NO160140B - PROCEDURE FOR THE PREPARATION OF 5,11-DIHYDRO-6H-PYRIDO (2,3-B) (1,4) BENZODIAZEPIN-6-ON DERIVATIVES. - Google Patents

PROCEDURE FOR THE PREPARATION OF 5,11-DIHYDRO-6H-PYRIDO (2,3-B) (1,4) BENZODIAZEPIN-6-ON DERIVATIVES. Download PDF

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Publication number
NO160140B
NO160140B NO822182A NO822182A NO160140B NO 160140 B NO160140 B NO 160140B NO 822182 A NO822182 A NO 822182A NO 822182 A NO822182 A NO 822182A NO 160140 B NO160140 B NO 160140B
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formula
general formula
pyrido
dihydro
preparation
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NO822182A
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NO160140C (en
NO822182L (en
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Gerhard Nowak
Guenther Schmidt
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Thomae Gmbh Dr K
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pyridine Compounds (AREA)

Description

Denne oppfinnelse angår en ny fremgangsmåte for fremstilling av 5,ll-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-on-derivater med den generelle formel This invention relates to a new process for the preparation of 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine-6-one derivatives with the general formula

hvor R betyr et hydrogen- eller halogenatom eller en metylgruppe. Disse forbindelser representerer verdifulle utgangsmaterialer for fremstilling av legemidler, f.eks. for fremstilling av pirenzepin (5,11-dihydro-ll-[(4-metyl-l-piperazinyl)-acetyl]-6H-pyrido[2,3-b][1, 4]benzodiazepin-6-on-dihydroklorid), where R means a hydrogen or halogen atom or a methyl group. These compounds represent valuable starting materials for the manufacture of pharmaceuticals, e.g. for the preparation of pirenzepine (5,11-dihydro-11-[(4-methyl-1-piperazinyl)-acetyl]-6H-pyrido[2,3-b][1, 4]benzodiazepine-6-one dihydrochloride) ,

et stoff med en sterk sår- og mavesaftsekresjonshemmende virkning. a substance with a strong wound and gastric juice secretion-inhibiting effect.

Fremgangsmåten ifølge oppfinnelsen karakteriseres ved The method according to the invention is characterized by

at et 2-halogen-3-aminopyridin med den generelle formel that a 2-halo-3-aminopyridine of the general formula

hvor Hal betyr et halogenatom, fortrinnsvis et kloratom, omsettes med en antranilsyreester med den generelle formel hvor R er som ovenfor angitt, og R^ betyr en alkylgruppe med 1 til 3 karbonatomer, fortrinnsvis en metylgruppe, i nærvær av et basisk kondensasjonsmiddel, hvorved det først dannes en forbindelse med den generelle formel where Hal means a halogen atom, preferably a chlorine atom, is reacted with an anthranilic acid ester of the general formula where R is as stated above, and R^ means an alkyl group with 1 to 3 carbon atoms, preferably a methyl group, in the presence of a basic condensing agent, whereby the first a compound is formed with the general formula

hvor R og Hal har de angitte betydninger, hvorefter denne forbindelse ringsluttes i nøytralt eller surt miljø, fortrinnsvis i nærvær av svovelsyre, ved temperaturer fra 100 where R and Hal have the indicated meanings, after which this compound is ring-closed in a neutral or acidic environment, preferably in the presence of sulfuric acid, at temperatures from 100

til 200°C. to 200°C.

Den nye fremgangsmåten utføres som en ett-kars fremgangsmåte, idet den dannede forbindelse med formel IV ikke isoleres, men ringslutningen utføres i det samme reaksjonskar efter sur-gjøring av reaksjonsblandingen til en pH på 7 eller lavere. The new process is carried out as a one-vessel process, the compound of formula IV being formed is not isolated, but the ring closure is carried out in the same reaction vessel after acidifying the reaction mixture to a pH of 7 or lower.

Omsetningen av en forbindelse med formel II med en antranilsyreester med formel III skjer i nærvær av et organisk oppløsningsmiddel og, som ovenfor nevnt, i nærvær av et basisk kondensasjonsmiddel ved temperaturer mellom 10 og 120°C. The reaction of a compound of formula II with an anthranilic acid ester of formula III takes place in the presence of an organic solvent and, as mentioned above, in the presence of a basic condensation agent at temperatures between 10 and 120°C.

