WO2019122084A1 - Procédé de préparation de dérivés de chlorure de nicotinamide riboside - Google Patents

Procédé de préparation de dérivés de chlorure de nicotinamide riboside Download PDF

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WO2019122084A1
WO2019122084A1 PCT/EP2018/086118 EP2018086118W WO2019122084A1 WO 2019122084 A1 WO2019122084 A1 WO 2019122084A1 EP 2018086118 W EP2018086118 W EP 2018086118W WO 2019122084 A1 WO2019122084 A1 WO 2019122084A1
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formula
group
compound
optionally substituted
pgi
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PCT/EP2018/086118
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José Ignacio GAMBOA LANDA
Aitor LANDA ALVAREZ
Claudio PALOMO NICOLAU
Ángel GARCÍA MARTÍN
Olatz LEIS ESNAOLA
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Stemtek Therapeutics, S.L.
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Publication of WO2019122084A1 publication Critical patent/WO2019122084A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/048—Pyridine radicals
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a process for the preparation of nicotinamide riboside chloride derivatives as well as a process for the preparation for its protected intermediate.
  • Nicotinamide riboside (also known as 1-(3-D-ribofuranosyl)nicotinamide; CAS Registry Number 1341-23-7) is a pyridine-nucleoside form of vitamin B 3 .
  • NAR is critical for the biosynthesis of nicotinamide adenine dinucleotide (NAD), which is an enzyme co- factor that is essential for the function of several enzymes related to reduction-oxidation reactions and energy metabolism.
  • NAD nicotinamide adenine dinucleotide
  • NAD precursors The dietary administration of NAD precursors has long been known to promote beneficial effects on blood lipid and cholesterol profiles and even to induce short-term improvement of type 2 diabetes.
  • niacin also known as nicotinic NA
  • niacin treatment often leads to severe cutaneous flushing reaction, resulting in poor patient compliance.
  • dietary supplementation with nicotinamide riboside could represent an alternative to niacin, with the advantage of being a more efficient NAD precursor.
  • NAR has been implicated not only in raising tissue NAD concentrations but also in eliciting insulin sensitivity and enhancement of sirtuin functions. Additionally, NAR has been suggested to provide neuroprotective effects in models of Alzheimer's disease.
  • NAR supplementation is limited by the available commercial supply. Since it is difficult to isolate nicotinamide riboside from natural sources, it is typically produced by chemical synthesis.
  • the main limitation for preparing NAR salts and derivatives in commercial way is due to the fact that the known synthetic routes are often unsuitable for large scale procedures because of their instability and purification costs.
  • Nicotinamide riboside chloride (1-[(2R,3R,4S,5R)-3,4-dihydroxy-5- (hydroxymethyl)oxolan-2-yl]pyridin-1-ium-3-carboxamide; also referred to as 1-(b- ⁇ - ribofuranosyl)nicotinamide chloride) is a known salt form of nicotinamide riboside. It is not toxic and therefore a suitable promising alternative for dietary supplementation.
  • the acetate group in the anomeric position of the protected ribose is converted into a Cl group with HCI(g)/Et 2 0 for 3 days at 0 °C, which is later reacted with nicotinamide.
  • the hydroxy protective groups are removed.
  • the preparation of NAR chloride according to this article shows some drawbacks. The first reaction takes place within a long period of time and requires a treatment with benzene which is not appropriate for a product that must be ingested. Further, the reaction yields (only given for steps two and three) were low: 40% and 73%, respectively.
  • the NAR chloride was obtained as a mixture of b and a anomers in a 4:1 ratio, being the a anomer undesired. This means that in order to obtain the pure b anomer a further separation step should be performed.
  • US 2017/267709 and US 2007/117765 generally disclose nicotinate/nicotinamide riboside compounds and processes for their preparation. However, they do not specifically investigate NAR chlorides or derivatives thereof.
  • WO 2015/014722 discloses a process for preparing NAR chloride by reacting the reduced NAR obtained from NAR triflate.
