- Preparation method of carboprost tromethamine intermediate
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The invention provides a preparation method of a carboprost tromethamine intermediate. The method comprises the following steps: A) carrying out an oxidation reaction on benzoyl corey lactone alcohol shown in a formula I under the action of a catalyst and an oxidizing agent to obtain benzoyl corey lactone aldehyde shown in a formula II; B) reacting the benzoyl corey lactone aldehyde as shown in the formula II with dimethyl (2-oxoheptyl) phosphonate under the action of alkali to obtain a 15-ketone crude product as shown in a formula III, and recrystallizing the 15-ketone crude product to obtain a 15-ketone pure product; and C) carrying out methylation reaction on the 15-ketone pure product to obtain the carboprost tromethamine intermediate as shown in a formula IV. According to the invention, the use of reagents with high toxicity and serious environmental pollution is avoided; when the carboprost intermediate 15-ketone is prepared, a mixed solvent is adopted for recrystallization, so that column chromatography is omitted, operation is easy and convenient, reagents are saved, and cost is reduced; and in the methylate preparation process, ultralow temperature is avoided, and the reaction time is shortened, so that the energy consumption is reduced, and the purity and the yield are relatively high.
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Paragraph 0076-0079
(2021/06/22)
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- Carprost tromethamine related impurity levobutyl 15-ketone and preparation method thereof
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The invention relates to the technical field of compounds and preparation thereof, in particular to a prostaglandin tromethamine related impurity levobutyl 15-ketone and a preparation method thereof.The method comprises the following steps that 1, in the presence of a fifth organic solvent, strong base is used for carrying out dehydrogenation reaction on methyl triphenyl phosphine halide, ethyl butyrate is added after the reaction is carried out for a certain period of time, and a reaction solution is obtained; continuously reacting for a certain time to obtain 1-triphenylphosphine- 2-pentanone; and (2) carrying out wittig reaction on the 1-triphenylphosphine- 2-pentanone obtained in the step (1) and a second organic solvent solution of benzoyl corey lactone aldehyde to obtain butyl-15 ketone. The method has the characteristics that the operation is simple and convenient, the safety is high, the yield and the purity of the obtained product are high under optimal conditions, the requirements for impurity research can be met, and the like.
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Paragraph 0041-0043
(2021/01/15)
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- Carboprost tromethamine related impurity L-amyl 15-ketone and preparation method thereof
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The invention relates to a carboprost tromethamine related impurity L-amyl 15-ketone and a preparation method thereof. The preparation method comprises the following steps of: (1) in the presence of afifth organic solvent, carrying out dehydrogenation reaction on methyl triphenyl phosphine halide by using strong base, adding ethyl valerate after reaction for a certain time, continuously reactingfor a certain time to obtain 1-triphenylphosphine 2-hexanone; and (2) carrying out wittig reaction on the 1-triphenylphosphine 2-hexanone obtained in the step (1) and a second organic solvent solutionof benzoyl corey lactone aldehyde to obtain a pentyl-15 ketone crude product. The method has the advantages of simple and convenient operation, high safety, and high yield and purity of an obtained product under optimal conditions, and can meet the requirements for impurity research.
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Paragraph 0025-0026; 0048-0053
(2021/01/04)
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- Synthetic method of alfaprostol
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The invention relates to the field of medicine preparation, and particularly relates to a synthetic method of alfaprostol. The synthesis method comprises the following steps: subjecting levobenzoyl corey lactone adopted as a raw material to oxidization by primary alcohol, and reaction with azido phosphate to obtain a compound a3; inducing chiral addition of the compound a3 and aldehyde by chiral ligand amine to generate a compound a4; performing reduction and a Wittig reaction to generate a compound a6; and finally, carrying out methylation reaction on terminal carboxyl of the compound a6 to prepare the alfaprostol. According to the synthesis method of the alfaprostol, provided by the invention, the levobenzoyl corey lactone is directly used as a raw material, the raw material is simple and easy to obtain, and the operation is simple; reaction steps are short, the yield of the whole process route is about 55-60%, and industrial production is easy to realize; the process conditions of each step of reaction are easy to realize, post-treatment is simple, and intermediates are easy to purify; only one-step chiral reaction is adopted, isomer impurities are easy to control, and the obtained product is high in optical purity.
