CN103058946A - Preparation method for 2,5-disubstituted oxazole derivative - Google Patents
Preparation method for 2,5-disubstituted oxazole derivative Download PDFInfo
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Abstract
The invention discloses a preparation method for a 2,5-disubstituted oxazole derivative. The method includes that acyl chloride and 2-bromoallylamine serve as raw materials, and react fully in aprotic polar solvent at the temperature of 30-100 DEG C under the action of an acid-binding agent and alkaline matter, and the reaction solution is subjected to post treatment to obtain the 2,5-disubstituted oxazole derivative. The raw materials for the reaction are easy to obtain, non-toxic and cheap. No catalyst is needed during the reaction, and the preparation method is greener and more environment-friendly, and coat is reduced. The reaction conditions are relatively mild, and compared with traditional synthesis methods, the preparation method for the 2,5-disubstituted oxazole derivative is high in yield. The yield of the traditional methods is generally below 60%, but the yield of the preparation method for the 2,5-disubstituted oxazole derivative can be above 70%.
Description
(1) technical field
The present invention relates to a kind of 2, the chemical preparation process of 5-Er substituted oxazole derivative.
(2) background technology
Oxazole ring is as a kind of important oxygen nitrogen azole heterocycle that contains, have easy formation hydrogen bond, easily and metallic ion coordination and the characteristics such as hydrophobic interaction, pi-pi accumulation, electrostatic interaction easily occur, be widely used in various fields such as medicine, agricultural chemicals, chemistry and materials Yin the Ci oxazole compounds.Plurality of enzymes and receptor acting in oxazole compounds and the organism and present widely biological activity, such as antimycotic, antibiotic, anticancer, antiviral, tuberculosis, hypoglycemic, anticonvulsion, anti-inflammatory analgesic etc., thereby it is one of key areas of New Drug Research.For example, 2-(N, N '-dimethyl)-4-ethyl-5-Ben Ji oxazole and 2-(4,5-dimethyl) oxazole acetic acid is the medicine with anti-inflammatory and analgesic effect, 4-methyl-5-(2 '-chloroethyl) oxazole is the medicine with hypnosis and anticonvulsant action.
2-(N, N '-dimethyl)-4-ethyl-5-Ben Ji oxazole 2-(4,5-dimethyl) oxazole acetic acid
4-methyl-5-(2 '-chloroethyl) oxazole
Such as reaction formula (1): take Terminal Acetylenes and isonitrile as raw material, under the condition of gold as catalyzer, add the oxygenant of 1.3 equivalents, generated corresponding product in 3 hours 60 ℃ of reactions.
Reaction formula (1)
The main drawback of this reaction is: the raw material isonitrile is not easy to obtain, and uses Precious Metals-Gold as catalyzer, therefore is unfavorable for large-scale industrialization production.
Such as reaction formula (2): the people such as Jiang Huanfeng report in 2010 with uncle's butyric acid and the elemental iodine Domino reaction as regulating effect, under the condition of heating through the synthetic 2，5-diphenyloxazole of the steps such as peroxidation, cyclisation and derivative thereof.
Reaction formula (2)
The main drawback of this reaction is: this reaction needs just can carry out under the adjusting of uncle's butyric acid and elemental iodine, severe reaction conditions, and the reaction times is partially long, and energy consumption is larger.
Such as reaction formula (3): J. K., the people such as Ray are with aromatic amides and 2, and the 3-propylene bromide adds the Cs of 3.3 equivalents under the condition of nitrogen protection
2CO
3, reacting by heating is synthesized 5-methyl-2-Fang Ji oxazole and derivative thereof.
Reaction formula (3)
The main drawback of this reaction is: this reaction Cs
2CO
3Large usage quantity, and need under the condition of nitrogen protection, react.Reaction conditions is stricter, and is not easy to operate.
Such as reaction formula (4): the people such as Kyo Han Ahn report in 2011 under the condition of gold as catalyzer, with N-(propargyl) benzamide Cyclization 2, the oxazole compounds that 5-two replaces.
Reaction formula (4)
Although this method side reaction is less, use Precious Metals-Gold as catalyzer.Therefore, be unfavorable for large-scale industrialization production.
(3) summary of the invention
The object of the invention provides a kind of chemical preparation process of simple to operate, production safety is reliable, reaction yield is high, do not need catalyzer, production cost is low, ring border friend is good oxazole analog derivative.