  • Jarman et al disclose the condensation of nicotinamide or 4-methyl-nicotinamide with 3,5-di-O-benzoyl-O- ribofuranosyl chloride to give the chloride salt of the corresponding
  • the inventors have developed an efficient and process for the direct preparation of NAR chloride or a derivatives thereof that does not take place via any anion exchange.
  • the two-step process of the invention proceeds in good yield and results in the desired pure b anomeric form so that no final separation step from the a anomer is needed.
  • the process of the invention is easy to industrialize (e.g. on a multigram scale). This is due to the fact that firstly, the reaction conditions are mild and few by- products are formed and, secondly, because it uses simple and no expensive purification processes (i.e. no tedious chromatographic methods or extraction is required).
  • a first aspect of the invention relates to a process for the preparation of nicotinamide riboside chloride of formula (I),
  • each of R 5 -R 6 is independently selected from the group consisting of H and (Ci-C 6 )alkyl optionally substituted with one or more halogen atoms;
  • R 7 is independently selected from (Ci-C 6 )alkyl optionally substituted with one or more halogen atoms, and phenyl optionally substituted with one or more halogen atoms;
  • each R 8 is independently selected from (Ci-C 6 )alkyl optionally substituted with one or more halogen atoms;
  • each R 9 is independently selected from H, and (Ci-C 6 )alkyl; and
  • n is 0 or 1 ; the process comprising the following steps:
  • each of PGi, PG 2 , PG 3 , and PG 4 is independently a hydroxyl protective group and PG 2 , PG 3 , and PG 4 have a nature such that they are removed under the same reaction conditions; with a nicotinamide compound of formula (IV)
  • R r R 4 are as previously defined;
  • R r R 4 and PGrPG are as previously defined;
  • step b) removing the protective groups of the compound of formula (III) obtained in step a) to give a compound of formula (I).
  • a second aspect of the invention relates to a process for the preparation of an
  • protecting group refers to a grouping of atoms that when attached to a reactive group in a molecule masks, reduces or prevents that reactivity.
  • hydroxy protective group refers to the protective group used to protect the hydroxyl groups of the ribose. This term encompasses all the protective groups defined in e.g. T. W. Green and P. G. M. Wuts, Protective Groups in Organic Chemistry (Wiley, 3rd ed. 1999, Chapter 2, pp. 17-200).
  • anomer refers to a cyclic saccharide (in this case ribose) that differs in the configuration at the hemiacetal/acetal carbon, also called the anomeric carbon.
  • the configuration at the anomeric centre is denoted alpha- (a-) or beta- (b-).
  • a- alpha-
  • beta- beta-
  • (Ci-C n )alkyl refers to a saturated branched or linear hydrocarbon chain which contains from 1 to n carbon atoms and only single bonds.
  • Non-limiting examples of (CrC n )alkyl include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, neopentil, hexyl, and the like.
  • the term (C 2 -C n )alkenyl refers to an unsaturated branched or linear hydrocarbon chain which comprises from 2 to n carbon atoms and at least one or more double bonds.
  • Non-limiting examples of (C 2 -C n )alkenyl include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, t-butenyl, and the like.
  • a halogen substituent means fluoro, chloro, bromo or iodo.
  • the process of the invention for the preparation of NAR chloride derivatives substantially yields the b anomeric form.
  • the NAR chloride derivative obtained in step b) of the preparation process is the b-anomer and contains equal or less than about 1 %, more particularly equal or less than about 0.5%, by weight of the oanomer with respect to the total weight of the NAR chloride derivative.
  • the intermediate of formula (III) obtained in step a) of the preparation process is the b-anomer and contains equal or less than about 1 %, more particularly equal or less than about 0.5%, by weight of the o anomer with respect to the total weight of the compound of formula (III).