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Paragraph 0084-0086
(2019/12/02)
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- 15-ketone preparation method
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The present invention relates to a drug intermediate 15-ketone preparation method in chemical field. The preparation method comprises the following steps: (1) (-)-Corey lactone benzoate, an oxidizing agent and a catalyst are added into a first organic solvent for oxidation to obtain a reaction solution A; (2) after a dilute acid is dropwise added into the reaction solution A obtained in the step (1), the solution is stirred and filtered, the filtrate is extracted directly with the first organic solvent, an organic phase is washed with water, dehydrated with a desiccant and filtered to obtain a (-)-Corey lactone benzoate aldehyde solution; (3) Wittig reagent is added into the (-)-Corey lactone benzoate aldehyde solution obtained in the step (2) for Wittig reaction to obtain a reaction solution B, the reaction solution B is concentrated, a second organic solvent is added, and after cooling and crystallization, a crystallization liquid is obtained; and (4) the crystallization liquid obtained in the step (3) is filtered, the filter cake is washed with a third organic solvent, the filter cake is dissolved by the first organic solvent for impurity removal, and after filteration and concentration, an oil matter is obtained. The drug intermediate 15-ketone preparation method has the advantages of good product quality and the like.
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Paragraph 0014
(2016/10/10)
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- PREPARATION OF LUBIPROSTONE
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Aspects of the present application relate to process for the preparation of lubiprostone.
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Paragraph 0094
(2013/07/25)
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- Improved Process for the Production of Prostaglandins and Prostaglandin Analogs
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The present invention relates to an improved process for the production of prostaglandins and prostaglandin analogs. In particular, this invention relates to the production of prostaglandins of the PGF2α-series, including latanoprost, travoprost, and bimatoprost, which are active pharmaceutical ingredients used for the reduction of elevated intraocular pressure in patients with glaucoma and ocular hypertension.
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Page/Page column 53
(2010/01/29)
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- An improved synthesis of the selective EP4 receptor agonist ONO-4819
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(Chemical Equation Presented) An improved synthesis of the highly selective EP4-receptor agonist ONO-4819 has been developed. The previous synthesis suffered from several drawbacks, in which a critical one is the difficulty in the removal of byproducts leading to unsatisfactory quality of the active pharmaceutical ingredient (API). Furthermore, on stereoselective reduction of an enone intermediate by binaphthol-modified lithium aluminum hydride, low concentration of the reaction conditions and tedious purification procedures to remove excess binaphthol were critical issues for the manufacturing process of the API. In the improved process,we have developed improved conditions using γ-thiobutyrolactone as sulfur source instead of potassium thioacetate to introduce the sulfur-containing C4 side chain without formation of byproducts. For stereoselective synthesis of the chiral alcohol, (-)-DIP-chloride reduction is found to be the best method, which can improve not only the enantioselectivity but also the workload for removing the chiral modifier in a purification process. Furthermore, benzoyl and tert-butyldimethylsilyl groups as protecting groups for hydroxyl functions were used for precise process controls of all intermediates. By changing these protecting groups, the purity of ONO-4819 was strictly controlled through crystalline intermediates. Thus, an improved robust process for ONO-4819 with a high chemical purity was developed. 2009 American Chemical Society.
- Ohta, Chisa,Kuwabe, Shin-Itsu,Shiraishi, Tai,Shinohara, Ikuo,Araki, Hiroshi,Sakuyama, Shigeru,Makihara, Takayuki,Kawanaka, Yasufumi,Ohuchida, Shuichi,Takuya, Seko
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experimental part
p. 8298 - 8308
(2010/02/17)
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- Method for preparing prostaglandin derivative
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A method for preparing a prostaglandin derivative represented by the following general formula (I): (wherein Ph represents phenyl group, R1 represents a C1-7 alkyl group, a C1-7 alkenyl group, phenyl group, or benzyl group), which comprises the successive steps (1) to (8) described in the specification, or any one step or two or more successive steps selected from the group consisting of the steps (1) to (8). A method for efficiently, inexpensively and safely preparing prostaglandin derivatives, of which typical example is latanoprost, is provided.
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Page/Page column 8
(2008/06/13)
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- METHOD FOR PREPARING PROSTAGLANDIN DERIVATIVE
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A method for preparing a prostaglandin derivative represented by the following general formula (I): (wherein Ph represents phenyl group, R1 represents a C1-7 alkyl group, a C1-7 alkenyl group, phenyl group, or benzyl group), which comprises the successive steps (1) to (8) described in the specification, or any one step or two or more successive steps selected from the group consisting of the steps (1) to (8). A method for efficiently, inexpensively and safely preparing prostaglandin derivatives, of which typical example is latanoprost, is provided.
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Page/Page column 5-6
(2008/06/13)
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- Novel 5-cyano-prostacyclin derivatives as agents for the treatment of autoimmune diseases
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This invention is directed to compounds of formula (I): where A, B, D, E, m, and R1-R5 are as described herein, as single stereoisomers or as mixtures of stereoisomers, or pharmaceutically acceptable salts, clathrates, or prodrugs thereof, which compounds are useful in treating autoimmune diseases. Pharmaceutical compositions comprising the compounds of the invention and methods of preparing the compounds of the invention are also disclosed.