Som basiske kondensasjonsmidler kan anvendes slike forbindelser som tetrabutylammoniumhydroksyd, natrium- eller kaliummetylat, natrium- eller kaliumisopropylat, natrium- eller kalium-t-butylat, natriumhydrid, litium-, natrium- eller kaliumamid eller natriumhydroksyd. Som oppløsninsmidler anvendes f.eks. etanol, toluen, xylen, dimetylsulfoksyd, sulfolan eller triklorbenzen, men man kan også anvende overskudd av antranil-syrealkylester som oppløsningsmiddel. As basic condensation agents, such compounds as tetrabutylammonium hydroxide, sodium or potassium methylate, sodium or potassium isopropylate, sodium or potassium t-butylate, sodium hydride, lithium, sodium or potassium amide or sodium hydroxide can be used. Solvents are used, e.g. ethanol, toluene, xylene, dimethyl sulfoxide, sulfolane or trichlorobenzene, but an excess of anthranilic acid alkyl ester can also be used as a solvent.

Ringslutningen av den dannede forbindelse med formel IV skjer som en ett-kars-reaksjon, ved temperaturer, fra 100 til 200°C i et oppløsningsmiddel, fortrinnsvis triklorbenzen og sulfolan, ved nøytral eller sur pH. Ved utførelse som en ett-kars reaksjon surgjøres den alkalisk reagerende reaksjonsblanding som inneholder forbindelsen med formel IV, fortrinnsvis med svovelsyre, hvorefter ringslutningen gjennomføres ved opp-varmning til de nevnte temperaturer. The cyclization of the formed compound of formula IV takes place as a one-pot reaction, at temperatures from 100 to 200°C in a solvent, preferably trichlorobenzene and sulfolane, at neutral or acidic pH. When carried out as a one-pot reaction, the alkaline-reacting reaction mixture containing the compound of formula IV is acidified, preferably with sulfuric acid, after which the ring closure is carried out by heating to the aforementioned temperatures.

Forbindelsene med den generelle formel II, den generelle formel III og det basiske kondensasjonsmiddel anvendes i molare mengder, eller det anvendes et overskudd av forbindelsen med formel III og/eller av det basiske kondensasjonsmiddel. Utbyttene av sluttproduktene med formel I utgjør opptil 87%. The compounds of the general formula II, the general formula III and the basic condensing agent are used in molar amounts, or an excess of the compound of the formula III and/or of the basic condensing agent is used. The yields of the final products with formula I are up to 87%.

En fremgangsmåte for fremstilling av forbindelsene med formel I er kjent fra tysk patent 1.179.943. Denne kjente fremgangsmåte er en 3-trinns fremgangsmåte, hvor først et 2-halogen-3-amino-pyridin med formel II omsettes med et reaktivt nitrobenzoesyrederivat, fortrinnsvis dets syre-halogenid, den oppnådde nitroforbindelse reduseres, og den således oppnådde forbindelse med formel IV ringsluttes i smelte eller i nærvær av et høytkokende oppløsningsmiddel A method for preparing the compounds of formula I is known from German patent 1,179,943. This known process is a 3-step process, where first a 2-halo-3-amino-pyridine of formula II is reacted with a reactive nitrobenzoic acid derivative, preferably its acid halide, the obtained nitro compound is reduced, and the thus obtained compound of formula IV cyclized in melt or in the presence of a high-boiling solvent