  • each of R r R 4 is independently selected from the group consisting of H, halogen, -N0 2 , methyl, ethyl, isopropyl, trihalomethyl such as trifluoromethyl, -OH, methoxy, amino, formyl, acetyl, acetylamino, trihalomethylacetyl such as trifluoromethylacetyl, acetoxy, trihalomethylacetoxy, and trifluoromethylacetoxy.
  • each of R r R 4 is H.
  • R-i is H and each of R 2 -R 4 is independently as previously defined.
  • R 2 is H and each of Ri and R 3 -R 4 is independently as previously defined.
  • R 3 is H and each of R1-R2, and R 4 is independently as previously defined. More particularly, R 3 is H and each of R1-R2, and R is other than H.
  • R 4 is H and each of R r R 3 is independently as previously defined.
  • each of PG1, PG 2 , PG 3 , and PG is
  • hydroxyl protective group e.g. as defined in T. W. Green and P. G. M. Wuts, Protective Groups in Organic Chemistry (Wiley, 3rd ed. 1999, Chapter 2, pp. 17- 200).
  • the specific conditions for the introduction and removal of the hydroxyl protective groups are well-known in the art and are included in this bibliographic reference.
  • representative hydroxy protective groups include, without limitation, methyl, methoxymethyl (MOM), methylthiomethyl (MTM), (phenyldimethylsilyl)-methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), p-nitrobenzyloxy- methyl, o-nitrobenzyloxymethyl (NBOM), (4-methoxyphenoxy)methyl (p-AOM), guaiacol- methyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxy- ethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2- (trimethylsilyl)ethoxymethyl (SEM), menthoxymethyl (MM), tetrahydropyranyl (THP), 3- bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxymethyl (
  • TMS trimethylsilyl
  • TES triethylsilyl
  • TIPS dimethylisopropylsilyl
  • IPDMS dimethylisopropylsilyl
  • DEIPS diethylisopropylsilyl
  • TDS dimethylthexylsilyl
  • TDS t-butyldimethylsilyl
  • TDPS t-butyldiphenylsilyl
  • tribenzylsilyl tri-p- xylylsilyl, triphenylsilyl (TPS), diphenylmethylsilyl (DPMS), di-t-butylmethylsilyl (DTBMS), tris(trimethylsilyl)silyl, (2-hydroxystyryl)dimethylsilyl (HSDMS), (2-hydroxystyryl)diiso- propylsilyl (HSDIS), t-butylmethoxyphenylsilyl (TBMPS), t-butoxydiphenylsilyl (DPTBOS), formyl, benzoylformyl
  • each of PGi, PG 2 , PG 3 , and PG 4 is independently selected from the group consisting of:
  • a benzyl group wherein the phenyl ring is optionally substituted with one or more substituents selected from the group consisting of -0(CrC )alkyl, nitro, halogen, cyano, phenyl, p-pivaloylamido, p-acetamido, azido, and methylsulfinyl; and
  • dichloroacetyl trichloroacetyl, trifluoroacetyl, methoxyacetyl, formyl, propionyl,
  • formula -SiReRzRs is selected from the group consisting of trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl (TDS), t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl (TPS), diphenylmethylsilyl (DPMS), di- t-butylmethylsilyl (DTBMS), tris(trimethylsilyl)silyl, (2-hydroxystyryl)dimethylsilyl (HSDMS), (2-hydroxystyryl)diisopropylsilyl (HSDIS), t-butylmethoxyphen
  • silyl group of the formula -SiReRzRs is selected from the group consisting of t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), triisopropylsilyl (TIPS), and triphenylsilyl (TPS).
