IT202100019529A1 - METHOD OF SYNTHESIS OF GLUTATHIONE DERIVATIVES - Google Patents
METHOD OF SYNTHESIS OF GLUTATHIONE DERIVATIVES Download PDFInfo
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- IT202100019529A1 IT202100019529A1 IT102021000019529A IT202100019529A IT202100019529A1 IT 202100019529 A1 IT202100019529 A1 IT 202100019529A1 IT 102021000019529 A IT102021000019529 A IT 102021000019529A IT 202100019529 A IT202100019529 A IT 202100019529A IT 202100019529 A1 IT202100019529 A1 IT 202100019529A1
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- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical class OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 title claims description 53
- 238000000034 method Methods 0.000 title claims description 8
- 230000015572 biosynthetic process Effects 0.000 title description 10
- 238000003786 synthesis reaction Methods 0.000 title description 10
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 52
- 229960003180 glutathione Drugs 0.000 claims description 31
- 108010024636 Glutathione Proteins 0.000 claims description 29
- 238000005917 acylation reaction Methods 0.000 claims description 17
- 230000010933 acylation Effects 0.000 claims description 16
- 238000001308 synthesis method Methods 0.000 claims description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 9
- 238000001556 precipitation Methods 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 8
- 239000007864 aqueous solution Substances 0.000 claims description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- 229920006395 saturated elastomer Polymers 0.000 claims description 5
- 125000005915 C6-C14 aryl group Chemical group 0.000 claims description 4
- 125000001931 aliphatic group Chemical group 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 239000004215 Carbon black (E152) Substances 0.000 claims description 2
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 150000004703 alkoxides Chemical class 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000003277 amino group Chemical group 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 229930195733 hydrocarbon Natural products 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 238000010189 synthetic method Methods 0.000 claims 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 10
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 10
- 239000000243 solution Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- -1 acyl imidazole Chemical compound 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 230000006181 N-acylation Effects 0.000 description 1
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 description 1
- FVRWSIPJNWXCEO-YUMQZZPRSA-N S-acetylglutathione Chemical compound OC(=O)CNC(=O)[C@H](CSC(=O)C)NC(=O)CC[C@H](N)C(O)=O FVRWSIPJNWXCEO-YUMQZZPRSA-N 0.000 description 1
- 230000006191 S-acylation Effects 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- DTOSIQBPPRVQHS-PDBXOOCHSA-N alpha-linolenic acid Chemical compound CC\C=C/C\C=C/C\C=C/CCCCCCCC(O)=O DTOSIQBPPRVQHS-PDBXOOCHSA-N 0.000 description 1
- 235000020661 alpha-linolenic acid Nutrition 0.000 description 1
- 125000002714 alpha-linolenoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])/C([H])=C([H])\C([H])([H])/C([H])=C([H])\C([H])([H])/C([H])=C([H])\C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229960004488 linolenic acid Drugs 0.000 description 1
- KQQKGWQCNNTQJW-UHFFFAOYSA-N linolenic acid Natural products CC=CCCC=CCC=CCCCCCCCC(O)=O KQQKGWQCNNTQJW-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 1
- 229960002009 naproxen Drugs 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- QNXIYXGRPXRGOB-UHFFFAOYSA-N oxolane;propan-2-one Chemical compound CC(C)=O.C1CCOC1 QNXIYXGRPXRGOB-UHFFFAOYSA-N 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000004963 pathophysiological condition Effects 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/0215—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing natural amino acids, forming a peptide bond via their side chain functional group, e.g. epsilon-Lys, gamma-Glu
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/0606—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing heteroatoms not provided for by C07K5/06086 - C07K5/06139, e.g. Ser, Met, Cys, Thr
Description
DESCRIZIONE DESCRIPTION
del brevetto per invenzione industriale dal titolo: of the patent for industrial invention entitled:
?METODO DI SINTESI DI DERIVATI DEL GLUTATIONE? ?METHOD OF SYNTHESIS OF GLUTATHIONE DERIVATIVES?
La presente invenzione ? relativa a un metodo di sintesi di derivati del glutatione. The present invention ? relating to a method of synthesis of glutathione derivatives.