The technical solution used in the present invention is:
Shown in a kind of formula IV 2, the preparation method of 5-Er substituted oxazole derivative, described method is: take the allylamine of 2-bromine shown in acyl chlorides shown in the formula I and the formula II as raw material, under the effect of acid binding agent and alkaline matter, in aprotic polar solvent, 30 ~ 110 ℃ react completely after, with the reaction solution aftertreatment, make 2 shown in the formula IV, 5-Er substituted oxazole derivative; Described acid binding agent is pyridine or triethylamine; Described alkaline matter is organic bases or mineral alkali; The feed intake ratio of amount of substance of described acyl chlorides and 2-bromine allylamine is 1:0.8 ~ 1.0;
In formula (I) and the formula IV, R is: phenyl, substituted-phenyl, hydrocinnamyl, styryl or C
11-C
17Branched-chain alkyl, the substituting group of described substituted-phenyl is adjacent bromo, adjacent methyl, adjacent nitro, adjacent chloro or to methoxyl group.
Further, in preferred described formula (I) and the formula IV, R is: phenyl, o-bromophenyl, o-methyl-phenyl-, O-Nitrophenylfluorone, Chloro-O-Phenyl, p-methoxyphenyl, styryl, hydrocinnamyl, undecyl or heptadecyl.
Further, described mineral alkali is KOH, NaOH, K
2CO
3, Na
2CO
3Or Cs
2CO
3, preferred KOH or Na
2CO
3
Further, described organic bases is potassium tert.-butoxide, sodium ethylate, potassium ethylate or sodium methylate, particular methanol sodium.
Further, described aprotic polar solvent is DMF, dimethyl sulfoxide (DMSO), acetonitrile or tetrahydrofuran (THF).
Further, described reaction is at 30 ~ 110 ℃ of lower reaction 2 ~ 10h.
Further, described acyl chlorides is 1:1.2 ~ 1.8 with the ratio of the amount of substance that feeds intake of acid binding agent, preferred 1:1.5, described acyl chlorides is 1:1.2 ~ 1.8 with the ratio of the amount of substance that feeds intake of alkaline matter, preferred 1:1.5, the volumetric usage of described aprotic polar solvent is counted 4 ~ 7ml/mmol with the acyl chlorides amount of substance.
Further, described reaction solution post-treating method is: TLC follows the tracks of detection, after reaction finishes, reaction solution is cooled to room temperature, under agitation in reaction solution, add the aqueous ammonium chloride solution adjusting pH of mass concentration 15% to neutrality, with ethyl acetate extraction three times, merge organic layer and with after the saturated common salt water washing again through anhydrous sodium sulfate drying, rotary evaporation is concentrated, get enriched material and carry out silica gel column chromatography with sherwood oil and the ethyl acetate mixed solution of volume ratio 4:1 as eluent, TLC follows the tracks of detection, collection contains the elutriant of target components, obtains described 5-methyl-2-Ben oxazole derivatives.
Further, shown in the described formula IV 2, the preparation method of 5-Er substituted oxazole derivative recommends to carry out as follows: mix acyl chlorides shown in the formula I (1) with aprotic polar solvent, then slowly drip the bromine allylamine of 2-shown in the formula II and acid binding agent, at 30 ~ 40 ℃ of lower stirring reactions, TLC follows the tracks of and detects to the disappearance of acyl chlorides raw material point, reacts completely, and obtains to contain the reaction solution a of intermediate shown in the formula III; The feed intake ratio of amount of substance of described acyl chlorides and 2-bromine allylamine is 1:0.85 ~ 0.95; Described acyl chlorides is 1:1.3 ~ 1.5 with the ratio of the amount of substance that feeds intake of acid binding agent, and the volumetric usage of described aprotic polar solvent is counted 4 ~ 6ml/mmol with the acyl chlorides amount of substance; Described acid binding agent is pyridine or triethylamine, and described aprotic polar solvent is DMF or dimethyl sulfoxide (DMSO); (2) in the reaction solution a of step (1) acquisition, add alkaline matter, be warming up to 70 ~ 90 ℃, TLC follows the tracks of to detect to intermediate point shown in the formula III and disappears, obtain reaction solution b, reaction solution b is cooled to room temperature, under agitation in reaction solution b, add the aqueous ammonium chloride solution adjusting pH of mass concentration 15% to neutrality, with ethyl acetate extraction three times, merge organic layer and with after the saturated common salt water washing again through anhydrous sodium sulfate drying, rotary evaporation is concentrated, get enriched material and carry out silica gel column chromatography with sherwood oil and the ethyl acetate mixed solution of volume ratio 4:1 as eluent, TLC follows the tracks of detection, collection contains the elutriant of target components, obtains described 5-methyl-2-Ben oxazole derivatives; Described acyl chlorides is 1:1.3 ~ 1.5 with the ratio of the amount of substance that feeds intake of alkaline matter; Described alkaline matter is potassium tert.-butoxide or sodium ethylate;
In the formula III, R is: phenyl, substituted-phenyl, hydrocinnamyl, styryl or C
11-C
17Branched-chain alkyl, the substituting group of described substituted-phenyl is adjacent bromo, adjacent methyl, adjacent nitro, adjacent chloro or to methoxyl group.
