DK142282B

DK142282B - BENZOXAZINES FOR USE IN THE PREPARATION OF 2-BENZOYL-BENZYLAMINES AND PROCEDURES FOR THEIR PREPARATION

Info

Publication number: DK142282B
Application number: DK560976A
Authority: DK
Inventors: G Krueger; J Keck
Original assignee: Thomae Gmbh Dr K
Priority date: 1973-07-24
Filing date: 1976-12-14
Publication date: 1980-10-06
Also published as: DK142282C; DK560976A

Description

(11) FREMLÆGGELSESSKRIFT 142282 DANMARK cel) Int. Cl.a c 07 D 265/ 16 §(21) Ansøgning nr. 5βθ9/7β (22) Indleveret den 14. deC. 1976 (24) Løbødag 23» Jul. 1974 (44) Ansøgningen fremlagt og fremlæggelsesekrfftet offentliggjort den 6. okt. 1 98Ο(11) PRESENTATION 142282 DENMARK cell) Int. Cl.a c 07 D 265/16 § (21) Application No. 5βθ9 / 7β (22) Filed on the 14th December. 1976 (24) Running Day 23 »Jul. 1974 (44) The application presented and the publication order published on 6 October. 1 98Ο

DIREKTORATET FORDIRECTORATE OF

PATENT-OG VAREMÆRKEVÆSENET (30) Prioritet begærst fra den 24. jul. 1973a 2327^56, de W) DR. KARL THOMAE GMBH, 7950 Blberach/Rise, DE.PATENT AND TRADE MARKET (30) Priority requested from 24 July. 1973a 2327 ^ 56, the W) DR. KARL THOMAE GMBH, 7950 Blberach / Rise, DE.

(72) Opfinder: Gerd Krueger, Johann-Sebastlan-Baeh-Strasse 29, 7950(72) Inventor: Gerd Krueger, Johann-Sebastlan-Baeh-Strasse 29, 7950

Biberach/Riss, HE: Johannes Keck, Talfeldstrasse 27, 795Ο Biberach/Biberach / Riss, HE: Johannes Keck, Talfeldstrasse 27, 795Ο Biberach /

Riss, DE.Riss, DE.

(74) Fuldmægtig under sagena behandling:(74) Clerk of the case:

Internationalt Patent-Bureau.International Patent Office.

<S4) Benzoxaziner til brug ved fremstilling af 2-benzoyl-benzylaminer og fremgangsmåde til deres fremstilling.<S4) Benzoxazines for use in the preparation of 2-benzoyl-benzylamines and process for their preparation.

Den foreliggende opfindelse angår hidtil ukendte benzoxaziner tilThe present invention relates to novel benzoxazines for

brug ved fremstillingen af 2-benzoyl-benzylaminer med den almene formel Iuse in the preparation of 2-benzoyl-benzylamines of the general formula I

1 2 (se krav 1), hvor Hal og R har de nedenfor angivne betydninger, og R betyder 3 en alkylgruppe med l-3carbonatomer, R betyder en cyclohexyl-, isopropylamino-carbonylmethyl- eller morpholinocarbonylmethylgruppe, eller fysiologisk acceptable salte deraf med uorganiske og organiske syrer, hvilke benzoxaziner er kendetegnet ved, at de har den almene formel II (se krav 1), hvor Hal betyder et chlor- eller bromatom, R* betyder et hydrogen-, chlor- eller bromatom, eller er syreadditionssalte deraf.1 2 (see claim 1), wherein Hal and R have the meanings set forth below and R is 3 is an alkyl group having 1-3 carbon atoms, R is a cyclohexyl, isopropylamino carbonylmethyl or morpholinocarbonylmethyl group, or physiologically acceptable salts thereof with inorganic and organic acids, which benzoxazines are characterized in that they have the general formula II (see claim 1) wherein Hal represents a chlorine or bromine atom, R * means a hydrogen, chlorine or bromine atom, or are acid addition salts thereof.

Fra litteraturen er det kendt, at 4H-3,l-benzoxaziner med aminer giver tilsvarende 2—amino-benzylaminer (se f.eks. R.C.Elderfield "Heterocyclic Compounds", Vol. 6, side 574).It is known from the literature that 4H-3,1-benzoxazines with amines give similar 2-amino-benzylamines (see, e.g., R.C.Elderfield "Heterocyclic Compounds", Vol. 6, page 574).

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Endvidere kendes der fra beskrivelserne til de danske patenter nr.Furthermore, from the descriptions of the Danish patents no.