Il glutatione ? sicuramente uno dei pi? importanti agenti antiossidanti e disintossicanti che l?organismo ? in grado di produrre ed ha un ruolo importante nella risposta immunitaria. Glutathione? certainly one of the most? important antioxidant and detoxifying agents that the body? able to produce and has an important role in the immune response.
A livello cellulare il glutatione ? sintetizzato a partire dal glutammato, dalla glicina e dalla cisteina, la quale ? il donatore del gruppo tiolico (-SH) responsabile dell'attivit? biologica del glutatione. At the cellular level, glutathione? synthesized from glutamate, glycine and cysteine, which is the donor of the thiol group (-SH) responsible for the activity? glutathione biology.
Numerose condizioni fisiopatologiche (invecchiamento, malattie degenerative, ecc.) sono caratterizzate da stress ossidativo e deplezione di glutatione. In questi stati ? senz?altro vantaggioso ripristinare i livelli fisiologici di glutatione stesso nei tessuti. Numerous pathophysiological conditions (aging, degenerative diseases, etc.) are characterized by oxidative stress and glutathione depletion. In these states? certainly advantageous to restore the physiological levels of glutathione itself in the tissues.
Tuttavia, l?assunzione di glutatione da fonti esterne ? risultata scarsamente efficace, in quanto manca un suo carrier specifico per permetterne l?attraversamento della membrana cellulare. However, the intake of glutathione from external sources? was found to be scarcely effective, as it lacks a specific carrier to allow it to cross the cell membrane.
Da tempo la ricerca ha focalizzato la sua attenzione sui derivati del glutatione, in modo da poter superare i problemi relativi alle sfavorevoli propriet? farmacocinetiche del glutatione stesso. Research has focused its attention on glutathione derivatives for some time, in order to overcome the problems related to the unfavorable properties of glutathione. pharmacokinetics of glutathione itself.
Uno dei derivati che ha suscitato il maggiore interesse ? il S-acil glutatione. Infatti, ad oggi sono riconosciute le importanti propriet? terapeutiche del S-acil glutatione nel trattamento di molte patologie quali ad esempio l?Alzheimer, il Parkinson e il diabete. One of the derivatives that has aroused the greatest interest? the S-acyl glutathione. In fact, today the important properties are recognized? therapeutics of S-acyl glutathione in the treatment of many pathologies such as Alzheimer's, Parkinson's and diabetes.
Il S-acil glutatione, una volta assorbito dalle cellule, rilascia il glutatione e l?acido carbossilico. In questo modo, quindi, ? possibile ripristinare i livelli fisiologici di glutatione nei tessuti assicurando, cos?, la sua azione antiossidante e disintossicante. S-acyl glutathione, once absorbed by cells, releases glutathione and carboxylic acid. In this way, then, ? It is possible to restore the physiological levels of glutathione in the tissues thus ensuring its antioxidant and detoxifying action.
Ad oggi sono stati proposti diversi metodi di sintesi in cui ? prevista una S-acilazione del glutatione. A titolo di esempio, uno di questi metodi di sintesi prevede l?utilizzo di acil cloruri o anidridi in presenza di acido trifluoroacetico. Un altro metodo di sintesi, invece, prevede una sintesi enzimatica da ?-oxo aldeidi in presenza di glioxalasi. To date, various synthesis methods have been proposed in which ? expected S-acylation of glutathione. By way of example, one of these synthesis methods involves the use of acyl chlorides or anhydrides in the presence of trifluoroacetic acid. Another synthesis method, on the other hand, involves an enzymatic synthesis from ?-oxo aldehydes in the presence of glioxalase.
Tuttavia, i metodi ad oggi proposti si sono dimostrati di scarso interesse industriale sia a causa della bassa produttivit? dovuta alle basse rese e agli elevati costi sia, in particolare, a causa della natura dei reagenti e dei solventi in termini di tossicit?, di aggressivit? e di inquinamento. However, the methods proposed to date have proved to be of little industrial interest both because of the low productivity? due to the low yields and high costs and, in particular, due to the nature of the reagents and solvents in terms of toxicity, aggressiveness? and of pollution.
Era quindi sentita l?esigenza di disporre di una metodologia di sintesi del S-acil glutatione, le cui caratteristiche tecniche fossero tali da garantire una sua vantaggiosa applicazione su scala industriale. The need was therefore felt to have available a methodology for the synthesis of S-acyl glutathione, the technical characteristics of which were such as to guarantee its advantageous application on an industrial scale.
