NO170078B - PROCEDURE FOR THE PREPARATION OF 3-INDOLYPYRODRUIC ACID OR 5-OH DERIVATIVE THEREOF - Google Patents
PROCEDURE FOR THE PREPARATION OF 3-INDOLYPYRODRUIC ACID OR 5-OH DERIVATIVE THEREOF Download PDFInfo
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- 238000000034 method Methods 0.000 title claims description 17
- 238000002360 preparation method Methods 0.000 title description 7
- 239000002253 acid Substances 0.000 title description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 39
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 27
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 22
- RSTKLPZEZYGQPY-UHFFFAOYSA-N 3-(indol-3-yl)pyruvic acid Chemical compound C1=CC=C2C(CC(=O)C(=O)O)=CNC2=C1 RSTKLPZEZYGQPY-UHFFFAOYSA-N 0.000 claims description 21
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 claims description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 13
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 11
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 9
- 239000002244 precipitate Substances 0.000 claims description 9
- 235000005074 zinc chloride Nutrition 0.000 claims description 7
- 239000011592 zinc chloride Substances 0.000 claims description 7
- BGUWFUQJCDRPTL-UHFFFAOYSA-N pyridine-4-carbaldehyde Chemical compound O=CC1=CC=NC=C1 BGUWFUQJCDRPTL-UHFFFAOYSA-N 0.000 claims description 6
- 239000003495 polar organic solvent Substances 0.000 claims description 5
- 239000011541 reaction mixture Substances 0.000 claims description 5
- CSDSSGBPEUDDEE-UHFFFAOYSA-N 2-formylpyridine Chemical compound O=CC1=CC=CC=N1 CSDSSGBPEUDDEE-UHFFFAOYSA-N 0.000 claims description 4
- 239000012024 dehydrating agents Substances 0.000 claims description 4
- 150000003512 tertiary amines Chemical class 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 238000005859 coupling reaction Methods 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- LDCYZAJDBXYCGN-VIFPVBQESA-N 5-hydroxy-L-tryptophan Chemical compound C1=C(O)C=C2C(C[C@H](N)C(O)=O)=CNC2=C1 LDCYZAJDBXYCGN-VIFPVBQESA-N 0.000 claims description 2
- 229940000681 5-hydroxytryptophan Drugs 0.000 claims description 2
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 125000005907 alkyl ester group Chemical group 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- LDCYZAJDBXYCGN-UHFFFAOYSA-N oxitriptan Natural products C1=C(O)C=C2C(CC(N)C(O)=O)=CNC2=C1 LDCYZAJDBXYCGN-UHFFFAOYSA-N 0.000 claims description 2
- 239000000243 solution Substances 0.000 description 18
- 238000003756 stirring Methods 0.000 description 15
- 229960004799 tryptophan Drugs 0.000 description 12
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical group C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 5
- ODUKZJKEVZCMRV-MERQFXBCSA-N (2s)-3-(1h-indol-3-yl)-2-(methylamino)propanoic acid;hydrochloride Chemical compound Cl.C1=CC=C2C(C[C@H](NC)C(O)=O)=CNC2=C1 ODUKZJKEVZCMRV-MERQFXBCSA-N 0.000 description 4
- 238000007792 addition Methods 0.000 description 4
- 239000012299 nitrogen atmosphere Substances 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 239000002585 base Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- OLNJUISKUQQNIM-UHFFFAOYSA-N indole-3-carbaldehyde Chemical compound C1=CC=C2C(C=O)=CNC2=C1 OLNJUISKUQQNIM-UHFFFAOYSA-N 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- QIAFMBKCNZACKA-UHFFFAOYSA-N N-benzoylglycine Chemical compound OC(=O)CNC(=O)C1=CC=CC=C1 QIAFMBKCNZACKA-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- GVRWIAHBVAYKIZ-UHFFFAOYSA-N dec-3-ene Chemical compound CCCCCCC=CCC GVRWIAHBVAYKIZ-UHFFFAOYSA-N 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- WJRBRSLFGCUECM-UHFFFAOYSA-N hydantoin Chemical compound O=C1CNC(=O)N1 WJRBRSLFGCUECM-UHFFFAOYSA-N 0.000 description 2
- 229940091173 hydantoin Drugs 0.000 description 2
- 239000013067 intermediate product Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- -1 methylene indole acetate Chemical compound 0.000 description 2