128.890 og 131.852, beskrivelsen til dansk patentansøgning nr. 2618/73 og beskrivelsen til U.S.A.-patent nr. 3.712.924 et antal fremgangsmåder til fremstilling af 2-benzoylamino-benzylaminer med formlen I. For så vidt angår patent nr. 131.852 og U.S.-patent nr. 3.712.924, er det ikke oplyst, hvilke udbytter der opnås ved de deri omhandlede fremgangsmåder, medens der vedrørende fremgangsmåden ifølge patent nr. 128.890 i patentets eksempel 10 er anført opnåelse af et udbytte på 20% af det teoretiske. Endelig er der i beskrivelsen til dansk patentansøgning nr. 2618/73 angivet opnåelse af udbytter på 40,8%(eksempel 5) og på 32,4% (eksempel 7) af det teoretiske. Disse udbytter er ikke tilfredsstillende.No. 128,890 and 131,852, the disclosure of Danish Patent Application No. 2618/73 and the disclosure of U.S. Patent No. 3,712,924 to a number of processes for preparing 2-benzoylamino-benzylamines of formula I. Patent No. 3,712,924, it is not disclosed which yields are obtained by the methods disclosed therein, while obtaining a yield of 20% of theory in respect of the method of Patent No. 128,890 of Example 10. Finally, the specification for Danish Patent Application No. 2618/73 discloses yields of 40.8% (Example 5) and 32.4% (Example 7) of the theoretical. These yields are not satisfactory.

Det har imidlertid nu overraskende vist sig, at de angivne benzoxaziner med den almene formel II eller syreadditionssalte heraf med fordel kan benyttes til fremstilling af de angivne farmaceutisk værdifulde 2-benzoylamino-benzylaminer med formlen I i høje og ofte næsten kvantitative udbytter. Denne fremstilling kan hensigtsmæssigt ske ved, at en benzoxazin med den angivne formel II, omsættes med en amin med den almene formel IIIHowever, it has now surprisingly been found that the indicated benzoxazines of the general formula II or their acid addition salts can advantageously be used to prepare the stated pharmaceutically valuable 2-benzoylamino-benzylamines of the formula I in high and often almost quantitative yields. This preparation may conveniently be effected by reacting a benzoxazine of the formula II indicated with an amine of the general formula III

//

H-lf IIIH-lf III

VV

2 3 hvor R og R er som defineret i det foregående, ved en temperatur mellem 100 og 200°C, eventuelt i et opløsningsmiddel, og en opnået base med formlen I om ønsket derpå omdannes til et fysiologisk acceptabelt salt deraf med en organisk eller uorganisk syre.Wherein R and R are as defined above, at a temperature between 100 and 200 ° C, optionally in a solvent, and an obtained base of formula I, if desired, is then converted to a physiologically acceptable salt thereof with an organic or inorganic salt. acid.

Denne omsætning kan gennemføres uden opløsningsmiddel, men gennemføres hensigtsmæssigt i et opløsningsmiddel, såsom tetralin, eller med fordel i et overskud af den anvendte amin med den almene formel III. Den gennemføres fortrinsvis ved temperaturer mellem 130 og 180°C.This reaction may be carried out without solvent, but conveniently carried out in a solvent such as tetralin, or advantageously in excess of the amine of general formula III used. It is preferably carried out at temperatures between 130 and 180 ° C.

Fysiologisk acceptable salte med uorganiske eller organiske syrer er især salte med saltsyre, hydrogenbromidsyre, svovlsyre, phosphorsyre, mælkesyre, citronsyre og maleinsyre.Physiologically acceptable salts with inorganic or organic acids are especially salts with hydrochloric, hydrobromic, sulfuric, phosphoric, lactic, citric and maleic acids.

At man ved den angivne omsætning opnår de omtalte store udbytter er så meget mere overraskende, som man ved omsætningen egentlig måtte forvente dannelse af de tilsvarende 2-amino-benzylaminer.That the large yields obtained at the indicated reaction are obtained is much more surprising than one would actually expect the corresponding 2-amino-benzylamines to produce.

Forbindelserne med formlen I besidder navnlig værdifulde sekretolytiske, hostestillende og/eller åndedrætstimulerende virkninger.In particular, the compounds of formula I possess valuable secretolytic, cough relieving and / or respiratory stimulating effects.