Room temperature of the present invention refers to 20 ~ 30 ℃.
Reaction solution a of the present invention and reaction solution b are reaction solution, name for the ease of distinguishing different step gained reaction solution difference, and letter itself does not have implication.
Compared with prior art, beneficial effect of the present invention is mainly reflected in: (1) reaction raw materials of the present invention is easy to get, toxicological harmless, low price; (2) reaction does not need catalyzer, and more environmental protection reduces cost; (3) reaction conditions is relatively gentle; (4) with respect to prior synthesizing method, present method yield is higher, and the traditional method yield is substantially all below 60%, and present method yield can reach more than 70%.
(4) description of drawings
The 5-methyl of Fig. 1 embodiment 1 preparation-2-Ben Ji oxazole (1a)
1H NMR collection of illustrative plates.
The 5-methyl of Fig. 2 embodiment 1 preparation-2-Ben Ji oxazole (1a)
13C NMR collection of illustrative plates.
The 5-methyl of Fig. 3 embodiment 2 preparations-2-Lin Xiu Ben Ji oxazole (2a)
1H NMR collection of illustrative plates.
The 5-methyl of Fig. 4 embodiment 2 preparations-2-Lin Xiu Ben Ji oxazole (2a)
13C NMR collection of illustrative plates.
The 5-methyl of Fig. 5 embodiment 3 preparations-2-Lin Jia base Ben Ji oxazole (3a)
1H NMR collection of illustrative plates.
The 5-methyl of Fig. 6 embodiment 3 preparations-2-Lin Jia base Ben Ji oxazole (3a)
13C NMR collection of illustrative plates.
The 5-methyl of Fig. 7 embodiment 4 preparations-2-ortho-nitrophenyl Ji oxazole (4a)
1H NMR collection of illustrative plates.
The 5-methyl of Fig. 8 embodiment 4 preparations-2-ortho-nitrophenyl Ji oxazole (4a)
13C NMR collection of illustrative plates.
The 5-methyl of Fig. 9 embodiment 5 preparations-2-Lin Lv Ben Ji oxazole (5a)
1H NMR collection of illustrative plates.
The 5-methyl of Figure 10 embodiment 5 preparations-2-Lin Lv Ben Ji oxazole (5a)
13C NMR collection of illustrative plates.
The 5-methyl of Figure 11 embodiment 6 preparations-2-Dui Jia oxygen base Ben Ji oxazole (6a)
1H NMR collection of illustrative plates.
The 5-methyl of Figure 12 embodiment 6 preparations-2-Dui Jia oxygen base Ben Ji oxazole (6a)
13C NMR collection of illustrative plates.
The 5-methyl of Figure 13 embodiment 7 preparations-2-Ben Yi Xi Ji oxazole (7a)
1H NMR collection of illustrative plates.
The 5-methyl of Figure 14 embodiment 7 preparations-2-Ben Yi Xi Ji oxazole (7a)
13C NMR collection of illustrative plates.
The 5-methyl of Figure 15 embodiment 8 preparations-2-phenylpropyl alcohol Ji oxazole (8a)
1H NMR collection of illustrative plates.
The 5-methyl of Figure 16 embodiment 8 preparations-2-phenylpropyl alcohol Ji oxazole (8a)
13C NMR collection of illustrative plates.
The 5-methyl of Figure 17 embodiment 9 preparations-2-Shi Yi Wan Ji oxazole (9a)
1H NMR collection of illustrative plates.
The 5-methyl of Figure 18 embodiment 9 preparations-2-Shi Yi Wan Ji oxazole (9a)
13C NMR collection of illustrative plates.
5-methyl-2-17 Wan Ji oxazoles (10a) of Figure 19 embodiment 10 preparations
1H NMR collection of illustrative plates.
5-methyl-2-17 Wan Ji oxazoles (10a) of Figure 20 embodiment 10 preparations
13C NMR collection of illustrative plates.
