NO128712B

NO128712B -

Info

Publication number: NO128712B
Application number: NO04609/69A
Authority: NO
Inventors: P Mamalis; D Outred
Original assignee: Beecham Group Ltd
Priority date: 1968-11-22
Filing date: 1969-11-20
Publication date: 1974-01-02
Also published as: LU59866A1; FR2023866B1; OA03394A; GB1270831A; AT303748B; DE1957769A1; BE741996A; SE383883B; DK134521C; ES373657A1; CH554350A; DE1965925A1; FR2023866A1; NL6917536A; DK134521B; DE1957769B2; DE1957769C3

Description

Analogifremgangsmåte for fremstilling Analogy method of manufacture

av anti-malaria-aktive forbindelser.. of anti-malarial active compounds..

Foreliggende oppfinnelse vedrører en fremgangsmåte for fremstilling av N-substituerte symmetriske dihydrotriazinderivater. Forbindelsene som fremstilles innenfor rammen av foreliggende opp- The present invention relates to a method for the production of N-substituted symmetrical dihydrotriazine derivatives. The compounds produced within the framework of the present

finnelse, er i besittelse av anti-malaria-aktivitet. invention, is possessed of anti-malarial activity.

I henhold til oppfinnelsen tilveiebringes nye N-substi- According to the invention, new N-substi-

tuerte symmetriske dih'ydrotriazinderivater av den generell-e formel: tuated symmetrical dihydrotriazine derivatives of the general formula:

hvor er en cykloheksyl-, fenyl- eller naftylgruppe som eventuelt er substituert med 1, 2 eller 3 halogenatomer, 1 eller 2 nitro- eller metylgrupper, en trifluormetyl-, benzyl-, metoksyl-, etyl- eller propylgruppe eller en usubstituert tetrahydronaftyl-eller butyl-, propenyl- eller 2,3-diklorpropylgruppe, where is a cyclohexyl, phenyl or naphthyl group optionally substituted with 1, 2 or 3 halogen atoms, 1 or 2 nitro or methyl groups, a trifluoromethyl, benzyl, methoxy, ethyl or propyl group or an unsubstituted tetrahydronaphthyl or butyl, propenyl or 2,3-dichloropropyl group,

1*2 er en mettet, toverdig, ikke-forgrenet alifatisk gruppe 1*2 is a saturated, divalent, unbranched aliphatic group

med 1-10 karbonatomer , en -CH=CH-CH2- eller -CHCl-CHCl-CH2-gruppe , with 1-10 carbon atoms, a -CH=CH-CH2- or -CHCl-CHCl-CH2 group,

og R^ er begge metylgrupper eller danner sammen med karbonatomet som de er knyttet til, en cykloheksyl- eller metyl-substituert cykloheksylring, and R^ are both methyl groups or together with the carbon atom to which they are attached form a cyclohexyl or methyl-substituted cyclohexyl ring,

X er et oksygen- eller svovelatom eller en gruppe NR^, hvor X is an oxygen or sulfur atom or a group NR^, where

R5 er H eller en metyl- eller etylgruppe, og salter og acetylderivater av disse. Fremgangsmåten er karakterisert ved at i nærvær av en syre omsettes et substituert diguanid av den generelle formel: R5 is H or a methyl or ethyl group, and salts and acetyl derivatives thereof. The method is characterized by the fact that, in the presence of an acid, a substituted diguanide of the general formula is reacted:

hvor R, er R,XR-0-, hvorved man fremstiller forbindelsen av formel b 1 Z (I) direkte, eller R^ er en slik gruppe at det resulterende triazin av formel (III) når det utsettes for hydrogenering, omdannes til et hydroksytriazin av formelen where R, is R,XR-O-, whereby the compound of formula b 1 Z (I) is prepared directly, or R^ is such a group that the resulting triazine of formula (III) when subjected to hydrogenation, is converted into a hydroxytriazine of the formula

som deretter alkyleres ved omsetning med en forbindelse R^XR2Z, hvor Z er en gruppe som lett erstattes ved nukleofil forskyvning, slik at man får forbindelsen av formel (I), og eventuelt dannelse av et salt ved omsetning med minst én mol-ekvivalent av en syre, og eventuelt dannelse av et acetylderivat ved omsetning med et acetyle-ringsmiddel. which is then alkylated by reaction with a compound R^XR2Z, where Z is a group that is easily replaced by nucleophilic displacement, so that one obtains the compound of formula (I), and optionally formation of a salt by reaction with at least one molar equivalent of an acid, and possibly formation of an acetyl derivative by reaction with an acetylating agent.

Selv om det her er anvendt formler for å angi forbindelsene som fremstilles ifølge oppfinnelsen, så bestemmes■dog ikke omfanget av oppfinnelsen av den nøyaktige teoretiske riktighet av disse formler. Navnene og formlene som anvendes her, skal derfor ikke forståes å begrense oppfinnelsen til en eller annen spesifikk tautomer form eller til en spesifikk optisk eller geometrisk iso-mer. Although formulas have been used here to indicate the compounds produced according to the invention, the scope of the invention is not determined by the exact theoretical correctness of these formulas. The names and formulas used here are therefore not to be understood as limiting the invention to one or another specific tautomeric form or to a specific optical or geometric isomer.

Strukturformler av den følgende form kan f.eks. omfattes av formelen I Structural formulas of the following form can e.g. covered by formula I

Forbindelsene som fremstilles i henhold til foreliggende oppfinnelse, fremstilles hensiktsmessig i form av syreaddisjonssal-ter, da den frie base har en tendens til å være noe ustabil, og et vidt område av syrer kan anvendes. Hvis forbindelsene skal anvendes farmasøytisk, må syren naturligvis oppvise aksepterbare farma-søytiske egenskaper, som lav toksisitet. The compounds produced according to the present invention are conveniently produced in the form of acid addition salts, as the free base tends to be somewhat unstable, and a wide range of acids can be used. If the compounds are to be used pharmaceuticals, the acid must of course exhibit acceptable pharmaceutical properties, such as low toxicity.

Forbindelsene i henhold til oppfinnelsen kan fremstilles The compounds according to the invention can be prepared

i form av monohydrohalogensyre-addisjonssalter, f.eks. hydrobro-midet eller hydrokloridet. Andre salter kan imidlertid fremstilles ved en enkel reaksjon av basen med syrer , og dette kan være ønskelig for å modi<4>' sere egenskapene til produktet, som f.eks. dets toksisitet, smaK, -fysikal'k;: form eller frigjøringshastighet i organismen. F.eks. kan forbindelsene fremstilles i form av pikrater, sakkarinater, acetater , syremaleater, syreftalater, sukki-nater, fosfater, p-nitrobenzoater, stearater, mandelater, N-ace-tyl-glycinater; pamoater, cykloheksylsulfamater, citrater, tar-trater eller glukonater. in the form of monohydrohaloacid addition salts, e.g. the hydrobromide or the hydrochloride. However, other salts can be prepared by a simple reaction of the base with acids, and this may be desirable in order to modify the properties of the product, such as e.g. its toxicity, smaK, -physical'k;: form or rate of release in the organism. E.g. the compounds can be prepared in the form of picrates, saccharinates, acetates, acid maleates, acid phthalates, succinates, phosphates, p-nitrobenzoates, stearates, mandelates, N-acetyl glycinates; pamoates, cyclohexyl sulfamates, citrates, tartrates or gluconates.

Stabile salter fremstilles vanligvis med et forhold av Stable salts are usually prepared with a ratio of

1 molekyl.triazin til 1 molekyl av en enverdig syre (eller mer enn 1 molekyl triazin i tilfelle av fierverdige syrer) , men mulig-heten av at forbindelsen oppviser basiske grupper som x eller som substituenter i f.eks. , betyr at ytterligere mengde av syre i enkelte tilfeller kan forenes med triazinet. 1 molecule of triazine to 1 molecule of a monovalent acid (or more than 1 molecule of triazine in the case of tetravalent acids), but the possibility that the compound exhibits basic groups such as x or as substituents in e.g. , means that a further amount of acid can in some cases be combined with the triazine.

Tilstedeværelsen av aminogrupper på triazinringen av formel I muliggjør fremstilling av acetylderivater ved reaksjon med acyleringsmidler som acylhalogenider, anhydrider og acylazider» 1 til 4 acetylgrupper kan f.eks. innføres i forbindelsen av formel I, skjønt det i enkelte tilfeller kan være vanskelig å frem-stille derivater med et høyere antall av acetylgrupper. The presence of amino groups on the triazine ring of formula I enables the production of acetyl derivatives by reaction with acylating agents such as acyl halides, anhydrides and acyl azides' 1 to 4 acetyl groups can e.g. is introduced into the compound of formula I, although in some cases it may be difficult to produce derivatives with a higher number of acetyl groups.