- 239000002808 molecular sieve Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 2
- 230000020477 pH reduction Effects 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 102000004625 Aspartate Aminotransferases Human genes 0.000 description 1
- 108010003415 Aspartate Aminotransferases Proteins 0.000 description 1
- 244000135860 Capparis spinosa subsp spinosa Species 0.000 description 1
- QNVNLUSHGRBCLO-UHFFFAOYSA-N H2BDC Natural products OC(=O)C1=CC(O)=CC(C(O)=O)=C1 QNVNLUSHGRBCLO-UHFFFAOYSA-N 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- 239000002262 Schiff base Substances 0.000 description 1
- 150000004753 Schiff bases Chemical class 0.000 description 1
- 241000287219 Serinus canaria Species 0.000 description 1
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical group [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 210000001557 animal structure Anatomy 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 1
- 229910001863 barium hydroxide Inorganic materials 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- LBJNMUFDOHXDFG-UHFFFAOYSA-N copper;hydrate Chemical compound O.[Cu].[Cu] LBJNMUFDOHXDFG-UHFFFAOYSA-N 0.000 description 1
- WYACBZDAHNBPPB-UHFFFAOYSA-N diethyl oxalate Chemical compound CCOC(=O)C(=O)OCC WYACBZDAHNBPPB-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 150000004715 keto acids Chemical class 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- KCUNTYMNJVXYKZ-JTQLQIEISA-N methyl (2s)-2-amino-3-(1h-indol-3-yl)propanoate Chemical compound C1=CC=C2C(C[C@H](N)C(=O)OC)=CNC2=C1 KCUNTYMNJVXYKZ-JTQLQIEISA-N 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- IFGCUJZIWBUILZ-UHFFFAOYSA-N sodium 2-[[2-[[hydroxy-(3,4,5-trihydroxy-6-methyloxan-2-yl)oxyphosphoryl]amino]-4-methylpentanoyl]amino]-3-(1H-indol-3-yl)propanoic acid Chemical compound [Na+].C=1NC2=CC=CC=C2C=1CC(C(O)=O)NC(=O)C(CC(C)C)NP(O)(=O)OC1OC(C)C(O)C(O)C1O IFGCUJZIWBUILZ-UHFFFAOYSA-N 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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- Indole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Den foreliggende oppfinnelse vedrører en fremgangsmåte for fremstilling av 3-indolpyrodruesyre eller 5-OH-derivatet derav med formel: hvori X er hydrogen eller hydroksy, og det særegne ved fremgangsmåten i henhold til oppfinnelsen er at tryptofan eller 5-hydroksytryptofan med formel: The present invention relates to a method for the production of 3-indole pyruvic acid or its 5-OH derivative with the formula: in which X is hydrogen or hydroxy, and the peculiarity of the method according to the invention is that tryptophan or 5-hydroxytryptophan with the formula:
hvori X har den ovennevnte betydning, eller en lavere alkylester derav, omsettes med et pyridinaldehyd i et polart organisk løsningsmiddel ved en koblingsreaksjon i nærvær av en tertiær aminbase som protonakseptor og dehydratiserings-middel under dannelse av en Schiffs base som mellomprodukt, hvoretter reaksjonsblandingen hydrolyseres med en sterkt sur vandig løsning til dannelse av et bunnfall bestående i det vesentlige av 3-indolpyrodruesyre eller dens 5-OH-derivat, in which X has the above meaning, or a lower alkyl ester thereof, is reacted with a pyridine aldehyde in a polar organic solvent in a coupling reaction in the presence of a tertiary amine base as proton acceptor and dehydrating agent, forming a Schiff's base as an intermediate, after which the reaction mixture is hydrolyzed with a strongly acidic aqueous solution to form a precipitate consisting essentially of 3-indolepyruvic acid or its 5-OH derivative,
som isoleres. which is isolated.
Disse og andre trekk ved oppfinnelsen fremgår av patent-kravene. These and other features of the invention appear in the patent claims.
Forskjellige metoder for syntese av 3-indolpyrodruesyre er beskrevet i litteraturen. Various methods for the synthesis of 3-indole pyruvic acid are described in the literature.
