NO148372B - PROCEDURE FOR THE PREPARATION OF BROOM HEXINE. - Google Patents
PROCEDURE FOR THE PREPARATION OF BROOM HEXINE.Info
- Publication number
- NO148372B NO148372B NO801617A NO801617A NO148372B NO 148372 B NO148372 B NO 148372B NO 801617 A NO801617 A NO 801617A NO 801617 A NO801617 A NO 801617A NO 148372 B NO148372 B NO 148372B
- Authority
- NO
- Norway
- Prior art keywords
- reaction
- procedure
- bromhexine
- dihydro
- methylcyclohexylamine
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 14
- 238000002360 preparation method Methods 0.000 title description 2
- 238000006243 chemical reaction Methods 0.000 claims description 12
- OJGDCBLYJGHCIH-UHFFFAOYSA-N bromhexine Chemical compound C1CCCCC1N(C)CC1=CC(Br)=CC(Br)=C1N OJGDCBLYJGHCIH-UHFFFAOYSA-N 0.000 claims description 9
- 229960003870 bromhexine Drugs 0.000 claims description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- XTUVJUMINZSXGF-UHFFFAOYSA-N N-methylcyclohexylamine Chemical compound CNC1CCCCC1 XTUVJUMINZSXGF-UHFFFAOYSA-N 0.000 claims description 6
- PAMIQIKDUOTOBW-UHFFFAOYSA-N N-methylcyclohexylamine Natural products CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 claims description 6
- RQJFMNQNCRVVFJ-UHFFFAOYSA-N 6,8-dibromo-1,4-dihydro-3,1-benzoxazin-2-one Chemical compound N1C(=O)OCC2=CC(Br)=CC(Br)=C21 RQJFMNQNCRVVFJ-UHFFFAOYSA-N 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 239000011541 reaction mixture Substances 0.000 claims description 4
- SYZIUAAQNFJPJY-UHFFFAOYSA-N 1,4-dihydro-3,1-benzoxazin-2-one Chemical compound C1=CC=C2COC(=O)NC2=C1 SYZIUAAQNFJPJY-UHFFFAOYSA-N 0.000 claims description 3
- ATHHXGZTWNVVOU-UHFFFAOYSA-N N-methylformamide Chemical compound CNC=O ATHHXGZTWNVVOU-UHFFFAOYSA-N 0.000 claims description 3
- 229960000583 acetic acid Drugs 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- 239000012362 glacial acetic acid Substances 0.000 claims description 3
- 239000012442 inert solvent Substances 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 239000000126 substance Substances 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- -1 dibromine compound Chemical class 0.000 description 3
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 3
- VYFOAVADNIHPTR-UHFFFAOYSA-N isatoic anhydride Chemical compound NC1=CC=CC=C1CO VYFOAVADNIHPTR-UHFFFAOYSA-N 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- HQQTZCPKNZVLFF-UHFFFAOYSA-N 4h-1,2-benzoxazin-3-one Chemical class C1=CC=C2ONC(=O)CC2=C1 HQQTZCPKNZVLFF-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- UCDKONUHZNTQPY-UHFFFAOYSA-N bromhexine hydrochloride Chemical compound Cl.C1CCCCC1N(C)CC1=CC(Br)=CC(Br)=C1N UCDKONUHZNTQPY-UHFFFAOYSA-N 0.000 description 2
- 238000005893 bromination reaction Methods 0.000 description 2
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 2
- 239000004202 carbamide Substances 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 150000003673 urethanes Chemical class 0.000 description 2
- NQPJDJVGBDHCAD-UHFFFAOYSA-N 1,3-diazinan-2-one Chemical class OC1=NCCCN1 NQPJDJVGBDHCAD-UHFFFAOYSA-N 0.000 description 1
- JVTRZJXFAOQMRA-UHFFFAOYSA-N 1,3-oxazin-2-one Chemical class O=C1N=CC=CO1 JVTRZJXFAOQMRA-UHFFFAOYSA-N 0.000 description 1
- BCHZICNRHXRCHY-UHFFFAOYSA-N 2h-oxazine Chemical group N1OC=CC=C1 BCHZICNRHXRCHY-UHFFFAOYSA-N 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000000954 anitussive effect Effects 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 150000001722 carbon compounds Chemical class 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 238000011083 clear filtration Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003172 expectorant agent Substances 0.000 description 1
- 230000003419 expectorant effect Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 239000004289 sodium hydrogen sulphite Substances 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 238000005809 transesterification reaction Methods 0.000 description 1
- XFNJVJPLKCPIBV-UHFFFAOYSA-N trimethylenediamine Chemical class NCCCN XFNJVJPLKCPIBV-UHFFFAOYSA-N 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 150000003672 ureas Chemical class 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
- C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
- C07D265/12—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems
- C07D265/14—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D265/18—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with hetero atoms directly attached in position 2
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)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
Foreliggende oppfinnelse vedrører en spesiell fremgangsmåte The present invention relates to a special method
til fremstilling av bromheksin, som er trivialbetegnelsen for N-(2-amino-3,5-dibrombenzyl)-N-metylcykloheksylamin, og som er et kjent stoff med slimløsende og hostestillende virkning. for the production of bromhexine, which is the trivial term for N-(2-amino-3,5-dibromobenzyl)-N-methylcyclohexylamine, and which is a known substance with expectorant and antitussive effects.
