IT8922003A1 - Processo per la preparazione dell'acido 3-(l-piroglutamil)-l- tiazolidin-4-carbossilico e suoi derivati. - Google Patents
Processo per la preparazione dell'acido 3-(l-piroglutamil)-l- tiazolidin-4-carbossilico e suoi derivati. Download PDFInfo
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- IT8922003A1 IT8922003A1 IT1989A22003A IT2200389A IT8922003A1 IT 8922003 A1 IT8922003 A1 IT 8922003A1 IT 1989A22003 A IT1989A22003 A IT 1989A22003A IT 2200389 A IT2200389 A IT 2200389A IT 8922003 A1 IT8922003 A1 IT 8922003A1
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- hydrogen
- thiazolidin
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- 238000000034 method Methods 0.000 title claims description 14
- 239000002253 acid Substances 0.000 title claims description 8
- 238000002360 preparation method Methods 0.000 title claims description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- -1 aliphatic cyclic amine Chemical class 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 125000004104 aryloxy group Chemical group 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 125000003107 substituted aryl group Chemical group 0.000 claims description 4
- 239000000010 aprotic solvent Substances 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 2
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 2
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 2
- 125000003277 amino group Chemical group 0.000 claims description 2
- 150000003974 aralkylamines Chemical class 0.000 claims description 2
- 125000005099 aryl alkyl carbonyl group Chemical group 0.000 claims description 2
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- 150000005619 secondary aliphatic amines Chemical class 0.000 claims description 2
- 125000005389 trialkylsiloxy group Chemical group 0.000 claims description 2
- 125000004665 trialkylsilyl group Chemical group 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 4
- 238000005904 alkaline hydrolysis reaction Methods 0.000 claims 1
- 125000003545 alkoxy group Chemical group 0.000 claims 1
- 125000005129 aryl carbonyl group Chemical group 0.000 claims 1
- 150000002431 hydrogen Chemical class 0.000 claims 1
- ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical compound OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 abstract description 7
- ODHCTXKNWHHXJC-UHFFFAOYSA-N acide pyroglutamique Natural products OC(=O)C1CCC(=O)N1 ODHCTXKNWHHXJC-UHFFFAOYSA-N 0.000 abstract description 5
- 238000009833 condensation Methods 0.000 abstract description 3
- 230000005494 condensation Effects 0.000 abstract description 3
- 238000006467 substitution reaction Methods 0.000 abstract description 3
- DZLNHFMRPBPULJ-UHFFFAOYSA-N thioproline Chemical class OC(=O)C1CSCN1 DZLNHFMRPBPULJ-UHFFFAOYSA-N 0.000 abstract description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- IZUPBVBPLAPZRR-UHFFFAOYSA-N pentachlorophenol Chemical compound OC1=C(Cl)C(Cl)=C(Cl)C(Cl)=C1Cl IZUPBVBPLAPZRR-UHFFFAOYSA-N 0.000 description 3
- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 description 2
- CFMZSMGAMPBRBE-UHFFFAOYSA-N 2-hydroxyisoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(O)C(=O)C2=C1 CFMZSMGAMPBRBE-UHFFFAOYSA-N 0.000 description 2
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- MJLQPFJGZTYCMH-LURJTMIESA-N (2s)-1-[(2-methylpropan-2-yl)oxycarbonyl]-5-oxopyrrolidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1[C@H](C(O)=O)CCC1=O MJLQPFJGZTYCMH-LURJTMIESA-N 0.000 description 1
- RMHPSSGICDJKDR-VKHMYHEASA-N (2s)-5-oxopyrrolidine-2-carbonyl chloride Chemical compound ClC(=O)[C@@H]1CCC(=O)N1 RMHPSSGICDJKDR-VKHMYHEASA-N 0.000 description 1
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 1
- XBNGYFFABRKICK-UHFFFAOYSA-N 2,3,4,5,6-pentafluorophenol Chemical compound OC1=C(F)C(F)=C(F)C(F)=C1F XBNGYFFABRKICK-UHFFFAOYSA-N 0.000 description 1