Forbindelsene som fremstilles innenfor rammen av oppfinnelsen, oppviser aktivitet overfor bakterier, protazoa, parasitter, innbefattet Plasmodia av malaria, fungi innbefattet dermatofytter og candida, og oppviser i enkelte tilfeller kokkidiostatiske egenskaper„ The compounds produced within the scope of the invention exhibit activity against bacteria, protazoa, parasites, including Plasmodia of malaria, fungi including dermatophytes and candida, and in some cases exhibit coccidiostatic properties.

Således har man iakttatt aktivitet overfor Staph. aureus, Escherichia coli, Candida albicans, Proteus mirabilis, Pseudomonas pyocyanea og Streptococcus haemolyticus. Thus, activity against Staph has been observed. aureus, Escherichia coli, Candida albicans, Proteus mirabilis, Pseudomonas pyocyanea and Streptococcus haemolyticus.

F.eks. oppviser 4,6-diamino-l,2-dihydro-2,2-dimetyl-l-[3'-(2,4,5-triklorfenoksy)-propyloksv]-1,3,5-triazinhydrobro-mid av formelen E.g. exhibits 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-[3'-(2,4,5-trichlorophenoxy)-propyloxy]-1,3,5-triazine hydrobromide of the formula

aktivitet overfor cykloguanil-følsomme og cykloguanil-resistente stammer av Plasmodium berghei hos mus. activity against cycloguanil-sensitive and cycloguanil-resistant strains of Plasmodium berghei in mice.

I enkelte serier av forbindelser som fremstilles i henhold til oppfinnelsen har det vist seg at det oppnås optimal aktivitet når R^ er aryl bundet direkte til X (se formel I). Det er også å foretrekke at X er oksygen og/eller at R^ er ~(CH2^n~' hvor n er 2 - 8. In some series of compounds prepared according to the invention, it has been shown that optimal activity is achieved when R 1 is aryl bonded directly to X (see formula I). It is also preferred that X is oxygen and/or that R^ is ~(CH2^n~' where n is 2 - 8.

Fortrinnsvis er syren som anvendes ved fremgangsmåten i henhold til oppfinnelsen, en sterk syre som saltsyre eller maur-syre, og det anvendes i det minste 1 mol-ekvivalent. Reaksjonen kan i enkelte tilfeller utføres uten ytterligere oppløsningsmid-ler eller fortynningsmidler, men vanligvis foretrekkes et inert oppløsningsmiddel, som f.eks. en lavere alifatisk alkohol (f.eks. metanol). Preferably, the acid used in the method according to the invention is a strong acid such as hydrochloric acid or formic acid, and at least 1 mol equivalent is used. The reaction can in some cases be carried out without additional solvents or diluents, but usually an inert solvent is preferred, such as e.g. a lower aliphatic alcohol (eg methanol).

Når R6 er R^-X-R.,-0-, blir det substituerte diguanid II When R 6 is R 1 -X-R 1 -O-, the substituted diguanide becomes II

og følgelig omfatter oppfinnelsen også fremstilling av forbindelser av denne art for anvendelse som mellomprodukter ved fremgangs- and consequently the invention also encompasses the production of compounds of this kind for use as intermediates in the process

måten ifølge oppfinnelsen. Forbindelsene Ila kan f.eks. fremstilles ved at et bromid av den generelle formel R^XR^Br bringes til å reagere med benzhydroksaminsyre og dette behandles med syre slik at det dannes et oksyamin av formelen R^XR^Nf^, som deretter bringes til å reagere med dicyandiamid. the method according to the invention. The compounds Ila can e.g. is prepared by reacting a bromide of the general formula R^XR^Br with benzhydroxamic acid and this is treated with acid so that an oxamine of the formula R^XR^Nf^ is formed, which is then reacted with dicyandiamide.

Alternativt kan gruppen R^ velges slik at den kan omdannes til gruppen R^-X-R2~0-. F.eks. kan R^ være en gruppe R^O, som har evne til å bli utsatt for katalytisk hydrogenolyse. Således kan et R^ON- substituert triazin fremstilles fra et passende substituert diguanid og derpå hydrogenolyseres slik at det dannes hydroksytriazin IV Alternatively, the group R^ can be chosen so that it can be converted into the group R^-X-R2~O-. E.g. can R^ be a group R^O, which has the ability to be subjected to catalytic hydrogenolysis. Thus, an R^ON-substituted triazine can be prepared from an appropriately substituted diguanide and then hydrogenolyzed to form hydroxytriazine IV

R^ kan f.eks. være substituert eller usubstituert benzyl eller substituert eller usubstituert naftylmetyl, og hydrogenoly-sen kan utføres med hydrogen i nærvær av en palladiumkatalysator. R^ can e.g. be substituted or unsubstituted benzyl or substituted or unsubstituted naphthylmethyl, and the hydrogenolysis can be carried out with hydrogen in the presence of a palladium catalyst.

Hydroksytriazinet IV kan derpå "bringes til å reagere på mange forskjellige måter som lett forståes av fagfolk for å danne det ønskede substituerte triazin av formel I. The hydroxytriazine IV can then be "reacted in many different ways readily understood by those skilled in the art to form the desired substituted triazine of formula I.

Fagmannen vil forstå at sidekjeden R^-X-R2~0- kan opp-bygges eller tilknyttes i trinn, enten før eller etter at det substituerte diguanid II omdannes til det i ibstii-uerte triazin III. Vanligvis anvendes et ninimumsantall av arbeidstrinn for å oppnå maksimale utbytter og for bekvem.iets skyld. The person skilled in the art will understand that the side chain R^-X-R2~0- can be built up or attached in steps, either before or after the substituted diguanide II is converted to the unsubstituted triazine III. Generally, a minimum number of work steps are used to achieve maximum yields and for convenience.

Således kan velkjente eter-dannende syntetiske metoder anvendes for å binde side-kjeden til triazinet med O-atomet på forhånd på plass enten på sidekjeden eller på triazinet. Typis-ke eksempler er: 1. Reaksjon med halogenidet med en hydroksylforbindelse med eller uten tilsatt base. 2. Reaksjon av en reaktiv ester, som f.eks. et sulfonat med en hydroksylforbindelse. Thus, well-known ether-forming synthetic methods can be used to bind the side chain to the triazine with the O atom pre-positioned either on the side chain or on the triazine. Typical examples are: 1. Reaction with the halide with a hydroxyl compound with or without added base. 2. Reaction of a reactive ester, such as a sulfonate with a hydroxyl compound.

Analoge reaksjoner kan anvendes for å binde R^.-fragmentet til en partiell sidekjede omfattende R2■ fragmentet og med X-atomet eller -gruppen på forhånd på plass på et a-? fragmentene. Analogous reactions can be used to attach the R 2 fragment to a partial side chain comprising the R 2 fragment and with the X atom or group pre-positioned on an α-? the fragments.

Sluttproduktet kan fåes i form av et syreaddisjonssalt som en følge av reaksjonen uten at det er nødvendig å anvende et særskilt trinn for saltdannelse, men om nødvendig kan anvendes det ytterligere arbeidstrinn å la den frie base reagere med en syre slik at det dannes et salt. Salter kan overføres til den frie ba-se ved behandling med alkali (f.eks. KOH) og derpå omdannes til andre salter etter som det er ønskelig, ved hjelp av vanlig ar-beidsmidler. The end product can be obtained in the form of an acid addition salt as a result of the reaction without it being necessary to use a separate step for salt formation, but if necessary, the additional working step of allowing the free base to react with an acid so that a salt is formed can be used. Salts can be transferred to the free base by treatment with alkali (e.g. KOH) and then converted into other salts as desired, with the help of ordinary working agents.

Ve*d en foretrukket fremgangsmåte bringes en 'forbindelse R1-X-R2-Z-, hvor Z er klor eller brom til å reagere med hydroksytriazinet IV i et inert oppløsningsmiddel eller fortynningsmiddel. Ek*mpler på egnede oppløsningsmidler er dimetylsulfoksyd, dimetylformamid eller etanol« <a In a preferred method, a compound R1-X-R2-Z-, where Z is chlorine or bromine, is reacted with the hydroxytriazine IV in an inert solvent or diluent. Examples of suitable solvents are dimethylsulfoxide, dimethylformamide or ethanol

Hydroksytriazinderivatet IV fåes vanligvis i form av et syreaddisjonssalt (f.eks. hydrokloridet), hvorfra den frie base kan frigjøres ved en ekvivalent av base, som f.ek;, et alkalimetall-hydroksyd (f.eks. kaliumhvdroksyd) eller natrium i etanol eller metanol. Blandingen kan derpå inndampes og bringes til å reagere i et passende oppløsningsmiddel (f.eks. dimetylformamid eller dimetylsulfoksyd). Fortrinnsvis tilsettes ikke ekstra base, da det med 2 ekvivalenter av natrium i alkohol fåes f.eks. et mindre rent produkt. The hydroxytriazine derivative IV is usually obtained in the form of an acid addition salt (e.g. the hydrochloride), from which the free base can be liberated by an equivalent of base, such as, an alkali metal hydroxide (e.g. potassium hydroxide) or sodium in ethanol or methanol. The mixture can then be evaporated and reacted in a suitable solvent (eg dimethylformamide or dimethylsulfoxide). Preferably no extra base is added, as with 2 equivalents of sodium in alcohol, e.g. a less pure product.

