- Method for preparing oxazole carboxylic acid ester
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The invention relates to the technical field of organic synthesis of medicines, and discloses a method for preparing oxazole carboxylic acid ester. The method provided by the invention comprises the following steps: in the presence of a catalyst, a dehydrating agent and organic alkali, carrying out cyclization reaction on a compound as shown in a formula (II) to obtain a compound as shown in a formula (I), the catalyst is an imidazole compound; wherein in the formula (I) and the formula (II), R1, R2 and R3 are respectively and independently C1-C6 alkyl groups. According to the method, the imidazole compound is used as the catalyst for preparing the oxazole carboxylic ester, so that the reaction yield can be remarkably improved. In addition, the method provided by the invention is simple in process, does not involve the use of other auxiliaries, does not generate phosphorus-containing wastewater, belongs to a green process, and is beneficial to industrial production.
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Paragraph 0054-0098
(2021/09/04)
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- Environment-friendly preparation method of substituted oxazole compound
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The invention provides an environment-friendly preparation method of a substituted oxazole compound, which takes N-substituted formyl alpha-substituted glycine ester as an initial raw material; the substituted oxazole compound is obtained through a cyclization reaction under the action of a dehydrating agent such as trisubstituted phosphine dihalide, a combination of trisubstituted phosphine dihalide and an acyl halide reagent or a combination of trisubstituted phosphine oxide and an acyl halide reagent and organic amine. The obtained substituted oxazole compound can be further saponified anddecarboxylated to obtain a medical intermediate 4-substituent-5-substituent oxazole. The method can be carried out in a continuous flow manner, so that the production efficiency is improved, and the operation is reduced; a byproduct trisubstituted phosphine oxide is generated in the reaction process and can be recycled, so that the cost is reduced; phosphorus oxychloride and phosphorus pentoxide which are high in price and large in preparation process wastewater amount are not used as dehydrating agents, a high-temperature cyclization reaction is not needed, the process is simple, operation iseasy and convenient, no phosphorus-containing wastewater is discharged, and the method is environmentally friendly and low in cost. The method is high in atom economy, high in target product yield and purity and suitable for industrial application.
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Paragraph 0088-0094; 0098-0119; 0148; 0149
(2021/01/12)
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- Synthesis method of ethyl 4-methyl-5-ethoxy-oxazole carboxylate
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The invention discloses a synthetic method of ethyl 4-methyl-5-ethoxy-oxazole carboxylate. The method specifically comprises the following steps: mixing N-ethoxyoxalyl alanine ethyl ester with an organic solvent, cooling the mixture, adding a solution containing triphenylphosphine, iodine and alkali, then raising the temperature, continuing to carry out a reaction while maintaining the temperature, adding a quenching agent for terminating the reaction; and carrying out separation treatment to obtain the ethyl 4-methyl-5-ethoxy-oxazole carboxylate. According to the method, the triphenylphosphine, the iodine and the alkali are used as reaction reagents, so that the use of highly toxic products is reduced, the reaction conditions are mild, the reaction yield is high, no special requirement onequipment exists, the cost is low, and the yield is high.
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Paragraph 0037-0056
(2019/12/02)
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- Method for preparing multi-substitution oxazole compound
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The invention discloses a method for preparing a multi-substitution oxazole compound. The method comprises the following steps: in the presence of an acid-binding agent, adding a phosgene, two-phosgene or three-phosgene solution into a solution of a compound of a formula II shown in the specification, and further adding an aid to implement a reaction after the solution is added, so as to obtain the multi-substitution oxazole compound of a formula (I) shown in the specification. By adopting the method, the yield of a product oxazole can be increased, and meanwhile, the content of a byproduct N,N-diethyl formyl chloride can be reduced.
