- EFFICIENT CRYSTALLIZATION PROCESS FOR PREPARING ULTRAPURE TREPROSTINIL AND CRYSTAL PREPARED THEREFROM
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There is provided a crystalline Form I of anhydrous Treprostinil and processes for the preparation thereof. The crystalline Form I of anhydrous Treprostnil is a stable crystalline form, which can provide steady physicochemical properties for pharmaceutical formulations, and is advantageous widely and safety used in storage, shipment, and handling for commercially considerations.
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Paragraph 0083-0084
(2021/06/26)
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- Synthetic routes to treprostinil N-acyl methylsulfonamide
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The synthesis of the prodrug candidate, treprostinil N-acyl methylsulfonamide 5 was accomplished from treprostinil 2 utilising protecting group strategies. A more direct synthesis for the prodrug was also achieved using a treprostinil triol precursor 12 and bromoacetyl acylmethylsulfonamide 14. The overall yield of treprostinil N-acyl sulfonamide 5 directly from the triol precursor 12 is similar to the protecting group strategies because deprotonation of the acidic proton in the bromoacetyl acylmethylsulfonamide 14 reduces electrophilicity. However, the more direct route using the treprostinil triol precursor holds greater promise as a strategy to prepare a wide range of treprostinil prodrug candidates. Treprostinil N-acyl methylsulfonamide prodrug 5 exhibited a 30-fold decrease in the potency at the human prostacyclin (IP) receptor compared to treprostinil 2 in an in vitro cyclic AMP assay.
- Brocchini, Steve,Clapp, Lucie H.,Laing, Peter,Picken, Christina,Shen, Lei
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- Synthesis of treprostinil: Key claisen rearrangement and catalytic pauson-khand reactions in continuous flow
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A new synthesis of treprostinil is described using a plug flow reactor in two of the key steps. First, a Claisen rearrangement reaction is described in scaled flow at multigram amounts. Yields and selectivity of this step are sharply improved compared to those from previous syntheses. Second, the key Pauson-Khand reaction in flow is described under catalytic conditions with 5 mol% of cobalt carbonyl and only 3 equiv. of CO. Scaling up of this reaction safely ensures a good yield of an advanced intermediate which is transformed into treprostinil in three steps. Other improvements are the introduction of the carboxymethyl chain into the phenol from the beginning to reduce the protection-deprotection steps. The synthesis is completed in 14% global yield after 12 linear steps from (S)-epichlorhydrin.
- García-Lacuna, Jorge,Domínguez, Gema,Blanco-Urgoiti, Jaime,Pérez-Castells, Javier
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p. 9489 - 9501
(2019/11/14)
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- Synthesis method of treprostinil
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The invention discloses a synthesis method of treprostinil. The synthesis method comprises the following main steps: connecting acetal, hydrolyzing the acetal and oxidizing aldehyde hydrate. On the basis of the prior art, the synthesis method disclosed by the invention has the advantages that raw material ratio is optimized by virtue of a large number of experiments and exploration, so that reaction conditions are milder, reaction time is shortened, yield of a product is improved, and the yield reaches up to 68%; the technology is simple, industrialization large-scale production can be realized, and good economic benefit can be provided for an enterprise, so that the synthesis method disclosed by the invention has a broad prospect.
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Paragraph 0043; 0047; 0056; 0060; 0061; 0062-0077
(2018/03/28)
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- Process for Preparing Treprostinil and Intermediate Therefor
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The present invention relates to a synthesis method of high-purity treprostinil, and an intermediate for the same. According to the synthesis method of the present invention, high-purity treprostinil can be synthesized in an economical and efficient manner by using intramolecular Friedel-Crafts allylic alkylation. Accordingly, the synthesis method of the present invention may be effectively used for commercial mass-production of treprostinil.COPYRIGHT KIPO 2017
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- Process for Preparing Treprostinil
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The present invention relates to a synthesis method of treprostinil, and more specifically, to a method of synthesizing high-purity treprostinil in an economical and efficient manner; and to high-purity treprostinil crystals synthesized by the method. According to the synthesis method of the present invention, treprostinil having a purity of 99.9% or more can be produced in an economical and efficient manner.COPYRIGHT KIPO 2017
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Paragraph 0027-0028; 0071-0072
(2018/02/20)
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- Intermediate for preparing treprostinil, preparation method of intermediate and method for preparing treprostinil through intermediate
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The invention relates to an intermediate for preparing treprostinil, a preparation method of the intermediate and a method for preparing the treprostinil through the intermediate. Specifically, the invention relates to a compound which is shown as a formula (VI) and is used for preparing the treprostinil (shown as a formula (I)), a preparation method of the compound and a method for preparing the treprostinil through the compound. The method for preparing the treprostinil comprises the following steps: carrying out reduction and hydroxyl removal protection on the compound shown as the formula (VI) to obtain a compound shown as a formula (III); taking the compound shown as the formula (III) and chloroacetonitrile to react and hydrolyzing to prepare the treprostinil shown as the formula (I). The method is simple and convenient to operate, high in synthesis yield and suitable for large-scale production. (The formula (I) is shown in the description, the formula (III) is shown in the description and the formula (VI) is shown in the description.).
