- Use of 'small but smart' libraries to enhance the enantioselectivity of an esterase from Bacillus stearothermophilus towards tetrahydrofuran-3-yl acetate
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Two libraries of simultaneous double mutations in the active site region of an esterase from Bacillus stearothermophilus were constructed to improve the enantioselectivity in the hydrolysis of tetrahydrofuran-3-yl acetate. As screening of large mutant libraries is hampered by the necessity for GC/MS analysis, mutant libraries were designed according to a 'small but smart' concept. The design of focused libraries was based on data derived from a structural alignment of 3317 amino acid sequences of α/β-hydrolase fold enzymes with the bioinformatic tool 3dm. In this way, the number of mutants to be screened was substantially reduced as compared with a standard site-saturation mutagenesis approach. Whereas the wild-type esterase showed only poor enantioselectivity (E = 4.3) in the hydrolysis of (S)-tetrahydrofuran-3-yl acetate, the best variants obtained with this approach showed increased E-values of up to 10.4. Furthermore, some variants with inverted enantiopreference were found. A semi-rational approach was applied for the enhancement of the enantioselectivity of an esterase from Bacillus stearothermophilus towards the industrially interesting substrate tetrahydrofuran-3-yl acetate, based on data derived from structural alignment. The design of 'small but smart' libraries led to a 2.4-fold increase of (S)-selectivity compared to wild type enzyme, while some mutants with marginal (R)-selectivity were found.
- Nobili, Alberto,Gall, Markus G.,Pavlidis, Ioannis V.,Thompson, Mark L.,Schmidt, Marlen,Bornscheuer, Uwe T.
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Read Online
- Asymmetric hydrosilylation of dihydrofurans by use of palladium-MOP catalyst
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Catalytic asymmetric hydrosilylation of dihydrofuran derivatives including 7-oxabicyclo[2.2.1]heptenes with trichlorosilane proceeded in the presence of 0.1 mol % of palladium catalyst bearing (R)-2-methoxy-2'-diphenyl-phosphino-1,1'-binaphthyl ((R)-MOP) to give the corresponding hydrosilylation products of up to 95% ee. A regio-selective opening of the bicyclic system gave a highly functionalized cyclohexane in an optically active form.
- Uozumi,Hayashi
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Read Online
- Preparation method of hydroxyl oxacycloalkane derivative
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The invention relates to a preparation method of a hydroxyl oxacycloalkane derivative, which comprises the following steps: 1) preparing an initial reaction raw material compound and a catalyst into a raw material solution by using a solvent, and respectively pumping the raw material solution and an oxide material into a continuous flow reactor preheating module from different material conveying equipment for preheating; 2) feeding the material passing through the preheating module into a mixing module, feeding the mixed material into a reaction module, and continuously reacting in the reaction module to obtain a reaction mixture; (3) after the reaction, enabling a reaction mixture to enter a product separation module, and carrying out organic-inorganic separation or solvent removal on reaction liquid at cooling or reaction temperature or raised temperature to obtain a crude product; and refining the crude product to obtain a pure product. According to the method disclosed by the invention, the reaction process can be simplified, the reaction time can be shortened, and the hydroxyl oxacycloalkane derivative can be more efficiently synthesized.
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Paragraph 0049-0070
(2021/08/14)
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- Preparation method of hydroxytetrahydrofuran compound
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The invention discloses a preparation method of a hydroxytetrahydrofuran compound. The method adopts a heterogeneous catalytic reaction step, and is characterized by taking a 3, 4-epoxy tetrahydrofuran compound as a raw material, and carrying out hydrolysis or alcoholysis ring opening, catalytic hydrogenolysis and other catalytic processes to obtain the 3-hydroxytetrahydrofuran compound. The method is green in process, simple to operate, low in catalyst price, relatively simple in separation, efficient and simple to operate, and beneficial to large-scale industrial production of the 3-hydroxytetrahydrofuran compound.
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Paragraph 0044-0069
(2021/08/19)
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- A S - (+) -3 - hydroxy tetrahydrofuran chemical synthesis method
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The invention discloses a S - (+) - 3 - hydroxy tetrahydrofuran chemical synthesis method, includes the following operation steps: 1, compound 1 in the presence of thionyl chloride and methanol reaction to obtain compound 2; 2, in the solvent, compound 2 in the presence of a reducing agent and the reaction to obtain compound 3; 3, compound 3 in the presence of paratoluene sulfonic acid, reaction to obtain compound S - (+) - 3 - hydroxy tetrahydrofuran.
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Paragraph 0023-0025
(2019/04/04)
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- Preparation method of (s)-3-hydroxytetrahydrofuran
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The invention provides a preparation method of (s)-3-hydroxytetrahydrofuran. According to the preparation method, ethyl 4-chloroacetoacetate is taken as an initial raw material, (s)-4-chloro-3 hydroxyl-1-butanol is prepared, wherein a substrate is dissolved in a first solvent, an alkali is added, under the catalytic effect of a first catalyst and a second catalyst, asymmetric hydrogenation reaction with hydrogen gas is carried out to produce (s)-4-chloro-3 hydroxyl-1-butanol; chiral 3-hydroxytetrahydrofuran is prepared, wherein prepared chiral 4-chloro-3 hydroxyl-1-butanol is dissolved in a second solvent, an acid is added as a catalyst, and reaction is carried out to obtain (s)-3-hydroxytetrahydrofuran; wherein the first catalyst is a complex generated through reaction of [Ir(COD)Cl]2 with phosphine-pyridine ligand, and the second catalyst is Ru-MACHO complex. The reaction route is short; technology is simple; raw materials are cheap and easily available; production cost is low; reaction process environment pollution is low; product optical purity is high; and the preparation method is suitable for industrialized production.
