- Catalytic Syn-Selective Nitroaldol Approach to Amphenicol Antibiotics: Evolution of a Unified Asymmetric Synthesis of (-)-Chloramphenicol, (-)-Azidamphenicol, (+)-Thiamphenicol, and (+)-Florfenicol
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A unified strategy for an efficient and high diastereo- and enantioselective synthesis of (-)-chloramphenicol, (-)-azidamphenicol, (+)-thiamphenicol, and (+)-florfenicol based on a key catalytic syn-selective Henry reaction is reported. The stereochemistry of the ligand-enabled copper(II)-catalyzed aryl aldehyde Henry reaction of nitroethanol was first explored to forge a challenging syn-2-amino-1,3-diol structure unit with vicinal stereocenters with excellent stereocontrol. Multistep continuous flow manipulations were carried out to achieve the efficient asymmetric synthesis of this family of amphenicol antibiotics.
- Chen, Fener,Cheng, Dang,Huang, Huashan,Jiang, Meifen,Liu, Minjie,Qu, Hongmin,Xia, Yingqi,Xiong, Tong,Zhang, Yan
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p. 11557 - 11570
(2021/09/02)
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- METHODS FOR PREPARING FLORFENIOL AND INTERMEDIATE THEREOF
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The present invention discloses a method for preparing florfenicol and its intermediate (V), comprising an addition reaction, a ring closure reaction, a hydrolysis reaction, a ring opening reaction, a reduction reaction, a ring reaction, a fluorination reaction and a ring opening reaction. In the present method for preparing florfenicol, respective reaction steps can be continuously operated, therefore the methods of the present invention features simplified process and shorter synthetic route, and obtained florfenicol has high chiral purity and is of high yield. The method of the present invention for preparing florfenicol (TM) using the intermediate (V) avoids waste water pollution and reduces the cost for treating wastewater and alleviates environmental pollution. At the same time, the methods of the present invention eliminates a chiral resolution procedure, thus increasing the utilization rate of atoms in the reaction. As a result, cost is reduced and process is simplified.
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Paragraph 0128; 0129
(2021/07/02)
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- One-Pot Asymmetric Synthesis of an Aminodiol Intermediate of Florfenicol Using Engineered Transketolase and Transaminase
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Florfenicol is the 3′-fluoro derivative of thiamphenicol and has been widely used in veterinary medicine for its high antibacterial activity and safety. However, the development of simplified and environmentally friendly catalytic methods for the stereoselective production of florfenicol is a key challenge. Herein, we established a highly stereoselective enzymatic one-pot reaction for the synthesis of an aminodiol intermediate of florfenicol bearing two stereocenters from industrial raw material 4-(methylsulfonyl) benzaldehyde by coupling transketolase (TK) and ω-transaminase (TA). The enantioselectivity of TK from E. coli was converted from (S) (93% ee) to (R) (95% ee), and we also inverted the enantiopreference (E(S) = 9 to E(R) = 12) and ketone/aldehyde substrate selectivity of TA ATA117 via structure-guided enzyme engineering. Docking calculations and molecular dynamics simulations of the wild-type and mutant enzymes unveiled the molecular basis for enzymatic stereocontrol. Using the engineered TK and TA, (1R,2R)-p-methylsulfonyl phenylserinol was biosynthesized with good yield (76%) and high stereoselectivity (96% de and >99% ee). Our work established an enzymatic synthetic route to (1R,2R)-p-methylsulfonyl phenylserinol, facilitating the development of a chemoenzymatic method for producing florfenicol.
- Deng, Zixin,Huang, Tingting,Lin, Shuangjun,Liu, Qi,Shi, Ting,Tang, Mancheng,Tao, Wentao,Xie, Xinyue,Zhang, Yuanzhen,Zhao, Yilei
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p. 7477 - 7488
(2021/06/30)
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- Preparation method of florfenicol intermediate
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The invention relates to the technical field of veterinary drugs, in particular to a preparation method of a florfenicol intermediate. The preparation method comprises the following steps: using D-threo-p-methyl sulfonyl phenyl serine as a raw material, adding a solvent, heating, and directly generating amino diol under the actions of a reducing agent and a reduction assistant. The preparation method is simple in process, low in production cost and quick in reaction, and the product yield is greatly improved.
