NO144884B - PROCEDURE FOR THE PREPARATION OF OPTIC ACTIVALLY LOWER ALKYL-IMIEDAZOLE CARBOXYLATES - Google Patents
PROCEDURE FOR THE PREPARATION OF OPTIC ACTIVALLY LOWER ALKYL-IMIEDAZOLE CARBOXYLATES Download PDFInfo
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- NO144884B NO144884B NO760790A NO760790A NO144884B NO 144884 B NO144884 B NO 144884B NO 760790 A NO760790 A NO 760790A NO 760790 A NO760790 A NO 760790A NO 144884 B NO144884 B NO 144884B
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- Prior art keywords
- imidazole
- lower alkyl
- carboxylates
- phenylethyl
- preparation
- Prior art date
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- 238000000034 method Methods 0.000 title claims description 10
- 238000002360 preparation method Methods 0.000 title claims description 3
- 150000007942 carboxylates Chemical class 0.000 title 1
- 239000002253 acid Substances 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- RGYCCBLTSWHXIS-UHFFFAOYSA-N 3-(1-phenylethyl)imidazole-4-carboxylic acid Chemical compound C1=NC=C(C(O)=O)N1C(C)C1=CC=CC=C1 RGYCCBLTSWHXIS-UHFFFAOYSA-N 0.000 claims description 7
- RQEUFEKYXDPUSK-UHFFFAOYSA-N 1-phenylethylamine Chemical compound CC(N)C1=CC=CC=C1 RQEUFEKYXDPUSK-UHFFFAOYSA-N 0.000 claims description 6
- -1 alkyl 1-(1-phenylethyl)-1H-imidazole-5-carboxylates Chemical class 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 239000011707 mineral Substances 0.000 claims description 2
- 230000001590 oxidative effect Effects 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 229910002651 NO3 Inorganic materials 0.000 claims 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 21
- 239000000243 solution Substances 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 230000032050 esterification Effects 0.000 description 3
- 238000005886 esterification reaction Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- RGYCCBLTSWHXIS-SECBINFHSA-N 1-[(1R)-1-phenylethyl]-1H-imidazole-5-carboxylic acid Chemical compound C1([C@@H](C)N2C(=CN=C2)C(O)=O)=CC=CC=C1 RGYCCBLTSWHXIS-SECBINFHSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- FHFZEKYDSVTYLL-UHFFFAOYSA-N Methomidate Chemical compound COC(=O)C1=CN=CN1C(C)C1=CC=CC=C1 FHFZEKYDSVTYLL-UHFFFAOYSA-N 0.000 description 2
- 125000005907 alkyl ester group Chemical group 0.000 description 2
- 229960001701 chloroform Drugs 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- NPUKDXXFDDZOKR-LLVKDONJSA-N etomidate Chemical compound CCOC(=O)C1=CN=CN1[C@H](C)C1=CC=CC=C1 NPUKDXXFDDZOKR-LLVKDONJSA-N 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 239000003326 hypnotic agent Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- LKGPZAQFNYKISK-UHFFFAOYSA-N propoxate Chemical compound CCCOC(=O)C1=CN=CN1C(C)C1=CC=CC=C1 LKGPZAQFNYKISK-UHFFFAOYSA-N 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000012258 stirred mixture Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- KYWMCFOWDYFYLV-UHFFFAOYSA-N 1h-imidazole-2-carboxylic acid Chemical class OC(=O)C1=NC=CN1 KYWMCFOWDYFYLV-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 229960001690 etomidate Drugs 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Substances C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229960002047 metomidate Drugs 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 229950005930 propoxate Drugs 0.000 description 1
- 238000007790 scraping Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
Foreliggende oppfinnelse' vedrører fremstilling av optisk aktive imidazolkarboksylater med'den generelle formel The present invention relates to the production of optically active imidazole carboxylates with the general formula
og stereokjemisk optiske isomerer av disse hvor uttrykket "lavere alkyl" er valgt fra gruppen som består av metyl, and stereochemical optical isomers thereof wherein the term "lower alkyl" is selected from the group consisting of methyl,
etyl og propyl. De farmasøytiske akseptable syreaddisjonssalter av disse forbindelser ligger også innenfor rammen av formelen (i). ethyl and propyl. The pharmaceutically acceptable acid addition salts of these compounds are also within the scope of formula (i).