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Page/Page column 10
(2008/12/07)
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- Novel 5-cyano-prostacyclin derivatives and their use as agents for the treatment of influenza a viral infection
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This invention is directed to compounds of formula (I): where A, B, D, E, m, and R1 - R5 are as described herein, as single stereoisomers or as mixtures of stereoisomers, or pharmaceutically acceptable salts, clathrates, or prodrugs thereof, which compounds are useful in treating respiratory diseases associated with influenza A viruses, such as for example H5N1 and its mutations. Pharmaceutical compositions comprising the compounds of the invention and methods of preparing the compounds of the invention are also disclosed.
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Page/Page column 14
(2008/12/07)
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- Novel 5-cyano-prostacyclin derivatives as agents for the treatment of influenza a viral infection
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This invention is directed to compounds of formula (I): where A, B, D, E, m, and R1-R5 are as described herein, as single stereoisomers or as mixtures of stereoisomers, or pharmaceutically acceptable salts, clathrates, or prodrugs thereof, which compounds are useful in treating respiratory diseases associated with influenza A viruses, such as for example H5N1 and its mutations. Pharmaceutical compositions comprising the compounds of the invention and methods of preparing the compounds of the invention are also disclosed.
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Page/Page column 10
(2008/12/07)
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- NOVEL 5-CYANO-PROSTACYCLIN DERIVATIVES AND THEIR USE AS AGENTS FOR THE TREATMENT OF AUTOIMMUNE DISEASES
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This invention is directed to compounds of formula (I): where A, B, D, E, m, and R1 - R5 are as described herein, as single stereoisomers or as mixtures of stereoisomers, or pharmaceutically acceptable salts, clathrates, or prodrugs thereof, which compounds are useful in treating autoimmune diseases. Pharmaceutical compositions comprising the compounds of the invention and methods of preparing the compounds of the invention are also disclosed.
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Page/Page column 21
(2008/12/04)
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- Effect of allylic and homoallylic substituents on cross metathesis: syntheses of prostaglandins F2α and J2
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We describe the effect of allylic (C15) and homoallylic (C11) substituents on cross metathesis reactions with Corey lactone derivatives. This strategy has led to the successful syntheses of PGF2α and PGJ2.
- Sheddan, Neil A.,Arion, Vladimir B.,Mulzer, Johann
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p. 6689 - 6693
(2007/10/03)
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- Stereocontrol in organic synthesis using silicon-containing compounds. A formal synthesis of prostaglandins controlling the stereochemistry at C-15 using a silyl-to-hydroxy conversion following a stereochemically convergent synthesis of an allylsilane
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Hydrosilylation of isoprene with chloro(diphenyl)silane gave (Z)-chloro(2-methylbut-2-enyl)-diphenylsilane 7. The cuprate reagent derived from this chloride underwent conjugate addition to methyl cinnamate 11, 1,2-silylcupration with hex-1-yne 16 and allene 18, and allylic displacement reactions with 1-vinylcyclohexyl acetate 20 and (Z)-1-cyclopentyloct-2-en-1-yl acetate 22. The silyl group in each of the products was converted into a hydroxy, with the removal of the 2-methylbut-2-enyl group taking place under much milder acidic conditions than those needed to remove the phenyl group from the dimethyl(phenyl)silyl group, and making this group suitable for the conversion of an allylsilane into an allyl alcohol. A stereospecifically anti conjugate displacement of the allylic benzoate group in (Z)-(1S,5R,6R,7R,1′S)-7-benzoyloxy-6-(1′-benzoyloxyoct-2′- enyl)-2-oxabicyclo[3.3.0]octan-3-one 52, and a stereospecifically syn conjugate displacement of the carbamate group in (Z)-(1S,5R,6R,7R,1′R)-7-benzoyloxy-6-(1′-N-phenylcarbamoyloxyoct- 2′-enyl)-2-oxabicyclo[3.3.0]octan-3-one 51, gave stereo-convergently the same allylsilane (1′ E,2″Z)-(1S,5S,6R,7R,3′S)-7-benzoyloxy-6-[3′-(2″- methylbut-2″-enyl)-diphenylsilyloct-1′-enyl]-2-oxabicyclo[3.3.0] octan-3-one 53. Silyl-to-hydroxy conversion gave the allyl alcohol (E)-(1S,5S,6R,7R,3′S)-7-benzoyloxy-6-(3′-hydroxyoct-1′-enyl)- 2-oxabicyclo[3.3.0]octan-3-one 54, having the relative and absolute stereochemistry at C-15 of the prostaglandins.
- Fleming, Ian,Winter, Stephen B. D.
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p. 2687 - 2700
(2007/10/03)
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