NO128572B - - Google Patents
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- NO128572B NO128572B NO03766/68A NO376668A NO128572B NO 128572 B NO128572 B NO 128572B NO 03766/68 A NO03766/68 A NO 03766/68A NO 376668 A NO376668 A NO 376668A NO 128572 B NO128572 B NO 128572B
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- Norway
- Prior art keywords
- benzoxazine
- formula
- lower alkyl
- chloro
- compound
- Prior art date
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- 150000001875 compounds Chemical class 0.000 claims description 16
- 125000000217 alkyl group Chemical group 0.000 claims description 13
- 238000002360 preparation method Methods 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- SWDJXULAVXHWBD-UHFFFAOYSA-N 4,6-dichloro-1h-2,3-benzoxazine Chemical compound C1=C(Cl)C=C2C(Cl)=NOCC2=C1 SWDJXULAVXHWBD-UHFFFAOYSA-N 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- BZQYQHBLAIWZAC-UHFFFAOYSA-N 1h-2,3-benzoxazine Chemical class C1=CC=C2CON=CC2=C1 BZQYQHBLAIWZAC-UHFFFAOYSA-N 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 150000001728 carbonyl compounds Chemical class 0.000 claims description 4
- -1 hydrazone compounds Chemical class 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- XBQCPGQMXAXYME-UHFFFAOYSA-N 6-chloro-n-(propan-2-ylideneamino)-1h-2,3-benzoxazin-4-amine Chemical compound C1=C(Cl)C=C2C(NN=C(C)C)=NOCC2=C1 XBQCPGQMXAXYME-UHFFFAOYSA-N 0.000 claims description 3
- MFHUOYADTVLXMD-UHFFFAOYSA-N 6-chloro-n-methyl-n-(propan-2-ylideneamino)-1h-2,3-benzoxazin-4-amine Chemical compound C1=C(Cl)C=C2C(N(N=C(C)C)C)=NOCC2=C1 MFHUOYADTVLXMD-UHFFFAOYSA-N 0.000 claims description 3
- KJDQNEMYJJCGMR-UHFFFAOYSA-N 4-chloro-1h-2,3-benzoxazine Chemical compound C1=CC=C2C(Cl)=NOCC2=C1 KJDQNEMYJJCGMR-UHFFFAOYSA-N 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 230000007306 turnover Effects 0.000 claims 1
- 239000002023 wood Substances 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 17
- 239000000243 solution Substances 0.000 description 11
- 239000000203 mixture Substances 0.000 description 10
- 238000002844 melting Methods 0.000 description 8
- 230000008018 melting Effects 0.000 description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- ZCKSETHMUBXEOS-UHFFFAOYSA-N 1-(6-chloro-1h-2,3-benzoxazin-4-yl)-1-methylhydrazine Chemical compound C1=C(Cl)C=C2C(N(N)C)=NOCC2=C1 ZCKSETHMUBXEOS-UHFFFAOYSA-N 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- HJEALFMKMBRWQO-UHFFFAOYSA-N (6-chloro-1h-2,3-benzoxazin-4-yl)hydrazine Chemical compound C1=C(Cl)C=C2C(NN)=NOCC2=C1 HJEALFMKMBRWQO-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- IZXHRPUCSXCXSO-UHFFFAOYSA-N 6-chloro-n,n-dimethyl-1h-2,3-benzoxazin-4-amine Chemical compound C1=C(Cl)C=C2C(N(C)C)=NOCC2=C1 IZXHRPUCSXCXSO-UHFFFAOYSA-N 0.000 description 2
- JKOGLZJKPQGMRA-UHFFFAOYSA-N 6-chloro-n-(ethylideneamino)-n-methyl-1h-2,3-benzoxazin-4-amine Chemical compound C1=C(Cl)C=C2C(N(C)N=CC)=NOCC2=C1 JKOGLZJKPQGMRA-UHFFFAOYSA-N 0.000 description 2
- GUXQXIRGDSFDLP-UHFFFAOYSA-N 6-chloro-n-methyl-1h-2,3-benzoxazin-4-amine Chemical compound C1=C(Cl)C=C2C(NC)=NOCC2=C1 GUXQXIRGDSFDLP-UHFFFAOYSA-N 0.000 description 2
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 230000001143 conditioned effect Effects 0.000 description 2
- 239000012259 ether extract Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 230000001624 sedative effect Effects 0.000 description 2