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Paragraph 0032; 0037-0039; 0044-0046; 0051-0053; 0058-0060
(2019/11/13)
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- Preparation of Highly Active Monometallic Rhenium Catalysts for Selective Synthesis of 1,4-Butanediol from 1,4-Anhydroerythritol
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1,4-Butanediol can be produced from 1,4-anhydroerythritol through the co-catalysis of monometallic mixed catalysts (ReOx/CeO2+ReOx/C) in the one-pot reduction with H2. The highest yield of 1,4-butanediol was over 80 %, which is similar to the value obtained over ReOx–Au/CeO2+ReOx/C catalysts. Mixed catalysts of CeO2+ReOx/C showed almost the same performance, giving 89 % yield of 1,4-butanediol. The reactivity trends of possible intermediates suggest that the reaction mechanism over ReOx/CeO2+ReOx/C is similar to that over ReOx–Au/CeO2+ReOx/C: deoxydehydration (DODH) of 1,4-anhydroerythritol to 2,5-dihydrofuran over ReOx species on the CeO2 support with the promotion of H2 activation by ReOx/C, isomerization of 2,5-dihydrofuran to 2,3-dihydrofuran catalyzed by ReOx on the C support, hydration of 2,3-dihydrofuran catalyzed by C, and hydrogenation to 1,4-butanediol catalyzed by ReOx/C. The reaction order of conversion of 1,4-anhydroerythritol with respect to H2 pressure is almost zero and this indicates that the rate-determining step is the formation of 2,5-dihydrofuran from the coordinated substrate with reduced Re in the DODH step. The activity of ReOx/CeO2+ReOx/C is higher than that of ReOx–Au/CeO2+ReOx/C, which is probably related to the reducibility of ReOx/C and the mobility of the Re species between the supports. High-valent Re species such as Re7+ on the CeO2 and C supports are mobile in the solvent; however, low-valent Re species, including metallic Re species, have much lower mobility. Metallic Re and cationic low-valent Re species with high reducibility and low mobility can be present on the carbon support as a trigger for H2 activation and promoter of the reduction of Re species on CeO2. The presence of noble metals such as Au can enhance the reducibility through the activation of H2 molecules on the noble metal and the formation of spilt-over hydrogen over noble metal/CeO2, as indicated by H2 temperature-programmed reduction. The higher reducibility of ReOx–Au/CeO2 lowers the DODH activity of ReOx–Au/CeO2+ReOx/C in comparison with ReOx/CeO2+ReOx/C by restricting the movement of Re species from C to CeO2.
- Wang, Tianmiao,Tamura, Masazumi,Nakagawa, Yoshinao,Tomishige, Keiichi
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p. 3615 - 3626
(2019/07/15)
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- A strategy of ketalization for the catalytic selective dehydration of biomass-based polyols over H-beta zeolite
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Biomass contains plentiful hydroxyl groups that lead to an oxygen-rich structure compared to petroleum-based chemicals. Dehydration is the most energy-efficient technique to remove oxygen; however, multiple similar vicinal hydroxyl groups in sugar alcohols impose significant challenges for their selective dehydration. Here, we present a novel strategy to control the etherification site in sugar alcohols by the ketalization of the vicinal-diol group for the highly selective formation of tetrahydrofuran derivatives. A ketone firstly reacts with terminal vicinal hydroxyl groups to form the 1,3-dioxolane structure. This structure of the constrained 1,3-dioxolane ring would improve the accessibility of reactive groups to facilitate intramolecular etherification. As a better leaving group than water, the ketone can also promote intramolecular etherification. Consequently, a range of tetrahydrofuran derivatives are produced in excellent yields with the H-beta zeolite catalyst under mild reaction conditions. This strategy opens up new opportunities for the efficient upgrading of biomass via the modification or protection of hydroxyl groups.
- Che, Penghua,Lu, Fang,Si, Xiaoqin,Ma, Hong,Nie, Xin,Xu, Jie
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supporting information
p. 634 - 640
(2018/02/14)
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- Preparation method of (S)-3-hydroxytetrahydrofuran
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The invention discloses a preparation method of (S)-3-hydroxytetrahydrofuran. The problems that butantriol is difficult to separate in the production process, the yield is not high and the impurity content and the isomer content of the products are high are mainly solved. The preparation method of (S)-3-hydroxytetrahydrofuran comprises the following steps: under the existence of sulfoxide chloride, malic acid reacts with methanol to generate a compound II; under the existence of silver oxide, performing reaction on the compound II and benzyl bromide to generate a compound III; reducing the compound III by sodium borohydride to generate a compound IV; performing dehydration and ring closing on the compound IV by p-toluenesulfonic acid to generate a compound V; and taking palladium carbon asa catalyst and performing hydrogen reduction treatment on the compound V to obtain the product. The method is simple in aftertreatment and environment-friendly; the yield of the products is increasedby 80 percent or more, the purity is more than 99.5 percent and the chiral purity is more than 99.2 percent; and the method is suitable for industrialized production. (The formulas are as shown in the description).
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Paragraph 0043
(2018/06/15)
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- Methodology Development in Directed Evolution: Exploring Options when Applying Triple-Code Saturation Mutagenesis
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Directed evolution of stereo- or regioselective enzymes as catalysts in asymmetric transformations is of particular interest in organic synthesis. Upon evolving these biocatalysts, screening is the bottleneck. To beat the numbers problem most effectively, methods and strategies for building “small but smart” mutant libraries have been developed. Herein, we compared two different strategies regarding the application of triple-code saturation mutagenesis (TCSM) at multiresidue sites of the Thermoanaerobacter brockii alcohol dehydrogenase by using distinct reduced amino-acid alphabets. By using the synthetically difficult-to-reduce prochiral ketone tetrahydrofuran-3-one as a substrate, highly R- and S-selective variants were obtained (92–99 % ee) with minimal screening. The origin of stereoselectivity was provided by molecular dynamics analyses, which is discussed in terms of the Bürgi–Dunitz trajectory.
