CN102532049B - Method for preparing 2-aldehyde oxazole - Google Patents
Method for preparing 2-aldehyde oxazole Download PDFInfo
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- CN102532049B CN102532049B CN201110435667.0A CN201110435667A CN102532049B CN 102532049 B CN102532049 B CN 102532049B CN 201110435667 A CN201110435667 A CN 201110435667A CN 102532049 B CN102532049 B CN 102532049B
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- 0 C*1c[o]cc1 Chemical compound C*1c[o]cc1 0.000 description 1
- YWOIQIYQBRDOQA-UHFFFAOYSA-N C1COC=NC1 Chemical compound C1COC=NC1 YWOIQIYQBRDOQA-UHFFFAOYSA-N 0.000 description 1
- WDRAAGQRZVGCKJ-UHFFFAOYSA-N CCC1=C(C=O)OC=C(C)C1 Chemical compound CCC1=C(C=O)OC=C(C)C1 WDRAAGQRZVGCKJ-UHFFFAOYSA-N 0.000 description 1
- TYHOSUCCUICRLM-UHFFFAOYSA-N O=Cc1ncc[o]1 Chemical compound O=Cc1ncc[o]1 TYHOSUCCUICRLM-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention relates to a method for preparing 2-aldehyde oxazole, comprising the steps of selecting commercial material on the market or easily-prepared oxazole as original raw material; dropping n-butyllithium to the organic phase solution of the main material oxazole at low temperature; and adding N-formoxyl piperidine to the reaction system, and obtaining solid lithium salt with high nuclear magnetic purity. The nuclear magnetic purity is higher than 98.0% stably and the yield is 75.0-85.0%. The synthetic method for obtaining 2-aldehyde oxazole by diluted acid hydrolysis has stable process condition, moderate chemical reaction conditions, simple operation and low pollution during the whole production and provides a new idea and a method for preparing 2-aldehyde oxazole.
Description
(1) technical field:
The present invention relates to a kind of method of Bei oxazole compounds processed, particularly a kind of method of preparing 2-Quan Ji oxazole.
(2) background technology:
Oxazole is 1,3 five-ring that contains O, N atom, and being has smell and liquid soluble in water as pyridine, is highly stable compound, and it is very stable in hot strong acid, and autoxidation reaction does not occur, and does not participate in any normal Biochemical processes.Oxazole compounds is the important heterogeneous ring compound of a class, and some tools have the compound of oxazole ring to have biological activity, simultaneously they in intermediate, medicine are synthetic also tool have been widely used.On oxazole-2-formaldehyde Shi oxazole ring, increasing an aldehyde radical replaces, the reactive behavior of Zeng Jia oxazole, can be synthetic with the bioactive compound of having of oxazole ring by conventional Biochemical processes, in intermediate, medicine synthesize, tool has been widely used.Therefore, develop the synthesis technique of the 2-Quan Ji oxazole that a kind of purity is high, yield is high significant.
Present stage, the method of preparing 2-Quan Ji oxazole is mainly organolithium reagent method, Xian You oxazole and organolithium generation lithiation, again with N, dinethylformamide or the upper aldehyde radical of N-N-formyl morpholine N-reaction, the aftertreatment of these two kinds of methods is all more loaded down with trivial details, use N, the method of aldehyde radical on dinethylformamide, need to obtain product by silica gel column chromatography partition method, because product has lower boiling, the feature of highly water-soluble, cause yield very low, the method is not suitable for large-scale production, use the method reaction of the upper aldehyde radical of N-N-formyl morpholine N-reaction, the product obtaining is oily mixture, can not obtain the sterling compound of this product, and be unsuitable for and store and transportation.
(3) summary of the invention:
The object of the present invention is to provide a kind of high yield to prepare highly purified 2-Quan Ji oxazole
method, select on market business-like raw material or easily prepare oxazole
for initial feed, under the condition of low temperature, n-Butyl Lithium is splashed into main Yuan Liao oxazole
organic phase solution in, then add N-formyl piperidine in reaction system
obtain the solid lithium salts that nuclear-magnetism purity is high
through hydrolysis, be prepared into 2-Quan Ji oxazole
reaction process is referring to Fig. 2.Particularly the method obtains highly purified solid lithium salts
intermediate, has greatly simplified aftertreatment purification process, and is convenient to store and transportation.The method stable process conditions, simple to operate, be applicable to large-scale production, for preparation 2-Quan Ji oxazole provides a kind of new thinking and method.
