- Original and efficient synthesis of D-cycloserine
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A simple pathway for the preparation of D-cycloserine is presented. The intermediates and D-cycloserine were characterized by FT-IR, 1H-NMR spectra and elemental analysis. D-Cycloserine can inhibit the growth of Mycobacterium tuberculosis and can be used as a second-line drug for the treatment of tuberculosis, especially for the use in developing countries.
- Li, Xiaomeng,Meng, Xia,Duan, Hongdong,Wang, Lizhen,Wang, Shixiao,Zhang, Yi,Qin, Dawei
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Read Online
- Cyclization mechanism catalyzed by an ATP-grasp enzyme essential for d-cycloserine biosynthesis
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In the biosynthetic pathway of an antitubercular antibiotic d-cycloserine (d-CS), O-ureido-d-serine (d-OUS) is converted to d-CS. We have previously demonstrated that DcsG, classified into the ATP-grasp superfamily enzyme, catalyzes the ring formation to generate d-CS, which is accompanied by the cleavage of a bond in the urea moiety of d-OUS to remove a carbamoyl group. Although the general ATP-grasp enzymes catalyze an ATP-dependent ligation reaction between two substrates, DcsG catalyzes specifically the generation of an intramolecular covalent bond. In the present study, cyanate was found in the reaction mixture, suggesting that carbamoyl group is eliminated as an isocyanic acid during the reaction. By the crystallographic and mutational investigations of DcsG, we anticipate the residues necessary for the binding of d-OUS. An acylphosphate intermediate must be bound at the narrow pocket of DcsG in a folded conformation, inducing the bond cleavage and the new bond formation to generate cyanate and d-CS, respectively. Database: Structural data are available in Protein Data Bank database under the accession number 6JIL.
- Matoba, Yasuyuki,Uda, Narutoshi,Kudo, Mako,Sugiyama, Masanori
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p. 2763 - 2778
(2020/01/24)
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- Method for preparing D-cycloserine through one-pot method
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The invention discloses a method for preparing D-cycloserine through a one-pot method. The method comprises: carrying out a reaction on 3-chloro-D-serine and thionyl chloride in a solvent to obtain anintermediate 3-chloro-D-alanyl chloride hydrochloride solution; preparing a 35% sodium hydroxide aqueous solution, cooling to a temperature of less than 0 DEG C, controlling the temperature at -5 to5 DEG C, and adding the 3-chloro-D-alanyl chloride hydrochloride solution; uniformly stirring after completing the adding, controlling the temperature at -5 to 5 DEG C, and adding a hydroxylamine hydrochloride solution; slowly heating to a temperature of 20-30 DEG C after the adding, and adjusting the pH value of the solution to 10.5-12.0 by adding a 35% sodium hydroxide aqueous solution; carryingout standing liquid separation after completing the reaction; taking the water phase, and concentrating to achieve a near dry state; adding methanol, dissolving, and filtering to obtain a methanol solution; cooling to a temperature of -5 to 5 DEG C, and adjusting the pH value of the solution to 6.0-6.5 with a 60% acetic acid methanol solution; and carrying out stirring crystallization, carrying out centrifugation, drying the obtained wet product to obtain crude D-cycloserine, and refining to obtain the D-cycloserine finished product. According to the present invention, the product prepared bythe method has a liquid phase purity of more than 99.6% and a specific rotation of more than +110 DEG.
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Paragraph 0026-0033
(2019/10/01)
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- A D - cycloserines synthesis method
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The invention belongs to the field of drug synthesis, discloses a method for synthesizing D - cycloserines of: R - 3 - chloro serine methyl ester hydrochloride in methanol, adding hydrochloric acid, then adding acetone oxime, temperature reaction, cooling, methanol sodium maintain the pH to 8 - 9 reaction, filtering to salt, concentrated to a small volume of one-step to obtain D - cycloserines. The method process is simple in operation, environment friendly, mild reaction conditions, the final product purity is up to 99%, yield is as high as 94.25%, and favorable to industrial production.
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Paragraph 0037-0042
(2019/05/22)
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- A D - cycloserines preparation method
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The invention relates to a preparation method of D-cycloserine. The preparation method comprises steps of preparation of N-trifluoroacetyl-D-serine, preparation of (1-trifluoroacetylamino-2-hydroxyl) ethyl hydroxamate, preparation of D-4-trifluoroacetylamino-3-oxazolidinone and hydrolysis of D-4-trifluoroacetylamino-3-oxazolidinone. The preparation method has the benefits as follows: raw materials are easy to obtain, the reaction condition is mild, and the technological operation is simple; the racemization degree of D-cycloserine prepared with a synthetic route is reduced, the optical purity is improved, the product quality is stable, the follow-up three steps are performed with a 'one-pot' method, accordingly, emission of the three wastes and product loss are reduced, and the total yield of a reaction is improved.
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Paragraph 0026; 0035; 0036
(2018/04/21)
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- An efficient and facile synthesis of D-cycloserine substantially free from potential impurities
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An efficient and facile synthesis of D-cycloserine has been developed from D-serine with 61% overall yield employing protectiondeprotection strategy. Different parameters affecting the impurities content and yield of D-cycloserine have been studied. Mild reaction conditions provided the product with remarkable purity (>99%) and high stability.
