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    method for preparing a compost. the invention relates to methods of preparing the nicotinamide riboside and its derivatives. on the one hand, the invention relates to a method of preparing a compound of formula (i), where n is 0 or 1; m is 0 or 1; y is o or s; r1 is selected from h, substituted or unsubstituted alkyl, substituted or unsubstituted alkene, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted primary or secondary amino, and substituted or unsubstituted azido; r 2 -r 5 , which may be the same or different, are each independently selected from h, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkenyl, and substituted or unsubstituted aryl; and x? is an anion, selected from an anion of a substituted or unsubstituted carboxylic acid, a halide, a substituted or unsubstituted sulfonate, a substituted or unsubstituted phosphate, a substituted or unsubstituted sulfate, a substituted or unsubstituted carbonate, and a substituted or unsubstituted carbamate.
    公开号:BR112016001774B1
    申请号:R112016001774-9
    申请日:2014-07-24
    公开日:2021-06-22
    发明作者:Marie MIGAUD；Philip REDPATH；Kerri CROSSEY；Mark Doherty
    申请人:The Queen's University Of Belfast；
    IPC主号:
    专利说明:

    Field of Invention
    [001] The invention relates to methods of preparing nicotinamide riboside and its derivatives. Fundamentals of the Invention
    [002] The nicotinamide riboside and its derivatives, including nicotinate riboside, nicotinamide mononucleotide and nicotinate mononucleotide, are metabolites of nicotinamide adenine dinucleotide (NAD+). The β-anomer forms of nicotinamide riboside, nicotinate riboside, nicotinamide mononucleotide, and nicotinate mononucleotide are shown, without the counterions, in Figure 1. As a precursor of NAD*, it was shown that the nicotinamide riboside, in mice, increases oxidative metabolism and protects against high-fat diet-induced obesity, which resulted in significant interest in nicotinamide riboside and its derivatives. Since nicotinamide riboside is a naturally occurring compound, nicotinamide riboside and its derivatives have great potential as natural nutritional supplements, which can provide health benefits without causing side effects. A limitation in the commercial exploitation of nicotinamide riboside and its derivatives, as nutritional supplements, or other forms, is that known synthetic protocols for the preparation of nicotinamide riboside and its derivatives have disadvantages, making them unsuitable for expansion for commercial use or industrial.
    [003] WO 2007/061798 describes a method for preparing the nicotinamide riboside and its derivatives. However, the disclosed method has a number of disadvantages. For example, trimethylsilyl trifluoromethanesulfonate (TMSOTf) is used as the catalyst in the disclosed method, and results in the prepared compounds being inevitably in the form of their triflate salts (OTf). The triflate salt form of nicotinamide riboside, or its derivatives, is not suitable for use as a nutritional supplement because of its associated toxicity. Thus, compounds produced by the disclosed method are not suitable for use as they are prepared, and require an additional step to exchange the triflate anion for an anion that would be pharmaceutically acceptable and therefore suitable for commercialization, using, for example , reversed phase liquid chromatography as disclosed. Additionally, the nicotinamide riboside is chemically labile, in particular, under the chromatographic conditions used in the disclosed method. Therefore, it is proposed that the chromatographic conditions used result in batches of less than ideal purity and, within batches, greater variability in terms of the derived products produced. Another disadvantage is that careful control of the reaction temperature is necessary to minimize decomposition in the final stages of nicotinamide riboside synthesis, and yet the disclosed method is exothermic and is therefore prone to thermal fluctuation in the microenvironment, especially in the case of a large-scale production scenario.
    [004] Tannimori et al (S. Tannimori, T. Ohta and Kirihata, Bioorganic & Medicinal Chemistry Letters, 2002, 12, 1135-1137) and Franchetti et al. (P. Franchetti, M. Pasqualini, R. Petrelli, M. Ricciutelli, P. Vita and L. Cappellacci, Bioorganic & Medicinal Chemistry Letters, 2004, 14, 4655-4658) also describe methods for preparing the nicotinamide riboside. However, these methods also have the disadvantage that they inevitably result in the preparation of the triflate salt due to the use of TMSOTf as the catalyst.
    [005] In summary, the described methods have disadvantages that present obstacles to the expansion of the method for commercial or industrial use and that, therefore, greatly limit the commercial opportunities for the methods and resulting compounds.
    [006] It is, therefore, an objective of the invention to avoid or mitigate the disadvantages of the prior art.
    [007] It is also an object of the invention to provide a new, useful and efficient method for the preparation of nicotinamide riboside and its derivatives.
    [008] It is also an object of the invention to provide a method for the preparation of nicotinamide riboside and its derivatives, whereby the method can be used to introduce a counterion of choice to the prepared compounds, thereby producing compounds suitable for use as nutritional supplements or other forms. Invention Summary
    [009] According to the present invention, there is provided a method of preparing a compound of formula (I)
    (I) where n is 0 or 1; m is 0 or 1; Y is O or S; R1 is selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted primary or secondary amino, and substituted or unsubstituted azido; R2-R5, which may be the same or different, are each independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted aryl; and X- is an anion selected from an anion of a substituted or unsubstituted carboxylic acid, a halide, a substituted or unsubstituted sulfonate, a substituted or unsubstituted phosphate, a substituted or unsubstituted sulfate, a substituted or unsubstituted carbonate , and a substituted or unsubstituted carbamate; comprising the reaction of a compound of formula (II) R3
    (II) wherein n, m, Y and R1-R5 are as defined above; with a compound of the formula Z+X-, wherein X- is as defined above, and wherein Z+ is an N-containing cation; in the presence of an aqueous solution and a carbon-containing catalyst; to form the compound of formula (I).
    [0010] Optionally, Z+ is selected from a substituted or unsubstituted ammonium, substituted or unsubstituted pyridinium, a substituted or unsubstituted pyrrolidinium, substituted or unsubstituted imidazolium, and a substituted or unsubstituted triazolium.
    [0011] Optionally, Z+ is a substituted or unsubstituted ammonium of the formula N+HR'R''R''', where R', R" and R''', which may be the same or different, are each one, independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted aryl.
    [0012] Optionally, Z+ is an unsubstituted ammonium of the formula NH4+.
    [0013] Optionally, X- is a substituted or unsubstituted carboxylic acid anion selected from a substituted or unsubstituted monocarboxylic acid anion and a substituted or unsubstituted dicarboxylic acid anion.
    [0014] Optionally, X- is a substituted monocarboxylic acid anion, further optionally a substituted propanoic acid anion or a substituted acetic acid anion. Optionally, X- is a substituted propanoic acid anion, still optionally a hydroxypropanoic acid anion, still optionally a 2-hydroxypropanoic acid anion being lactic acid, the lactic acid anion being lactate. Optionally, X- is a substituted acetic acid anion, a substituted acetate being, optionally further, a trihaloacetate selected from trichloroacetate, tribromoacetate and trifluoroacetate. Optionally, the trihaloacetate is trifluoroacetate.
    [0015] Optionally, X- is an anion of an unsubstituted monocarboxylic acid selected from formic acid, acetic acid, propionic acid and butyric acid, being formate, acetate, propionate and butyrate, respectively.
    Optionally, X- is a substituted or unsubstituted amino-monocarboxylic acid anion or a substituted or unsubstituted amino-dicarboxylic acid anion. Still optionally, X- is an anion of an amino-dicarboxylic acid, optionally selected from glutamic acid and aspartic acid, being glutamate and aspartate, respectively.
    [0017] Optionally, X- is an anion of ascorbic acid, being ascorbate.
    [0018] Optionally, X- is a halide selected from chlorine, bromine, fluorine and iodine, optionally further chlorine or bromine.
    [0019] Optionally, X- is a substituted or unsubstituted sulfonate. Optionally, X- is a trihalomethanesulfonate selected from trifluoromethanesulfonate, tribromomethanesulfonate and trichloromethanesulfonate. Optionally further, the trihalomethanesulfonate is trifluoromethanesulfonate.
    [0020] Optionally, X- is a substituted or unsubstituted carbonate, optionally further hydrogen carbonate.