Ellinger og Matsouka (Hoppe-Seylers s.109, 259 (1920)) oppnådde ketosyren ved kondensering av indol-3-aldehyd og ben-zoylglycin, etterfulgt av hydrolyse av reaksjonsproduktet (2-fenyl-4-indolyl-metylen-5-oksazolon). Ellinger and Matsouka (Hoppe-Seylers p.109, 259 (1920)) obtained the keto acid by condensation of indole-3-aldehyde and benzoylglycine, followed by hydrolysis of the reaction product (2-phenyl-4-indolyl-methylene-5-oxazolone ).
Bentley et al (Biochem. J. 64, 44 (1956)) kondenserte derimot indol-3-aldehyd med hydantoin, etterfulgt av surgjøring med svovelsyre. Bentley et al (Biochem. J. 64, 44 (1956)), on the other hand, condensed indole-3-aldehyde with hydantoin, followed by acidification with sulfuric acid.
Kaper et al (Arch. Bioch, Biophys. 103, 469 (1963)), omsatte forbindelsen oppnådd etter kondenseringsreaksjonen av indol-3-aldehyd med hydantoin med bariumhydroksyd, etterfulgt av surgjøring med saltsyre. Kaper et al (Arch. Bioch, Biophys. 103, 469 (1963)), reacted the compound obtained after the condensation reaction of indole-3-aldehyde with hydantoin with barium hydroxide, followed by acidification with hydrochloric acid.
Sakurai (J. Biochem. 44, 47 (1957)) anvendte metylindolacetat som et utgangsmaterial ved en omsetning med dietyloksalat. Sakurai (J. Biochem. 44, 47 (1957)) used methylene indole acetate as a starting material in a reaction with diethyl oxalate.
US patentskrift 4.551.471 beskriver en syntese av 3-indolpyrodruesyre ved å gå ut fra L-tryptofan, under innvirkning av enzymet aspartat-aminotransferase, oppnådd fra mitochond-rier fra dyreorganer, men de oppnådde utbytter er bare 5 - 10 % og det oppnådde indolderivat er ikke stabilt i vandig oppløsning. US patent document 4,551,471 describes a synthesis of 3-indole pyruvic acid starting from L-tryptophan, under the action of the enzyme aspartate aminotransferase, obtained from mitochondria from animal organs, but the yields obtained are only 5 - 10% and the obtained indole derivative is not stable in aqueous solution.
Basis for den forliggende oppfinnelse er at tryptofan, både i form av de enkelte L- og D-isomerer, og D,L-blandingen, anvendes som en utgangsforbindelse for kjemisk syntese av 3-indolpyrodruesyre med høye utbytter. Dette gjelder til-svarende for 5-OH-forbindelsene. The basis of the present invention is that tryptophan, both in the form of the individual L- and D-isomers, and the D,L mixture, is used as a starting compound for the chemical synthesis of 3-indolepyruvic acid with high yields. This applies similarly to the 5-OH compounds.
Reaksjonen gjennomføres ved bruk av et middel med en høy dehydratiserende evne i forbindelse med en koblingsreaksjon idet reaksjonen antas å føre til en en Schiffbase. Det vises for dette til det anførte reaksjonsskjerna. The reaction is carried out using an agent with a high dehydrating ability in connection with a coupling reaction, as the reaction is assumed to lead to a Schiff base. For this, reference is made to the stated reaction nucleus.