Forbindelser med formelen (I) i rasemisk form og fremgangsmåter for fremstilling av disse er beskrevet i US-patent nr. 3 354 173. Compounds with the formula (I) in racemic form and methods for their preparation are described in US patent no. 3,354,173.
Forbindelsene med formelen (I) og spesielt høyre-dreiende isomerer av disse med R-konfigurasjon, er meget anvendelige som kort-virkende hypnotiske midler og noen av dem er for tiden i bruk og er velkjente. Viktige medlemmer av gruppen av forbindelser innenfor rammen av formelen (I) - er f.eks. ( + )-metyl-1 -(1-fenyletyl)-imidazol-5-karboksylat, som generisk betegnes som metomidat og som er kommersielt tilgjengelig i Europa som et injiserbart, hypnotisk middel for anvendelse i veterinærmedisinen, R-(+)-etyl-1-(1-fenyl-etyl) -1H-imidazol-5-karboksylat, som generisk betegnes som etomidat og som er blitt rapportert i Arzneim.-Eorsch., The compounds of formula (I) and especially dextrorotatory isomers thereof with R configuration, are very useful as short-acting hypnotic agents and some of them are currently in use and are well known. Important members of the group of compounds within the framework of formula (I) - are e.g. ( + )-methyl-1-(1-phenylethyl)-imidazole-5-carboxylate, which is generically known as metomidate and is commercially available in Europe as an injectable hypnotic agent for use in veterinary medicine, R-(+)-ethyl -1-(1-phenyl-ethyl)-1H-imidazole-5-carboxylate, which is generically designated as etomidate and which has been reported in Arzneim.-Eorsch.,
21 (8), 1234 (1971), Brit. J. Anaesthesia, 45, 1097 (1973) 21 (8), 1234 (1971), Brit. J. Anesthesia, 45, 1097 (1973)
og Anaesthesist, 23 150 (1974), og (+)-propyl-1-(1-fenyl-etyl) -1 H-imidazol-5-karboksylat som generisk betegnes som propoksat. and Anaesthesist, 23 150 (1974), and (+)-propyl-1-(1-phenyl-ethyl)-1H-imidazole-5-carboxylate which is generically referred to as propoxate.
Den foreliggende oppfinnelse tilveiebringer som nevnt ovenfor fremgangsmåte for å fremstille i det vesent-lige rene optiske antipoder med formelen (I) som i hoved-trekkene er fri for hverandre med utgangspunkt i rasemiske forstadier. Det er et meget ønskelig mål å tilveiebringe en slik fremgangsmåte siden det gjør det mulig å fremstille optiske rene sluttprodukter som i mindre utstrekning er avhengig av tilgjengeligheten av optiske rene forstadier. The present invention provides, as mentioned above, a method for producing essentially pure optical antipodes with the formula (I) which are essentially independent of each other starting from racemic precursors. It is a very desirable goal to provide such a method since it makes it possible to produce optically pure end products which are to a lesser extent dependent on the availability of optically pure precursors.
Fremgangsmåten ifølge foreliggende oppfinnelse for å fremstille hovedsakelig rene R- og S-former av formel (I)-forbindelser omfatter å oppløse rasemisk 1 -(1-fenyletyl)-1H-imidazol-5-karboksylsyre i sine optisk aktive enantio-morfer og deretter omdanne hver av de optiske isomerer av syren til den ønskede lavere alkylester ved hjelp av kjente forestringsmetoder. The process according to the present invention for preparing essentially pure R and S forms of compounds of formula (I) comprises dissolving racemic 1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid in its optically active enantiomorphs and then converting each of the optical isomers of the acid to the desired lower alkyl ester using known esterification methods.
