CN110240573A - A method of preparing polysubstituted evil azole compounds - Google Patents
A method of preparing polysubstituted evil azole compounds Download PDFInfo
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- CN110240573A CN110240573A CN201910599896.2A CN201910599896A CN110240573A CN 110240573 A CN110240573 A CN 110240573A CN 201910599896 A CN201910599896 A CN 201910599896A CN 110240573 A CN110240573 A CN 110240573A
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- azole compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/36—One oxygen atom
- C07D263/42—One oxygen atom attached in position 5
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The polysubstituted method for disliking azole compounds is prepared the invention discloses a kind of, the following steps are included: under acid binding agent existence condition, phosgene or surpalite or triphosgene solution are added into the solution of compound shown in formula II, auxiliary agent is added after adding to be reacted, and the polysubstituted evil azole compounds as described in formula (I) are obtained；The auxiliary agent is organic acid.This method can improve the yield of product oxazole, while reduce by-product N, the content of N- diethyl formyl chloride.
Description
Technical field
The invention belongs to technical field of organic synthesis, and in particular to a method of prepare polysubstituted evil azole compounds.
Background technique
Oxazole is a kind of important five-ring heterocycles in nature.Wherein, 2,4,5- tri- substituted oxazolines are widely present in naturally
In the various bioactive compounds such as product, drug, such as the nonsteroidal anti-inflammatory Ao Shapu Qin, peptide alkaloid A and anti-diabetic
Drug AD-5061, at the same can also be used as synthesis vitamin B6 intermediate [Selected papers:(a) Todd, P.A.；
Brogden,R.N.Drugs,1986,32,291-312；(b)Nagatsu,A.；Kajitani,H.；Sakakibara,
J.Tetrahedron Lett.1995,36,4097-4100；(c)Momose,Y.；Maekawa,T.；Odaka,H.；Ikeda,
H.；Sohda,T.J.Med.Chem.2002,45,1518-1534].Therefore the novel synthesis of polysubstituted oxazole has and actually answers
Highest attention with value, by related fields researcher.
The method that azole compounds are disliked in synthesis at present includes Robinson-Gabriel synthesis, the synthesis of Fischer oxazole etc.
Method [Turchi, I.J.Ind.Eng.Chem.Prod.Res.Dev.1981,20,32-75].Wherein Robinson-Gabriel
Synthetic method is most effective but is also that one of the method for azole compounds is disliked in the synthesis most challenged.Robinson-Gabriel synthesis
Method is raw material using 2- amide ketone, makees dehydrating agent using the concentrated sulfuric acid, and reaction condition is very harsh, is not suitable for synthesizing acid labile
Compound.Maeda et al. utilizes POCl3Dehydrating agent is made, so that reaction carries out [Maeda, I. under mild conditions；
Takehara,M.；Togo,K.；Asai,S.；Yoshida,R.；Bull.Chem.Soc.Japan.1974,44,1435-
1437].But reaction generates a large amount of phosphorus-containing wastewaters, is unfavorable for industrialized production.Therefore suitable dehydrating agent is selected to carry out cyclization
Reaction is a urgent problem to be solved.
Patent application GB1195854 disclose it is a kind of using phosgene as dehydrating agent, triethylamine as acid binding agent, chloroform work
For the method that reaction dissolvent carries out cyclization, which avoids the generation of phosphorus-containing wastewater, but yield is lower.
Patent application CN105985297A disclose it is a kind of using solid phosgene as dehydrating agent, triethylamine as acid binding agent,
The method that stannous chloride carries out cyclization as catalyst.But reaction yield is not high, by-products content is higher.
Summary of the invention
The polysubstituted method for disliking azole compounds is prepared the object of the present invention is to provide a kind of, this method aims to solve the problem that utilization
Phosgene does the not high problem of dehydrating agent synthesis oxazoline compound yield, while effectively inhibiting by-product N, N- diethyl formyl chloride
It generates.
It is provided by the invention to prepare the polysubstituted method for disliking azole compounds, include the following steps:
Under acid binding agent existence condition, phosgene or surpalite is added into the solution of compound shown in formula II or triphosgene is molten
Liquid adds auxiliary agent after adding and is reacted, and obtains the polysubstituted evil azole compounds；
Shown in the structure such as formula (I) of the polysubstituted evil azole compounds:
In formula (I)~(II), R1、R2And R3Independently selected from C1-C6Alkyl in any one；
The auxiliary agent is organic acid.