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- NOVEL INTERMEDIATE FOR SYNTHESIZING TREPROSTINIL DIETHANOLAMINE AND METHOD FOR PREPARING THE SAME
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The present invention relates to a method for treprostinil diethanolamine synthesis. The present invention also relates to a novel intermediate used in the method for treprostinil diethanolamine synthesis. The novel intermediate is shown in the following formula (II): wherein R1 and R2 are described in the description.
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Paragraph 0059; 0077; 0078
(2016/06/28)
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- PROCESS FOR THE PREPARATION OF TREPROSTINIL
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The invention provides a new process for the preparation of treprostinil of formula (I) and its salts using several new intermediates during the building of the ringsystem.
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- AMINE SALTS OF A PROSTACYCLIN ANALOG
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The present invention provides amine salts of the prostacyclin analogue of Formula I and processes for generating these amine salts.
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- METHODS OF SYNTHESIZING A PROSTACYCLIN ANALOG
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The present invention provides processes for preparing a prostacyclin analogue of Formula (I) or a pharmaceutically acceptable salt thereof, wherein R10 is a linear or branched C1-6 alkyl. The processes of the present invention comprise steps that generate improved yields and fewer byproducts than traditional methods. The processes of the present invention employ reagents (e.g., the oxidizing reagent) that are less toxic that those used in the traditional methods (e.g., oxalyl chloride). Many of the processes of the present invention generate intermediates with improved e.e. and chemical purity; thereby eliminating the need of additional chromatography steps. And, the processes of the present invention are scalable to generate commercial quantities of the final compound.
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- Process for the preparation of treprostinil and derivatives thereof
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A method for the preparation of treprostinil and its derivatives is described. In contrast to prior art, this method utilizes an easily scalable enzymatic resolution of a key intermediate for making these compounds. Another significant improvement of the described method over prior methods is the regioselective Claisen rearrangement of a 5-allyloxy-benzaldehyde precursor, which is facilitated by a bromo substituent in 2-position.
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- Synthesis Of Treprostinil And Intermediates Useful Therein
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Treprostinil is prepared by a process which involves Pauson-Khan cyclization of an an alkene-substituted, alkyne-substituted benzene corresponding to formula: (I) where PMB represents para-methoxy benzyl protecting group and R1 and R2 are alcohol protecting groups. Following cyclization, the resulting compound can be subjected to several chemical trans-formations followed by alkylation, hydrolysis and salt formation to yield treprostinil sodium. The use of para-methoxybenzyl group as the phenolic protecting group confers several process advantages that result in simplified purification of the final product and improved yields.
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- IMPROVED PROCESS FOR THE PREPARATION OF TREPROSTINIL AND DERIVATIVES THEREOF
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An improved method for the preparation of treprostinil and its derivatives is described. In contrast to prior art, this method utilizes an easily scalable enzymatic resolution of a key intermediate for making these compounds. Another significant improvement of the described method over prior methods is the regioselective Claisen rearrangement of a 5-allyloxy-benzaldehyde precursor, which is facilitated by a bromo substituent in 2-position.
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Page/Page column 27-28
(2014/01/07)
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- Intermediates for the synthesis of benzindene prostaglandins and preparations thereof
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Novel processes for preparing optically active cyclopentanones 1 which are useful for the preparation of benzindene Prostaglandins and novel cyclopentanones are provided. The invention also provides novel processes of preparing benzindene Prostaglandins and novel intermediates for benzindene Prostaglandins.