3-INDOLPYRODRUESYRE 3-INDOL PYRUDRUVIC ACID
I henhold til oppfinnelsen er et særlig foretrukket dehydratiserende middel 1.8-diazabisyklo(5.4.0)undec-7-en, i det følgende betegnet ved forkortelsen DBU, og også et salt inne-holdende et metall som kan danne en stabil binding med reak-sj onsmellomproduktene . Spesielt foretrukket blant slike salter er sinkklorid som antas å danne et kompleks med mellomproduktet ved syntesen. DBU er en reaksjonskomponent som har vært anvendt tidligere i helt andre prosesser, som for eksempel innføring av silangrupper i organiske forbindel-ser (Tetrahedron Lett. 26, 475, 1985), forestring av karboksylsyre (Bull. Chem. Soc. Jap. 51, 2401, 1978) eller fremstilling av peptider (Tetrahedron 40, 4237, 1984). Der er ingen antydning i litteraturen om en bruk av DBU som foreskrevet ved den foreliggende oppfinnelse. Som dehydratiserende middel og tertiær aminbase kan det også fordelaktig anvendes trietylamin eller blandinger av dette med DBU. According to the invention, a particularly preferred dehydrating agent is 1,8-diazabicyclo(5.4.0)undec-7-ene, hereinafter denoted by the abbreviation DBU, and also a salt containing a metal which can form a stable bond with react the intermediate products. Particularly preferred among such salts is zinc chloride, which is believed to form a complex with the intermediate product during the synthesis. DBU is a reaction component that has been used in the past in completely different processes, such as the introduction of silane groups in organic compounds (Tetrahedron Lett. 26, 475, 1985), esterification of carboxylic acid (Bull. Chem. Soc. Jap. 51, 2401, 1978) or preparation of peptides (Tetrahedron 40, 4237, 1984). There is no suggestion in the literature of a use of DBU as prescribed by the present invention. As a dehydrating agent and tertiary amine base, triethylamine or mixtures thereof with DBU can also advantageously be used.
1.5.7-triazobisyklo[4.4.0]dec-7-en (TBD) kan oså med fordel anvendes. 1.5.7-triazobicyclo[4.4.0]dec-7-ene (TBD) can also be used with advantage.
Representative for de nevnte pyridinaldehyder er isonikotinaldehyd. ET annet velegnet pyridinaldehyd er pyridin-2-karboksyaldehyd (PCA). Representative of the aforementioned pyridine aldehydes is isonicotinaldehyde. Another suitable pyridine aldehyde is pyridine-2-carboxyaldehyde (PCA).
Det polare , organiske løsningsmidlet som anvendes ved reaksjonen kan være et i det vesentlige vannfritt løsnings-middel. Representative løsningsmidler er dimetylformamid (DMF) og acetonitril. Et vannholdig løsningsmiddel kan anvendes og eksempler på slike er DMF og metanol. The polar organic solvent used in the reaction can be an essentially anhydrous solvent. Representative solvents are dimethylformamide (DMF) and acetonitrile. An aqueous solvent can be used and examples of such are DMF and methanol.
Reaksjonen kan gjennomføres ved romtemperatur med gode resultater. The reaction can be carried out at room temperature with good results.
Fremgangsmåten i henhold til den foreliggende oppfinnelse har vist seg særlig effektiv for fremstilling av 3-indolpyrodruesyre, d.v.s. at reaksjonen forløper med meget høye utbytter (over 50 %) i forhold til tryptofan eller dets ester. Som angitt i det foregående er prosessen også anvendelig for tryptofan som er OH-substituert i 5-stillingen. The method according to the present invention has proven particularly effective for the production of 3-indole pyruvic acid, i.e. that the reaction proceeds with very high yields (over 50%) in relation to tryptophan or its ester. As indicated above, the process is also applicable to tryptophan which is OH-substituted in the 5-position.
Eksempler på gjennomføringen av fremgangsmåten i henhold til oppfinnelsen er illustrert i det følgende. Examples of the implementation of the method according to the invention are illustrated in the following.
Eksempel 1. Example 1.
Fremstilling av indolpyrodruesyre fra tryptofan Preparation of indole pyruvic acid from tryptophan
En suspensjon av 0,658 g tryptofan i 10 ml dimetylformamid (DMF) som er gjort vannfri ved å føres gjennom molekylsikter eller på nøytrale aluminiumoksydkolonner og under tørr nitrogenatmosfære, tilføres hurtig 0,688 ml isonikotinaldehyd. En nesten fullstendig oppløseliggjøring av suspensjonen foregår med en fargeendring mot gult. Systemet avkjøles med et isblandet vannbad og det tilsettes med en gang sakte 1,0 ml 1.8-diazabisyklo(5.4.0)-undec-7-en (DBU) på forhånd oppløst i 5 ml DMF, som er gjort vannfritt som ovenfor angitt. A suspension of 0.658 g of tryptophan in 10 ml of dimethylformamide (DMF) which has been made anhydrous by passing through molecular sieves or on neutral aluminum oxide columns and under a dry nitrogen atmosphere, is rapidly added to 0.688 ml of isonicotinaldehyde. An almost complete dissolution of the suspension takes place with a color change to yellow. The system is cooled with an ice-water bath and 1.0 ml of 1.8-diazabicyclo(5.4.0)-undec-7-ene (DBU) previously dissolved in 5 ml of DMF, which has been rendered anhydrous as above, is slowly added at once.
