WO1996010036A1 - A process for the quantitative synthesis of 3-(l-pyroglutamyl)-l-thiazolidine-4-carboxylic acid and derivatives thereof - Google Patents
A process for the quantitative synthesis of 3-(l-pyroglutamyl)-l-thiazolidine-4-carboxylic acid and derivatives thereof Download PDFInfo
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- WO1996010036A1 WO1996010036A1 PCT/EP1995/003720 EP9503720W WO9610036A1 WO 1996010036 A1 WO1996010036 A1 WO 1996010036A1 EP 9503720 W EP9503720 W EP 9503720W WO 9610036 A1 WO9610036 A1 WO 9610036A1
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- Prior art keywords
- halide
- process according
- compound
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- carboxylic acid
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- 238000000034 method Methods 0.000 title claims abstract description 24
- 230000015572 biosynthetic process Effects 0.000 title description 2
- 238000003786 synthesis reaction Methods 0.000 title description 2
- ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical compound OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 claims abstract description 8
- ODHCTXKNWHHXJC-UHFFFAOYSA-N acide pyroglutamique Natural products OC(=O)C1CCC(=O)N1 ODHCTXKNWHHXJC-UHFFFAOYSA-N 0.000 claims abstract description 7
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims abstract description 5
- 230000007062 hydrolysis Effects 0.000 claims abstract description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 4
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 3
- 239000003444 phase transfer catalyst Substances 0.000 claims abstract description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- -1 ligrom Chemical compound 0.000 claims description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 11
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 6
- 239000000010 aprotic solvent Substances 0.000 claims description 6
- 150000004820 halides Chemical class 0.000 claims description 6
- 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
- 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
- 125000004494 ethyl ester group Chemical group 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 claims description 4
- 239000000203 mixture Substances 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
- 238000002360 preparation method Methods 0.000 claims description 4
- 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
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 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
- 230000003213 activating effect Effects 0.000 claims description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 2
- 125000005099 aryl alkyl carbonyl group Chemical group 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 claims description 2
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 2
- JVSWJIKNEAIKJW-UHFFFAOYSA-N dimethyl-hexane Natural products CCCCCC(C)C JVSWJIKNEAIKJW-UHFFFAOYSA-N 0.000 claims description 2
- 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 description 2
- XKBGEWXEAPTVCK-UHFFFAOYSA-M methyltrioctylammonium chloride Chemical compound [Cl-].CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC XKBGEWXEAPTVCK-UHFFFAOYSA-M 0.000 claims description 2
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 239000003208 petroleum Substances 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims 4
- 239000001257 hydrogen Substances 0.000 claims 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 3
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 claims 1
- 125000000753 cycloalkyl group Chemical group 0.000 claims 1
- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 claims 1
- 125000003107 substituted aryl group Chemical group 0.000 claims 1
- DZLNHFMRPBPULJ-UHFFFAOYSA-N thioproline Chemical class OC(=O)C1CSCN1 DZLNHFMRPBPULJ-UHFFFAOYSA-N 0.000 abstract description 3
- 230000005494 condensation Effects 0.000 abstract 2
- 238000009833 condensation Methods 0.000 abstract 2
- 239000002904 solvent Substances 0.000 abstract 2
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 abstract 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 abstract 1
- 125000006239 protecting group Chemical group 0.000 abstract 1
- 238000006467 substitution reaction Methods 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 150000002148 esters Chemical class 0.000 description 5
- 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
- 238000003756 stirring Methods 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 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
- 239000002253 acid 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
- 239000012071 phase Substances 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
- 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
- 239000008346 aqueous phase Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-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
- DZLNHFMRPBPULJ-GSVOUGTGSA-N D-thioproline Chemical compound OC(=O)[C@H]1CSCN1 DZLNHFMRPBPULJ-GSVOUGTGSA-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
- 239000003513 alkali Substances 0.000 description 1
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 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
- 125000005129 aryl carbonyl group Chemical group 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000001035 drying Methods 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
- ZRBNETYZYOXTLS-UHFFFAOYSA-N ethyl 1,3-thiazolidine-4-carboxylate Chemical compound CCOC(=O)C1CSCN1 ZRBNETYZYOXTLS-UHFFFAOYSA-N 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000002496 methyl group Chemical group [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
- 238000010992 reflux Methods 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
- 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
- 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
Definitions
- the present invention relates to a process for the preparation of L-pyroglutamic acid or derivatives thereof.