(5) embodiment
The present invention is described further below in conjunction with specific embodiment, but protection scope of the present invention is not limited in this:
Synthesizing of embodiment 1:5-methyl-2-Ben Ji oxazole
Step (1) adds 0.169g(1.2mmol in two mouthfuls of round-bottomed flasks of the 25mL that is furnished with reflux condensing tube, drying tube and constant pressure funnel) dimethyl sulfoxide (DMSO) (DMSO) of Benzoyl chloride and 5mL drying, in reaction system, slowly drip 0.136g (1mmol) 2-bromine allylamine and 0.145g(1.44mmol) triethylamine, open magnetic force and at room temperature stir 0.5h, follow the tracks of reaction process with tlc (TLC), until Benzoyl chloride completely dissolve, react completely, obtain to contain N-(2-bromine allyl group) reaction solution of benzamide intermediate; (2) in the reaction solution of step (1) acquisition, add 0.112g (2mmol) KOH and be warming up to gradually 90 ℃, follow the tracks of reaction process until intermediate N (2-bromine allyl group) benzamide completely dissolve with tlc (TLC), reaction in about 2 hours finishes, reaction solution is cooled to room temperature, after the aqueous ammonium chloride solution that under agitation adds mass concentration 15% in the reaction solution is regulated pH to 6.5 ~ 7, with ethyl acetate extraction three times, each 30mL ethyl acetate, after merging organic layer and using the water washing once of 10mL saturated common salt, again through anhydrous sodium sulfate drying, steaming desolventizes the rear sherwood oil of using: ethyl acetate=4:1(volume ratio) carry out silica gel column chromatography (300 ~ 400 order silica gel) for eluent, the TLC follow-up investigations, collection contains the elutriant of target components, the product liquid 5-methyl that obtains-2-Ben Ji oxazole (1a) 0.124g, yield is 78%.
1H NMR collection of illustrative plates as shown in Figure 1,
13C NMR as shown in Figure 2.
1H NMR (500 MHz, CDCl
3) δ 8.21 – 7.90 (m, 2H), 7.63 – 7.15 (m, 3H), 6.85 (d, J = 1.0 Hz, 1H), 2.40 (d, J = 1.1 Hz, 3H).
13C NMR (125 MHz, CDCl
3) δ 160.69, 148.83, 129.81, 128.66, 127.83, 126.12, 125.93, 124.19, 10.95。
Synthesizing of embodiment 2:5-methyl-2-Lin Xiu Ben Ji oxazole
Adjacent feeding intake of bromo-benzoyl chloride is 0.262g(1.2mmol), DMSO is 6mL, is warming up to gradually 80 ℃ behind the adding KOH, other operates with embodiment 1 described preparation method.Through separating to get product liquid 5-methyl-2-Lin Xiu Ben Ji oxazole (2a) 0.212 g, yield is 89%.
1H NMR collection of illustrative plates as shown in Figure 3,
13C NMR as shown in Figure 4.
1H NMR (500 MHz, CDCl
3) δ 7.90 (dd, J = 1.7, 1.7 Hz, 1H), 7.70 (dd, J = 1.1, 1.0 Hz, 1H), 7.39 (td, J = 7.7, 1.1 Hz, 1H), 7.32 – 7.18 (m, 1H), 6.93 (d, J = 1.0 Hz, 1H), 2.41 (d, J = 1.1 Hz, 3H).
13C NMR (125 MHz, CDCl
3) δ 158.97, 149.36, 134.44, 130.93, 130.74, 128.66, 127.27, 124.17, 120.79, 11.01.
Synthesizing of embodiment 3:5-methyl-2-Lin Jia base Ben Ji oxazole
Feeding intake of o-methyl-benzene formyl chloride is 0.185g(1.2mmol), other operates with embodiment 1 described preparation method.Through separating to get product liquid 5-methyl-2-Lin Jia base Ben Ji oxazole (3a) 0.133 g, yield is 77%.
1H NMR collection of illustrative plates as shown in Figure 5,
13C NMR as shown in Figure 6.
1H NMR (500 MHz, CDCl
3) δ 8.11 – 7.84 (m, 1H), 7.47 – 7.17 (m, 3H), 6.89 (d, J = 1.0 Hz, 1H), 2.69 (s, 3H), 2.41 (d, J = 1.0 Hz, 3H).
13C NMR (125 MHz, CDCl
3) δ 161.01, 148.31, 137.06, 131.49, 129.46, 128.49, 126.83, 125.84, 123.95, 21.86, 10.94.
Synthesizing of embodiment 4:5-methyl-2-ortho-nitrophenyl Ji oxazole
Feeding intake of ortho-nitrophenyl formyl chloride is 0.223g(1.2mmol), DMSO is 6mL, is warming up to gradually 110 ℃ behind the adding KOH, other operates with embodiment 1 described preparation method.Through separating to get yellow solid product 5-methyl-2-ortho-nitrophenyl Ji oxazole (4a) 0.102 g, fusing point: 89 ~ 91 oC, yield are 50%.
1H NMR collection of illustrative plates as shown in Figure 7,
13C NMR as shown in Figure 8.
1H NMR (500 MHz, CDCl
3) δ 7.97 (dd, J = 7.8, 1.4 Hz, 1H), 7.75 (dd, J = 8.0, 1.1 Hz, 1H), 7.65 (td, J = 7.6, 1.3 Hz, 1H), 7.60 – 7.52 (m, 1H), 6.90 (q, J = 1.2 Hz, 1H), 2.37 (d, J = 1.2 Hz, 3H).