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Paragraph 0021-0045
(2020/10/05)
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- Preparation method of florfenicol intermediate (by machine translation)
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The compound is obtained by carrying out asymmetric addition reaction with nitroethanol under the catalysis of Cu (OTf) and a copper salt complex formed by chiral ligand L, and then carrying out catalytic hydrogenation on palladium carbon . the compound is obtained after catalytic hydrogenation of palladium carbon. 2The route synthesis method is simple to operate, environmentally friendly, and wide in application prospect. (by machine translation)
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Paragraph 0039; 0040
(2019/09/13)
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- A new key intermediate of preparation method of florfenicol (by machine translation)
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The present invention discloses a new method for the preparation of the key intermediate of the florfenicol, including asymmetric addition reactions and the cyclization reaction, of the present invention simplify the whole line, simple operation, chiral control better, there are broad application prospects. The invention only 2 step reaction, compared with the traditional process of 5 step reaction, is greatly simplified, the operation is simpler, adopts the chiral asymmetric addition reactions, realizes the efficient use of the substrate, compared with the traditional process of less than half of the resolution of the utilization rate of atom, greatly improves the economy of the process, because of the short route, cheap raw materials, and thus greatly reduces the cost of the product, improving the quality of products. (by machine translation)
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Paragraph 0037-0041; 0045-0049; 0053-0057; 0061-0065
(2019/10/04)
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- A florfenicol also the original method for the preparation of (by machine translation)
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The invention discloses a florfenicol also the original of a preparation method of the midbody, is to the chlorobenzene as a starting material, through the asymmetric addition reaction, sodium methyl mercaptan/oxidation reaction to prepare the florfenicol intermediate (1 R, 2 R) - 2 - amino - 1 - (4 - methanesulfonyl) phenyl) propane - 1, 3 - diol, simplify the entire route of the present invention, simple operation, chiral control better, there are broad application prospects. The invention only 2 step reaction, compared with the traditional process of the 4 step reaction, is greatly simplified, the operation is simpler, the efficient use of the substrate, compared to traditional chiral separation process of less than half of the utilization rate of atom, greatly improves the economy of the process. (by machine translation)
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Paragraph 0042-0043; 0050-0051; 0058-0059; 0066-0067
(2019/10/23)
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- Method for purifying (1R,2R)-1-[(4-methylsulfonyl)phenyl]-2-amino-1,3-propanediol
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The invention relates to a method for purifying (1R,2R)-1-[(4-methylsulfonyl)phenyl]-2-amino-1,3-propanediol. A reaction of an amine and a ketone to form a Schiff base, which is a reversible reaction,is used to remove some impurities that are difficult to remove. The method comprises the following steps: crude (1R,2R)-1-[(4-methylsulfonyl)phenyl]-2-amino-1,3-propanediol is mixed with a solvent and a ketone, the obtained mixture is stirred and reacted at 10-80 DEG C, the reacted mixture is cooled to -20-20 DEG C for crystallization, and the obtained mixture is filtered and dried to obtain a Schiff base; and the Schiff base reacts with water at 30-105 DEG C, reaction, the obtained solution is distilled and concentrated, an organic solvent is added, the obtained solution is cooled to -15-25DEG C for crystallization, and the obtained solution is filtered and dried to obtain high-quality (1R,2R)-1-[(4-methylsulfonyl)phenyl]-2-amino-1,3-propanediol with an HPLC purity of above 99.8% andany single impurity content of below 0.1%. The method has the advantages of good purification effect, high product purity, mild reaction conditions, simplicity in operation, and easiness in realization of enlarged production.
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Paragraph 0047; 0049; 0054; 0056
(2019/10/01)
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- A (1R, 2R) - 1 - substituted phenyl - 2 - amino - 1, 3 - propanediol
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The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a synthesis method of (1R,2R)-1-substituted-phenyl-2-amino-1,3-propanediol. The preparation method comprises the following steps: rearranging 2-(N-substituted-oxyformacyl-substituted-benzoylamino)acetate to obtain 2-substituted-oxyformamido-3-substituted-phenyl-3-oxopropionate; and carrying out asymmetric transfer hydrogenation with dynamic resolution to obtain (2S,3S)-alpha-substituted-amino-beta-hydroxy ester, and carrying out configuration reversion and deprotection to obtain the (1R,2R)-1-substituted-phenyl-2-amino-1,3-propanediol. The method has the advantages of mild conditions and high optical purity, and is simple to operate and suitable for industrial production.