Ved en modifisert fremgangsmåte som vanligvis gir dårli-gere utbytter, bringes hydroklorider av forbindelsen IV i dimetylformamid eller dimetylsulfoksyd til å reagere med en ekvivalent av vandig kaliumhydroksyd (det anvendes så lite vann som mulig) og den resulterende blanding bringes til å reagere for å gi et tria-zinhydrohalogenid. In a modified procedure which usually gives poorer yields, hydrochlorides of compound IV in dimethylformamide or dimethylsulfoxide are reacted with one equivalent of aqueous potassium hydroxide (using as little water as possible) and the resulting mixture is reacted to give a triazine hydrohalide.

Som nevnt foran kan sidekjeden R-^-X-R-^-O- tilknyttes på forskjellige måter og kan tilknyttes i én reaksjon eller i fragmen-ter. F.eks. kan en forbindelse av den generelle formel As mentioned above, the side chain R-^-X-R-^-O- can be attached in different ways and can be attached in one reaction or in fragments. E.g. can a compound of the general formula

bringes til å reagere med hydroksytriazinet IV, hvor R'2 er de samme som R2 i formelen I, men minus to karbonatomer„ Alternative forbindelser innenfor rammen av oppfinnelsen kan fremstilles ved å la hydroksytriazinet IV reagere med formaldehyd i nærvær av saltsyre så at det dannes en forbindelse av formelen og denne bringes til å reagere med en forbindelse av formelen hvor R"2 er den samme som R2 i formel I minus ett karbonatom, for å danne forbindelser av den generelle formel is reacted with the hydroxytriazine IV, where R'2 is the same as R2 in formula I, but minus two carbon atoms„ Alternative compounds within the scope of the invention can be prepared by reacting the hydroxytriazine IV with formaldehyde in the presence of hydrochloric acid to form a compound of the formula and this is reacted with a compound of the formula where R"2 is the same as R2 in formula I minus one carbon atom, to form compounds of the general formula

Alternativt kan visse hydroksy-substituerte forbindelser innenfor rammen av foreliggende oppfinnelse fremstilles ved å la et passende substituert etylenoksyd reagere med hydroksytriazin IV slik som vist ved reaksjonsskjemaet:hvor Tr anvendes for å representere Alternatively, certain hydroxy-substituted compounds within the scope of the present invention may be prepared by reacting an appropriately substituted ethylene oxide with hydroxytriazine IV as shown by the reaction scheme: where Tr is used to represent

På lignende måte kan visse hydroksysubstituerte forbindelser innenfor rammen av oppfinnelsen fremstilles ved å la ep;.-klorhydrin eller et derivat herav reagere med hydroksytriazinet IV for å danne et klor-hydroksysubstituert eter-mellqmprodukt, og dette bringes fil ytterligere å reagere med en passende substituert forbindelse som har en hydroksylgruppe eller et reaktivt derivat herav, slik som vist ved følgende reaksjonsskjerna: Similarly, certain hydroxy-substituted compounds within the scope of the invention can be prepared by reacting ep;-chlorohydrin or a derivative thereof with the hydroxytriazine IV to form a chloro-hydroxy-substituted ether intermediate, and this is further reacted with an appropriately substituted compound having a hydroxyl group or a reactive derivative thereof, as shown by the following reaction nucleus:

Reaksjoner av de ovenfor viste typer kan utføres under anvendelse av enten hydroksytriazinet IV som et utgangsmateriale eller et triazin med en partiell sidekjede som allerede er på plass, skjønt i mange tilfeller kan et slikt partielt sidekjede-triazin fremstilles fra det opprinnelige hydroksytriazin. Reactions of the types shown above can be carried out using either the hydroxytriazine IV as a starting material or a triazine with a partial side chain already in place, although in many cases such a partial side chain triazine can be prepared from the starting hydroxytriazine.

Således kan f.eks. en forbindelse Thus, e.g. a connection

hvor Y^er en reaktiv gruppe, bringes ti]/å reagere med en forbindelse R-^Y-j hvor Y^ er en reaktiv gruppe og R-|_Y3 og Y4 er i stand til å reagere slik at Y^ omdannes til R^X. For å gi et mer spesifikt eksempel kan en forbindelse R^Z, hvor Z er brom eller klor, bringes til å reagere med en forbindelse where Y^ is a reactive group, ti]/ is brought to react with a compound R-^Y-j wherein Y^ is a reactive group and R-|_Y3 and Y4 are capable of reacting so that Y^ is converted to R^X . To give a more specific example, a compound R^Z, where Z is bromine or chlorine, may be reacted with a compound

så at det dannes en forbindelse R-^OR^Tr,, so that a compound R-^OR^Tr,, is formed

Forbindelsene som fremstilles ved fremgangsmåten i henhold til oppfinnelsen, kan brukes som aktive bestanddeler i farma-søytiske preparater for anvendelse mot malaria, sammen med en far-masøytisk aksepterbar bærer. The compounds produced by the method according to the invention can be used as active ingredients in pharmaceutical preparations for use against malaria, together with a pharmaceutically acceptable carrier.

De aktive forbindelser kan således anvendes for behandling og forebyggelse av malaria hos mennesker. For å forebygge malaria administreres en av de aktive forbindelser til personer som er infisert eller som lett vil kunne bli utsatt for sykdommen. Forbindelsen kan administreres oralt, parenteralt eller ved hjelp av suppositorier, men oral administrering foretrekkes. The active compounds can thus be used for the treatment and prevention of malaria in humans. To prevent malaria, one of the active compounds is administered to people who are infected or who could easily be exposed to the disease. The compound can be administered orally, parenterally or by means of suppositories, but oral administration is preferred.

I det følgende skal oppfinnelsen klargjøres ved en del eksempler. In the following, the invention will be clarified by a number of examples.

Eksempel 1 Example 1

4 ,6-diamino-l ,2-dihydro-2 ,2-dimetyl-1-[ 3 '^-(2 ,4 ,5-triklorfenoksy) - propyloksy]-1,3,5-triazinhydrobromid o 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-[3'^-(2,4,5-trichlorophenoxy)-propyloxy]-1,3,5-triazine hydrobromide o

En blanding av 18,98 g 2,4,5-triklorfenol, 3,85 g natriumhydroksyd, 15,5 ml vann og 39/3 g 1,3-dibrompropan ble opphetet under tilbakeløp i 60-90 minutter, 25 ml 14% vandig natriumhydroksyd ble tilsatt og blandingen opphetet ved 50-70°C i 30 minutter» Ekstraksjon med eter og inndampning av det tørkede eter-lag ga ved destillasjon 16,4 g av 3-(2,4,5-triklorfenoksy)-propylbromid, kp. _150-154°C (hovedsakelig 150°C), smp. 34-35°C, sammen med 2,4 g av et høyerekokende materiale, kp. u, /154-164 oG og et forløp av 1,75 g olje. A mixture of 18.98 g of 2,4,5-trichlorophenol, 3.85 g of sodium hydroxide, 15.5 ml of water and 39/3 g of 1,3-dibromopropane was heated under reflux for 60-90 minutes, 25 ml of 14% aqueous sodium hydroxide was added and the mixture heated at 50-70°C for 30 minutes" Extraction with ether and evaporation of the dried ether layer gave by distillation 16.4 g of 3-(2,4,5-trichlorophenoxy)-propyl bromide, kp. _150-154°C (mainly 150°C), m.p. 34-35°C, together with 2.4 g of a higher boiling material, b.p. u, /154-164 oG and a flow of 1.75 g of oil.

En oppløsning av 5,5 g kaliumhydroksyd i 100 ml metanol ble opphetet under tilbakeløp med 15,23 g 4,6-diamino-l,2-dihydro-2,2-dimetyl-1-hydroksy-l,3,5-triazinhydroklorid i 10-30 minutter, blandingen ble inndampet og det gjenværende faste stoff omrørt med 25 g av det tidligere fremstilte bromid i 100 ml dimetylformamid i 3-24 timer ved romtemperatur. Blandingen ble filtrert, filtra-tet inndampet og det gjenværende faste stoff omrørt med aceton for å gi 23,7 g produkt- Vaskning med vann og med eter gav 19,12 g 4,6-diamino-l,2-dihydro-2,2-dimetyl-1-[3'-(2,4,5-triklorfenoksy)- - propyloksy]-1,3,5-triazinhydrobromid, 178-181°C. A solution of 5.5 g of potassium hydroxide in 100 ml of methanol was heated under reflux with 15.23 g of 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-hydroxy-1,3,5-triazine hydrochloride for 10-30 minutes, the mixture was evaporated and the remaining solid stirred with 25 g of the previously prepared bromide in 100 ml of dimethylformamide for 3-24 hours at room temperature. The mixture was filtered, the filtrate evaporated and the remaining solid stirred with acetone to give 23.7 g of product. Washing with water and with ether gave 19.12 g of 4,6-diamino-1,2-dihydro-2, 2-dimethyl-1-[3'-(2,4,5-trichlorophenoxy)--propyloxy]-1,3,5-triazine hydrobromide, 178-181°C.