13C NMR (125 MHz, CDCl
3) δ 156.01, 150.52, 148.51, 131.93, 130.51, 130.08, 124.79, 123.76, 121.29, 10.89.
Synthesizing of embodiment 5:5-methyl-2-Lin Lv Ben Ji oxazole
Feeding intake of o-chlorobenzoyl chloride is 0.210g(1.2mmol), other operates with embodiment 1 described preparation method.Through separating to get product liquid 5-methyl-2-Lin Lv Ben Ji oxazole (5a) 0.135 g, yield is 70%.
1H NMR collection of illustrative plates as shown in Figure 9,
13C NMR as shown in Figure 10.
1H NMR (500 MHz, CDCl
3) δ 8.05 – 7.88 (m, 1H), 7.55 – 7.43 (m, 1H), 7.39 – 7.30 (m, 2H), 6.93 (d, J = 1.1 Hz, 1H), 2.42 (d, J = 1.2 Hz, 3H).
13C NMR (125 MHz, CDCl
3) δ 158.41, 149.31, 132.17, 131.10, 130.55, 130.50, 126.71, 126.58, 124.24, 10.97.
Synthesizing of embodiment 6:5-methyl-2-Dui Jia oxygen base Ben Ji oxazole
Feeding intake of anisoyl chloride is 0.205g(1.2mmol), other operates with embodiment 1 described preparation method.Through separating to get product liquid 5-methyl-2-Dui Jia oxygen base Ben Ji oxazole (6a) 0.132 g, yield is 70%.
1H NMR collection of illustrative plates as shown in Figure 11,
13C NMR as shown in Figure 12.
1H NMR (500 MHz, CDCl
3) δ 7.93 (d, J = 8.9 Hz, 2H), 6.94 (d, J = 8.9 Hz, 2H), 6.78 (d, J = 1.2 Hz, 1H), 3.83 (s, 3H), 2.36 (d, J = 1.2 Hz, 3H).
13C NMR (126 MHz, CDCl
3) δ 160.96, 160.74, 148.20, 127.53, 123.85, 120.71, 114.09, 55.29, 10.93.
Synthesizing of embodiment 7:5-methyl-2-Ben Yi Xi Ji oxazole
Feeding intake of styryl acyl chlorides is 0.200g(1.2mmol), other operates with embodiment 1 described preparation method.Through separating to get white solid product 5-methyl-2-Ben Yi Xi Ji oxazole (7a) 0.117 g, fusing point: 69 ~ 71 ℃, yield is 63%.
1H NMR collection of illustrative plates as shown in Figure 13,
13C NMR as shown in Figure 14.
1H NMR (500 MHz, CDCl
3) δ 7.55 – 7.50 (m, 2H), 7.46 – 7.36 (m, 3H), 7.35 – 7.25 (m, 1H), 6.91 (d, J = 16.4 Hz, 1H), 6.80 (d, J = 1.0 Hz, 1H), 2.37 (d, J = 1.1 Hz, 3H).
13C NMR (125 MHz, CDCl
3) δ 160.59, 148.56, 135.77, 134.73, 128.87, 128.82, 127.17, 127.02, 124.43, 114.26, 10.99.
Synthesizing of embodiment 8:5-methyl-2-phenylpropyl alcohol Ji oxazole
Feeding intake of hydrocinnamyl acyl chlorides is 0.202g(1.2mmol), the reaction times is 5 hours, other operates with embodiment 1 described preparation method.Through separating to get product liquid 5-methyl-2-phenylpropyl alcohol Ji oxazole (8a) 0.116 g, yield is 62%.
1H NMR collection of illustrative plates as shown in Figure 15,
13C NMR as shown in Figure 16.
1H NMR (500 MHz, CDCl
3) δ 7.33 – 7.27 (m, 2H), 7.21 (dd, J = 10.5, 4.2 Hz, 3H), 6.62 (d, J = 1.1 Hz, 1H), 3.12 – 3.06 (m, 2H), 3.02 (ddd, J = 9.0, 6.1, 1.9 Hz, 2H), 2.27 (d, J = 0.8 Hz, 3H).
13C NMR (125 MHz, CDCl
3) δ 162.79, 148.21, 140.55, 128.77, 128.49, 128.39, 128.34, 128.28, 128.03, 126.46, 126.28, 122.50, 33.18, 29.99, 29.70, 10.77.
Synthesizing of embodiment 9:5-methyl-2-Shi Yi Wan Ji oxazole
Feeding intake of undecyl acyl chlorides is 0.245g(1.2mmol), DMSO is 6mL, and 130 ℃ of lower reactions, afterreaction finished in about 5 hours behind the adding KOH, and other operates with embodiment 1 described preparation method.Through separating to get product liquid 5-methyl-2-Shi Yi Wan Ji oxazole (9a) 0.178 g, yield is 80%.