Oggetto della presente invenzione ? un metodo di sintesi per la preparazione di S-acil glutatione caratterizzato dal fatto di comprendere (i) una fase di acilazione, in cui in una soluzione acquosa a pH compreso tra 6 e 10, glutatione reagisce con N-acil imidazolo di formula I, e (ii) una fase di precipitazione in cui la soluzione acquosa proveniente da detta fase di acilazione ? acidificata fino al raggiungimento di un pH compreso tra 1 e 5; Object of the present invention ? a synthesis method for the preparation of S-acyl glutathione characterized in that it comprises (i) an acylation step, in which in an aqueous solution at a pH between 6 and 10, glutathione reacts with N-acyl imidazole of formula I, and (ii) a precipitation step in which the aqueous solution from said acylation step is acidified until a pH between 1 and 5 is reached;
in cui R ? un gruppo radicale idrocarburico lineare o ramificato con un numero di atomi di carbonio compreso tra 1 e 30. in which R? a straight or branched hydrocarbon radical group having from 1 to 30 carbon atoms.
Preferibilmente, in detta fase di acilazione glutatione ha una concentrazione compresa tra 0,5 e 1,0 M e N-acil imidazolo di formula I ha una concentrazione compresa tra 0,5 e 2,0 M. Preferably, in said acylation step glutathione has a concentration between 0.5 and 1.0 M and N-acyl imidazole of formula I has a concentration between 0.5 and 2.0 M.
Preferibilmente, in detta fase di acilazione il pH ? compreso tra 6 e 8. Preferably, in said acylation step the pH ? between 6 and 8.
Preferibilmente, in detta fase di precipitazione il pH ? compreso tra 2 e 3. Preferably, in said precipitation step the pH ? between 2 and 3.
Preferibilmente, detta fase di acilazione e detta fase di precipitazione avvengono a temperatura ambiente. Preferably, said acylation step and said precipitation step take place at room temperature.
Preferibilmente, R ? scelto nel gruppo composto da un gruppo achilico C1-C30 lineare o ramificato, un gruppo achenilico C2-C30 linear o ramificato, un gruppo arilico C6-C30, un gruppo con una porzione arilica C6-C14 e una porzione achilica C1-C6 lineare o ramificato, un gruppo misto arilico C6-C14 e achilico o alchenilico C1-C6; detto gruppo arilico avendo da 0 a pi? sostituenti uguali o differenti tra loro e compresi nel gruppo composto da atomo di alogeno, idrossile, alcossido lineare o ramificato C1-C6 saturo o insaturo, ammino eventualmente mono o disostituito sostituito con un gruppo alchilico lineare o ramificato C1 ? C6. Preferably, R? selected from the group consisting of a linear or branched C1-C30 akyl group, a linear or branched C2-C30 akyl group, a C6-C30 aryl group, a group with a C6-C14 aryl moiety and a linear C1-C6 akyl moiety or branched, a mixed C6-C14 aryl and C1-C6 akyl or alkenyl group; said aryl group having from 0 to pi? substituents that are the same or different from each other and included in the group consisting of halogen atom, hydroxyl, saturated or unsaturated C1-C6 linear or branched alkoxide, optionally mono- or disubstituted amino substituted with a linear or branched C1 alkyl group? C6.
Preferibilmente, R ? una catena alifatica satura o insatura con un numero di atomi di carbonio compreso tra 1 e 30; pi? preferibilmente tra 16 e 22. ? stato riscontrato che S-acil glutadione ottenuto con un N-acil imidazolo in cui R ? una catena alifatica C16 ? C22 presenta delle attivit? farmacologiche estremamente interessanti. Preferably, R? a saturated or unsaturated aliphatic chain with a number of carbon atoms between 1 and 30; more preferably between 16 and 22. ? It has been found that S-acyl glutadione obtained with an N-acyl imidazole in which R ? a C16 aliphatic chain? Does C22 have activities? extremely interesting pharmacological.