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De omhandlede benzoxaziner med dem almene formel II kan ifølge opfindelsen fordelagtigt fremstilles ved, at en benzylalkohol med den almene formel IVThe benzoxazines of the general formula II according to the invention can advantageously be prepared by a benzyl alcohol of the general formula IV

Hai^cV0HHai ^ cV0H

RlkXm-„c^> hvor r\ og Hal er som defineret i det foregående, omsættes med et surt dehydratiseringsmiddel.RlkXm- "c ^> where r \ and Hal are as defined above are reacted with an acidic dehydrating agent.

Denne omsætning gennemføres fortrinsvis i et opløsningsmiddel, såsom ether, tetrahydrofuran eller dioxan.Som et dehydratiseringsmiddel kan der f.eks. anvendes en mineralsyre, såsom hydrogenchlorid, svovlsyre, phosphorsyre eller hydrogenbromid. Omsætningen gennemføres hensigtsmæssigt ved temperaturer mellem 0 og 50°C, fortrinsvis dog ved temperaturer mellem 15 og 25°C.This reaction is preferably carried out in a solvent such as ether, tetrahydrofuran or dioxane. As a dehydrating agent, e.g. a mineral acid such as hydrogen chloride, sulfuric acid, phosphoric acid or hydrogen bromide is used. The reaction is conveniently carried out at temperatures between 0 and 50 ° C, preferably at temperatures between 15 and 25 ° C.

De som udgangsstoffer anvendte benzylalkoholer med den almene formel IV får man f.eks. ved omsætning af passende 2-amino-benzylalkoholer, der fås ved reduktion af tilsvarende benzylaldehyder med natriumborhydrid, med et benzoe syreha logenid i pyridin og påfølgende alkalisk forsæbning af den fremkomne ester.The benzyl alcohols of the general formula IV used as starting materials are obtained e.g. by reacting appropriate 2-amino-benzyl alcohols obtained by reduction of corresponding benzyl aldehydes with sodium borohydride with a benzoic acid halogenide in pyridine and subsequent alkaline saponification of the resulting ester.

Opfindelsen forklares nærmere ved hjælp af følgende eksempler, der viser såvel fremstillingen af de omhandlede benzoxaziner med formlen II som omdannelsen af disse til 2-benzoylemino-benzylaminer med formlen I.The invention is further explained by the following examples which show both the preparation of the subject benzoxazines of formula II and their conversion to 2-benzoylemino-benzylamines of formula I.

Eksempel 1 6,8-Dibrom-2-pheny1-4H-3,1-benzoxazin.Example 1 6,8-Dibromo-2-phenyl-4H-3,1-benzoxazine.

11 g 2-benzoylamino-3,5-dibrom-benzylalkohol tilsættes 600 ml absolut ether. I blandingen ledes under omrøring i 30 minutter hydrogenbromidgas. Derved går iidgangsproduktet i opløsning, og 6,8-dibrom>*2-phenyl-4H-3,l-benzoxazin-hydrobromid udfældes. Efter 6 timers omrøring frasuges bundfaldet, og der ora-krystalllseres fra absolut ethanol. Smp. af hydrobromidet 218-221°G.11 g of 2-benzoylamino-3,5-dibromo-benzyl alcohol are added to 600 ml of absolute ether. In the mixture, hydrogen bromide gas is passed under stirring for 30 minutes. Thereby, the initiation product dissolves and 6,8-dibromo> 2-phenyl-4H-3,1-benzoxazine hydrobromide precipitates. After 6 hours of stirring, the precipitate is suctioned off and crystallized from absolute ethanol. Mp. of the hydrobromide 218-221 ° G.

Eksempe1 2 5-Chlor-2-phenyl-4H-3,1-benzoxazin.Example 2 5-Chloro-2-phenyl-4H-3,1-benzoxazine.

Smp.: 88,5-89,5°C. Fremstillet ud fra 2-benzoylamino-6-chlor-benzylal-kohol analogt med eksempel 1.Mp: 88.5-89.5 ° C. Prepared from 2-benzoylamino-6-chloro-benzylalcohol by Example 1.

Eksempel AExample A

2-Benzoylamino-N-cyclohexyl-3,5-dibrom-N-methyl-benzylamin.2-benzoylamino-N-cyclohexyl-3,5-dibromo-N-methyl-benzylamine.