Oppløsningen endrer farge fra gul til blodrød. The solution changes color from yellow to blood red.
Reaksjonsblandingen bringes til romtemperatur og holdes under omrøring og tørt nitrogen over natten. The reaction mixture is brought to room temperature and kept under stirring and dry nitrogen overnight.
Blandingen helles inn i et dobbelt volum på forhånd avkjølt 1,0 N HC1 idet systemet holdes under omrøring i 15 minutter. Det ekstraheres med etylacetat (5 x 25 ml). Den organiske fase vaskes i rekkefølge med 0,1 N HCl, og deretter med en mettet NaCl-oppløsning. Den organiske fase tørkes over vann-• fritt Na2SC>4 over natten. Det filtreres, det organiske løsningsmiddel avdampes og etter rensning oppnås 329 mg indolpyrodruesyre med 5 0 % utbytte i forhold til initialt tryptofan. The mixture is poured into a double volume of pre-cooled 1.0 N HCl, keeping the system under stirring for 15 minutes. It is extracted with ethyl acetate (5 x 25 ml). The organic phase is washed successively with 0.1 N HCl, and then with a saturated NaCl solution. The organic phase is dried over water-• free Na2SC>4 overnight. It is filtered, the organic solvent is evaporated and, after purification, 329 mg of indole pyruvic acid is obtained with a 50% yield in relation to initial tryptophan.
NMR, IR-analyse og smeltepunktet for indolpyrodruesyren er i samsvar med data fra litteraturen. NMR, IR analysis and the melting point of the indolepyruvic acid are in agreement with data from the literature.
Eksempel 2.Example 2.
Fremstilling av indolpyrodruesyre fra metyltryptofanhydroklorid Preparation of indole pyruvic acid from methyl tryptophan hydrochloride
Til 10'ml DMF eller acetonitril (CH3CN) som er blitt gjort vannfritt ved å føres gjennom molekylsikter eller nøytrale aluminiumoksydkolonner tilføres 300 mg metyltryptofanhydroklorid og deretter 0,17 0 ml trietylamin under tørr nitrogenatmosfære, idet systemet holdes under omrøring i 30 minutter ved romtemperatur. På nytt under tørr nitrogenatmosfære tilsettes hurtig 0,280 ml isonikotinaldehyd under omrøring og det oppnås en blekgul oppløsning. Deretter tilsettes sakte 0,5 ml DBU oppløst i vannfri DMF-oppløsning. Reaksjonsopp-løsningen endrer farge fra gul til blodrød. To 10 ml of DMF or acetonitrile (CH3CN) which has been made anhydrous by passing through molecular sieves or neutral aluminum oxide columns, add 300 mg of methyltryptophan hydrochloride and then 0.170 ml of triethylamine under a dry nitrogen atmosphere, the system being kept under stirring for 30 minutes at room temperature. Again under a dry nitrogen atmosphere, 0.280 ml of isonicotinaldehyde is quickly added while stirring and a pale yellow solution is obtained. Then slowly add 0.5 ml of DBU dissolved in anhydrous DMF solution. The reaction solution changes color from yellow to blood red.
Systemet opprettholdes under omrøring og tørr nitrogenatmosfære over natten. Ved slutten av denne tid helles blandingen inn i et dobbelt volum 1 N HC1 og oppvarmes til 60°C under oppvarming. Reaksjonsblandingen avkjøles og ekstraheres med etylacetat (5x15 ml). Den organiske fase vaskes i rekkefølge med 0,1 N HC1 og en mettet NaCl-oppløsning. Den organiske fase tørkes over Na2S04 over natten. Den filtreres, det organiske løsningsmiddel avdampes og etter rensing oppnås 155 mg indolpyrodruesyre med 65 % utbytte i forhold til initial tryptofanmetylester HC1. The system is maintained under stirring and a dry nitrogen atmosphere overnight. At the end of this time, the mixture is poured into a double volume of 1 N HCl and heated to 60°C under heating. The reaction mixture is cooled and extracted with ethyl acetate (5x15 ml). The organic phase is washed successively with 0.1 N HCl and a saturated NaCl solution. The organic phase is dried over Na2SO4 overnight. It is filtered, the organic solvent is evaporated and after purification 155 mg of indole pyruvic acid is obtained with a 65% yield in relation to the initial tryptophan methyl ester HC1.
