PL181824B1 - Method of quantitatively synthesising 3-(l-pyrrogutamyl)-l-thiazolydino-4-carbpxylic acid and its derivatives - Google Patents
Method of quantitatively synthesising 3-(l-pyrrogutamyl)-l-thiazolydino-4-carbpxylic acid and its derivativesInfo
- Publication number
- PL181824B1 PL181824B1 PL95319380A PL31938095A PL181824B1 PL 181824 B1 PL181824 B1 PL 181824B1 PL 95319380 A PL95319380 A PL 95319380A PL 31938095 A PL31938095 A PL 31938095A PL 181824 B1 PL181824 B1 PL 181824B1
- Authority
- PL
- Poland
- Prior art keywords
- formula
- compound
- halide
- hydrogen
- acid
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 32
- 239000002253 acid Substances 0.000 title description 5
- -1 3-(L-pyroglutamyl)-L-thiazolidyl Chemical group 0.000 claims abstract description 26
- 150000001875 compounds Chemical class 0.000 claims abstract description 17
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims abstract description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 10
- 239000001257 hydrogen Substances 0.000 claims abstract description 8
- 239000000010 aprotic solvent Substances 0.000 claims abstract description 7
- 239000003444 phase transfer catalyst Substances 0.000 claims abstract description 6
- 125000004494 ethyl ester group Chemical group 0.000 claims abstract description 5
- 125000003118 aryl group Chemical group 0.000 claims abstract description 4
- 230000007062 hydrolysis Effects 0.000 claims abstract description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 4
- 230000003213 activating effect Effects 0.000 claims abstract description 3
- 125000005099 aryl alkyl carbonyl group Chemical group 0.000 claims abstract description 3
- 125000005129 aryl carbonyl group Chemical group 0.000 claims abstract description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical compound OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 claims description 8
- ODHCTXKNWHHXJC-UHFFFAOYSA-N acide pyroglutamique Natural products OC(=O)C1CCC(=O)N1 ODHCTXKNWHHXJC-UHFFFAOYSA-N 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 7
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 6
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 claims description 4
- RWGFKTVRMDUZSP-UHFFFAOYSA-N cumene Chemical compound CC(C)C1=CC=CC=C1 RWGFKTVRMDUZSP-UHFFFAOYSA-N 0.000 claims description 4
- DIOQZVSQGTUSAI-UHFFFAOYSA-N decane Chemical compound CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 claims description 4
- BKIMMITUMNQMOS-UHFFFAOYSA-N nonane Chemical compound CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 claims description 4
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 claims description 4
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 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 claims description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- NHTMVDHEPJAVLT-UHFFFAOYSA-N Isooctane Chemical compound CC(C)CC(C)(C)C NHTMVDHEPJAVLT-UHFFFAOYSA-N 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 229960004830 cetylpyridinium Drugs 0.000 claims description 2
- JVSWJIKNEAIKJW-UHFFFAOYSA-N dimethyl-hexane Natural products CCCCCC(C)C JVSWJIKNEAIKJW-UHFFFAOYSA-N 0.000 claims description 2
- 150000004820 halides Chemical class 0.000 claims description 2
- 239000003208 petroleum Substances 0.000 claims description 2
- 125000003107 substituted aryl group Chemical group 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
- NEUSVAOJNUQRTM-UHFFFAOYSA-N cetylpyridinium Chemical compound CCCCCCCCCCCCCCCC[N+]1=CC=CC=C1 NEUSVAOJNUQRTM-UHFFFAOYSA-N 0.000 claims 1