    [0021] Optionally, X- is selected from chloride, acetate, formate, trifluoroacetate, ascorbate, aspartate, glutamate and lactate. Optionally, X- is selected from chloride, acetate, formate and trifluoroacetate.
    [0022] Optionally, the compound of formula Z+X- is selected from ammonium chloride, ammonium acetate, ammonium formate, ammonium trifluoroacetate, ammonium ascorbate, ammonium aspartate, ammonium glutamate and ammonium lactate. Also optionally, the compound of formula Z+X- is selected from ammonium chloride, ammonium acetate, ammonium formate and ammonium trifluoroacetate.
    Optionally, the compound of formula (II) and the carbon-containing catalyst are present in a respective molar ratio of from about 10:1 to about 1:10, optionally from about 5:1 to about 1:5, optionally further from about 4:1 to about 1:4, optionally further from about 1:1 or 1:2 or 1:3 or 1:4.
    [0024] Suitable carbon containing catalysts include, but are not limited to, activated carbon or graphite.
    [0025] As used herein, the term "activated carbon" is intended to mean a material containing carbon processed to be highly porous, thereby increasing the surface area of the material. The term "activated carbon" is intended to be synonymous with the term "activated carbon". Activated charcoal can be in the form of powders and/or fibers and/or granules and/or pellets. Optionally, activated carbon can act as a support for a metal. Suitable metals include, but are not limited to, transition metals. Suitable transition metals include, but are not limited to, platinum group metals, optionally selected from ruthenium, rhodium, palladium, osmium, iridium and platinum, or a combination thereof.
    [0026] Optionally, the aqueous solution consists essentially of water.
    [0027] Optionally, the aqueous solution comprises, in addition to water, an organic solvent.
    Suitable organic solvents include, but are not limited to, substituted or unsubstituted ethers, substituted or unsubstituted esters, substituted or unsubstituted ketones, substituted or unsubstituted aliphatic or aromatic hydrocarbons, and combinations thereof.
    [0029] Optionally, the organic solvent, when present, comprises an ether selected from diethyl ether, methyl tert-butyl ether, ethyl tert-butyl ether, di-tert-butyl ether, di-isopropyl ether, dimethoxymethane, tetrahydrofuran, 2- methyltetrahydrofuran and tetrahydropyran, or a combination thereof.
    [0030] Optionally, the organic solvent, when present, comprises an ester selected from methyl acetate, ethyl acetate, isopropyl acetate, n-propyl acetate, isobutyl acetate and n-butyl acetate, or a combination thereof .
    [0031] Optionally, the organic solvent, when present, comprises a ketone selected from methyl isobutyl ketone and methyl isopropyl ketone, or a combination thereof.
    [0032] Optionally, the organic solvent, when present, comprises an unsubstituted aliphatic hydrocarbon solvent selected from pentane, hexane, cyclohexane and heptane, or a combination thereof.
    Optionally, the organic solvent, when present, comprises a substituted aliphatic hydrocarbon solvent, optionally a halogenated aliphatic hydrocarbon solvent, optionally further a chlorinated aliphatic hydrocarbon solvent selected from dichloromethane, trichloromethane, tetrachloromethane, 1,2- chloroethane, 1,1,1-trichloroethane and trichloroethylene, or a combination thereof.
    [0034] Optionally, the organic solvent, when present, comprises an aromatic hydrocarbon solvent selected from benzene, toluene, ethylbenzene and xylene, or a combination thereof.
    [0035] Optionally, the aqueous solution comprises water and the organic solvent in a respective ratio by volume of from about 1:5 to about 5:1, optionally from about 1:3 to about 3:1, further optionally from about 1:2 to about 2:1, optionally further from about 1:1.
    [0036] Optionally, the reaction is carried out in a pH range of about 6 to about 8, optionally, of about 6.5 to about 7.5.
    [0037] Optionally, the reaction is carried out at a temperature from about 10°C to about 40°C, optionally from about 15°C to about 35°C, optionally further from about 15°C to about from 30°C, further optionally from about 15°C to about 20°C, even more optionally from about 20°C to about 25°C, even more optionally at a temperature of about 20°C or 21°C or 22°C or 23°C or 24°C or 25°C.
    [0038] Optionally, the reaction is carried out for a time period of from about 1 minute to about 180 minutes, optionally from about 2 minutes to about 120 minutes, optionally further from about 5 minutes to about 120 minutes. minutes, further optionally, from about 10 minutes to about 120 minutes, even more optionally, from about 20 minutes to about 120 minutes, even more optionally, from about 30 minutes to about 120 minutes, even more optionally, from about 60 minutes to about 120 minutes, even more optionally, from about 60 minutes to about 90 minutes, even more optionally, from about 60 minutes or 70 minutes or 80 minutes.
    Optionally, the method further comprises a filtration step to remove the carbon-containing catalyst from the prepared compound of formula (I). Suitable filtration media for use in the filtration step include, but are not limited to, syringe filters and/or paper filters, and/or any insoluble inert substance capable of acting as a filter, e.g., alumina and/or silica and/or diatomaceous earth. It will be contemplated that any other suitable filtration means can be used.
    [0040] As used herein, the term "substituted" is intended to mean that any one or more hydrogen atoms are replaced by any substituent, provided that the normal valence is not exceeded and the substitution results in a stable compound. Suitable substituents include, but are not limited to, alkyl, alkylaryl, aryl, heteroaryl, halide, hydroxyl, carboxylate, carbonyl (including alkylcarbonyl and arylcarbonyl), phosphate, amino (including alkylamino, dialkylamino, hydroxylamino, dihydroxylamino, alkyl hydroxylamino, arylamino, diarylamino and alkylarylamino), thiol (including alkylthiol, arylthiol and thiocarboxylate), sulfate, nitro, cyano and azido.
    [0041] As used herein, the term "alkyl" is intended to mean an aliphatic, linear, branched or cyclic, saturated or unsaturated, optionally saturated, substituted or unsubstituted hydrocarbon having from 1 to 12 carbon atoms, optionally of 1 to 10 carbon atoms, further optionally from 1 to 8 carbon atoms, further optionally from 1 to 6 carbon atoms, even more optionally 1 or 2 or 3 or 4 or 5 carbon atoms. Suitable alkyls include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, iso-pentyl, n-hexyl, iso-hexyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Optionally, when Y is O, n is 1, and m is 1, ethyl is preferred.
    [0042] As used herein, the term "alkenyl" is intended to mean an aliphatic, linear, branched or cyclic hydrocarbon, substituted or unsubstituted with at least one carbon-carbon double bond, and having from 2 to 12 atoms of carbon, optionally from 2 to 10 carbon atoms, still optionally, from 2 to 8 carbon atoms, still optionally, from 2 to 6 carbon atoms, even more optionally, 2 or 3 or 4 or 5 carbon atoms. Suitable alkenyl groups include, but are not limited to, ethenyl, propenyl and butenyl.
    [0043] As used herein, the term "alkynyl" is intended to mean an aliphatic, linear, branched or cyclic hydrocarbon, substituted or unsubstituted with at least one carbon-carbon triple bond, and having from 2 to 12 atoms of carbon, optionally 2 to 10 carbon atoms, still optionally 2 to 8 carbon atoms, still optionally 2 to 6 carbon atoms, even more optionally 2 or 3 or 4 or 5 carbon atoms. Suitable alkynyl groups include, but are not limited to, ethenyl, propynyl, butynyl and the like.
    [0044] As used herein, the term "aryl" is intended to mean a substituted or unsubstituted aromatic, monocyclic or polycyclic hydrocarbon. Suitable aryls include, but are not limited to, substituted or unsubstituted phenyl, and substituted or unsubstituted heteroaryl.
    Optionally, the substituted or unsubstituted primary or secondary amino is selected from substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted hydroxylamino, substituted or unsubstituted dihydroxylamino, and substituted or unsubstituted alkyl hydroxylamino.
