- Direct and Chemoselective Electrophilic Monofluoromethylation of Heteroatoms (O-, S-, N-, P-, Se-) with Fluoroiodomethane
-
The commercially available fluoroiodomethane represents a valuable and effective electrophilic source for transferring the CH2F unit to a series of heteroatom-centered nucleophiles under mild basic conditions. The excellent manipulability offered by its liquid physical state (bp 53.4 °C) enables practical and straightforward one-step nucleophilic substitutions to retain the chiral information embodied, thus allowing it to overcome de facto the requirement for fluoromethylating agents with no immediate access. The high-yielding methodology was successfully applied to a variety of nucleophiles including a series of drugs currently in the market.
- Senatore, Raffaele,Malik, Monika,Spreitzer, Markus,Holzer, Wolfgang,Pace, Vittorio
-
supporting information
p. 1345 - 1349
(2020/02/13)
-
- Fluticasone propionate synthesis method
-
The embodiments of the invention provide a fluticasone propionate synthesis method, which comprises: a thioesterification reaction: adding a first intermediate, an first organic alkali, dimethylaminothioformyl chloride, sodium iodide and a first organic solvent into a reaction kettle, carrying out a reaction, adding a polar aprotic solvent and water after the reaction, carrying out cooling crystallizing, filtering, washing, and drying to obtain a second intermediate; an alcoholysis reaction: adding the second intermediate, a first inorganic alkali and a second organic solvent into a reaction kettle, carrying out a reaction, adding water or water and an extracting agent after the reaction, extracting, taking the water phase, adding hydrochloric acid in a dropwise manner, crystallizing, filtering, washing, and drying to obtain a third intermediate; and a substitution esterification reaction: adding the third intermediate, a second inorganic alkali and a third organic solvent into a reaction kettle, adding fluorobromomethane, adding hydrochloric acid in a dropwise manner, crystallizing, filtering, washing, and drying to obtain fluticasone propionate. According to the embodiments of the invention, the low-cost production can be realized, and the reaction yield and the purity are high.
- -
-
Page/Page column 7-15
(2020/02/10)
-
- Preparation method of fluticasone propionate
-
The invention provides a preparation method of fluticasone propionate. The preparation method comprises the following steps that (1) a compound 5 is hydrolyzed in the presence of a base and an alcoholsolvent to obtain a compound 6; and (2) the compound 6 reacts with fluorohalomethane to obtain fluticasone propionate (compound 1) under the condition that a reducing salt is used as a catalyst. According to the preparation method of fluticasone propionate, the reducing inorganic salt is used as the catalyst to greatly reduce the formation of impurities, such as disulfide impurities, sulfhydryl oxide impurities and haloalkylate impurities introduced by sulfhydryl oxides.
- -
-
Paragraph 0037; 0046-0052
(2019/10/29)
-
- Discovery of Pyrophosphate Diesters as Tunable, Soluble, and Bioorthogonal Linkers for Site-Specific Antibody-Drug Conjugates
-
As part of an effort to examine the utility of antibody-drug conjugates (ADCs) beyond oncology indications, a novel pyrophosphate ester linker was discovered to enable the targeted delivery of glucocorticoids. As small molecules, these highly soluble phosphate ester drug linkers were found to have ideal orthogonal properties: robust plasma stability coupled with rapid release of payload in a lysosomal environment. Building upon these findings, site-specific ADCs were made between this drug linker combination and an antibody against human CD70, a receptor specifically expressed in immune cells but also found aberrantly expressed in multiple human carcinomas. Full characterization of these ADCs enabled procession to in vitro proof of concept, wherein ADCs 1-22 and 1-37 were demonstrated to afford potent, targeted delivery of glucocorticoids to a representative cell line, as measured by changes in glucocorticoid receptor-mediated gene mRNA levels. These activities were found to be antibody-, linker-, and payload-dependent. Preliminary mechanistic studies support the notion that lysosomal trafficking and enzymatic linker cleavage are required for activity and that the utility for the pyrophosphate linker may be general for internalizing ADCs as well as other targeted delivery platforms.