Eksempel 2 Example 2

4,6-diamino-l,2-dihyd o-2,2-dimetyl-l-[2'-(p-klorfenyltio)etoksy]-1 , 3 ,5-triazinhydrobromid 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-[2'-(p-chlorophenylthio)ethoxy]-1,3,5-triazine hydrobromide

p-klorbenzentiol (14,5 g, 0,1 mol) oppløst i en metanolisk oppløsning av natriumhydroksyd (4 g i 200 ml) ble behandlet med dibrometan (37,6 g, 2,0 mol} og blandingen omrørt og opphetst under tilbakeløp i 1 1/2 timer, avkjølt og noe uoppløselig materiale fjernet ved filtrering. Oppløsningsmidlet ble fjernet i va-kuum, oljen ble fraskilt anorganiske salter, vasket med vann, tør-ket og destillert for å gi 1-(p-klorfenyl)-2-brometylsulfid (11,9g kp. 116°/2 mm). 4 ,6-diamino-l ,2-dihydro-2 ,2-dimetyl-1-hydroksy-l , 3-,5-triazinhydroklorid (3,87 g) ble i metanol bragt til reaksjon med kaliumhydroksyd (1,4 g), metanolen fordampet og oet gjenværende suspendert i formdimetylamid og avkjølt ved -10°C. Det ovennevnte bromid (5,05 g) ble tilsatt og blandingen omrørt i flere timer, p-Chlorobenzenethiol (14.5 g, 0.1 mol) dissolved in a methanolic solution of sodium hydroxide (4 g in 200 mL) was treated with dibromoethane (37.6 g, 2.0 mol) and the mixture stirred and refluxed in 1 1/2 hours, cooled and some insoluble material removed by filtration.The solvent was removed in vacuo, the oil separated from inorganic salts, washed with water, dried and distilled to give 1-(p-chlorophenyl)-2 -bromomethyl sulfide (11.9g bp. 116°/2 mm). 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-hydroxy-1,3-,5-triazine hydrochloride (3.87 g ) in methanol was reacted with potassium hydroxide (1.4 g), the methanol evaporated and the residue suspended in formdimethylamide and cooled at -10° C. The above bromide (5.05 g) was added and the mixture stirred for several hours,

og temperaturen fikk anledning til å stige langsomt til 20°C. and the temperature was allowed to rise slowly to 20°C.

Da man hadde fått en klar oppløsning, ble oppløsningsmidlet fo-dampet og den gjenværende gummiaktige substans utgnidd med aceton for å gi et hvitt, fast stoff (4,9 g). Etter omhyggelig vaskning med vann og tørkning veiet det faste stoff 2,52 g, smp. 193-195°C. Omkrystallisering fra etanol gav et materiale med smp. 202°C, 4,6-diamino-l,2-dihydro-2,2-dimetyl-1-[2'- (p-klorfenyltio)-etoksy]-1,3,5-triazinhydrobromid. When a clear solution was obtained, the solvent was evaporated and the remaining gummy substance triturated with acetone to give a white solid (4.9 g). After careful washing with water and drying, the solid weighed 2.52 g, m.p. 193-195°C. Recrystallization from ethanol gave a material with m.p. 202°C, 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-[2'-(p-chlorophenylthio)-ethoxy]-1,3,5-triazine hydrobromide.

Eksempel 3 Example 3

4,6-diamino-l,2-dihydro-2,2-dimetyl-l-[2'-(2-naftoksy)-etoksy]-1,3,5-triazinhydrobromid 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-[2'-(2-naphthoxy)-ethoxy]-1,3,5-triazine hydrobromide

2- (2-naftoksy)-etylbromid fremstilt fra 2-naftol og 1,2-dibrometan, på lignende måte som beskrevet i eksempel 1, hadde et smeltepunkt 90-91°C etter omkrystallisering fra etanol. 2-(2-Naphthoxy)-ethyl bromide prepared from 2-naphthol and 1,2-dibromoethane, in a similar manner as described in Example 1, had a melting point of 90-91°C after recrystallization from ethanol.

4,6-diamino-1,2-dihydro-2,2-dimetyl-1-hydroksy-1,3,5-triazinhydroklorid (3,67 g) ble bragt til reaksjon i metanol med kaliumhydroksyd (1,4 g), metanolen fjernet og det gjenværende suspendert i formdimetylamid og omrørt ved romtemperatur med 2-(2-naftoksy)-etylbromid (5,0 g) i 2 timer. Opparbeidelse på vanlig måte ga et hvitt, fast stoff (3,4 g), smp. 195-197°C. Omkrystallisering fra etanol ga rent 4,6-diamino-l,2-dihydro-2,2-dimetyl-l-[ 2 1 -(2-naftoksy) -etoksy] -1 ,3 ,5-triazinhydrobromid , smp. 196°C. 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-hydroxy-1,3,5-triazine hydrochloride (3.67 g) was reacted in methanol with potassium hydroxide (1.4 g), the methanol removed and the residue suspended in formdimethylamide and stirred at room temperature with 2-(2-naphthoxy)-ethyl bromide (5.0 g) for 2 hours. Work-up in the usual way gave a white solid (3.4 g), m.p. 195-197°C. Recrystallization from ethanol gave pure 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-[21-(2-naphthoxy)-ethoxy]-1,3,5-triazine hydrobromide, m.p. 196°C.

Eksempel 4 Example 4

4,6-diamino-l,2-dihydro-2,2-dimetyl-l-[3'-(p-nitrofenoksy)propyl-oksy] -1,3, 5-triazinhydrobromid 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-[3'-(p-nitrophenoxy)propyl-oxy]-1,3, 5-triazine hydrobromide

3- (p-nitrofenoksy)-propylbromid fremstilt fra p-nitro-fenyl og 1,3-dibrompropan, på lignende måte som beskrevet i eksempel 1, hadde et smp. 50-52°C. 3-(p-nitrophenoxy)-propyl bromide prepared from p-nitro-phenyl and 1,3-dibromopropane, in a similar manner as described in Example 1, had a m.p. 50-52°C.

Den frie base fra 2,96 g 4,6-diamino-l,2-dihydro-2,2-dimetyl-1-hydroksy-1,3,5-triazinhydroklorid ble suspendert i formdimetylamid og behandlet med det ovennevnte bromid (4,0 g) ved romtemperatur. Opparbeidelse på vanlig måte ga 4,6-diamino-l,2-dihydro-2,2-dimetyl-l-[3'-(p-nitrofenoksy)-propyloksy]-1,3,5-tri-azinhydrobromid (4,25 g), smp. 216-217°C. The free base from 2.96 g of 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-hydroxy-1,3,5-triazine hydrochloride was suspended in formdimethylamide and treated with the above bromide (4, 0 g) at room temperature. Workup in the usual manner afforded 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-[3'-(p-nitrophenoxy)-propyloxy]-1,3,5-triazine hydrobromide (4, 25 g), m.p. 216-217°C.

Eksempel 5 Example 5

4 ,6-diamino-l,2-dihydro-2,2-dimetyl-l-[3'-(2,4-dinitroanilin)-propyloksy]-1,3,5-triazinhydroklorid 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-[3'-(2,4-dinitroaniline)-propyloxy]-1,3,5-triazine hydrochloride

3-(2,4-dinitroanilin)-propan-l-ol fremstilt fra 2,4-dinitroklorbenzen og n-propanolamin i metanol inneholdende natrium-acetat, dannet gule nåler, smp. 72°C ,. etter krystallisering fra metanol. 3-(2,4-dinitroaniline)-propan-l-ol prepared from 2,4-dinitrochlorobenzene and n-propanolamine in methanol containing sodium acetate, formed yellow needles, m.p. 72°C,. after crystallization from methanol.

Det ovennevnte materiale (10 g) ble oppløst i kloroform (15 ml) og dimetylanilin (8 ml). En oppløsning av tionylklorid (5 ml) i kloroform (10 ml) ble tilsatt langsomt under omrøring. Da tilsetningen var fullstendig, ble blandingen behandlet mildt under tilbakeløp i 5 minutter, avkjølt og helt i en blanding av is og N-HCl (100 ml). Det gule, faste stoff som falt ut (5,84 g) var det krevede 3-(2,4-dinitroanilino)-propylklorid og hadde smp. 82°C. The above material (10 g) was dissolved in chloroform (15 ml) and dimethylaniline (8 ml). A solution of thionyl chloride (5 mL) in chloroform (10 mL) was added slowly with stirring. When the addition was complete, the mixture was gently refluxed for 5 min, cooled and poured into a mixture of ice and N-HCl (100 mL). The yellow solid that precipitated (5.84 g) was the required 3-(2,4-dinitroanilino)-propyl chloride and had m.p. 82°C.