- LHJGJYXLEPZJPM-UHFFFAOYSA-N 2,4,5-trichlorophenol Chemical compound OC1=CC(Cl)=C(Cl)C=C1Cl LHJGJYXLEPZJPM-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- DZLNHFMRPBPULJ-GSVOUGTGSA-N D-thioproline Chemical compound OC(=O)[C@H]1CSCN1 DZLNHFMRPBPULJ-GSVOUGTGSA-N 0.000 description 1
- 229920002472 Starch Chemical class 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000003712 anti-aging effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000001147 anti-toxic effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- SQRLNYSSTHJCIU-JEDNCBNOSA-N ethyl (4r)-1,3-thiazolidine-4-carboxylate;hydrochloride Chemical compound Cl.CCOC(=O)[C@@H]1CSCN1 SQRLNYSSTHJCIU-JEDNCBNOSA-N 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 229960001438 immunostimulant agent Drugs 0.000 description 1
- 239000003022 immunostimulating agent Substances 0.000 description 1
- 230000003308 immunostimulating effect Effects 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- 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
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
- C07K5/06173—Dipeptides with the first amino acid being heterocyclic and Glp-amino acid; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Genetics & Genomics (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Immunology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Peptides Or Proteins (AREA)
- Thiazole And Isothizaole Compounds (AREA)
Description
Descrizione dell'invenzione industriale avente per titolo: "PROCESSO PER LA PREPARAZIONE DELL'ACIDO 3-(L-PIROGLUTA-MIL)?L-TIAZOLIDIN?4-CARBOSSILICO E SUOI DERIVATI"
RIASSUNTO
L'acido 3-(L-piroglutamil)-L-tiazolidin-4-carbossilico e suoi derivati di sostituzione vengono preparati con un procedimento per condensazione di acido L-piroglutammico o suoi prodotti di sostituzione, in presenza di dicicloesilcarbodiimide o simili,o per condensazione di derivati attivi di acido L-piroglutammico, con derivati dell'acido 4-tiazolidin-carbossilico.
DESCRIZIONE DELL'INVENZIONE
La presente invenzione riguarda un procedimento per la preparazione di acido 3-(-L-piroglutamil)-L-tiazolidin-4-carbossilico e suoi derivati.
Nel brevetto italiano 1 202 426 ? stato descritto l'acido 3-(-L-piroglutamil)-L-tiazolidin-4-carbossilico, dotato di propriet? immunostimolanti, antitossiche, antiinfiammatorie, antiossidanti ed antiinvecchiamento, preparato a partire da un estere attivato dell'acido L-piroglutammco o dal suo cloruro acido e da L-tiazolidin-4--carbossilico.
In particolare il procedimento utilizza ad esempio gli esteri attivi dell'acido L-piroglutammico con pentaclorofenolo, pentafluorofenolo, 2,4,5-triclorofenolo,N-idrossisuccinimide,N-idrossiftalimide,che vengono posti a reagire con l'acido L-tiazolidin-4-carbossilico in solventi aprotici in presenza di basi terziarie, o il cloruro dell'acido L-piroglutammico che viene fatto reagire con acido L-tiazolidin-4-carbossilico in ambiente alcalino.
Nella domanda di brevetto italiano 19401 A/89 sono stati descritti derivati dell'acido 3-(L-piroglutamil)-L-tiazolidin-4-carbossilico, che presentano le stesse propriet? farmacologiche, preparati con procedimenti del tutto analoghi da esteri od amidi attivati dell'acido L-piroglutamil-L-tiazolidin?4-carbossilico ed alcooli o ammine.
Questi procedimenti presentano alcuni svantaggi quali per esempio l'impiego di sostanze tossiche come gli alogenofenoli, la scarsa stabilit? degli esteri dell'acido L-piroglutaimmico co N-idrossisuccinimide e N-idrossiftalimide, le rese non soddisfacenti, l'estrema instabilit? e difficolt? di manipolazione del L-piroglutamilcloruro.
Tali svantaggi sono superati dal procedimento dell'invenzione che permette di ottenere questi composti in maniera pi? semplice, con rese pi? elevate e senza l'impiego di intermedi tossici e/o instabili.