- Kern, Jeffrey C.,Cancilla, Mark,Dooney, Deborah,Kwasnjuk, Kristen,Zhang, Rena,Beaumont, Maribel,Figueroa, Isabel,Hsieh, SuChun,Liang, Linda,Tomazela, Daniela,Zhang, Jeffrey,Brandish, Philip E.,Palmieri, Anthony,Stivers, Peter,Cheng, Mangeng,Feng, Guo,Geda, Prasanthi,Shah, Sanjiv,Beck, Andrew,Bresson, Damien,Firdos, Juhi,Gately, Dennis,Knudsen, Nick,Manibusan, Anthony,Schultz, Peter G.,Sun, Ying,Garbaccio, Robert M.
-
p. 1430 - 1445
(2016/02/18)
-
- PROCESS FOR PREPARING FLUTICASONE PROPIONATE/FUROATE
-
The present invention relates to an improved process for the preparation of substituted Fluticasone derivatives. The invention also reveals the processes for the purification of Fluticasones and related intermediates to provide the highly pure product.
- -
-
Paragraph 0057
(2014/06/11)
-
- Improved synthesis of fluticasone propionate
-
A novel process for the preparation of fluticasone propionate (1), a corticosteroid, is reported. In this paper, compound 2 was used as starting material to prepare 6 by using NaClO or NaBrO which was much cheaper than H 5IO6 as an oxidizing agent. Furthermore, toxic, expensive, and pollutive BrCH2F was replaced by AgNO3 and Selectfluor in decarboxylative fluorination.
- Zhou, Jiadi,Jin, Can,Su, Weike
-
p. 928 - 933
(2014/10/16)
-
- Method for the Production of Fluoromethyl Esters of Androstan-17 beta Carboxylic Acids
-
Described herein are processes for the preparation of monofluoromethylated organic biologically active compounds, starting from protected intermediates and/or reagents to obtain compounds such as fluticasone propionate and fluticasone furoate, in presence of decarboxylating reagents XeF2 and BrF3, or using FCH2SH as a reagent.
- -
-
Paragraph 0057
(2014/07/23)
-
- METHOD FOR THE PRODUCTION OF FLUOROMETHYL - ESTERS OF ANDROSTAN- 17 - BETA - CARBOXYLIC ACIDS
-
The present invention relates to a method of preparing an organic biologically active compound of formula (I), wherein R1, R2, R3, R4,. X1, X2 and X3 are as defined in the specification, to certain novel intermediates obtainable from such a method and their use.
- -
-
Page/Page column 14
(2012/12/13)
-
- METHOD FOR MONOFLUOROMETHYLATION OF ORGANIC SUBSTRATES TO PREPARE BIOLOGICALLY ACTIVE ORGANIC COMPOUNDS
-
The present invention describes a process for the preparation of monofluoromethylated organic biologically active compounds using monofluoromethylated reagents. Fluticasone Propionate and Fluticasone Furoate can be prepared using, for example, S-monofluoromethyl-S-phenyl-2,3,4,5- tetramethylphenylsulfonium tetrafluoroborate as monofluoromethylating reagent instead of bromofluoromethane.
- -
-
Page/Page column 5; 6
(2011/12/14)
-
- NOVEL PROCESS AND INTERMEDIATES
-
The present invention relates to a process for the preparation of steroidal 17β-carboxylic thioates. More particularly the present invention relates to a convenient and efficient synthesis of steroidal 17β-carboxylic thioates, such as fluticasone propionate I, using soluble mixed fluorides to introduce fluorine by displacing an appropriate leaving group X in compounds II resulting in selective and controlled fluorination. The present invention also relates to intermediates II and their preparation.
- -
-
Page/Page column 12
(2009/07/18)
-
- METHOD FOR PREPARATION OF FLUTICASONE PROPIONATE
-
Taught is a method for preparing S-fluoromethyl-6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxoandrosta-1,4-diene-17β-carbothioate (fluticasone propionate). The present method is simple, convenient, and mild, yields highly pure product, and is suitable for use commercially on a large scale.
- -
-
Page/Page column 2
(2008/12/05)
-
- METHOD FOR THE PREPARATION OF FLUTICASONE PROPIONATE
-
Taught is a method for preparing S-fluoromethyl-6α,9α- difluroro-11β-hydroxy-16α-methyl-17α- propionyloxy-3-oxoandrosta-1,4-diene-17β-carbothioate (fluticasone propionate). The present method is simple, convenient, and mild, yields highly pure product, and is suitable for use commercially on a large scale.