- Qu, Ge,Lonsdale, Richard,Yao, Peiyuan,Li, Guangyue,Liu, Beibei,Reetz, Manfred T.,Sun, Zhoutong
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p. 239 - 246
(2018/02/09)
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- Processes for the Preparation of SGLT-2 Inhibitors, Intermediates Thereof
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The present invention relates to novel, improved processes for the preparation of sodium glucose co-transporter 2 (SGLT-2) inhibitors and novel intermediates thereof. More particularly, the present invention relates to a novel, improved process for the preparation of gliflozin compounds such as empagliflozin and dapagliflozin, intermediates thereof. The product obtained from the processes of present invention may be amorphous or crystalline, or in the form of amorphous/crystalline solid dispersions/solutions with pharmaceutically acceptable polymers and preparation process thereof. Also, the products obtained from the present invention may be used for the preparation of medicaments for the prevention and/or treatment of diseases and conditions associated with SGLT-2 inhibition.
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Paragraph 0161
(2019/01/04)
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- One-pot catalytic selective synthesis of 1,4-butanediol from 1,4-anhydroerythritol and hydrogen
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A physical mixture of ReOx-Au/CeO2 and carbon-supported rhenium catalysts effectively converted 1,4-anhydroerythritol to 1,4-butanediol with H2 as a reductant. The combination of these two catalysts in a one-pot reaction dramatically increased the selectivity of 1,4-butanediol as well as the conversion of 1,4-anhydroerythritol. The yield of 1,4-butanediol reached ~90%, which is the highest yield from erythritol and 1,4-anhydroerythritol so far, furthermore, at a relatively low reaction temperature of 413 K. This reaction involves the ReOx-Au/CeO2-catalyzed deoxydehydration of 1,4-anhydroerythritol to 2,5-dihydrofuran and ReOx/C-catalyzed successive isomerization, hydration and reduction reactions of 2,5-dihydrofuran.
- Wang, Tianmiao,Liu, Sibao,Tamura, Masazumi,Nakagawa, Yoshinao,Hiyoshi, Norihito,Tomishige, Keiichi
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supporting information
p. 2547 - 2557
(2018/06/18)
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- A pharmaceutical intermediates (S)-3 - hydroxy tetrahydrofuran preparation method (by machine translation)
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The invention provides a pharmaceutical intermediate (S)- 3 - hydroxy tetrahydrofuran preparation method. The method other than racemic 1, 2, 4 - butanetriol as raw materials synthesis of racemic 3 - hydroxy tetrahydrofuran, then esterification of racemic tetrahydrofuran-yl - 3 - fatty acid ester. By lipase hydrolysis in the racemic mixture of (R)- tetrahydrofuran-based - 3 - fatty acid ester after, in in the hydrolysis product under the condition of separating, using the mitsunobu reaction will be hydrolyzed to obtain the of (R)- 3 - hydroxy tetrahydrofuran is converted into (S)- tetrahydrofuran-based - 3 - carboxylic acid ester, finally under alkaline condition all of the tetrahydrofuran ester hydrolyzed to obtain the final product (S)- 3 - hydroxy tetrahydrofuran. (by machine translation)
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Paragraph 0040
(2017/08/31)
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- SYNTHESIS OF R-GLUCOSIDES, SUGAR ALCOHOLS, REDUCED SUGAR ALCOHOLS, AND FURAN DERIVATIVES OF REDUCED SUGAR ALCOHOLS
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Disclosed herein are methods for synthesizing 1,2,5,6-hexanetetrol (HTO), 1,6 hexanediol (HDO) and other reduced polyols from C5 and C6 sugar alcohols or R glycosides. The methods include contacting the sugar alcohol or R-glycoside with a copper catalyst, most desirably a Raney copper catalyst with hydrogen for a time, temperature and pressure sufficient to form reduced polyols having 2 to 3 fewer hydoxy groups than the starting material. When the starting compound is a C6 sugar alcohol such as sorbitol or R-glycoside of a C6 sugar such as methyl glucoside, the predominant product is HTO. The same catalyst can be used to further reduce the HTO to HDO.
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Paragraph 0077
(2017/05/31)
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- Production technology of 3-hydroxytetrahydrofuran with high optical purity
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The invention discloses a production technology of3-hydroxytetrahydrofuran with high optical purity. The production technology comprises the following steps: (1) taking chloroacetoacetic acid ethyl ester as a starting raw material, adding appropriate amount of solvents, chiral catalysts and reducing agents, and reacting at an appropriate temperature to obtain chiral ethyl 4-chloro-3-hydroxybutyrate; (2) taking the chiral ethyl 4-chloro-3-hydroxybutyrate obtained in step (1) as a raw material, adding the appropriate amount of solvents and metal borohydride reducing agents, and reacting at the appropriate temperature to obtain chiral 4-chloro-3-hydroxy-1-butanol; (3) taking the chiral 4-chloro-3-hydroxy-1-butanol obtained in step (2) as the raw material, adding appropriate amount of catalysts and solvents, and reacting at the appropriate temperature to obtain chiral 3-hydroxytetrahydrofuran. According to the production technology of the 3-hydroxytetrahydrofuran with the high optical purity, the chiral 3-hydroxytetrahydrofuran can be produced through a three-step reaction, the shortcomings of complicated production operation and high production cost are solved, and products with high optical purity can be produced.
