- A steric tethering approach enables palladium-catalysed C-H activation of primary amino alcohols
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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.
- Calleja, Jonas,Pla, Daniel,Gorman, Timothy W.,Domingo, Victoriano,Haffemayer, Benjamin,Gaunt, Matthew J.
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- Modular Photocatalytic Synthesis of α-Trialkyl-α-Tertiary Amines
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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.
- Gaunt, Matthew J.,Harris, Georgia R.,Henry Blackwell, J.,Smith, Milo A.
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supporting information
p. 15946 - 15959
(2021/10/12)
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- Photocatalytic Hydroaminoalkylation of Styrenes with Unprotected Primary Alkylamines
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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.
- 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.
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supporting information
p. 15936 - 15945
(2021/10/12)
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- Preparation method of fingolimod hydrochloride
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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.
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- Site-Selective γ-C(sp3)?H and γ-C(sp2)?H Arylation of Free Amino Esters Promoted by a Catalytic Transient Directing Group
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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.
- Lin, Hua,Wang, Chao,Bannister, Thomas D.,Kamenecka, Theodore M.
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p. 9535 - 9541
(2018/07/14)
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- A novel synthetic method of fingolimod
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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.
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- A PROCESS FOR THE PREPARATION OF 2-AMINO-1,3-PROPANE DIOL COMPOUNDS AND SALTS THEREOF
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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.
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Paragraph 0114
(2016/03/01)
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- A intermediate [...]profuse spear method for reduction of nitro to amino
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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.
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Paragraph 0032-0034
(2017/02/02)
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- PROCESS FOR PREPARATION OF FINGOLIMOD
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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
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Paragraph 0195
(2015/02/18)
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- Synthesis and evaluation of fluorinated fingolimod (FTY720) analogues for sphingosine-1-phosphate receptor molecular imaging by positron emission tomography
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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).
- Shaikh, Rizwan S.,Schilson, Stefanie S.,Wagner, Stefan,Hermann, Sven,Keul, Petra,Levkau, Bodo,Sch?fers, Michael,Haufe, Günter
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p. 3471 - 3484
(2015/05/05)
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- NEW LIGANDS FOR TARGETING OF S1P RECEPTORS FOR IN VIVO IMAGING AND TREATMENT OF DISEASES
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The present invention relates to novel compounds of formulae (I) and (II) which are useful in the prevention, treatment and diagnosis, in vivo diagnosis of diseases or disorders related to S1P receptors, in particular, in diseases which are connected to the regulatory function of sphingosine-1-phosphate (S1P) and its analogues, such as inflammation, pain, autoimmune diseases and cardiovascular diseases.
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- INTERMEDIATES AND PROCESS FOR THE PREPARATION OF HIGH PURITY FINGOLIMOD HYDROCHLORIDE
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The present invention relates to a simple and commercially feasible preparation of Fingolimod hydrochloride with high purity of greater than 99.9%. The.present invention also provides novel intermediates for the preparation of Fingolimod Hydrochloride of Formula 1.
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- PREPARATION OF FINGOLIMOD AND ITS SALTS
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The present application provide processes for the preparation of fingolimod and its pharmaceutically acceptable salts, process for the purification of fingolimod hydrochloride and process for the preparation of amorphous fingolimod hydrochloride.
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- Suzuki coupling based synthesis and in vitro cytotoxic evaluation of Fingolimod and analogues
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A concise synthesis of Fingolimod (FTY720) and its analogues was described. The key step involved Suzuki coupling of arylboronate 11 with different bromides. In addition, the newly synthesized Fingolimod analogues (5a-i and 6a-c) were evaluated for their in vitro cytotoxicity against SMCC-7721 and HL-60 cell lines. The preliminary SAR was discussed.