- MZMRZONIDDFOGF-UHFFFAOYSA-M hexadecyl(trimethyl)azanium;4-methylbenzenesulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1.CCCCCCCCCCCCCCCC[N+](C)(C)C MZMRZONIDDFOGF-UHFFFAOYSA-M 0.000 claims 1
- 150000002431 hydrogen Chemical class 0.000 claims 1
- 239000002904 solvent Substances 0.000 claims 1
- 125000005098 aryl alkoxy carbonyl group Chemical group 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 150000002500 ions Chemical class 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 150000002148 esters Chemical class 0.000 description 6
- DZLNHFMRPBPULJ-GSVOUGTGSA-N D-thioproline Chemical compound OC(=O)[C@H]1CSCN1 DZLNHFMRPBPULJ-GSVOUGTGSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 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
- 239000012071 phase Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- RMHPSSGICDJKDR-VKHMYHEASA-N (2s)-5-oxopyrrolidine-2-carbonyl chloride Chemical compound ClC(=O)[C@@H]1CCC(=O)N1 RMHPSSGICDJKDR-VKHMYHEASA-N 0.000 description 2
- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- ZRBNETYZYOXTLS-UHFFFAOYSA-N ethyl 1,3-thiazolidine-4-carboxylate Chemical compound CCOC(=O)C1CSCN1 ZRBNETYZYOXTLS-UHFFFAOYSA-N 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- REACWASHYHDPSQ-UHFFFAOYSA-N 1-butylpyridin-1-ium Chemical compound CCCC[N+]1=CC=CC=C1 REACWASHYHDPSQ-UHFFFAOYSA-N 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
- 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 1
- XXYNZSATHOXXBJ-UHFFFAOYSA-N 4-hydroxyisoindole-1,3-dione Chemical compound OC1=CC=CC2=C1C(=O)NC2=O XXYNZSATHOXXBJ-UHFFFAOYSA-N 0.000 description 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001408 amides 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
- 239000008346 aqueous phase Substances 0.000 description 1
- ZRBNETYZYOXTLS-YFKPBYRVSA-N ethyl (4r)-1,3-thiazolidine-4-carboxylate Chemical compound CCOC(=O)[C@@H]1CSCN1 ZRBNETYZYOXTLS-YFKPBYRVSA-N 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
- 239000000706 filtrate Substances 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 230000003308 immunostimulating effect Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- XKBGEWXEAPTVCK-UHFFFAOYSA-M methyltrioctylammonium chloride Chemical compound [Cl-].CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC XKBGEWXEAPTVCK-UHFFFAOYSA-M 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- DZLNHFMRPBPULJ-UHFFFAOYSA-N thioproline Chemical class OC(=O)C1CSCN1 DZLNHFMRPBPULJ-UHFFFAOYSA-N 0.000 description 1
- 125000003944 tolyl group Chemical group 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
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
- C07K5/04—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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biophysics (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Catalysts (AREA)
- Pyrrole Compounds (AREA)
Abstract
1. Sposób w ytw arzaniakw asu3-(L-piroglutam ylo)-L-tiazolid y n o -4 -k arb o k sy lo w eg o i jeg o pochodnych, o wzorze (III) ( I I I ) w którym R 1 oznacza wodór, C 1-C6-alkil, C 3-C 7-cykloalkiI, C 4-C 1 0 -cykloalkiIoalkil. aryl i podstaw iony aryl. C2-C5 - yalkoksykarbonyl, C2-C 1 0 -alkilokarbonyl. arylokarbonyl i aryloalkilokarbonyl. C 8-C 1 3 -aryloalkoksykarbonyl, podsta- w iony aryloalkoksykarbonyl, polegajacy na tym, ze zwiazek o wzorze (I) ( I ) w którym R, ma wyzej podane znaczenie, a X oznacza OH, Cl lub O R2, gdzie R2 oznacza grupe aktyw ujaca, poddaje sie reakcji ze zwiazkiem o wzorze (11) ( I I ) w którym R3 oznacza H. C 3-C9-trialkilosilil. w