11,2 g (0,025 mol) 6,8-dibrom-2-phenyl-4H~3,l-benzoxazin-hydrobromld 142282 4 koges med 17,0 g (0,15 mol) N-methyl-cyclohexylamin 1,5 timer under tilbagesvaling. Derpå sætter man til reaktionsblandingen 2N natriumhydroxid, udryster flere gange med ether, tørrer den organiske fase med natriumsulfat og inddamper til tørhed. Resten opløser man i absolut ethanol, og ether og gør sur med ethanolisk saltsyre, hvorved 2-benzoylamino-N-cyclohexyl-3,5-dibrom-N-methyl-benzylamin-hydrochlorid udkrystalliserer.11.2 g (0.025 mol) of 6,8-dibromo-2-phenyl-4H-1,3-1-benzoxazine hydrobromide is boiled with 17.0 g (0.15 mol) of N-methyl-cyclohexylamine 1.5 hours under reflux. Then, to the reaction mixture, 2N sodium hydroxide is added, quenched with ether several times, the organic phase is dried with sodium sulfate and evaporated to dryness. The residue is dissolved in absolute ethanol and ether and acidified with ethanolic hydrochloric acid to crystallize 2-benzoylamino-N-cyclohexyl-3,5-dibromo-N-methyl-benzylamine hydrochloride.

Udbytte: 12,1 g (93,77. af det teoretiske).Yield: 12.1 g (93.77 of theory).

Smp.: 270-272°C (sønderdeling).Mp: 270-272 ° C (dec.).

Eksempel BExample B

2-Benzoylamino-6-chlor-N-methyl-N-(morpholino-carbonyl-methyl)-benzylamin.2-benzoylamino-6-chloro-N-methyl-N- (morpholino-carbonyl-methyl) -benzylamine.

Smp.: 122,5-123°C. Fremstillet ud fra 5-chlor-2-phenyl-4H-3,l-benzoxa-zin og sarkosinmorpholid analogt med eksempel A.Mp: 122.5-123 ° C. Prepared from 5-chloro-2-phenyl-4H-3,1-benzoxazine and sarcosine morpholide analogous to Example A.

Eksempel CExample C

2-Benzoylamino-6-chlor-N-isopropyl-N-(morpholino-carbonyl-methyl)-benzylamin.2-benzoylamino-6-chloro-N-isopropyl-N- (morpholino-carbonyl-methyl) -benzylamine.

Smp.: 125-127°C. Fremstillet ud fra 5-chlor-2-phenyl-4H-3,l-benzoxazin og N-isopropyl-glycin-morpholid analogt med eksempel A.Mp: 125-127 ° C. Prepared from 5-chloro-2-phenyl-4H-3,1-benzoxazine and N-isopropyl-glycine morpholide analogous to Example A.

Eksempel DExample D

2-Benzoylamino-4-chlor-N-methyl-N-(isopropylamino-carbonyl-methyl)-benzylamin.2-benzoylamino-4-chloro-N-methyl-N- (isopropylamino-carbonyl-methyl) -benzylamine.

Smp.: 140-142°G. Fremstillet ud fra 7-chlor-2-phenyl-4H-3,l-benzoxazin og sarkosinisopropylamid analogt med eksempel a.Mp: 140-142 ° G. Prepared from 7-chloro-2-phenyl-4H-3,1-benzoxazine and sarcosine isopropylamide analogous to Example a.

EksempelEEksempelE

2-Benzoylamino-6-brom-N-methyl-N-(morpholino-carbonyl-methyl)-benzylamin.2-benzoylamino-6-bromo-N-methyl-N- (morpholino-carbonyl-methyl) -benzylamine.

Smp.: 159-161°C. Fremstillet ud fra 5-brom-2-phenyl-4H-3,l-benzoxazin og sarkosinmorpholid analogt med eksempel a.Mp: 159-161 ° C. Prepared from 5-bromo-2-phenyl-4H-3,1-benzoxazine and sarcosine morpholide analogous to Example a.

EksempelFEksempelF

2-Benzoylamino-3,5-dibrom-N-methyl-N-(morpholino-carbonyl-methyl) -benzylamin.2-Benzoylamino-3,5-dibromo-N-methyl-N- (morpholino-carbonyl-methyl) -benzylamine.

Smp.: 164-166°C. Fremstillet ud fra 6,8-dibrom-2-phenyl-4H-3,l-benzoxa-zin og sarkosinmorpholid analogt med eksempel A.Mp: 164-166 ° C. Prepared from 6,8-dibromo-2-phenyl-4H-3,1-benzoxazazine and sarcosine morpholide analogous to Example A.