- Mei, Tie-Wen,Luo, Yu,Feng, Xiang-Jun,Lu, Wei,Yang, Bo
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p. 2927 - 2932
(2013/04/23)
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- NEW LIGANDS FOR TARGETING OF S1P RECEPTORS FOR IN VIVO IMAGING AND TREATMENT OF DISEASES
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The present invention relates to novel compounds of formulae (I) and (II) which are useful in the prevention, treatment and diagnosis, in vivo diagnosis of diseases or disorders related to S1P receptors, in particular, in diseases which are connected to the regulatory function of sphingosine-1-phosphate (S1P) and its analogues, such as inflammation, pain, autoimmune diseases and cardiovascular diseases.
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- INTERMEDIATE COMPOUNDS AND PROCESS FOR THE PREPARATION OF FINGOLIMOD
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The present invention relates to processes for the preparation of (2-Amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol hydrochloride (Fingolimod) and pharmaceutically acceptable salts thereof, and intermediates formed in such processes.
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- PROCESS FOR MAKING FINGOLIMOD
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The invention relates to a process of making fingolimod of formula (1), or an acid addition salt thereof comprising a step of reacting the compound of formula (11) and/or a compound of formula (14) or an acid addition salt thereof, in a solvent with hydrogen in a presence of a hydrogenation catalyst, preferably palladium catalyst, and optionally converting fingolimod of formula (1) into an acid addition salt, to compounds of formula (11) and (14), processes of making them and to their use in making fingolimod.
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Page/Page column 17-18
(2012/04/17)
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- PROCESS FOR MAKING FINGOLIMOD
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The invention relates to a process of making fingolimod of formula (1), or an acid addition salt thereof comprising a step of reacting the compound of formula (11) and/or a compound of formula (14) or an acid addition salt thereof, in a solvent with hydrogen in a presence of a hydrogenation catalyst, preferably palladium catalyst, and optionally converting fingolimod of formula (1) into an acid addition salt, to compounds of formula (11) and (14), processes of making them and to their use in making fingolimod.
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Page/Page column 15
(2012/04/17)
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- PROCESS FOR MAKING FINGOLIMOD
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The invention relates to a process of making fingolimod of formula (1), or an acid addition salt thereof comprising a step of reacting the compound of formula (11) and/or a compound of formula (14) or an acid addition salt thereof, in a solvent with hydrogen in a presence of a hydrogenation catalyst, preferably palladium catalyst, and optionally converting fingolimod of formula (1) into an acidaddition salt, to compounds of formula (11) and (14) and their use in making fingolimod.
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Page/Page column 13-14
(2012/04/17)
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- PROCESS FOR PRODUCING FINGOLIMOD SALTS
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The invention relates to a process for producing pharmaceutically acceptable salts of fingolimod (I), comprising the step of reacting N-[1,1-bis hydroxymethyl-3-(4-octyl phenyl)-propyl]-acylamide (II) with an acidic compound. Furthermore, the invention provides different pharmaceutically acceptable salts of fingolimod and a polymorphic form of fingolimod hydrochloride.
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Page/Page column 8
(2012/07/28)
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- A convergent synthesis of the immunosuppressant FTY720 employing aqueous Wittig chemistry
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A short, convergent synthesis of the immunosuppressant FTY720 is described involving the use of 4-hydroxymethylbenzaldehyde as a pivotal intermediate. A double Wittig strategy was developed to connect this dual-functional aldehyde with an alkyl-tether and to a readily available TRIS-derivative leading to an efficient synthesis of the target molecule.
- Calzavara, Janice,McNulty, James
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supporting information; experimental part
p. 5672 - 5675
(2011/11/06)
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- PROCESS FOR PRODUCING FINGOLIMOD SALTS
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The invention relates to a process for producing pharmaceutically acceptable salts of fingolimod (I), comprising the step of reacting N-[1,1-bis hydroxymethyl-3-(4-octyl phenyl)-propyl]-acylamide (II) with an acidic compound. Furthermore, the invention provides different pharmaceutically acceptable salts of fingolimod and a polymorphic form of fingolimod hydrochloride.