  • TDMS t-butyldimethylsilyl
  • TDPS t-butyldiphenylsilyl
  • TIPS triisopropylsilyl
  • TPS triphenylsilyl
  • the benzyl group is selected from the group consisting of benzyl (Bn), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), o-nitrobenzyl, p-nitrobenzyl, p-bromobenzyl, p-chlorobenzyl, 2,6-dichlorobenzyl, p- cyanobenzyl, p-phenylbenzyl, 2,6-difluorobenzyl, p-pivaloylamidobenzyl, p- acetamidobenzyl, p-azidobenzyl (Azb), 4-azido-3-chlorobenzyl, 2-tritluoromethyl-benzyl, and p-(methylsulfinyl)benzyl (Msib). More particularly, the benzyl group is selected from the group consisting of benzyl (Bn), p-methoxybenzyl
  • each of PGi, PG 2 , PG 3 , and PG 4 is independently selected from the group consisting of trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl (TDS), t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl (TPS), diphenylmethylsilyl (DPMS), di- t-butylmethylsilyl (DTBMS), tris(trimethylsilyl)silyl, (2-hydroxystyryl)dimethylsilyl (
  • each of PGi, PG 2 , PG 3 , and PG 4 is independently selected from the group consisting of acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, formyl, propionyl, isopropionyl, benzoyl (Bz), t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), triisopropylsilyl (TIPS), triphenylsilyl (TPS), p-methoxybenzyl (PMB), p-nitrobenzyl, and 3,4-dimethoxybenzyl (DMPM).
  • acetyl chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, formyl, propionyl,
  • the hydroxide protective groups PGi, PG 2 , PG 3 and PG 4 may be equal or different provided that they have a nature such that they can be removed under the same reaction conditions. This way the process steps are reduced. It is also advantageous that the groups PG 2 , PG 3 , PG can be introduced under the same reaction conditions.
  • an optionally substituted benzyl group as defined above can be generally introduced as a protective group by reacting the hydroxyl group or groups to be protected with the corresponding benzyl halide in the presence of a base such as e.g. KOH, or NaH in a suitable solvent such as tetrahydrofuran (THF) or dimethylformamide (DMF).
  • a base such as e.g. KOH, or NaH
  • a suitable solvent such as tetrahydrofuran (THF) or dimethylformamide (DMF).
  • a silyl group as defined above can be generally introduced as a protective group by reacting the hydroxyl group or groups to be protected with the corresponding silyl halide in the presence of e.g. imidazole, triethylamine, dimethylaminopyridine (DMAP) or pyridine, optionally in a solvent such as acetonitrile (ACN) or dimethylformamide (DMF).
  • imidazole triethylamine
  • DMAP dimethylaminopyridine
  • pyridine optionally in a solvent such as acetonitrile (ACN) or dimethylformamide (DMF).
  • ACN acetonitrile
  • DMF dimethylformamide
  • an acyl group as defined above can be generally introduced as a protective group by reacting the hydroxyl group or groups to be protected with the corresponding acid or acyl halide optionally in the presence of pyridine and dimethylaminopyridine (DMAP) in a solvent such as dimethylformamide (DMF).
  • DMAP dimethylaminopyridine
  • DMF dimethylformamide
  • the hydroxyl group or groups to be protected could be reacted with the corresponding anhydride in the presence of N,N'-dicyclohexylcarbodiimide (DCC) or 1- Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDO) as coupling agents.
  • the t-butyl group can be typically introduced as a protective group by reacting the hydroxyl group or groups to be protected with isobutylene in the presence of BF 3 -Et 2 0 and H 3 P0 .
  • PG 2 , PG 3 , PG 4 are equal. More particularly, PG 2 , PG 3 , PG 4 are acetyl or benzoyl. In a more particular embodiment of the latter embodiment, PGi is equal to PG 2 , PG 3 , and PG . In an alternative more
  • PGi is different from PG 2 , PG 3 , and PG .
  • PGi is acetyl
  • the process of the invention comprises a step a) of reacting a compound of formula (II) as defined above with nicotinamide (also known as 3- pyridinecarboxamide) in the presence of a Lewis acid selected from SnCI and TiCI in an appropriate solvent to give compound of formula (III) as defined above.
  • nicotinamide also known as 3- pyridinecarboxamide
  • the Lewis acid is SnCI .
  • the compound of formula (II) and nicotinamide are used in stoichiometric amounts.