- -
-
Page/Page column 6
(2010/11/30)
-
- NOVEL PROCESS AND INTERMEDIATES
-
The present invention relates to a process for the preparation of steroidal 17β-carboxylic thioates. More particularly the present invention relates to a convenient and efficient synthesis of steroidal 17β-carboxylic thioates, such as fluticasone propionate formula (I), using soluble mixed fluorides to introduce fluorine by displacing an appropriate leaving group X in compounds formula (II) resulting in selective and controlled fluorination. The present invention also relates to intermediates formula (II) and their preparation.
- -
-
Page/Page column 27; 30
(2008/06/13)
-
- Convenient synthesis of s-fluoromethyl 6alpha, 9alpha-difluoro-11beta-hydroxy-16alpha-methyl-17alpha-propionyloxy-3-oxoandrosta-1,4-diene-17beta-carbothioate
-
The present invention provides a convenient process for the preparation of S-fluoromethyl 6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxoandrosta-1,4-diene-17β-carbothioate, a compound of formula 1, comprising (a) treating 17β-[(N,N-dimethylcarbamoyl)thio]carbonyl-6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxoandrosta-1,4-diene, a compound of formula 3 with alkali metal carbonate-alcohol system to obtain 6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxoandrosta-1,4-diene-17β-carbothioic acid, a compound of formula 4; (b) reacting the compound of formula 4 with bromofluoromethane to yield the compound of formula 1. The present invention also provides an improved process for preparation of compound of formula 1 comprising (a) reacting 6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17-(propionyloxy)androsta-1,4-dien-17β-carboxylic acid, a compound of formula 2, with N,N-dimethylthiocarbamoyl chloride in an inert aprotic solvent in the presence of an iodide catalyst and a base to give a compound of formula 3, (b) reacting the compound of formula 3 with a hydrosulfide reagent and bromofluromethane to obtain a compound of formula 1.
- -
-
Page/Page column 9
(2010/02/14)
-
- Thiocarboxylic acid organic salts and processes utilizing the same
-
The invention provides a thiocarboxylic acid organic salt of the formula: wherein B is an organic base.
- -
-
-
- Thiocarboxylic acid organic salts and processes utilizing the same
-
The invention provides a thiocarboxylic acid organic salt of the formula: wherein B is an organic base.
- -
-
Page/Page column 4
(2010/02/07)
-
- Process for the preparation of steroidal 17 beta-carbothioates
-
A novel method for the conversion of steroidal 17β-carboxylic acids to carbothioates such as fluticasone propionate via novel in situ generated 17β-carboxy imidazolyl- or succinimidyl esters.
- -
-
-
- Administration of medicinal dry powders
-
A method as well as a therapeutic metered combined dose are disclosed for a combined administration of medicinal dry powders. A metered medicinal dry powder combined dosage comprising at least two medicaments of separate dry powder formulations is prepared, whereby the metered powder quantity per medicament is deposited in a dose forming step creating the medicinal combined dose. The deposits of the at least two medicaments are suitably kept separated from each other, such that the medicaments cannot detrimentally interact after forming of the combined dose, and the medicinal combined dose is introduced into an inhaler device for a delivery of the powder dose during the course of a single inhalation. The therapeutic metered medicinal, combined dosage of finely divided dry medication powders disclosed comprises metered quantities of at least two medicaments, separately deposited and the medicinal combined dosage is adapted for a user initiated delivery of the dosage during a single inhalation through an inhaler device. The at least two medicaments of the medicinal combined dosage will generally be aerosolized simultaneously or sequentially during the inhalation such that a large proportion of each medicament will settle in the intended target area of the airways and lungs of a user.
- -
-
-
- 17.BETA- (ALPHA-HYDROXY) -ESTERS OF ANDROSTANES AS INTERMEDIATES FOR THE PREPARATION FOR THE PREPARATION OF 17Β-FLUORINATED-ANDROSTANE ESTERS
-
Process for the preparation of polyhalogenated steroids, in particular of androstanic fluoro derivatives corticosteroids by means of the formation of new androstanic S-hydroxy alkyl or aralkyl-17-carbothioate intermediates.