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Paragraph 0028; 0032; 0037; 0038; 0043
(2017/10/06)
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- (S)- 3 - hydroxy tetrahydrofuran and (R)- 3 - hydroxy tetrahydrofuran preparation method
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The invention discloses a preparation method of (S)-3-hydroxytetrahydrofuran and (R)-3-hydroxytetrahydrofuran, relating to the technical field of preparation of five-element heterocyclic compounds containing one oxygen atom as the only heterocyclic atom. The method comprises the following steps: by using (S)-carnitine or (R)-carnitine as the initial raw material, carrying out reduction reaction in a reducer and an organic solvent to obtain (S) or (R)-2,4-dihydroxy-N,N,N-trimethyl butyl amine alkali; adding a hydrogen chloride organic solvent solution into an organic solvent to perform salification reaction to obtain (S) or (R)-2,4-dihydroxy-N,N,N-trimethyl butyl amine hydrochloride; and finally, adding alkali into a polar solvent, heating, and carrying out cyclization reaction to obtain the (S) or (R)-3-hydroxytetrahydrofuran. The method has the advantages of low cost, simple technique, high yield, cheap and accessible raw materials, short reaction steps, short period and low pollution, and is suitable for industrial production.
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Paragraph 0050; 0051; 0052
(2017/08/02)
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- THE PRESENT INVENTION RELATES TO PROCESS FOR THE PREPARATION OF D-GLUCITOL, 1,5- ANHYDRO-1-C-[4-CHLORO-3-[[4-[[(3S)-TETRAHYDRO-3-FURANYL] OXY]PHENYL] METHYL]PHENYL]-, (1S) AND ITS CRYSTALLINE FORMS THEREOF.
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The present invention relates to process for the preparation of D-glucitol, 1,5- anhydro-l-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furanyl]oxy]phenyl] methyl]phenyl]-, (1S) formula- 1 and its crystalline forms thereof.
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Page/Page column 22; 35
(2017/08/22)
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- Selective C?O Hydrogenolysis of Erythritol over Supported Rh-ReOx Catalysts in the Aqueous Phase
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Bimetallic Rh-ReOx (Re/Rh molar ratio 0.4–0.5) catalysts supported on TiO2 and ZrO2 were prepared by the successive impregnation of dried and calcined unreduced supported Rh catalysts. Their catalytic performances were evaluated in the hydrogenolysis of erythritol to butanetriols (BTO) and butanediols (BDO) in aqueous solution at 150–240 °C under 30–120 bar H2. The activity depended on the nature of the support, and the highest selectivity to BTO and BDO at 80 % conversion was 37 and 29 %, respectively, in the presence of 3.7 wt %Rh-3.5 wt %ReOx/ZrO2 at 200 °C under 120 bar. The characterization of the catalysts by CO chemisorption, TEM with energy-dispersive X-ray spectroscopy, thermogravimetric analysis with MS, and X-ray photoelectron spectroscopy suggests a different distribution and reducibility of Re species over the supported Rh nanoparticles, which depends on the support.
- Said, Achraf,Da Silva Perez, Denilson,Perret, Noémie,Pinel, Catherine,Besson, Michèle
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p. 2768 - 2783
(2017/07/28)
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- Preparation Method for 3-Hydroxytetrahydrofuran
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The present invention relates to a method for preparing 3-hydroxytetrahydrofuran, and more specifically, to a method for preparing 3-hydroxytetrahydrofuran (3) from 4-halo-3-hydroxybutyric acid ester by means of Reaction Formula 1 below, wherein the method comprises the steps of: reacting 4-halo-1,3-butanediol with an inorganic base in C1-C4 alcohol; and then refining 3-hydroxytetrahydrofuran (3) by removing filtering and removing generated salt and performing vacuum distillation thereonto. [Reaction Formula 1] Wherein X=Cl, Br or I, and R=C1-C4 alkyl group or aryl group.
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Paragraph 0021; 0024; 0027; 0028
(2017/08/02)
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- Catalytic Asymmetric Reduction of Difficult-to-Reduce Ketones: Triple-Code Saturation Mutagenesis of an Alcohol Dehydrogenase
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Catalytic asymmetric reduction of prochiral ketones with the formation of enantio-pure secondary alcohols is of fundamental importance in organic chemistry, chiral man-made transition-metal catalysts, or organocatalysts and enzymes of the alcohol dehydrogenase (ADH) type. A distinct limitation is the traditional requirement that the α- and α′-moieties flanking the carbonyl function differ sterically and/or electronically. Difficult-to-reduce ketones such as tetrahydrofuran-3-one and tetrahydrothiofuran-3-one and related substrates are particularly challenging, irrespective of the catalyst type. The ADH from Thermoethanolicus brockii (TbSADH) is an attractive industrial biocatalyst, because of its high thermostability, but it also fails in the reduction of such ketones. We have successfully applied directed evolution using the previously developed concept of triple-code saturation mutagenesis at sites lining the TbSADH binding pocket with tetrahydrofuran-3-one serving as the model compound. Highly (R)- and (S)-selective variants were evolved (95%-99% ee) with minimal screening. These robust catalysts also proved to be effective in the asymmetric reduction of tetrahydrothiofuran-3-one and other challenging prochiral ketones as well. The chiral products, which are generally prepared by multistep routes, serve as synthons in the preparation of several important therapeutic drugs.
- Sun, Zhoutong,Lonsdale, Richard,Ilie, Adriana,Li, Guangyue,Zhou, Jiahai,Reetz, Manfred T.
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p. 1598 - 1605
(2016/03/15)
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- PROCESS FOR PRODUCTION OF (S)-(TETRAHYDROFURAN-3-YL)HYDRAZINE
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A process for production of (S)-(tetrahydrofuran-3-yl)hydrazine of formula I or an acid addition salt thereof, comprising hydrolysis or hydrogenation step of protected hydrazine compound of formula VII, wherein Ra is a tert-butyl group or a benzyl group, is disclosed. (S)-(Tetrahydrofuran-3-yl)hydrazine of formula I or an acid addition salt thereof is a useful intermediate in the preparation of a PDE9 inhibitor.