Dannelsen av de forannevnte diastereomere salter utføres i et passende inert organisk oppløsningsmiddel, så som f.eks. en lavere alkanol, f.eks. etanol, propanol, 2-propanol og lignende, fortrinnsvis under tilbakeløpsbeting-elser. Den optisk aktive base som anvendes ifølge oppfinnelsen er høyre- og venstreformene av a-metylbenzen-metanamin. The formation of the aforementioned diastereomeric salts is carried out in a suitable inert organic solvent, such as e.g. a lower alkanol, e.g. ethanol, propanol, 2-propanol and the like, preferably under reflux conditions. The optically active base used according to the invention is the right and left forms of α-methylbenzenemethanamine.
Når den optisk aktive base. tilsettes til en opp-løsning av rasemisk 1-(1-fenyletyl)-1H-imidazol-5-karboksyl-syre i et passende oppløsningsmiddel, utfelles et addi-sjonssalt av R-( + )-1 -(1-fenyletyl)-1H-imidazol-5-karboksyl-syre med basen i stort sett ren form hvorfra den fri syre kan tilveiebringes i stort sett optisk ren form. When the optically active base. is added to a solution of racemic 1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid in a suitable solvent, an addition salt of R-( + )-1-(1-phenylethyl)- 1H-imidazole-5-carboxylic acid with the base in largely pure form from which the free acid can be provided in largely optically pure form.
Den på denne måten tilveiebragte R-( + )-1 -(1-fenyl-etyl )-1 H-imidazol-5-karboksylsyre eller et addisjons-salt av denne med basen omdannes lett til R-^( + )~ The R-( + )-1-(1-phenyl-ethyl)-1H-imidazole-5-carboxylic acid obtained in this way or an addition salt thereof with the base is easily converted to R-^( + )~
lavere alkyl 1-(1-fenyletyl)-1H-imidazol-5-karboksylat som betegnes R-( + )(I), ved vanlige f orestringsmetoder, f.eks', ved å koke syren eller addisjonssaltet under tilbakeløp i en passende lavere alkanol i nærvær av eri passende sterk, ikke oksyderende mineralsyre så som f.eks. saltsyre eller svovelsyre. lower alkyl 1-(1-phenylethyl)-1H-imidazole-5-carboxylate designated R-( + )(I), by usual esterification methods, e.g., by refluxing the acid or addition salt in a suitable lower alkanol in the presence of a suitably strong, non-oxidizing mineral acid such as e.g. hydrochloric or sulfuric acid.
Den samme fremgangsmåte kan like godt anvendes . under-ellers like betingelser for å skille S-(-)1-(1-fenyl-etyl)-1 H-imidazol-5-karboksylsyre , men under anvendelse av den. annen S-(-)isomere form av den optisk aktive base. ,På tilsvarende måte vil forestring av den på denne måte til veiebragte S-(-) syre gi S-(-) formen av estere med formel (I) som benevnes S-(-) (I): Enten R-(+) eller S-(-) formen av karboksylsyren fjernes fra mediet i diastereomerisk saltform, kan den gjenværende enantiomer i oppløsningen gjenvinnes ved den vanlige fremgangsmåten, f.eks. ved fordampning av moder-luten hvorfra den utfelte diastereomere var tilveiebragt, eller ved fortynning med et passende oppløsningsmiddel og om ønsket omdanningen til en lavere alkylester med formelen (I) med den tilsvarende konfigurasjon. The same procedure can just as well be used. under otherwise similar conditions for separating S-(-)1-(1-phenyl-ethyl)-1H-imidazole-5-carboxylic acid, but using it. other S-(-)isomeric form of the optically active base. In a similar way, esterification of the S-(-) acid produced in this way will give the S-(-) form of esters with formula (I), which is called S-(-) (I): Either R-(+) or the S-(-) form of the carboxylic acid is removed from the medium in diastereomeric salt form, the remaining enantiomer in the solution can be recovered by the usual method, e.g. by evaporation of the mother liquor from which the precipitated diastereomer was obtained, or by dilution with a suitable solvent and, if desired, the conversion to a lower alkyl ester of the formula (I) with the corresponding configuration.
