acyl group-5-(2-hydroxy phenyl)-5H-thiazole is [3,2-a] pyrimidine also
With thiazolamine (5.5 mmol), salicylaldhyde (5.0 mmol), methyl aceto acetate (6.0 mmol) and ionic liquid 1-butyl-3-methyl imidazolium hydrosulfate ([bmim] HSO
4) (0.3 g) join in the methyl alcohol (30 mL), heating, back flow reaction 14 h, decompression steams solvent and obtains yellow solid behind the ether recrystallization, productive rate 75%, 137.7-139.2 ℃ of m. p..
1H?NMR（CDCl
3）?δ:?7.26-7.29(m,?4H),?6.50?(d,?J=4.8Hz,?1H),?6.21?(d,?J=4.8Hz,?1H),?6.08?(s,?1H),?4.09-4.19?(m,?2H),?2.45(s,?3H),?1.17?(t,?J=14.4Hz,?3H);?IR?(KBr,?cm
-1):?3433,?2934,?1667,?1515,?1275;?Anal.?Calcd.?for?C
16H
16N
2O
3S：C,?60.74;?H,?5.10,?N,?8.85;?Found:?C,?60.92;?H,?5.15,?N,?8.91.
Example 4:7-methyl-6-ethoxy acyl group-5-(4-p-methoxy-phenyl)-5H-thiazole is [3,2-a] pyrimidine also
With thiazolamine (5.4 mmol), aubepine (5.5 mmol), methyl aceto acetate (6.5 mmol) and ionic liquid 1-butyl-3-methyl imidazolium hexafluorophosphate ([bmim] PF
6(0.5 g) joins in the butanols (30 mL), heating reflux reaction 11 h, and decompression steams solvent, obtains yellow solid behind the tetrahydrofuran (THF) recrystallization, productive rate 76%, 135.0-135.6 ℃ of m. p..
1H?NMR（CDCl
3）?δ:?7.26-7.28?(m,?2H),?6.83(d,?J=8.4Hz,?2H),?6.55?(d,?J=4.8Hz,?1H),?6.26(d,?J=4.8Hz,?1H),?6.13(s,?1H),?4.05-4.09?(m,?2H),?3.78(s,?3H),?2.44?(s,?3H),?1.18(t,?J=14.4Hz,?3H);?IR?(KBr,?cm
-1):?3114,?2981,?1683,?1573,?1317;?Anal.?Calcd.?for?C
17H
18N
2O
3S:?C,?61.80;?H,?5.49,?N,?8.48;?Found:?C,?61.61;?H,?5.65,?N,?8.29.
Example 5:7-methyl-6-ethoxy acyl group-5-(3-methoxyl group-4-hydroxy phenyl)-5H-thiazole is [3,2-a] pyrimidine also
With thiazolamine (5.7 mmol), Vanillin (6.0 mmol), methyl aceto acetate (6.0 mmol) and ionic liquid 1-butyl-3-methyl imidazolium a tetrafluoro borate ([bmim] BF
4) (0.1g) join in the water (30 mL), heating reflux reaction 24 hours, decompression steams solvent, obtains yellow solid behind the ether recrystallization, productive rate 82%, 142.3-143.9 ℃ of m. p..
1H?NMR（CDCl
3）?δ:?7.26-7.29(m,?4H),?6.54?(d,?J=4.8Hz,?1H),?6.29(d,?J=4.8Hz,?1H),?6.17(s,?1H),?4.09-4.15?(m,?2H),?3.85?(s,?3H),?2.52(s,?3H),?1.19?(t,?J=14.4Hz,?3H);?IR?(KBr,?cm
-1):?3324,?2982,?1711,?1561,?1298;?Anal.?Calcd.?for?C
17H
18N
2O
4S:?C,?58.94;?H,?5.24,?N,?8.09;?Found:?C,?58.75;?H,?5.36,?N,?8.18.