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Page/Page column 17
(2011/02/24)
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- Efficient synthesis of the immunosuppressive agent FTY720
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The concise and practical synthesis of the biologically important FTY720 was achieved employing the palladium-catalyzed Sonogashira coupling reaction as a key step. The commercial tris(hydroxymethyl)aminomethane was converted to alkyne 2 via a three-step synthesis. The coupling reactions of alkyne 2 with aryl iodide 3, followed by subsequent hydrogenation of the internal alkyne and removal of the protecting groups provided FTY720 in high overall yield. Georg Thieme Verlag Stuttgart.
- Kim, Sanghee,Lee, Hyeseung,Lee, Minhee,Lee, Taeho
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p. 753 - 755
(2007/10/03)
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- Synthesis of 2-nitroalcohols by regioselective ring opening of epoxides with MgSO4/MeOH/NaNO2 system: A short synthesis of immunosuppressive agent FTY-720
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It has been demonstrated that a variety of epoxides can easily be opened with a system consisting of MgSO4/MeOH/NaNO2 giving the corresponding 2-nitroalcohols in excellent yields. This strategy has been applied to achieve a short synthesis of Immunosuppressive Agent FTY - 720.
- Kalita,Barua,Bezbarua,Bez
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p. 1411 - 1414
(2007/10/03)
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- Synthesis and immunosuppressive activity of 2-substituted 2- aminopropane-1,3-diols and 2-aminoethanols
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A series of 2-substituted 2-aminopropane-1,3-diols was synthesized and evaluated for their lymphocyte-decreasing effect and immunosuppressive effect on rat skin allograft. A phenyl ring was introduced into the alkyl chain of the lead compound 3, which is an immunosuppressive agent structurally simplified from myriocin (1, ISP-I) via compound 2. The potency of the various compounds was dependent upon the position of the phenyl ring within the alkyl side chain. The most suitable length between the quaternary carbon atom and the phenyl ring was two carbon atoms. 2-Substituted 2-aminoethanols were successively synthesized and evaluated for their T-cell-decreasing effect and immunosuppressive effect using a popliteal lymph node gain assay in rats. The absolute configuration at the quaternary carbon affected the activity, and the (pro-S)-hydroxymethyl group of compound 6 was essential for potent immunosuppressive activity. Favorable substituents for the (pro-R)- hydroxymethyl group of 6 were hydroxyalkyl (hydroxyethyl and hydroxypropyl) or lower alkyl (methyl and ethyl) groups. 2-Amino-2-[2-(4- octylphenyl)ethyl]propane-1,3-diol hydrochloride (6, FTY720) was found to possess considerable activity and is expected to be useful as an immunosuppressive drug for organ transplantation.
- Kiuchi, Masatoshi,Adachi, Kunitomo,Kohara, Toshiyuki,Minoguchi, Masanori,Hanano, Tokushi,Aoki, Yoshiyuki,Mishina, Tadashi,Arita, Masafumi,Nakao, Noriyoshi,Ohtsuki, Makio,Hoshino, Yukio,Teshima, Koji,Chiba, Kenji,Sasaki, Shigeo,Fujita, Tetsuro
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p. 2946 - 2961
(2007/10/03)
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- 2-amino-1,3-propanediol compound and immunosuppressant
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2-Amino-1,3-propanediol compounds of the formula (I) STR1 wherein R is an optionally substituted straight- or branched carbon chain, an optionally substituted aryl, an optionally substituted cycloalkyl or the like, and R2, R3, R4 and R5 are the same or different and each is a hydrogen, an alkyl, an aralkyl, an acyl or an alkoxycarbonyl, pharmaceutically acceptable salts thereof and immunosuppressants comprising these compounds as active ingredients. The 2-amino-1,3-propanediol compounds of the present invention show immunosuppressive action and are useful for suppressing rejection in organ or bone marrow tranplantation, prevention and treatment of autoimmune diseases or as reagents for use in medicinal and pharmaceutical fields.
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