- ODKARNMCYIQDOK-UHFFFAOYSA-N 6-chloro-n-methyl-n-(propylideneamino)-1h-2,3-benzoxazin-4-amine Chemical compound C1=C(Cl)C=C2C(N(C)N=CCC)=NOCC2=C1 ODKARNMCYIQDOK-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 125000001118 alkylidene group Chemical group 0.000 description 1
- BIVUUOPIAYRCAP-UHFFFAOYSA-N aminoazanium;chloride Chemical compound Cl.NN BIVUUOPIAYRCAP-UHFFFAOYSA-N 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000009194 climbing Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000007857 hydrazones Chemical class 0.000 description 1
- 239000005554 hypnotics and sedatives Substances 0.000 description 1
- 229940005535 hypnotics and sedatives Drugs 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- HDZGCSFEDULWCS-UHFFFAOYSA-N monomethylhydrazine Chemical compound CNN HDZGCSFEDULWCS-UHFFFAOYSA-N 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 229940124641 pain reliever Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 230000008925 spontaneous activity Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 231100000048 toxicity data Toxicity 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/02—1,2-Oxazines; Hydrogenated 1,2-oxazines
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Analogifremgangsmåte til fremstilling av tera- Analogy method for the production of tera-
peutisk virksomme 1H-2,3-benzoksazinforbindelser. therapeutically active 1H-2,3-benzoxazine compounds.
Foreliggende oppfinnelse vedrører en analogifremgangsmåte The present invention relates to an analog method
til fremstilling av nye terapeutisk virksomme 1H-2,3-benzoksazinfor-bindelser med den generelle formel: for the production of new therapeutically effective 1H-2,3-benzoxazine compounds with the general formula:
hvor R er hydrogen eller lavere alkyl} R' er lavere alkyl, gruppen where R is hydrogen or lower alkyl} R' is lower alkyl, the group
-NHR" hvor R" er hydrogen eller lavere alkyl, eller gruppen -NR'" , -NHR" where R" is hydrogen or lower alkyl, or the group -NR'",
hvor R'" er en lavere alkylidengruppe. where R'" is a lower alkylidene group.
Ifølge oppfinnelsen fremstilles 1H-2,3-benzoksazinforbind-elsene ved at 4-klor-lH-2,3-benzoksazin med formelen: According to the invention, the 1H-2,3-benzoxazine compounds are prepared by 4-chloro-1H-2,3-benzoxazine with the formula:
oppvarmes ved en temperatur på mellom 70° og 150°C i 0.5 - 6 timer sammen med minst en ekvimolekylær mengde av en forbindelse med formelen: is heated at a temperature of between 70° and 150°C for 0.5 - 6 hours together with at least an equimolecular amount of a compound with the formula:
NHRY NHRY
hvor R har den ovenfor angitte betydning og Y er lavere-alkyl eller gruppen -NHR" hvor R" har den ovenfor angitte betydning, og, om ønsket, omsettes den oppnådde forbindelse hvor R<1> er gruppen NH2 med minst en ekvimolekylær mengde av en karbonylforbindelse med formelen: where R has the meaning given above and Y is lower alkyl or the group -NHR" where R" has the meaning given above, and, if desired, the compound obtained where R<1> is the group NH2 is reacted with at least an equimolecular amount of a carbonyl compound of the formula:
hvor Z er hydrogen eller lavere-alkyl og X er lavere-alkyl, for opp-nåelse av de tilsvarende hydrazonforbindelser. where Z is hydrogen or lower alkyl and X is lower alkyl, to obtain the corresponding hydrazone compounds.