Det ovennevnte klorid (2,6 g) ble tilsatt porsjonsvis The above chloride (2.6 g) was added portionwise

til en suspensjon av 4,6-diamino-l,2-dihydro-2,2-dimetyl-l,3,5-triazin (1,57 g) i formdimetylamid, avkjølt til 0°C, blandingen hensto til den fikk romtemperatur og ble så omrørt i 3 timer. Opparbeidelse på vanlig må-fee—gav en første--mengde (0,7 g) av 4,6-diamino-1,2-dihydro-2,2-dimetyl-1-hydroksy-l,3,5-triazinhydroklorid, den annen mengde av fast stoff, etter vaskning med vann, veiet 1,03 g og var det ønskede 4,6-diamino-l,2-dihydro-2,2-dimetyl-1-[3<1->(2,4-dinitroanilino)-propyloksy]-1,3,5-triazinhydroklorid, smp. 220-224°C. to a suspension of 4,6-diamino-1,2-dihydro-2,2-dimethyl-1,3,5-triazine (1.57 g) in formdimethylamide, cooled to 0°C, the mixture was allowed to reach room temperature and was then stirred for 3 hours. Work-up on a regular basis gave a first amount (0.7 g) of 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-hydroxy-1,3,5-triazine hydrochloride, the second amount of solid, after washing with water, weighed 1.03 g and was the desired 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-[3<1->(2, 4-dinitroanilino)-propyloxy]-1,3,5-triazine hydrochloride, m.p. 220-224°C.

Eksempel 6 Example 6

4,6-diamino-l,2-dihydro-2,2-dimetyl-l-[2-(n-butyloksy)-etoksy]-1 , 3 , 5- triazinhydroklorid 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-[2-(n-butyloxy)-ethoxy]-1,3,5-triazine hydrochloride

2-(n-butylc sy)-etylklor-'d ble frems :.lt ved omsetning av tionylklorid med 2-(n-butylo y)-etanol ("Butyl cellosolve") 2-(n-butyl cy)-ethyl chloro-'d was produced by reacting thionyl chloride with 2-(n-butyl y)-ethanol ("Butyl cellosolve")

og hadde kp. 60°/l,5 mm. and had kp. 60°/l.5 mm.

4,6-diamino-l,2-dihydro-2,2-dimetyl-1-hydroksy-l,3,5-triazinhydroklorid (7,7 g) oppløst i metanol ble behandlet med en oppløsning av kaliumhydroksyd (2,8 g) i metanol som tidligere beskrevet. "Hydroksytriazinbasen" som ble dannet, ble suspendert formdimetylamid og n-butyloksyetylkloridet (6,0 g) tilsatt. Blan-dingen ble omrørt og opphetet på et dampbad i 5 timer. Opparbeidelse på vanlig måte gav 2,5 g av det ønskede triazin-4,6-diamino-1,2-dihydro-2,2-dimetyl-l-t 2-(n-butyloksy)-etoksy]-1,3,5-triazin-hydroklorid, smpv 208°C . 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-hydroxy-1,3,5-triazine hydrochloride (7.7 g) dissolved in methanol was treated with a solution of potassium hydroxide (2.8 g ) in methanol as previously described. The "hydroxytriazine base" formed was suspended formdimethylamide and the n-butyloxyethyl chloride (6.0 g) added. The mixture was stirred and heated on a steam bath for 5 hours. Work-up in the usual way gave 2.5 g of the desired triazine-4,6-diamino-1,2-dihydro-2,2-dimethyl-1-t 2-(n-butyloxy)-ethoxy]-1,3,5- triazine hydrochloride, m.p. 208°C.

Eksempel 7 Example 7

4 ,6-diamino-l ,2-dihydrp-2 , 2-dimetyl-l-[ 3 ' -(2 ,4,,5-triklorfenoksy) - 4,6-diamino-1,2-dihydrop-2,2-dimethyl-1-[3'-(2,4,,5-trichlorophenoxy)-

propyloksy]- 1, 3, 5- triazinhydrobromid propyloxy]-1,3,5-triazine hydrobromide

1. 3-( 2, 4, 5- triklorfenoksy)- propylbromid 1. 3-(2,4,5-trichlorophenoxy)-propyl bromide

2,4,5-triklorfenol (39,5 g) (1 mol) ble oppløst i 25% NaOH oppløsning, (33 ml) og tilsatt 1,3-dibrompropan (81g, 2 mol). Blandingen ble omrørt og opphetet under mild tilbakeløpsbehandling i 2 timer. Opphetningen ble stanset, 14% NaOH oppløsning (51 ml) ble tilsatt og blandingen holdt ved 50-70°C i30minutter. Reaksjonen ble avkjølt og det nederste laget fraskilt og vasket 5 ganger med vann. Oljen ble destillert ved 1 mm for å gi: 2,4,5-trichlorophenol (39.5 g) (1 mol) was dissolved in 25% NaOH solution, (33 ml) and 1,3-dibromopropane (81 g, 2 mol) was added. The mixture was stirred and heated under gentle reflux for 2 hours. The heating was stopped, 14% NaOH solution (51 ml) was added and the mixture held at 50-70°C for 30 minutes. The reaction was cooled and the bottom layer separated and washed 5 times with water. The oil was distilled at 1 mm to give:

1. 30-60°C 25 g nQ = 1,5230 (Gjenvunnet dibrompropan + vann). 1. 30-60°C 25 g nQ = 1.5230 (Recovered dibromopropane + water).

2. 130-60°C 50 g n^<3>= 1,5838 (Det ønskede bromid stivner langsomt til smp. 34-35°C). 2. 3-( 2, 4, 5- triklorfenoksy)-- ropylbenzhydr oksamat 2. 130-60°C 50 g n^<3>= 1.5838 (The desired bromide solidifies slowly to m.p. 34-35°C). 2. 3-( 2, 4, 5- trichlorophenoxy)-- ropylbenzhydr oxamate

Benzhydroksamirsyre (22,5 g) ble oppløst i metanol (300 ml), og en oppløsning av NaOH (4,8 g) i vann (15 ml) ble tilsatt under omrøring. 3-(2,4,5-triklorfenoksy)-propylbromid (37 g) ble derpå tilsatt, blandingen opphetet under tilbakeløp i 1 time og man lot deretter blandingen stå i noen dager. Oppløsningen ble inndampet under redusert trykk, og den gjenværende gummisubstans ble oppløst i eter (noe anorganisk materiale ble fjernet ved filtrering) . Eterekstrakten stivnet ved inndampning, og det faste stoff ble omkrystallisert fra petroleter (40-60°C)/etylacetat. Benzhydroxamiric acid (22.5 g) was dissolved in methanol (300 ml) and a solution of NaOH (4.8 g) in water (15 ml) was added with stirring. 3-(2,4,5-trichlorophenoxy)-propyl bromide (37 g) was then added, the mixture was heated under reflux for 1 hour and the mixture was then allowed to stand for a few days. The solution was evaporated under reduced pressure, and the remaining gum substance was dissolved in ether (some inorganic material was removed by filtration). The ether extract solidified by evaporation, and the solid was recrystallized from petroleum ether (40-60°C)/ethyl acetate.

Man fikk en totalmengde av 30 g benzhydroksamat, smp. 73-75°C A total amount of 30 g of benzhydroxamate, m.p. 73-75°C

i to arbeidstrinn. En prøve omkrystallisert fra de samme oppløs-ningsmidler hadde smp. 76-77°C. in two work steps. A sample recrystallized from the same solvents had m.p. 76-77°C.

3. 3-( 2, 4, 5- triklorfenoksy)- propyloksyaminhydroklorid 3. 3-(2,4,5-trichlorophenoxy)-propyloxyamine hydrochloride

Benzhydroksamatet (32,7 g) fra (3) ovenfor ble behandlet med en blanding av konsentrert HCl (18,5 ml) og metanol (300 ml) The benzhydroxamate (32.7 g) from (3) above was treated with a mixture of concentrated HCl (18.5 mL) and methanol (300 mL)

og blandingen ble opphetet under tilbakeløp i 3 timer. Etter inndampning av oppløsningsmidlet ble den gjenværende olje avkjølt, and the mixture was heated under reflux for 3 hours. After evaporation of the solvent, the remaining oil was cooled,

og eter ble tilsatt.. Det faste stoff som utfeltes, ble oppsamlet, vasket med eter og tørket (21 g), smp. 134-136°C. 4. 3'-( 2, 4, 5- triklorfenoksy)- propyloksydiguanid 2 ,4,5-triklorfenoksypropyloksyaminhydroklorid (61,4 g) fra trinn 3, ble oppløst i etanol (1 liter) og dicyandiamid and ether was added. The solid which precipitated was collected, washed with ether and dried (21 g), m.p. 134-136°C. 4. 3'-(2,4,5-trichlorophenoxy)-propyloxydiguanide 2,4,5-trichlorophenoxypropyloxyamine hydrochloride (61.4 g) from step 3 was dissolved in ethanol (1 liter) and dicyandiamide

(25,2 g) ble tilsatt. Blandingen ble omrørt og tilbakeløpsbehand-let i 3 timer, hvorpå oppløsningsmidlet ble inndampet under redusert trykk. Residuet ble oppløst i vann (ca. 300 ml) og tilsatt (25.2 g) was added. The mixture was stirred and refluxed for 3 hours, after which the solvent was evaporated under reduced pressure. The residue was dissolved in water (approx. 300 ml) and added

sterk vandig NaOH-oppløsning, en olje skilte seg ut som straks stivnet. Det faste stoff ble oppsamlet ved filtrering, vasket med vann og bensin og tørket ved 60°C slik at man fikk et lyserødt, strong aqueous NaOH solution, an oil separated which immediately solidified. The solid was collected by filtration, washed with water and gasoline and dried at 60°C to give a light red,

fast stoff (49,5 g), smp. 107-110°C. solid (49.5 g), m.p. 107-110°C.