Den rasemiske 1-(1-fenyletyl)-1H-imidazol-5-karboks-ylsyre som anvendes som utgangsmateriale er beskrevet i US-patent 3 354 173 og denne kan fremstilles ved hjelp av The racemic 1-(1-phenylethyl)-1H-imidazol-5-carboxylic acid used as starting material is described in US patent 3,354,173 and this can be prepared using
fremgangsmåter som er beskrevet der. procedures described there.
De følgende eksempler er gitt for å illustrere og ikke begrense oppfinnelsen. Hvis ikke annet er sagt er alle deler vektdeler og symbolet faj står for aD 20 . The following examples are given to illustrate and not limit the invention. Unless otherwise stated, all parts are parts by weight and the symbol faj stands for aD 20.
Eksempel _1_ Example _1_
a) Til en blanding som ble omrørt og kokt under tilbakeløp og som besto av 13 deler ( + )-1 -(1-fenyletyl)-5-imidazolkarboksylsyre og 200 deler 2-propanol ble tilsatt 3,6 deler (-)-a-metylbenzen-metanamin og blandingen ble omrørt og kokt under tilbakeløp i 10 minutter. Reaksjons-blandingen fikk deretter anledning til å avkjøles til værelsetemperatur. Det utfelte produkt ble'frafiltrert (filtratet ble satt til side), vasket med 2-propanol og krystallisert fra 160 deler 2-propanol. Det ble frafiltrert og tørket over week-end i vakuum ved 60°C og ga (-)-1 -(1-fenyletyl)-1H-imidazol-5-karboksylsyresalt med (-) -a-metylbenzenmétanamin, smeltepunkt 194"°C , /a/D = -51,0° (c = 1% i vann). a) To a mixture which was stirred and refluxed and which consisted of 13 parts of ( + )-1 -(1-phenylethyl)-5-imidazole carboxylic acid and 200 parts of 2-propanol was added 3.6 parts of (-)-a -methylbenzene-methanamine and the mixture was stirred and refluxed for 10 minutes. The reaction mixture was then allowed to cool to room temperature. The precipitated product was filtered off (the filtrate was set aside), washed with 2-propanol and crystallized from 160 parts of 2-propanol. It was filtered off and dried over the week-end in vacuum at 60°C and gave (-)-1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid salt with (-)-α-methylbenzenemethanamine, melting point 194"°C , /a/D = -51.0° (c = 1% in water).
