BG63895B1 - Method for quantitative synthesis of 3-(pyroglutamyl)-l-thiazolydine-4-carboxylic acid and its derivatives - Google Patents
Method for quantitative synthesis of 3-(pyroglutamyl)-l-thiazolydine-4-carboxylic acid and its derivatives Download PDFInfo
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- BG63895B1 BG63895B1 BG101310A BG10131097A BG63895B1 BG 63895 B1 BG63895 B1 BG 63895B1 BG 101310 A BG101310 A BG 101310A BG 10131097 A BG10131097 A BG 10131097A BG 63895 B1 BG63895 B1 BG 63895B1
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- Prior art keywords
- formula
- halide
- carboxylic acid
- pyroglutamyl
- thiazolidine
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- 238000000034 method Methods 0.000 title claims abstract description 22
- 230000015572 biosynthetic process Effects 0.000 title 1
- 238000003786 synthesis reaction Methods 0.000 title 1
- ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical compound OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 claims abstract description 7
- ODHCTXKNWHHXJC-UHFFFAOYSA-N acide pyroglutamique Natural products OC(=O)C1CCC(=O)N1 ODHCTXKNWHHXJC-UHFFFAOYSA-N 0.000 claims abstract description 6
- 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 5
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 5
- 239000003054 catalyst Substances 0.000 claims abstract description 4
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 3
- -1 L-pyroglutamyl Chemical group 0.000 claims description 20
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 5
- 125000004494 ethyl ester group Chemical group 0.000 claims description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 4
- 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
- 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
- 150000004820 halides Chemical class 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 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
- 239000000010 aprotic solvent Substances 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-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
- 230000003213 activating effect Effects 0.000 claims description 2
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 2
- 235000019270 ammonium chloride Nutrition 0.000 claims description 2
- 125000005099 aryl alkyl carbonyl group Chemical group 0.000 claims description 2
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 2
- 125000003118 aryl group Chemical group 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
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 claims description 2
- JVSWJIKNEAIKJW-UHFFFAOYSA-N dimethyl-hexane Natural products CCCCCC(C)C JVSWJIKNEAIKJW-UHFFFAOYSA-N 0.000 claims description 2
- 239000003208 petroleum Substances 0.000 claims description 2
- 239000003880 polar aprotic solvent Substances 0.000 claims description 2
- 125000003107 substituted aryl group Chemical group 0.000 claims description 2
- 150000003548 thiazolidines Chemical class 0.000 claims description 2
- 125000004665 trialkylsilyl group Chemical group 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims 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 claims 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 1
- MHHHOBASFJDXNM-UHFFFAOYSA-M ethyl(trimethyl)azanium 4-methylbenzenesulfonate Chemical compound CC[N+](C)(C)C.Cc1ccc(cc1)S([O-])(=O)=O MHHHOBASFJDXNM-UHFFFAOYSA-M 0.000 claims 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
- 230000002441 reversible effect Effects 0.000 claims 1
- 238000009833 condensation Methods 0.000 abstract description 4
- 230000005494 condensation Effects 0.000 abstract description 4
- 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
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 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
- 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
- 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
- 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
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 2
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-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
- 238000001914 filtration Methods 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- LIKMAJRDDDTEIG-UHFFFAOYSA-N 1-hexene Chemical compound CCCCC=C LIKMAJRDDDTEIG-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
- 235000001258 Cinchona calisaya Nutrition 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
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 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
- 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
- 230000003308 immunostimulating effect Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- ODOPKAJVFRHHGM-UHFFFAOYSA-N phenyltin Chemical compound [Sn]C1=CC=CC=C1 ODOPKAJVFRHHGM-UHFFFAOYSA-N 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
- 239000003586 protic polar solvent Substances 0.000 description 1
- 229960000948 quinine Drugs 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
- DZLNHFMRPBPULJ-UHFFFAOYSA-N thioproline Chemical class OC(=O)C1CSCN1 DZLNHFMRPBPULJ-UHFFFAOYSA-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
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- 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
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- 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
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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)
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Abstract
Description
Област на техникатаTechnical field
Изобретението се отнася до метод за получаване на L-пироглутаминова киселина или на нейни производни.The invention relates to a process for the preparation of L-pyroglutamic acid or derivatives thereof.