Preferibilmente, il N-acil imidazolo ? aggiunto alla soluzione acquosa disciolto in un solvente organico miscibile con acqua; pi? preferibilmente, detto solvente organico miscibile con acqua ? compreso nel gruppo composto da acetone, tetraidrofurano, acetonitrile o isopropanolo. Preferably, the N-acyl imidazole ? added to the aqueous solution dissolved in a water miscible organic solvent; more preferably, said water-miscible organic solvent ? included in the group consisting of acetone, tetrahydrofuran, acetonitrile or isopropanol.
In questo modo sar? possibile aggiungere il N-acil imidazolo direttamente dalla soluzione di sintesi in cui ? stato preparato, con gli ovvi vantaggi in termini di produttivit? che questo comporta. In this way it will be possible to add the N-acyl imidazole directly from the synthesis solution in which ? been prepared, with the obvious advantages in terms of productivity? that this entails.
Di seguito sono riportati degli esempi a scopo illustrativo e non limitativo per una migliore comprensione dell?invenzione. Examples are given below for illustrative and non-limiting purposes for a better understanding of the invention.
Di seguito ? riportato lo schema generale di reazione del metodo oggetto della presente invenzione secondo una preferita forma di realizzazione. Right away ? reported the general reaction scheme of the method object of the present invention according to a preferred embodiment.
Preparazione del N-acil imidazolo Preparation of N-acyl imidazole
Un Becker da tre litri equipaggiato con una ancoretta magnetica ? stato caricato con l?acido carbossilico prescelto (1023 mmol, 1.05 equiv) e un solvente organico miscibile con acqua quale ad esempio acetone tetraidrofurano, acetonitrile o isopropanolo (600 mL, circa 1,7M). A three-liter Becker equipped with a magnetic stir bar? charged with the selected carboxylic acid (1023 mmol, 1.05 equiv) and a water miscible organic solvent such as acetone tetrahydrofuran, acetonitrile or isopropanol (600 mL, about 1.7M).
La soluzione ? stata mantenuta sotto agitazione a temperatura ambiente per 10 minuti e, successivamente, ? stato aggiunto in piccole dosi e in un arco di 20 minuti 1,1?-Carbonildiimidazolo (CDI) (174 g, 1072 mmol, 1,1 equiv). Durante l?aggiunta va prestata attenzione allo sviluppo di CO2. Nel caso si utilizzi acido stearico, ? necessario un leggero calore per mantenere limpida la soluzione. La soluzione cos? realizzata ? stata mantenuta sotto agitazione a temperatura ambiente per 2 h. The solution ? been kept under stirring at room temperature for 10 minutes and, subsequently, ? 1,1?-Carbonyldiimidazole (CDI) (174 g, 1072 mmol, 1.1 equiv) was added in small doses over a period of 20 minutes. When adding, pay attention to the development of CO2. If you use stearic acid, ? A slight heat is needed to keep the solution clear. What is the solution? accomplished ? was kept under stirring at room temperature for 2 h.
Preparazione di S-acil glutatione Preparation of S-acyl glutathione
Un Becker da dieci litri dotato di imbuto gocciolatore e di un agitatore motorizzato ? stato caricato con glutatione (300 g, 975 mmol, 1 equiv) e H2O (1,2 L, circa 0,8 M). Dopo aver aggiunto in piccole dosi KHCO3 (98 g, 975 mmol, 1 equiv) facendo attenzione allo sviluppo di CO2, la soluzione ? stata mantenuta sotto agitazione a temperatura ambiente per 10 minuti. A questo punto, la soluzione di acil imidazolo, proveniente dalla fase di preparazione del N-acil imidazolo, ? stata aggiunta goccia a goccia nell?arco di 1 h mediante l?imbuto gocciolatore. La soluzione cos? realizzata ? stata mantenuta sotto agitazione a temperatura ambiente per 3 h. Successivamente, la soluzione ? stata acidificata a pH 2,5 - 3,0 con KHSO4 3M (circa 1,2 L). Durante l'acidificazione si ? verificata una precipitazione del prodotto che ha reso difficile l'agitazione, quindi ? stata aggiunta ulteriore H2O. La sospensione ? stata agitata lentamente a temperatura ambiente per una notte. Il solido ottenuto ? stato filtrato su carta da filtro e lavato pi? volte con acqua (4 x 4 L). Dopo essiccamento, il S-acil glutatione ottenuto si ? presentato come un solido bianco. A ten-litre Becker equipped with a drip funnel and a motorized stirrer ? loaded with glutathione (300 g, 975 mmol, 1 equiv) and H2O (1.2 L, approximately 0.8 M). After adding KHCO3 in small doses (98 g, 975 mmol, 1 equiv) paying attention to the evolution of CO2, the solution is ? was kept under stirring at room temperature for 10 minutes. At this point, the acyl imidazole solution, coming from the N-acyl imidazole preparation phase, is was added drop by drop over 1 h using the dropping funnel. What is the solution? accomplished ? was kept under stirring at room temperature for 3 h. Next, the solution? was acidified to pH 2.5 - 3.0 with 3M KHSO4 (about 1.2 L). During the acidification yes ? precipitation of the product occurred which made stirring difficult, so ? more H2O was added. The suspension ? stirred slowly at room temperature overnight. The solid obtained? been filtered on filter paper and washed pi? times with water (4 x 4 L). After drying, the S-acyl glutathione obtained presented as a white solid.