- Italian Patent N° 1.202.426 discloses L- pyroglutamyl-L-thiazolidine-4-carboxylic acid, having immunost lmulating, antitoxic, anti-inflammatory, antioxidant and anti-agemg properties, which is prepared starting from a L-pyroglutamic acid reactive ester or from the acid chloride thereof and L- thiazolidme-4-carboxylic acid.
- the process makes use of, for example, the reactive esters of L-pyroglutamic with pentachlorophenol, pentafluorophenol, 2,4,5- trichlorophenol, N-hydroxysuccimmide, N- hydroxyphthalimide, which are reacted with L- thiazolidine-4-carboxylic acid in aprotic solvents in the presence of tertiary bases, or of L-pyroglutamic acid chloride which is reacted with L-thiazolidme-4- carboxylic acid in alkali medium.
- 3-(L-pyroglutamyl)-L-thiazolidme-4-carboxylie acid derivatives having the same pharmacological properties, which are prepared by similar processes from L- pyroglutamyl-L-thiazolidine-4-carboxylic acid reactive esters or amides and alcohols or amines.
- Italian Patent N° 1229029 disclosed a process wherein the above mentioned problems had been partially solved by means of a simpler process, making no use of particularly toxic substances, laborious and/or unstable intermediates, and with higher yields. Such a process evidenced the surprising stability of ethyl thiazolidine-4-carboxylate to give yields substantially higher than those obtained with other simple esters such as the methyl and isopropyl ones.
- the invention provides a process for the preparation of a compound of formula (III)
- R 1 is H, C 1 -C 6 alkyl C 3 -C 7 cycloalky, C 4 - C 10 cycloalkylalkyl, aryl and sunstituted ary,.
- R 1 is as defined above and X is OH, Cl or OR 2 wherein R 2 is an activating group, with a compound of formula (II)
- R 3 is H, C 3 -C 9 trialkylsiiyl, in apolar aprotic solvents
- step b) the basic hydrolysis of the ethyl ester obtained in step a) in phase transfer conditions.
- the apolar aprotic solvents are selected preferably from n-pentane, n-hexane, n-heptane, n-octane, isooctane, nonane, decane, petroleum ether, ligrom, toluene, xylene, cumene, dichloromethane, chloroform, dichloroethane and mixtures tnereof.
- a condensing agent such as dicyclohexylcarbodiimide or diisopropyicarbodimide.
- the ethyl ester obtained from step a) is transformed into the corresponding acid, in quantitative yields, in mild hydrolysis conditions by means of phase transfer catalysts in basic medium.
- catalysts such as tetrabutyl ammonium halide or hydrogen sulfate or tetrafluoroborate, tetraethylammonium halide or hydrogen sulfate or tetraf luoroborate; cetyl pyridimum halide, methyltributyl halide, Adogen 464, trimethyl cetyl ammonium p-toluenesulfonate, tetrabutylphosphonium halide, tetraphenyi phosphonium halide, triphenyimethyl phosphonium halide, butyl pyridimum halide, are used.
- the filtered solution is added with 20 mi of water, 0.64 g of tetrabutylammonium hydrogen sulfate (0.0042 moles), cooled at 0-5oC, then a solution of 3.36 g of sodium hydroxide (0.034 moles) in 20 mi of water is added thereto. After stirring for 30 mm, the aqueous phase is separated, acidified to pH 1 with hydrochloric acid, after 2 hours is filtered, washing with some water and drying to obtain 19.5 g (96%) of 3-(L-pyrogiutam ⁇ l)- L-thiazolidme-4-carboxylic acid, m.p. 193-194°C.
- Dicyciohexyiurea is filtered off, then the filtrate is added with 50 ml of water, 0.75 g of tetrabutylammonium hydrogen sulfate (0.005 moles).
- the mixture is cooled to 0-5oC, then a solution of 6.6 g of potassium hydroxide (0.1 moles) m 30 mi of water is added thereto, stirring at this temperature for 30 mm, then the two phases are separated.
- the aqueous phase is acidified to pH 1 with cone, hydrochloric acid.
- the precipitated solid is filtered, washed with water and dried. 21.3 g of 3-(L-pyroglutamyl)-L-thiazolidine-4- carooxylic acid are obtained, m.p. 193-194oC, yield 33%.
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- 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)
- Pyrrole Compounds (AREA)
- Catalysts (AREA)
Abstract
3-(L-Pyroglutamyl)-L-thiazolidine-4-carboxylic acid and the derivatives thereof are prepared in quantitative yields by a condensation process between L-pyroglutamic acid or substitution products thereof in the presence of an aliphatic or aromatic hydrocarbon solvent, or of chlorinated solvents in the presence of dicyclohexylcarbodiimide or similar condensing agents, or by condensation of L-pyroglutamic acid reactive derivatives with thiazolidine-4-carboxylic acid derivatives. The hydrolysis of the protective groups of thiazolidine-4-carboxylic acid is carried out by phase transfer catalysts in quantitative yields.
