- A unified strategy to prostaglandins: chemoenzymatic total synthesis of cloprostenol, bimatoprost, PGF2α, fluprostenol, and travoprost guided by biocatalytic retrosynthesis
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Development of efficient and stereoselective synthesis of prostaglandins (PGs) is of utmost importance, owing to their valuable medicinal applications and unique chemical structures. We report here a unified synthesis of PGs cloprostenol, bimatoprost, PGF2α, fluprostenol, and travoprost from the readily available dichloro-containing bicyclic ketone6aguided by biocatalytic retrosynthesis, in 11-12 steps with 3.8-8.4% overall yields. An unprecedented Baeyer-Villiger monooxygenase (BVMO)-catalyzed stereoselective oxidation of6a(99% ee), and a ketoreductase (KRED)-catalyzed diastereoselective reduction of enones12(87?:?13 to 99?:?1 dr) were utilized in combination for the first time to set the critical stereochemical configurations under mild conditions. Another key transformation was the copper(ii)-catalyzed regioselectivep-phenylbenzoylation of the secondary alcohol of diol10(9.3?:?1 rr). This study not only provides an alternative route to the highly stereoselective synthesis of PGs, but also showcases the usefulness and great potential of biocatalysis in construction of complex molecules.
- Chen, Fener,Huang, Zedu,Jiang, Meifen,Li, Weijian,Tang, Pei,Ye, Baijun,Zhang, Guo-Tai,Zhu, Kejie
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p. 10362 - 10370
(2021/08/16)
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- Preparation method of Biomatoprost intermediate
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In the present invention, provided is a method for manufacturing a compound of chemical formula 1, comprising the steps of: manufacturing a compound of chemical formula 3 by deoxidizing a compound of chemical formula 2 by using a reducing agent (S1); and turning the compound of chemical formula 3 into of a crystalline chemical formula 1 of (S)-form (S2). In the manufacturing method of the present invention, the compound of chemical formula 1 which is biomatoprost intermediate is easily obtained by using alcohol-based solvents at warm temperatures in a simple manner and thus a high purity biomatoprost can be manufactured by using the same.
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Paragraph 0043-0050
(2016/12/16)
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- Diastereoselective reduction of the enone intermediate of Travoprost
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A scalable process for the diastereoselective reduction of the prochiral enone intermediate 1 has been developed with DEANB/(R)-methyl CBS as reducing agent, to obtain the key intermediate alcohol 15R-isomer 2, used in a process for the manufacture of Travoprost (3). Various advantages of this process against the DMSB reduction assisted by (R)-methyl CBS have been studied. Specific comparison has been made to highlight the salient features of the chosen process on yield and optical purity with those of the DMSB reduction.
- Aswathanarayanappa, C.,Bodke, Yadav D.,Bheemappa, E.
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experimental part
p. 1085 - 1087
(2011/12/21)
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- PROCESS FOR THE PREPARATION OF F-SERIES PROSTAGLANDINS
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A process for the synthesis and purification of F-series prostaglandin compounds and synthetic intermediates used to prepare them. The synthetic intermediates are solid and may be purified by precipitation and therefore may form the representative F-series prostaglandin compounds such as latanoprost, bimatoprost, fluprostenol, cloprostenol, and substituted analogs therefrom in highly pure forms.
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Page/Page column 36-38; 41-42
(2011/05/05)
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- IMPROVED PROCESS FOR THE PREPARATION OF PROSTAGLANDINS AND ANALOGUES THEREOF
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The present invention relates to an improved process for the preparation of prostaglandin and prostaglandin analogues, particularly PGF2α derivatives.
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Page/Page column 14
(2010/11/03)
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- Bimatoprost crystalline form I
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The invention provides a novel polymorphic form I of crystalline bimatoprost, method for preparation thereof and new crystalline intermediates in the preparation. This form I of crystalline bimatoprost is used in purification of crude bimatoprost and in storage of bimatoprost as active pharmaceutical intermediate. Use of the physical form of bimatoprost in the manufacture of a medicament is also disclosed.
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Page/Page column 11-12
(2009/07/10)
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- Composition and method for the treatment of psoriasis
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The use of a prostaglandin A2 derivative, and prodrugs of the compound, for the manufacture of a medicament for the treatment and/or alleviation of psoriasis is presented, as well as a method of treatment, involving the topical application of such prostaglandins. Compositions containing a therapeutically active, and physiologically acceptable amount of the above compound or derivatives thereof, as such or in the form of a prodrug, in a suitable vehicle are also described. Importantly, the derivatives can be applied in therapeutically active amounts without or with only minimal side effects, such as hyperemia, irritation or pain.
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Page/Page column 4
(2008/06/13)
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- Phenyl-Substituted Prostaglandins: Potent and Selective Antiglaucoma Agents
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A series of phenyl-substituted analoques of prostaglandin F2α (PGF2α) were prepared and evaluated for ocular hypotensive effect and side effects in different animal models.In addition, the activity of the analogues on FP receptors was studied in vitro.The results were compared with those of PGF2α and its isopropyl ester.The phenyl-substituted PGF2α analogues exhibited good intraocular pressure reducing effect, were more selective, and exhibited a much higher therapeutic index in the eye than PGF2α or its isopropyl ester.The analogues exhibited high activity on FP receptors in a stereoselective manner for the 15a-hydroxyl group.
- Resul, Bahram,Stjernschantz, Johan,No, Kiyo,Liljebris, Charlotta,Selen, Goeran,et al.
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p. 243 - 248
(2007/10/02)
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- N-(Methanesulfonyl)-16-phenoxyprostaglandincarboxamides: Tissue-Selective, Uterine Stimulants
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In an effort to develop tissue-selective prostaglandin analogues resistant to the metabolic inactivating pathways of the natural materials, hybrid compounds modified both at C-1 with a sulfonimide moiety and in the n-amylcarbinol side chain with substituted phenoxy groups were synthesized and evaluated in a variety of in vitro and in vivo models.Several of these analogues exhibited potent, tissue-selective, uterine stimulant activity, a finding subsequently confirmed in clinical studies with one member of this series, N-(methanesulfonyl)-16-phenoxy-ω-tetranor-PGE2-carboxamide (CP-34089/ZK-57671, sulprostone).
- Schaaf, Thomas K.,Bindra, Jasjit S.,Eggler, James F.,Plattner, Jacob J.,Nelson, A. James,et al.
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p. 1353 - 1359
(2007/10/02)
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