I overensstemmelse med utgangs forbindelsenes natur, kan det noen ganger være hensiktsmessig å oppløse disse i en liten mengde av et organisk oppløsningsmiddel slik som en lavere alkanol; i dette til-felle er reaksjonstemperaturen tilbakeløpstemperaturen for blandingen. In accordance with the nature of the starting compounds, it may sometimes be convenient to dissolve these in a small amount of an organic solvent such as a lower alkanol; in this case the reaction temperature is the reflux temperature of the mixture.
Reaksjonen med karbonylforbindelsen foretas i en oppløsning av et organisk oppløsningsmiddel, men karbonylforbindelsen kan i visse tilfeller, avhengig av dens natur, virke som oppløsningsmiddel. The reaction with the carbonyl compound is carried out in a solution of an organic solvent, but the carbonyl compound can in certain cases, depending on its nature, act as a solvent.
De fremstilte forbindelser har virkning som smertestillende, hypnotiske og beroligende midler. The compounds produced act as pain relievers, hypnotics and sedatives.
4-(1-mety1-hydrazino)-6-klor-1H-2,3-benzoksazin nedsetter f.eks. i betydelig grad den spontane aktivitet i mus ved en dose på 10 mg/kg i.p. Forbindelsens aktivitet på det skundære betingede av-vergereaksjon hos rotter, er allerede tydelig ved dosenivåer på 15 mg/ kg i.p. og 30 mg/kg oralt; idet hemning av den primære betingede, av-vergereaksjon frembringes ved doser på 30 mg/kg i.p. og 60 mg/kg oralt. 4-(1-methyl-hydrazino)-6-chloro-1H-2,3-benzoxazine reduces e.g. significantly the spontaneous activity in mice at a dose of 10 mg/kg i.p. The compound's activity on the secondary conditioned avoidance response in rats is already evident at dose levels of 15 mg/kg i.p. and 30 mg/kg orally; whereas inhibition of the primary conditioned avoidance response is produced at doses of 30 mg/kg i.p. and 60 mg/kg orally.
Toksisitetdataene er også gunstige fordi LD^q hos mus ble funnet å være 323.0 mg/kg intraperitonealt og 452.0 mg/kg oralt, hvilket således gjør forbindelsen helt sikker når det gjelder klinisk anvendelse. The toxicity data are also favorable because the LD^q in mice was found to be 323.0 mg/kg intraperitoneally and 452.0 mg/kg orally, thus making the compound completely safe for clinical use.
De fremstilte forbindelsene kan anvendes i farmasøutiske The prepared compounds can be used in pharmaceuticals
preparater slik som tabletter og ampuller for injeksjon i doser på preparations such as tablets and ampoules for injection in doses of
10 - 100 mg oralt og' 10 - - k0 mg intravenøst elier"intramuskulært.'10 - 100 mg orally and' 10 - - k0 mg intravenously or intramuscularly.'
Fra belgisk patent nr..695 670 er det kjent fremstilling av 1H-2,3-benzoksazinderivater med en farmakologisk virkning i likhet med den som utvises av de ifølge foreliggende oppfinnelse fremstilte forbindelser, som imidlertid er langt mer aktive og er mindre toksiske enn de kjente forbindelsene. Ifølge oppfinnelsen fremstilles også hydrazonderivater som ikke omhandles i det belgiske patent, og disse hydrazonforbindelser er av stor interesse på grunn av deres fordel-aktige farmakologiske aktivitet. Dette fremgår også fra de neden-stående tabeller 1 og 2. I tabell 1 er den beroligende aktivitet og den lave toksisitet for forbindelser fremstilt ifølge foreliggende oppfinnelse sammenlignet i forbindelser fra belgisk patent nr. 695 670, og i tabell 2 angis samme type egenskaper for fremstilte hydrazonforbindelser. For undersøkelse av den beroligende aktivitet benyttet man seg av "pole climbing avoidance test", som ble foretatt ifølge den eksperimentelle metode som er beskrevet av G. Maffii i J. Pharm. Pharmacol. 11, 129, 1959. From Belgian patent no. knew the connections. According to the invention, hydrazone derivatives are also produced which are not dealt with in the Belgian patent, and these hydrazone compounds are of great interest because of their beneficial pharmacological activity. This is also evident from the tables 1 and 2 below. In table 1, the sedative activity and the low toxicity of compounds produced according to the present invention are compared to compounds from Belgian patent no. 695 670, and in table 2 the same type of properties are indicated for prepared hydrazone compounds. For investigation of the sedative activity, the "pole climbing avoidance test" was used, which was carried out according to the experimental method described by G. Maffii in J. Pharm. Pharmacol. 11, 129, 1959.