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- A D-threo-2 - (b chloromethyl) - 4,5-dihydro-5 - [P-(methyl sulfuryl) phenyl] - 4-oxazole methanol preparation method
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The invention relates to a chemical preparation method, and particularly relates to a preparation method of a florfenicol intermediate, namely D-threo-2-(dichloromethyl)-4, 5-dihydro-5-[p-(methylsulfonyl)phenyl]-4-oxazole methanol. The preparation method comprises the following steps of: by taking D-threo-p-methylsulfonyl phenyl ethyl serinate as a starting material, reducing the starting material into a D-threo-2-amino-1-[p-(methylsulfonyl)phenyl]-1,3-propylene glycol through potassium borohydride, adjusting pH to subacidity by short-chain fatty acids, and then reacting with dichloromethyl cyanide under a high-temperature condition to obtain a target compound, namely the D-threo-2-(dichloromethyl)-4, 5-dihydro-5-[p-(methylsulfonyl)phenyl]-4-oxazole methanol. According to the technical scheme of the invention, glycerol is not used in the preparation process of the D-threo-2-(dichloromethyl)-4, 5-dihydro-5-[p-(methylsulfonyl)phenyl]-4-oxazole methanol, the reaction time is shortened, the benefits are increased, and the environments are protected.
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Paragraph 0025-0026
(2017/02/09)
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- Catalytic asymmetric transfer hydrogenation/dynamic kinetic resolution: an efficient synthesis of florfenicol
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A robust and practical method has been developed for the synthesis of florfenicol (1) starting from commercial available 4-(methylsulfonyl) benzoic acid. The key step in this synthesis was the Ru-chloramphenicol base catalyzed asymmetric transfer hydrogenation of N-Boc α-amino-β-ketoester 5 through a dynamic kinetic resolution, which afforded the key chiral building block, anti-(2S,3S)-α-Boc-amino-β-hydroxyl ester 4, with high diastereoselectivity (92% de) and enantioselectivity (78% ee). The synthesis of a series of novel chloramphenicol base ligands L1–L10 is also included. This protocol could also be used for the asymmetric synthesis of fully synthetic analogs of florfenicol.
- Wang, Xinlong,Xu, Lingjun,Yan, Lingjie,Wang, Haifeng,Han, Sheng,Wu, Yan,Chen, Fener
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p. 1787 - 1793
(2018/03/29)
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- Stereocontrolled synthesis of syn-β-hydroxy-α-amino acids by direct aldolization of pseudoephenamine glycinamide
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β-Hydroxy-α-amino acids figure prominently as chiral building blocks in chemical synthesis and serve as precursors to numerous important medicines. Reported herein is a method for the synthesis of β-hydroxy- α-amino acid derivatives by aldolization of pseudoephenamine glycinamide, which can be prepared from pseudoephenamine in a one-flask protocol. Enolization of (R,R)- or (S,S)-pseudoephenamine glycinamide with lithium hexamethyldisilazide in the presence of LiCl followed by addition of an aldehyde or ketone substrate affords aldol addition products that are stereochemically homologous with L- or D-threonine, respectively. These products, which are typically solids, can be obtained in stereoisomerically pure form in yields of 55-98 %, and are readily transformed into β-hydroxy-α-amino acids by mild hydrolysis or into 2-amino-1,3-diols by reduction with sodium borohydride. This new chemistry greatly facilitates the construction of novel antibiotics of several different classes. On aldol: Enolization of (R,R)- or (S,S)-pseudoephenamine glycinamide with lithium hexamethyldisilazide (LiHMDS) in the presence of LiCl followed by addition of either an aldehyde or ketone substrate affords aldol addition products which are stereochemically homologous with L- or D-threonine, respectively. These products can be obtained in stereoisomerically pure form in yields of 55-98 %, and are readily transformed into β-hydroxy-α-amino acids by mild hydrolysis or into 2-amino-1,3-diols by reduction.
- Seiple, Ian B.,Mercer, Jaron A. M.,Sussman, Robin J.,Zhang, Ziyang,Myers, Andrew G.
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supporting information
p. 4642 - 4647
(2014/05/20)
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- Stereoselective synthesis of (-)-chloramphenicol, (+)-thiamphenicol and (+)-sphinganine via chiral tricyclic iminolactone
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The stereoselective syntheses of (-)-chloramphenicol, (+)-thiamphenicol and (+)-sphinganine are described. The two continuous chiral centers within three target molecules were constructed through aldol reaction of chiral tricyclic iminolactone and aldehyde. Concise and efficient syntheses of (-)-chloramphenicol, (+)-thiamphenicol and (+)-sphinganine have been accomplished in practical four or three steps. The synthetic route featured in an aldol reaction between iminolactone 1a and 1b with aldehyde, which introduced the two continuous chiral centers within three target molecules. Copyright
- Li, Qiong,Zhang, Hongbo,Li, Chenguang,Xu, Pengfei
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p. 149 - 153
(2013/08/24)
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- A facile and efficient asymmetric synthesis of florfenicol
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A facile and efficient enantioselective synthesis of flor-fenicol starting from commercially available 4-methylthiobenzaldehyde is described. Key features of the synthesis include a one-step oxidation of allyl and thioether groups in allylic alcohol to form (2S,3S)-epoxide under Sharpless epoxidation conditions and a highly efficient conversion of (1R,2R)-azide into amino alcohol via debenzylation and reduction of an azido moiety in one-pot operation. Georg Thieme Verlag Stuttgart. New York.