En liten prøve ble krystallisert fra etylacetat og hadde smp. 125-126°C (analytisk rent) . A small sample was crystallized from ethyl acetate and had m.p. 125-126°C (analytically pure) .

5. 4,6-diamino-l,2-dihydro-2,2-dimetyl-l-[31-(2,4 ,5-triklorfenoksy)- propyloksy]- 1, 3, 5- triazinhydrobromid Diguanidet (45 g) fra trinn 4 ble oppløst i metanol 5. 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-[31-(2,4,5-trichlorophenoxy)-propyloxy]-1,3,5-triazine hydrobromide Diguanide (45 g) from step 4 was dissolved in methanol

(200 ml), og konsentrert hydroklorid (25 ml) og aceton (300 ml) (200 ml), and concentrated hydrochloride (25 ml) and acetone (300 ml)

ble tilsatt. Reaksjonen lot man pågå i 3 døgn ved romtempera- was added. The reaction was allowed to proceed for 3 days at room temperature

tur. Oppløsningsmidlet ble inndampet under redusert trykk og den gjenværende gummisubstans utgnidd med aceton for å gi det ønskede triazin (23,5 g), smp. 187-189°C pluss en liten, annen mengde (vekt ikke bestemt), smp. 181-186°C. Det første materiale gav en riktig analyse uten ytterligere omkrystallisering. trip. The solvent was evaporated under reduced pressure and the remaining gum triturated with acetone to give the desired triazine (23.5 g), m.p. 187-189°C plus a small, other amount (weight not determined), m.p. 181-186°C. The first material gave a correct analysis without further recrystallization.

Eksempel 8 Example 8

4,6-diamino-l,2-dihydro-2,2-dimetyl-1-[2 -(naftoksy)-etyloksy]-1,3,5-triazinhydroklorid 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-[2-(naphthoxy)-ethyloxy]-1,3,5-triazine hydrochloride

1. 2-( 2- naftoksy)- etylbenzhydroksamat 1. 2-(2-Naphthoxy)-ethylbenzhydroxamate

2-(2-naftoksy)-etylbromid, smp. 90-91°C_ (se eksempel 3) 2-(2-naphthoxy)-ethyl bromide, m.p. 90-91°C_ (see example 3)

(21,4 g) ble oppløst i metanol (50 ml) og langsomt tilsatt til en oppløsning av natriumbenzhydroksamat (15,05 g) i metanol (100 ml). Blandingen ble derpå tilbakeløpsbehandlet kraftig i 6 timer. Uorganisk fast stoff ble fjernet ved filtrering, og oppløsnings-midlet inndampet under redusert trykk. Den gjenværende, gummiaktige substans ble oppløst i etylacetat og vasket flere ganger med vann. Oppløsningsmiddelsjiktet ble tørket med magnesiumsulfat, filtrert og inndampet. Den gjenværende gummisubstans ble utgnidd med petroleumeter (kp. 60-80°C), og det ønskede benzhydroksamat krystalliserte ut (15,6 g), smp. 90-93°C. En liten mengde ble omkrystallisert fra etylacetat for å gi enanalytisk ren prøve, smp. 100-101°C. (21.4 g) was dissolved in methanol (50 mL) and slowly added to a solution of sodium benzhydroxamate (15.05 g) in methanol (100 mL). The mixture was then vigorously refluxed for 6 hours. Inorganic solids were removed by filtration, and the solvent was evaporated under reduced pressure. The remaining gummy substance was dissolved in ethyl acetate and washed several times with water. The solvent layer was dried with magnesium sulfate, filtered and evaporated. The remaining gum substance was rubbed with petroleum ether (b.p. 60-80°C), and the desired benzhydroxamate crystallized out (15.6 g), m.p. 90-93°C. A small amount was recrystallized from ethyl acetate to give an analytically pure sample, m.p. 100-101°C.

2. 2-( 2- naftoksy)- etyloksyaminhydroklorid 2-(2-naftoksy)-etylbenzhydroksamat (7,5 g) ble oppløst 2. 2-(2-naphthoxy)-ethyloxyamine hydrochloride 2-(2-naphthoxy)-ethylbenzhydroxamate (7.5 g) was dissolved

i metanol (30 ml) og konsentrert saltsyre (10 ml) tilsatt. Blan-dingen ble behandlet under tilbakeløp i 3 timer. Etter 2 timer begynte det faste stoff å skille seg ut„ Reaksjonen ble avkjølt in methanol (30 ml) and concentrated hydrochloric acid (10 ml) added. The mixture was treated under reflux for 3 hours. After 2 hours, the solid began to separate out. The reaction was cooled

og filtrert slik at man fikk 4,6 g av det ønskede oksyamin, smp. 192-194°Co En liten mengde ble omkrystallisert fra metanol for å gi en analytisk ren prøve, smp. 195°C. and filtered so that 4.6 g of the desired oxyamine was obtained, m.p. 192-194°Co A small amount was recrystallized from methanol to give an analytically pure sample, m.p. 195°C.

Inndampning av modeclutene og behandling av residuet Evaporation of the modeclutes and treatment of the residue

med eter gav ytterligere 0,9 g av et noe mindre rent produkt. with ether gave a further 0.9 g of a somewhat less pure product.

3. 2-( 2- naftoksy)- etyloksydiguanid 3. 2-(2-naphthoxy)-ethyloxydiguanide

2-(2-naftoksy)-etyloksyaminhydroklorid (7,8 g) ble opp-løst i etanol (100 ml), og dicyandiamid (4,1 g) ble tilsatt. Blan-dingen ble derpå tilbakeløpsbehandlet i 3 timer, filtrert og inndampet under redusert trykk. Den gjenværende gummisubstans ble oppløst i vann ved oppvarmning og oppløsningen gjort alkalisk med sterk NaOH-oppløsning. En olje skilte seg ut, som krystalliserte langsomt. Etter vaskning av det faste stoff med vann og petroleum-etér (kp. 60-80°C), hadde det faste stoff (8,1 g) smp. 135-137°C. En prøve, omkrystallisert fra etylacetat, hadde smp„ 139-140°C og gav riktig analyse for det ønskede diguanid. 2-(2-Naphthoxy)-ethyloxyamine hydrochloride (7.8 g) was dissolved in ethanol (100 ml) and dicyandiamide (4.1 g) was added. The mixture was then refluxed for 3 hours, filtered and evaporated under reduced pressure. The remaining rubber substance was dissolved in water by heating and the solution made alkaline with a strong NaOH solution. An oil separated out, which crystallized slowly. After washing the solid with water and petroleum ether (bp. 60-80°C), the solid (8.1 g) had m.p. 135-137°C. A sample, recrystallized from ethyl acetate, had mp 139-140°C and gave the correct analysis for the desired diguanide.

4. 4,6-diamino-l,2-dihydro-2,2-dimetyl-l-[2-(2-naftoksy)-etyloksy]- 1, 3, 5- triazinhydroklorid 4. 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-[2-(2-naphthoxy)-ethyloxy]- 1, 3, 5- triazine hydrochloride

2-(2-naftoksy)-etyloksydiguanid (8,0 g) ble oppløst i metanol (50 ml), og konsentrert saltsyre (8 ml) og aceton (75 ml) ble tilsatt. Blandingen lot man henstå i 3 døgn ved romtemperatur. Oppløsningsmidlet ble inndampet under redusert trykk, og residuet utgnidd med aceton, slik at man fikk det ønskede triazin (5,4 g) , smp. 190-193°C. Omkrystallisering fra etanol gav det analytisk rene triazin, smp. 195-196°C (jfr. eksempel 3). 2-(2-Naphthoxy)-ethyloxydiguanide (8.0 g) was dissolved in methanol (50 mL), and concentrated hydrochloric acid (8 mL) and acetone (75 mL) were added. The mixture was allowed to stand for 3 days at room temperature. The solvent was evaporated under reduced pressure, and the residue triturated with acetone, so that the desired triazine (5.4 g) was obtained, m.p. 190-193°C. Recrystallization from ethanol gave the analytically pure triazine, m.p. 195-196°C (cf. example 3).