Følgende eksempler illustrerer oppfinnelsen. The following examples illustrate the invention.
Eksempel 1 Example 1
Fremstilling av 6- klor- 4- metylamino- lH- 2, 3- benzoksazin. Preparation of 6-chloro-4-methylamino-1H-2,3-benzoxazine.
3 g 4,6-dik'lor-lH-2,3-benzoksazin oppvarmes i 4 timer i et forseglet rør ved 120°C sammen med 25 g monometylamin. 3 g of 4,6-dichloro-1H-2,3-benzoxazine are heated for 4 hours in a sealed tube at 120°C together with 25 g of monomethylamine.
Blandingen settes tilside for avkjøling og taes deretter opp i dietyleter og ekstraheres med saltsyre. The mixture is set aside to cool and then taken up in diethyl ether and extracted with hydrochloric acid.
Eterlaget kasseres og den vandige oppløsning gjøres alkalisk med 30 % natriumhydroksydoppløsning hvoretter blandingen ekstraheres med dietyleter. Eterekstraktene vaskes med vann, tørkes over vannfritt natriumsulfat og destilleres under' forminsket trykk. Resten krystalliseres fra etylacetat hvilket gir 2.4 g 6-klor-4-metylamino-1H-2,3-benzoksazin. Utbytte 82 %, smeltepunkt 147.5° - 149°C Analyse: Beregnet for C9HgClN20: C 55.00; H 4.58; N 14.24; Cl 18.03 The ether layer is discarded and the aqueous solution is made alkaline with 30% sodium hydroxide solution, after which the mixture is extracted with diethyl ether. The ether extracts are washed with water, dried over anhydrous sodium sulfate and distilled under reduced pressure. The residue is crystallized from ethyl acetate, which gives 2.4 g of 6-chloro-4-methylamino-1H-2,3-benzoxazine. Yield 82%, melting point 147.5° - 149°C Analysis: Calculated for C9HgClN20: C 55.00; H 4.58; N 14.24; Cl 18.03
Funnet: C 55.29; H 4.70; N 13-62; Cl 17.84 Eksempel 2 Found: C 55.29; H 4.70; N 13-62; Cl 17.84 Example 2
Fremstilling av 6- klor- 4- dimetylamino- lH- 2, 3- benzoksazin. Preparation of 6-chloro-4-dimethylamino-1H-2,3-benzoxazine.
1 g 4,6-diklor-lH-2,3-benzoksazin oppvarmes i 4 timer i et forseglet rør ved 120°C sammen med 25 ml dimetylamin. Blandingen settes tilside for avkjøling og helles deretter i et glasskår, idet røret skylles med vann og dietyleter. Blandingen ekstraheres med saltsyre og den organiske fasen kasseres. Det vandige laget gjøres alkalisk med en 30 % natriumhydroksydoppløsning og oppløsningen ekstraheres flere ganger med dietyleter. De kombinerte eterekstraktene vaskes med vann, tørkes over vannfritt natriumsulfat og destilleres under forminsket trykk. Resten krystalliseres fra diisopropyleter hvilket gir 0.75 g 6-klor-4-dimetylamino-lH-2,3-benzoksazin. Utbytte 72 % s 'smeltepunkt 88° - 88.5°C. 1 g of 4,6-dichloro-1H-2,3-benzoxazine is heated for 4 hours in a sealed tube at 120°C together with 25 ml of dimethylamine. The mixture is set aside to cool and then poured into a shard of glass, the tube being rinsed with water and diethyl ether. The mixture is extracted with hydrochloric acid and the organic phase is discarded. The aqueous layer is made alkaline with a 30% sodium hydroxide solution and the solution is extracted several times with diethyl ether. The combined ether extracts are washed with water, dried over anhydrous sodium sulfate and distilled under reduced pressure. The residue is crystallized from diisopropyl ether, which gives 0.75 g of 6-chloro-4-dimethylamino-1H-2,3-benzoxazine. Yield 72% s 'melting point 88° - 88.5°C.