så som paraffin eller dekalin, eventuelt i nærvær av en basisk katalysator eller av kobberpulver. Bortsett fra at utbyttene ved denne fremgangsmåte er lavere, anvendes det der også et vanskelig håndterbart og farlig 2-nitro-benzoyl-klorid, mens antranilsyreesteren er et særlig billig utgangs-materiale. Dessuten er det tale om en 3-trinns fremgangsmåte, mens ved fremgangsmåten ifølge oppfinnelsen kan forbindelsene oppnås ved en ett-kars reaksjon. Også ringslutningen kan utføres i nøytralt eller surt miljø i nærvær av de angitte oppløsningsmidler, vesentlig bedre og med høyere utbytter enn ved den kjente fremgangsmåte, hvor man normalt arbeider i en smelte. Utbyttene ved ringslutningen ligger ved den kjente fremgangsmåte under utbyttene ved fremgangsmåten ifølge oppfinnelsen, hvor man oppnår et samlet utbytte på 87%. such as paraffin or decalin, optionally in the presence of a basic catalyst or of copper powder. Apart from the fact that the yields in this method are lower, a difficult-to-handle and dangerous 2-nitro-benzoyl chloride is also used, while the anthranilic acid ester is a particularly cheap starting material. Moreover, it is a 3-stage process, whereas in the process according to the invention, the compounds can be obtained by a one-pot reaction. The ring closure can also be carried out in a neutral or acidic environment in the presence of the indicated solvents, significantly better and with higher yields than in the known method, where one normally works in a melt. The yields of the ring closure in the known method are below the yields of the method according to the invention, where a total yield of 87% is achieved.

Det er dessuten overraskende at ved omsetningen av forbindelser med den generelle formel II med forbindelser med den generelle formel III i nærvær av sterke baser oppnås de ønskede forbindelser med formel IV, eftersom det er kjent at pyridiner med halogenatomer i 2- eller 4-stilling, særlig i alkalisk miljø, meget raskt omdannes til de tilsvarende pyridinoler. Det er her f.eks. tilstrekkelig med en alkoholisk natriumhydroksydoppløsning eller en vandig kaliumhydroksyd-oppløsning og temperaturer på 90°C. Slike reaksjoner er også kjent fra litteraturen, f.eks. beskrev 0. von Schickh et al. i Ber. Dtsch. Chem. Ges. 1936, Nr. 12, s. 2594, 2600 og 2602 omsetningen av 2-klor-3-amino-pyridin med en natriummetylat-oppløsning til 2-metoksy-3-amino-pyridin. Av de ovenfor angitte grunner var det derfor ved foreliggende fremgangsmåte særlig overraskende ikke bare at halogenatomet i forbindelsen med formel II ikke utskiftes med den anioniske rest i det basiske kondensasjonsmiddel, men også at forbindelsene med formel IV og I oppnås i et meget høyt utbytte. Overføringen av en forbindelse med den generelle formel I til det innlednings-vis nevnte pirenzepin eller pirenzepin-lignende forbindelser er beskrevet i tysk patent 1.795.183. It is also surprising that by reacting compounds of the general formula II with compounds of the general formula III in the presence of strong bases, the desired compounds of the formula IV are obtained, since it is known that pyridines with halogen atoms in the 2- or 4-position, especially in an alkaline environment, very quickly converted to the corresponding pyridinols. It is here e.g. sufficient with an alcoholic sodium hydroxide solution or an aqueous potassium hydroxide solution and temperatures of 90°C. Such reactions are also known from the literature, e.g. described 0. von Schickh et al. in Ber. Dtsch. Chem. Ges. 1936, No. 12, pp. 2594, 2600 and 2602 the reaction of 2-chloro-3-amino-pyridine with a sodium methylate solution to 2-methoxy-3-amino-pyridine. For the reasons stated above, it was therefore particularly surprising in the present method not only that the halogen atom in the compound of formula II is not replaced by the anionic residue in the basic condensing agent, but also that the compounds of formula IV and I are obtained in a very high yield. The transfer of a compound of the general formula I to the initially mentioned pirenzepine or pirenzepine-like compounds is described in German patent 1,795,183.

Europeisk patentansøkning, publikasjon 22 174, beskriver en fremgangsmåte for fremstilling av pirenzepin via 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-on. Dette sistnevnte mellomprodukt skal angivelig kunne dannes ved omsetning av antranilsyremetylester med 3-aminopyridin i 70 %-ig utbytte. European patent application, publication 22 174, describes a process for the preparation of pirenzepine via 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine-6-one. This latter intermediate product can allegedly be formed by reaction of anthranilic acid methyl ester with 3-aminopyridine in 70% yield.

Søkeren har i sitt laboratorium gjentatt denne syntese. The applicant has repeated this synthesis in his laboratory.

Det ble da funnet at reaksjonen bare førte til 3-[2'-amino-benzoyl)aminopyridin-dihydroklorid og ikke 5,ll-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-on. It was then found that the reaction only led to 3-[2'-amino-benzoyl)aminopyridine dihydrochloride and not 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine-6-one .