    [0046] Optionally, the substituted or unsubstituted azido is selected from substituted or unsubstituted alkyl azido and substituted or unsubstituted aryl azido.
    [0047] It will be contemplated that when n is 0 and m is 0, R1 will be directly attached to the pyridine ring or the pyridinium ring, as appropriate.
    Optionally, in one embodiment of formula (I), n is 0, m is 1, R1 is NH2, R2-R5 are each H, and X- is selected from chloride, acetate, formate, and trifluoroacetate.
    Optionally, in one embodiment of formula (II), n is 0, m is 1, R1 is NH2, and R2-R5 are each H.
    Optionally, the compound of formula (II) and the compound of formula Z+X- are present in a respective molar ratio of from about 1:5 to about 5:1, optionally from about 1:3 to about from 3:1, further optionally from about 1:2 to about 2:1, optionally further from about 1:1.
    [0051] Optionally, the method comprises stirring the reagents, optionally using a magnetic or mechanical stirrer, further optionally, an overhead mechanical stirrer.
    [0052] In one embodiment, the carbon-containing catalyst used in the preparation of a compound of formula (I) may be supplied in the form of an activated carbon column, for example, an activated carbon material such as that supplied by Sigma Aldrich under the NORIT (trademark) or DARCO (trademark) brand names, or CarboChem, W Lancaster Ave, Ardmore, PA 19003, USA, or a carbon supported catalyst in a column from ThalesNano CatCart Packer (trademark) , Graphisoft Park, Zahony u. 7. H-1031 Budapest, Hungary. In this embodiment, the activated carbon column can be used as part of any suitable liquid chromatography system, including, but not limited to, a fast protein liquid chromatography (FPLC) or a high performance liquid chromatography (HLPC) system , or a flow chemistry system, such as ThalesNano (trademark) H-cube systems and related flow reactors, available from ThalesNano, details given above. In this case, the reagents would be circulated again in the column continuously until the compound of formula (II) was no longer detected by UV at 340 nm.
    [0053] Optionally, the compound of the formula (II) is prepared by the reaction of a compound of the formula (III)
    (III) wherein n, m, Y and R1-R5 are as defined above; and R6, R7 and R8, which may be the same or different, are each independently a hydroxy protecting group; with a deprotection agent; to form the compound of formula (II).
    Suitable R6, R7 and R8 moieties include, but are not limited to, ester-type protecting groups, ether-type protecting groups, and silyl-type protecting groups.
    [0055] As used herein, the term "ester-type protecting group" is intended to mean a protecting group which forms an ester bond for the purpose of hydroxyl protection and which may be substituted or unsubstituted. Suitable ester-type protecting groups include, but are not limited to, acetyl, propionyl, isopropionyl, benzoyl and trihaloacetyl, optionally, trifluoroacetyl or trichloroacetyl.
    [0056] As used herein, the term "ether-type protecting group" is intended to mean a protecting group which forms an ether bond for the purpose of hydroxyl protection and which may be substituted or unsubstituted. Suitable ether-type protecting groups include, but are not limited to, benzyl, p-methoxybenzyl, methoxymethyl and allyl ethers.
    [0057] As used herein, the term "silyl-type protecting group" refers to a protecting group that forms a silyloxy bond for the purpose of hydroxyl protection. Examples thereof are trimethylsilyl, triethylsilyl, triisopropylsilyl, 2-(trimethylsilyl)ethoxymethyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl and tetraisopropyldisilyl.
    [0058] Optionally, the R6, R7 and R8 moieties are selected from substituted and unsubstituted acetyl, and substituted and unsubstituted benzoyl.
    [0059] Optionally, at least two of R6, R7 and R8 are selected from unsubstituted acetyl or unsubstituted benzoyl.
    [0060] Optionally, the deprotecting agent is an acid or a base. Deprotection can also be achieved by catalytic hydrogenation (Pd/C; H2) for the aromatic ether protecting groups and by fluoride catalyzed chemistry (eg TBAF in THF) for all silyl ethers. Optionally, when R6, R7 and R8 each comprise an unsubstituted acetyl or unsubstituted benzoyl, the deprotecting agent is a base, optionally selected from NH3, Na2CO3 and NaOH. It will be contemplated by one of ordinary skill in the art that any other conventional deprotection agent can be used.
    [0061] Optionally, the reaction is carried out in the presence of a protic or aprotic solvent or a combination thereof.
    [0062] Suitable protic solvents include, but are not limited to, water, substituted or unsubstituted alcohol, or a combination thereof. Suitable substituted alcohols include substituted or unsubstituted fluorinated alcohols. Suitable unsubstituted alcohols include methanol, ethanol and propanol, optionally methanol.
    [0063] Suitable aprotic organic solvents include, but are not limited to, substituted or unsubstituted ethers, substituted or unsubstituted esters, substituted or unsubstituted ketones, substituted or unsubstituted aliphatic or aromatic hydrocarbons, and combinations thereof, as defined above .
    [0064] Optionally, the reagents are subjected to mechanical grinding, still optionally using a spherical or planetary spherical grinding machine.
    Optionally, in one embodiment of formula (III), n is 0, m is 1, R1 is NH2, R2-R5 are each H, and R6-R8 are each acetyl.
    [0066] Still optionally, in another embodiment of formula (III), n is 1, Y is O, m is 1, R1 is ethyl, R2-R5 are each H, and R6-R8 are each acetyl.
    [0067] Still optionally, in another embodiment of formula (III), n is 0, m is 1, R1 is NH2, R2-R5 are each H, and R6-R8 are each benzoyl.
    [0068] Optionally, the compound of the formula (III) is prepared by the reaction of a compound of the formula (IV)
    (IV) wherein n, m, Y, R1-R8 and X- are as defined above; with a reducing agent, an aqueous solution, and an organic solvent to form a compound of formula (III).
    [0069] Optionally, X- is selected from ascorbate, glutamate, aspartate, lactate and acetate.
    [0070] Suitable organic solvents are as defined above in relation to the preparation of a compound of formula (I) from formula (II).
    [0071] Optionally, when at least two of R6, R7 and R8 comprise an unsubstituted acetyl, the organic solvent is selected from dichloromethane, 1,2-chloroethane, n-butyl acetate, chloroform and ethyl acetate, or a combination thereof, optionally further ethyl acetate.
    [0072] Optionally, when at least two of R2, R3 and R4 comprise unsubstituted benzoyl, the organic solvent is selected from trichloroethylene, carbon tetrachloride, di-isopropyl ether, toluene, methyl tert-butyl ether, benzene and diethyl ether, or a combination thereof, further optionally diethyl ether.
    [0073] Optionally, the reducing agent is selected from sodium dithionite or sodium borohydride.
    [0074] Optionally, the method may comprise the simultaneous addition of the reducing agent, the aqueous solution and the organic solvent; or sequentially adding the reducing agent, the aqueous solution and the organic solvent, in any order; or a combination of them.
    [0075] Optionally, the aqueous solution consists essentially of water.
    [0076] It will be contemplated that, optionally, the aqueous solution and the organic solvent form a biphasic solution comprising an aqueous phase and an organic phase.
    [0077] Optionally, the method comprises the additional steps of separating the organic phase from the aqueous phase; and extracting the compound of formula (III) from the organic solvent.
    [0078] It will be appreciated by a person skilled in the art that the hydroxyl protecting groups, R6, R7 and R8, need to be lipophilic as the reduced compound of formula (III), once prepared, migrates to the organic phase of the medium of biphasic reaction formed by the aqueous solution (aqueous phase) and by the organic solvent (organic phase).
    [0079] Optionally, the reagents are subjected to mechanical grinding, still optionally using a spherical or planetary spherical grinding machine.
    [0080] Optionally, in one embodiment of formula (IV), n is 0, m is 1, R1 is NH2, R2-R5 are each H, R6-R8 are each acetyl, and X- is -OTf.
    [0081] Still optionally, in another embodiment of formula (III), n is 1, Y is O, m is 1, R1 is ethyl, R2-R5 are each H, R6-R8 are each acetyl , and X- is -OTf.