Analyse: Analysis:
Beregnet for C^H^ClNgO: C 57-.02; H 5.20; N 13-30; Cl 16.84 Calculated for C^H^ClNgO: C 57-.02; H 5.20; N 13-30; Cl 16.84
Funnet: C 57-20; H 5-04; N 13-38; Cl 17.00 Eksempel 3 Found: C 57-20; H 5-04; N 13-38; Cl 17.00 Example 3
Fremstilling av 6- klor- 4- hydrazino- lH- 2, 3- benzoksazin. Preparation of 6-chloro-4-hydrazino-1H-2,3-benzoxazine.
3.6 g 4,6-diklor-lH-2,3-benzoksazin og 1.8 ml vannfri hydrazin, oppløses i 18 ml absolutt etanol og kokes under "tilbakeløp i 30 minutter. Blandingen settes tilside, for avkjøling og destilleres deretter under forminsket trykk. Resten opptaes i metylenklorid og utfelt hydrazinhydroklorid frafiltreres. Den filtrerte oppløsning destilleres til tørrhet og resten krystalliseres fra etanol, hvilket gir 2.10 g 6-klor-4-hydrazino-lH-2,3-benzoksazin.' Utbytte 60 %, smeltepunkt 148° - 149°C. 3.6 g of 4,6-dichloro-1H-2,3-benzoxazine and 1.8 ml of anhydrous hydrazine are dissolved in 18 ml of absolute ethanol and refluxed for 30 minutes. The mixture is set aside to cool and then distilled under reduced pressure. The residue is taken up in methylene chloride and the precipitated hydrazine hydrochloride is filtered off. The filtered solution is distilled to dryness and the residue is crystallized from ethanol, which gives 2.10 g of 6-chloro-4-hydrazino-1H-2,3-benzoxazine.' Yield 60%, melting point 148° - 149°C.
Analyse: Analysis:
Beregnet for CgHgClNjO: C 48.63; H 4.05; N 21.27; Cl 17.95 Calculated for CgHgClNjO: C 48.63; H 4.05; N 21.27; Cl 17.95
Funnet: C 48.81; H 4.28; N 21.50; Cl 18.21. Found: C 48.81; H 4.28; N 21.50; Cl 18.21.
Eksempel 4 Example 4
Fremstilling av 6- klor- 4-( 1- metylhydrazino)- lH- 2, 3- benzoksazin. Preparation of 6-chloro-4-(1-methylhydrazino)-1H-2,3-benzoxazine.
Til 2.52 g 4.6-diklor-lH-2,3-benzoksazin oppløst i 13 ml absolutt etanol, tilsettes 1.73 g metylhydrazin. -Blandingen kokes under tilbakeløp i 30 minutter, får avkjøles og blir deretter destil-lert under forminsket trykk. Resten opptas i dietyleter og oppløs-ningen frafiltreres eventuelle uoppløselige forbindelser. Den filtrerte oppløsning destilleres til tørrhet og resten opptaes i 10 ml diisopropyleter. Etter avkjøling ved hjelp av is i 0.5 timer filt-reres blandingen og det oppsamlede faste stoff krystalliseres fra etylacetat hvilket gir 2.0 g 6-klor^4-(l-metylhydrazino)-lH-2,3-benzoksazin. Utbytte 65 %, smeltepunkt 124° - 125°C.'.. To 2.52 g of 4,6-dichloro-1H-2,3-benzoxazine dissolved in 13 ml of absolute ethanol, 1.73 g of methylhydrazine is added. -The mixture is boiled under reflux for 30 minutes, allowed to cool and is then distilled under reduced pressure. The residue is taken up in diethyl ether and the solution is filtered to remove any insoluble compounds. The filtered solution is distilled to dryness and the residue is taken up in 10 ml of diisopropyl ether. After cooling with ice for 0.5 hours, the mixture is filtered and the collected solid is crystallized from ethyl acetate, which gives 2.0 g of 6-chloro-4-(1-methylhydrazino)-1H-2,3-benzoxazine. Yield 65%, melting point 124° - 125°C.'..