Technical scheme of the present invention: a kind of method of preparing 2-Quan Ji oxazole, is characterized in that concrete steps are as follows:
(1) feed intake: in reactor, add and become owner of former material oxazole
ether solvent, starts stirring, Qi Zhong oxazole
with the amount ratio of ether solvent be 1g/5～50mL;
(2) drip n-butyllithium solution: system is cooled to-90～-60 ℃, and drips n-butyllithium solution at-90～-60 ℃, drip and finish, in-90～-60 ℃ of insulation 2～8h; Qi Zhong oxazole
with the mol ratio of n-Butyl Lithium be 1:1.0～1.5;
(3) drip N-formyl piperidine: under-90～-60 ℃ of conditions, in system, drip N-formyl piperidine
drip and finish, system is risen again to 20～30 ℃, at 20～30 ℃, is incubated 32～72h, Qi Zhong oxazole
with the mol ratio of N-formyl piperidine be 1:1.0～10.0;
(4) aftertreatment: system is cooled to-5～10 ℃, stirring and crystallizing, suction filtration, filter cake ether solvent drip washing, dries under nitrogen protection, obtains solid lithium salts
qi Zhong oxazole
with the amount ratio of ether solvent be 1g/2～10mL;
(5) hydrolysis: be 5～20% dilute acid solution to dripping concentration in step (4) gained solid lithium salts, until system clarification, hydrolysis completely, obtains 2-aldehyde base oxazole
In above-mentioned steps (1), said ether solvent is ether, tetrahydrofuran (THF) or 2-methyltetrahydrofuran.
In above-mentioned steps (4), said ether solvent is ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran or methyl tertiary butyl ether.
In above-mentioned steps (5), said diluted acid is that concentration is the aqueous solution of 5～15% formic acid, acetic acid, dilute hydrochloric acid, dilute sulphuric acid, rare nitric acid or dilute phosphoric acid.
Above-mentioned said step (1) Zhong oxazole
with the amount ratio of ether solvent be 1g/10～40mL, said step (2) Zhong oxazoles
with the mol ratio of n-Butyl Lithium be 1:1.1～1.4, said step (3) Zhong oxazoles
with the mol ratio of N-formyl piperidine be 1:3.0～8.0, said step (4) Zhong oxazoles
with the amount ratio of ether solvent be 1g/2～8mL.
In above-mentioned steps (1), said ether solvent is tetrahydrofuran (THF) or 2-methyltetrahydrofuran.
In above-mentioned steps (4), said ether solvent is ether or methyl tertiary butyl ether.
In above-mentioned steps (5), said diluted acid is that concentration is 10～15% acetic acid,diluteds, dilute hydrochloric acid or dilute sulfuric acid aqueous solution.
Above-mentioned said step (1) Zhong oxazole
with the amount ratio of ether solvent be 1g/25～35mL, said step (2) Zhong oxazoles
with the mol ratio of n-Butyl Lithium be 1:1.2～1.4, said step (3) Zhong oxazoles
with the mol ratio of N-formyl piperidine be 1:4.0～6.0, said step (4) Zhong oxazoles
with the amount ratio of ether solvent be 1g/3～6mL.
In above-mentioned steps (1), said ether solvent is tetrahydrofuran (THF), and in step (4), said ether solvent is methyl tertiary butyl ether, and in step (5), said dilute acid soln is that concentration is 10% acetic acid,diluted or diluted hydrochloric acid aqueous solution.
Superiority of the present invention: 1, current synthesizing about 2-Quan Ji oxazole, the product obtaining exists mainly with the form of oily mixture greatly, and chemical purity is lower, the present invention adopts method, can obtain the lithium salts solid that nuclear-magnetism purity is high, in nuclear-magnetism, mark purity is stabilized in more than 98.0%, is convenient to store and transportation, through hydrolysis, obtains 2-Quan Ji oxazole; 2, the DMF that the present invention adopts traditional method or the upper aldehyde radical of N-N-formyl morpholine N-reaction, replace with N-aldehyde radical piperidines, makes post-treating method simpler; 3, reaction yield of the present invention is up to 75.0%～85.0%, and stable process conditions is simple to operate, possesses the ability of large-scale production.
(4) accompanying drawing explanation:
Fig. 1: the chemical reaction step schema of a kind of related method of preparing 2-Quan Ji oxazole of the present invention.
Fig. 2: the chemical reaction process schema of a kind of related method of preparing 2-Quan Ji oxazole of the present invention.
In conjunction with Fig. 1 and Fig. 2, can understand more intuitively the technical scheme of foregoing invention.
(5) embodiment:
For the interval range occurring in embodiment, be because temperature in single test is with certain the floating of there will be of reaction process; The statement of pH value test result is also the routine statement in the synthetic field of chemical industry.