1H NMR collection of illustrative plates as shown in Figure 17,
13C NMR as shown in Figure 18.
1H NMR (500 MHz, CDCl
3) δ 6.57 (d, J = 1.1 Hz, 1H), 2.70 – 2.65 (m, 2H), 2.25 (d, J = 1.1 Hz, 3H), 1.72 (dt, J = 15.2, 7.7 Hz, 2H), 1.37 – 1.21 (m, 16H), 0.87 (t, J = 7.0 Hz, 3H).
13C NMR (125 MHz, CDCl
3) δ 163.84, 147.91, 122.30, 31.87, 29.56, 29.42, 29.29, 29.20, 29.09, 28.12, 27.01, 22.63, 14.04, 10.74.
Synthesizing of embodiment 10:5-methyl-2-17 Wan Ji oxazoles
Feeding intake of heptadecyl acyl chlorides is 0.363g(1.2mmol), DMSO is 6mL, other operates with embodiment 1 described preparation method.Through separating to get product liquid 5-methyl-2-17 Wan Ji oxazoles (10a) 0.266 g, yield is 83%.
1H NMR collection of illustrative plates as shown in Figure 19,
13C NMR as shown in Figure 20.
1H NMR (500 MHz, CDCl
3) δ 6.57 (d, J = 1.0 Hz, 1H), 2.68 (t, J = 7.7 Hz, 2H), 2.26 (d, J = 0.9 Hz, 3H), 1.83 – 1.61 (m, 2H), 1.44 – 1.16 (m, 28H), 0.88 (t, J = 6.9 Hz, 3H).
13C NMR (125 MHz, CDCl
3) δ 163.83, 147.89, 122.31, 31.89, 29.66, 29.62, 29.57, 29.43, 29.32, 29.20, 29.10, 28.12, 27.01, 22.64, 14.04, 10.73.
Synthesizing of embodiment 11:5-methyl-2-Ben Ji oxazole
The charging capacity of Benzoyl chloride changes 0.14g(1.0mmol into), solvent changes DMF (DMF) into, and input amount changes 7mL into, and acid binding agent changes pyridine into, input amount is 0.142g(1.8mmol), the alkali of input changes Na into
2CO
3, input amount is 0.153g(0.144mmol), other operations are identical with embodiment 1, obtain product liquid 5-methyl-2-Ben Ji oxazole (1a) 0.116g, and yield is 73%.
Synthesizing of embodiment 12:5-methyl-2-Ben Ji oxazole
Solvent changes tetrahydrofuran (THF) into, and input amount changes 6mL into, and the charging capacity of acid binding agent triethylamine changes 0.218g(2.16mmol into), the alkali of input changes sodium ethylate into, charging capacity is 0.147g(2.16mmol), other operates with embodiment 1 described preparation method.Obtain product liquid 5-methyl-2-Ben Ji oxazole (1a) 0.129g, yield is 81%.
Synthesizing of embodiment 13:5-methyl-2-Ben Ji oxazole
Solvent changes acetonitrile into, and input amount changes 6.5mL into, and the alkali of input changes sodium methylate into, and temperature of reaction changes 30 ℃ into, and other operates with embodiment 1 described preparation method.Obtain product liquid 5-methyl-2-Ben Ji oxazole (1a) 0.087g, yield is 55%.
Claims (9)
1. shown in the formula IV 2, the preparation method of 5-Er substituted oxazole derivative, it is characterized in that described method is: take the allylamine of 2-bromine shown in acyl chlorides shown in the formula I and the formula II as raw material, under the effect of acid binding agent and alkaline matter, in aprotic polar solvent, 30 ~ 110 ℃ react completely after, with the reaction solution aftertreatment, make 2 shown in the formula IV, 5-Er substituted oxazole derivative; Described acid binding agent is pyridine or triethylamine; Described alkaline matter is organic bases or mineral alkali; The feed intake ratio of amount of substance of described acyl chlorides and 2-bromine allylamine is 1:0.8 ~ 1.0;
In formula (I) and the formula IV, R is: phenyl, substituted-phenyl, hydrocinnamyl, styryl or C
11-C
17Branched-chain alkyl, the substituting group of described substituted-phenyl is adjacent bromo, adjacent methyl, adjacent nitro, adjacent chloro or to methoxyl group.
2. as claimed in claim 1 shown in the formula IV 2, the preparation method of 5-Er substituted oxazole derivative, it is characterized in that R is in described formula (I) and the formula IV: phenyl, o-bromophenyl, o-methyl-phenyl-, O-Nitrophenylfluorone, Chloro-O-Phenyl, p-methoxyphenyl, styryl, hydrocinnamyl, undecyl or heptadecyl.