De opplysninger som finnes i nevnte europeiske ansøkning, stemmer således ikke overens med virkeligheten, eftersom det uten halogenatomet i 2-stilling i pyridinringen ikke finner sted noen ringslutning. The information contained in the aforementioned European application thus does not correspond to reality, since without the halogen atom in the 2-position in the pyridine ring no ring closure takes place.

Det nedenstående eksempel skal illustrere oppfinnelsen ytterligere. The following example shall further illustrate the invention.

Eksempel på fremstilling av 5, ll- dihydro- 6H- pyrido[ 2, 3- b][ 1, 4]-benzodiazepin- 6- on Example of preparation of 5,11-dihydro-6H-pyrido[2,3-b][1,4]-benzodiazepine-6-one

51,4 g (0,4 mol) 2-klor-3-aminopyridin suspenderes i 51.4 g (0.4 mol) of 2-chloro-3-aminopyridine are suspended in

160 ml 1,2,4-triklorbenzen, og 58,4 g (0,52 mol) kalium-tert.butylat tilsettes. I løpet av 30 minutter tilsettes dråpevis 78,6 g (0,52 mol) 2-aminobenzoesyremetylester, og man omrører i 1 time ved 50°C. Derefter fortynnes reaksjonsblandingen med 220 ml 1,2,4-triklorbenzen, 22,8 ml konsentrert svovelsyre tilsettes, og under anvendelse av vakuum avdestil-leres den tertiære butanol. Man omrører i 2 4 timer ved 115°C og derefter i ytterligere 2 timer ved 160°C. For opparbeidelse avkjøles reaksjonsblandingen til romtemperatur, krystall-suspensjonen avsuges og eftervaskes med 300 ml petroleter. Den godt tørrsugede filterkaken suspenderes i 670 ml 50%ig vandig aceton ved en temperatur på ca. 50°C, 60 ml konsentrert ammoniakk tilsettes, og omrøring foretas i 1 time ved ca. 50°C. Derefter avsuges, eftervaskes med vann og tørres natten over ved 80°C. Det oppnådde stoff finknuses, utrøres i 500 ml petroleter, avsuges og eftervaskes med petroleter. 160 ml of 1,2,4-trichlorobenzene and 58.4 g (0.52 mol) of potassium tert-butylate are added. Over the course of 30 minutes, 78.6 g (0.52 mol) of 2-aminobenzoic acid methyl ester are added dropwise, and the mixture is stirred for 1 hour at 50°C. The reaction mixture is then diluted with 220 ml of 1,2,4-trichlorobenzene, 22.8 ml of concentrated sulfuric acid is added, and the tertiary butanol is distilled off using a vacuum. The mixture is stirred for 24 hours at 115°C and then for a further 2 hours at 160°C. For work-up, the reaction mixture is cooled to room temperature, the crystal suspension is suctioned off and washed with 300 ml of petroleum ether. The well-dried filter cake is suspended in 670 ml of 50% aqueous acetone at a temperature of approx. 50°C, 60 ml of concentrated ammonia is added, and stirring is carried out for 1 hour at approx. 50°C. It is then suctioned off, washed with water and dried overnight at 80°C. The substance obtained is finely crushed, stirred in 500 ml of petroleum ether, filtered off with suction and then washed with petroleum ether.

Den godt tørrsugede filterkake vaskes til slutt klorid- og sulfatfri med avionisert vann, og tørres til konstant vekt The well-sucked filter cake is finally washed free of chloride and sulfate with deionized water, and dried to a constant weight

ved 80°C. at 80°C.

Utbytte: 58,7 g (69,5% av det teoretiske). Yield: 58.7 g (69.5% of the theoretical).

Smeltepunkt: 279-281°C (dekomp.) Melting point: 279-281°C (decomp.)

Istedenfor 1,2,4-triklorbenzen kan f.eks. også sulfolan anvendes som oppløsningsmiddel. Instead of 1,2,4-trichlorobenzene, e.g. sulfolane is also used as a solvent.

Utbytte: 87,4% av det teoretiske. Yield: 87.4% of the theoretical.