The phosgene or surpalite or the adding manner of triphosgene solution are preferably the mode injected, and are added in this way convenient for control
Enter speed.
Preferably, in formula (I)~(II), R1、R2And R3Independently selected from methyl, ethyl, propyl, normal-butyl, isobutyl
Base, tert-butyl, any one in hexyl.
The present invention is added in alkaline environment contains proton for the first time using phosgene, the dewatering system of organic base and organic solvent
Organic acid as auxiliary agent, improve reaction yield, specific reaction mechanism given below:
The phosgene mole dosage is 1.0-2.1 times of II compound of formula or surpalite mole dosage is II compound of formula
0.5-1.05 times or triphosgene mole dosage be 0.33-0.7 times of II compound of formula.
The acid binding agent is N-ethylpiperidine, triethylamine, pyridine, diisopropylethylamine, tetramethylguanidine, 1,8- diaza two
11 carbon -7- alkene of ring [5.4.0], 4-N, N- dimethylamino naphthyridine or 4-methylimidazole, are particularly preferred N-ethylpiperidine.
The mole dosage of the acid binding agent is 1.0~4 equivalents of phosgene usage, or is the 0.5~2 of surpalite mole dosage
Equivalent, or 0.33~1.33 equivalent for triphosgene mole dosage.
The auxiliary agent is formic acid, glacial acetic acid, propionic acid, butyric acid, trifluoroacetic acid, oxalic acid, malonic acid, benzoic acid, phenylacetic acid etc.
Glacial acetic acid is particularly preferred in organic acid.
The dosage of the auxiliary agent is 0.005~0.25 times of II compound amount of formula.
The temperature controlled processes include, during the organic solution for injecting phosgene or surpalite or triphosgene, temperature
It is -50 DEG C~10 DEG C, 0 DEG C of preferable temperature；The organic solution of injection phosgene or surpalite or triphosgene finishes, and reaction temperature is-
50 DEG C~10 DEG C, 5 DEG C of preferable temperature.
Cyclization reaction solvent for use be selected from n-hexane, normal octane, hexamethylene, petroleum ether, cyclohexanone, acetone, benzene, toluene,
Dimethylbenzene, ethyl acetate, propyl acetate, dioxane, methyl tertiary butyl ether(MTBE), isopropyl ether, cyclopentyl-methyl ether, glycol dinitrate
Ether, tetrahydrofuran, methylene chloride, chloroform, 1,2- dichloroethanes, 1,1,2- trichloroethanes, chlorobenzene, 2- methyltetrahydrofuran
Or the mixed solvent of these solvents, preferably chloroform, 1,1,2- trichloroethanes, chlorobenzene, methylene chloride or these solvents
Mixed solvent.
Wherein, the solvent of dissolution type II compound and phosgene or the solvent of surpalite or triphosgene can be identical, can also be with
Difference, preferably identical solvent.
Before the cyclization reaction starts, the concentration of formula II is 0.15g/mL~1.6g/mL, preferably 0.75g/mL~1.5g/
mL。
Before the cyclization reaction starts, phosgene or surpalite or triphosgene concentration are 0.05g/mL~2g/mL, preferably
0.2g/mL~1g/mL.
The injection time of phosgene or surpalite or triphosgene is 0.5h~3h, preferably 0.5h.
Phosgene or the injection of surpalite or triphosgene finish, and the reaction was continued, and the time is 0.1h~3h, preferably 0.1h.
During the cyclization reaction, reaction unit is the reaction unit of sealing.
The polysubstituted method for disliking azole compounds shown in synthesis Formulas I provided by the invention is one-step synthesis, this method tool
Have following characteristics: (1) yield of reaction product oxazole is very high, while the content of by-product N, N- diethyl formyl chloride is very
It is low；(2) waste water that reaction generates is easily processed, and is convenient for industrialized production；(3) dehydrating agent (phosgene or surpalite or triphosgene) is honest and clean
Valence, production cost are low.
Specific embodiment
Below with reference to specific implementation example, the present invention is further elaborated, but the present invention is not limited to following embodiments.