Di seguito sono riportati i valori di spettroscopia di massa e di risonanza magnetica ottenuti per ognuno dei quattro S-acil glutatione preparati: The following are the mass spectroscopy and magnetic resonance values obtained for each of the four prepared S-acyl glutathione:
N5-((R)-3-(acetylthio)-1-((carboxymethyl)amino)-1-oxopropan-2-yl)-L-glutamine N5-((R)-3-(acetylthio)-1-((carboxymethyl)amino)-1-oxopropan-2-yl)-L-glutamine
L?acido carbossilico utilizzato per la sintesi del relativo N-acil imidazolo ? l?acido acetico. The carboxylic acid used for the synthesis of the related N-acyl imidazole ? the acetic acid.
R = Me R = Me
Resa: 96% Yield: 96%
MS (ESI): 350 (M 1)<+>MS (ESI): 350 (M 1)<+>
Mp: 200?202 ?C Mp: 200?202 ?C
[?]D<20 >= ?11.5 (c 1.0, H2O). [?]D<20 >= ?11.5 (c 1.0, H2O).
<1>H NMR (400 Hz, DMSO-d6): ? (ppm) 8.65 (t, J = 6.0 Hz, 1H), 8.49 (d, J = 9.0 Hz, 1H), 4.44 ? 4.38 (m, 1H), 3.68 (d, J = 6.0 Hz, 2H), 3.38 ? 3.32 (m, 2H), 2.96 (dd, J = 13.5 and 9.5, 1H), 2.32 (s, 3H), 2.32 ? 2.28 (m, 2H), 1.98 ? 1.81 (m, 2H). <1>H NMR (400Hz, DMSO-d6): ? (ppm) 8.65 (t, J = 6.0 Hz, 1H), 8.49 (d, J = 9.0 Hz, 1H), 4.44 ? 4.38 (m, 1H), 3.68 (d, J = 6.0Hz, 2H), 3.38 ? 3.32 (m, 2H), 2.96 (dd, J = 13.5 and 9.5, 1H), 2.32 (s, 3H), 2.32 ? 2.28 (m, 2H), 1.98 ? 1.81 (m, 2H).
<13>C NMR (100 Hz, DMSO-d6): ? (ppm) 195.4, 172.2, 171.3, 170.9, 170.6, 53.5, 52.3, 41.7, 31.8, 31.0, 30.9, 27.2. <13>C NMR (100Hz, DMSO-d6): ? (ppm) 195.4, 172.2, 171.3, 170.9, 170.6, 53.5, 52.3, 41.7, 31.8, 31.0, 30.9, 27.2.
N5-((R)-1-((carboxymethyl)amino)-1-oxo-3-(stearoylthio)propan-2-yl)-L-glutamine N5-((R)-1-((carboxymethyl)amino)-1-oxo-3-(stearoylthio)propan-2-yl)-L-glutamine
L?acido carbossilico utilizzato per la sintesi del relativo N-acil imidazolo ? l?acido stearico. The carboxylic acid used for the synthesis of the related N-acyl imidazole ? stearic acid.
