DK157999B - METHOD FOR PREPARING 5,11-DIHYDRO-6H-PYRIDOOE2,3-BAAOE1,4AABENZODIAZEPIN-6-ONER - Google Patents
METHOD FOR PREPARING 5,11-DIHYDRO-6H-PYRIDOOE2,3-BAAOE1,4AABENZODIAZEPIN-6-ONER Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- 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
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- 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
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Description
iin
DK 157999 BDK 157999 B
Opfindelsen angår en særlig fremgangsmåde til fremstilling af 5,ll-dihydro-6H-pyrido[2,3-b][1,4]-benzodiazepin-6-oner med den almene formel Is 5 NH - CO ^ ^The invention relates to a particular process for the preparation of 5,11-dihydro-6H-pyrido [2,3-b] [1,4] -benzodiazepine-6-ones of the general formula Is 5 NH - CO
HH
10 hvor R er et hydrogen- eller halogenatom eller en me-thylgruppe.Wherein R is a hydrogen or halogen atom or a methyl group.
Disse forbindelser er værdifulde udgangsforbindelser for fremstillingen af lægemidler, for eksempel for fremstillingen af pirenzepin (5,ll-dihydro-ll-[(4- 15 methyl-l-piperazinyl)acetylJ-6H-pyrido[2,3-b][l,4]benzo-diazepin-6-on-dihydrochlorid), der er et stof med en stærk ulcus- og mavesaftsekretionshæmmende virkning.These compounds are valuable starting compounds for the preparation of drugs, for example, for the preparation of pirenzepine (5,11-dihydro-11 - [(4-methyl-1-piperazinyl) acetyl] -6H-pyrido [2,3-b] [1 (4] benzo-diazepine-6-one dihydrochloride), a substance with a strong ulcer and gastric juice secretion inhibitory effect.
Fremgangsmåden ifølge opfindelsen er ejendommelig ved, at en 2-halcgen-3-amincpyridin med den almene formel II: 20 ^ I (II) fcr Hal 25 hvor Hal er et halogenatom, fortrinsvis et chloratom, omsættes med en anthranilsyreester med den almene formel III: r-l - o - c 30 ^Y^TT^R (I111 hvor R er som ovenfor defineret, og R^ er en alkylgruppe med 1-3 C-atomer, fortrinsvis en methylgruppe, i et or- 35 ganisk opløsningsmiddel i nærværelse af et basisk kon-densaticnsmiddel ved temperaturer mellem 10° og 12o°C, hvorefter den opnåede forbindelse med den almene formel IV:The process of the invention is characterized in that a 2-halogen-3-amine pyridine of the general formula II: 20 µl (II) of Hal 25 wherein Hal is a halogen atom, preferably a chlorine atom, is reacted with an anthranilic acid ester of the general formula III wherein R is as defined above and R 1 is an alkyl group having 1-3 C atoms, preferably a methyl group, in an organic solvent in the presence of a basic condensing agent at temperatures between 10 ° and 120 ° C, after which the obtained compound of the general formula IV:
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22
NH - CONH - CO
I I -j—R (IV) 5 hvor R og Hal er som ovenfor defineret, ringsluttes ved en pH-værdi på 7 eller derunder, fortrinsvis i nærværelse af svovlsyre, ved temperaturer mellem 100 og 200°C i et opløsningsmiddel.In I-j-R (IV) 5 where R and Hal are as defined above, cyclize at a pH of 7 or less, preferably in the presence of sulfuric acid, at temperatures between 100 and 200 ° C in a solvent.
10 Den omhandlede fremgangsmåde gennemføres hen sigtsmæssigt i form af en énbeholder-metode, idet den dannede forbindelse med formlen IV ikke isoleres, men ringslutningen gennemføres i samme reaktionsbeholder efter syrning af reaktionsblandingen til en pH-værdi på 7 15 eller derunder.The process according to the invention is conveniently carried out in the form of a single-container method, since the compound of formula IV formed is not isolated, but the cyclization is carried out in the same reaction vessel after acidification of the reaction mixture to a pH of 7 or less.
Omsætningen af en forbindelse med formlen II med en anthranilsyreester med formlen III foregår som allerede nævnt i nærværelse af et organisk opløsningsmiddel og i nærværelse af et basisk kondensationsmiddel ved tempe-20 raturer mellem 10° og 120°C. Som basisk kondensationsmid-* del kan der anvendes sådanne forbindelser som tetrabutyl-ammoniumhydroxid, natrium- eller kaliummethylat, natriumeller kaliumisopropylat, natrium- eller kalium-t-butylat, natriumhydrid, lithium-, natrium- eller kaliumamid eller 25 natriumhydroxid. Som opløsningsmiddel benyttes for eksempel ethanol, toluen, xylen, dimethylsulfoxid, sulfolan eller trichlorbenzen, men der kan som opløsningsmiddel også anvendes overskud af anthranilsyrealkylester.The reaction of a compound of formula II with an anthranilic acid ester of formula III takes place as already mentioned in the presence of an organic solvent and in the presence of a basic condensing agent at temperatures between 10 ° and 120 ° C. As the basic condensing agent, such compounds as tetrabutyl ammonium 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. As the solvent, for example, ethanol, toluene, xylene, dimethylsulfoxide, sulfolane or trichlorobenzene are used, but excess of anthranilic acid alkyl ester can be used as solvent.