Description
A PROCESS FOR THE QUANTITATIVE SYNTHESIS OF 3-(L-
PYROGLUTAMYL)-L-THIAZOLIDINE-4-CARBOXYLIC ACID AND DERIVATIVES THEREOF
The present invention relates to a process for the preparation of L-pyroglutamic acid or derivatives thereof.
Italian Patent N° 1.202.426 discloses L- pyroglutamyl-L-thiazolidine-4-carboxylic acid, having immunost lmulating, antitoxic, anti-inflammatory, antioxidant and anti-agemg properties, which is prepared starting from a L-pyroglutamic acid reactive ester or from the acid chloride thereof and L- thiazolidme-4-carboxylic acid.
In particular, the process makes use of, for example, the reactive esters of L-pyroglutamic with pentachlorophenol, pentafluorophenol, 2,4,5- trichlorophenol, N-hydroxysuccimmide, N- hydroxyphthalimide, which are reacted with L- thiazolidine-4-carboxylic acid in aprotic solvents in the presence of tertiary bases, or of L-pyroglutamic acid chloride which is reacted with L-thiazolidme-4- carboxylic acid in alkali medium.
Italian Patent application Nº 19401 A/89 described
3-(L-pyroglutamyl)-L-thiazolidme-4-carboxylie acid derivatives, having the same pharmacological properties, which are prepared by similar processes from L- pyroglutamyl-L-thiazolidine-4-carboxylic acid reactive esters or amides and alcohols or amines.
These processes suffer from some drawbacks from the practical point of view, namely: cumbersome processes
with exceedingly low giobal yields, use of substances highly toxic to man and environment such as halogen phenols, use of L-pyroglutamyl chloride which is highly difficult to prepare and handle, and poor stability of the reactive esters of L-pyroglutamic acid with N- hydroxysuccinimide and N-hydroxγphthalimide.
Italian Patent N° 1229029 disclosed a process wherein the above mentioned problems had been partially solved by means of a simpler process, making no use of particularly toxic substances, laborious and/or unstable intermediates, and with higher yields. Such a process evidenced the surprising stability of ethyl thiazolidine-4-carboxylate to give yields substantially higher than those obtained with other simple esters such as the methyl and isopropyl ones.
Now it has been found that said process can further be improved, to obtain nearly quantitative yields of the desired products, condensing ethyl thiazclidine-4- carboxylate or a derivative thereof with a L- pyroglutamic acid derivative in apolar aprotic solvents and hydrolysmg finally the ethyl ester in phase transfer conditions.
Therefore, the invention provides a process for the preparation of a compound of formula (III)
which comprises:
a) the reaction of a compound of formula (I)
wherein R1 is as defined above and X is OH, Cl or OR2 wherein R2 is an activating group, with a compound of formula (II)
b) the basic hydrolysis of the ethyl ester obtained in step a) in phase transfer conditions.
The apolar aprotic solvents are selected preferably from n-pentane, n-hexane, n-heptane, n-octane, isooctane, nonane, decane, petroleum ether, ligrom, toluene, xylene, cumene, dichloromethane, chloroform, dichloroethane and mixtures tnereof. When using a compound of formula I wherein X = OH, the reactio n wi th the compound of formula II is carried out in the
presence of a condensing agent such as dicyclohexylcarbodiimide or diisopropyicarbodimide.
The ethyl ester obtained from step a) is transformed into the corresponding acid, in quantitative yields, in mild hydrolysis conditions by means of phase transfer catalysts in basic medium.
For this step, catalysts such as tetrabutyl ammonium halide or hydrogen sulfate or tetrafluoroborate, tetraethylammonium halide or hydrogen sulfate or tetraf luoroborate; cetyl pyridimum halide, methyltributyl halide, Adogen 464, trimethyl cetyl ammonium p-toluenesulfonate, tetrabutylphosphonium halide, tetraphenyi phosphonium halide, triphenyimethyl phosphonium halide, butyl pyridimum halide, are used.
In these conditions, using thiazolidine-4- carboxylic acid derivatives esterified with methanol, propanol or isopropanol, remarkably lower yields are obtained.
The following examples illustrate the present invention.