R = C17H33R = C17H33
Resa: 93% Yield: 93%
MS (ESI): 574 (M 1)<+>MS (ESI): 574 (M 1)<+>
Mp: 194 ? 196 ?C MP: 194 ? 196?C
<1>H NMR (400 Hz, DMSO-d6): ? (ppm) 8.65 (t, J = 6.0 Hz, 1H), 8.49 (d, J = 9.0 Hz, 1H), 4.42 ? 4.36 (m, 1H), 3.69 (d, J = 6.0, 2H), 3.37 (dd, J = 13.5, 4.5 Hz, 1H), 3.31 (t, J = 7.0 Hz, 1H), 2.95 (dd, J = 13.5, 10.0 Hz, 1H), 2.55 (t, J = 8.0 Hz, 2H), 2.34-2.24 (m, 2H), 1.98-1.89 (m, 1H), 1.87-1.80 (m, 1H), 1.56 ? 1.50 (m, 2H), 1.30-1.14 (m, 28H), 0.86 (t, J = 7.0 Hz, 3H). <1>H NMR (400Hz, DMSO-d6): ? (ppm) 8.65 (t, J = 6.0 Hz, 1H), 8.49 (d, J = 9.0 Hz, 1H), 4.42 ? 4.36 (m, 1H), 3.69 (d, J = 6.0, 2H), 3.37 (dd, J = 13.5, 4.5 Hz, 1H), 3.31 (t, J = 7.0 Hz, 1H), 2.95 (dd, J = 13.5, 10.0 Hz, 1H), 2.55 (t, J = 8.0 Hz, 2H), 2.34-2.24 (m, 2H), 1.98-1.89 (m, 1H), 1.87-1.80 (m, 1H), 1.56 ? 1.50 (m, 2H), 1.30-1.14 (m, 28H), 0.86 (t, J = 7.0 Hz, 3H).
N5-((R)-1-((carboxymethyl)amino)-3-(((9Z,12Z,15Z)-octadeca-9,12,15-trienoyl)thio)-1-oxopropan-2-yl)-Lglutamine N5-((R)-1-((carboxymethyl)amino)-3-(((9Z,12Z,15Z)-octadeca-9,12,15-trienoyl)thio)-1-oxopropan-2-yl)- Lglutamine
L?acido carbossilico utilizzato per la sintesi del relativo N-acil imidazolo ? l?acido linolenico. The carboxylic acid used for the synthesis of the related N-acyl imidazole ? linolenic acid.
R = C17H29 R = C17H29
Resa: 90% Yield: 90%
MS (ESI): 568 (M 1)<+>MS (ESI): 568 (M 1)<+>
Mp: 220-222 ?C Mp: 220-222?C
<1>H-NMR (400 Hz, DMSO-d6) ? 8.66 (br s, 1H), 8.41 (d, J = 7.0 Hz, 1H), 5.37-5.22 (m, 6H), 4.35 (td, J = 9.0 and 5.0 Hz, 1H), 3.66 (d, J = 6.0 Hz, 2H), 3.35 (dd, J = 13.5, 5.0 Hz, 1H), 3.24 (t, J = 7.0 Hz, 1H), 2.92 (dd, J = 13.5, 10.0 Hz, 1H), 2.75 (t, J = 6.0 Hz, 4H), 2.52 (t, J = 7.5 Hz, 2H), 2.34-2.20 (m, 2H), 2.06-1.97 (m, 4H), 1.93-1.86 (m, 1H), 1.82-1.75 (m, 1H), 1.51 (m, 2H), 1.32-1.19 (m, 8H), 0.90 (t, J = 7.0 Hz, 3H). <1>H-NMR (400Hz, DMSO-d6) ? 8.66 (br s, 1H), 8.41 (d, J = 7.0 Hz, 1H), 5.37-5.22 (m, 6H), 4.35 (td, J = 9.0 and 5.0 Hz, 1H), 3.66 (d, J = 6.0 Hz, 2H), 3.35 (dd, J = 13.5, 5.0 Hz, 1H), 3.24 (t, J = 7.0 Hz, 1H), 2.92 (dd, J = 13.5, 10.0 Hz, 1H), 2.75 (t, J = 6.0 Hz, 4H), 2.52 (t, J = 7.5 Hz, 2H), 2.34-2.20 (m, 2H), 2.06-1.97 (m, 4H), 1.93-1.86 (m, 1H), 1.82-1.75 ( m, 1H), 1.51 (m, 2H), 1.32-1.19 (m, 8H), 0.90 (t, J = 7.0 Hz, 3H).