Il procedimento dell'invenzione, consiste nella reazione di un composto di formula (X)
in cui:
R1 rappresenta H, alchile C1-C6, cicloalchile C3-C7, cicloalchilalchile C 4-C10, arile e arile sostituito, alcossicarbonile C 2-C5, alchilcarbonile C2-C10 arilcarbonile e aralchilcarbonile , aralcossicarbonile C8?C13 ,e aralcossicarbonile sostituito;
R2 rappresenta H, diclorofosforile , COOR5 dove R5 ? alchile C1-C8, arile e arile sostituito, aralchile C7-C12 e aralchile sostituito; con un conposto di formula (II)
dove R3 rappresenta H, trialchilsilile C3-C9
R4 rappresenta alcossi C1-C6, arilossi o arilossi sostituito, aralcossi C7-C o aralcossi sostituito, trialchilsililossi C3-C un gruppo aminico, il residuo di un'amina alifatica primaria o secondaria con 1-8 atemi di carbonio eventualmente contenente 1 o pi? doppi e/o tripli legami, di un'aralchilamina primaria, di un'amina ciclica alifatica con 4-8 atomi di carbonio e un atomo di ossigeno, con la condizione che quando R2 ? idrogeno, si opera in presenza di agenti condensati cane dicicloesilcarbodiimide , di?sopropilcarbodiimide o carbodiimidi basiche, in solventi aprotici cane diossano, tetraidrofurano, etile acetato, dimetilformamide , dimetilsolfossido, esametilfosfotriamide o miscela di questi, a dare un derivato di formula (III)
dell'acido 3-(L-piroglutamil)-L-tiazolidin-4-carbossilico in cui R3, R4 ed R5 hanno i significati sopra menzionati, che pu? essere eventualmente trasformato con eccellenti rese nell'acido 3-(L-piroglutamil)--L-tiazolidin-4-carbossilico (R4=H) in blande condizioni d'idrolisi acida o basica. Gli esempi che seguono illustrano la presente invenzione.
ESEMPIO 1
Una soluzione di 16,78 g (0,084 moli) di etile L-tiazolidin-4--carbossilato cloridrato in 33 mi di acqua viene trattata con 16,78 g di potassio carbonato ed estratta con 40 ml di etile acetato. La fase organica viene essiccata su sodio solfato,filtrata e portata a 85 ml con etile acetato. Alla soluzione agitata a 0-5?C vengano quindi aggiunti 19,2 g (0,093 moli) di dicicloesilcarbodiimide sciolti in 20 ml di etile acetato e 12 g (0,093 noli) di acido L-piroglutannico- Si agita 1 ora a 0-5?C,12 ore a temperatura ambiente, si filtra la dicicloesilurea, si evapora il filtrato sotto vuoto e si riprende il residuo oleoso costituito da etile 3-(L-piroglutamil)-L-tiazolidin-4-carbossilato in 25 ml di acqua. Nella soluzione cos? ottenuta vengono gocciolati a 5-10?C 3,73 g di sodio idrossido sciolti in 13,3 ml di acqua. Dopo 30 min a 10?C si acidifica con acido cloridrico concentrato a 0-5?C, si mantiene 2 ore a 5?C, si filtra lavando con poca acqua fredda e si secca ottenendo 17,8 g (87,6%) di acido 3-(L-piroglutamil)-L-tiazolidin-4-carbossilico, Pf. 193-194?C
ESEMPIO 2
6,65 g (0,05 moli) di acido L-tiazolidin-4-carbossilico vengono rifluiti per 24 ore in 50 mi di etile acetato con 32,25 g di esametildisilazano.La soluzione ottenuta viene evaporata sotto vuoto a peso costante ed il residuo ridisciolto in 30 ml di etile acetato anidro. Questa soluzione viene aggiunta in 30 min a 0?C ad un'altra ottenuta precedentemente gocciolando 6,8 g (0,05 moli) di isobutilcloroformiato in 5 ml di diossano in una miscela di 6,45 g (0,05 moli) di acido L-piroglutammico, 7 ml (0,05 moli) di trietilammina e 50 ml di diossano. Si agita 90 min a temperatura ambiente, 20 min a riflusso, si raffredda, si filtra il materiale insolubile, si evapora il filtrato sotto vuoto a residuo costante,a questo si aggiungono 20 ml di acqua, si porta all'ebollizione per 5 min, quindi si raffredda a 0-5?C per 2 ore. Cristallizza l'acido 3-(L-piroglutamil)-L-tiazolidin-4-carbossilico.Pf 193-194?C
ESEMPIO 3
23 g (0,1 moli) di acido L-N-t-butossicarbonilpiroglutammico (E. Schroder e E.Klinger,Ann.dar Ch., 673, 1964 p.202) e 16,1 g di etile L-tiazolidin-4-carbossilato vengono disciolti in 150 mi di tetraidrofurano, alla soluzione a 0-5?C si aggiungono 21 g (0,105 moli) di dicicloesilcarbodiimide e si agita per 15 ore a temperatura ambiente. Si filtra la dicicloesilurea, si evapora il filtrato sotto vuoto e si ri? prende il residuo con 40 ml di acqua. Alla soluzione si aggiungano a gocce 6,6 g di potassio idrossido sciolto in poca acqua in 30 min mantenendo la temperatura a 15-20?C e la soluzione cos? ottenuta viene acidificata a pH 2 a 0-5?C con acido cloridrico concentrato. Dopo 2 ore, l'acido L-piroglutamil-L-tiazolidin-4-carbossilico viene filtrato e seccato, Pf 193-194?C.