    [0082] Still optionally, in another embodiment of formula (III), n is 0, m is 1, R1 is NH2, R2-R5 are each H, and R6-R8 are each benzoyl, and X - is -OTf.
    [0083] According to the invention, compounds derivable from the methods disclosed in this document are also provided.
    [0084] According to the invention, there is further provided a compound of the formula (I)
    (I) where n, m, Y, R1-R5 and X- are as defined above.
    [0085] Optionally, X- is selected from acetate, formate and trifluoroacetate.
    [0086] Optionally, the compound of formula (I) has formula (IA), that is, it is the β anomer,
    (IA) where n, m, Y, R1-R5 and X- are as defined above.
    [0087] Optionally, the compound of formula (II) has formula (IIA), that is, it is the β anomer,
    (1IA) where n, m, Y and R1-R5 are as defined above.
    [0088] Optionally, the compound of the formula (III) has the formula (IIIA), that is, it is the β anomer,
    (IIIA) wherein n, m, Y and R1-R8 are as defined above.
    [0089] Optionally, the compound of the formula (IV) has the formula (IVA), that is, it is the β anomer, R3
    (IVA) where n, m, Y, R1-R8 and X- are as defined above.
    The advantages of the invention include, but are not limited to the following: (1) The preparation of compounds of formula (I) from compounds of formula (II) provides an efficient method of introducing a counterion of choice for the nicotinamide riboside and its derivatives. Starting from a compound of formula (II), eg reduced NRH, a desired counterion can be introduced. Furthermore, even if the method starts with the use of compounds of formula (IV) in the form of the triflate salt, the methods of the invention allow the triflate anion to be exchanged during the method in a simple and efficient way, by a counterion of choice. Thus, the disclosed methods conveniently allow the preparation of compounds with potential use as nutritional supplements or other forms. (2) The invention provides stereoselective methods for preparing the nicotinamide riboside and its derivatives, producing the desired β anomer. This contrasts, for example, with Tannimori et al., which is not stereoselective and produces significant amounts of the α-anomer, which is undesirable. Additionally, the methods of the invention are useful, efficient, and can be easily extended to industry and commercialization, and provide for minimization of solvent use, purification, and reaction time. For example, the methods of the invention for preparing compounds of formula (I) from compounds of formula (II), are conveniently completed in less than 2 hours in quantitative yields. Methods for preparing compounds of formula (I) starting from compounds of formula (IV) are also very efficient and produce very good yields. Methods can be conveniently performed at room temperature. (3) The methods described in this document are capable of preparing not only the nicotinamide riboside, but also an entire range of derivatives, which is not disclosed in Tannimori et al. nor in Franchetti et al. Derivatives include not only the nicotinamide riboside derivatives, but also the reduced form of the nicotinamide riboside and its derivatives. In addition, although not described in this document, one skilled in the art will contemplate that, from the compounds of formula (II), it is possible to easily access the phosphorylated origins of the nicotinamide riboside and its derivatives, for example, nicotinamide mononucleotide and nicotinamide mononucleotide nicotinate. (4) The protecting groups used in the preparation of the compounds of the formula (III) from the compounds of the formula (IV) may advantageously be chosen as being sufficiently lipophilic, thus, they facilitate the migration of the compounds of the formula (III) in the organic phase of the reaction medium to facilitate extraction. (5) The methods described herein conveniently use reagents which allow the compounds of formula (I) to be prepared in a neutral pH range of about 6 to about 8. For example, in the preparation of the compounds of formula (I) from the compounds of the formula (II), this neutral pH range allows both the raw materials (compounds of the formula (II)), which are acid labile, and the final products (compounds of the formula ( I)), which are labels to the base, are stable during the reaction. (6) The inventors have surprisingly found that the use of an N-containing cation as Z+ (the proton source) conveniently allows for the efficient preparation of compounds of formula (I) from compounds of formula (II) in yield quantitative and, as mentioned in point (5), in a neutral pH range. Without wishing to be bound by theory, it is proposed that Z+, the proton source, should be a conjugate acid of an organic base that is protonated in a balanced way within the neutral pH range. The inventors propose that, by using an N-containing cation as the Z+ proton source, the N atom of the proton source has a pKa greater than the pKa of the dihydropyridine N atom of the compound of formula (II). Therefore, in simple terms, due to the relative pKa values, the N atom of the Z+ proton source (ie, N-H+) settles into the H+ proton until after the N atom of the dihydropyridine has been oxidized (whose oxidation, the inventors propose, be facilitated by the carbon-containing catalyst). It is only after the N atom of the dihydropyridine has been oxidized that it will be protonated by the Z+ proton source. The inventors propose that if a proton source other than that containing an N atom is used, for example a phosphonium cation containing P-H+ or a sulfonium cation containing S-H+, it is proposed that these proton sources would cause the pH of the reaction medium would fall below the neutral pH range, and proton sources would release their protons in this lower pH range. It is proposed that this change would cause the dihydropyridine N atom to be protonated prior to oxidation, thereby resulting in the undesirable hydrolysis of a dihydropyridine C-N bond. It is also proposed that this instability resulting from dihydropyridine due to the undesirable cleavage of a C-N bond would also occur using a weak acid (eg carboxylic acid) or a strong acid (eg hydrochloric acid, phosphoric acid or sulfuric acid). Thus, it is proposed that only an N-containing cation, as proposed, is capable of releasing a proton in a pH range (neutral), which allows the reaction to proceed as desired to form the compounds of formula (I) from the compounds of the formula (II). Examples
    [0091] The embodiments of the present invention will now be described, with reference to the accompanying non-limiting examples and figures, in which:
    [0092] Figure 1 shows the β anomer forms of nicotinamide riboside, nicotinate riboside, nicotinamide mononucleotide and nicotinate mononucleotide, without counterions;
    Figure 2 represents Scheme A, which is a scheme illustrating in general terms that compounds of formula (IV) can be used to prepare compounds of formula (III) as described in Example 1; that compounds of formula (III) can be used to prepare compounds of formula (II) as described in Example 2; and that compounds of formula (II) can be used to prepare compounds of formula (I) as described in Example 3; wherein n, m, Y, R1-R8 and X- are as defined above;
    [0094] Figure 3 represents scheme B, which is a scheme illustrating, in general terms, that the triacetyl nicotinamide riboside and triflate salt can be used to prepare the triacetyl-1,4-dihydronicotinamide riboside as described in Example 1 (A), and that triacetyl-1,4-dihydronicotinamide riboside can be used to prepare 1-(beta-D-ribofuranosyl)-1,4-dihydronicotinamide, as described in Example 2, and that to 1 -(beta-D-ribofuranosyl)-1,4-dihydronicotinamide can be used to prepare the nicotinamide riboside and chloride salt as described in Examples 3(A), 3(E) and 3(F). The β anomers of all mentioned compounds are shown. It will be contemplated that Scheme B is merely exemplary and should not be construed as limiting the invention thereto;
    [0095] Figure 4 shows the β anomer forms of triacetyl-1,4-dihydronicotinamide riboside (Example 1 (A)), triacetyl O-ethyl-1,4-dihydronicotinate riboside, (Example 1 (B)) , tribenzoyl-1,4-dihydronicotinamide riboside (Example 1(C)), and 1-(beta-D-ribofuranosyl)-1,4-dihydronicotinamide (Example 2); and
    [0096] Figure 5 shows the β anomer forms of nicotinamide riboside, chloride salt (Examples 3(A), 3(E) and 3(F)), nicotinamide riboside, acetate salt (Example 3(B)) , nicotinamide riboside, formate salt (Example 3(C)), and nicotinamide riboside, trifluoroacetate salt (Example 3(D)). Example 1
    The compounds of formula (III) were prepared according to the invention as follows. The pH of the reaction medium described in the following examples was in the region of about 6-8. Example 1 (A): Preparation of reduced triacetyl nicotinamide riboside, i.e. triacetyl-1,4-dihydronicotinamide riboside, a compound of formula (III) (the β anomer form which is shown in Figure 4).