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Paragraph 0085
(2016/04/19)
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- Origins of stereoselectivity in evolved ketoreductases
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Mutants of Lactobacillus kefir short-chain alcohol dehydrogenase, used here as ketoreductases (KREDs), enantioselectively reduce the pharmaceutically relevant substrates 3-thiacyclopentanone and 3-oxacyclopentanone. These substrates differ by only the heteroatom (S or O) in the ring, but the KRED mutants reduce them with different enantioselectivities. Kinetic studies show that these enzymes are more efficient with 3-thiacyclopentanone than with 3-oxacyclopentanone. X-ray crystal structures of apo- and NADP+-bound selected mutants show that the substrate-binding loop conformational preferences are modified by these mutations. Quantum mechanical calculations and molecular dynamics (MD) simulations are used to investigate the mechanism of reduction by the enzyme. We have developed an MD-based method for studying the diastereomeric transition state complexes and rationalize different enantiomeric ratios. This method, which probes the stability of the catalytic arrangement within the theozyme, shows a correlation between the relative fractions of catalytically competent poses for the enantiomeric reductions and the experimental enantiomeric ratio. Some mutations, such as A94F and Y190F, induce conformational changes in the active site that enlarge the small binding pocket, facilitating accommodation of the larger S atom in this region and enhancing S-selectivity with 3-thiacyclopentanone. In contrast, in the E145S mutant and the final variant evolved for large-scale production of the intermediate for the antibiotic sulopenem, R-selectivity is promoted by shrinking the small binding pocket, thereby destabilizing the pro-S orientation.
- Noey, Elizabeth L.,Tibrewal, Nidhi,Jiménez-Osés, Gonzalo,Osuna, Sílvia,Park, Jiyong,Bond, Carly M.,Cascio, Duilio,Liang, Jack,Zhang, Xiyun,Huisman, Gjalt W.,Tang, Yi,Houk, Kendall N.
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p. E7065 - E7072
(2016/01/09)
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- METHOD FOR PRODUCING 3-HYDROXYTETRAHYDROFURAN AND METHOD FOR PRODUCING 1, 3-BUTANE DIOL
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An object of the present invention is to provide a method for producing 3-hydroxytetrahydrofuran that can be used as a raw material for 1,3-butane diol, using as a raw material a compound that can be derived from biomass. The present invention relates to a method for producing 3-hydroxytetrahydrofuran including a step of reacting 1,4-anhydroerythritol and hydrogen to produce 3-hydroxytetrahydrofuran. In the production method, the step of reacting 1,4-anhydroerythritol and hydrogen is preferably allowed to proceed in the presence of a catalyst comprising a carrier and at least one oxide selected from the group consisting of an oxide of a Group 6 element and an oxide of a Group 7 element, the oxide being supported on the carrier.
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- Mild deprotection of PMB ethers using tert-butyl bromide
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A convenient and high yielding method for the cleavage and scavenging of p-methoxybenzyl protecting group of several alcohols using tert-butyl bromide in refluxing acetonitrile is described. Under these mild conditions other protecting groups such as acid sensitive allyl, benzyl, and Me3CPh2Si ethers, or isopropylidene acetals were unchanged. Interestingly, a selective alkoxy-PMB cleavage was observed in the presence of a PMB phenoxy ether.
- Rival, Nicolas,Albornoz Grados, Arantxa,Schiavo, Lucie,Colobert, Fran?oise,Hanquet, Gilles
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p. 6823 - 6826
(2015/11/27)
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- Cyclic Ether Synthesis via Palladium-Catalyzed Directed Dehydrogenative Annulation at Unactivated Terminal Positions
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Here, a palladium-catalyzed functionalization of unactivated sp3 C-H bonds with internal alcohol nucleophiles is described. Directed by an oxime-masked alcohol, annulation chemoselectively occurs at the β position, leading to a range of aliphatic cyclic ethers with four- to seven-membered rings. Tethered primary, secondary, and tertiary free hydroxyl groups can all react to give the corresponding cyclized products. In addition, benzyl and silyl protected alcohols can also be directly coupled. An sp3 C-H activation/intramolecular SN2 pathway was proposed.
- Thompson, Samuel J.,Thach, Danny Q.,Dong, Guangbin
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supporting information
p. 11586 - 11589
(2015/09/28)
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- Lewis acid promoted ruthenium(II)-catalyzed etherifications by selective hydrogenation of carboxylic acids/esters
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Ethers are of fundamental importance in organic chemistry and they are an integral part of valuable flavors, fragrances, and numerous bioactive compounds. In general, the reduction of esters constitutes the most straightforward preparation of ethers. Unfortunately, this transformation requires large amounts of metal hydrides. Presented herein is a bifunctional catalyst system, consisting of Ru/phosphine complex and aluminum triflate, which allows selective synthesis of ethers by hydrogenation of esters or carboxylic acids. Different lactones were reduced in good yields to the desired products. Even challenging aromatic and aliphatic esters were reduced to the desired products. Notably, the in situ formed catalyst can be reused several times without any significant loss of activity. An assist from Al: A bifunctional catalyst system consisting of a Ru/phosphine complex and aluminum triflate allows selective hydrogenation of esters to ethers. A variety of lactones were reduced to the desired products in good yields. The catalyst further provides a general method for the reduction of linear esters and reductive etherification of carboxylic acids with alcohols.
