- Regioselective preparation of thiamphenicol esters through lipase-catalyzed processes
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The lipase-catalyzed synthesis of thiamphenicol derivatives has been studied through complementary acylation and hydrolytic approaches, finding Candida antarctica lipase B as the most efficient biocatalyst for the selective modification of both thiampheni
- Da Silva, Marcos R.,Montenegro, Tasso G.C.,De Mattos, Marcos C.,De Oliveira, Maria Da Conceic?a?o F.,De Lemos, Telma L.G.,De Gonzalo, Gonzalo,Lavandera, Iva?n,Gotor-Ferna?ndez, Vicente,Gotor, Vicente
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- An Efficient Stereoselective Total Synthesis of All Stereoisomers of the Antibiotic Thiamphenicol through Ruthenium-Catalyzed Asymmetric Reduction by Dynamic Kinetic Resolution
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Thiamphenicol is a widely used antibiotic that exhibits activity against numerous Gram-positive and Gram-negative pathogens. Here, we describe the expedient synthesis of its four stereoisomers through a dynamic kinetic resolution that follows a ruthenium-catalyzed asymmetric hydrogenation or a hydrogen transfer reaction as the key step.
- Perez, Marc,Echeverria, Pierre-Georges,Martinez-Arripe, Elsa,Ez Zoubir, Mehdi,Touati, Ridha,Zhang, Zhaoguo,Genet, Jean-Pierre,Phansavath, Phannarath,Ayad, Tahar,Ratovelomanana-Vidal, Virginie
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Read Online
- Method for continuously preparing thiamphenicol by using micro-reaction system
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The invention belongs to the technical field of pharmaceutical engineering, and particularly relates to a method for continuously preparing thiamphenicol by using a micro-reaction system. A micro-reaction system used in the method comprises a micro-mixer, a micro-channel reactor and a back pressure device, and during preparation, a solution of raw materials (1R,2R)-2-amino-1-(4-(methylsulfonyl)phenyl)propane-1,3-diol and an alkaline solution of methyl dichloroacetate are simultaneously injected into the micro-reactor by a pump respectively for condensation reaction, and concentrating, recrystallizing, filtering, washing and drying are conducted on the reaction product to obtain a thiamphenicol product. According to the method provided by the invention, the reaction time is only several minutes, the yield of the product thiamphenicol is greater than 99%, the purity is greater than 99%, the operation is convenient, continuous and controllable, the amplification effect is avoided, the efficiency of the technological process is high, and the method has a very good industrial application prospect.
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Paragraph 0021-0043
(2021/08/14)
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- 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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- Unified Strategy to Amphenicol Antibiotics: Asymmetric Synthesis of (-)-Chloramphenicol, (-)-Azidamphenicol, and (+)-Thiamphenicol and Its (+)-3-Floride
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The asymmetric synthesis of (-)-chloramphenicol, (-)-azidamphenicol, and (+)-thiamphenicol and its (+)-3-floride, (+)-florfenicol, is reported. This approach toward the amphenicol antibiotic family features two key steps: (1) a cinchona alkaloid derived urea-catalyzed aldol reaction allows highly enantioselective access to oxazolidinone gem-diesters and (2) a continuous flow diastereoselective decarboxylation of thermally stable oxazolidinone gem-diesters to form the desired trans-oxazolidinone monoesters with two adjacent stereocenters that provide the desired privileged scaffolds of syn-vicinal amino alcohols in the amphenicol family.
- Liu, Jinxin,Li, Yaling,Ke, Miaolin,Liu, Minjie,Zhan, Pingping,Xiao, You-Cai,Chen, Fener
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p. 15360 - 15367
(2020/11/30)
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- Thiamphenicol synthesis method
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The invention discloses a thiamphenicol synthesis method which comprises the following steps: by adopting D-p-methylsulfonylphenyl serine ethyl ester as a starting raw material, performing reduction with potassium borohydride or sodium borohydride, cyclizing the starting raw material with dichloroacetonitrile in an environment that an organic acid is added to adjust a pH value, and performing hydrolysis with hydrochloric acid to obtain thiamphenicol. The method is simple in process operation, easily available in raw material and high in conversion rate, and the cost can be greatly reduced.