  • the Lewis acid particularly SnCI
  • the Lewis acid is used in slightly excess with respect to the compound of formula (II), more particularly is used in an excess equal or lower than 0.2 equivalents, more particularly in an excess equal or lower than 0.1 equivalents, even more particularly in an excess of 0.05 equivalents.
  • the use of the above-mentioned Lewis acids in these amounts has the advantage that gives fewer by-products and avoids excess of starting materials. Further the Lewis acid can be easily removed from the reaction mixture by e.g.
  • Step a) is carried out in the presence of an appropriate solvent at a suitable temperature, more particularly at a temperature from 15 °C to 25 °C, even more particularly at a temperature about 20 °C.
  • appropriate solvent as used herein is meant a solvent which is suitable for carrying the reaction of step a) including non-polar solvents and polar aprotic solvents.
  • Non-limiting examples of appropriate solvents for step a) include (C 2 -C 6 )ethers such as tetrahydrofuran; (C 2 -C 6 )sulfoxides such as dimethylsulfoxide (DMSO), (C 2 -C 6 )amides such as dimethylformamide (DMF), and dimethylacetamide (DMA), (CrC 6 )ketones such as methyl ethyl ketone (MEK), methyl isobutyl ketone (MIK), and acetone; (Ci-C 6 )chlorinated hydrocarbons such as dichloromethane (DCM), chloroform, and dichloroethane;
  • the solvent of step a) is selected from dimethylsulfoxide (DMSO), dimethylformamide (DMF), dimethylacetamide (DMA), tetrahydrofuran (THF), acetone, methyl ethyl ketone (MEK), methyl isobutyl ketone (MIK), dichloromethane (DCM), acetonitrile (ACN), and mixtures thereof; more particularly, the solvent is ACN (optionally dry ACN).
  • DMSO dimethylsulfoxide
  • DMF dimethylformamide
  • DMA dimethylacetamide
  • THF tetrahydrofuran
  • MEK methyl ethyl ketone
  • MIK methyl isobutyl ketone
  • DCM dichloromethane
  • ACN acetonitrile
  • Step b) of the process corresponds to the deprotection of the hydroxy protective groups PG 2 , PG 3 , and PG 4 .
  • the skilled person will know which condition can be applied.
  • the deprotection can be generally carried out in NH 3 in a suitable solvent such as methanol, at a suitable temperature from -30 °C to -40 °C, even more particularly at a temperature about -32 °C.
  • a suitable solvent such as methanol
  • the deprotection can be typically carried out by hydrogenation on Pd-C, in a suitable solvent such as ethanol.
  • the deprotection can be typically carried out with Bu 4 NF, K 2 C0 3 or an acid such as HCI or acetic acid in the presence of a solvent such as tetrahydrofuran (THF), methanol, ethanol or ethyl acetate. If the protective group is t-butyl it can be removed with an acid such as trifluoroacetic acid, HBr or acetic acid.
  • a solvent such as tetrahydrofuran (THF), methanol, ethanol or ethyl acetate.
  • the compound of formula (I) can be isolated by crystallization or precipitation in a solvent or mixture of solvents, such as for example a solvent selected from the group consisting of benzene, toluene, 1 ,4-dioxane, chloroform, diethyl ether, methyl tert-butyl ether, dichloromethane, tetrahydrofuran, ethyl acetate, isopropyl acetate, acetone or
  • the compound of formula (I) can be crystallized or precipitated in a solvent or mixture of solvents and separated from the reaction medium, e.g. by filtration or centrifugation.
  • the compound of formula (I) is isolated from the reaction medium by precipitation in methanol, diethyl ether or dichloromethane.
  • Solvents and reagents All reagents bought from commercial sources were used as sold. Anhydrous acetonitrile was dried over phosphorus pentoxide (P205) prior to use.