    [0098] Reduction: All solvents were degassed prior to use by sonication and argon bubbling. Sodium dithionite (0.656 g, 3.76 mmol, 2 eq) and sodium hydrogen carbonate (0.79 g, 9.40 mmol, 5 eq) were added to a clean dry round bottom flask with a magnetic stirrer and placed under inert atmosphere. A compound of formula (IV), ie triacetyl nicotinamide riboside and triflate salt (CF3SO3- , also known as -OTf) (1 g, 1.88 mmol, 1 eq) were then dissolved in a minimal amount of water (< 10 ml) and slowly added to the reaction vessel. Once the reaction was established, more water was added to the reaction until all the reactants had dissolved (<10 ml) and was allowed to stir for 20 minutes. The aqueous solution was then extracted with three half parts of dichloromethane (DCM). The DCM fractions were collected and concentrated under reduced pressure, generating the triacetyl-1,4-dihydronicotinamide riboside derivative (triacetyl-NRH) with residual amounts of raw material (<5%). The aqueous layer was subjected to the above conditions a second time to increase yields, which averaged 65%. Ethyl acetate was also an excellent alternative solvent in place of DCM, producing a 75% yield.
    [0099] 1H-NMR (MeOD, 400MHz) - δ7.15 (s, 1H, H-5), 5.95 (d, 1H, J=7.21 Hz, H-6), 5.25 (d, 1H, J=2.84Hz) & 5.17 (d, 1H, J=1.80Hz) (H-8 & H-7), 4.96 (d, 1H, J=7 .09Hz, H-4), 4.87 (ABX, 1H, Jaa=8.18Hz, Jab=3.60Hz, H-9), 4.26 (d, 2H, J=3.20Hz, H- 10 & H-10') 4.19 (m, 1H, J=3.00Hz, H-3), 3.13 (m, 2H, J=1.18Hz, H-2), 2.13 ( s, 3H), 2.11 (s, 3H), 2.10 (s, 3H) (H-13, H-15, H-17). 13C-NMR (MeOD, 125MHz) - δ172.80 (C-11), 170.40 (C-12, C-14, C16), 137.90 (C-5), 125.20 (C-4) , 105.12 (C-6), 95.24 (C-3), 83.49 (C-9), 71.18 (C-8), 70.26 (C-7), 61.55 ( C-10), 22.16 (C-2), 21.52 (C-13, C-15, C-17). HMRS m/z: 383.1445; calculated mass: 383.1454.
    The compound of the formula (IV), i.e. triacetyl nicotinamide riboside and the triflate salt (-OTf) were prepared as follows. Nicotinamide (10 g, 81, 89 mmol, 1eq) was silylated using TMSCI (15.6 ml, 122.85 mmol, 1.5 eq) in HMDS (100 ml) at 130°C in quantitative yield to force β-selectivity through the following Vorbruggen reaction. Ribose tetraacetate (also known as tetraacetate riboside) was reacted with the resulting silylated nicothimanide in the presence of 5 equivalents of TMSOTf. The reagents were stirred in a 1.5 ml steel vessel with a 5 mm diameter steel ball bearing in a Retsch M400 mixer grinder at 25 Hz for 0.5 h. At this point, the formed triacetylated nicotinamide riboside (compound of formula (IV)) could be isolated. It will be contemplated that the triacetyl nicotinamide riboside is not limited to being produced by this exact method, and could, for example, be produced using a conventional Vorbruggen reaction, as described, for example, in PCT International Patent Publication No. WO 2007 /061798 or in T. Yang, NYK Chan and AA Sauve, Journal of Medicinal Chemistry, 2007, 50, 6458-6461.
    [00101] 1H-NMR (MeOD, 400MHz) - δ 9.61 (s, 1H, aromatic), 9.30 (dt, 1H, J=6.3, 1.4 Hz, aromatic), 9, 10 (dt, 10 1 H, J=8.2, 1.4 Hz, aromatic), 8.37 (dd, 1 H, J=8.2, 6.3 Hz, aromatic), 6.60 (d , 1H, J=3.9Hz, H-1 (anomeric)), 5.60 (dd, 1H, J=5.6, 3.9Hz, H-2), 5.46 (t, 1 H, J=5.6Hz, H-3), 4.81-4.84 (m, 1H, H-4), 4.61 (ABX, 1H, J'=3.1Hz, Ja ,b=3.5Hz, H-5), 4.51 (ABX, 1H, Ja,a'=13.0Hz, Ja,b=2.8Hz, H-5), 2.20 ( s, 3H, OAc), 2.17 (s, 3H, OAc), 2.16 (s, 3H, OAc).
    [00102] 13C-NMR (MeOD, 125MHz) - δ 172.1, 171.6, 171.2 (3x C=OCH3), 164.9 (C=ONH2) 147.0, 144.3, 142.3 , 136.2, 129.6, (aromatic), 121.6 (q, J= 320.2 Hz, CF3), 99.4 (C-1 (anomeric)), 84.4 (C-4), 77.6 (C-2), 70.7 (C-3), 63.5 (C-5), 20.7 (OAc), 20.3 (OAc), 20.2 (OAc).
    [00103] 19F-NMR (MeOD, 376MHz) - δ -79.9 (triflate counter ion) Example 1 (B): Preparation of reduced triacetyl nicotinate ester riboside, i.e. triacetyl O-ethyl-1 riboside ,4-dihydronicotinate, a compound of formula (III) (the form of the β anomer which is shown in Figure 4).
    [00104] Reduction: A compound of the formula (IV), ie, triacetyl O-ethyl nicotinate riboside and triflate salt (-OTf) (2.30 g, 4.2 mmol, 1 eq) were dissolved in 20 mL of H2O and a solution of NaHCO3 (1.77 g, 21.0 mmol, 5 eq) and sodium dithionite (1.47 g, 8.22 mmol, 2 eq) in 30 mL of H2O was added and stirred for 2hrs. The yellow solution obtained was then washed with 2x ethyl acetate (EtOAc, 40 mL), the organic layer was dried over MgSO4, filtered and concentrated to provide 900 mg (39% yield) of 2,3,5-riboside. triacetyl O-ethyl-1,4-dihydronicotinate (a yellow oil) without further purification. 80% purity based on 1H-NMR.
    [00105] 1H-NMR-δ 7.27 (1H, s, H-6), 6.05 (1H, dd, J=8.2, 1.5Hz, H-7), 5.26( 1H, dd, J=5.8, 2.8Hz, H-3), 5.23 (1H, dd, J=6.9, 5.8Hz, H-2), 5.08 (1H , d, J=6.9Hz, H-1), 4.91 (1H, dt, J=8.3, 3.5Hz, H-8), 4.24-4.30 (3H,m, H-4, H-5, H-5'), 4.11 (2H, q, J=7.2Hz, H-11), 3.04-3.06 (2H, m, H-9), 2.16 (3H, s, OAc), 2.12 (3H, s, OAc), 2.09 (3H, s, OAc), 1.25 (3H, t, J=7.2Hz, H-12 ).
    [00106] 13C-NMR-δ 172.2, 171.5, 171.3, 169.8, (3x C=O-CH3 and C=O-OEt), 139.9 (C-6), 126, 3 (C-7), 106.4 (C-8), 101.5 (C-10), 94.2 (C-1), 80.4 (C4), 72.3 (C-2), 72.1 (C-3), 64.8 (C-5), 61.0 (C-11), 23.4 (C-9), 20.7, 20.5, 20.3 (3x C =O-CH3), 14.8 (C-12).