The method is conventional method unless otherwise instructed.The raw material can obtain unless otherwise instructed from public commercial source
?.
Embodiment 1
The preparation of 4- methyl -5- ethyoxyl oxazole carboxylic acid, ethyl ester
In reaction flask, 15.10g N- ethoxy oxalyl alanine ethyl ester (0.07mol) and 25.00mL N- ethyl piperazine is added
Pyridine (0.18mol), injected after the dissolution of 20mL chloroform, under 0 DEG C and stirring condition phosgene solution (7.91g, 0.08mol, it is molten
Solution is in 20mL chloroform), 20min is added dropwise.5 DEG C are then heated to, 0.5h is reacted.After reaction, gas-chromatography is examined
The internal standard yield for surveying discovery product is 94.2% (n-dodecane is internal standard), while generating 3.1% N, N- diethyl formyl chloride
(area normalization method).
Embodiment 2
The preparation of 4- methyl -5- ethyoxyl oxazole carboxylic acid, ethyl ester
In reaction flask, 15.41g N- ethoxy oxalyl alanine ethyl ester (0.07mol) and 25.00mL N- ethyl piperazine is added
Pyridine (0.18mol), injected after the dissolution of 20mL chloroform, under 0 DEG C and stirring condition phosgene solution (9.48g, 0.10mol, it is molten
Solution is in 20mL chloroform), 20min is added dropwise.5 DEG C are then heated to, 0.5h is reacted.After reaction, gas-chromatography is examined
The internal standard yield for surveying discovery product is 94.9% (n-dodecane is internal standard), while generating 5.4% N, N- diethyl formyl chloride
(area normalization method).
Embodiment 3
The preparation of 4- methyl -5- ethyoxyl oxazole carboxylic acid, ethyl ester
In reaction flask, 15.41g N- ethoxy oxalyl alanine ethyl ester (0.07mol) and 25.00mL N- ethyl piperazine is added
Pyridine (0.18mol), injected after the dissolution of 20mL chloroform, under 5 DEG C and stirring condition phosgene solution (7.91g, 0.08mol, it is molten
Solution is in 20mL chloroform), 20min is added dropwise.The reaction was continued 0.5h.After reaction, gas chromatographic detection finds product
Internal standard yield be 88.10% (n-dodecane is internal standard), while generate 12.23% N, N- diethyl formyl chloride (return by area
One method).
Embodiment 4
The preparation of 4- methyl -5- ethyoxyl oxazole carboxylic acid, ethyl ester
In reaction flask, 15.41g N- ethoxy oxalyl alanine ethyl ester (0.07mol) and 25.00mL N- ethyl piperazine is added
Pyridine (0.18mol), injected after the dissolution of 20mL chloroform, under 0 DEG C and stirring condition phosgene solution (7.91g, 0.08mol, it is molten
Solution is in 20mL chloroform), 20min is added dropwise.5 DEG C are then heated to, is added glacial acetic acid (0.11ml, 0.002mol), instead
Answer 0.5h.After reaction, the internal standard yield of gas chromatographic detection discovery product is 99.4% (n-dodecane is internal standard), simultaneously
Generate 0.8% N, N- diethyl formyl chloride (area normalization method).Gained reaction solution 60mL is washed three times, water phase 40mL
Chloroform is stripped twice, merges organic phase.Collect reaction solution after ten batch processings.Gained reaction solution carries out rectification under vacuum, obtains
Qualified products 136.5g, yield 96.58%.
Embodiment 5
The preparation of 4- methyl -5- ethyoxyl oxazole carboxylic acid, ethyl ester
In reaction flask, 15.41g N- ethoxy oxalyl alanine ethyl ester (0.07mol) and 18.05g triethylamine is added
(0.18mol), injected after the dissolution of 20mL chloroform, under 0 DEG C and stirring condition triphosgene solution (7.91g, 0.08mol, it is molten
Solution is in 20mL chloroform), 0.5h is added dropwise.5 DEG C are then heated to, is added glacial acetic acid (0.11ml, 0.002mol), reaction
0.5h.After reaction, the internal standard yield of gas chromatographic detection discovery product is 98.4% (n-dodecane is internal standard), raw simultaneously
At 1.8% N, N- diethyl formyl chloride (area normalization method).