- Li, Yuehui,Topf, Christoph,Cui, Xinjiang,Junge, Kathrin,Beller, Matthias
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supporting information
p. 5196 - 5200
(2015/04/27)
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- NOVEL PROCESS FOR THE MANUFACTURE OF 3-OXO-TETRAHYDROFURAN
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This invention relates to a novel method for the preparation of 3-oxotetrahydrofuran comprising oxidating 3-hydroxy-tetrahydrofuran in the presence of a catalytic amount of TEMPO with trichloroisocyanuric acid.
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Page/Page column 7
(2014/09/29)
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- NOVEL PROCESS FOR THE MANUFACTURE OF 3-OXO-TETRAHYDROFURAN
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This invention relates to a novel method for the preparationof 3-oxotetrahydrofurancomprising oxidating 3-hydroxy-tetrahydrofuran in the presence of a catalytic amount of TEMPO with trichloroisocyanuric acid.
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Page/Page column 6
(2014/09/29)
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- NOVEL PROCESS FOR THE MANUFACTURE OF 3-OXO-TETRAHYDROFURAN
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This invention relates to a novel method for the preparation of 3-oxo-tetrahydrofuran comprising oxidizing 3-hydroxy-tetrahydrofuran in the presence of a catalytic amount of 2,2,6,6-tetramethyl-piperidine-N-oxyl (TEMPO) with trichloroisocyanuric acid.
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Paragraph 0027
(2014/09/30)
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- Oxorhenium-catalyzed deoxydehydration of glycols and epoxides
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The conversion of renewable cellulosic biomass into hydrocarbons has attracted significant attention with a growing demand of sustainability. MeReO3 catalyzes the deoxydehydration (DODH) of glycols and epoxides to alkenes by primary and secondary alcohols (5-nonanol, 3-octanol, 1-butanol) in the benzene solvent. The product yield range from moderate to excellent.
- Davis, Jacqkis,Srivastava, Radhey S.
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supporting information
p. 4178 - 4180
(2014/07/22)
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- SPIROHYDANTOIN COMPOUNDS AND THEIR USE AS SELECTIVE ANDROGEN RECEPTOR MODULATORS
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The present invention relates to a compound of formula (1-1 ) in free form or in pharmaceutically acceptable salt form in which the substituents are as defined in the specification; to its preparation, to its use as a medicament and to medicaments comprising it. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical composition.
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Page/Page column 94
(2013/09/12)
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- 3-PYRIDYL CARBOXAMIDE-CONTAINING SPLEEN TYROSINE KINASE (Syk) INHIBITORS
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The invention provides certain 3-pyridyl carboxamide-containing compounds of the Formula (I) (I) or pharmaceutically acceptable salts thereof, wherein A and B are as defined herein. The invention also provides pharmaceutical compositions comprising such compounds, and methods of using the compounds for treating diseases or conditions mediated by Spleen Tyrosine Kinase (Syk) kinase.
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Paragraph 00181
(2013/04/24)
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- 2-PYRIDYL CARBOXAMIDE-CONTAINING SPLEEN TYROSINE KINASE (SYK) INHIBITORS
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The invention provides certain 2-pyridyl carboxamide-containing compounds of the Formula (I) or pharmaceutically acceptable salts thereof, wherein A and B are as defined herein. The invention also provides pharmaceutical compositions comprising such compounds, and methods of using the compounds for treating diseases or conditions mediated by Spleen Tyrosine Kinase (Syk) kinase.
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Paragraph 00265
(2013/04/24)
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- Mitsunobu reaction with 4-(diphenylphosphino)benzoic acid: A separation-friendly bifunctional reagent that serves as both a reductant and a pronucleophile
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4-(Diphenylphosphino)benzoic acid was used for the Mitsunobu reaction as a bifunctional reagent that served as both a reductant and a pronucleophile. When combined with di-2-meth-oxyethyl azodicarboxylate, inversion of a secondary alcohol stereospecifically occurred to give an ester carrying a phosphine oxide group. The reaction mixture was directly hydrolyzed to give an inverted secondary alcohol in sufficient stereo and chemical purities by the presently developed chromatography-free process in conjunction with basic extraction, drying, and concentration. Georg Thieme Verlag Stuttgart - New York.
- Muramoto, Natsuko,Yoshino, Kazuki,Misaki, Tomonori,Sugimura, Takashi
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p. 931 - 935
(2013/05/21)
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- Intramolecular etherification of five-membered cyclic carbonates bearing hydroxyalkyl groups
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We report a new one-pot synthetic route to tetrahydrofuran derivatives, which were unexpectedly produced under basic conditions by intramolecular etherification of substituted five-membered cyclic carbonates. For alcohols with vicinal hydroxyl groups, and additional OH groups at the β-position, intramolecular etherification leading to 3-hydroxytetrahydrofuran derivatives was observed. These reactions were studied for compounds having from 2 to 6 hydroxyl groups per molecule, and the mechanism was proposed. The developed method provides a new environmentally friendly approach to the synthesis of five-membered cyclic ether derivatives under non-acidic conditions. The Royal Society of Chemistry.
- Tomczyk, Karolina M.,Gunka, Piotr A.,Parzuchowski, Pawel G.,Zachara, Janusz,Rokicki, Gabriel
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p. 1749 - 1758
(2013/02/22)
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- Enantioselective synthesis of HIV protease inhibitor amprenavir via Co-catalyzed HKR of 2-(1-azido-2-phenylethyl)oxirane
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A short and efficient enantioselective synthesis of the HIV protease inhibitor amprenavir 1 (99% ee) as well as a formal synthesis of saquinavir 3 have been achieved in high enantiomeric purity starting from commercially available materials. Our strategy mainly comprises a Co-catalyzed two-stereocentred hydrolytic kinetic resolution (HKR) of racemic 2-(1-azido-2-phenylethyl)oxirane as the chirality inducing step. Also presented is a concise synthesis of (S)-3-hydroxytetrahydrofuran 4, the key structural feature, in high enantiomeric purity (98% ee).