    [00107] The compound of the formula (IV), i.e. triacetyl O-ethyl nicotinate riboside and the triflate salt (-OTf) were prepared as follows. Ribose tetraacetate (also known as tetraacetate riboside) was reacted with ethyl nicotinate (Sigma Aldrich) using the general Vorbruggen bead trituration procedure described in Example 1(A) above. The reagents, ie 1 eq tetraacetate riboside, 1 eq TMSOTf, 1 eq ethyl nicotinate, were reacted for 30 min in a 1.5 ml steel container with a 1 steel ball bearing. .5 cm in diameter in a Retsch MM400 mixer grinder at 25 Hz. The crude reaction mixture (containing some ethyl nicotinate and starting sugar, < 10%) was used for the reduction step (described above) without further purification . It will be contemplated that the triacetyl O-ethyl nicotinate riboside and the triflate salt (-OTf) are not limited to being produced by this exact method, and could, for example, be produced using a conventional Vorbruggen reaction, as described, for example , in PCT International Patent Publication No. WO 2007/061798 or in T. Yang, NYK Chan and AA Sauve, Journal of Medicinal Chemistry, 2007, 50, 6458-6461.
    [00108] 1H-NR (D2O, 400MHz) - δ 9.45 (s, 1 H, aromatic), 9.14 (d, 1 H, J=6.1 Hz, aromatic), 9.02 (d, 1 H , J=7.8 Hz, aromatic), 8.18 (t, 1 H, J=6.7 Hz, aromatic), 6.51 (d, 1 H, J=4.1 Hz, H-1 ( anomeric)), 5.47 (t, 1 H, J=4.4 Hz, H-2), 5.36 (t, 1 H, J=4.7 Hz, H-3), 4.81- 4.84 (m, 1H, H-4), 4.45-4.48 (m, 2H, H-5), 4.36 (q, 2H, j=7.0 Hz, C=OCH2CHs) , 2.04 (s, 3H, OAc), 2.02 (s, 3H, OAc), 1.98 (s, 3H, OAc), 1.25 (t, 3H, J=7.0 Hz, C =OCH2CH3).
    [00109] 19F-NMR (D2O, 376MHz) - δ -79.0 (triflate counter ion) Example 1(C): Preparation of reduced tribenzoyl nicotinamide riboside, i.e. tribenzoyl-1,4-dihydronicotinamide riboside, a compound of formula (III) (the β anomer form which is shown in Figure 4).
    [00110] Reduction (not optimized): A compound of formula (IV), ie tribenzoyl nicotinamide riboside and the triflate salt (-OTf) were dissolved in minimal methanol and transferred to a round bottom flask, 10 mL of H2O were added to the solution and most of the methanol was removed by rotary evaporation. The raw material disintegrated into solution and 20 mL of diethyl ether (Et2O) was added until the solids were solubilized in a two-phase system. A solution of NaHCO3 (420 mg, 5 mmol, 5 eq) and sodium dithionite (348 mg, 2 mmol, 2 eq) in 10 mL of H2O was added and stirred for 2 hours. The layers were separated and the ether layer was dried over MgSO4 and concentrated to provide 428 mg (76% yield) of tribenzoyl-1,4-dihydronicotinamide riboside (yellow solid) without further purification. 80% purity based on 1H-NMR. Pure material is obtained by Biotage purification.
    [00111] 1H-NMR- δ 8.01-8.04 (2H, m, OBz), 7.81-7.86 (4H, m, OBz), 7.25-7.55 (9H, m, OBz), 7.13 (1H, s, H-6), 6.01 (1H, dd, J=8.2, 1.5Hz, H-7), 5.68 (1H, dd, J=6.2, 3.5Hz, H-3), 5.57 (1H, dd, J=6.7, 6.2Hz, H-2), 5.29 (1H, d, J= 6.7Hz, H-1), 4.61-4.68 (2H, m, H-8, H-5), 4.50-4.55 (2H, m, H-4, H-5' ), 3.93-3.94 (2H, m, H-9).
    [00112] 13C-NMR- δ 172.7, 167.6, 166.7, 166.6 (3x C=O-C6H5, C=ONH2), 138.1 (C-6), 134.9, 134 .8, 134.6, 130.9, 130.8, 130.7, 130.3, 130.0, 129.8, 129.7 (3x OBz), 125.7 (C-7), 105, 9 (C-8), 94.9 (C-1), 80.3 (C4), 72.9 (C-2), 72.7 (C-3), 65.4 (C-5), 23.6 (C-9).
    [00113] The compound of the formula (IV), i.e. tribenzoyl nicotinamide riboside and the triflate salt (-OTf) were prepared as follows. Ribose tetraacetate (also known as tetraacetate riboside) was reacted with TMS-nicotinamide (trimethylsilyl N-trimethylsilylpyridine-3-carboximidate, available from Sigma-Aldrich) using the general Vorbruggen bead trituration procedure described in Example 1(A) above. The reagents, ie 1 eq of 1-acetate-tribenzoate riboside, 1 eq of TMSOTf and 1 eq of TMS-nicotinamide were reacted for 30 min in a 1.5 ml steel vessel with a steel ball bearing. 1.5 cm diameter in a Retsch MM400 mixer grinder at 25 Hz. 1 eq of DCE (dichloroethylene) was needed and the crude reaction mixture (containing some unreacted nicotinamide and starting sugar, <10%) was used to the reduction step (described above) without further purification. It will be contemplated that the tribenzoyl nicotinamide riboside and the triflate salt (-OTf) are not limited to being produced by this exact method, and could, for example, be produced using a conventional Vorbruggen reaction, as described, for example, in the publication International PCT Patent No. WO 2007/061798 or in T. Yang, NYK Chan and AA Sauve, Journal of Medicinal Chemistry, 2007, 50, 6458-6461.
    [00114] 1H-NMR (MeOD, 400MHz) - δ 9.59 (s, 1H, aromatic), 9.31 (d, 1H, J=6.4Hz, aromatic), 8.94 (d, 1H, J=8.1 Hz, aromatic), 8.15 (dd, 1H, J=8.1, 6.4 Hz, aromatic), 7.90-7.94 (m, 6H, OBz) , 7.50-7.54 (m, 3H, OBz), 7.31-7.38 (m, 6H, OBz), 6.79 (d, 1H, J=3.9Hz, H-1 (anomeric)), 5.97 (dd, 1H, 5.6, 3.9Hz, H-2), 5.87 (t, 1H, J=5.6Hz, H-3), 5, 13-5.16 (m, 1H, H-4), 4.83-4.91 (m, 2H, H-5).
    [00115] 19F-NMR (MeOD, 376MHz) - δ -79.1 (triflate counter-ion) Example 2
    [00116] A compound of the formula (II), ie NRH (reduced nicotinamide riboside, also known as 1-(beta-D-ribofuranosyl)-1,4-dihydronicotinamide) (the form of the β anomer which is shown in Figure 4) was prepared as follows. The pH of the reaction medium described in the following example was in the region of about 6-8.
    [00117] The reduced triacetyl nicotinamide riboside, i.e. triacetyl-1,4-dihydronicotinamide riboside, a compound of formula (III), prepared in Example 1(A) above, was deprotected using mechanochemical processes (MeOH, NaOH) to remove the NRH generated by the acetyl fraction quantitatively. 100mg of (III) was dissolved in 0.5ml MeOH containing 0.05g NaOH. The compounds were reacted for 30 min in a 1.5 ml steel vessel with a 1.5 cm diameter steel ball bearing in a Retsch MM400 mixer grinder at 25 Hz.
    [00118] 1H-NMR (MeOD, 400MHz) - δ 7.18 (s, 1H, H-5), 6.14 (d, 1H, J= 8.28Hz, H-6), 4, 85 (m, 1H, H-3), 4.76 (d, 1H, J= 5.77Hz, H-4), 4.04 (m, 2H, H-7&H-8), 3.93 (m, 1H, J=2.76, H-9), 3.72 (ABX, 1H, Jaa=12.55Hz, Jab=3.51Hz, H-10), 3.65 (ABX, 1H, Jaa=12.55Hz, Jab=4.02Hz, H-10'), 3.10 (q, 2H, J=1.51Hz H-2). 13C-NMR (MeOD, 125MHz) - δ 172.88 (C-11), 137.83 (C-5), 125.29 (C-4), 105.19 (C-6), 95.00 ( C-3), 83.54 (C-9), 71.10 (C8), 70.20 (C-7), 61.61 (C-10), 22.09 (C-2); HRMS m/z: 257.1130; calculated mass: 257.1137.