apolarnych rozpuszczalnikach aprotycznych; znam ienny tym. ze uzy- skany ester etylowy poddaje sie hydrolizie zasadowej, z zastosowaniem zasady wybranej sposród w odorotlenku sodu lub po- tasu. w obecnosci katalizatora przeniesienia fazy. w tem peraturze m ieszczacej sie w zakresie 0-5°C w czasie 30-60 minut. PL 1. Method for the production of 3-(L-pyroglutamyl)-L-thiazolidyl n o -4-carboxylic acid and its derivatives, with formula (III) (I I I) in which R 1 is hydrogen, C 1-C6-alkyl, C3-C7-cycloalkyl, C4-C10-cycloalkylalkyl. aryl and aryl substituted ions. C2-C5 - yalkoxycarbonyl, C2-C 1 0 -alkylcarbonyl. arylcarbonyl and arylalkylcarbonyl. C 8 -C 1 3 -arylalkoxycarbonyl, substituted arylalkoxycarbonyl, in that the compound of formula (I) (I) in which R has the meaning given above and X is OH, Cl or O R2, where R2 means an activating group, is reacted with a compound of formula (11) (I I) in which R3 is H. C3-C9-trialkylsilyl. in apolar aprotic solvents; I know another one. that the obtained ethyl ester is subjected to basic hydrolysis, using a base selected from sodium hydroxide or potassium hydroxide. in the presence of a phase transfer catalyst. at a temperature ranging from 0-5°C for 30-60 minutes. PL
Description
Niniejszy wynalazek dotyczy sposobu wytwarzania kwasu L-piroglutaminowego lub jego pochodnych.The present invention relates to a process for the production of L-pyroglutamic acid or its derivatives.
Opis patentowy włoski nr 1 202 426 ujawnia kwas L-piroglutamylo-L-tiazolidyno-4-karboksylowy o właściwościach immunostymulujących, antytoksycznych, przeciwzapalnych, przeciwutleniających i przeciwstarzeniowych, który wytwarza się wychodząc z reaktywnego estru kwasu L-piroglutaminowego lub z jego chlorku kwasowego i kwasu L-tiazolidyno-4-karboksylowego.Italian Patent No. 1 202 426 discloses L-pyroglutamyl-L-thiazolidine-4-carboxylic acid with immunostimulating, antitoxic, anti-inflammatory, antioxidant and anti-aging properties, which is produced starting from the reactive ester of L-pyroglutamic acid or from its acid chloride and acid L-thiazolidine-4-carboxylic acid.
W szczególności, sposób wykorzystuje, np., reaktywne estry kwasu L-piroglutaminowego z pentachlorofenolem, pentafluorofenolem, 2,4,5-trichlorofenolem, N-hydroksysukcynimidem, hydroksyftalimidem, które poddaje się reakcji z kwasem L-tiazolidyno-4-karboksylowym w rozpuszczalnikach aprotycznych w obecności zasad trzeciorzędowych, lub chlorek kwasu L-piroglutaminowego, który poddaje się reakcji z kwasem L-tiazolidyno-4-karboksylowym w środowisku zasadowym.In particular, the method uses, e.g., reactive esters of L-pyroglutamic acid with pentachlorophenol, pentafluorophenol, 2,4,5-trichlorophenol, N-hydroxysuccinimide, hydroxyphthalimide, which are reacted with L-thiazolidine-4-carboxylic acid in aprotic solvents in the presence of tertiary bases, or L-pyroglutamic acid chloride which is reacted with L-thiazolidine-4-carboxylic acid in a basic medium.
Włoskie zgłoszenie patentowe nr 19401 A/89 opisuje pochodne kwasu 3-(L-piroglutamylo)-L-tiazolidyno-4-karboksylowego, o takich samych właściwościach farmakologicznych, wytwarzane podobnymi sposobami z reaktywnych estrów lub amidów kwasu L-piroglutamylo-L-tizaolidyno-4-karboksylowego i alkoholi lub amin.Italian patent application No. 19401 A / 89 describes 3- (L-pyroglutamyl) -L-thiazolidine-4-carboxylic acid derivatives with the same pharmacological properties, prepared by similar methods from reactive esters or amides of L-pyroglutamyl-L-tizaolidine-acid. 4-carboxylic acid and alcohols or amines.
