- Preparation process of optically pure 2-tetrahydrofuroic acid
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The invention discloses a preparation process of optically pure 2-tetrahydrofuroic acid. The preparation process comprises the following steps: carrying out a splitting reaction on L-phenylalaninol with (RS)-2-tetrahydrofuroic acid in a first organic solvent to obtain a diastereoisomer salt, carrying out recrystallization to obtain an (S)-2-tetrahydrofuroic acid crude product, and carrying out post-treatment on the crude product to obtain high-optical purity (S)-2-tetrahydrofuroic acid with an enantiomeric excess (ee) value larger than 99%; and combining the mother liquor with the recrystallization mother liquor to obtain a mixed solution containing (R)-2-tetrahydrofuroic acid, then carrying out a reaction on the (R)-2-tetrahydrofuroic acid in the mixed solution with D-phenylalaninol for saltifying, recrystallizing the obtained salt to obtain an (R)-2-tetrahydrofuroic acid crude product, and carrying out post-treatment on the crude product to obtain high-optical purity (R)-2-tetrahydrofuroic acid with an ee value larger than 99%. According to the invention, the 2-tetrahydrofuroic acid is effectively split by using the two configurations of optically pure phenylalaninol, and the twooptical isomers of the 2-tetrahydrofuroic acid are separately obtained, and the ee values of the two optical isomers are both larger than 99%; secondly, the solvents, such as acetone, ethyl acetate and the like which are low in price and low in boiling point are used as solvents for the splitting reaction and recrystallization, the solvents are easy to recycle, and the recovery rate is high.
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Paragraph 0020; 0022; 0023; 0024; 0025; 0036
(2019/05/15)
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- A scalable chemoenzymatic preparation of (R)-tetrahydrofuran-2-carboxylic acid
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To develop a practical scalable approach to (R)-tetrahydrofuran-2-carboxylic acid (THFC) 1, a chiral building block for furopenem 2, enantioselective hydrolysis of its esters is explored: When ethyl (±)-tetrahydrofuran-2-carboxylate 3d (2 M, 288 g/L) is digested by an Aspergillus melleus protease {0.2% (w/v)} in a 1.5 M potassium phosphate buffer (pH 8) for 20 h, enantioselective hydrolysis proceeds with E=60 to give (R)-THFC 1 in 94.4% ee. On separation from the left-over antipodal ester (S)-3d by partition, (R)-THFC 1 is treated with N,N-dicyclohexylamine (DCHA) in methyl ethyl ketone/methanol (5:1) to precipitate the crystalline salt 4 that contains (R)-THFC 1 of >99% ee in 22% overall yield from (±)-3d.
- Fujima, Yoshito,Hirayama, Yoshihiro,Ikunaka, Masaya,Nishimoto, Yukifumi
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p. 1385 - 1391
(2007/10/03)
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- Process for resolving chiral acids with 1-aminoindan-2-ols
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A process for the full or partial resolution of a mixture of enantiomers of a genus of chiral carboxylic acids is disclosed. The process uses a pure enantiomer of 1-aminoindan-2-ol as the resolving agent and achieves separation of the diastereomeric salts by fractional crystallization followed by liberation of the chiral acid from the salt by treatment with mineral acid. Diastereomeric salts and solyates of those salts are disclosed. The production of ketoprofen, flurbiprofen and other chiral medicaments and precursors thereto is disclosed.
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- Synthesis, Structure, and Pharmacological Evaluation of the Stereoisomers of Furnidipine
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The synthesis and pharmacological activities of the four stereoisomers of methyl tetrahydrofuran-2-ylmethyl 2,6-dimethyl-4-(2'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (furnidipine) are reported.The four isomers were synthesized by a modified Hantzsch synthesis by reaction of (-)- or (+)-tetrahydrofuran-2-ylmethyl 3-aminocrotonate and methyl 2-acetoacetate or, alternatively, by reaction of (-)- or (+)-tetrahydrofuran-2-ylmethyl 2-acetoacetate and methyl 3-aminocrotonate.The 1:1 diasteromeric mixture thus obtained were separated by chromatography, using poly(D-phenylglycine) as the chiral stationary phase.The enantiomeric purity of the stereoisomers was determined by high-performance liquid chromatography-chiral stationary phase technique (HPLC-CSP).Attempts to obtain crystals of a single stereoisomer failed in different solvent, while methanol crystallization of the product obtained from (+/-)-tetrahydrofuran-2-ylmethyl 2-acetoacetate and methyl 3-aminocrotonate yielded good-quality crystals of the most insoluble racemate which proved to be a mixture of the (SS)/(RR) enantiomers by X-ray crystaloography.Conformational analysis of the stereoisomers, assuming rotation of the aryl substituent and ester groups, shows small energy differences (about 4 kcal*mol-1) between the most and the least favorable conformations.Binding studies were performed using isradipine as a reference ligand.The results showed stereospecificity of the furnidipine isomers in brain, ileum, and cardiac tissues, the (SS) and (SR)-isomers clearly being more potent than their (RR)- and (RS)-enantiomers.The (SS)- and (SR)-isomers were also more selective on cerebral tissue when compared with ileal and cardiac preparations.
- Alajarin, Ramon,Vaguero, Juan J.,Alvarez-Builla, Julio,Pastor, Manuel,Sunkel, Carlos,et al.
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p. 2830 - 2841
(2007/10/02)
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- Synthesis and Chromatographic Separation of the Stereoisomers of Furnidipine
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The four stereoisomers of methyl tetrahydrofuran-2-ylmethyl 2,6-dimethyl-4-(o-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (furnidipine), have been synthesized and separated by chiral chromatography using D-phenylglycine as chiral stationary phase.Enantiomeric purity of stereoisomers is determined by HPLC-CSP technique and configurations deduced via X-ray crystallography.
- Alajarin, Ramon,Alvarez-Builla, Julio,Vaguero, Juan J.,Sunkel, Carlos,Casa-Juana, Miguel Fau de,et al.
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p. 617 - 620
(2007/10/02)
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- Syntheses of optically active 2-tetrahydrofuran derivatives
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The resolution of 2-tetrahydrofuran-carboxylic acid and assignment of configuration to the enantiomers are reported.New syntheses of the enantiomers of 2-tetrahydofurancarboxaldehyde are also described.
- Belanger, Patrice C.,Williams, Haydn W. R.
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p. 1383 - 1386
(2007/10/02)
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