En rekke forskjellige fremgangsmåter til fremstilling av bromheksin er kjent og beskrevet i de danske patenter nr. 101.066, 101.301, 101.795 og 119.408, og i de danske fremlegnings-skrifter nr. 135.499, 135.574 og 135.680, samt i DE-OS 2.273.193. A number of different methods for the production of bromhexine are known and described in Danish patents no. 101,066, 101,301, 101,795 and 119,408, and in Danish patent documents no. 135,499, 135,574 and 135,680, as well as in DE-OS 2,273,193.
Disse kjente fremgangsmåter har hver for seg ulemper enten These known methods each have disadvantages either
i form av midlertidige beskyttelsesforanstaltninger for ikke-reagerende substituenter, eller i form av vanskelig tilgjengelig utgangsmaterialer eller av kostbare reduksjons-midlar, og felles for dem er at ulempene medfører reduserte utbytter. in the form of temporary protective measures for non-reacting substituents, or in the form of difficult-to-access starting materials or of expensive reducing agents, and common to them is that the disadvantages entail reduced yields.
Oppfinnelsens formål er å tilveiebringe en fremgangsmåte til fremstilling av bromheksin hvorved nevnte ulemper unngås og hvorved bromheksinet oppnås i høyt utbytte og i meget ren tilstand. The purpose of the invention is to provide a method for the production of bromhexine whereby the aforementioned disadvantages are avoided and whereby the bromhexine is obtained in high yield and in a very pure state.
Ifølge foreliggende oppfinnelse er det således tilveiebragt According to the present invention, it is thus provided
en fremgangsmåte for fremstilling av bromheksin med formelen: a process for the preparation of bromhexine with the formula:
og denne fremgangsmåte er kjennetegnet ved at 1,4-dihydro-2H-3,l-benzoksazin-2-on med formelen: and this method is characterized by the fact that 1,4-dihydro-2H-3,1-benzoxazin-2-one with the formula:
omsettes i iseddik eller annet egnet organisk oppløsnings-middel med fritt brom til 6,8-dibrom-l,4-dihydro-2H-3,1-benzoksazin-2-on, som deretter ved forhøyet temperatur og fortrinnsvis i nærvær av et inert oppløsningsmiddel omsettes med N-metylcykloheksylamin til bromheksin, som utvinnes av reaksjonsblandingen i form av et syreaddisjonssalt. reacted in glacial acetic acid or other suitable organic solvent with free bromine to 6,8-dibromo-1,4-dihydro-2H-3,1-benzoxazin-2-one, which then at elevated temperature and preferably in the presence of an inert solvent is reacted with N-methylcyclohexylamine to bromhexine, which is recovered from the reaction mixture in the form of an acid addition salt.
Omsetningene skjer ifølge nedenstående reaksjonsskjema. Turnovers take place according to the reaction chart below.
Utgangsstoffet I er et kjent stoff som kan fremstilles fra o-aminobenzylalkohol ved kondensasjon f.eks. med fosgen. The starting substance I is a known substance that can be prepared from o-aminobenzyl alcohol by condensation, e.g. with phosgene.