Til det ovennevnte filtrat (se ovenfor) tilsettes 3,6 deler (+)-a-metylbenzenmetanamin og blandingen ble omrørt og kokt under tilbakeløp i 10 minutter. Reaksjons-blandingen ble avkjølt ved værelsetemperatur. Det utfelte produkt ble frafiltrert, vasket med 2-propanol og tørket i vakuum i 4 timer ved 6 0°C, noe som.ga ( + )-1 -(1-fenyl- etyl)-lH-imidazol-5-karboksylsyresalt. med ( + )-a-metylbenzen-metanamin, smeltepunkt 190,3°C, f& JD = +52,9° (c = 1% i vann). b) En omrørt blanding av 2,55 deler (+)-a-metyl-benzylaminsalt med R-( + )-1 -(a-metylbenzyl)-5-imidazol-karboksylsyre og 24 deler tørr absolutt etanol mettes med gassformet hydrogenklorid. Etterat tilsatsen er avsluttet fortsettes omrøringen i 7 timer ved tilbakeløpstemperatur mens gassformet hydrogenklorid fremdeles tilføres. Reak-sjonsblandingen fordampes og residuet tas opp i 30 deler vann. Den resulterende oppløsning justeres til pH = 6 med natriumhydroksydoppløsning 10N og produktet ekstraheres tre ganger med triklormetan. De sammenslåtte ekstrakter tørkes, filtreres og fordampes. Residuet tas opp i 2,4 deler 2-propanol og oppløsningen filtreres. Filtratet sur-gjøres med svovelsyre og oppvarmes en stund. 2,2'-oksybis-propan tilsettes til blandingen er nesten grumset og ved skraping utfelles produktet under avkjøling i et isbad. Det frafiltreres, vaskes med en blanding av 2-propanol og 2,2'-oksybispropan og tørket gir det 80% R-(+)etyl-1-(a-metyl-benzyl) -5-imidazolkarboksylatsulf at , [ aj = +22,5° (c = 0,1% H20) . To the above filtrate (see above) is added 3.6 parts of (+)-α-methylbenzenemethanamine and the mixture is stirred and refluxed for 10 minutes. The reaction mixture was cooled at room temperature. The precipitated product was filtered off, washed with 2-propanol and dried in vacuo for 4 hours at 60°C, which gave (+)-1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid salt. with ( + )-α-methylbenzene-methanamine, m.p. 190.3°C, f& JD = +52.9° (c = 1% in water). b) A stirred mixture of 2.55 parts of (+)-a-methyl-benzylamine salt with R-( + )-1 -(a-methylbenzyl)-5-imidazole-carboxylic acid and 24 parts of dry absolute ethanol is saturated with gaseous hydrogen chloride. After the addition has ended, stirring is continued for 7 hours at reflux temperature while gaseous hydrogen chloride is still added. The reaction mixture is evaporated and the residue is taken up in 30 parts of water. The resulting solution is adjusted to pH = 6 with sodium hydroxide solution 10N and the product is extracted three times with trichloromethane. The combined extracts are dried, filtered and evaporated. The residue is taken up in 2.4 parts of 2-propanol and the solution is filtered. The filtrate is acidified with sulfuric acid and heated for a while. 2,2'-oxybis-propane is added until the mixture is almost cloudy and by scraping the product precipitates while cooling in an ice bath. It is filtered off, washed with a mixture of 2-propanol and 2,2'-oxybispropane and dried to give 80% R-(+)ethyl-1-(a-methyl-benzyl)-5-imidazole carboxylate sulfate, [ aj = + 22.5° (c = 0.1% H 2 O).
Eksemgel_2 Eczema gel_2