Claims (5)
- RIVENDICAZIOI I. Processo per la preparazione di un composto di formula (III) -in cui R rappresenta H, alchile C1-C6, cicloalchile C3-C7, cicloalchilalchile C4-C10, arile e arile sostituito, alcossicarbonile C2-C5, alchilcarbonile C2-C10 , arilcarbonile e aralchilcarbonile, aralcossicarbonile C8-C13 e aralcossicarbonile sostituito e rappresenta alcossi C1-C6, arilossi o arilossi sostituito, aralcossi C7-C12 o aralcossi sostituito, trialchilsililossi C3-C9, un gruppo aminico, il residuo di un'amina alifatica primaria o secondaria con 1?8 atomi di carbonio eventualmente contenente 1 o pi? doppi e/o tripli legami, di un'aralchilamina primaria, di un'amina ciclica alifatica con 4-8 atomi di carbonio e un atomo di ossigeno, che comprende la reazione di un composto di formula (I)in cui R1 ? come sopra definito e R2 rappresenta H, diclorofosforile, COOR5 dove ? alchile C1-C8, arile e arile sostituito, aralchile C7-C12 e aralchile sostituito; con un composto di formula (II)in cui R4 ? come sopra definito e R3 rappresenta H, trialchilsilile C3-C9 con la condizione che, quando ? idrogeno, si opera in presenza degli agenti condensanti dicicloesilcarbodiimide, diisopropilcarboodiimide o simili.
- 2. Processo secondo la rivendicazione 1 caratterizzata dal fatto che si opera in solventi aprotici scelti fra diossano, tetraidrofurano, etile acetato, dimetilformamide, dimetilsolfossido, esametilfosfotriamide o loro miscele.
- 3. Processo secondo la rivendicazione 1 o 2 caratterizzata dal fatto che il composto ottenuto di formula (III) in cui ? diverso da idrogeno ? ulteriormente sottoposto a idrolisi acida o basica a dare un composto di formula (III) in cui R4 ? idrogeno.
- 4. Processo secondo una qualunque delle rivendicazioni precedenti per la preparazione di acido 3-(L-piroglutamil)-L-tiazolidin-4-carbossilico.
- 5. Processo secondo la rivendicazione 4 caratterizzata dal fatto che si fa reagire un composto di formula (I) in cui R1 e R2 sono idrogeno con un ccnposto di formula (II) in cui Rg ? idrogeno e R4? alcossi, e successiva idrolisi alcalina.
