CN103012440B

CN103012440B - Method for synthesizing thiazolo [3,2-a] pyrimidine derivative by one pot process

Info

Publication number: CN103012440B
Application number: CN201310016623.3A
Authority: CN
Inventors: 赵冰; 阚伟; 刘卓; 王丽艳; 邓启刚
Original assignee: Qiqihar University
Current assignee: Qiqihar University
Priority date: 2013-01-17
Filing date: 2013-01-17
Publication date: 2015-04-15
Anticipated expiration: 2033-01-17
Also published as: CN103012440A

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

The method of one pot process thiazole also [3,2-a] pyridine derivatives

Technical field

The present invention relates to a kind of synthetic method of Thiazolopyrimidine derivative, particularly the synthetic method of one pot process thiazole also [3,2-a] pyridine derivatives.

Background technology

Chinese patent CN 101613362A reports 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, the white crystal the first step obtained and Mono Chloro Acetic Acid, acetic acid sodium reaction, obtain yellow crystals after treated, recrystallization; 3rd step, the yellow crystals obtained by second step and the aromatic aldehyde of replacement back flow reaction under catalyst action, after column chromatography for separation, then obtains target product with after alkali, acid neutralization respectively.In addition, the patent such as Chinese patent CN 102002044A, CN 101932587A, CN101899058 all reports 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, uses catalyzer in synthesis more, relates to the use of separating for several times and, purifying and multiple organic solvent in building-up process.Such reaction process makes whole operation complicated, and productive rate declines, and reaction time is longer; The catalyzer used in reaction process and organic solvent make synthesis cost increase, and cause bad impact to environment, and its application prospect is subject to certain restrictions.

In view of the shortcoming and defect of these synthetic methods above, and the advantage of thiazolopyrimidine in 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 is to provide a kind of synthetic method by thiazolamine, aromatic aldehyde and Acetacetic acid alkyl ester one kettle way synthetizing thiazolium also [3,2-a] pyridine derivatives under 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 pot process thiazole also [3,2-a] method of pyridine derivatives, comprise the following steps: the phenyl aldehyde of thiazolamine, phenyl aldehyde or replacement, Acetacetic acid alkyl ester and ionic liquid are joined in reaction solvent, react in 35 DEG C to solvent boiling point interval after 2 ~ 12 hours, decompression steams solvent, obtained thiazole also [3,2-a] pyridine derivatives after recrystallization.

The synthetic route of technical solution of the present invention is as follows:

R in reaction formula ₁choose the phenyl of phenyl or replacement, the phenyl of replacement comprises 2-hydroxy phenyl, 4-chloro-phenyl-, 4-p-methoxy-phenyl, 4-hydroxy 3-methoxybenzene base, R ₂choose the alkyl of C1 ~ C4;

In reaction system, the mol ratio of each material is: 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; Ionic liquid consumption is 0.1 ~ 0.5 g.

Ionic liquid selected in reaction is 1-butyl-3-Methylimidazole villaumite ([bmim] Cl), 1-butyl-3-Methylimidazole bromine salt ([bmim] Br), 1-butyl-3-methylimidazolium hydrogen sulphate salt ([bmim] HSO ₄), 1-butyl-3-methyl imidazolium tetrafluoroborate ([bmim] BF ₄), 1-butyl-3-Methylimidazole hexafluorophosphate ([bmim] PF ₆) any one;

Reacting solvent for use in the present invention is methyl alcohol, ethanol, Virahol, any one in fourth alcohol and water;

The solvent that in the present invention, recrystallization is used is ethyl acetate, acetonitrile, tetrahydrofuran (THF), any one in ether.

The invention has the beneficial effects as follows one pot process thiazole also [3,2-a] pyridine derivatives, raw material is easy to get, simple to operate, mild condition, is easy to be separated, and productive rate is high, is suitable for suitability for industrialized production.

Embodiment

Below by concrete embodiment, synthetic method of the present invention is described further.

Example 1:7-methyl-6-ethoxy acyl group-5-phenyl-5H-thiazole also [3,2-a] pyrimidine

By 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) joins in ethanol (30 mL), heating, back flow reaction 8 h, decompression steams solvent, light yellow solid is obtained after re-crystallizing in ethyl acetate, productive rate 86%, m. p. 240.4-240.8 DEG C.

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 also [3,2-a] pyrimidine

By 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) joins in Virahol (30 mL), heating, back flow reaction 6h, decompression steams solvent, yellow solid is obtained after recrystallized from acetonitrile, p.138.6-139.6 DEG C productive rate 80%, m..

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. forC 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 also [3,2-a] pyrimidine

By 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) joins in methyl alcohol (30 mL), heating, back flow reaction 14 h, and decompression steams solvent and after Diethyl ether recrystallization, obtains yellow solid, productive rate 75%, m. p. 137.7-139.2 DEG C.

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 also [3,2-a] pyrimidine

By 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 butanols (30 mL), heating reflux reaction 11 h, and decompression steams solvent, obtains yellow solid, productive rate 76%, m. p. 135.0-135.6 DEG C after tetrahydrofuran (THF) recrystallization.

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 also [3,2-a] pyrimidine

By 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 water (30 mL), heating reflux reaction 24 hours, decompression steams solvent, obtains yellow solid, productive rate 82%, m. p. 142.3-143.9 DEG C after Diethyl ether recrystallization.

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 is only specific embodiments of the invention.Obviously, the present invention is not limited only to above example, can also have many distortion.All distortion that those of ordinary skill in the art can directly derive from content disclosed by the invention or associate, all should think the scope of protection of the present invention.

Claims

1. the method for one pot process thiazole also [3,2-a] pyridine derivatives, comprises the following steps:

The phenyl aldehyde of thiazolamine, phenyl aldehyde or replacement, Acetacetic acid alkyl ester and ionic liquid are joined in organic solvent, react 2 ~ 12h in 35 DEG C to solvent boiling point interval after, decompression steams solvent, obtained thiazole also [3,2-a] pyridine derivatives after recrystallization;

Its reaction formula is as follows:

R in reaction formula ₁be selected from phenyl, 2-hydroxy phenyl, 4-chloro-phenyl-, 4-p-methoxy-phenyl and 4-hydroxy 3-methoxybenzene base, R ₂be selected from the alkyl of C1 ~ C4;

In reaction system, the mol ratio of each material is:

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 ~ 0.5g;

Ionic liquid selected in reaction is any one in 1-butyl-3-Methylimidazole villaumite, 1-butyl-3-Methylimidazole bromine salt, 1-butyl-3-methylimidazolium hydrogen sulphate salt, 1-butyl-3-methyl imidazolium tetrafluoroborate, 1-butyl-3-Methylimidazole hexafluorophosphate;

Organic solvent described in reaction is methyl alcohol, ethanol, Virahol or butanols;

Product recrystallization organic solvent used is any one in ethyl acetate, acetonitrile, tetrahydrofuran (THF) and ether.