Sposoby te mająpewne cechy niekorzystne z praktycznego punktu widzenia, mianowicie: kłopotliwe procesy z nadmiernie niskimi wydajnościami całkowitymi, użycie substancji wysoce toksycznych dla człowieka oraz środowiska, takich jak chlorowcofenole, stosowanie chlorku L-piroglutamylu, który bardzo trudno wytworzyć i którym trudno operować i niska trwałość reaktywnych estrów kwasu L-piroglutaminowego z N-hydrosukcynimidem i N-hydroksyftalimidem.These methods have some disadvantages from a practical point of view, namely: cumbersome processes with excessively low total yields, the use of substances highly toxic to humans and the environment, such as halophenols, the use of L-pyroglutamyl chloride, which is very difficult to produce and which is difficult to handle, and low durability reactive esters of L-pyroglutamic acid with N-hydrosuccinimide and N-hydroxyphthalimide.
Opis patentowy włoski nr 1239029 ujawnia sposób, w którym wyżej wspomniane problemy częściowo rozwiązano za pomocą prostszego procesu, bez użycia szczególnie toksycznych substancji, pracochłonnych i/lub nietrwałych półproduktów oraz z wyższymi wydajnościami. Taki proces unaocznił zaskakującą trwałość tiazolidyno-4-karboksylanu etylu, dając wydajności zasadniczo wyższe niż uzyskane w przypadku innych prostych estrów, takich jak metylowy i izopropylowy.Italian Patent No. 1,239,029 discloses a method in which the above-mentioned problems are partially solved by a simpler process, without the use of particularly toxic substances, labor-intensive and / or unstable intermediates, and with higher yields. This process demonstrated the surprising stability of the ethyl thiazolidine-4-carboxylate with yields substantially higher than those obtained with other simple esters such as methyl and isopropyl.
Obecnie stwierdzono, że wspomniany sposób można dalej ulepszyć, uzyskując niemal ilościowe wydajności żądanych produktów, kondensując tiazolidyno-4-karboksylan etylu lub jego pochodną z pochodną kwasu L-piroglutaminowego w apolamych rozpuszczalnikach aprotycznych i hydrolizując ostatecznie ester etylowy w warunkach przeniesienia międzyfazowego.It has now been found that said process can be further improved to near quantitative yields of the desired products by condensing ethyl thiazolidine-4-carboxylate or a derivative thereof with a L-pyroglutamic acid derivative in aprotic solvents and finally hydrolyzing the ethyl ester under phase transfer conditions.
181 824181 824
Zatem, wynalazek dostarcza sposobu wytwarzania związku o wzorze (III)Thus, the invention provides a method for the preparation of a compound of formula (III)
w którym Ri oznacza H, Ci-Cć-alkil, C3-C7-cykloalkil, C4-Cio-cykloalkiloalkil, aryl i podstawiony aryl, C2-Cs-alkoksykarbonyl, C2-Cio-alkilokarbonyl, arylokarbonyl i aryloalkilokarbonyl, Cg-C13-aryloalkoksykarbonyl, podstawiony aryloalkoksykarbonyl, charakteryzujący tym, że związek o wzorze (I)wherein R 1 is H, C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, C 4 -C 10 -cycloalkylalkyl, aryl and substituted aryl, C 2 -C 8 -alkoxycarbonyl, C 2 -C 6 -alkylcarbonyl, arylcarbonyl and arylalkylcarbonyl, C8- C13-arylalkoxycarbonyl, substituted arylalkoxycarbonyl, characterized in that the compound of formula (I)
w którym Ri jest takie jak określony wyżej, a X oznacza OH, Cl lub OR2, w którym R2 oznacza grupę aktywującą, poddaje się reakcji ze związkiem o wzorze (II)wherein R is as defined above and X is OH, Cl or OR2 wherein R2 is an activating group, is reacted with a compound of formula (II)
COOCjHg w którym R3 oznacza H, Cs-Cg-trialkilosilil, w apolamych rozpuszczalnikach aprotycznych, a uzyskany ester etylowy poddaje się hydrolizie zasadowej, z zastosowaniem zasady wybranej spośród wodorotlenku sodu lub potasu, w obecności katalizatora przeniesienia fazy, w temperaturze mieszczącej się w zakresie 0-5 °C w czasie 30-60 minut.COOCjHg where R 3 is H, C 8 -C 6 -trialkylsilyl, in aprotic solvents, and the resulting ethyl ester is subjected to basic hydrolysis with a base selected from sodium or potassium hydroxide in the presence of a phase transfer catalyst at a temperature in the range of 0-5 ° C for 30-60 minutes.