    [00119] It will be contemplated that the deprotection step, as described above, can be used to deprotect any other compound of formula (III), including, but not limited to, triacetyl nicotinate ester riboside, i.e., 2 riboside ,3,5-triacetyl O-ethyl-1,4-dihydronicotinate, prepared in Example 1(B), and reduced tribenzoyl nicotinamide riboside, i.e., tribenzoyl-1,4-dihydronicotinamide riboside, prepared in Example 1(C ). The deprotection step can also be modified to suit specific needs. Example 3
    The compounds of formula (I) were prepared according to the invention as follows. The pH of the reaction medium described in the following examples was in the region of about 6-8. Example 3(A): Preparation of nicotinamide riboside and chloride salt (the form of the β anomer which is shown in Figure 5).
    [00121] A compound of formula (II), ie NRH (reduced nicotinamide riboside shown in Figure 2; 50 mg, 0.20 mmol, 1 eq), was dissolved in 5 mL of H2O and then 1 eq (this is, 0.20 mmol) of ammonium chloride was added in one part. Activated charcoal (~10 mg, ie 0.80 mmol) was then added and the mixture stirred at RT for ~1 hour and then filtered and lyophilized to give the nicotinamide riboside chloride salt, quantitatively, this is, 100% conversion and pure product.
    [00122] 1H-NMR (D2O, 400MHz) - δ 9.46 (s, 1H, aromatic), 9.12 (dt, 1H, J=6.3, 1.4 Hz, aromatic), 8. 83 (dt, 1 H, J=8.2, 1.4 Hz, aromatic), 8.13 (dd, 1 H, J=8.2, 6.3 Hz, aromatic), 6.13 (d, 1H, J=4.3Hz, H-1 (anomeric)), 4.37 (t, 1H, J=4.7Hz, H-2), 4.31 -4.34 (m, 1H , H-4), 4.21 (t, 1H, J=4.7Hz, H-3), 3.90 (ABX, 1H, Ja,a=13.0Hz, Ja,b=3, 5Hz, H-5), 3.75 (ABX, 1H, Ja,a=13.0Hz, Ja',b=2.8Hz, H-5).
    [00123] It will be contemplated that the NHR may be that obtained in Example 2, or may be obtained commercially, for example, from Diverchim, 100, rue Louis Blanc, 60 765 Montataire Cedex, France - (CAS Registry Number: 19132-12-12 -8) either as a pure product or as a mixture of anomers. Example 3(B): Preparation of nicotinamide riboside and acetate salt (the form of the β anomer which is shown in Figure 5).
    [00124] The method described in Example 3(A) was carried out, except that 1 eq (ie 0.20 mmol) of ammonium acetate was added. The acetate salt of the nicotinamide riboside was obtained quantitatively.
    [00125] 1H-NMR (D2O, 400MHz) - δ 9.46 (s, 1H, aromatic), 9.12 (d, 1H, J=6.3 Hz, aromatic), 8.83 (d, 1H, J=3.2 Hz, aromatic), 8.12 (m, 1H, aromatic), 6.09 (d, 1H, J=4.4 Hz, H-1 (anomeric)), 4.36 (t, 1H, J=4.7Hz, H-2), 4.32-4.35 (m, 1H, H-4), 4.21 (t, 1H, J=4.7Hz, H-3), 3 .91 (ABX, 1H, Ja,a=13.1 Hz, Ja,b=2.8 Hz, H-5), 3.75 (ABX, 1H, Ja,a.=13.0 Hz, Ja' ,b=3.5Hz, H-5'), 1.79 (s, 3H, OAc). Example 3(C): Preparation of nicotinamide riboside and formate salt (the form of the β anomer which is shown in Figure 5).
    [00126] The method described in Example 3(A) was carried out, except that 1 eq (ie 0.20 mmol) of ammonium formate (methanoate) was added. The nicotinamide riboside formate salt was obtained quantitatively.
    [00127] 1H-NMR (D2O, 400MHz) - δ 9.46 (s, 1H, aromatic), 9.12 (d, 1H, J=6.3Hz, aromatic), 8.83 (d, 1 H, J=8.2 Hz, aromatic), 8.29 (s, 1 H, formate), 8.12 (m, 1 H, aromatic), 6.09 (d, 1 H, J=4, 4Hz, H-1 (anomeric)), 4.36 (t, 1H, J=4.7Hz, H-2), 4.31-4.34 (m, 1H, H-4), 4 .21 (t, 1H, J=4.7Hz, H-3), 3.91 (ABX, 1H, Ja,a'=13.1Hz, Ja,b=3.5Hz, H-5 ), 3.79 (ABX, 1H, Ja,a'=13.0Hz, Ja',b=2.8Hz, H-5). Example 3(D): Preparation of the nicotinamide riboside and trifluoroacetate salt (the form of the β anomer which is shown in Figure 5).
    [00128] The method described in Example 3(A) was carried out, except that 1 eq (ie 0.20 mmol) of ammonium trifluoroacetate was added. The trifluoroacetate salt of nicotinamide riboside was obtained quantitatively.
    [00129] 1H-NMR (D2O, 400MHz) - δ 9.46 (s, 1H, aromatic), 9.12 (d, 1H, J=6.3Hz, aromatic), 8.83 (d, 1 H, J=8.2, aromatic), 8.13 (dd, 1H, J=8.2, 6.3 Hz, aromatic), 6.13 (d, 1H, J=4.3 Hz, H-1 (anomeric)), 4.35 (t, 1H, J=4.7Hz, H-2), 4.31-4.34 (m, 1H, H-4), 4.20 ( t, 1H, J=4.7Hz, H-3), 3.89 (ABX, 1H, Ja,a=13.0Hz, Ja,b=3.6Hz, H-5), 3, 74 (ABX, 1H, Ja,a=13.0 Hz, Ja',b=2.9 Hz, H-5). 19F-NMR (D2O, 376MHz)- δ -75.7 (CF3COO-). Example 3(E): Preparation of nicotinamide riboside and chloride salt (the form of the β anomer which is shown in Figure 5).
    [00130] An alternative method to that described in Example 3(A) was carried out as follows. NRH (reduced nicotinamide riboside shown in Figure 4; 50 mg, 0.20 mmol, 1 eq) was dissolved in 5mL of H2O:EtOAc (1:1) and then 1 eq. (ie 0.20 mmol) of ammonium chloride was added in one part. After the 1 hour follow-up, no oxidation had occurred and the raw materials were fully recovered. The recovered NRH and ammonium chloride were resuspended in the same solvent system with the addition of activated carbon (~10 mg ie 0.8 mmol) and stirred at RT for 1 hour. Subsequent filtration and lyophilization generated the riboside chloride salt of nicotinamide in quantitative yield. Thus, it was concluded that a carbon-containing catalyst, eg activated carbon, was essential for the method. 1H-NMR (D2O, 400MHz) - δ 9.46 (s, 1H, aromatic), 9.12 (dt, 1H, J=6.3, 1.4 Hz, aromatic), 8.83 (dt, 1 H, J=8.2, 1.4 Hz, aromatic), 8.13 (dd, 1 H, J=8.2, 6.3 Hz, aromatic), 6.13 (d, 1 H, J= 4.3 Hz, H-1 (anomeric)), 4.37 (t, 1 H, J=4.7Hz, H-2), 4.31-4.34 (m, 1 H, H-4) , 4.21 (t, 1H, J=4.7Hz, H-3), 3.90 (ABX, 1H, Ja,a'=13.0Hz, Ja,b=3.5Hz, H -5), 3.75 (ABX, 1H, Ja,a'=13.0Hz, Ja',b=2.8Hz, H-5). Example 3(F): Preparation of nicotinamide riboside and chloride salt (the form of the β anomer which is shown in Figure 5).