Priority Applications (19)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT22003A IT1239029B (it) | 1989-10-12 | 1989-10-12 | Processo per la preparazione dell'acido 3-(l-piroglutamil)-l- tiazolidin-4-carbossilico e suoi derivati. |
| DE69018755T DE69018755T2 (de) | 1989-10-12 | 1990-10-08 | Verfahren zur Herstellung von 3-(L-Pyroglutamyl)-L-thiazolidin-4-carbonsäure-Derivaten. |
| EP90119271A EP0422566B1 (en) | 1989-10-12 | 1990-10-08 | A process for the preparation of 3-(L-pyroglutamyl)-L-thiazolidine-4-carboxylic acid derivatives |
| DK90119271.6T DK0422566T3 (da) | 1989-10-12 | 1990-10-08 | Fremgangsmåde til fremstilling af 3-(L-pyroglutamyl)-L-thiazolidin-4-carboxylsyre og derivater deraf |
| DE199090119271T DE422566T1 (de) | 1989-10-12 | 1990-10-08 | Verfahren zur herstellung von 3-(l-pyroglutamyl)-l-thiazolidin-4-carbonsaeure-derivaten. |
| ES90119271T ES2028766T3 (es) | 1989-10-12 | 1990-10-08 | Un procedimiento para la preparacion de derivados de acido 3-(l-piroglutamil)-l-tiazolidina-4-carboxilico. |
| AT90119271T ATE121420T1 (de) | 1989-10-12 | 1990-10-08 | Verfahren zur herstellung von 3-(l-pyroglutamyl)- l-thiazolidin-4-carbonsäure-derivaten. |
| IE359990A IE67047B1 (en) | 1989-10-12 | 1990-10-08 | A process for the preparation of 3-(L-pyroglutamyl)-L-thiazolidine-4-carboxylic acid derivatives |
| ZA908097A ZA908097B (en) | 1989-10-12 | 1990-10-09 | A process for the preparation of 3-(l-pyroglutamyl)-l-thiazolidine-4-carboxylic acid and its derivatives |
| US07/594,313 US5110936A (en) | 1989-10-12 | 1990-10-09 | Process for the preparation of 3-(lpyroglutamyl)-l-thiazolidine-4-carboxylic acid derivatives |
| KR1019900015999A KR100195895B1 (ko) | 1989-10-12 | 1990-10-10 | 3-(l-피로글루타밀)-l-티아졸리딘-4-카르복실산 및 그 유도체의 제조방법) |
| IL9594990A IL95949A (en) | 1989-10-12 | 1990-10-10 | Process for the preparation of L-) - 3 pyroglutamil (- L-thiolidine-4-carboxylic acid and its history |
| AU64521/90A AU644379B2 (en) | 1989-10-12 | 1990-10-11 | A process for the preparation of 3-(l-pyroglutamyl)-l- thiazolidine-4-carboxylic acid and its derivatives |
| NO904404A NO178028C (no) | 1989-10-12 | 1990-10-11 | Fremgangsmåte ved fremstilling av 3-(L-pyroglutamyl)-L-tiazolidin-4-karboksylsyre samt derivater derav |
| HU906417A HU210213B (en) | 1989-10-12 | 1990-10-11 | A process for preparation of 3-(l-pyroglutamyl)-l-thiazolidine-4-carboxylic acid and it's derivatives |
| CA002027341A CA2027341C (en) | 1989-10-12 | 1990-10-11 | Process for the preparation of 3-(l-pyroglutamyl)-l-thiazolidine-4-carboxylic acid and its derivatives |
| FI905011A FI95271C (fi) | 1989-10-12 | 1990-10-11 | Menetelmä 3-(L-pyroglutamyyli)-L-tiatsolidiini-4-karboksyylihapon ja sen N-substituoitujen johdannaisten valmistamiseksi |
| JP2275100A JP2813450B2 (ja) | 1989-10-12 | 1990-10-12 | ３―（ｌ―ピログルタミル）―ｌ―チアゾリジン―４―カルボン酸およびその誘導体の製造方法 |
| GR91300072T GR910300072T1 (en) | 1989-10-12 | 1991-11-15 | A process for the preparation of 3-(l-pyroglutamyl)-l-thiazolidine-4-carboxylic acid derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT22003A IT1239029B (it) | 1989-10-12 | 1989-10-12 | Processo per la preparazione dell'acido 3-(l-piroglutamil)-l- tiazolidin-4-carbossilico e suoi derivati. |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| IT8922003A0 IT8922003A0 (it) | 1989-10-12 |
| IT8922003A1 true IT8922003A1 (it) | 1991-04-12 |
| IT1239029B IT1239029B (it) | 1993-09-20 |
Family
ID=11190043
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IT22003A IT1239029B (it) | 1989-10-12 | 1989-10-12 | Processo per la preparazione dell'acido 3-(l-piroglutamil)-l- tiazolidin-4-carbossilico e suoi derivati. |