- Gadakh, Sunita K.,Santhosh Reddy,Sudalai, Arumugam
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experimental part
p. 898 - 903
(2012/09/22)
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- A novel lipase enzyme panel exhibiting superior activity and selectivity over lipase B from Candida antarctica for the kinetic resolution of secondary alcohols
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A novel, commercially available lipase enzyme panel performing kinetic bioresolutions of a number of secondary alcohols is reported. The secondary alcohols that have been chosen are known from the literature to be particularly challenging substrates to resolve. Following initial screening, four co-solvents were investigated for each lead enzyme in an effort to assess their tolerance to common organic solvents. The superiority of these novel enzymes over lipase B from Candida antarctica (CALB) has been demonstrated.
- O'Neill, Maeve,Beecher, Denis,Mangan, David,Rowan, Andrew S.,Monte, Agnieszka,Sroka, Stefan,Modregger, Jan,Hundle, Bhupinder,Moody, Thomas S.
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experimental part
p. 583 - 586
(2012/08/13)
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- Iridium-catalyzed borylation of secondary C-H bonds in cyclic ethers
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The borylation of secondary C-H bonds, specifically secondary C-H bonds of cyclic ethers, with a catalyst generated from tetramethylphenanthroline and an iridium precursor is reported. This borylation occurs with unique selectivity for the C-H bonds located β to the oxygen atoms over the weaker C-H bonds located α to oxygen atoms. Mechanistic studies imply that the C-H bond cleavage occurs directly at the β position rather than at the α position followed by isomerization of a reaction intermediate.
- Liskey, Carl W.,Hartwig, John F.
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supporting information; experimental part
p. 12422 - 12425
(2012/09/05)
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- METHODS OF PURIFYING 1,2,4-BUTANETRIOL AND COMPOSITIONS INCLUDING 1,2,4-BUTANETRIOL
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Methods of purifying BT are disclosed. The method comprises adding at least one polyhydroxyl compound to a crude BT mixture comprising BT and at least one boron-containing compound to form a polyhydroxyl compound/BT mixture. In one embodiment, the polyhydroxyl compound/BT mixture is then heated to a temperature greater than the boiling point of BT but less than the boiling point of the at least one polyhydroxyl compound. In another embodiment, the polyhydroxyl compound/BT mixture is heated to a temperature greater than the melting point of the polyhydroxyl compound, and then to a temperature greater than the boiling point of BT but less than the boiling point of the at least one polyhydroxyl compound. A composition comprising BT is also disclosed.
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Page/Page column 3-4
(2011/06/10)
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- Enhancement of cyclic ether formation from polyalcohol compounds in high temperature liquid water by high pressure carbon dioxide
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Cyclic ethers were produced by a dehydration reaction of polyalcohol compounds in high temperature liquid water, which was accelerated by the presence of carbon dioxide dissolved in the water. 3-hydroxytetrahydrofuran was produced by the dehydration of 1,2,4-butanetriol. Both tetrahydrofurfuryl alcohol and 3-hydroxytetrahydropyran were produced by the dehydration of 1,2,5-pentanetriol. Five-membered cyclic ethers were formed faster than six-membered cyclic ethers and the formation rates of the cyclic ethers depended strongly on the structure of the polyalcohol compounds. The position of the hydroxyl groups is crucial for the efficient intramolecular dehydration.
- Yamaguchi, Aritomo,Hiyoshi, Norihito,Sato, Osamu,Bando, Kyoko K.,Shirai, Masayuki
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experimental part
p. 48 - 52
(2010/04/22)
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- Thermodynamic equilibria between polyalcohols and cyclic ethers in high-temperature liquid water
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Thermodynamic equilibrium constants between polyalcohols and cyclic ethers in water at 573 K were determined by measuring their concentrations after the long-term reaction in a batch reactor. Intramolecular dehydration reactions of polyalcohols were important for conversion of biomass-derived carbohydrates; however, the yields of products were limited by thermodynamic equilibria between polyalcohols and products. All the thermodynamic equilibrium constants were estimated by the long-term dehydration reaction of 1 mol ·dm-3 polyalcohol aqueous solutions at 573 K. The thermodynamic equilibrium constants between butanepolyols or pentanepolyols and five-membered or six-membered cyclic ethers were within a range from (39 to 337) mol ·dm-3.
- Yamaguchi, Aritomo,Hiyoshi, Norihito,Sato, Osamu,Bando, Kyoko K.,Masuda, Yoshio,Shirai, Masayuki
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experimental part
p. 2666 - 2668
(2010/07/08)
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- PROCESS FOR THE EFFICIENT PREPARATION OF 3-HYDROXYTETRAHYDROFURAN
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Disclosed is a process for the efficient preparation of 3-hydroxytetrahydrofuran. In particular, the present invention provides a process for the preparation of 3-hydroxytetrahydrofuran by performing cyclization of 4-halo-1,3-butanediol either neat or in an organic solvent by heating to 75°C to 18O°C. In the present invention, acidic solution is not used in the cyclization and, thus, the reaction environment is improved. Further, the cyclization product 3-hydroxytetrahydrofuran is purified by a simple process. In addition, according to the present invention, chirality of the starting material is substantially maintained. Consequently, chiral 3-hydroxytetrahydrofuran with a high optical purity of 99.0% ee or better can be prepared economically, in high yield.