Korzystnie stosuje się apolame rozpuszczalniki aprotyczne wybrane z grupy obejmującej: n-pentan, n-heksan, n-heptan, n-oktan, izooktan, nonan, dekan, eter naftowy, ligroinę, toluen, ksylen, kumen, dichlorometan, chloroform, dichloroetan i ich mieszaniny.Preference is given to using apolar aprotic solvents selected from the group consisting of: n-pentane, n-hexane, n-heptane, n-octane, isooctane, nonane, decane, petroleum ether, ligroin, toluene, xylene, cumene, dichloromethane, chloroform, dichloroethane and mixtures thereof.
Korzystnie stosuje się związek o wzorze 1 w którym X = OH, a reakcję przeprowadza się w obecności środka kondensującego, takiego jak dicykloheksylokarbodiimid lub diizopropylokarbodiimid.Preferably a compound of formula I is used in which X = OH and the reaction is performed in the presence of a condensing agent such as dicyclohexylcarbodiimide or diisopropylcarbodiimide.
Korzystnie stosuje się katalizatory przeniesienia międzyfazowego wybrane z grupy obejmującej: halogenek tetrabutyloamoniowy lub wodorosiarczan lub tetrafluoroboran, halogenek tetraetylamoniowy lub wodorosiarczan lub tetrafluoroboran; halogenek cetylopirydyniowy, halogenek metylotributylu, chlorek metylotrialkiloamoniowy w którym grupy alkilowe stanowią mieszaninę prostych łańcuchów Cg-Cl0, (Adogen 464), p-toluenosulfonian trimetylocetyloamoniowy, halogenek tetrabutylofosfoniowy, halogenek tetrafenylofosfoniowy, halogenek trifenylometylofosfoniowy, halogenek butylopirydyniowy.Preference is given to using phase transfer catalysts selected from the group consisting of: tetrabutylammonium halide or bisulfate or tetrafluoroborate, tetraethylammonium halide or bisulfate or tetrafluoroborate; halide, cetylpyridinium halide, metylotributylu chloride metylotrialkiloamoniowy wherein the alkyl groups are a mixture of straight chain C g-C l0 (Adogen 464), p-toluenesulphonate halide, tetrabutylphosphonium halide, tetraphenylphosphonium halide, triphenylmethylphosphonium halide, butylpyridinium.
Korzystnie stosuje się związek o wzorze 1 w którym R] jest wybrany z grupy obejmującej atom wodoru i C2-C5-alkoksykarbonyl.Preferably, a compound of formula 1 wherein R] is selected from the group consisting of hydrogen and C 2 -C 5 -alkoxycarbonyl.
Korzystnie jako związek o wzorze (I) stosuje się kwas L-piroglutaminowy lub kwas L-N-t-butoksykarbonylopiroglutaminowy.Preferably the compound of formula (I) is L-pyroglutamic acid or L-N-t-butoxycarbonylpyroglutamic acid.