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Paragraph 0008
(2020/01/25)
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- Florfenicol intermediate synthesis method
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The invention belongs to the field of synthesis of pharmaceutical raw materials, and specifically discloses a florfenicol intermediate synthesis method, which comprises: (1) carrying out a reaction ona compound (II) and an acylating reagent in an organic solvent to form a compound (III); (2) carrying out a reaction on the compound (III) and an oxidizing agent in an organic solvent in the presenceof a catalyst to form a compound (IV); (3) carrying out a reaction on the compound (IV) and a fluorinating reagent in an organic solvent to form a compound (V); and (4) carrying out acidolysis on thecompound (V) in an organic solvent, and carrying out deprotection to obtain a compound (I), wherein various groups in the formulas are defined in the specification. According to the present invention, the florfenicol intermediate can be used for preparing florfenicol; and the method has characteristics of novel design, mild conditions and simple operation, and is suitable for industrial production.
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Paragraph 0187-0191
(2019/07/04)
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- Asymmetric Synthesis of Florfenicol by Dynamic Reductive Kinetic Resolution with Ketoreductases
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A chemoenzymatic synthesis of the veterinary antibiotic florfenicol is described. The key step involves the dynamic reductive kinetic resolution (DYRKR) of a keto ester by using a ketoreductase-02 (KRED-02) to afford the two contiguous stereocenters of the (2S,3R)-cis-1,2-amino alcohol intermediate in >99 % ee and a diastereomeric ratio (dr) of 99 %. This green biocatalysis is environmental friendly with high enantioselectivity and product yields. Two methods for the nucleophilic fluorination step involved the use of aziridines and cyclic sulfates to safely prepare fluoroamines with high regioselectivity. Additional studies have indicated that KRED-02 can also be used to afford chiral alcohol (S)-21 in good yields with high enantioselectivity. This study shows that the integration of biocatalysis into organic synthesis can be useful and provide industrial opportunities for applications of florfenicol.
- Zou, Jie,Ni, Guowei,Tang, Jiawei,Yu, Jun,Jiang, Luobin,Ju, Dianwen,Zhang, Fuli,Chen, Shaoxin
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p. 5044 - 5053
(2018/10/05)
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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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supporting information
p. 149 - 153
(2013/08/24)
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- New stereoselective synthesis of thiamphenicol and florfenicol from enantiomerically pure cyanohydrin: a chemo-enzymatic approach
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Thiamphenicol and florfenicol have been synthesized stereoselectively from enantiomerically pure 4-methylsulfanyl-mandelonitrile, which was obtained by hydrocyanation reaction of 4-methylsulfanyl-benzaldehyde catalyzed by (R)-hydroxynitrile lyase of Badamu (Prunus communis L. var. dulcis Borkh, almond from Xinjiang, China). It was found to be a highly effective bio-catalyst for this reaction after an extensive screening.
- Lu, Wenya,Chen, Peiran,Lin, Guoqiang
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p. 7822 - 7827
(2008/12/20)
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- Stereoselective syntheses of (-)-chloramphenicol and (+)-thiamphenicol
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Chloramphenicol and thiamphenicol have been enantioselectively synthesized using an asymmetric halohydrin reaction as a key step. In particular, halomethoxylation reaction was used, where O-methyl functions as a hydroxyl protecting group and eliminates an additional protection step.
- Hajra, Saumen,Karmakar, Ananta,Maji, Tapan,Medda, Amiya Kumar
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p. 8959 - 8965
(2007/10/03)
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- A short enantioselective synthesis of (-)-chloramphenicol and (+)-thiamphenicol using tethered aminohydroxylation
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An efficient enantioselective synthesis of (-)-chloramphenicol (1) and (+)-thiamphenicol (2) is described. These antibiotics have been synthesized from commercially available 4-nitrobenzaldehyde and 4-(methylthio)benzaldehyde, respectively, using tethered aminohydroxylation and Sharpless asymmetric epoxidation as the chirality inducing steps.
- George, Shyla,Narina, Srinivasarao V.,Sudalai, Arumugam
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p. 10202 - 10207
(2007/10/03)
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- A short stereoselective synthesis of (-)-chloramphenicol and (+)-thiamphenicol
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A common strategy for the synthesis of (-)-chloramphenicol and (+)-thiamphenicol is described. These antibiotics have been synthesized from commercially available 4-nitrobenzaldehyde and 4-(methylthio)benzaldehyde in three and four steps, respectively.