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Paragraph 81-82
(2008/12/07)
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- Synthesis of a variety of optically active hydroxylated heterocyclic compounds using epoxide hydrolase technology
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Novel epoxide hydrolases in Yarrowia lipolytica have been shown to hydrolyse a variety of functionalised epoxides with good to excellent stereoselectivity and at high volumetric productivities. Individual biotransformation products have been converted into optically active (R)-(tetrahydrofuran-2-yl)methanol (6), (S)-N-benzyl-3-hydroxypyrrolidine (7), (S)-3-hydroxytetrahydrothiophene (8), (S)-N-benzyl-3-acetoxypiperidine (10), (S)-3-hydroxytetrahydrofuran (16) and (R)-[(S)-N-benzylpyrrolidin-2-yl](phenyl)methanol (20).
- Pienaar, Daniel P.,Mitra, Robin K.,Deventer, Thomas I. van,Botes, Adriana L.
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body text
p. 6752 - 6755
(2009/04/06)
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- METHOD FOR PREPARING 3-HYDROXYTETRAHYDROFURAN USING CYCLODEHYDRATION
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Disclosed is a method of preparing 3-hydroxytetrahydrofuran using cyclodehydration. More particularly, this invention relates to a method of preparing 3-hydroxytetrahydrofuran, including subjecting 1,2,4-butanetriol to cyclodehydration under reaction conditions of a reaction temperature of 30~180°C and reaction pressure of 5000 psig or less in the presence of a strong acid cation exchange resin catalyst having a sulfonic acid group as an exchange group. According to the method of this invention, 3-hydroxytetrahydrofuran can be economically prepared at higher yield and productivity than when using conventional methods.
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Page/Page column 6
(2008/06/13)
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- METHOD FOR PRODUCING 3-AMINOMETHYLTETRAHYDROFURAN DERIVATIVE
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An object of the present invention is to provide a process for producing a 3-cyanotetrahydrofuran derivative in a high yield from inexpensive industrial materials. According to the present invention, a 3-aminomethyltetrahydrofuran derivative is produced by preparing a 3-cyanotetrahydrofuran derivative in a high yield from an inexpensive and industrially easily available malic acid derivative, and reducing the cyano group of the 3-cyanotetrahydrofuran derivative.
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- METHOD FOR PRODUCING 3-AMINOMETHYLTETRAHYDROFURAN DERIVATIVE
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Disclosed is a method for highly efficiently producing a 3-aminomethyltetrahydrofuran derivative from a low-cost industrial raw material. Specifically, a 3-cyanotetrahydrofuran derivative is produced at high yield from a low-cost, industrially easily-available malic acid derivative, and then a 3-aminomethyltetrahydrofuran derivative is produced by reducing the cyano group of the 3-cyanotetrahydrofuran derivative.
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Page/Page column 33
(2008/06/13)
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- New approaches to the industrial synthesis of HIV protease inhibitors
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Efficient and industrially applicable synthetic processes for precursors of HIV protease inhibitors (Amprenavir, Fosamprenavir) are described. These involve a novel and economical method for the preparation of a key intermediate, (3S)-hydroxytetrahydrofuran, from L-malic acid. Three new approaches to the assembly of Amprenavir are also discussed. Of these, a synthetic route in which an (S)-tetrahydrofuranyloxy carbonyl is attached to L-phenylalanine appears to be the most promising manufacturing process, in that it offers satisfactory stereoselectivity in fewer steps.
- Honda, Yutaka,Katayama, Satoshi,Kojima, Mitsuhiko,Suzuki, Takayuki,Kishibata, Naomi,Izawa, Kunisuke
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p. 2061 - 2070
(2007/10/03)
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- Deprotection of benzyl and p-methoxybenzyl ethers by chlorosulfonyl isocyanate-sodium hydroxide
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CSI-NaOH procedure provided a new and mild methodology for the deprotection of benzyl and p-methoxybenzyl ethers without affecting the other functional groups under similar reaction conditions.
- Kim, Ji Duck,Han, Gyoonhee,Zee, Ok Pyo,Jung, Young Hoon
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p. 733 - 735
(2007/10/03)
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- Stereospecific hydrolysis of optically active esters
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A new, more efficient and highly stereospecific process is described for the preparation of compounds with general formula (R)-(I) and of absolute configuration (R), where the groups M, W, Q and Q1 are as defined in the description, starting from compounds of absolute configuration (S) by hydrolysis, in the presence of acids, of the corresponding esterified derivatives. The (R)-(I) products obtained with the process described herein are chiral synthons useful for the production of enanthiomerically pure drugs. The preparation of (R)-carnitine is also provided.
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- Process for the preparation of 3-hydroxytetrahydrofuran
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An industrial advantage process for producing high-purity 3-hydroxytetrahydrofuran easily and simply, which comprises reducing a 4-halo-3-hydroxybutyric acid ester (1) with a boron hydride compound and/or an aluminum hydride compound as a reducing agent in an organic solvent immiscible with water; treating the reaction mixture with an acid and water to thereby effect conversion to the corresponding 4-halo-1,3-butanediol and at the same time giving an aqueous solution containing said compound; carrying out the cyclization reaction of the 4-halo-1,3-butanediol in said aqueous solution; extracting the resulting 3-hydroxytetrahydrofuran from the 3-hydroxytetrahydrofuran-containing aqueous solution using an organic solvent immiscible with water; and isolating the 3-hydroxytetrahydrofuran by concentration and/or distillation of the solution obtained.
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Page column 13, 14-15
(2008/06/13)
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- A high-throughput-screening method for the identification of active and enantioselective hydrolases
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A rapid and reliable test for the determination of hydrolase activity and enantioselectivity comprises the conversion of acetic acid released from acetates to NADH by using a commercially available enzymatic test-kit (see scheme). The NAHDH is spectrophotometrically quantified in a microtiter plate format.
- Baumann, Markus,Stuermer, Rainer,Bornscheuer, Uwe T.
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p. 4201 - 4204
(2007/10/03)
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