Korzystnie sposób według wynalazku stosuje się do wytwarzania kwasu 3-(L-piroglutamylo)-L-tiazolidyno-4-karboksylowego.Preferably the process of the invention is used for the preparation of 3- (L-pyroglutamyl) -L-thiazolidine-4-carboxylic acid.
Korzystnie związek o wzorze (I), w którym R, oznacza atom wodoru, a X oznacza OH, poddaje się reakcji ze związkiem o wzorze (II), w którym R3 oznacza atom wodoru.Preferably a compound of formula (I) in which R 1 is hydrogen and X is OH is reacted with a compound of formula (II) in which R 3 is hydrogen.
181 824181 824
Stosując związek o wzorze I, w którym X = OH, reakcję ze związkiem o wzorze II przeprowadza się w obecności środka kondensującego, takiego jak dicykloheksylokarbodiimid lub diizopropylokarbodiimid.When using a compound of formula I in which X = OH, the reaction with a compound of formula II is carried out in the presence of a condensing agent such as dicyclohexylcarbodiimide or diisopropylcarbodiimide.
Otrzymany ester etylowy jest przekształcany w odpowiedni kwas, przy wydajnościach ilościowych, w warunkach łagodnej hydrolizy za pomocą katalizatorów przeniesienia międzyfazowego w środowisku zasadowym.The obtained ethyl ester is converted to the corresponding acid, in quantitative yields, under mild hydrolysis conditions with the aid of phase transfer catalysts in basic medium.
W tych warunkach, stosując pochodne kwasu tiazolidyno-4-karboksylowego estryfikowane metanolem, propanolem lub izopropanolem, otrzymuje się znacząco niższe wydajności. Poniższe przykłady ilustrują niniejszy wynalazek.Under these conditions, significantly lower yields are obtained using thiazolidine-4-carboxylic acid derivatives esterified with methanol, propanol or isopropanol. The following examples illustrate the present invention.
Przykład 1Example 1
16.78 g chlorowodorku L-tiazolidyno-4-karboksylanu etylu (0.084 mol) przeprowadzono w stan zawiesiny w 160 ml toluenu, dodano 7.06 g wodorowęglanu sodu (0.085 mol), ogrzewano do temperatury wrzenia mieszając przez 5 godz., azeotropowo usuwając utworzoną wodę. Mieszaninę ochłodzono do 0-5°C, dodano 12 g kwasu L-piroglutaminowego (0.093 mol), następnie wkroplono roztwór 19.2 g dicykloheksylokarbodiimidu w 20 ml toluenu. Po 1 godz. w 0°C, temperaturę podwyższono do 20-25°C przez dalsze 12 godz., a następnie odsączono dicykloheksylomocznik.16.78 g of ethyl L-thiazolidine-4-carboxylate hydrochloride (0.084 mol) were suspended in 160 ml of toluene, 7.06 g of sodium bicarbonate (0.085 mol) were added, refluxed with stirring for 5 hours, azeotropically removing the water formed. The mixture was cooled to 0-5 ° C, 12 g of L-pyroglutamic acid (0.093 mol) were added, then a solution of 19.2 g of dicyclohexylcarbodiimide in 20 ml of toluene was added dropwise. After 1 hour at 0 ° C, the temperature was increased to 20-25 ° C for a further 12 h and then the dicyclohexylurea was filtered off.
Do przesączonego roztworu dodano 20 ml wody, 0.64 g wodorosiarczanu tetrabutyloamoniowego (0.0042 mol), ochłodzono do 0-5°C, następnie dodano do tego roztwór 3.36 g wodorotlenku sodu (0.084 mol) w 20 ml wody. Po mieszaniu przez 30 min., oddzielono fazę wodną zakwaszono do pH 1 kwasem solonym, po 2 godz. odsączono, przemyto pewną ilością wody i osuszono otrzymując 19.5 g (96%) kwasu 3-(L-piroglutamylo)-L-tiazolidyno-4-karboksylowego.To the filtered solution was added 20 ml of water, 0.64 g of tetrabutylammonium bisulfate (0.0042 mol), cooled to 0-5 ° C, then a solution of 3.36 g of sodium hydroxide (0.084 mol) in 20 ml of water was added thereto. After stirring for 30 minutes, the water phase was separated, acidified to pH 1 with hydrochloric acid, after 2 hours. filtered, washed with some water and dried to give 19.5 g (96%) of 3- (L-pyroglutamyl) -L-thiazolidine-4-carboxylic acid.
temp. topn. 193-194°C.mp temp. 193-194 ° C.