Предшестващо състояние на техникатаBACKGROUND OF THE INVENTION
В патент на IT 1 202 426 е описана Lпироглутамил-Ь-тиазолидин-4-карбоксилна киселина, която има имуностимулиращи, противотоксични, противовъзпалителни, противоокислителни и противостареещи свойства. Получава се, като се излезе от реактивен естер на L-пироглутаминовата киселина или от нейния киселинен хлорид и Ь-тиазолидин-4-карбоксилна киселина.Patent IT 1 202 426 discloses Lpyroglutamyl-L-thiazolidine-4-carboxylic acid, which has immunostimulatory, anti-toxic, anti-inflammatory, antioxidant and anti-aging properties. Obtained from the ester of L-pyroglutamic acid or its acid chloride and L-thiazolidine-4-carboxylic acid.
По-специално методът използва например реактивни естери на L-пироглутаминовата киселина с пентахлорофенол, пентафлуорофенол, 2,4,5-трихлорофенол, N-хидроксисукцинимид, N-хидроксифталимид, които се подлагат на взаимодействие с Ь-тиазолидин-4-карбоксилна киселина в среда на непротонен разтворител, в присъствието на третична основа или Lпироглутаминов киселинен хлорид, който взаимодейства с Ь-тиазолидин-4-карбоксилна киселина в алкална среда.In particular, the method uses, for example, the reactive esters of L-pyroglutamic acid with pentachlorophenol, pentafluorophenol, 2,4,5-trichlorophenol, N-hydroxysuccinimide, N-hydroxyphthalimide, which are reacted with L-thiazolidine-4-carboxylic acid of a non-protic solvent, in the presence of a tertiary base or L-pyroglutamic acid chloride, which reacts with L-thiazolidine-4-carboxylic acid in an alkaline medium.
В патентна заявка на IT 19401 А/89 се описват производни на 3-(Ь-пироглутамил)-Етиазолидин-4-карбоксилната киселина със същите фармакологични свойства, които се получават по подобни методи от реактивни естери или амиди на Ь-пироглутамил-Е-тиазолидин-4-карбоксилната киселина и алкохоли и амини.Patent Application IT 19401 A / 89 describes 3- (L-pyroglutamyl) -Ethiazolidine-4-carboxylic acid derivatives having the same pharmacological properties as are obtained by similar methods from the reactive esters or amides of L-pyroglutamyl-E- thiazolidine-4-carboxylic acid and alcohols and amines.
От практическа гледна точка тези методи имат следните недостатъци. Утежнени са процесите, общите добиви са изключително ниски, използват се силно токсични за хората и околната среда вещества, като халогенофеноли, използват се L-пироглутамилхлорид, който е труден за получаване и съхранение, а реактивните естери на L-пироглутаминовата ки селина с N-хидроксисукцинимид и N-хидроксифталимид имат слаба стабилност.In practical terms, these methods have the following disadvantages. Processes are complicated, total yields are extremely low, substances that are highly toxic to humans and the environment are used, such as halophenols, L-pyroglutamyl chloride, which is difficult to obtain and store, and L-pyroglutamine quinine reactive esters with N- hydroxysuccinimide and N-hydroxyphthalimide have poor stability.
В патент на IT 1 239 029 се разкрива метод, по който посочените проблеми са час5 тично разрешени с по-опростен метод, при който не се използват особено токсични вещества, трудоемки и/или нестабилни междинни съединения при по-висок добив. Стабилността на етилтиазолидин-4-карбоксилата е висока, при това се получават значително по-високи добиви от тези, получени с други прости естери като метиловия и изопропиловия.IT 1 239 029 discloses a method in which said problems are partially solved by a simpler method that does not use particularly toxic substances, labor-intensive and / or unstable intermediates in higher yields. The stability of ethylthiazolidine-4-carboxyl is high, yielding significantly higher yields than those obtained with other simple esters such as methyl and isopropyl.