    [00131] The method described in Example 3(E) was carried out, except that the NRH (reduced nicotinamide riboside shown in Figure 4; 50 mg, 0.20 mmol, 1 eq) was dissolved in 5 mL of H2O:THF ( 1:1) instead of H2O:EtOAc (1:1) and then 1 eq (ie, 0.20 mmol) of ammonium chloride was added in one part. After the 1 hour follow-up, no oxidation had occurred and the raw materials were fully recovered. The recovered NRH and ammonium chloride were resuspended in the same solvent system with the addition of activated carbon (~10 mg ie 0.8 mmol) and stirred at RT for 1 hour. Subsequent filtration and lyophilization generated the riboside chloride salt of nicotinamide in quantitative yield. Thus, it was concluded that a carbon-containing catalyst, eg activated carbon, was essential for the method.
    [00132] 1H-NMR (D2O, 400MHz) - δ 9.46 (s, 1H, aromatic), 9.12 (dt, 1H, J=6.3, 1.4 Hz, aromatic), 8. 83 (dt, 1 H, J=8.2, 1.4 Hz, aromatic), 8.13 (dd, 1 H, J=8.2, 6.3 Hz, aromatic), 6.13 (d, 1H, J=4.3Hz, H-1 (anomeric)), 4.37 (t, 1H, J=4.7Hz, H-2), 4.31-4.34 (m, 1H , H-4), 4.21 (t, 1H, J=4.7Hz, H-3), 3.90 (ABX, 1H, Ja,a'=3.0Hz, Ja.b=3 .5Hz, H-5), 3.75 (ABX, 1H, Ja,a'=13.0Hz, Ja',b=2.8Hz, H-5).
    权利要求:
    Claims (19)
    [0001]
    1. Method for preparing a compound of formula (I)
    [0002]
    2. Method according to claim 1, characterized in that Z+ is selected from a substituted or unsubstituted ammonium, a substituted or unsubstituted pyridinium, a substituted or unsubstituted pyrrolidinium, a substituted or unsubstituted imidazole and a substituted or unsubstituted triazole.
    [0003]
    3. Method according to claim 1 or 2, characterized in that the compound of formula (II) and the compound of formula Z+X- are present in a respective molar ratio of from about 1:5 to about of 5:1.
    [0004]
    4. Method according to any one of claims 1 to 3, characterized in that the compound of formula (II) and the carbon-containing catalyst are present in a respective molar ratio of from about 10:1 to about 1 :10.
    [0005]
    5. Method according to any one of claims 1 to 4, characterized in that the reaction is carried out in a range in which the pH is from about 6 to about 8.
    [0006]
    6. Method according to any one of claims 1 to 5, characterized in that X- is an anion of a substituted or unsubstituted carboxylic acid selected from an anion of a substituted or unsubstituted monocarboxylic acid and an anion of a substituted or unsubstituted dicarboxylic acid.
    [0007]
    7. Method according to any one of claims 1 to 5, characterized in that the compound with the formula Z+X- is selected from ammonium chloride, ammonium acetate, ammonium formate, ammonium trifluoroacetate, of ammonium ascorbate, ammonium aspartate, ammonium glutamate and ammonium lactate.
    [0008]
    8. Method according to any one of claims 1 to 5, characterized in that, in the compound of formula (I), n is 0, m is 1, R1 is NH2, R2-R5 are each H, and X- is selected from chloride, acetate, formate and trifluoroacetate.
    [0009]
    9. Method according to any one of claims 1 to 8, characterized in that the compound of formula (II) is prepared by reacting a compound of formula (III)
    [0010]
    10. The method of claim 9, characterized in that R6, R7 and R8 are each independently an ester-type protecting group, an ether-type protecting group, or a silyl-type protecting group.
    [0011]
    11. Method according to claim 9 or 10, characterized in that the radicals R6, R7 and R8 are selected from substituted acetyl or a substituted or unsubstituted benzoyl.
    [0012]
    12. Method according to any one of claims 9 to 11, characterized in that the deprotection agent is an acid or a base.
    [0013]
    13. Method according to any one of claims 9 to 12, characterized in that the reaction is carried out in the presence of a protic or aprotic solvent or a combination thereof.
    [0014]
    14. Method according to any one of claims 9 to 13, characterized in that in the compound of formula (III), n is 0, m is 1, R1 is NH2, R2-R5 are each H, and R6 - R8 are each acetyl; or wherein, in the compound of formula (III), n is 1, Y is O, m is 1, R1 is ethyl, R2-R5 are each H, and R6-R8 are each acetyl; or wherein, in the compound of formula (III), n is 0, m is 1, R1 is NH2, R2-R5 are each H, and R6-R8 are each benzoyl.
    [0015]
    15. Method according to any one of claims 9 to 14, characterized in that the compound of the formula (III) is prepared by the reaction of a compound of the formula (IV)
    [0016]
    16. Method according to claim 15, characterized in that when at least two of R6, R7 and R8 include substituted acetyl, the organic solvent is selected from dichloromethane, 1,2-chloroethane, n -butyl-acetate, chloroform and ethyl acetate, or a combination thereof.
    [0017]
    17. Method according to claim 15, characterized in that when at least two of R2, R3 and R4 include unsubstituted benzoyl, the organic solvent is selected from trichloroethylene, carbon tetrachloride, diisopropyl ether , toluene, methyl tert-butyl ether, benzene and diethyl ether, or a combination thereof.
    [0018]
    18. Method according to any one of claims 15 to 17, characterized in that the reducing agent is selected from sodium dithionite or sodium borohydride.
    [0019]
    19. Method according to any one of claims 15 to 18, characterized in that, in the compound of formula (IV), n is 0, m is 1, Ri is NH2, R2-R5 are each, H, R6-R8 are each acetyl, and X- is -Otf; or wherein, in the compound of formula (IV), n is 1, Y is O, m is 1, R1 is ethyl, R2-R5 are each, H, R6-R8 are each acetyl, and X- is -Otf ; or wherein, in the compound of formula (IV), n is 0, m is 1, R1 is NH2, R2-R5 are each H, and R6-R8 are each benzoyl, and X- is -OTf.
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    CA2918955A1|2015-02-05|
    MX2016001211A|2016-10-28|
    AU2020201254A1|2020-03-12|
    CN105636973A|2016-06-01|
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    NZ716277A|2021-03-26|
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    KR20210038718A|2021-04-07|
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    KR20160043974A|2016-04-22|
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    HK1255037A1|2019-08-02|
    WO2015014722A1|2015-02-05|
    MX349969B|2017-08-23|
    US20180186824A1|2018-07-05|
    JP2016530248A|2016-09-29|
    GB201313465D0|2013-09-11|
    CN108707174A|2018-10-26|
    US20200291055A1|2020-09-17|
    US10815262B2|2020-10-27|
    BR112016001774A2|2017-08-01|
    EP3321274A1|2018-05-16|
    JP6208352B2|2017-10-04|
    AU2018211238A1|2018-08-16|
    BR112016001774A8|2020-01-21|
    US20160168184A1|2016-06-16|
    HK1218918A1|2017-03-17|
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    法律状态:
    2019-11-19| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|Free format text: DE ACORDO COM O ARTIGO 229-C DA LEI NO 10196/2001, QUE MODIFICOU A LEI NO 9279/96, A CONCESSAO DA PATENTE ESTA CONDICIONADA A ANUENCIA PREVIA DA ANVISA. CONSIDERANDO A APROVACAO DOS TERMOS DO PARECER NO 337/PGF/EA/2010, BEM COMO A PORTARIA INTERMINISTERIAL NO 1065 DE 24/05/2012, ENCAMINHA-SE O PRESENTE PEDIDO PARA AS PROVIDENCIAS CABIVEIS. |
    2020-08-18| B07E| Notice of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|
    2020-10-06| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|
    2021-04-06| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    2021-06-22| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 24/07/2014, OBSERVADAS AS CONDICOES LEGAIS. |
    优先权:
    申请号 | 申请日 | 专利标题
    GBGB1313465.5A|GB201313465D0|2013-07-29|2013-07-29|Methods of preparing nicotinamide riboside and derivatives thereof|
    GB1313465.5|2013-07-29|
    PCT/EP2014/065971|WO2015014722A1|2013-07-29|2014-07-24|Methods of preparing nicotinamide riboside and derivatives thereof|
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