EXAMPLE 1
16.73 g of ethyl L-thiazolidine-4-carboxylate hydrochloride (0.034 moles) are suspended in 160 ml of toluene, 7.06 g of sodium bicarbonate (0.085 moles) are added, heating to reflux with stirring for 5 hours , azeotropically removing the formed water. The mixture is cooled to 0-5°C, 12 g of L-pyroglutamic acid (0.093 moles) are added, then a solution of 19.2 g of dicyclohexylcarbodiimide in 20 mi of toluene is dropped therein. After 1 hour at C°C, temperature is raised to
20-25ºC for a further 12 hours, after that
dicyclohexylurea is filtered off.
The filtered solution is added with 20 mi of water, 0.64 g of tetrabutylammonium hydrogen sulfate (0.0042 moles), cooled at 0-5ºC, then a solution of 3.36 g of sodium hydroxide (0.034 moles) in 20 mi of water is added thereto. After stirring for 30 mm, the aqueous phase is separated, acidified to pH 1 with hydrochloric acid, after 2 hours is filtered, washing with some water and drying to obtain 19.5 g (96%) of 3-(L-pyrogiutamγl)- L-thiazolidme-4-carboxylic acid, m.p. 193-194°C.
EXAMPLE 2
The procedure of example 1 is followed, replacing toluene with dichloromethane, to obtain 19.2 g (95%) of 3-(L-pyrogiutamyl)-L-thiazolidine-4-carboxylic acid, m.p. 193-194°C.
EXAMPLE 3
The procedure of example 1 is followed, replacing toluene with N-hexane, to obtain 19.1 g (94%) of 3-(L- pyrogiutamyl)-L-thiazolidine-4-carboxylic acid, m.p. 193-194ºC.
EXAMPLE 4
23 g of L-N-t-butoxycarbonyl pyroglutamic acid and
16.1 g of ethyl L-thiazoIidine-4-carboxylate are dissolved in 150 mi of dichloromethane, cooling to 0-5ºC then adding 21 g of dicyclohexylcarbodiimide (0.105 moles) and stirring for 15 hours at this temperature.
Dicyciohexyiurea is filtered off, then the filtrate is added with 50 ml of water, 0.75 g of tetrabutylammonium hydrogen sulfate (0.005 moles). The mixture is cooled to 0-5ºC, then a solution of 6.6 g of potassium hydroxide (0.1 moles) m 30 mi of water is
added thereto, stirring at this temperature for 30 mm, then the two phases are separated. The aqueous phase is acidified to pH 1 with cone, hydrochloric acid. The precipitated solid is filtered, washed with water and dried. 21.3 g of 3-(L-pyroglutamyl)-L-thiazolidine-4- carooxylic acid are obtained, m.p. 193-194ºC, yield 33%.
The following table shows the results obtained using different L-thiazolidme-4-carboxylic acid esters, reacted in the same conditions as in the above examples.
Claims
1. A process for the preparation of a compound formula (III)
which comprises:
a) the reaction of a compound of formula (I)
b) the basic hydrolysis of the ethyl ester obtained in step a) m phase transfer conditions.
2. A process according to claim 1, wherein the apolar aprotic solvents are selected from n-pentane, n-hexane, n-heptane, n-octane, isooctane , nonane, decane, petroleum ether, ligrom, toluene, xylene, cumene, dichloromethane, chloroform, dichloroethane and mixtures thereof.
3. A process according to claim 1, wherein X is OH and step a) is effected m the presence of a condensing agent selected from dicyclohexylcarbodiimide and diisopropylcarbodiimide.
4. A process according to claim 1 characterized in that the phase transfer catalysts are selected from tetrabutyl ammonium halide or hydrogen sulfate or tetrafluoroborate, tetraethylammonium halide or hydrogen sulfate or tetraf luoroborate; cetyl pyridimum halide, methyltributyl halide, Adogen 464, trimethyl cetyl ammonium p-toluenesulfonate, tetrabutylphosphonium halide, tetraphenyl phosphonium halide, triphenyimethyl phosphonium halide, butyl pyridimum halide.
5. A process according to claim 1 characterized in that R1 is selected from hydrogen and C2-C5 alkcxycarbonyl.
6. A process according to claim 1 characterized in that the compound of formula (I) is L-pyroglutamic acid.
7. A process according to claim 1 characterized in that the compound of formula (I) is L-N-t-butoxycarbonyl pyroglutamic acid.
3. A process according to any one of above claims, for
the preparation of 3-(L-pyrogiutamyl)-L-thiazolidme-4- carboxylic acid.
9. A process according to claim 8, characterized in that a compound of formula (I), wherein R1 is hydrogen and X is OH, is reacted with a compound of formula (II), wherein R3 is hydrogen.