Embodiment 6
The preparation of 4- methyl -5- n-butoxy oxazole butyl carboxylate
In reaction flask, 19.00g N- fourth oxygen butoxalyl-alaninate (0.07mol) and 27.30mL N- ethyl piperazine is added
Pyridine (0.20mol), injected after the dissolution of 20mL chloroform, under 0 DEG C and stirring condition phosgene solution (9.89g, 0.10mol, it is molten
Solution is in 20mL chloroform), 0.5h injection finishes.5 DEG C are then heated to, is added glacial acetic acid (0.11ml, 0.002mol), reaction
0.5h.After reaction, the internal standard yield of gas chromatographic detection discovery product is 98.9% (n-dodecane is internal standard), raw simultaneously
At 0.6% N, N- diethyl formyl chloride (area normalization method).
Embodiment 7
The preparation of 4- methyl -5- n-butoxy oxazole butyl carboxylate
In reaction flask, 19.00g N- fourth oxygen butoxalyl-alaninate (0.07mol) and 27.30mL N- ethyl piperazine is added
Pyridine (0.20mol), injected after the dissolution of 20mL chloroform, under 0 DEG C and stirring condition phosgene solution (9.89g, 0.10mol, it is molten
Solution is in 20mL chloroform), 1h injection finishes.5 DEG C are then heated to, is added trifluoroacetic acid (0.14ml, 0.002mol), reaction
0.5h.After reaction, the internal standard yield of gas chromatographic detection discovery product is 96.1% (n-dodecane is internal standard), raw simultaneously
At 3.6% N, N- diethyl formyl chloride (area normalization method).
Embodiment 8
The preparation of 4- methyl -5- methoxyl group -2- oxazole carboxylate methyl ester
In reaction flask, 13.24g N- methoxy methoxalyl-alaninate (0.07mol) and 27.30mL N- ethyl piperazine is added
Pyridine (0.20mol), injected after the dissolution of 20mL chloroform, under 0 DEG C and stirring condition phosgene solution (9.89g, 0.10mol, it is molten
Solution is in 20mL chloroform), 20min injection finishes.Then heat to 5 DEG C, be added 0.11ml glacial acetic acid (0.11ml,
0.002mol), 0.5h is reacted.After reaction, the internal standard yield of gas chromatographic detection discovery product is 98.6% (n-dodecane
For internal standard), at the same the N of generation 0.9%, N- diethyl formyl chloride (area normalization method).
Embodiment 9
The preparation of 4- methyl -5- methoxyl group -2- oxazole carboxylate methyl ester
In reaction flask, 13.24g N- methoxy methoxalyl-alaninate (0.07mol) and 22.64g triethylamine is added
(0.20mol), injected after the dissolution of 20mL chloroform, under 0 DEG C and stirring condition triphosgene solution (9.89g, 0.10mol, it is molten
Solution is in 20mL chloroform), 20min injection finishes.Then heat to 5 DEG C, be added 0.11ml glacial acetic acid (0.11ml,
0.002mol), 0.5h is reacted.After reaction, the internal standard yield of gas chromatographic detection discovery product is 97.2% (n-dodecane
For internal standard), at the same the N of generation 2.3%, N- diethyl formyl chloride (area normalization method).
Claims (10)
1. a kind of prepare the polysubstituted method for disliking azole compounds, which comprises the following steps:
Under acid binding agent existence condition, phosgene or surpalite or triphosgene solution are added into the solution of compound shown in formula II,
Auxiliary agent is added after adding to be reacted, and the polysubstituted evil azole compounds are obtained；
Shown in the structure such as formula (I) of the polysubstituted evil azole compounds:
In formula (I)~(II), R1、R2And R3Independently selected from C1-C6Alkyl in any one；
The auxiliary agent is organic acid.
2. according to claim 1 prepare the polysubstituted method for disliking azole compounds, which is characterized in that phosgene mole dosage
For 0.5-1.05 times or three that 1.0-2.1 times of compound shown in formula II or surpalite mole dosage are compound shown in formula II
Phosgene mole dosage is 0.33-0.7 times of compound shown in formula II.