- Bhaskar,Satish Kumar,Venkateswara Rao
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p. 1279 - 1283
(2007/10/03)
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- Aziridine compounds, methods of preparation and reactions thereof
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Novel N-sulfinyl-2-carboxyaziridine compounds and novel N-hydrogen-2-hydroxymethylaziridine compounds are provided. The asymmetric synthesis of N-sulfinylaziridines is readily accomplished in high diastereomeric purity and good yield by the Darzens-type reaction of the metal enolate of an α-haloester and an enantiopure sulfinimine. Ring-opening of these aziridines affords α-amino acids and the otherwise difficult to prepare syn-β-hydroxy-α-amino acids, both key structural units found in many bioactive materials. The N-sulfinyl radical may be selectively removed from the novel aziridine compounds by treatment with acid or base. Alternatively, the N-sulfinyl radical may be oxidized to provide the corresponding N-sulfonyl-aziridine, or reduced to form the corresponding 1H-2-hydroxymethylaziridine, either of which may subsequently be ring-opened to provide precursors to bioactive compounds.
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- Asymmetric synthesis using sulfinimines (thiooxime S-oxides)
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The addition of diethylaluminum cyanide and the lithium enolate of methyl α-bromoacetate to sulfinimines (thiooxime S-oxides) is highly diastereoselective affording α-amino nitriles and N-sulfinylaziridines, respectively. Hydrolysis of the α-amino nitriles gives α-amino acids in high ee, while hydrolysis of N-sulfinylaziridine carboxylic acids give β-hydroxy-α-amino acids. The latter compounds were transformed into (+)-thiamphenicol, a broad spectrum antibiotic and sphingosine, an important component of the sphingolipids.
- Davis, Franklin A.,Portonovo, Padma S.,Reddy, Rajarathnam E.,Reddy, G. Venkat,Zhou, Ping
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p. 291 - 303
(2007/10/03)
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- Asymmetric synthesis of the antibiotic (+)-thiamphenicol using cis-N-(p-toluenesulfinyl)aziridine 2-carboxylic acids
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A concise, highly efficient asymmetric synthesis of aminopropanediol (1R,2R)-(-)-3, precursor to the broad spectrum antibiotics thiamphenicol/florfenicol 1/2, was prepared in two steps from cis-aziridine 2-carboxylic acid (2S,3S)-(-)-5.
- Davis, Franklin A.,Zhou, Ping
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p. 7525 - 7528
(2007/10/02)
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- Stereoisomeric enrichment of 2-amino-3-hydroxy-3-phenyl-propionic acids
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Mixtures of enantiomeric D,L-threo 2-amino-3-hydroxy-3-phenylpropionic acids can be stereoisomerically enriched by contacting the mixture with a D-threonine aldolase. In a typical embodiment, D- and L-threo 2-amino-3-hydroxy-3-(4-methylsulfonylphenyl)propionic acid is treated with D-threonine aldolase to produce L-threo 2-amino-3-hydroxy-3-(4-methylsulfonylphenyl)propionic acid with a high ee. The benzaldehyde and amino acid formed from the D-threo isomer can be recycled.
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- Process of preparing thiamphenicol
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Process of preparing thiamphenicol represented by formula [II] below which comprises:, a step of diazotizing the aromatic amino group of the compound represented by formula [I] below;, a step of subsequently reacting a methylthio metal salt with said diazonium compound to convert the amino group into a methylthio group; and, a combination of a step of dichloroacetylating the aliphatic amino group and a step of oxidizing the methylthio group.
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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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- 2-OXAZOLIDINONES AS REGIOSELECTIVE PROTECTION OF β-AMINO ALCOHOLS IN THE SYNTHESIS OF 2-AMINO-1-ARYL-3-FLUORO-1-PROPANOLS
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The regioselective conversion of threo-2-ethoxycarbonylamino-1--1,3-propanediol, 4, into 4-hydroxymethyl-5--2-oxazolidinone, 8, is described as well as the use of this protection procedure in the synthesis of the fluoro analogue, 2, of thiamphenicol, 1.Methods of hydrolysis of the oxazolidinone ring are revisited for compound 11; new procedures via N-acylated intermediates have been investigated and their application is reported.
- Jommi, Giancarlo,Pagliarin, Roberto,Tavecchia, Paolo,Chiarino, Dario,Fantucci, Mario
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p. 485 - 490
(2007/10/02)
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