NMR, iR-analyse og smeltepunkt for indolpyrodruesyren er i samsvar med data fra litteraturen. NMR, IR analysis and melting point of the indole pyruvic acid are in agreement with data from the literature.
Eksempel 3. Example 3.
Fremstilling av indolpyrodruesyre fra metyltryptofanhydroklorid Preparation of indole pyruvic acid from methyl tryptophan hydrochloride
Eksempel 2 gjentas inntil den blekgule oppløsning oppnås. Example 2 is repeated until the pale yellow solution is obtained.
Ved dette tidspunkt, før tilsetning av DBU, tilsettes sakte 96 mg vannfritt ZnCl2 under omrøring. Reaksjonsblandingen endrer farge fra gul til blodrød. At this point, before adding DBU, slowly add 96 mg of anhydrous ZnCl2 with stirring. The reaction mixture changes color from yellow to blood red.
Ved å arbeide som beskrevet i eksempel 2, oppnås 155 mg indolpyrodruesyre med 65 % utbytte i forhold til initialt metyltryptofanhydroklorid. By working as described in example 2, 155 mg of indolepyruvic acid is obtained with a 65% yield in relation to initial methyltryptophan hydrochloride.
Eksempel 4. Example 4.
Fremstilling av indolpyrodruesyre fra L- eller D,L-tryptofan i metanol Preparation of indole pyruvic acid from L- or D,L-tryptophan in methanol
34 ml metanol tilsettes ved romtemperatur (omtrent 20°C) 34 ml of methanol are added at room temperature (approximately 20°C)
5 g tryptofan og under omrøring tilsettes 4 ml trietylamin 5 g of tryptophan and 4 ml of triethylamine are added while stirring
(TEA). (TEA).
Etter ti minutter tilsettes hurtig 3,98 ml isonikotinaldehyd (ISNA) under omrøring. Oppløsningen endrer farge fra melke-hvit til gylden grønngul. After ten minutes, quickly add 3.98 ml of isonicotinaldehyde (ISNA) while stirring. The solution changes color from milky white to golden greenish yellow.
Omrøring fortsettes i ytterligere 15 til 20 minutter. Deretter tilsettes hurtig 2,0 ZnCl2 og det oppnås et rikelig gult bunnfall. Dette omrøres kraftig i ytterligere ti minutter og 8,07 ml DBU på forhånd oppløst i 6 ml metanol tilsettes hurtig dråpevis. Tilsetningene foretas i løpet av omtrent fem minutter. En oransjerød oppløsning oppnås til slutt som har tendens til meget hurtig mørkfarging, mens en sakte oppløsning av bunnfallet foregår. Stirring is continued for another 15 to 20 minutes. Then 2.0 ZnCl2 is quickly added and an abundant yellow precipitate is obtained. This is stirred vigorously for a further ten minutes and 8.07 ml of DBU previously dissolved in 6 ml of methanol is quickly added dropwise. The additions are made within approximately five minutes. An orange-red solution is finally obtained which tends to darken very quickly, while a slow dissolution of the precipitate takes place.
Etter omtrent 80 til 90 minutter fra den siste tilsetning tilsettes hurtig den mørkerøde blanding uten bunnfallet dråpevis under kraftig omrøring i omtrent 300 ml 1 N HC1 på forhånd oppvarmet til omtrent 55°C. Det oppnås en klar oransjefarget oppløsning. After about 80 to 90 minutes from the last addition, the dark red mixture without the precipitate is rapidly added dropwise with vigorous stirring into about 300 mL of 1 N HCl preheated to about 55°C. A clear orange colored solution is obtained.
Etter omtrent ti minutters omrøring og ved omtrent 55°C foregår en betraktelig utfelling av et voluminøst gult faststoff som har tendens økende fortykning. After about ten minutes of stirring and at about 55°C, a considerable precipitation of a voluminous yellow solid takes place which tends to thicken.