Техническа същност на изобретениетоSUMMARY OF THE INVENTION
Установено е, че цитираният метод може допълнително да бъде подобрен, така че да се получат почти количествени добиви от же2θ ланите продукти чрез кондензиране на етилтиазолидин-4-карбоксилат или негово производно с производно на L-пироглутаминовата киселина в неполярни, непротонни разтворители и накрая - хидролизиране на етилестера в ус25 ловия, при които се обръщат фазите.It has been found that the cited method can be further improved to obtain almost quantitative yields of the 2θ products by condensation of ethylthiazolidine-4-carboxylate or a derivative thereof with a L-pyroglutamic acid derivative in non-polar, aprotic solvents and finally - hydrolysis of ethyl ester at the reversed phase.
Съгласно изобретението’ есъздаден метод за получаване на 3-(Е-пироглутамил)-Етиазолидин-4-карбоксилна киселина с формулаAccording to the invention, a process for the preparation of 3- (E-pyroglutamyl) -ethiazolidine-4-carboxylic acid of the formula
в която R, е Н, С]-С6 алкил, С3-С7 циклоалкил, С4-С10 циклоалкилалкил, арил и заместен арил, С2-С3 алкоксикарбонил, С2-С10алкилкарбонил, арилкарбонил и аралкйлкарбонил, С8-С13 аралкоксикарбонил, заместен арал40 коксикарбонил, който включва следните етапи: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 3 alkoxycarbonyl, C 2 -C 10 alkylcarbonyl, arylcarbonyl and aralkylcarbonyl , C 8 -C 13 aralkoxycarbonyl, substituted aral40 coxycarbonyl, which includes the following steps:
а) взаимодействие на карбоксилат с формулаa) reacting the carboxylate with the formula
в която Rt има значенията определени по-горе, a X е OH, С1 или OR2, като R2 е активираща група, с тиазолидиново производно с формулаin which R t has the meanings defined above and X is OH, Cl or OR 2 , with R 2 being an activating group having a thiazolidine derivative of the formula
СООС2Н5 в която R3 е Н, С3-С9 триалкилсилил, в неполярни, непротонни разтворители;COOO 2 H 5 in which R 3 is H, C 3 -C 9 trialkylsilyl, in non-polar, aprotic solvents;
Ь) основна хидролиза на получения в етап а) етилестер в условия, при които се обръщат фазите.B) basic hydrolysis of the ethyl ester obtained in step a) under reversed conditions.
Неполярните непротонни разтворители са избрани за предпочитане между н-хептан, нхексан, н-хептан, н-октан, изооктан, нонан, декан, петролев етер, лигроин, толуен, хексен, кумен, дихлорометан, хлороформ, дихлороетан и смес от тях. Когато се използва съединение с формула I, в която X = ОН, реакцията със съединение с формула II се извършва в присъствието на кондензиращо средство като дициклохексилкарбодиимид или диизопропилкарбодиимид.Non-polar aprotic solvents are preferably selected from n-heptane, nhexane, n-heptane, n-octane, isooctane, nonane, decane, petroleum ether, ligroin, toluene, hexene, cumene, dichloromethane, chloroform, dichloroethane and a mixture thereof. When a compound of formula I is used 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.
Етиловият естер, получен в етап а), се превръща с количествен добив в съответната киселина в условия на мека хидролиза в основна среда чрез обръщащ фазите катализатор.The ethyl ester obtained in step a) is converted quantitatively to the corresponding acid under soft hydrolysis conditions in the basic medium by a phase-reversing catalyst.
За тази степен се използват катализатори като тетрабутиламониев халогенид, или хидрогенсулфат, или тетрафлуороборат; тетраетиламониев халогенид, или хидрогенсулфат, или тетрафлуороборат; цетилпиридинхалогенид, метилтрибутилхалогенид, метилтриалкил(С8С]0) амониев хлорид (търговска марка AdogenR 464 на фирмата Ashland Chemical Co.) триметилцетиламониев р-толуенсулфонат, тетрабутилфосфониев халогенид, тетрафенилфосфониев халогенид, трифенилметилфосфониев халогенид, бутилпиридинхалогенид.To this extent, catalysts such as tetrabutylammonium halide or hydrogen sulfate or tetrafluoroborate are used; tetraethylammonium halide or hydrogen sulfate or tetrafluoroborate; cetylpyridine halide, methyl tributyl halide, methyltrialkyl (C 8 C ) O ) ammonium chloride (Adland R 464 trademark by Ashland Chemical Co.) trimethyl acetylammonium p-toluenesulfonate, tetrabutylphosphenium trifenyltin phenyltin, butyl
При тези условия, когато се използват производни на тиазолидин-4-карбоксилната киселина, естерифицирани с метанол, пропанол и изопропанол, се получават значително пониски добиви.Under these conditions, when thiazolidine-4-carboxylic acid derivatives esterified with methanol, propanol and isopropanol are used, significantly lower yields are obtained.