Mellomproduktet II er en ny dibromforbindelse som er tungt-oppløselig i vann og danner hvite krystaller som smelter ved 218-220°C (kfr. norsk patentsøknad 823977) . Intermediate II is a new dibromine compound that is poorly soluble in water and forms white crystals that melt at 218-220°C (cf. Norwegian patent application 823977).
Ved en foretrukken utførelsesform for foreliggende fremgangsmåte foretas omsetningen med N-metylcykloheksylamin i opp-løsning i N-monometylformamid, idet det således oppnås et utbytte på opptil 90% ved omsetningen. In a preferred embodiment of the present method, the reaction is carried out with N-methylcyclohexylamine in solution in N-monomethylformamide, thus achieving a yield of up to 90% in the reaction.
Når det gjelder bromeringsreaksjonen i foreliggende frem-gangsmåtes første trinn, så representerer den ikke en helt vanlig aromatisk bromeringsreaksjon idet man meget vel kunne tenke seg at de to bromatomer som innføres angripes av det reaktive hydrogenatom ved nitrogenatomet i det sekundære amin, som anvendes som reaktant. As regards the bromination reaction in the first step of the present method, it does not represent a completely normal aromatic bromination reaction, since one could very well imagine that the two bromine atoms that are introduced are attacked by the reactive hydrogen atom at the nitrogen atom in the secondary amine, which is used as reactant .
Fremgangsmåtens annet trinn og det uventede som her skjer, skal i det følgende belyses under henvisning til litteraturen. Som eksempel kan nevnes at J.F. Brunet og M. Benton Naff, kfr. J.Am.Chem.Soc. 88, side 4001 (1966) inngående be-handler omsetningen av isatoinsyreanhydrid med aminer som fører til to forskjellige produkter The second step of the procedure and the unexpected that occurs here will be explained below with reference to the literature. As an example, it can be mentioned that J.F. Brunet and M. Benton Naff, see J.Am.Chem.Soc. 88, page 4001 (1966) discusses in detail the reaction of isatoic anhydride with amines leading to two different products
Betrakter man nå det andre trinn i foreliggende fremgangsmåte, er det klart at man a priori måtte forvente flere mulige reaksjonsprodukter, nemlig If one now considers the second step in the present method, it is clear that a priori one would have to expect several possible reaction products, viz
Forbindelsen med formel A kan betraktes som en cyklisk uretan-forbindelse, idet den inneholder grupperingen -Ct^-O-CO-NH-,. og man skulle derfor ifølge litteraturen forvente reaksjonen A —> B'. Således angis i E.H. Rodd Chemistry of Carbon Compounds, IB, 901 (1953), at uretanene er stabile, flyktige krystallinske forbindelser som er lett oppløselige i vann, alkohol og eter. Mange av deres kjemiske egenskaper ville være forventet utfra deres gitte strukturer. Således er-stattes alkoksygruppen ved oppvarming med ammoniakk, hvilket gir urea. Ved analogikonklusjon kan det derfor sies at substituerte ureaforbindelser oppnås med aminer. The compound of formula A can be considered a cyclic urethane compound, in that it contains the grouping -Ct^-O-CO-NH-,. and one should therefore, according to the literature, expect the reaction A —> B'. Thus stated in E.H. Rodd Chemistry of Carbon Compounds, IB, 901 (1953), that the urethanes are stable, volatile crystalline compounds which are readily soluble in water, alcohol and ether. Many of their chemical properties would be expected from their given structures. Thus, the alkoxy group is replaced by heating with ammonia, which gives urea. By analogy, it can therefore be said that substituted urea compounds are obtained with amines.
I D.H.R. Barton og W.D. Ollis "Comprehensive Organic Chemistry", 2, 1084 (1979) beskrives uretaners, betegnet karbamater, kjemi. Det,angis her at den mest karakteristiske reaksjon for karbamater er med nukleofile materialer, og at den totale reaksjon (kfr. skjema 7) er erstatning av alkoksy-eller aryloksygruppen med f.eks. aminer (for dannelse av ureaforbindelser) eller alkoholer (transforestring). In D.H.R. Barton and W.D. Ollis "Comprehensive Organic Chemistry", 2, 1084 (1979) describes the chemistry of urethanes, termed carbamates. It is stated here that the most characteristic reaction for carbamates is with nucleophilic materials, and that the overall reaction (cf. scheme 7) is replacement of the alkoxy or aryloxy group with e.g. amines (for the formation of urea compounds) or alcohols (transesterification).