Etter omtrent 30 minutter avbrytes oppvarmingen og blandingen får fritt synke til romtemperatur (omtrent 20°C) under om-røring. After approximately 30 minutes, the heating is interrupted and the mixture is allowed to cool down to room temperature (approximately 20°C) with stirring.
Etter omtrent tre timer blir et kanarigult faststoff After about three hours, a canary yellow solid forms
avsuget på filter, og vasket flere ganger først med 20 ml IN HCl/metanol (10:1), og deretter med koldt vann til å gi et ufarget og nøytralt filtrat. filtered off, and washed several times first with 20 ml IN HCl/methanol (10:1), and then with cold water to give a colorless and neutral filtrate.
Dette anbringes i en vakuumtørke over natten. Det oppnås This is placed in a vacuum dryer overnight. It is achieved
3,1 g (omtrent 62 % utbytte) indolpyrodruesyre med 100 % renhet (HPLC, NMR, IR, UV i samsvar). 3.1 g (ca. 62% yield) indole pyruvic acid with 100% purity (HPLC, NMR, IR, UV in agreement).
Eksempel 5.Example 5.
Fremstilling av 5-OH indolpyrodruesyre (5HIPA) Preparation of 5-OH indole pyruvic acid (5HIPA)
Ved å følge prosedyren beskrevet i eksemplene i, 2 og 3 i vesentlig grad omdannes 5-OH-tryptofan eller 5-OH-tryptofanmetylester til 5-OH-IPA. By following the procedure described in examples i, 2 and 3, 5-OH-tryptophan or 5-OH-tryptophan methyl ester is substantially converted to 5-OH-IPA.
De foregående eksempler viser at oppfinnelsen er særlig effektiv ved en fremgangsmåte for kjemisk syntese av 5-OH-indolpyrodruesyre. The preceding examples show that the invention is particularly effective in a method for the chemical synthesis of 5-OH-indole pyruvic acid.
Eksempel 6 Example 6
En suspensjon av 500 mg L-tryptofan i 10 ml metanol ble ved romtemperatur under omrøring tilsatt 0,4 ml TEA idet tempera-turen ble holdt under 30°C med et isblandet vannbad. Etter ca 10 minutter ble 0,4 ml pyridin-2-karboksyaldehyd (PCA) tilsatt. Det fremkom en oppløsning med intens gulfarge. Etter 20 minutter ble 0,2 g vannfritt sinkklorid tilsatt hvorved det fremkom et gult bunnfall og en oppløsning som tenderte mot orange. På dette tidspunkt ble det i små porsjoner tilsatt 0,8 ml DBU oppløst i 2 ml metanol hvorved det fremkom en klar blodrød oppløsning. Etter 45 minutter ble det tilsatt 100 ml 1 M HC1 som var forvarmet til 55 - 60°C. Det derved dannede gule bunnfall ble vasket og tørket og viste seg å være 3-indolpyrodruesyre i en mengde på 310 mg (utbytte 62 %). A suspension of 500 mg of L-tryptophan in 10 ml of methanol was added at room temperature with stirring to 0.4 ml of TEA, the temperature being kept below 30°C with an ice-mixed water bath. After about 10 minutes, 0.4 ml of pyridine-2-carboxyaldehyde (PCA) was added. A solution with an intense yellow color appeared. After 20 minutes, 0.2 g of anhydrous zinc chloride was added, resulting in a yellow precipitate and a solution tending towards orange. At this point, 0.8 ml of DBU dissolved in 2 ml of methanol was added in small portions, resulting in a clear blood-red solution. After 45 minutes, 100 ml of 1 M HCl which had been preheated to 55-60°C was added. The resulting yellow precipitate was washed and dried and proved to be 3-indolepyruvic acid in an amount of 310 mg (yield 62%).