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- INTERMEDIATES FOR THE SYNTHESIS OF BENZINDENE PROSTAGLANDINS AND PREPARATIONS THEREOF
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Novel processes for preparing optically active cyclopentanones 1 which are useful for the preparation of benzindene Prostaglandins and novel cyclopentanones are provided. The invention also provides novel processes of preparing benzindene Prostaglandins and novel intermediates for benzindene Prostaglandins.
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- PROCESS FOR TREPROSTINIL SALT PREPARATION
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Disclosed is a process for preparing a treprostinil salt. The process involves the step of dissolving treprostinil in a water-miscible organic solvent to form a treprostinil solution. The treprostinil solution is reacted with an aqueous basic solution containing an alkali metal cation to form treprostinil salt. Allowing crystallization of the treprostinil salt to take place, and then collecting the treprostinil salt formed.
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Page/Page column 10
(2012/07/14)
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- SYNTHESIS OF TREPROSTINIL AND INTERMEDIATES USEFUL THEREIN
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Treprostinil is prepared by a process which involves Pauson - Khan cyclization of an an alkene-substituted, alkyne-substituted benzene corresponding to formula : (I) where PMB represents para-methoxy benzyl protecting group and R1 and R2 are alcohol protecting groups. Following cyclization, the resulting compound can be subjected to several chemical transformations followed by alkylation, hydrolysis and salt formation to yield treprostinil sodium. The use of para-methoxybenzyl group as the phenolic protecting group confers several process advantages that result in simplified purification of the final product and improved yields.
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- TREPROSTINIL PRODUCTION
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A method is disclosed for preparing a synthetic intermediate for treprostinil via a stereoselective alkyne addition reaction using a chiral inducing agent. Also described are methods of preparing treprostinil or a pharmaceutically acceptable salt thereof comprising the alkyne addition reaction as well as novel intermediates useful for synthesis prostacyclin derivatives. A functional alcohol protecting group protects the alcohol group from participating in reactions that are occurring in other parts of the molecule. The intermediate is later deprotected prior to conversion and hydrolyzing to obtain the final treprostinil product.
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Page/Page column 38-39
(2011/12/14)
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- PROCESS TO PREPARE TREPROSTINIL, THE ACTIVE INGREDIENT IN REMODULIN
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This present invention relates to an improved process to prepare prostacyclin derivatives. One embodiment provides for an improved process to convert benzindene triol to treprostinil via salts of treprostinil and to purify treprostinil.
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Page/Page column 7-8
(2009/07/10)
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- TREPROSTINIL FORMULATION
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There is provided a stable monohydrate form of treprostinil and pharmaceutical formulation comprising the same, method of making and using the same.
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Page/Page column 4
(2009/12/04)
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- The Intramolecular Asymmetric Pauson-Khand Cyclization As A Novel and General Stereoselective Route to Benzindene Prostacyclins: Synthesis of UT-15 (Treprostinil)
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A general and novel solution to the synthesis of biologically important stable analogues of prostacyclin PGI2, namely benzindene prostacyclins, has been achieved via the stereoselective intramolecular Pauson-Khand cyclization (PKC). This work illustrates for the first time the synthetic utility and reliability of the asymmetric PKC route for synthesis and subsequent manufacture of a complex drug substance on a multikilogram scale. The synthetic route surmounts issues of individual step stereoselectivity and scalability. The key step in the synthesis involves efficient stereoselection effected in the PKC of a benzoenyne under the agency of the benzylic OTBDMS group, which serves as a temporary stereodirecting group that is conveniently removed via benzylic hydrogenolysis concomitantly with the catalytic hydrogenation of the enone PKC product. Thus the benzylic chiral center dictates the subsequent stereochemistry of the stereogenic centers at three carbon atoms (C3a, C9a, and C1).
- Moriarty, Robert M.,Rani, Neena,Enache, Livia A.,Rao, Munagala S.,Batra, Hitesh,Guo, Liang,Penmasta, Raju A.,Staszewski, James P.,Tuladhar, Sudersan M.,Prakash, Om,Crich, David,Hirtopeanu, Anca,Gilardi, Richard
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p. 1890 - 1902
(2007/10/03)
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