N5-((R)-1-((carboxymethyl)amino)-3-(((S)-2-(6-methoxynaphthalen-2-yl)propanoyl)thio)-1-oxopropan-2-yl)-L-glutamine N5-((R)-1-((carboxymethyl)amino)-3-(((S)-2-(6-methoxynaphthalen-2-yl)propanoyl)thio)-1-oxopropan-2-yl)-L -glutamines
L?acido carbossilico utilizzato per la sintesi del relativo N-acil imidazolo ? il naprossene. The carboxylic acid used for the synthesis of the related N-acyl imidazole ? the naproxen.
R = C13H13O R = C13H13O
Resa: 85% Yield: 85%
MS (ESI): 520 (M 1)+ MS (ESI): 520 (M 1)+
Mp: 200 ? 202 ?C. MP: 200 ? 202?C.
<1>H NMR (400 MHz, DMSO-d6): ? 8.80 (t, J = 6.0 Hz, 1H), 8.39 (d, J = 8.0 Hz, 1H), 7.82 ? 7.75 (m, 3H), 7.39-7.36 (m, 1H), 7.31 (s, 1H), 7.17 ? 7.12 (m, 1H), 4.39 ? 4.34 (m, 1H), 4.12 (q, J = 7.0 Hz, 1H), 3.86 (s, 3H), 3.71 ? 3.68 (m, 2H), 3.35 ? 3.24 (m, 2H), 2.96 (dd, J = 13.5 and 9.5, 1H), 2.30 ? 2.20 (m, 2H), 1.95 ? 1.85 (m, 2H), 1.49 (d, J = 7.0 Hz, 3H). <1>H NMR (400 MHz, DMSO-d6): ? 8.80 (t, J = 6.0 Hz, 1H), 8.39 (d, J = 8.0 Hz, 1H), 7.82 ? 7.75 (m, 3H), 7.39-7.36 (m, 1H), 7.31 (s, 1H), 7.17 ? 7.12 (m, 1H), 4.39 ? 4.34 (m, 1H), 4.12 (q, J = 7.0 Hz, 1H), 3.86 (s, 3H), 3.71 ? 3.68 (m, 2H), 3.35 ? 3.24 (m, 2H), 2.96 (dd, J = 13.5 and 9.5, 1H), 2.30 ? 2.20 (m, 2H), 1.95 ? 1.85 (m, 2H), 1.49 (d, J = 7.0 Hz, 3H).
Come risulta dai dati sopra riportati, l?acilazione del glutatione da parte del N-acil imidazolo ? estremamente S selettiva senza, quindi, produrre, se non in quantit? irrilevanti, la N-acilazione come sottoprodotto. As can be seen from the above data, the acylation of glutathione by N-acyl imidazole is ? extremely S selective without, therefore, producing, if not in quantity? irrelevant, N-acylation as a byproduct.
Il metodo di sintesi oggetto della presente invenzione risulta vantaggiosamente applicabile su scala industriale. Infatti, oltre a garantire elevate rese e richiedere tempi contenuti, offre il grande vantaggio di essere estremamente economico e sicuro sia in termini ambientali sia in termini di salute degli operatori. The synthesis method object of the present invention is advantageously applicable on an industrial scale. In fact, in addition to guaranteeing high yields and requiring short times, it offers the great advantage of being extremely economical and safe both in environmental terms and in terms of operator health.
Infatti, va evidenziato che le reazioni di acilazione e di precipitazione avvengono a temperatura ambiente, e che ? previsto l?utilizzo di solventi quale l?acqua (per la fase di acilazione e precipitazione) e quale un liquido organico miscibile con l?acqua (per la fase di acilazione). In fact, it should be highlighted that the acylation and precipitation reactions take place at room temperature, and that ? the use of solvents such as water (for the acylation and precipitation phase) and an organic liquid miscible with water (for the acylation phase) is foreseen.