Przykład 2Example 2
Postępowano według procedury z przykładu 1, zastępując toluen dichlorometanem i otrzymując 19.2 g (95%) kwasu 3-(L-piroglutamylo)-L-tiazolidyno-4-karboksylowego.The procedure of Example 1 was followed by substituting toluene with dichloromethane to give 19.2 g (95%) of 3- (L-pyroglutamyl) -L-thiazolidine-4-carboxylic acid.
temp. topn. 193-194°C.mp temp. 193-194 ° C.
Przykład 3Example 3
Postępowano według procedury z przykładu 1, zastępując toluen N-heksanem i otrzymując 19.1 g (94%) kwasu 3-(L-piroglutamylo)-L-tizaolidyno-4-karboksylowego.The procedure of Example 1 was followed by replacing toluene with N-hexane to give 19.1 g (94%) of 3- (L-pyroglutamyl) -L-tizaolidine-4-carboxylic acid.
temp. topn. 193-194°C.mp temp. 193-194 ° C.
Przykład 4 g kwasu L-N-t-butoksykarbonylopiroglutamionowego i 16.1 g L-tiazolidyno-4-karboksylanu etylu rozpuszczono w 150 ml dichlorometanu, ochłodzono do 0-5°C, a następnie dodano 21 g dicykloheksylokarbodiimidu (0.105 mol) i mieszano przez 15 godz., w tej temperaturze.Example 4 g of LNt-butoxycarbonylpyroglutamic acid and 16.1 g of ethyl L-thiazolidine-4-carboxylate were dissolved in 150 ml of dichloromethane, cooled to 0-5 ° C, then 21 g of dicyclohexylcarbodiimide (0.105 mol) were added and stirred for 15 hours at this temperature.
Dicykloheksylomocznik odsączono, następnie do przesączu dodano 50 ml wody, 0.75 g wodorosiarczanu tetrabutylamoniowego (0.005 mol). Mieszaninę ochłodzono do 0-5°C, następnie do mieszaniny dodano roztwór 6.6 g wodorotlenku potasu (0.1 mol) w 30 ml wody, mieszając w tej temperaturze przez 30 min, następnie dwie fazy rozdzielono. Fazę wodną zakwaszono do pH 1 stęż, kwasem solnym. Wytrącony stały osad odsączono, przemyto wodą i osuszono. Otrzymano 21.3 g kwasu 3-(L-piroglutamylo)-L-tiazolidyno-4-karboksylowego.Dicyclohexylurea was filtered off, then 50 ml of water, 0.75 g of tetrabutylammonium bisulfate (0.005 mol) were added to the filtrate. The mixture was cooled to 0-5 ° C, then a solution of 6.6 g of potassium hydroxide (0.1 mol) in 30 ml of water was added to the mixture under stirring at this temperature for 30 min, then the two phases were separated. The aqueous phase was acidified to pH 1 with conc. Hydrochloric acid. The precipitated solid was filtered off, washed with water and dried. 21.3 g of 3- (L-pyroglutamyl) -L-thiazolidine-4-carboxylic acid are obtained.
temp. topn. 193-194°C, wydajność 88%.mp temp. 193-194 ° C, 88% yield.
Poniższa tabela podaje otrzymane wyniki przy użyciu różnych estrów kwasu L-tiazolidyno-4-karboksylowego, przy czym reakcję przeprowadzano w tych samych warunkach jak w powyższych przykładach.The table below summarizes the results obtained using the various L-thiazolidine-4-carboxylic acid esters, the reaction being carried out under the same conditions as in the above examples.