Eksempel 7 Example 7
En suspensjon av 500 mg L-tryptofan i en blanding av 6 ml metanol og 4 ml acetonitril ble ved romtemperatur under omrøring tilsatt 1,4 ml TEA. Til denne suspensjon ble det tilsatt 0,4 ml PCA. Det fremkom en klar blekgul oppløsning. Ved tilsetning av 0,2 g vannfritt sinkklorid fremkom en opalescerende orangefarget oppløsning som ble holdt under omrøring etter tilsetning av 0,41 g 1.5.7-triazabisyklo-[4.4.0]-dec-7-en (TBD) oppløst i 2 ml metanol hvorved fargen ble endret til rødlig. Den således oppnådde metanoloppløsning ble dråpevis tilsatt til 100 ml 1 M HC1 som var forvarmet til 55 - 60°C. Det ble iaktatt en gradvis utfelling av et halm-gult fast stoff som etter frafiltrering, vasking og tørking viste seg å være 3-indolpyrodruesyre i en mengde 353 mg (utbytte 71 %). A suspension of 500 mg of L-tryptophan in a mixture of 6 ml of methanol and 4 ml of acetonitrile was added to 1.4 ml of TEA at room temperature with stirring. To this suspension was added 0.4 ml of PCA. A clear pale yellow solution appeared. On addition of 0.2 g of anhydrous zinc chloride, an opalescent orange colored solution appeared which was kept under stirring after the addition of 0.41 g of 1.5.7-triazabicyclo-[4.4.0]-dec-7-ene (TBD) dissolved in 2 ml methanol whereby the color was changed to reddish. The methanol solution thus obtained was added dropwise to 100 ml of 1 M HCl which had been preheated to 55-60°C. A gradual precipitation of a straw-yellow solid was observed which, after filtration, washing and drying, turned out to be 3-indolepyruvic acid in an amount of 353 mg (yield 71%).
Eksempel 8 Example 8
En suspensjon av 500 mg L-tryptofan i 10 ml metanol ble tilsatt 0,4 ml TEA og 0,4 ml PCA. Til den dermed fremkomne klare oppløsning ble det tilsatt 200 mg vannfritt sinkklorid. Det ble dannet et bunnfall av en gul forbindelse som viste tendens til å gå i oppløsning. Ytterligere 0,4 ml TEA oppløst i 2 ml metanol ble tilsatt i løpet av 5 minutter. Det fremkom en klar oppløsning av rødlig orange farge som dråpevis ble tilsatt til 100 ml 1 M HC1 forvarmet til 55 - 60°C. Det fremkomne blekgule bunnfall ble vasket og tørket og viste seg å være 3-indopyrodruesyre i en mengde på 295 mg (utbytte 60 %). A suspension of 500 mg of L-tryptophan in 10 ml of methanol was added to 0.4 ml of TEA and 0.4 ml of PCA. 200 mg of anhydrous zinc chloride was added to the resulting clear solution. A precipitate of a yellow compound was formed which showed a tendency to dissolve. An additional 0.4 ml of TEA dissolved in 2 ml of methanol was added over 5 minutes. A clear solution of reddish orange color appeared which was added dropwise to 100 ml of 1 M HC1 preheated to 55 - 60°C. The resulting pale yellow precipitate was washed and dried and proved to be 3-indopyruvic acid in an amount of 295 mg (yield 60%).
Claims (7)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT48295/85A IT1184282B (en) | 1985-06-28 | 1985-06-28 | PROCEDURE FOR THE PRODUCTION OF INDOLIC ALPHA-KETOACIDS STARTING FROM A RESPECT ALPHA-AMINO-ACID, IN PARTICULAR TO PRODUCE INDOLPIRUVIC ACID |
| PCT/IT1986/000045 WO1987000169A1 (en) | 1985-06-28 | 1986-06-24 | Production of indole alpha-ketoacids from alpha-aminoacid, particularly of indolepyruvic acid |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| NO870748D0 NO870748D0 (en) | 1987-02-24 |
| NO870748L NO870748L (en) | 1987-02-24 |
| NO170078B true NO170078B (en) | 1992-06-01 |
| NO170078C NO170078C (en) | 1992-09-09 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO870748A NO170078C (en) | 1985-06-28 | 1987-02-24 | PROCEDURE FOR THE PREPARATION OF 3-INDOLYPYRODRUIC ACID OR 5-OH DERIVATIVE THEREOF |
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| Country | Link |
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| NO (1) | NO170078C (en) |
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- 1987-02-24 NO NO870748A patent/NO170078C/en not_active IP Right Cessation
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| Publication number | Publication date |
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| NO870748D0 (en) | 1987-02-24 |
| NO870748L (en) | 1987-02-24 |
| NO170078C (en) | 1992-09-09 |
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