A favore del metodo di sintesi oggetto della presente invenzione va, inoltre, considerato che durante la fase di acilazione il N-acil imidazolo rilascia imidazolo come sottoprodotto, che ? sia atossico sia solubile in acqua e facilmente rimovibile dalle miscele di reazione. Differentemente, diversi metodi di sintesi dell?arte nota comportano il rilascio di acido cloridrico o di acido carbossilico con gli ovvi svantaggi noti ad un tecnico del ramo. In favor of the synthesis method object of the present invention it must also be considered that during the acylation phase the N-acyl imidazole releases imidazole as a by-product, which is both non-toxic and water soluble and easily removable from reaction mixtures. Differently, various synthesis methods of the prior art involve the release of hydrochloric acid or carboxylic acid with the obvious drawbacks known to a person skilled in the art.
Infine, va considerata la semplicit? e la vantaggiosit? con cui si pu? realizzare il N-acil imidazolo, nonch? l?elevata discrezionalit? con cui si pu? scegliere il radicale R che sar? incorporato nel S-acil glutatione. Infatti, il N-acil imidazolo viene realizzato in rese quantitative e a temperatura ambiente per semplice reazione di un acido carbossilico appositamente scelto in funzione del gruppo R, con il 1,1?-Carbonildiimidazolo (CDI) in un solvente organico miscibile con l?acqua come l'acetone, THF, acetonitrile o isopropanolo. Il CDI ? economico, facilmente disponibile in grandi quantit? e solubile in numerosi solventi organici e comunemente usato nell'industria farmaceutica. Inoltre, i sottoprodotti della reazione di preparazione del N-acil imidazolo (CO2 e imidazolo) possono essere facilmente rimossi dalla miscela di reazione dopo l'estinzione. Finally, it should be considered the simplicity? and the advantage? with which you can? make the N-acyl imidazole, as well as? the high discretion? with which you can? choose the radical R that will be? incorporated into S-acyl glutathione. In fact, N-acyl imidazole is obtained in quantitative yields and at room temperature by the simple reaction of a carboxylic acid specially selected according to the R group, with 1,1?-Carbonyldiimidazole (CDI) in an organic solvent miscible with water such as acetone, THF, acetonitrile or isopropanol. The CDI? cheap, easily available in large quantities? and soluble in numerous organic solvents and commonly used in the pharmaceutical industry. Furthermore, the by-products of the N-acyl imidazole preparation reaction (CO2 and imidazole) can be easily removed from the reaction mixture after quenching.
? importante anche sottolineare che il N-acil imidazolo prodotto ? aggiunto alla soluzione acquosa della fase di acilazione direttamente diluito nel solvente organico in cui ? stato realizzato. In questo modo non vi ? la necessit? di isolare il N-acil imidazolo prima di aggiungerlo alla miscela della reazione di acilazione, con gli ovvi vantaggi in termini di produttivit? che questo comporta. ? It is also important to point out that the N-acyl imidazole product is added to the aqueous solution of the acylation phase directly diluted in the organic solvent in which ? been accomplished. In this way there is no ? the need? to isolate the N-acyl imidazole before adding it to the acylation reaction mixture, with the obvious advantages in terms of productivity? that this entails.
Un altro aspetto importante da evidenziare ? relativo alla praticamente completa discrezionalit? nella scelta dell?acido carbossilico con cui preparare il N-acil imidazolo, come ? possibile rilevare dagli esempi sopra riportati. Questo comporta che possono essere scelti degli acidi carbossilici che, una volta liberati nella cellula dopo l?ingresso nella stessa del relativo S-acil glutatione, possono svolgere anch?essi una azione farmacologica. In questo modo, il S-acil glutatione ? in grado di svolgere una doppia azione farmacologia, quella del glutatione e quella dell?acido carbossilico. Another important aspect to highlight? relative to the practically complete discretionality? in the choice of the carboxylic acid with which to prepare the N-acyl imidazole, how? can be seen from the examples above. This implies that carboxylic acids can be chosen which, once released into the cell after the relative S-acyl glutathione enters it, can also perform a pharmacological action. In this way, the S-acyl glutathione ? capable of carrying out a double pharmacological action, that of glutathione and that of carboxylic acid.
Per concludere, i vantaggi di cui sopra fanno s? che il metodo di sintesi oggetto della presente invenzione possa essere applicato su scala industriale senza soffrire di problemi di produttivit? tipici dei metodi dell?arte nota. To conclude, the above advantages do s? that the synthesis method object of the present invention can be applied on an industrial scale without suffering from productivity problems? typical of the methods of the prior art.
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