Изобретението се илюстрира със следните примери.The invention is illustrated by the following examples.
Пример 1.Example 1.
16,78 g етилов Ь-тиазолидин-4-карбоксилат хидрохлорид (0,084 mol) се суспендира в 160 ml толуен, прибавя се 7.06 g натриев бикарбонат (0,085 mol) и водата се отстраня ва ацеотропно Чрез загряване на обратен хладник, с разбъркване в продължение на 5 h. Сместа се охлажда до 0-5°С, прибавя се 12 g Lпироглутаминова киселина (0,093 mol), след което на капки се добавя разтвор на 19,2 g дициклохексилкарбодиимид в 20 ml толуен. След престояване 1 h при 0°С температурата на сместа се повишава до 20-25°С за следващите 12 h, след които дициклохексилуреята се отделя чрез филтруване.16.78 g of ethyl L-thiazolidine-4-carboxylate hydrochloride (0.084 mol) was suspended in 160 ml of toluene, 7.06 g of sodium bicarbonate (0.085 mol) was added and the water was removed azeotropically by refluxing with continued stirring. at 5 h. The mixture was cooled to 0-5 ° C, 12 g of Lpyroglutamic acid (0.093 mol) was added, and a solution of 19.2 g of dicyclohexylcarbodiimide in 20 ml of toluene was added dropwise. After standing for 1 hour at 0 ° C, the temperature of the mixture was raised to 20-25 ° C for the next 12 hours, after which the dicyclohexylurea was separated by filtration.
Към филтрувания разтвор се прибавят 0,64 g тетрабутиламониев хидрогенсулфат (0,0042 mol) с 20 ml вода, охладени до 0-5°С, и след това към тях се добавя разтвор на 3,36 g натриев хидроксид (0,084 mol) в 20 ml вода. След разбъркване в продължение на 30 min водната фаза се отделя, подкислява се до pH 1 със солна киселина, след 2 h се филтрува, измива се с известно количество вода и се изсушава, при което се получава 19,5 g (96%)To the filtered solution was added 0.64 g of tetrabutylammonium hydrogen sulfate (0.0042 mol) with 20 ml of water, cooled to 0-5 ° C, and then a solution of 3.36 g of sodium hydroxide (0.084 mol) in was added thereto. 20 ml of water. After stirring for 30 min, the aqueous phase was separated, acidified to pH 1 with hydrochloric acid, filtered after 2 hours, washed with some water and dried to give 19.5 g (96%)
3- (L-пироглутамил) -1.-тиазолидин-4-карбоксилна киселина, температура на топене 193-194°С.3- (L-Pyroglutamyl) -1.-thiazolidine-4-carboxylic acid, mp 193-194 ° C.
Пример 2.Example 2.
Изпълнява се процедурата от пример 1, като толуенът се замества сдйхлорометан, при което се получава 19,2 g (95%) 3-(L-пироглутамил) -Ь-тиазолидин-4-карбоксилна киселина, температура на топене 193-194°С.Follow the procedure of Example 1 replacing toluene with dichloromethane to give 19.2 g (95%) of 3- (L-pyroglutamyl) -L-thiazolidine-4-carboxylic acid, mp 193-194 ° C. .
Пример 3.Example 3.
Изпълнява се процедурата от пример 1, като толуенът се замества с н-хексан, при което се получават 19,1 g (94%) 3-(L-пироглутамил) -Ь-тиазолидин-4-карбоксилна киселина, температура на топене 193-194°С.The procedure of Example 1 was followed by replacing toluene with n-hexane to give 19.1 g (94%) of 3- (L-pyroglutamyl) -L-thiazolidine-4-carboxylic acid, mp 193- 194 ° C.