TabelaTable
181 824181 824
Claims (9)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITMI941955A IT1270017B (en) | 1994-09-27 | 1994-09-27 | "QUANTITATIVE SYNTHESIS OF 3- (L-PIROGLUTAMIL) -L-THIAZOLIDIN-4- CARBOXYLIC ACID AND ITS DERIVATIVES" |
| PCT/EP1995/003720 WO1996010036A1 (en) | 1994-09-27 | 1995-09-21 | A process for the quantitative synthesis of 3-(l-pyroglutamyl)-l-thiazolidine-4-carboxylic acid and derivatives thereof |
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| Publication Number | Publication Date |
|---|---|
| PL319380A1 PL319380A1 (en) | 1997-08-04 |
| PL181824B1 true PL181824B1 (en) | 2001-09-28 |
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| PL95319380A PL181824B1 (en) | 1994-09-27 | 1995-09-21 | Method of quantitatively synthesising 3-(l-pyrrogutamyl)-l-thiazolydino-4-carbpxylic acid and its derivatives |
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| Country | Link |
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| CN (1) | CN1143863C (en) |
| BG (1) | BG63895B1 (en) |
| BR (1) | BR9509087A (en) |
| CO (1) | CO4480030A1 (en) |
| CZ (1) | CZ91597A3 (en) |
| IT (1) | IT1270017B (en) |
| PL (1) | PL181824B1 (en) |
| RO (1) | RO115957B1 (en) |
| SK (1) | SK40097A3 (en) |
| WO (1) | WO1996010036A1 (en) |
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| CN108715598A (en) * | 2018-06-13 | 2018-10-30 | 峨眉山宏昇药业股份有限公司 | A kind of preparation method of Pidotimod |
| CN117088939A (en) * | 2022-05-11 | 2023-11-21 | 江苏吴中医药集团有限公司 | Preparation method of pidotimod |
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| IT1202426B (en) * | 1987-01-26 | 1989-02-09 | Poli Ind Chimica Spa | THIAZOLIDIN-4-CARBOXYLIC ACID DERIVATIVE, ITS PREPARATION AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN IT |
| IT1239029B (en) * | 1989-10-12 | 1993-09-20 | Poli Ind Chimica Spa | PROCESS FOR THE PREPARATION OF 3- (L-PYROGLUTAMYL) -L- THIAZOLIDIN-4-CARBOXYLIC ACID AND ITS DERIVATIVES. |
-
1994
- 1994-09-27 IT ITMI941955A patent/IT1270017B/en active IP Right Grant
-
1995
- 1995-09-21 WO PCT/EP1995/003720 patent/WO1996010036A1/en not_active Application Discontinuation
- 1995-09-21 BR BR9509087A patent/BR9509087A/en not_active Application Discontinuation
- 1995-09-21 CZ CZ97915A patent/CZ91597A3/en unknown
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- 1995-09-21 PL PL95319380A patent/PL181824B1/en unknown
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| SK40097A3 (en) | 1997-09-10 |
| BG101310A (en) | 1997-12-30 |
| CO4480030A1 (en) | 1997-07-09 |
| PL319380A1 (en) | 1997-08-04 |
| WO1996010036A1 (en) | 1996-04-04 |
| RO115957B1 (en) | 2000-08-30 |
| BR9509087A (en) | 1998-07-21 |
| CZ91597A3 (en) | 1997-09-17 |
| ITMI941955A1 (en) | 1996-03-27 |
| CN1143863C (en) | 2004-03-31 |
| CN1158620A (en) | 1997-09-03 |
| ITMI941955A0 (en) | 1994-09-27 |
| BG63895B1 (en) | 2003-05-30 |
| IT1270017B (en) | 1997-04-16 |
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