Analyse: Analysis:
Beregnet for CgH10ClN-5O: C 51.10; H 4.77; N 19-87; Cl 16.76 Calculated for CgH10ClN-5O: C 51.10; H 4.77; N 19-87; Cl 16.76
Funnet: C.50.82; H 4.72; N 19-65; Cl 16.90. Found: C.50.82; H 4.72; N 19-65; Cl 16.90.
Eksempel 5 Example 5
Fremstilling av 6- klor- 4-( isopropyliden- hydrazino)- 1H- 2, 3- benzoksazin. Preparation of 6-chloro-4-(isopropylidene-hydrazino)-1H-2,3-benzoxazine.
0.15 g 6-klor-4-hydrazino-lH-2,3-benzoksazin oppløses i 15 ml vannfri aceton ved hjelp av forsiktig oppvarming. Oppløsningen får stå i 1 time hvoretter oppløsningsmidlet fjernes under forminsket trykk ved romtemperatur. Resten opptaes i heksan og får stå i 2 dager. Etter filtrering, konsentreres oppløsningen til tørrhet under forminsket trykk og resten omkrystalliseres fra samme oppløsningsmiddel. Utbygge 0.1 g 6-klor-4-(isopropyliden-hydrazino)-1H-2,3-benzoksazin 0.15 g of 6-chloro-4-hydrazino-1H-2,3-benzoxazine is dissolved in 15 ml of anhydrous acetone by means of gentle heating. The solution is allowed to stand for 1 hour, after which the solvent is removed under reduced pressure at room temperature. The residue is taken up in hexane and allowed to stand for 2 days. After filtration, the solution is concentrated to dryness under reduced pressure and the residue is recrystallized from the same solvent. Develop 0.1 g 6-chloro-4-(isopropylidene-hydrazino)-1H-2,3-benzoxazine
(55 %), smeltepunkt 76° - 77°C (55%), melting point 76° - 77°C
Analyse: Analysis:
Beregnet for C-qH^CIN^O: C 55-60; H 5-09; N 17-68; Cl 14.92 Calculated for C-qH^CIN^O: C 55-60; H 5-09; N 17-68; Cl 14.92
Funnet: C 55-79; H 4.88; N 17.60; Cl 14.75-Eksempel 6 Found: C 55-79; H 4.88; N 17.60; Cl 14.75-Example 6
Fremstilling av 6- klor- 4-( 2- isopropyliden- 1- metylhydrazino)- 1H- 2, 3- benzoksazin. Preparation of 6-chloro-4-(2-isopropylidene-1-methylhydrazino)-1H-2,3-benzoxazine.
0.5 g 6-klor-4-(l-metylhydrazino)-lH-2,3-benzoksazin oppløses i 0.5 g of 6-chloro-4-(1-methylhydrazino)-1H-2,3-benzoxazine is dissolved in
25 ml vannfri aceton ved romtemperatur. Blandingen får stå i 1 time hvoretter oppløsningsmidlet fjernes under forminsket trykk ved romtemperatur. Resten ekstraheres flere ganger med varm heksan, under 25 ml anhydrous acetone at room temperature. The mixture is allowed to stand for 1 hour, after which the solvent is removed under reduced pressure at room temperature. The residue is extracted several times with hot hexane, below
♦ ♦
anvendelse av 50 ml av oppløsningsmidlet hver gang. Fast stoff kasseres og oppløsningen inndampes til tørrhet under forminsket trykk. Resten omkrystalliseres fra diisopropyleter hvilket gir 0.25 g (42 %) 6-klor-4-(2-isopropyliden-l-metylhydrazino)-lH-2,3-benzoksazin, smeltepunkt 105° - 106°C. using 50 ml of the solvent each time. Solid material is discarded and the solution is evaporated to dryness under reduced pressure. The residue is recrystallized from diisopropyl ether which gives 0.25 g (42%) of 6-chloro-4-(2-isopropylidene-1-methylhydrazino)-1H-2,3-benzoxazine, melting point 105° - 106°C.