Forskjellige litteratursteder angir også at reaksjonen Various literature sources also state that the reaction
A —5> B" kunne forventes og at det derfor må anses som sær-egent og overraskende at man får forbindelsen B som hoved-produkt i høyt utbytte i foreliggende oppfinnelse. A —5> B" could be expected and that it must therefore be considered peculiar and surprising that compound B is obtained as the main product in high yield in the present invention.
Betraktninger med bakgrunn i de monocykliske analoge systemer Considerations with a background in the monocyclic analogue systems
har ikke kunnet foretas fordi disses kjemi ikke er ut-forsket. Derimot har den tilsvarende dihydroform: have not been able to be carried out because their chemistry has not been investigated. In contrast, it has the corresponding dihydro form:
vært gjenstand for kjemisk interesse. Omsetning av N-usubstituerte 1,3-oksazin-2-oner med aminer føres som regel til dannelse av tetrahydro-2-pyrimidoner, mens forbindelser med elektrondonerende substituenter på oksazinringens nitrogenatom har tendens til å gi trimetylendiaminderivater, kfr. CA. 83, 77996 a (1975) og CA. 86, 29126 g (1977), samt svensk utlegningsskrift nr. 322.529. been the subject of chemical interest. Reaction of N-unsubstituted 1,3-oxazin-2-ones with amines usually leads to the formation of tetrahydro-2-pyrimidones, while compounds with electron-donating substituents on the nitrogen atom of the oxazine ring tend to give trimethylenediamine derivatives, cf. CA. 83, 77996a (1975) and CA. 86, 29126 g (1977), as well as Swedish interpretation document no. 322,529.
Foreliggende fremgangsmåte belyses ved følgende utførelses-eksempler. The present method is illustrated by the following design examples.
Eksempel 1 Example 1
Til en oppløsning av 9,0 g (0,0604 mol) 1,4-dihydro-2H-3,1-benzoksazin-2-on i 40 ml iseddik ble det tilsatt 60,9 g To a solution of 9.0 g (0.0604 mol) 1,4-dihydro-2H-3,1-benzoxazin-2-one in 40 ml of glacial acetic acid was added 60.9 g
(0,38 mol) brom, hvorved temperaturen steg fra 24° til 74°C. Reaksjonsblandingen ble hensatt til den var avkjølt til rom-temperatur og ble deretter helt i 500 ml vann hvorved man fikk en utfelling av den bromerte benzoksazinon. Denne for-bindelse ble frafiltrert og vasket på filteret først med vann, deretter med en fortynnet oppløsning av natriumhydro-gensulfitt og tilslutt med heksan. (0.38 mol) of bromine, whereby the temperature rose from 24° to 74°C. The reaction mixture was left until it had cooled to room temperature and was then poured into 500 ml of water whereby a precipitate of the brominated benzoxazinone was obtained. This compound was filtered off and washed on the filter first with water, then with a dilute solution of sodium hydrogen sulphite and finally with hexane.
Fra modervæsken og vaskevann kunne overskudd av brom gjen-vinnes ved destillasjon. Excess bromine could be recovered from the mother liquor and wash water by distillation.
Utbyttet av den bromerte benzoksazinon var 16,5 g (0,0537 The yield of the brominated benzoxazinone was 16.5 g (0.0537
mol) tilsvarende 89% av det teoretiske utbytte. Smeltepunktet var 218-220°C og tynnsjiktskromatografi viste ingen urenheter. mol) corresponding to 89% of the theoretical yield. The melting point was 218-220°C and thin layer chromatography showed no impurities.