Embodiment 1: a kind of method of preparing 2-Quan Ji oxazole, is characterized in that concrete steps are as follows:
(1) feed intake: in 1500L reactor, add the main Yuan Liao of 20.0kg oxazole
600L tetrahydrofuran (THF), starts stirring;
(2) drip n-butyllithium solution: system is cooled to-65 ± 5 ℃, and at-65 ± 5 ℃, drips 24.1kg n-butyllithium solution, drip and finish, at-65 ± 5 ℃, be incubated 5h;
(3) drip N-formyl piperidine: system drips 163.8kgN-formyl piperidine at-65 ± 5 ℃, drip and finish, system is risen again to 25 ± 5 ℃, at 20 ± 5 ℃, is incubated 50h;
(4) aftertreatment: system is cooled to 0 ± 3 ℃, stirring and crystallizing, suction filtration, 80L methyl tertiary butyl ether drip washing for filter cake, dries under nitrogen protection, obtains solid lithium salts
mark purity (NMR) in nuclear-magnetism: 98.8%, yield 85.0%;
(5) hydrolysis: in step (4) gained solid lithium salts, the diluted hydrochloric acid aqueous solution 300L that dropping concentration is 10%, system clarification, hydrolysis completely, obtains product
The nuclear magnetic data of products obtained therefrom is as follows:
1h NMR:(60MHz), 7.09 (H, s, NCHC), 7.69 (H, s, OCHC), 9.61 (H, s, CHO).
Embodiment 2: a kind of method of preparing 2-Quan Ji oxazole, is characterized in that concrete steps are as follows:
(1) feed intake: in 500L reactor, add the main Yuan Liao of 6.5kg oxazole, 227.5L methyl tertiary butyl ether, starts stirring;
(2) drip n-butyllithium solution: system is cooled to-85 ± 5 ℃, and at-85 ± 5 ℃, drips 7.2kg n-butyllithium solution, drip and finish, at-85 ± 5 ℃, be incubated 5h;
(3) drip N-formyl piperidine: system drips 106.5kgN-formyl piperidine at-85 ± 5 ℃, drip and finish, system is risen again to 25 ± 5 ℃, at 25 ± 5 ℃, is incubated 48h;
(4) aftertreatment: system is cooled to 0 ± 3 ℃, stirring and crystallizing, suction filtration, 80L methyl tertiary butyl ether drip washing for filter cake, dries under nitrogen protection, obtains solid lithium salts
mark purity (NMR) in nuclear-magnetism: 98.2%, yield 80.5%;
(5) hydrolysis: in step (4) gained solid lithium salts, the acetic acid,diluted solution 65L that dropping concentration is 10%, system clarification, hydrolysis completely, obtains product
Embodiment 3: a kind of method of preparing 2-Quan Ji oxazole, is characterized in that concrete steps are as follows:
(1) feed intake: in 100L reaction flask, add the main Yuan Liao of 2.8kg oxazole, 20L tetrahydrofuran (THF), starts stirring;
(2) drip n-butyllithium solution: system is cooled to-65 ± 5 ℃, and at-65 ± 5 ℃, drips 2.8kg n-butyllithium solution, drip and finish, at-65 ± 5 ℃, be incubated 2h;
(3) drip N-formyl piperidine: system drips 4.6kgN-formyl piperidine at-65 ± 5 ℃, drip and finish, system is risen again to 25 ± 5 ℃, at 25 ± 5 ℃, is incubated 32h;
(4) aftertreatment: system is cooled to 0 ± 3 ℃, stirring and crystallizing, suction filtration, 2.8L methyl tertiary butyl ether drip washing for filter cake, dries under nitrogen protection, obtains solid lithium salts, mark purity (NMR) in nuclear-magnetism: 98.5%, yield 75.0%;
(5) hydrolysis: in step (4) gained solid lithium salts, drip 20% acetic acid,diluted solution 5.6L, system clarification, hydrolysis completely, obtains product
Embodiment 4: a kind of method of preparing 2-Quan Ji oxazole, is characterized in that concrete steps are as follows:
(1) feed intake: in 1000L reactor, add the main Yuan Liao of 15kg oxazole, 750L tetrahydrofuran (THF), starts stirring;
(2) drip n-butyllithium solution: system is cooled to-70 ± 5 ℃, and at-70 ± 5 ℃, drips 20.9kg n-butyllithium solution, drip and finish, at-70 ± 5 ℃, be incubated 8h;
(3) drip N-formyl piperidine: system drips 196.2kgN-formyl piperidine at-70 ± 5 ℃, drip and finish, system is risen again to 25 ± 5 ℃, at 25 ± 5 ℃, is incubated 72h;
(4) aftertreatment: system is cooled to 0 ± 3 ℃, stirring and crystallizing, suction filtration, 120L methyl tertiary butyl ether drip washing for filter cake, dries under nitrogen protection, obtains solid lithium salts, mark purity (NMR) in nuclear-magnetism: 98.5%, yield 77.8%;
(5) hydrolysis: in step (4) gained solid lithium salts, the formic acid solution 120L that dropping concentration is 10%, system clarification, hydrolysis completely, obtains product
As can be seen here, disclosed preparation 2-Quan Ji oxazole in the present invention
method can obtain the solid lithium salts that purity is high
in nuclear-magnetism, mark purity is stabilized in more than 98.0%, and yield is 75.0%～85.0%, through dilute acid hydrolysis, obtains 2-Quan Ji oxazole
the stable process conditions that synthetic method adopts, chemical reaction condition gentleness, simple to operate in whole production process, pollute lower, for preparation 2-Quan Ji oxazole provides a kind of new thinking and method.