Analyse: Analysis:
Beregnet for C-^HiijClN^O: C 57-25; H 5-6l; N 16.70; Cl 14.09 Calculated for C-^HiijClN^O: C 57-25; H 5-6l; N 16.70; Cl 14.09
Funnet: C 57-22; H 5-59; N 16.50; Cl 13-85-Eksempel 7 Found: C 57-22; H 5-59; N 16.50; Cl 13-85-Example 7
Fremstilling av 6- klor- 4-( 2- etyliden- 1- metylhydrazino)- 1H- 2, 3- benzoksazin. Preparation of 6-chloro-4-(2-ethylidene-1-methylhydrazino)-1H-2,3-benzoxazine.
Til en oppløsning av 3 g 6-klor-4-(l-metylhyd.razino)-lH-2,3-benzoksazin i 180 ml vannfri benzen, tilsettes 1 g acetaldehyd i 30 ml vannfri benzen. Blandingen får stå i 2 timer hvoretter oppløsnings-midlet avdestilleres i vakuum og resten omkrystalliseres fra isopro-pyleter. Utbytte 2.4 g (71.2 %) av 6-klor-4-(2-etyliden-l-metyl-hydrazino)-1H-2,3-benzoksazin; smeltepunkt 111° - 112°C. To a solution of 3 g of 6-chloro-4-(1-methylhydrazino)-1H-2,3-benzoxazine in 180 ml of anhydrous benzene, 1 g of acetaldehyde in 30 ml of anhydrous benzene is added. The mixture is allowed to stand for 2 hours, after which the solvent is distilled off in a vacuum and the residue is recrystallized from isopropyl ether. Yield 2.4 g (71.2%) of 6-chloro-4-(2-ethylidene-1-methyl-hydrazino)-1H-2,3-benzoxazine; melting point 111° - 112°C.
Analyse: Analysis:
Beregnet for C-^H-^CIN^O: C 55-60; H 5-08; N 17-69] Cl 14.92 Calculated for C-^H-^CIN^O: C 55-60; H 5-08; N 17-69] Cl 14.92
Funnet:- C 56.00; H 5.21; N 17-50; Cl 15.00. Found:- C 56.00; H 5.21; N 17-50; Cl 15.00.
Eksempel 8 Example 8
Følgende forbindelse fremstilles under anvendelse av i alt vesentlig The following compound is prepared using essentially
den samme fremgangsmåte som beskrevet i eksempel 7 6-klor-4-(1-mety1-2-propyliden-hydrazino)-lH-2,3-benzoksazin, i et utbytte på 79-0 % og med et smeltepunkt på 66° - 67°C. the same procedure as described in example 7 6-chloro-4-(1-methyl-2-propylidene-hydrazino)-1H-2,3-benzoxazine, in a yield of 79-0% and with a melting point of 66° - 67°C.