- Awasthi, Arun Kumar,Kumar, Brijesh,Aga, Mushtaq A,Tripathi, Punit,Reddy, Cirandur Suresh,Kumar, Pramod
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p. 1248 - 1253
(2018/02/14)
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- Simple and efficient synthetic routes to d-cycloserine
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d-Cycloserine has been successfully synthesized in good yields through three new synthetic routes from a readily available d-serine. In each synthesis, cyclization served as the key step, and two of the routes employed one-pot operations for the preparation of the target product. These methods featured the use of mild reaction conditions and simple treatments.
- Kim, Hee-Kwon,Park, Kyoung-Joo Jenny
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experimental part
p. 1668 - 1670
(2012/04/10)
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- Preparation of D-cycloserine and 13C-labeled D-cycloserine
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D-Cycloserine (DCS), a second stage drug for the treatment of tuberculosis, is synthesized in 19.8% overall yield from DL-serine methyl ester. This synthetic route gives both enantiomers of cycloserine via a corrected and improved one pot resolution procedure using D- and L-tartaric acids. The route is used to synthesize a 13C-labeled derivative for use in biological studies.
- Thacker, Nathan C.,Molnar-Toth, Judit,Miska, Judy L.,Barletta, Raul G.,Takacs, James M.
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p. 1575 - 1582
(2013/08/23)
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- Novel practical synthesis of d-cycloserine
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The synthesis of d-cycloserine has been successfully accomplished from the readily available d-serine through three simple and efficient routes. In each synthetic strategy, cyclization reactions are involved as the key step, and one-pot processes are employed. The simple treatment and mild reaction conditions are attractive features in this methodology.
- Kim, Hee-Kwon,Park, Kyoung-Joo Jenny
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experimental part
p. 4090 - 4092
(2012/09/07)
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- Apparatus And Methods For Delivering A Plurality Of Medicaments For Management Of Co-Morbid Diseases, Illnesses Or Conditions
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A method and apparatus for delivering a plurality of medicaments in a single delivery vehicle for the management of co-morbid diseases, illnesses and conditions. The present invention provides a novel delivery process for many medicaments. Medicaments may be encapsulated and stored separately within a larger capsule until the time of ingestion, consumption, or the like. Benefits of the present invention include maintaining separation of distinct ingredients within a single capsule and the capability to control the time release of multiple ingredients within the capsule.
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- Cycloserine fatty acid derivatives as prodrugs: Synthesis, degradation and in Vitro skin permeability
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Various 4,5-dihydroisoxazol-3-yl fatty acid ester derivatives of cycloserine were synthesized to improve skin permeation of cycloserine. The ester derivatives were prepared by using the tert-butoxycarbonyl (t-Boc) protection strategy. The 4,5-dihydroisoxazol-3-yl esters were readily hydrolysed in an aqueous buffer solution, and the degradation profiles showed both specific acid and specific base catalysis. In 50% human serum the formation of cycloserine was observed, but enzymatic catalysis was limited. Delivery through hairless mouse skin was investigated, and the apparent permeability coefficient was measured based on the flux of cycloserine into the receptor phase. The skin permeation of cycloserine across the hairless mouse skin was increased up to 20-fold by the fatty acid esters. The 4,5-dihydroisoxazol-3-yl fatty acid esters of cycloserine can therefore be considered as new topical prodrugs with the potential use in treatment of various skin infections.
- Thorsteinsson, Thorsteinn,Masson, Mar,Jarvinen, Tomi,Nevalainen, Tapio,Loftsson, Thorsteinn
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p. 554 - 557
(2007/10/03)
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- 3-tolylthio-4-amino-4,5-dihydro isoxazole as anthelmintic
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A novel tolylthioisoxazole compound is disclosed having activity against the pinworms S. obvelata and A. tetraptera. A process for making these compounds and a method of administering it to infested animals is also disclosed.
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- Phthalamide derivatives with anthelmintic activity
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Novel phthalamide compounds are disclosed having activity against a broad spectrum of parasitic worms and showing no toxicity to the host animal. These compounds are N-(3-chloro-4,5-dihydroisoxazol-4-yl)-N'-(substituted)phthalamides. A process for making these compounds and a method of administering them to animals are also disclosed.
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- Dihydroisoxazole compounds and anthelmintic use
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Novel dihydroisoxazole compounds are disclosed having activity against parasitic worms and showing little or no toxicity to the host animal. These compounds are 3-chloro-4-dialkylaminophthaloylamino-4,5-dihydroisoxazoles and 3-dialkylamino-4-dialkylaminophthaloylamino-4,5-dihydroisoxazoles. A process for making these compounds and a method of administering them to infested animals is also disclosed.
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- Method of therapeutically treating warm blooded animals and compositions therefor
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Tissue in warm blooded animals which is damaged and/or infected is treated by administering a therapeutically effective amount of a composition containing a novel catalyst and water soluble catalyst treated lignite. The treatment is also effective in relieving stress and/or shock. In a further variant, warm blooded animals having damaged and/or infected tissue are treated with a composition containing therapeutically effective amounts of at least one antibiotic, the novel catalyst, and the catalyst treated lignite. Novel compositions are provided which contain therapeutic amounts of at least one antibiotic, the catalyst, and the catalyst treated lignite. The novel catalyst and the catalyst treated lignite are prepared by processes described in detail hereinafter.
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