En omrørt blanding av 2,55 deler S-(-)-(1-fenyl-etyl)-1 H-imidazol-5-karboksylsyresalt med (-)-a-metylbenzen-metanamin og 24 deler tørr absolutt etanol mettes med gassformet hydrogenklorid. Etterat tilsatsen er avsluttet fortsettes omrøringen i 7 timer ved tilbakeløpstemperatur mens gassformet hydrogenklorid fremdeles tilføres. Reaksjons-blandingen fordampes og residuet tas opp i 30 deler vann. Oppløsningen justeres til.pH = 6 med en natriumhydroksyd-oppløsning 10N og produktet ekstraheres tre ganger med triklormetan. De sammenslåtte ekstrakter tørkes, filtreres og fordampes. Residuet omdannes til nitratsalt i metylbenzen under avkjøling av et isbad. Saltet frafiltreres, vaskes med metylbenzen og tørkes og gir 52% S-(-)-etyl 1-(a-metyl- A stirred mixture of 2.55 parts of S-(-)-(1-phenyl-ethyl)-1H-imidazole-5-carboxylic acid salt with (-)-α-methylbenzenemethanamine and 24 parts of dry absolute ethanol is saturated with gaseous hydrogen chloride . After the addition has ended, stirring is continued for 7 hours at reflux temperature while gaseous hydrogen chloride is still added. The reaction mixture is evaporated and the residue is taken up in 30 parts of water. The solution is adjusted to pH = 6 with a sodium hydroxide solution 10N and the product is extracted three times with trichloromethane. The combined extracts are dried, filtered and evaporated. The residue is converted to the nitrate salt in methylbenzene while cooling in an ice bath. The salt is filtered off, washed with methylbenzene and dried to give 52% S-(-)-ethyl 1-(α-methyl-
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US55719475A | 1975-03-10 | 1975-03-10 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO760790L NO760790L (en) | 1976-09-13 |
| NO144884B true NO144884B (en) | 1981-08-24 |
| NO144884C NO144884C (en) | 1981-12-02 |
Family
ID=24224401
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO760790A NO144884C (en) | 1975-03-10 | 1976-03-08 | PROCEDURE FOR THE PREPARATION OF OPTIC ACTIVALLY LOWER ALKYL-IMIEDAZOLE CARBOXYLATES |
Country Status (27)
| Country | Link |
|---|---|
| JP (1) | JPS51115473A (en) |
| AT (1) | AT353262B (en) |
| AU (1) | AU503733B2 (en) |
| BE (1) | BE839120A (en) |
| BG (1) | BG24806A3 (en) |
| CA (1) | CA1066709A (en) |
| CH (1) | CH629192A5 (en) |
| CS (1) | CS203116B2 (en) |
| DE (1) | DE2609573A1 (en) |
| DK (1) | DK99376A (en) |
| ES (1) | ES445450A1 (en) |
| FI (1) | FI62292C (en) |
| FR (1) | FR2318159A1 (en) |
| GB (1) | GB1535566A (en) |
| HU (1) | HU172026B (en) |
| IE (1) | IE42652B1 (en) |
| IL (1) | IL49190A (en) |
| IT (1) | IT1057941B (en) |
| LU (1) | LU74503A1 (en) |
| NL (1) | NL7602444A (en) |
| NO (1) | NO144884C (en) |
| PL (1) | PL99926B1 (en) |
| PT (1) | PT64879B (en) |
| SE (1) | SE7601959L (en) |
| SU (1) | SU677656A3 (en) |
| YU (1) | YU60876A (en) |
| ZA (1) | ZA761427B (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE871675A (en) * | 1977-12-02 | 1979-04-30 | Smithkline Corp | PROCESS FOR PREPARING DERIVATIVES OF IMIDAZOLE |
| JPS5671073A (en) | 1979-11-12 | 1981-06-13 | Takeda Chem Ind Ltd | Imidazole derivative |
| JPS5671074A (en) | 1979-11-12 | 1981-06-13 | Takeda Chem Ind Ltd | 1,2-disubstituted-4-halogenoimidazole-5-acetic acid derivative |
| JPS58157768A (en) * | 1982-03-16 | 1983-09-19 | Takeda Chem Ind Ltd | 4-chloro-2-phenylimidazole-5-acetic acid derivative |
| PL149675B1 (en) * | 1986-03-10 | 1990-03-31 | Method of obtaining novel derivatives of 1-methyl 1h-imidazolecarboxylic-5 acid | |