- -
-
-
- Automated radiosynthesis of no-carrier-added [S-fluoromethyl-18F] fluticasone propionate as a radiotracer for lung deposition studies with PET
-
Fluticasone propionate [(S)-fluoromethyl-6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α -(propionyloxy)-androsta-1,4-diene-17β-carbothioate; FP] is a potent anti-inflammatory steroid with several therapeutic indications, including use as an anti-asthmatic drug when administered as sized particles by inhalation from a pressurised metered-dose inhaler (pMDI). FP was successfully labelled with fluorine-18 (t( 1/4 ) = 109.6 min: β+ = 100%) by displacement of tosylate with cyclotron-produced no-carrier-added [18F]fluoride in an (S)-tosylmethyl precursor prepared from the known (S)-chloromethyl analogue of FP. Radiochemically pure [S-/fluoromethyl-18]FP was separated by reverse phase HPLC in 35% radiochemical yield (decay-corrected) within 80 min from the end of radionuclide production (as verified by, radio-HPLC, LC-MS and LC-NMR). The radiosynthesis was automated for the safe production of high radioactivities (20-50 mCi) of [18F]FP in a lead-shielded hot-cell for subsequent incorporation into formulated FP particles within a pMDI and subsequent study of FP deposition in human lung using positron emission tomography (PET).
- Aigbirhio, Franklin I.,Carr, Richard M.,Pike, Victor W.,Steel, Colin J.,Sutherland, Derek R.
-
p. 567 - 584
(2007/10/03)
-
- Synthesis and structure-activity relationships in a series of antiinflammatory corticosteroid analogues, halomethyl androstane-17β- carbothioates and -17β-carboselenoates
-
The preparation and topical antiinflammatory potencies of a series of halomethyl 17α-(acyloxy)-11β-hydroxy-3-oxoandrosta-1,4-diene-17β- carbothioates, carrying combinations of 6α-fluoro, 9α-fluoro, 16-methyl, and 16-methylene substituents, are described. Key synthetic stages were the preparation of carbothioic acids and their reaction with dihalomethanes. The carbothioic acids were formed from 17β-carboxylic acids by initial reaction with dimethylthiocarbamoyl chloride followed by aminolysis of the resulting rearranged mixed anhydride with diethylamine, or by carboxyl activation with 1,1'-carbonyldiimidazole (CDI) or 2-fluoro-N-methylpyridinium tosylate (FMPT) and reaction with hydrogen sulfide, the choice of reagent being governed by the 17α-substituent. Carboxyl activation with FMPT and reaction with sodium hydrogen selenide led to the halomethyl 16-methyleneandrostane-17β- carboselenoate analogues. Anti-inflammatory potencies were measured in humans using the vasoconstriction assay and in rats and mice by a modification the Tonelli croton oil ear assay. Best activities were shown by fluoromethyl and chloromethyl carbothioates with a 17α-propionyloxy group. S-Fluoromethyl 6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-(propionyloxy)androsta- 1,4-diene-17β-carbothioate (fluticasone propionate, FP) was selected for clinical study as it showed high topical antiinflammatory activity but caused little hypothalamic-pituitary-adrenal suppression after topical or oral administration to rodents.
- Phillipps,Bailey,Bain,Borella,Buckton,Clark,Doherty,English,Fazakerley,Laing,Lane-Allman,Robinson,Sandford,Sharratt,Steeples,Stonehouse,Williamson
-
p. 3717 - 3729
(2007/10/02)
-
- ANDROSTANE CARBOTHIOATES
-
Compounds of the formula wherein R1 represents a fluoro-, chloro- or bromo-methyl group or a 2'-fluoroethyl group, R2 represents a group COR6 where R6 is a C 1-3 alkyl group or OR2 and R3 together form a 16alpha,17alpha-isopropylidenedioxy group; R3 represents a hydrogen atom, a methyl group (which may be in either the alpha- or beta -configuration) or a methylene group; R4 represents a hydrogen, chlorine or fluorine atom; R5 represents a hydrogen or fluorine atom and symbol represents a single or double bond have good anti-inflammatory activity, particularly on topical applications. The compounds of formula I are prepared by esterification, halogenation, reduction, deprotection and reaction at a 9,11-double bond to form a 9alpha-halo-11 beta-hydroxy grouping. Pharmaceutical compositions containing the compounds of formula I and methods for the use of the compounds are described and claimed
- -
-
-