Claims (10)
1. prepare a method for 2-aldehyde base oxazole, it is characterized in that concrete steps are as follows:
(1) feed intake: in reactor, add and become owner of former material oxazole
ether solvent, starts stirring, Qi Zhong oxazole
with the amount ratio of ether solvent be 1g/5～50mL;
(2) drip n-butyllithium solution: system is cooled to-90～-60 ℃, and drips n-butyllithium solution at-90～-60 ℃, drip and finish, in-90～-60 ℃ of insulation 2～8h; Qi Zhong oxazole
with the mol ratio of n-Butyl Lithium be 1:1.0～1.5;
(3) drip N-formyl piperidine: under-90～-60 ℃ of conditions, in system, drip N-formyl piperidine
drip and finish, system is risen again to 20～30 ℃, at 20～30 ℃, is incubated 32～72h, Qi Zhong oxazole
with the mol ratio of N-formyl piperidine be 1:1.0～10.0;
(4) aftertreatment: system is cooled to-5～10 ℃, stirring and crystallizing, suction filtration, filter cake ether solvent drip washing, dries under nitrogen protection, obtains solid lithium salts
qi Zhong oxazole
with the amount ratio of ether solvent be 1g/2～10mL;
(5) hydrolysis: be 5～20% dilute acid solution to dripping concentration in step (4) gained solid lithium salts, until system clarification, hydrolysis completely, obtains 2-aldehyde base oxazole
2. a kind of method of preparing 2-Quan Ji oxazole according to claim 1, is characterized in that ether solvent described in step (1) is ether, tetrahydrofuran (THF) or 2-methyltetrahydrofuran.
3. a kind of method of preparing 2-Quan Ji oxazole according to claim 1, is characterized in that ether solvent described in step (4) is ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran or methyl tertiary butyl ether.
4. a kind of method of preparing 2-Quan Ji oxazole according to claim 1, is characterized in that diluted acid described in step (5) is that concentration is the aqueous solution of 5～15% formic acid, acetic acid, dilute hydrochloric acid, dilute sulphuric acid, rare nitric acid or dilute phosphoric acid.
5. a kind of method of preparing 2-Quan Ji oxazole according to claim 1, is characterized in that described step (1) Zhong oxazole
with the amount ratio of ether solvent be 1g/10～40mL, described step (2) Zhong oxazoles
with the mol ratio of n-Butyl Lithium be 1:1.1～1.4, described step (3) Zhong oxazoles
with the mol ratio of N-formyl piperidine be 1:3.0～8.0, described step (4) Zhong oxazoles
with the amount ratio of ether solvent be 1g/2～8mL.
6. according to a kind of method of preparing 2-Quan Ji oxazole described in claim 1 or 2, it is characterized in that ether solvent described in step (1) is tetrahydrofuran (THF) or 2-methyltetrahydrofuran.
7. according to a kind of method of preparing 2-Quan Ji oxazole described in claim 1 or 3, it is characterized in that described in step (4), ether solvent is ether or methyl tertiary butyl ether.
8. according to a kind of method of preparing 2-Quan Ji oxazole described in claim 1 or 4, it is characterized in that diluted acid described in step (5) is that concentration is 10～15% acetic acid,diluteds, dilute hydrochloric acid or dilute sulfuric acid aqueous solution.
9. according to a kind of method of preparing 2-Quan Ji oxazole described in claim 1 or 5, it is characterized in that described step (1) Zhong oxazole
with the amount ratio of ether solvent be 1g/25～35mL, described step (2) Zhong oxazoles
with the mol ratio of n-Butyl Lithium be 1:1.2～1.4, described step (3) Zhong oxazoles
with the mol ratio of N-formyl piperidine be 1:4.0～6.0, described step (4) Zhong oxazoles
with the amount ratio of ether solvent be 1g/3～6mL.
10. a kind of method of preparing 2-Quan Ji oxazole according to claim 1, it is characterized in that described in step (1), ether solvent is tetrahydrofuran (THF), described in step (4), ether solvent is methyl tertiary butyl ether, and dilute acid soln described in step (5) is that concentration is 10% acetic acid,diluted or diluted hydrochloric acid aqueous solution.
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