Пример 4.Example 4.
g L-N-трет.-бутоксикарбонилпироглутаминова киселина и 16,1 g етилов L-тиазолидин-4-карбоксилат се разтваря в 150 ml дихлорометан, охлажда се до 0-5°С, след което към тях се добавят 21 g дициклохексилкарбодиимид (0,105 mol) и сместа се разбърква 15 h при тази температура.g of LN-tert-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 thereto. and the mixture was stirred at this temperature for 15 h.
Дициклохексилуреята се отделя чрез филтруване, след което към филтрата се прибавя 0,75 g тетрабутиламониев хидрогенсулфат (0,005 mol) с 50 ml вода. Сместа се охлажда до 0-5°С и към нея се добавя разтвор на 6,6 g калиев хидроксид (0,1 mol) в 30 ml вода, разбърква се при тази температура вDicyclohexylurea was separated by filtration, then 0.75 g of tetrabutylammonium hydrogen sulfate (0.005 mol) in 50 ml of water was added to the filtrate. The mixture was cooled to 0-5 ° C and a solution of 6.6 g of potassium hydroxide (0.1 mol) in 30 ml of water was added thereto, stirred at this temperature in
продължение на 30 min и фазите се разделят. Водната фаза се подкислява до pH 1 с концентрирана солна киселина. Утаеното твърдо вещество се филтрува, измива се с вода и се изсушава. Получава се 21,3 g 3-(Ь-пироглутамил)-Ь-тиазолидин-4-карбоксилна киселина, температура на топене 193-194°С, добив 88%.for 30 min and the phases were separated. The aqueous phase was acidified to pH 1 with concentrated 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, mp 193-194 ° C, yield 88%.
Следващата таблица показва резултатите, получени с различни естери на L-тиазолидин-4-карбоксилната киселина, с използване на етилестер съгласно настоящата заявка, реагирали при същите условия, като тези в примерите по-горе.The following table shows the results obtained with different esters of L-thiazolidine-4-carboxylic acid using ethyl ester according to this application, which reacted under the same conditions as those in the examples above.
ТаблицаTable
Патентни претенцииClaims
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 |
|---|---|
| BG101310A BG101310A (en) | 1997-12-30 |
| BG63895B1 true BG63895B1 (en) | 2003-05-30 |
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| BG101310A BG63895B1 (en) | 1994-09-27 | 1997-03-11 | Method for quantitative synthesis of 3-(pyroglutamyl)-l-thiazolydine-4-carboxylic acid and its derivatives |
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| 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) |
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| 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 |
| CN117088939A (en) * | 2022-05-11 | 2023-11-21 | 江苏吴中医药集团有限公司 | A kind of 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 SK SK400-97A patent/SK40097A3/en unknown
- 1995-09-21 CN CNB951953222A patent/CN1143863C/en not_active Expired - Lifetime
- 1995-09-21 WO PCT/EP1995/003720 patent/WO1996010036A1/en not_active Ceased
- 1995-09-21 RO RO97-00611A patent/RO115957B1/en unknown
- 1995-09-21 PL PL95319380A patent/PL181824B1/en unknown
- 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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| Publication number | Publication date |
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| BG101310A (en) | 1997-12-30 |
| IT1270017B (en) | 1997-04-16 |
| ITMI941955A0 (en) | 1994-09-27 |
| SK40097A3 (en) | 1997-09-10 |
| WO1996010036A1 (en) | 1996-04-04 |
| PL319380A1 (en) | 1997-08-04 |
| PL181824B1 (en) | 2001-09-28 |
| BR9509087A (en) | 1998-07-21 |
| CZ91597A3 (en) | 1997-09-17 |
| ITMI941955A1 (en) | 1996-03-27 |
| CN1158620A (en) | 1997-09-03 |
| CN1143863C (en) | 2004-03-31 |
| RO115957B1 (en) | 2000-08-30 |
| CO4480030A1 (en) | 1997-07-09 |
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