| JP5580287B2 (en) * | 2008-03-31 | 2014-08-27 | ザ ジェネラル ホスピタル コーポレイション | Etomidate analogs with improved pharmacokinetic and pharmacodynamic properties |
| ES2617536T3 (en) | 2012-01-13 | 2017-06-19 | The General Hospital Corporation | Anesthetic compounds and related methods of use |
-
1976
- 1976-02-13 CA CA245,697A patent/CA1066709A/en not_active Expired
- 1976-02-18 GB GB6339/76A patent/GB1535566A/en not_active Expired
- 1976-02-19 SE SE7601959A patent/SE7601959L/en not_active Application Discontinuation
- 1976-02-23 ES ES445450A patent/ES445450A1/en not_active Expired
- 1976-03-01 FR FR7605762A patent/FR2318159A1/en active Granted
- 1976-03-03 BE BE164793A patent/BE839120A/en not_active IP Right Cessation
- 1976-03-05 CH CH280676A patent/CH629192A5/en not_active IP Right Cessation
- 1976-03-08 NO NO760790A patent/NO144884C/en unknown
- 1976-03-08 JP JP51024280A patent/JPS51115473A/en active Pending
- 1976-03-08 DK DK99376*#A patent/DK99376A/en not_active Application Discontinuation
- 1976-03-08 CS CS761495A patent/CS203116B2/en unknown
- 1976-03-08 IT IT48460/76A patent/IT1057941B/en active
- 1976-03-08 DE DE19762609573 patent/DE2609573A1/en not_active Withdrawn
- 1976-03-08 LU LU74503A patent/LU74503A1/xx unknown
- 1976-03-09 FI FI760601A patent/FI62292C/en not_active IP Right Cessation
- 1976-03-09 AU AU11806/76A patent/AU503733B2/en not_active Expired
- 1976-03-09 PT PT64879A patent/PT64879B/en unknown
- 1976-03-09 HU HU76JA00000750A patent/HU172026B/en unknown
- 1976-03-09 ZA ZA761427A patent/ZA761427B/en unknown
- 1976-03-09 AT AT171776A patent/AT353262B/en not_active IP Right Cessation
- 1976-03-09 YU YU00608/76A patent/YU60876A/en unknown
- 1976-03-09 IE IE482/76A patent/IE42652B1/en unknown
- 1976-03-09 NL NL7602444A patent/NL7602444A/en not_active Application Discontinuation
- 1976-03-10 SU SU762329945A patent/SU677656A3/en active
- 1976-03-10 BG BG032575A patent/BG24806A3/en unknown
- 1976-03-10 IL IL49190A patent/IL49190A/en unknown
- 1976-03-10 PL PL1976187827A patent/PL99926B1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| PT64879A (en) | 1976-04-01 |
| BG24806A3 (en) | 1978-05-12 |
| DE2609573A1 (en) | 1976-09-30 |
| ES445450A1 (en) | 1977-10-16 |
| IT1057941B (en) | 1982-03-30 |
| YU60876A (en) | 1983-01-21 |
| NO144884C (en) | 1981-12-02 |
| SU677656A3 (en) | 1979-07-30 |
| CH629192A5 (en) | 1982-04-15 |
| AU1180676A (en) | 1977-09-15 |
| AU503733B2 (en) | 1979-09-20 |
| FI62292C (en) | 1982-12-10 |
| NL7602444A (en) | 1976-09-14 |
| CS203116B2 (en) | 1981-02-27 |
| SE7601959L (en) | 1976-09-13 |
| GB1535566A (en) | 1978-12-13 |
| HU172026B (en) | 1978-05-28 |
| PL99926B1 (en) | 1978-08-31 |
| IE42652L (en) | 1976-09-10 |
| ATA171776A (en) | 1979-04-15 |
| LU74503A1 (en) | 1976-09-01 |
| JPS51115473A (en) | 1976-10-12 |
| FI62292B (en) | 1982-08-31 |
| PT64879B (en) | 1978-02-06 |
| DK99376A (en) | 1976-09-11 |
| CA1066709A (en) | 1979-11-20 |
| FI760601A (en) | 1976-09-11 |
| FR2318159A1 (en) | 1977-02-11 |
| IL49190A (en) | 1980-07-31 |
| AT353262B (en) | 1979-11-12 |
| ZA761427B (en) | 1977-10-26 |
| IL49190A0 (en) | 1976-05-31 |
| IE42652B1 (en) | 1980-09-24 |
| FR2318159B1 (en) | 1979-07-27 |
| BE839120A (en) | 1976-09-03 |
| NO760790L (en) | 1976-09-13 |
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