En blanding av 3,07 g (0,010 mol) av den oppnådde 6,8-dibrom-1,4-dihydro-2H-3,l-benzoksazin-2-on og 4,52 g (0,040 mol) N-metylcykloheksylamin i 10 ml N-monometylformamid, ble oppvarmet under omrøring og tilbakeløp i 2 timer på et 210°C varmt oljebad. Etter avkjøling ble reaksjonsblandingen helt i 70 ml vann og det ble tilsatt konsentrert saltsyre til sur reaksjon. A mixture of 3.07 g (0.010 mol) of the obtained 6,8-dibromo-1,4-dihydro-2H-3,1-benzoxazin-2-one and 4.52 g (0.040 mol) of N-methylcyclohexylamine in 10 ml of N-monomethylformamide, was heated with stirring and reflux for 2 hours in a 210°C hot oil bath. After cooling, the reaction mixture was poured into 70 ml of water and concentrated hydrochloric acid was added for an acidic reaction.
Ved avkjøling i isvann under omrøring fikk man utkrystalli-sert N-(2-amino-3,5-dibrombenzyl)-N-metyl-cykloheksylammonium-klorid (bromheksin, hydroklorid)', som etter 1 times forløp ble frafiltrert, vasket med vann og tørket. Utbyttet var 3,7 g (8,97 mmol), som tilsvarer 89,7% av det teoretiske. Smeltepunktet var 232-233,5°C og stoffet var analytisk rent. By cooling in ice water with stirring, N-(2-amino-3,5-dibromobenzyl)-N-methyl-cyclohexylammonium chloride (bromohexine, hydrochloride) crystallized out, which after 1 hour was filtered off, washed with water and dried. The yield was 3.7 g (8.97 mmol), which corresponds to 89.7% of the theoretical. The melting point was 232-233.5°C and the substance was analytically pure.
Eksempel 2 Example 2
En blanding av 1,65 g (5,4 mmol) av det ifølge eksempel 1 oppnådde 6,8-dibrom-l,4-dihydro-2H-3,l-benzoksazin-2-on og 2,4 g (21 mmol) N-metylcykloheksylamin i 10 ml dietylen-glykol, ble oppvarmet under omrøring og tilbakeløp i 20 timer på et 210°C varmt oljebad. Etter avkjøling ble 150 ml vann og konsentrert saltsyre tilsatt til sur reaksjon, hvoretter blandingen ble oppvarmet til tilbakeløpstemperatur. Til den kokende blanding ble det tilsatt 10 ml etanol og aktivt karbon, hvoretter det ble foretatt klarfiltrering ved til-bakeløpstemperaturen. A mixture of 1.65 g (5.4 mmol) of the 6,8-dibromo-1,4-dihydro-2H-3,1-benzoxazin-2-one obtained according to example 1 and 2.4 g (21 mmol ) N-methylcyclohexylamine in 10 ml of diethylene glycol, was heated with stirring and reflux for 20 hours in a 210°C hot oil bath. After cooling, 150 ml of water and concentrated hydrochloric acid were added to acid reaction, after which the mixture was heated to reflux temperature. 10 ml of ethanol and activated carbon were added to the boiling mixture, after which clear filtration was carried out at the reflux temperature.
Filtratet ble avkjølt i isvann, hvorved N-(2-amino-3,5-di-brombenzyl) -N-metylcykloheksylammoniumklorid ble utkrystal-lisert. Stoffet ble frafiltrert og vasket med vann. Utbyttet av det analytiske rene stoff var 1,1 g (2,67 mmol), tilsvarende 49,4% av det teoretiske. The filtrate was cooled in ice water, whereby N-(2-amino-3,5-dibromobenzyl)-N-methylcyclohexylammonium chloride was crystallized out. The substance was filtered off and washed with water. The yield of the analytically pure substance was 1.1 g (2.67 mmol), corresponding to 49.4% of the theoretical.