Claims (1)

Fremgangsmåte for fremstilling av 5,ll-dihydro-6H-pyrido-[2,3-b] [1,4]benzodiazepin-6-on-derivater med den generelle formelProcess for the preparation of 5,11-dihydro-6H-pyrido-[2,3-b] [1,4]benzodiazepine-6-one derivatives of the general formula hvor R betyr et hydrogen- eller halogenatom eller en metylgruppe, karakterisert ved at et 2-halogen-3-aminopyridin med den generelle formelwhere R means a hydrogen or halogen atom or a methyl group, characterized in that a 2-halo-3-aminopyridine of the general formula hvor Hal betyr et halogenatom, omsettes med en antranilsyreester med den generelle formelwhere Hal means a halogen atom, is reacted with an anthranilic acid ester of the general formula hvor R er som ovenfor angitt og R^ betyr en alkylgruppe med 1 til 3 karbonatomer, i et organisk oppløsningsmiddel i nærvær av et basisk kondensasjonsmiddel ved temperaturer mellom 10 og 120°C, og den oppnådde forbindelse med formel IVwhere R is as above and R^ means an alkyl group with 1 to 3 carbon atoms, in an organic solvent in the presence of a basic condensing agent at temperatures between 10 and 120°C, and the obtained compound of formula IV hvor R og Hal har de ovenfor angitte betydninger, ringsluttes uten isolering efter tilsetning av en mineralsyre, fortrinnsvis svovelsyre, til reaksjonsblandingen til en pH-verdi på 7 eller lavere, ved 100 til 200°C, til forbindelsen med formel I.where R and Hal have the above-mentioned meanings, is cyclized without isolation after addition of a mineral acid, preferably sulfuric acid, to the reaction mixture to a pH value of 7 or lower, at 100 to 200°C, to the compound of formula I.
NO822182A 1981-07-15 1982-06-28 PROCEDURE FOR THE PREPARATION OF 5,11-DIHYDRO-6H-PYRIDO (2,3-B) (1,4) BENZODIAZEPIN-6-ON DERIVATIVES. NO160140C (en)

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Application Number Priority Date Filing Date Title
DE3127849 1981-07-15

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NO822182L NO822182L (en) 1983-01-17
NO160140B true NO160140B (en) 1988-12-05
NO160140C NO160140C (en) 1989-03-15

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JP (1) JPS5818383A (en)
AT (1) AT379394B (en)
CH (1) CH649085A5 (en)
CS (1) CS226745B2 (en)
DD (1) DD202571A5 (en)
DK (1) DK157999C (en)
ES (1) ES8307248A1 (en)
FI (1) FI77860C (en)
GR (1) GR76198B (en)
HU (1) HU186090B (en)
NL (1) NL8202145A (en)
NO (1) NO160140C (en)
PL (1) PL237471A1 (en)
PT (1) PT75244B (en)
SE (1) SE449102B (en)
YU (1) YU43724B (en)

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TW300237B (en) * 1994-10-27 1997-03-11 Polyplastics Co
KR100358667B1 (en) * 1995-04-27 2003-04-16 폴리플라스틱스 가부시키가이샤 Thermoplastic Composition and Manufacturing Method thereof

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SE449102B (en) 1987-04-06
AT379394B (en) 1985-12-27
JPH0330596B2 (en) 1991-04-30
ATA263482A (en) 1985-05-15
FI822391L (en) 1983-01-16
NO160140C (en) 1989-03-15
YU43724B (en) 1989-10-31
HU186090B (en) 1985-05-28
DD202571A5 (en) 1983-09-21
PL237471A1 (en) 1983-01-17
SE8204330D0 (en) 1982-07-14
ES513293A0 (en) 1983-06-16
DK157999B (en) 1990-03-12
SE8204330L (en) 1983-01-16
YU151982A (en) 1986-04-30
FI822391A0 (en) 1982-07-06
JPS5818383A (en) 1983-02-02
PT75244A (en) 1982-08-01
FI77860C (en) 1989-05-10
DK311982A (en) 1983-01-16
GR76198B (en) 1984-08-03
DK157999C (en) 1990-08-13
FI77860B (en) 1989-01-31
CS226745B2 (en) 1984-04-16
PT75244B (en) 1985-10-04
NL8202145A (en) 1983-02-01
NO822182L (en) 1983-01-17
CH649085A5 (en) 1985-04-30
ES8307248A1 (en) 1983-06-16

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