Eksempel 9 Example 9

Fremstilling av 4,6-diamino-l,2-dihydro-2,2-dimetyl-1-[3'-(cykloheptyloksy)-propyloksy]-1,3,5-triazinhydroklorid 1. En blanding av cykloheptanon (43,3 g), benzen (250 ml) Preparation of 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-[3'-(cycloheptyloxy)-propyloxy]-1,3,5-triazine hydrochloride 1. A mixture of cycloheptanone (43.3 g), benzene (250 ml)

og p-toluensulfonsyre (0,5 g) ble tilbakeløpsbehandlet i noen få minutter og derpå destillert inntil 50 ml av oppløsningsmid-del -vannblandingen ble oppsamlet. 1,3-propandiol (29,4 g) ble tilsatt til reaksjonen og blandingen tilbakeløpsbehandlet i 5 timer. Vannet som ble dannet ved reaksjonen, ble oppsamlet i en Dean & stark-apparatur inntil volumet var 7 ml. Oppløsnings-midlet ble derpå inndampet og residuet destillert ved 12 mm trykk. Fraksjonen som koker ved 127-132°C og veiet 23,5., g, n^<3> 1,4791, var det ønskede produkt, 1,5-dioksaspiro-(5,6)-dodekan. and p-toluenesulfonic acid (0.5 g) was refluxed for a few minutes and then distilled until 50 mL of the solvent-water mixture was collected. 1,3-propanediol (29.4 g) was added to the reaction and the mixture refluxed for 5 hours. The water formed by the reaction was collected in a Dean & stark apparatus until the volume was 7 ml. The solvent was then evaporated and the residue distilled at 12 mm pressure. The fraction boiling at 127-132°C and weighing 23.5, g, n^<3> 1.4791, was the desired product, 1,5-dioxaspiro-(5,6)-dodecane.

2. Vannfritt aluminiumklorid (14 g) ble oppløst i tørr eter (100 ml) og filtrert ned i en 1 liters tre-halset kolbe ut-styrt med en rører, kondensator og dryppetrakt. Litiumaluminium-hydrid (1,5 g) oppløst i tørr eter (100 ml) ble tilsatt dråpevis ved romtemperatur og omrørt i 30 minutter. 1,5-dioksaspiro-(5,6)-dodekan (7,3 g), fremstilt som angitt ovenfor og oppløst i eter, ble tilsatt ved en slik hastighet at reaksjonsproduktet kokte svakt under tilbakeløp. Reaksjonen ble fortsatt ved romtemperatur under omrøring i ytterligere 2 timer. Reaksjonsproduktet ble avkjølt sterkt, og det ble tilsatt 10% vandig I^SO^^ langsomt inntil alt det utfelte faste stoff var oppløst. Eterlaget ble derpå fraskilt og vasket med vann inntil nøytralt. Oppløsningsmiddellaget ble tørket over MgSO^, filtrert og inndampet. 3-cykloheptyloksypropanol-residuet var-en farveløs lettflytende olje, som gav bare én topp på G.L.C. (gasskromatografi) og én flekk på T.L.C. (tynnsjiktkromatografi). Det ble derpå bromert uten ytterligere rensning. 30 3-cykloheptyloksypropanolen fra den siste reaksjon ble oppløst i benzen og avkjølt til -10°C. PBr3 (3 ml) i benzen (15 ml) ble tilsatt dråpevis under omrøring. Temperaturen fikk derpå stige til ca. 20°C og derpå til 50°C i 1 time. Blandingen ble av-kjølt og vasket med vann, NaHCO^ og vann. Oppløsningsmiddellaget ble tørket med MgSO^ og oppløsningsmidlet fjernet for å gi 3-cyklo-heptyloksypropylbromid, som en farveløs olje, homogen ved T.L.C. og G.L.C. Utbytte(5,3 g). 4. Det foran fremstilte bromid ble bragt til reaksjon med aA,6-diamino-l,2-dihydro-2,2-dimetyl-1-hydroksy-l,3,5-triazinba- sen oppnådd fra 3,9 g av hydrokloridet i DMF ved -10°C. Etter opparbeidelse på vanlig måte fikk man et hvitt, fast stoff (7,5 g) smp. 110°C. Dette faste stoff ble vasket med vann og omkrystallisert fra EtOH for å gi rent 4,6-diamino-l,2-dihydro-2,2-dimetyl-1-[3'-(cykloheptyloksy)-propyloksy]-1,3,5-triazinhydroklorid, smp. 133-135°C (5,6 g). 2. Anhydrous aluminum chloride (14 g) was dissolved in dry ether (100 ml) and filtered into a 1 liter three-necked flask equipped with a stirrer, condenser and dropping funnel. Lithium aluminum hydride (1.5 g) dissolved in dry ether (100 ml) was added dropwise at room temperature and stirred for 30 minutes. 1,5-Dioxaspiro-(5,6)-dodecane (7.3 g), prepared as above and dissolved in ether, was added at such a rate that the reaction product boiled gently under reflux. The reaction was continued at room temperature with stirring for a further 2 hours. The reaction product was cooled strongly, and 10% aqueous I^SO^^ was added slowly until all the precipitated solid had dissolved. The ether layer was then separated and washed with water until neutral. The solvent layer was dried over MgSO 4 , filtered and evaporated. The 3-cycloheptyloxypropanol residue was a colorless light-flowing oil, which gave only one peak on the G.L.C. (gas chromatography) and one spot on T.L.C. (thin layer chromatography). It was then brominated without further purification. The 3-cycloheptyloxypropanol from the last reaction was dissolved in benzene and cooled to -10°C. PBr 3 (3 mL) in benzene (15 mL) was added dropwise with stirring. The temperature was then allowed to rise to approx. 20°C and then to 50°C for 1 hour. The mixture was cooled and washed with water, NaHCO 3 and water. The solvent layer was dried with MgSO 4 and the solvent removed to give 3-cyclo-heptyloxypropyl bromide as a colorless oil, homogeneous by T.L.C. and G.L.C. Yield (5.3 g). 4. The bromide prepared above was reacted with αA,6-diamino-1,2-dihydro-2,2-dimethyl-1-hydroxy-1,3,5-triazineba- then obtained from 3.9 g of the hydrochloride in DMF at -10°C. After working up in the usual way, a white solid (7.5 g) was obtained m.p. 110°C. This solid was washed with water and recrystallized from EtOH to give pure 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-[3'-(cycloheptyloxy)-propyloxy]-1,3, 5-triazine hydrochloride, m.p. 133-135°C (5.6 g).

Eksempel 10 Example 10

4 ,6-diamino-l ,2-dihydro-2,2-dimetyl-l-[3'-(4-cykloheksylfenoksy)-propyloksy]-1,3,5-triazinhydrobromid 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-[3'-(4-cyclohexylphenoxy)-propyloxy]-1,3,5-triazine hydrobromide

4-cykloheksylfenoksypropylbromid ble fremstilt ved en lignende fremgangsmåte som beskrevet i eksempel 1 fra 4-cykloheksyl fenol og dibrompropan i nærvær av NaOH. 4-cyclohexylphenoxypropyl bromide was prepared by a similar method as described in example 1 from 4-cyclohexyl phenol and dibromopropane in the presence of NaOH.

Bromidet, kp. 150-160°c/2 mm, - 1,5468, stivnet langsomt og gav et voksaktig hvitt, fast stoff, smp. 45 C. The bromide, bp. 150-160°c/2 mm, - 1.5468, solidified slowly to give a waxy white solid, m.p. 45 C.

Den frie hydroksytriazinbase ble fremstilt fra 4,6-diamino-1,2-dihydro-2,2-dimetyl-1-hydroksy-1,3,5-triazinhydroklorid (3,87 g) ved reaksjon med en metanolisk oppløsning av KOH (1,4 g). Residuet ble etter fordampning av oppløsningsmidlet suspendert i formdimetylamid og omrørt ved romtemperatur i 2 døgn med 4-cykloheksyl fenoksypropylbromid (5,94 g). Reaksjonsblandingen ble filtrert og inndampet under redusert trykk. Residuet ble utgnidd med aceton, det faste stoff ble oppsamlet ved filtrering og vasket med vann og tørket. Produktet var det ønskede triazin, smp. 204-207°C (5,48 g), 4,6-diamino-l,2-dihydro-2,2-dimetyl-l-[3'-(4-cyklohek-sylfenoksy)-propyloksy]-1,3,5-triazinhydrobromid. The hydroxytriazine free base was prepared from 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-hydroxy-1,3,5-triazine hydrochloride (3.87 g) by reaction with a methanolic solution of KOH ( 1.4g). After evaporation of the solvent, the residue was suspended in formdimethylamide and stirred at room temperature for 2 days with 4-cyclohexyl phenoxypropyl bromide (5.94 g). The reaction mixture was filtered and evaporated under reduced pressure. The residue was triturated with acetone, the solid was collected by filtration and washed with water and dried. The product was the desired triazine, m.p. 204-207°C (5.48 g), 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-[3'-(4-cyclohexylphenoxy)-propyloxy]-1,3 ,5-triazine hydrobromide.