Claims (2)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK230179A DK145718C (en) | 1979-06-01 | 1979-06-01 | DIBROME COMPOUND USE AS INTERMEDIATE IN THE PREPARATION OF N- (2-AMINO-3,5-DIBROMBENZYL) -N-METYLCYCLOHEXYLAMINE |
| DK230079A DK145714C (en) | 1979-06-01 | 1979-06-01 | METHOD FOR PREPARING N- (2-AMINO-3,5-DIBROMBENZYL) -N-METYLYCYLOHEXYLAMINE |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO801617L NO801617L (en) | 1980-12-02 |
| NO148372B true NO148372B (en) | 1983-06-20 |
| NO148372C NO148372C (en) | 1983-09-28 |
Family
ID=26066477
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO801617A NO148372C (en) | 1979-06-01 | 1980-05-30 | PROCEDURE FOR THE PREPARATION OF BROOM HEXINE |
| NO823977A NO148415C (en) | 1979-06-01 | 1982-11-26 | INTERMEDIATE FOR USE IN PREPARATION OF N- (2-AMINO-3,5-DIBROMBENZYL) -N-METHYLYCYLOHEXYLAMINE |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO823977A NO148415C (en) | 1979-06-01 | 1982-11-26 | INTERMEDIATE FOR USE IN PREPARATION OF N- (2-AMINO-3,5-DIBROMBENZYL) -N-METHYLYCYLOHEXYLAMINE |
Country Status (11)
| Country | Link |
|---|---|
| AT (1) | AT371800B (en) |
| CH (1) | CH642617A5 (en) |
| DE (1) | DE3020604A1 (en) |
| ES (1) | ES492005A0 (en) |
| FI (1) | FI68808C (en) |
| GB (1) | GB2053900B (en) |
| IE (1) | IE49820B1 (en) |
| KE (1) | KE3302A (en) |
| NL (1) | NL8003153A (en) |
| NO (2) | NO148372C (en) |
| SE (1) | SE433847B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2881955B1 (en) | 2005-02-11 | 2007-05-11 | Oreal | COSMETIC NANOEMULSION CONTAINING HYDROXYL UREA COMPOUND |
| CN102775316B (en) * | 2012-08-17 | 2013-06-12 | 夏智红 | Bromhexine hydrochloride compound and medicine composition thereof |
| CN102924295B (en) * | 2012-10-09 | 2014-10-29 | 石家庄东方药业有限公司 | Bromhexine hydrochloride crystal as well as preparation method and application of crystal |
| CN103145564B (en) * | 2013-03-15 | 2014-06-18 | 湖北美林药业有限公司 | Bromhexine hydrochloride compound and pharmaceutical composition thereof |
-
1980
- 1980-05-23 IE IE1081/80A patent/IE49820B1/en unknown
- 1980-05-23 SE SE8003874A patent/SE433847B/en not_active IP Right Cessation
- 1980-05-27 FI FI801705A patent/FI68808C/en not_active IP Right Cessation
- 1980-05-29 GB GB8017619A patent/GB2053900B/en not_active Expired
- 1980-05-30 ES ES492005A patent/ES492005A0/en active Granted
- 1980-05-30 AT AT0288580A patent/AT371800B/en not_active IP Right Cessation
- 1980-05-30 NO NO801617A patent/NO148372C/en unknown
- 1980-05-30 CH CH423780A patent/CH642617A5/en not_active IP Right Cessation
- 1980-05-30 DE DE19803020604 patent/DE3020604A1/en not_active Withdrawn
- 1980-05-30 NL NL8003153A patent/NL8003153A/en not_active Application Discontinuation
-
1982
- 1982-11-26 NO NO823977A patent/NO148415C/en unknown
-
1983
- 1983-07-11 KE KE3302A patent/KE3302A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| GB2053900B (en) | 1983-04-20 |
| IE801081L (en) | 1980-12-01 |
| NL8003153A (en) | 1980-12-03 |
| FI68808B (en) | 1985-07-31 |
| NO148372C (en) | 1983-09-28 |
| SE433847B (en) | 1984-06-18 |
| NO823977L (en) | 1980-12-02 |
| ATA288580A (en) | 1982-12-15 |
| GB2053900A (en) | 1981-02-11 |
| DE3020604A1 (en) | 1980-12-11 |
| FI68808C (en) | 1985-11-11 |
| ES8104185A1 (en) | 1981-04-01 |
| NO148415B (en) | 1983-06-27 |
| FI801705A (en) | 1980-12-02 |
| SE8003874L (en) | 1980-12-02 |
| CH642617A5 (en) | 1984-04-30 |
| ES492005A0 (en) | 1981-04-01 |
| NO801617L (en) | 1980-12-02 |
| AT371800B (en) | 1983-07-25 |
| KE3302A (en) | 1983-08-19 |
| IE49820B1 (en) | 1985-12-25 |
| NO148415C (en) | 1983-10-12 |
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