3. as claimed in claim 1 shown in the formula IV 2, the preparation method of 5-Er substituted oxazole derivative is characterized in that described mineral alkali is KOH, NaOH, K
2CO
3, Na
2CO
3Or Cs
2CO
3
4. as claimed in claim 1 shown in the formula IV 2, the preparation method of 5-Er substituted oxazole derivative is characterized in that described organic bases is potassium tert.-butoxide, sodium ethylate, potassium ethylate or sodium methylate.
5. as claimed in claim 1 shown in the formula IV 2, the preparation method of 5-Er substituted oxazole derivative is characterized in that described aprotic polar solvent is DMF, dimethyl sulfoxide (DMSO), acetonitrile or tetrahydrofuran (THF).
6. as claimed in claim 1 shown in the formula IV 2, the preparation method of 5-Er substituted oxazole derivative is characterized in that described reaction is at 30 ~ 110 ℃ of lower reaction 2 ~ 10h.
7. as claimed in claim 1 shown in the formula IV 2, the preparation method of 5-Er substituted oxazole derivative, it is characterized in that described acyl chlorides and the ratio of the amount of substance that feeds intake of acid binding agent are 1:1.2 ~ 1.8, described acyl chlorides is 1:1.2 ~ 1.8 with the ratio of the amount of substance that feeds intake of alkaline matter, and the volumetric usage of described aprotic polar solvent is counted 4 ~ 7ml/mmol with the acyl chlorides amount of substance.
8. as claimed in claim 1 shown in the formula IV 2, the preparation method of 5-Er substituted oxazole derivative, it is characterized in that described reaction solution post-treating method is: TLC follows the tracks of detection, after reaction finishes, reaction solution is cooled to room temperature, under agitation in reaction solution, add the aqueous ammonium chloride solution adjusting pH of mass concentration 15% to neutrality, with ethyl acetate extraction three times, merge organic layer and with after the saturated common salt water washing again through anhydrous sodium sulfate drying, rotary evaporation is concentrated, get enriched material and carry out silica gel column chromatography with sherwood oil and the ethyl acetate mixed solution of volume ratio 4:1 as eluent, TLC follows the tracks of detection, collection contains the elutriant of target components, obtains described 5-methyl-2-Ben oxazole derivatives.
9. as claimed in claim 1 shown in the formula IV 2, the preparation method of 5-Er substituted oxazole derivative, it is characterized in that described method carries out as follows: mix acyl chlorides shown in the formula I (1) with aprotic polar solvent, then slowly drip the bromine allylamine of 2-shown in the formula II and acid binding agent, at 30 ~ 40 ℃ of lower stirring reactions, TLC follows the tracks of and detects to the disappearance of acyl chlorides raw material point, reacts completely, and obtains to contain the reaction solution a of intermediate shown in the formula III; The feed intake ratio of amount of substance of described acyl chlorides and 2-bromine allylamine is 1:0.85 ~ 0.95; Described acyl chlorides is 1:1.3 ~ 1.5 with the ratio of the amount of substance that feeds intake of acid binding agent, and the volumetric usage of described aprotic polar solvent is counted 4 ~ 7ml/mmol with the acyl chlorides amount of substance; Described acid binding agent is pyridine or triethylamine, and described aprotic polar solvent is DMF or dimethyl sulfoxide (DMSO); (2) in the reaction solution a of step (1) acquisition, add alkaline matter, be warming up to 70 ~ 90 ℃, TLC follows the tracks of to detect to intermediate point shown in the formula III and disappears, obtain reaction solution b, reaction solution b is cooled to room temperature, under agitation in reaction solution b, add the aqueous ammonium chloride solution adjusting pH of mass concentration 15% to neutrality, with ethyl acetate extraction three times, merge organic layer and with after the saturated common salt water washing again through anhydrous sodium sulfate drying, rotary evaporation is concentrated, get enriched material and carry out silica gel column chromatography with sherwood oil and the ethyl acetate mixed solution of volume ratio 4:1 as eluent, TLC follows the tracks of detection, collection contains the elutriant of target components, obtains described 5-methyl-2-Ben oxazole derivatives; Described acyl chlorides is 1:1.3 ~ 1.5 with the ratio of the amount of substance that feeds intake of alkaline matter; Described alkaline matter is potassium tert.-butoxide or sodium ethylate;
In the formula III, R is: phenyl, substituted-phenyl, hydrocinnamyl, styryl or C
11-C
17Branched-chain alkyl, the substituting group of described substituted-phenyl is adjacent bromo, adjacent methyl base, adjacent nitro, adjacent chloro or to methoxyl group.