Country Status (18)
| Country | Link |
|---|---|
| US (1) | US5110936A (it) |
| EP (1) | EP0422566B1 (it) |
| JP (1) | JP2813450B2 (it) |
| KR (1) | KR100195895B1 (it) |
| AT (1) | ATE121420T1 (it) |
| AU (1) | AU644379B2 (it) |
| CA (1) | CA2027341C (it) |
| DE (2) | DE69018755T2 (it) |
| DK (1) | DK0422566T3 (it) |
| ES (1) | ES2028766T3 (it) |
| FI (1) | FI95271C (it) |
| GR (1) | GR910300072T1 (it) |
| HU (1) | HU210213B (it) |
| IE (1) | IE67047B1 (it) |
| IL (1) | IL95949A (it) |
| IT (1) | IT1239029B (it) |
| NO (1) | NO178028C (it) |
| ZA (1) | ZA908097B (it) |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1230706B (it) * | 1989-02-10 | 1991-10-29 | Poli Ind Chimica Spa | Derivati dell'acido 3 piroglutamoil tiazolidin 4 carbossilico e loro proprieta' farmacologiche. |
| IT1237998B (it) * | 1990-01-23 | 1993-06-21 | Poli Ind Chimica Spa | Acido 3-l-(5-tioxo-l-prolil)tiazolidin-4-carbossilico e derivati, loro preparazione e composizioni farmaceutiche che li contengono |
| IT1270017B (it) * | 1994-09-27 | 1997-04-16 | Poli Ind Chimica Spa | "sintesi quantitativa dell'acido 3-(l-piroglutamil)-l-tiazolidin-4- carbossilico e suoi derivati" |
| CA2263764A1 (en) * | 1996-09-06 | 1998-03-12 | Michael John Martinelli | Process and novel intermediates |
| JP2010537984A (ja) * | 2007-08-28 | 2010-12-09 | イプセン ファルマ ソシエテ パール アクシオン サンプリフィエ | ポリペプチドおよび蛋白質の化学合成のための方法および中間体 |
| CN102167727B (zh) * | 2011-01-29 | 2013-05-15 | 浙江金立源药业有限公司 | 一种匹多莫德的合成方法 |
| WO2016112977A1 (en) | 2015-01-15 | 2016-07-21 | Polichem S.A. | Di-pidotimod benzathine and solid forms thereof |
| KR101642445B1 (ko) * | 2016-01-11 | 2016-07-26 | (주)남양통신 | 수상태양광 발전장치용 계류장치 |
| CN107383162A (zh) * | 2017-07-06 | 2017-11-24 | 成都美域高制药有限公司 | 一种匹多莫德的制备方法 |
| CN108640912A (zh) * | 2018-06-19 | 2018-10-12 | 广州大光制药有限公司 | 一种匹多莫德的工业化规模制备方法 |
| CN111233854A (zh) * | 2019-12-30 | 2020-06-05 | 常州寅盛药业有限公司 | 一种匹多莫德杂质的制备方法 |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1202426B (it) * | 1987-01-26 | 1989-02-09 | Poli Ind Chimica Spa | Derivato di acido tiazolidin-4-carbossilico,sua preparazione e composizioni farmaceutiche che lo contengono |
-
1989
- 1989-10-12 IT IT22003A patent/IT1239029B/it active IP Right Grant
-
1990
- 1990-10-08 ES ES90119271T patent/ES2028766T3/es not_active Expired - Lifetime
- 1990-10-08 DE DE69018755T patent/DE69018755T2/de not_active Expired - Fee Related
- 1990-10-08 EP EP90119271A patent/EP0422566B1/en not_active Expired - Lifetime
- 1990-10-08 DE DE199090119271T patent/DE422566T1/de active Pending
- 1990-10-08 IE IE359990A patent/IE67047B1/en not_active IP Right Cessation
- 1990-10-08 AT AT90119271T patent/ATE121420T1/de not_active IP Right Cessation
- 1990-10-08 DK DK90119271.6T patent/DK0422566T3/da active
- 1990-10-09 ZA ZA908097A patent/ZA908097B/xx unknown
- 1990-10-09 US US07/594,313 patent/US5110936A/en not_active Expired - Lifetime
- 1990-10-10 IL IL9594990A patent/IL95949A/en not_active IP Right Cessation
- 1990-10-10 KR KR1019900015999A patent/KR100195895B1/ko not_active IP Right Cessation
- 1990-10-11 AU AU64521/90A patent/AU644379B2/en not_active Ceased
- 1990-10-11 NO NO904404A patent/NO178028C/no unknown
- 1990-10-11 HU HU906417A patent/HU210213B/hu not_active IP Right Cessation
- 1990-10-11 FI FI905011A patent/FI95271C/fi active IP Right Grant
- 1990-10-11 CA CA002027341A patent/CA2027341C/en not_active Expired - Fee Related
- 1990-10-12 JP JP2275100A patent/JP2813450B2/ja not_active Expired - Fee Related
-
1991
- 1991-11-15 GR GR91300072T patent/GR910300072T1/el unknown
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