  • NMR spectra were recorded using a Bruker Avance 300 MHz
  • b-nicotinamide riboside tribenzoate chloride (1 .0 g, 1.66 mmol) was dissolved in MeOH (15 ml.) and the resulting solution was cooled to -32 °C. Over this cooled solution was added dropwise a solution of NH 3 7 N in methanol (280 mmol, 40 ml_). The resulting mixture was stirred at the same temperature for 120 h. Then, the MeOH and the ammonia in excess were removed using a high vacuum pump (Telstar 2G-6, 4.10-2 mbar) yielding the title compound together with benzamide as white syrup.
  • a high vacuum pump Teelstar 2G-6, 4.10-2 mbar

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Abstract

L'invention concerne un procédé de préparation de chlorure de nicotinamide riboside de formule (I) dans laquelle R1-R4 sont tels que définis dans la description, comprenant les étapes suivantes consistant à : a) faire réagir un précurseur de riboside, les groupes hydroxyle aux positions 1, 2, 3 et 5 du ribose étant protégés par des groupes protecteurs hydroxyle ; avec du nicotinamide en présence d'un acide de Lewis choisi parmi SnCI4 et TiCI4 dans un solvant approprié, pour donner le composé de chlorure de nicotinamide riboside protégé correspondant, les groupes hydroxyle aux positions 2, 3 et 5 étant protégés par des groupes protecteurs hydroxyle ; et b) éliminer les groupes protecteurs du composé obtenu à l'étape a) pour donner un composé de formule (I). La présente invention concerne également un procédé de préparation du composé de chlorure de nicotinamide riboside protégé.
PCT/EP2018/086118 2017-12-22 2018-12-20 Procédé de préparation de dérivés de chlorure de nicotinamide riboside WO2019122084A1 (fr)

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CN111909229A (zh) * 2020-08-12 2020-11-10 福建瑞博奥科技有限公司 一种β-烟酰胺核糖氯化物的制备方法
CN112457353A (zh) * 2020-12-31 2021-03-09 音芙医药科技(上海)有限公司 一种β-烟酰胺核苷氯化物的合成方法
WO2021092919A1 (fr) * 2019-11-15 2021-05-20 四川大学华西医院 Intermédiaire de mononucléotide de nicotinamide et procédé de synthèse d'un mononucléotide de nicotinamide
WO2022022472A1 (fr) * 2020-07-31 2022-02-03 高志玲 Utilisation d'un composé d'arylformiate de nicotinamide nucléoside, composition de celui-ci, et forme cristalline du composé
WO2023119230A1 (fr) 2021-12-22 2023-06-29 L'oreal Compositions de modulation de la voie de coagulation et de la voie de nicotinamide-adénine dinucléotide et leurs procédés d'utilisation

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WO2021092919A1 (fr) * 2019-11-15 2021-05-20 四川大学华西医院 Intermédiaire de mononucléotide de nicotinamide et procédé de synthèse d'un mononucléotide de nicotinamide
WO2022022472A1 (fr) * 2020-07-31 2022-02-03 高志玲 Utilisation d'un composé d'arylformiate de nicotinamide nucléoside, composition de celui-ci, et forme cristalline du composé
CN111909229A (zh) * 2020-08-12 2020-11-10 福建瑞博奥科技有限公司 一种β-烟酰胺核糖氯化物的制备方法
CN111909229B (zh) * 2020-08-12 2023-05-05 福建瑞博奥科技有限公司 一种β-烟酰胺核糖氯化物的制备方法
CN111892635A (zh) * 2020-09-04 2020-11-06 福建康鸿生物科技有限公司 一种烟酰胺核糖新的合成方法
CN112457353A (zh) * 2020-12-31 2021-03-09 音芙医药科技(上海)有限公司 一种β-烟酰胺核苷氯化物的合成方法
WO2023119230A1 (fr) 2021-12-22 2023-06-29 L'oreal Compositions de modulation de la voie de coagulation et de la voie de nicotinamide-adénine dinucléotide et leurs procédés d'utilisation

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