- Li, Feng,Wang, Zhong-Hua,Zhao, Lei,Chen, Fen-Er
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p. 2883 - 2885
(2012/01/11)
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- An efficient enantioselective synthesis of florfenicol via a vanadium-catalyzed asymmetric epoxidation
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An efficient and highly enantioselective synthesis of florfenicol 1 was achieved with 37% overall yield starting from commercially available 4-methylthiobenzaldehyde. A key feature of the synthesis is the vanadium-catalyzed asymmetric epoxidation of allylic alcohol 5 with aq tert-butyl hydroperoxide to form (2S,3S)-epoxide 6.
- Li, Feng,Wang, Zhong-Hua,Zhao, Lei,Xiong, Fang-Jun,He, Qiu-Qin,Chen, Fen-Er
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p. 1337 - 1341
(2011/11/29)
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- PROCESS FOR PREPARING OXAZOLINE-PROTECTED AMINODIOL COMPOUNDS USEFUL AS INTERMEDIATES TO FLORFENICOL
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Processes for preparing oxazoline compounds are disclosed. These oxazoline compounds are useful intermediates in the preparation of Florfenicol and related compounds.
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Page/Page column 50
(2010/04/03)
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- Process for preparing oxazolidine protected aminodiol compounds useful as intermediates to florfenicol
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An improved method of preparing oxazolidine protected aminodiol compounds is disclosed. These compounds are useful intermediates in processes for making Florfenicol.
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Page/Page column 7-8
(2008/06/13)
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- Reversed-phase liquid chromatographic separation of enantiomeric and diastereomeric bases related to chloramphenicol and thiamphenicol.
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The important antimicrobial agents chloramphenicol and thiamphenicol are N-acylated amines whose chemical structures include two chiral centers. Each drug is the single enantiomer of R,R configuration. The N-deacylated bases of the drugs are important intermediates in their synthesis and optical resolution. In this report, reversed-phase HPLC methods are described for the separation of enantiomeric and diastereomeric bases of the two drugs and of two closely related bases used in some syntheses of the drugs. The stereoisomeric bases were derivatized with a homochiral isothiocyanate and the resulting diastereomeric thioureas were separated on C18 columns with methanol:water mixtures as mobile phases and detection at 254 nm. The four stereoisomeric bases of chloramphenicol and those of its unnitrated analogue were thus separable after derivatization with 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl isothiocyanate. This reagent also allowed the separation of the D-threo isomer of the p-mercaptomethyl analogue of thiamphenicol base from its stereoisomers. The stereoisomers of thiamphenicol base were similarly separated with (R)-alpha-methylbenzyl isothiocyanate as the derivatizing agent. The diastereomers of chloramphenicol base and of thiamphenicol base were chromatographically separable after derivatization with the nonchiral reagent benzyl isothiocyanate. The procedures developed may be useful in the determination of the stereoisomeric composition of the drugs in research and in quality control, and may be applicable to other similar agents whose chemistry and pharmacology are receiving considerable attention.
- Gal,Meyer-Lehnert
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p. 1062 - 1065
(2007/10/02)
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- CYCLOFUNCTIONALISATION REACTIONS OF EPOXYALCOHOL DERIVATIVES. 3. CYCLISATION-ACYL MIGRATION OF N-BENZOYLCARBAMATES TO STEREODEFINED OXAZOLIDINONES. A NEW, DIASTEREOSPECIFIC ROUTE TO THIAMPHENICOL.
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N-Benzoylcarbamates formed in situ from 2,3-epoxyalcohols and PhCONCO undergo clean to C-2 cyclisation followed by N to O acyl migration on treatment with catalytic sodium imidazolide or other bases.Subsequent benzoate cleavage (NaOMe) is accompanied by equilibration of the N-unsubstituted oxazolidinones; cleavage without significant isomerisation is achieved with MeLi or Zn(BH4)2.This methodology is applied in a diastereospecific, 6-step conversion of methyl 4-bromophenyl sulfonate to racemic Thiamphenicol.
- McCombie, S. W.,Nagabhushan, T. L.
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p. 5395 - 5398
(2007/10/02)
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