Priority Applications (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| RO97-00611A RO115957B1 (en) | 1994-09-27 | 1995-09-21 | Process for preparing 3-(l-pyroglutamyl)-l-thiazolidine-4-carboxylic acid and derivatives thereof |
| BR9509087A BR9509087A (en) | 1994-09-27 | 1995-09-21 | Process for the quantitative synthesis of 3- (1-pyroglutamyl) -1-thiazolidine-4-carboxylic acid and derivatives thereof |
| PL95319380A PL181824B1 (en) | 1994-09-27 | 1995-09-21 | Method of quantitatively synthesising 3-(l-pyrrogutamyl)-l-thiazolydino-4-carbpxylic acid and its derivatives |
| SK400-97A SK40097A3 (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 |
| CZ97915A CZ91597A3 (en) | 1994-09-27 | 1995-09-21 | Process for preparing 3-(l-pyroglutamyl)-l-thiazolidine-4-carboxylic acid |
| BG101310A BG63895B1 (en) | 1994-09-27 | 1997-03-11 | Method for quantitative synthesis of 3-(pyroglutamyl)-l-thiazolydine-4-carboxylic acid and its derivatives |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITMI94A001955 | 1994-09-27 | ||
| ITMI941955A IT1270017B (en) | 1994-09-27 | 1994-09-27 | "QUANTITATIVE SYNTHESIS OF 3- (L-PIROGLUTAMIL) -L-THIAZOLIDIN-4- CARBOXYLIC ACID AND ITS DERIVATIVES" |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1996010036A1 true WO1996010036A1 (en) | 1996-04-04 |
Family
ID=11369599
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| 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 |
Country Status (10)
| Country | Link |
|---|---|
| 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) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108088936B (en) * | 2017-12-08 | 2020-05-22 | 常州寅盛药业有限公司 | Impurity obtained in preparation of pidotimod ethyl ester and quality detection method thereof |
| 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 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0276752A1 (en) * | 1987-01-26 | 1988-08-03 | POLI INDUSTRIA CHIMICA S.p.A. | Derivative of thiazolidine-4-carboxylic acid, its preparation and pharmaceutical compositions containing it |
| EP0422566A1 (en) * | 1989-10-12 | 1991-04-17 | POLI INDUSTRIA CHIMICA S.p.A. | A process for the preparation of 3-(L-pyroglutamyl)-L-thiazolidine-4-carboxylic acid derivatives |
-
1994
- 1994-09-27 IT ITMI941955A patent/IT1270017B/en active IP Right Grant
-
1995
- 1995-09-21 RO RO97-00611A patent/RO115957B1/en unknown
- 1995-09-21 CN CNB951953222A patent/CN1143863C/en not_active Expired - Lifetime
- 1995-09-21 PL PL95319380A patent/PL181824B1/en unknown
- 1995-09-21 CZ CZ97915A patent/CZ91597A3/en unknown
- 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 SK SK400-97A patent/SK40097A3/en unknown
- 1995-09-27 CO CO95044814A patent/CO4480030A1/en unknown
-
1997
- 1997-03-11 BG BG101310A patent/BG63895B1/en unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0276752A1 (en) * | 1987-01-26 | 1988-08-03 | POLI INDUSTRIA CHIMICA S.p.A. | Derivative of thiazolidine-4-carboxylic acid, its preparation and pharmaceutical compositions containing it |
| EP0422566A1 (en) * | 1989-10-12 | 1991-04-17 | POLI INDUSTRIA CHIMICA S.p.A. | A process for the preparation of 3-(L-pyroglutamyl)-L-thiazolidine-4-carboxylic acid derivatives |
Non-Patent Citations (1)
| Title |
|---|
| E.V. Dehmlow and S.S. Dehmlow 'Phase Transfer Catalysis', Monographs in Modern Chemistry, Vol. 11. ed. by H.F. Ebel, 2nd ed., Verlag Chemie, * |
Also Published As
| Publication number | Publication date |
|---|---|
| PL319380A1 (en) | 1997-08-04 |
| CZ91597A3 (en) | 1997-09-17 |
| ITMI941955A1 (en) | 1996-03-27 |
| IT1270017B (en) | 1997-04-16 |
| CN1143863C (en) | 2004-03-31 |
| RO115957B1 (en) | 2000-08-30 |
| PL181824B1 (en) | 2001-09-28 |
| ITMI941955A0 (en) | 1994-09-27 |
| SK40097A3 (en) | 1997-09-10 |
| CN1158620A (en) | 1997-09-03 |
| CO4480030A1 (en) | 1997-07-09 |
| BG63895B1 (en) | 2003-05-30 |
| BR9509087A (en) | 1998-07-21 |
| BG101310A (en) | 1997-12-30 |
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