162359-55-9Relevant articles and documents
A steric tethering approach enables palladium-catalysed C-H activation of primary amino alcohols
Calleja, Jonas,Pla, Daniel,Gorman, Timothy W.,Domingo, Victoriano,Haffemayer, Benjamin,Gaunt, Matthew J.
, p. 1009 - 1016 (2015)
Aliphatic primary amines are a class of chemical feedstock essential to the synthesis of higher-order nitrogen-containing molecules, commonly found in biologically active compounds and pharmaceutical agents. New methods for the construction of complex amines remain a continuous challenge to synthetic chemists. Here, we outline a general palladium-catalysed strategy for the functionalization of aliphatic C-H bonds within amino alcohols, an important class of small molecule. Central to this strategy is the temporary conversion of catalytically incompatible primary amino alcohols into hindered secondary amines that are capable of undergoing a sterically promoted palladium-catalysed C-H activation. Furthermore, a hydrogen bond between amine and catalyst intensifies interactions around the palladium and orients the aliphatic amine substituents in an ideal geometry for C-H activation. This catalytic method directly transforms simple, easily accessible amines into highly substituted, functionally concentrated and structurally diverse products, and can streamline the synthesis of biologically important amine-containing molecules.
Modular Photocatalytic Synthesis of α-Trialkyl-α-Tertiary Amines
Gaunt, Matthew J.,Harris, Georgia R.,Henry Blackwell, J.,Smith, Milo A.
supporting information, p. 15946 - 15959 (2021/10/12)
Molecules displaying an α-trialkyl-α-tertiary amine motif provide access to an important and versatile area of biologically relevant chemical space but are challenging to access through existing synthetic methods. Here, we report an operationally straightforward, multicomponent protocol for the synthesis of a range of functionally and structurally diverse α-trialkyl-α-tertiary amines, which makes use of three readily available components: dialkyl ketones, benzylamines, and alkenes. The strategy relies on the of use visible-light-mediated photocatalysis with readily available Ir(III) complexes to bring about single-electron reduction of an all-alkyl ketimine species to an α-amino radical intermediate; the α-amino radical undergoes Giese-type addition with a variety of alkenes to forge the α-trialkyl-α-tertiary amine center. The mechanism of this process is believed to proceed through an overall redox neutral pathway that involves photocatalytic redox-relay of the imine, generated from the starting amine-ketone condensation, through to an imine-derived product. This is possible because the presence of a benzylic amine component in the intermediate scaffold drives a 1,5-hydrogen atom transfer step after the Giese addition to form a stable benzylic α-amino radical, which is able to close the photocatalytic cycle. These studies detail the evolution of the reaction platform, an extensive investigation of the substrate scope, and preliminary investigation of some of the mechanistic features of this distinct photocatalytic process. We believe this transformation will provide convenient access to previously unexplored α-trialkyl-α-tertiary amine scaffolds that should be of considerable interest to practitioners of synthetic and medicinal chemistry in academic and industrial institutions.
Photocatalytic Hydroaminoalkylation of Styrenes with Unprotected Primary Alkylamines
Askey, Hannah E.,Grayson, James D.,Tibbetts, Joshua D.,Turner-Dore, Jacob C.,Holmes, Jake M.,Kociok-Kohn, Gabriele,Wrigley, Gail L.,Cresswell, Alexander J.
supporting information, p. 15936 - 15945 (2021/10/12)
Catalytic, intermolecular hydroaminoalkylation (HAA) of styrenes provides a powerful disconnection for pharmacologically relevant γ-arylamines, but current methods cannot utilize unprotected primary alkylamines as feedstocks. Metal-catalyzed HAA protocols are also highly sensitive to α-substitution on the amine partner, and no catalytic solutions exist for α-tertiary γ-arylamine synthesis via this approach. We report a solution to these problems using organophotoredox catalysis, enabling a direct, modular, and sustainable preparation of α-(di)substituted γ-arylamines, including challenging electron-neutral and moderately electron-rich aryl groups. A broad range of functionalities are tolerated, and the reactions can be run on multigram scale in continuous flow. The method is applied to a concise, protecting-group-free synthesis of the blockbuster drug Fingolimod, as well as a phosphonate mimic of itsin vivoactive form (by iterative α-C-H functionalization of ethanolamine). The reaction can also be sequenced with an intramolecularN-arylation to provide a general and modular access to valuable (spirocyclic) 1,2,3,4-tetrahydroquinolines and 1,2,3,4-tetrahydronaphthyridines. Mechanistic and kinetic studies support an irreversible hydrogen atom transfer activation of the alkylamine by the azidyl radical and some contribution from a radical chain. The reaction is photon-limited and exhibits a zero-order dependence on amine, azide, and photocatalyst, with a first-order dependence on styrene.
Preparation method of fingolimod hydrochloride
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Paragraph 0092-0095; 0105-0106, (2020/04/17)
The invention provides a preparation method of fingolimod hydrochloride. According to the preparation method, 2,2-disubstituent-5-hydroxymethyl-5-nitro-1,3-dioxane sequentially acts with a halogenating reagent and triphenylphosphine to prepare a corresponding Witting reagent; the Witting reagent and p-n-octylbenzaldehyde are subjected to a Witting reaction; nitro and carbon-carbon double bonds aresubjected to catalytic hydroreduction, and a hydrolysis reaction is performed to remove a hydroxyl protecting group aldehyde or ketone to prepare fingolimod; and the fingolimod and hydrogen chlorideare subjected to salt forming to obtain fingolimod hydrochloride. According to the invention, the method is high in reaction selectivity and yield, cheap and easily available in raw materials, high insafety operability, mild in reaction condition, low in wastewater yield and high in purity of obtained fingolimod, provides the guarantee for preparation of high-purity fingolimod hydrochloride, andeasily achieves the simple and convenient industrial production of fingolimod hydrochloride.