Eksempel 11 Example 11

4,6-diamino-l,2-dihydro-2,2-dimetyl-1-[3'-(4-klor-2-cykloheksylfenoksy)-propyloksy]-1,3,5-triazinhydrobromid 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-[3'-(4-chloro-2-cyclohexylphenoxy)-propyloxy]-1,3,5-triazine hydrobromide

4 t-klor-2-cykloheksylfenoksypropylbromid ble fremstilt 4 t -Chloro-2-cyclohexylphenoxypropyl bromide was prepared

på lignende måte som beskrevet i eksempel 1. Det hadde kp. 165-175°C/1,5 mm, n^° 1,5530. in a similar way as described in example 1. It had kp. 165-175°C/1.5 mm, n^° 1.5530.

Bromidet (6,63 g) ble bragt til reaksjon med den frie hydroksytriazinbase som man fikk fra hydroksytriazinhydrokloridet (3,87 g) suspendert i formdimetylamid slik som beskrevet i eksempel 10. Etter omrøring i 24 timer ved romtemperatur ble reaksjonsblandingen filtrert og inndampet til tørrhet. The bromide (6.63 g) was reacted with the free hydroxytriazine base obtained from the hydroxytriazine hydrochloride (3.87 g) suspended in formdimethylamide as described in example 10. After stirring for 24 hours at room temperature, the reaction mixture was filtered and evaporated to dryness .

Residuet ble omrørt med aceton, filtrert og det faste stoff vasket med vann og tørket. Det rå triazin hadde smp. 220-222°C , og ble omkrystallisert fra etanol for å gi det rene stoff, smp. 225°C (5,35 g) , 4,6-diamino-l,2-dihydro-2,2-dimetyl-l-[3'-(4-klor-2-cykloheksylfenoksy)propyloksy]-1,3,5-triazinhydrobromid. The residue was stirred with acetone, filtered and the solid washed with water and dried. The crude triazine had m.p. 220-222°C, and was recrystallized from ethanol to give the pure substance, m.p. 225°C (5.35 g), 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-[3'-(4-chloro-2-cyclohexylphenoxy)propyloxy]-1,3, 5-triazine hydrobromide.

Eksempel 12 Example 12

Di-acetylderivat av 4,6-diamino-l,2-dihydro-2,2-dimetyl-l-[3'-(2,4,5-triklorfenoksy)propyloksy]-1,3,5-triazin Di-acetyl derivative of 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-[3'-(2,4,5-trichlorophenoxy)propyloxy]-1,3,5-triazine

5 g av den frie base av tittel-substansen ble opphetet med 25 ml omdestillert eddiksyreanhydrid på et dampbad i 5 minutter og reaksjonsblandingen inndampet til tørrhet under redusert trykk, etterfulgt av ekstraksjon med etylacetat, vaskning med vann, krystallisering og omkrystallisering fra etanol. Di-acetylderi-våtet fikk man som små hvite nåler, smp. 171-172°C. 5 g of the free base of the title substance was heated with 25 ml of redistilled acetic anhydride on a steam bath for 5 minutes and the reaction mixture evaporated to dryness under reduced pressure, followed by extraction with ethyl acetate, washing with water, crystallization and recrystallization from ethanol. The di-acetyl deriwet was obtained as small white needles, m.p. 171-172°C.

Forbindelsene som er anført i den følgende tabell ble fremstilt ved fremgangsmåten lik den som er beskrevet i eksempel 1. Ved bruk av nomenklaturen for formel I var R2~(CH2^n~°^ R3 °^ R. var begge metyl unntatt hvor det er anført noe annet. The compounds listed in the following table were prepared by the procedure similar to that described in Example 1. Using the nomenclature of formula I, R2~(CH2^n~°^ R3 °^ R. were both methyl except where stated otherwise.

De følgende forbindelser ble cgså fremstilt ved en fremgangsmåte lik den som er beskrevet i eksempel 1. The following compounds were also prepared by a method similar to that described in example 1.

Eksempel 108 Example 108

4,6-diamino-l,2-dihydro-2,2-dimetyl-1-[4-(2,4,5-triklorfenoksy)-but-2-enyloksyj-1,3,5-triazinhydrobromid 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-[4-(2,4,5-trichlorophenoxy)-but-2-enyloxy-1,3,5-triazine hydrobromide

Eksempel 109 4,6-diamino-l,2-dihydro-2,2-dimetyl-l-[4-(2,4,5-triklorfenoksy)-2,3-diklorbutyloksy]-1,3,5-triazinhydrobromid Eksempel 110 4,6-diamino-l,2-dihydro-2,2-dimetyl-l-[2-(p-klorfenoksy)-2,2-di-metyletyloksy]-1,3,5-triazinhydrobromid Example 109 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-[4-(2,4,5-trichlorophenoxy)-2,3-dichlorobutyloxy]-1,3,5-triazine hydrobromide Example 110 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-[2-(p-chlorophenoxy)-2,2-dimethylethyloxy]-1,3,5-triazine hydrobromide

Eksempel 111 Example 111

En blanding av 2 g 4,6-diamino-l,2-dihydro-2,2-dimetyl-1-(2,4-diklbrbenzyloksypropyloksy)-1,3,5-triazinbase og 10 ml omdestillert eddiksyreanhydrid ble opphetet på dampbad i 5 minutter og inndampet ved redusert trykk. Omkrystallisering av det gjenværende faste stoff fra etylacetat-petroleumeter gav 1,7 g produkt, smp. 154-156°C. Ytterligere omkrystallisering gav diacetylderiva-tet av triazinet, smp. 154-155°C. A mixture of 2 g of 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-(2,4-dichlorobenzyloxypropyloxy)-1,3,5-triazine base and 10 ml of redistilled acetic anhydride was heated on a steam bath in 5 minutes and evaporated at reduced pressure. Recrystallization of the remaining solid from ethyl acetate-petroleum ether gave 1.7 g of product, m.p. 154-156°C. Further recrystallization gave the diacetyl derivative of the triazine, m.p. 154-155°C.

Eksempel 112 Example 112

En blanding av den foregående triazinbase etter eksempel 111, 10 ml omdestillert eddiksyreanhydrid og 5 ml trietylamin ble omrørt ved romtemperatur i 72 timer, helt på is, omrørt i 30 minutter og ekstrahert med etylacetat. Etter vaskning med vann ble opp-løsningen tørket, behandlet med benkull, konsentrert og tilsatt petroleumeter for å gi 0,7 g av tetraacetylderivatet. Smeltepunk-tet var uforandret ved ytterligere krystallisering, 124-125°C. A mixture of the preceding triazine base according to Example 111, 10 ml of redistilled acetic anhydride and 5 ml of triethylamine was stirred at room temperature for 72 hours, poured onto ice, stirred for 30 minutes and extracted with ethyl acetate. After washing with water, the solution was dried, treated with bone charcoal, concentrated and added with petroleum ether to give 0.7 g of the tetraacetyl derivative. The melting point was unchanged by further crystallization, 124-125°C.

Eksempel 113 Example 113

Ved en lignende fremgangsmåte som den som er anført i eksempel 112, ble 4,6-diamino-l,2-dihydro-2,2-dimetyl-l-[3'-(2,4,5-triklorfenoksy)propyloksy]-1,3,5-triazinbasen omdannet til dens tetra-acetylderivat, som etter omkrystallisering fra etanol-petroleumeter hadde et smp. av 117-118°C. By a similar procedure to that set forth in Example 112, 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-[3'-(2,4,5-trichlorophenoxy)propyloxy]- The 1,3,5-triazine base converted to its tetra-acetyl derivative, which after recrystallization from ethanol-petroleum ether had a m.p. of 117-118°C.

Claims

Analogous process for the preparation of an anti-malarial active compound of the formula (I):

where is a cyclohexyl, phenyl or naphthyl group optionally substituted with 1, 2 or 3 halogen atoms, 1 or 2 nitro or methyl groups, a trifluoromethyl, benzyl, methoxy, ethyl or propyl group or an unsubstituted tetrahydronaphthyl or butyl -, propenyl or 2,3-dichloropropyl group, R2 is a saturated, divalent, unbranched aliphatic group with 1-10 carbon atoms, a -CH=CH-CH2- or -CHCl-CHCl-CH2 group, R^ and R^ are both methyl groups or form together with the carbon atom which they are attached to, a cyclohexyl- or methyl-substituted cyclohexyl ring, X is an oxygen or sulfur atom or a ure group, where R,, is K or a methyl or ethyl group, and salts and acetyl derivatives thereof, characterized in that in the presence of an acid a substituted diguanide of the general formula is reacted: where Rg is R1XR20-, whereby the compound of formula (I) is prepared directly, or Rg is such a group that the resulting triazine of formula (III) when subjected to hydrogenation, is converted to a hydroxytriazine of the formula which is then alkylated by reaction with a compound R^XR2Z, where Z is a group that is easily replaced by nucleophilic displacement, so that one obtains the compound of formula (I), and optionally formation of a salt by reaction with at least one molar equivalent of an acid, and possibly forming an acetyl derivative by reaction with an acetylating agent