Note also that above example only is specific embodiments of the invention.Obviously, the present invention is not limited only to above example, and many distortion can also be arranged.All distortion that those of ordinary skill in the art can directly derive or associate from content disclosed by the invention all should be thought the scope of protection of the present invention.
Claims (3)
1. the one kettle way synthetizing thiazolium method of [3,2-a] pyridine derivatives also may further comprise the steps:
Phenyl aldehyde, Acetacetic acid alkyl ester and the ionic liquid of thiazolamine, phenyl aldehyde or replacement are joined in the organic solvent, at 35 ℃ to the interval internal reaction of solvent boiling point after 2 ~ 12 hours, decompression steams solvent, makes also [3,2-a] pyridine derivatives of thiazole behind recrystallization.
Its reaction formula is as follows:
R in the reaction formula
1Choose the phenyl of phenyl or replacement, the phenyl of replacement comprises the 2-hydroxy phenyl, 4-chloro-phenyl-, 4-p-methoxy-phenyl, 4-hydroxy 3-methoxybenzene base, R
2Choose the alkyl of C1 ~ C4;
The mol ratio of each material is in the reaction system:
Thiazolamine: the phenyl aldehyde of phenyl aldehyde or replacement: Acetacetic acid alkyl ester is 1.0 ~ 1.5:1.0 ~ 1.5:1.0 ~ 1.5;
Reaction system intermediate ion volume is 0.1 ~ 0.5 g;
Selected ionic liquid is 1-butyl-3-Methylimidazole villaumite ([bmim] Cl) in the reaction, 1-butyl-3-Methylimidazole bromine salt ([bmim] Br), 1-butyl-3-Methylimidazole hydrosulfate ([bmim] HSO
4), 1-butyl-3-methyl imidazolium tetrafluoroborate ([bmim] BF
4), 1-butyl-3-Methylimidazole hexafluorophosphate ([bmim] PF
6) any.
2. the described synthetizing thiazolium method of [3,2-a] pyridine derivatives also according to claim 1 is characterized in that described organic solvent is methyl alcohol, ethanol, Virahol, butanols or water.
3. the described synthetizing thiazolium method of [3,2-a] pyridine derivatives also according to claim 1 is characterized in that the used organic solvent of recrystallization is ethyl acetate, acetonitrile, tetrahydrofuran (THF), any in the ether.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010002483A1 (en) * | 2008-07-03 | 2010-01-07 | Cv Therapeutics, Inc. | Optionally condensed dihydro pyridine, dihydropyrimidine and dihydro pyrane derivatives acting as late sodium channel blockers |
| CN102002044A (en) * | 2010-09-29 | 2011-04-06 | 中国药科大学 | Purine-8-ketone and thiazolopyrimidine derivatives, and preparation method and medicinal application thereof |
| CN102241654A (en) * | 2011-05-13 | 2011-11-16 | 台州学院 | Environmentally-friendly synthetic method of pyrimidine compound |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010002483A1 (en) * | 2008-07-03 | 2010-01-07 | Cv Therapeutics, Inc. | Optionally condensed dihydro pyridine, dihydropyrimidine and dihydro pyrane derivatives acting as late sodium channel blockers |
| CN102002044A (en) * | 2010-09-29 | 2011-04-06 | 中国药科大学 | Purine-8-ketone and thiazolopyrimidine derivatives, and preparation method and medicinal application thereof |
| CN102241654A (en) * | 2011-05-13 | 2011-11-16 | 台州学院 | Environmentally-friendly synthetic method of pyrimidine compound |
Non-Patent Citations (1)
| Title |
|---|
| ROBERT P. BRIGANCE，等: "Synthesis and SAR of azolopyrimidines as potent and selective dipeptidyl peptidase-4 (DPP4) inhibitors for type 2 diabetes", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》, vol. 20, no. 15, 1 August 2010 (2010-08-01), pages 4395 - 4398 * |
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