3. according to claim 1 prepare the polysubstituted method for disliking azole compounds, which is characterized in that the acid binding agent
For N-ethylpiperidine, triethylamine, pyridine, diisopropylethylamine, tetramethylguanidine, 11 carbon -7- of 1,8- diazabicylo [5.4.0]
Alkene, 4-N, N- dimethylamino naphthyridine or 4-methylimidazole；Preferably N-ethylpiperidine.
4. according to claim 1 prepare the polysubstituted method for disliking azole compounds, which is characterized in that the acid binding agent
Mole dosage is 1.0~4 equivalents of phosgene usage, or is 0.5~2 equivalent of surpalite mole dosage, or is triphosgene mole
0.33~1.33 equivalent of dosage.
5. according to claim 1 prepare the polysubstituted method for disliking azole compounds, which is characterized in that the auxiliary agent is
Formic acid, glacial acetic acid, propionic acid, butyric acid, trifluoroacetic acid, oxalic acid, malonic acid, benzoic acid or phenylacetic acid；Preferably glacial acetic acid.
6. according to claim 1 prepare the polysubstituted method for disliking azole compounds, which is characterized in that the auxiliary agent rubs
Your dosage is 0.005~0.25 times of II compound amount of formula.
7. according to claim 1 prepare the polysubstituted method for disliking azole compounds, which is characterized in that phosgene or double is added
During phosgene or triphosgene solution, temperature is -50 DEG C~10 DEG C, preferably 0 DEG C；
After phosgene or surpalite or triphosgene solution is added, reaction temperature is -50 DEG C~10 DEG C, preferably 5 DEG C.
8. according to claim 1 prepare the polysubstituted method for disliking azole compounds, which is characterized in that reaction solvent for use
Selected from n-hexane, normal octane, hexamethylene, petroleum ether, cyclohexanone, acetone, benzene,toluene,xylene, ethyl acetate, propyl acetate,
Dioxane, methyl tertiary butyl ether(MTBE), isopropyl ether, cyclopentyl-methyl ether, glycol dimethyl ether, tetrahydrofuran, methylene chloride, trichlorine
The mixing of one or more of methane, 1,2- dichloroethanes, 1,1,2- trichloroethanes chlorobenzene, 2- methyltetrahydrofuran；It is preferred that
For the mixing of one or more of chloroform, 1,1,2- trichloroethanes, chlorobenzene, methylene chloride.
9. according to claim 1 prepare the polysubstituted method for disliking azole compounds, which is characterized in that shown in the formula II
The concentration of the solution of compound is 0.15g/mL~1.6g/mL；It is preferred that 0.75g/mL~1.5g/mL.
The phosgene or surpalite or triphosgene concentration are 0.05g/mL~2g/mL；It is preferred that 0.2g/mL~1g/mL.
10. according to claim 1 prepare the polysubstituted method for disliking azole compounds, which is characterized in that phosgene or double light
The addition time of gas or triphosgene is 0.5h~3h, the reaction was continued after addition 0.1h~3h.
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Cited By (3)
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| CN111153869A (en) * | 2020-01-19 | 2020-05-15 | 浙江新和成股份有限公司 | Method for preparing oxazole compound |
| CN114149379A (en) * | 2021-06-21 | 2022-03-08 | 温州大学 | Synthesis method for synthesizing multi-substituted oxazole product from simple aromatic carboxylic acid and cyano-substituted ester compound |
| CN114671823A (en) * | 2022-04-25 | 2022-06-28 | 浙江花园营养科技有限公司 | Preparation method of 4-methyl-5-ethoxy oxazole acid ethyl ester |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111153869A (en) * | 2020-01-19 | 2020-05-15 | 浙江新和成股份有限公司 | Method for preparing oxazole compound |
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| WO2021143181A1 (en) * | 2020-01-19 | 2021-07-22 | 上虞新和成生物化工有限公司 | Method for preparing oxazole compound |
| CN114149379A (en) * | 2021-06-21 | 2022-03-08 | 温州大学 | Synthesis method for synthesizing multi-substituted oxazole product from simple aromatic carboxylic acid and cyano-substituted ester compound |
| CN114671823A (en) * | 2022-04-25 | 2022-06-28 | 浙江花园营养科技有限公司 | Preparation method of 4-methyl-5-ethoxy oxazole acid ethyl ester |
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