Site-Selective γ-C(sp3)?H and γ-C(sp2)?H Arylation of Free Amino Esters Promoted by a Catalytic Transient Directing Group
Lin, Hua,Wang, Chao,Bannister, Thomas D.,Kamenecka, Theodore M.
, p. 9535 - 9541 (2018/07/14)
The first selective PdII-catalysed γ-C(sp3)?H and γ-C(sp2)?H arylation of free amino esters using a commercially available catalytic transient directing group. A variety of free amino esters, including α-amino esters and β-amino esters, amino monoesters and amino bis-esters, are shown to react with a diverse range of simple aryl and heteroaryl iodide reagents.
A novel synthetic method of fingolimod
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Paragraph 0012; 0028; 0029; 0030, (2017/08/27)
A novel synthetic method of fingolimod is disclosed. The method includes 1) protecting hydroxy in a compound 2 through subjecting the compound 2 to a silylation protection reaction under alkaline conditions to obtain a compound 3, 2) subjecting the hydroxy-protected compound 3 and a compound 4 to a coupling reaction to generate hydroxy-protected fingolimod, namely a compound 5, and 3) removing a hydroxy protective group of the compound 5 generated in the step 2) to obtain a target compound that is the fingolimod (shown as a compound 1). The method has characteristics of easily available raw materials, short and simple synthetic steps, environment protection and convenient after-treatment and has good industrial production value.
A intermediate [...]profuse spear method for reduction of nitro to amino
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Paragraph 0032-0034, (2017/02/02)
The invention discloses a method for reducing nitro of a Fingolimod intermediate to amino. The method comprises the following steps: firstly, carrying out a reaction on the Fingolimod intermediate and ammonium formate in the presence of a palladium catalyst in a solvent; and then, acidizing with hydrochloric acid to form salt. The invention adopts a method of combining ammonium formate and the palladium catalyst to replace use of a high pressure kettle and hydrogen or an active hydrogenation agent in conventional nitro hydrogenation reduction process, so as to overcome the deficiencies which are disadvantageous to industrialized production such as relatively high reaction control demand, low safety coefficient, relatively difficult operation. The invention provides a novel reducing method which has the advantages of mild reaction condition, simplicity in operation, high reducing rate, cost saving, high environment friendliness and the like, and is simple to operate and easy to industrially produce.
A PROCESS FOR THE PREPARATION OF 2-AMINO-1,3-PROPANE DIOL COMPOUNDS AND SALTS THEREOF
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Paragraph 0114, (2016/03/01)
The present disclosure relates to processes for the preparation of 2-amino-1,3-propane diol compounds and their hydrochloride salts. Particularly, the present disclosure relates to processes for synthesizing 2-amino-2-(2-(4-octylphenyl)ethyl)-1,3-propanediol and its hydrochloride salt 2-amino-2-(2-(4-octylphenyl)ethyl)-1,3-propanediol hydrochloride respectively. The said process is safe, commercially feasible for large-scale synthesis and has improved efficacy along with many other advantages. The present disclosure also relates to the novel polymorphs of 2-amino-1,3-propane diol compound and its hydrochloride salt, where in 2-amino-1,3-propane diol compound is 2-amino-2-(2-(4-octylphenyl)ethyl)-1,3-propanediol, and its hydrochloride salt is 2-amino-2-(2-(4-octylphenyl)ethyl)-1,3-propanediol hydrochloride.
Synthesis and evaluation of fluorinated fingolimod (FTY720) analogues for sphingosine-1-phosphate receptor molecular imaging by positron emission tomography
Shaikh, Rizwan S.,Schilson, Stefanie S.,Wagner, Stefan,Hermann, Sven,Keul, Petra,Levkau, Bodo,Sch?fers, Michael,Haufe, Günter
, p. 3471 - 3484 (2015/05/05)
Sphingosine-1-phosphate (S1P) is a lysophospholipid that evokes a variety of biological responses via stimulation of a set of cognate G-protein coupled receptors (GPCRs): S1P1-S1P5. S1P and its receptors (S1PRs) play important roles in the immune, cardiovascular, and central nervous systems and have also been implicated in carcinogenesis. Recently, the S1P analogue Fingolimod (FTY720) has been approved for the treatment of patients with relapsing multiple sclerosis. This work presents the synthesis of various fluorinated structural analogues of FTY720, their in vitro and in vivo biological testing, and their development and application as [18F]radiotracers for the study of S1PR biodistribution and imaging in mice using small-animal positron emission tomography (PET).
PROCESS FOR PREPARATION OF FINGOLIMOD
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Paragraph 0195, (2015/02/18)
The present invention provides a process for preparation of fingolimod, a compound of Formula I or a pharmaceutically acceptable salt thereof, free of regioisomeric impurity compound of Formula IA