Claims (3)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB4362167 | 1967-09-25 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NO128572B true NO128572B (en) | 1973-12-10 |
Family
ID=10429582
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO03766/68A NO128572B (en) | 1967-09-25 | 1968-09-24 |
Country Status (17)
| Country | Link |
|---|---|
| JP (1) | JPS4946630B1 (en) |
| AT (1) | AT278841B (en) |
| BE (1) | BE721356A (en) |
| CA (1) | CA929522A (en) |
| CH (1) | CH481934A (en) |
| DE (1) | DE1795384C3 (en) |
| DK (2) | DK124205B (en) |
| ES (1) | ES358442A1 (en) |
| FI (1) | FI48842C (en) |
| FR (2) | FR7757M (en) |
| GB (1) | GB1225612A (en) |
| IL (1) | IL30757A (en) |
| LU (1) | LU56962A1 (en) |
| NL (1) | NL6813657A (en) |
| NO (1) | NO128572B (en) |
| SE (2) | SE332988B (en) |
| YU (1) | YU31966B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4005082A (en) * | 1967-09-25 | 1977-01-25 | Gruppo Lepetit S.P.A. | 1H-2,3-Benzoxazines |
| FR2068436A6 (en) * | 1969-11-18 | 1971-08-27 | Lepetit Spa | 1h-2,3-benzoxazine derivs, nerve drugs and - anti-inflammatory agents |
| ZA738362B (en) * | 1972-12-22 | 1974-09-25 | Lepetit Spa | New 3,5-disubstituted triazole active on the c.n.s. |
-
1967
- 1967-09-25 GB GB4362167A patent/GB1225612A/en not_active Expired
-
1968
- 1968-09-18 AT AT910868A patent/AT278841B/en not_active IP Right Cessation
- 1968-09-18 FI FI682624A patent/FI48842C/en active
- 1968-09-22 IL IL30757A patent/IL30757A/en unknown
- 1968-09-23 DK DK456268AA patent/DK124205B/en unknown
- 1968-09-24 ES ES358442A patent/ES358442A1/en not_active Expired
- 1968-09-24 SE SE12868/68A patent/SE332988B/xx unknown
- 1968-09-24 NO NO03766/68A patent/NO128572B/no unknown
- 1968-09-24 NL NL6813657A patent/NL6813657A/xx unknown
- 1968-09-24 DE DE1795384A patent/DE1795384C3/en not_active Expired
- 1968-09-25 FR FR167488A patent/FR7757M/fr not_active Expired
- 1968-09-25 LU LU56962D patent/LU56962A1/xx unknown
- 1968-09-25 CA CA030877A patent/CA929522A/en not_active Expired
- 1968-09-25 YU YU2244/68A patent/YU31966B/en unknown
- 1968-09-25 CH CH1430868A patent/CH481934A/en not_active IP Right Cessation
- 1968-09-25 FR FR1598168D patent/FR1598168A/fr not_active Expired
- 1968-09-25 BE BE721356D patent/BE721356A/xx unknown
-
1970
- 1970-09-03 DK DK453470AA patent/DK124889B/en unknown
- 1970-10-29 SE SE14604/70A patent/SE351218B/xx unknown
-
1971
- 1971-02-10 JP JP46005918A patent/JPS4946630B1/ja active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| IL30757A (en) | 1973-05-31 |
| BE721356A (en) | 1969-03-03 |
| ES358442A1 (en) | 1970-06-16 |
| DE1795384C3 (en) | 1975-07-17 |
| AT278841B (en) | 1970-02-10 |
| FR1598168A (en) | 1970-07-06 |
| FI48842C (en) | 1975-01-10 |
| FR7757M (en) | 1970-03-16 |
| CH481934A (en) | 1969-11-30 |
| DK124205B (en) | 1972-09-25 |
| FI48842B (en) | 1974-09-30 |
| DK124889B (en) | 1972-12-04 |
| IL30757A0 (en) | 1970-03-22 |
| NL6813657A (en) | 1969-03-27 |
| LU56962A1 (en) | 1969-02-05 |
| SE332988B (en) | 1971-03-01 |
| YU224468A (en) | 1973-08-31 |
| SE351218B (en) | 1972-11-20 |
| DE1795384B2 (en) | 1974-10-03 |
| YU31966B (en) | 1974-02-28 |
| CA929522A (en) | 1973-07-03 |
| JPS4946630B1 (en) | 1974-12-11 |
| DE1795384A1 (en) | 1972-03-09 |
| GB1225612A (en) | 1971-03-17 |
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