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Paragraph 0033-0047
(2019/10/01)
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- Synthesis method of 4-methyl-5-ethyoxy oxazole
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The invention discloses a synthesis method of 4-methyl-5-ethyoxy oxazole. The synthesis method comprises the following steps: sequentially adding methylbenzene, N-ethoxyoxoacetyl alanine ethyl ester,triethylamine and phosphorus oxychloride, and heating for a cyclization reaction; adding water and liquid caustic soda into the product of the cyclization reaction; when the pH value shows alkalinity,performing a saponification reaction; after layering of the saponification reaction product, collecting the lower-layer reactant; adding an aqueous solution of hydrochloric acid into the lower-layerreactant till acidity, and heating for reacting, wherein the lower-layer reactant sequentially experiences acidification and decarboxylation to obtain a product solution generating 4-methyl-5-ethoxy oxazole; neutralizing the product solution with alkali till neutrality, and performing separation and purification to obtain 4-methyl-5-ethoxy oxazole. According to the synthesis method disclosed by the invention, the synthesis technology of 4-methyl-5-ethoxy oxazole is optimized, and the wastewater generated in the technological process is reduced.
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Paragraph 0044; 0069; 0070
(2019/02/19)
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- Improved oxazole Method for the Practical and Efficient Preparation of Pyridoxine Hydrochloride (Vitamin B6)
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Vitamin B6, a well-studied vitamin B, has been synthesized using an oxazole method for the past 20 years. The oxazole method provided 56.2% overall yield but also generated safety, environmental, and health problems, such as using toxic benzene as solvent and unstable, corrosive, and pollutive HCl and POCl3 as reagents. To use the same equipment but the least amount of toxic agents, we developed new reaction conditions for the early steps. For example, we successfully replaced toxic HCl/benzene conditions with NaHSO4/PhCH3 conditions and also developed a novel and efficient dehydrating agent trichloroisocyanuric acid/Ph3P/Et 3N to synthesize the key intermediate 5-butoxy-4-methyl oxazole, instead of using phosphorus oxychloride. These improvements resolved safety, waste avoidance, and workup issues that plagued the previous methodologies. Our process comprised six easy synthetic steps and generated vitamin B6 with 99.4% purity in 56.4% overall yield.
- Zou, Ye,Shi, Xiangjun,Zhang, Genbao,Li, Zhenhua,Jin, Can,Su, Weike
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p. 1498 - 1502
(2014/01/06)
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- Synthesis of 4-hydroxy-6,9-difluorobenz[g]isoquinoline-5,10-diones and conversions to 4-hydroxy-6,9-bis[(aminoalkyl)amino]-benz[g]isoquinoline-5,10-diones
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Synthetic procedures have been developed which lead to 4-hydroxy-6,9-difluorobenz[g]isoquinoline-5,10-dione (4a) and its 3-methyl analogue 4b. Attempts to displace the fluorides from 4a with N,N-dimethylethylenediamine were unsuccessful. Analogue 4a on treatment with N-(t-butoxycarbonyl)ethylene diamine led to 15, formed from addition of the nucleophilic amine to C-3. On the other hand, analogue 4b, on treatment with N,N-dimethylethylenediamine led to the anticipated difluoride displacement product 3c. The protection of the hydroxy group of 4a by benzylation with phenyldiazomethane led to 4c which on treatment with N-(t-butoxycarbonyl)ethylene diamine or N,N-dimethylethylenediamine led to the corresponding 6,9-bis-substituted analogues 18a and 18b, respectively. Reductive debenzylations of 18a and 18b by hydrogenation over Pearlman's catalyst also effected partial reductions of the quinone. However, air oxidation of the over reduced products led to 3a and 3b, respectively. Treatment of 3a with hydrogen chloride gas led to the hydrochloride salt of 3d. Addition of O-p-Methoxybenzyl-N,N'-diisopropylurea to 4a led to the p-methoxybenzyl analogue 4d. Treatment of 4d with N,N-dimethylethylene diamine or N-(t-butoxycarbonyl)ethylene diamine led to displacements of the fluorides to yield 18c and 18d, respectively. Deprotection of 18c to 3b was accomplished using methanesulfonic acid. Treatment of 18d with trifluoroacetic acid followed by addition of maleic acid led to dimaleate salt of 3d.
- Krapcho,Maresch,Gallagher,Hacker,Menta,Oliva,Di Domenico,Da Re,Spinelli
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p. 1693 - 1702
(2007/10/03)
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