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0094612A2 (en) * | 1982-05-19 | 1983-11-23 | Tanabe Seiyaku Co., Ltd. | Novel alkyloxazolylacetic acid derivative, processes for preparation and pharmaceutical compositions containing same |
| US5446170A (en) * | 1994-11-22 | 1995-08-29 | American Cyanamid Company | Process for the manufacture of insecticidal arylpyrroles via oxazole amine intermediates |
| US5631379A (en) * | 1994-11-22 | 1997-05-20 | American Cyanamid Company | Oxazole amines as intermediates in the manufacture of insecticidal pyrroles |
| WO2000014078A1 (en) * | 1998-09-03 | 2000-03-16 | Japan Tobacco Inc. | Process for producing oxazole compound |
| CN101307050A (en) * | 2008-06-19 | 2008-11-19 | 安徽工业大学 | Oxazole substituted dihydro pyrazol multi-heterocyclic ring derivates, preparation method and uses thereof |
| CN102060801A (en) * | 2010-12-31 | 2011-05-18 | 浙江工业大学 | Method for synthesizing 5-alkoxy-substituted oxazole compound |
| CN102702127A (en) * | 2012-05-24 | 2012-10-03 | 盛世泰科生物医药技术(苏州)有限公司 | Method for synthesizing N, 5-dimethyl-2-oxazolamine |
-
2012
- 2012-12-19 CN CN2012105572385A patent/CN103058946A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0094612A2 (en) * | 1982-05-19 | 1983-11-23 | Tanabe Seiyaku Co., Ltd. | Novel alkyloxazolylacetic acid derivative, processes for preparation and pharmaceutical compositions containing same |
| US5446170A (en) * | 1994-11-22 | 1995-08-29 | American Cyanamid Company | Process for the manufacture of insecticidal arylpyrroles via oxazole amine intermediates |
| US5631379A (en) * | 1994-11-22 | 1997-05-20 | American Cyanamid Company | Oxazole amines as intermediates in the manufacture of insecticidal pyrroles |
| WO2000014078A1 (en) * | 1998-09-03 | 2000-03-16 | Japan Tobacco Inc. | Process for producing oxazole compound |
| CN101307050A (en) * | 2008-06-19 | 2008-11-19 | 安徽工业大学 | Oxazole substituted dihydro pyrazol multi-heterocyclic ring derivates, preparation method and uses thereof |
| CN102060801A (en) * | 2010-12-31 | 2011-05-18 | 浙江工业大学 | Method for synthesizing 5-alkoxy-substituted oxazole compound |
| CN102702127A (en) * | 2012-05-24 | 2012-10-03 | 盛世泰科生物医药技术(苏州)有限公司 | Method for synthesizing N, 5-dimethyl-2-oxazolamine |
Non-Patent Citations (8)
| Title |
|---|
| BARLUENGA J ET AL: "N-substituted lithium 2-lithioallylamines: new intermediates in synthesis", 《JOURNAL OF THE CHEMICAL SOCIETY, PERKIN TRANSACTIONS I》, vol. 1, no. 3, 31 December 1989 (1989-12-31), pages 553 - 555 * |
| BHAT L ET AL: "Convenient Synthesis of Heterobicycles by Domino Heck− Diels− Alder Reactions", 《EUROPEAN JOURNAL OF ORGANIC CHEMISTRY》, vol. 2001, no. 9, 31 December 2001 (2001-12-31) * |
| KIM T Y ET AL: "Facile synthesis of 2, 4, 5-trisubstituted oxazole derivatives from deoxybenzoins", 《BULLETIN-KOREAN CHEMICAL SOCIETY》, vol. 21, no. 7, 31 December 2000 (2000-12-31) * |
| LIU X H ET AL: "Novel 2, 4, 5-trisubstituted oxazole derivatives: Synthesis and antiproliferative activity", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》, vol. 44, no. 10, 31 December 2009 (2009-12-31) * |
| YASMIN N ET AL: "A Simple One-Pot Synthesis of 2-Aryl-5-alkyl-Substituted Oxazoles by Cs2CO3-Mediated Reactions of Aromatic Primary Amides with 2, 3-Dibromopropene", 《SYNLETT》, vol. 1, no. 17, 31 December 2009 (2009-12-31), pages 2825 - 2827 * |
| 何家骥: "2, 5-二取代噁唑的合成及性能的研究", 《天津理工学院学报》, vol. 12, no. 1, 31 December 1996 (1996-12-31) * |
| 杜宗波: "噁唑类化合物的合成方法研究", 《中国优秀硕士论文电子期刊网》, 31 December 2011 (2011-12-31) * |
| 高振衡 ET AL: "2, 5-二取代噁唑的研究", 《高等学校化学学报》, vol. 3, no. 3, 31 December 1982 (1982-12-31) * |
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