Ringslutningen af den dannede forbindelse med form-30 len IV foregår, uanset om forbindelsen med formlen IV isoleres, eller fremgangsmåden gennemføres som en énbe-holder-reaktion, ved temperaturer på 100-200°C i et opløsningsmiddel, fortrinsvis trichlorbenzen og sulfolan, ved neutralt eller surt pH. Ved gennemførelse som énbe-35 holder-reaktion bliver den alkalisk reagerende reaktions-blanding, der indeholder forbindelsen IV, syrnet, fortrinsvis med svovlsyre, hvorefter ringslutningen gennemføres ved opvarmning til de nævnte temperaturer.The cyclization of the compound of formula IV formed, whether the compound of formula IV is isolated or the process is carried out as a single-container reaction, at temperatures of 100-200 ° C in a solvent, preferably trichlorobenzene and sulfolane, at neutral or acidic pH. When carried out as a single-container reaction, the alkaline reacting reaction mixture containing the compound IV is acidified, preferably with sulfuric acid, after which the cyclization is effected by heating to said temperatures.
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Forbindelserne med den almene formel II og den almene formel III og det basiske kondensationsmiddel benyttes i ækvimolære mængder, eller der anvendes et overskud af forbindelsen med formlen III og/eller af det basiske kon-5 densationsmiddel. Udbytterne af forbindelserne med formlen IV andrager op til 98%, og udbytterne af slutproduktet med formlen I andrager op til 87%.The compounds of the general formula II and the general formula III and the basic condensing agent are used in equimolar amounts or an excess of the compound of the formula III and / or of the basic condensing agent is used. The yields of the compounds of formula IV are up to 98% and the yields of the final product of formula I are up to 87%.
En fremgangsmåde til fremstilling af forbindelserne med formlen I er allerede kendt fra DE patentskrift nr.A process for preparing the compounds of formula I is already known from DE patent specification no.
10 1.179.943. Denne kendte fremgangsmåde er en 3-trins-meto-de, hvor først en 2-halogen-3-amino-pyridin med formlen II omsættes med et reaktionsdygtigt nitrobenzoesyrederi-vat, fortrinsvis dets syrehalogenid, og den dannede nitro-forbindelse reduceres, hvorefter den herved opnåede for-15bindelse med formlen IV ringsluttes i smeltetilstand eller i nærværelse af et højtkogende opløsningsmiddel, såsom paraffin eller dekalin, eventuelt i nærværelse af en basisk katalysator eller af kobberpulver.10 1,179,943. This known process is a 3-step method wherein first a 2-halo-3-amino-pyridine of formula II is reacted with a reactive nitrobenzoic acid derivative, preferably its acid halide, and the resulting nitro compound is reduced, thus obtained compound of formula IV is cyclized in the melting state or in the presence of a high boiling solvent, such as paraffin or decalin, optionally in the presence of a basic catalyst or of copper powder.
Mens denne kendte fremgangsmåde er en tretrins-20 metode, er fremgangsmåden ifølge den foreliggende opfindelse en ettrins-metode, der eventuelt kan gennemføres som en totrins-metode. Dette betyder en hurtigere og mere økonomisk proces. Endvidere eliminerer fremgangsmåden ifølge opfindelsen brugen af det ved den kendte frem-25 gangsmåde anvendte farlige o-nitrobenzoylchlorid, der kræver særlige sikkerhedsforanstaltninger (opløsninger deraf har en tendens til spontant at eksplodere).While this known method is a three-step method, the method of the present invention is a one-step method which may be optionally carried out as a two-step method. This means a faster and more economical process. Furthermore, the process of the invention eliminates the use of the hazardous o-nitrobenzoyl chloride used in the known method which requires special precautions (solutions thereof tend to spontaneously explode).
Den i nævnte kendte proces indgående reduktion af en dannet nitroforbindelse gennemføres enten katalytisk 30 i autoklav eller ved hjælp af tin(iDchlorid/saltsyre. Anvendelsen af autoklav begrænser imidlertid syntesekapaciteten, og anvendelsen af tinsalte stiller krav om senere eliminering af tinsalte fra spildvandet. Disse problemer undgås ved den omhandlede fremgangsmåde.The reduction of a nitro compound formed in said known process is either catalytically carried out in autoclave or by means of tin (chloride / hydrochloric acid. However, the use of autoclave limits the synthetic capacity and the use of tin salts requires later elimination of tin salts from the waste water. is avoided by the method in question.
35 Også ringslutningen, der ved den omhandlede frem gangsmåde foregår i neutralt eller surt miljø i nærværelse af det anførte opløsningsmiddel, gennemføres35 Also, the cyclization which takes place in the process in question in a neutral or acidic environment in the presence of the indicated solvent is also carried out.
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4 væsentligt bedre og under opnåelse af højere udbytter, end tilfældet er ved den kendte fremgangsmåde, hvor der i reglen opereres i en smelte. Totaludbytterne ligger ved den kendte fremgangsmåde ca. 10% lavere end ved frem-5 gangsmåden ifølge opfindelsen, med hvilken der er opnået et totaludbytte på 87% mod 77,9% ved den kendte fremgangsmåde.4 is significantly better and in obtaining higher yields than is the case in the known process, in which a melt is usually operated. The total yields in the known process are approx. 10% lower than in the method according to the invention, with which a total yield of 87% is obtained against 77.9% by the known method.
Fra DE offentliggørelsesskrift nr. 1.695.903 er det kendt at fremstille i 11-stillingen alkylsubstitue-10 rede 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin- 6-oner ved omsætning af et isatosyreanhydrid med en 2-ha-logen-3-aminopyridin. Denne kendte fremgangsmåde er imidlertid kun gennemførlig, hvis det som udgangsmateriale anvendte isatosyreanhydrid ved ringnitrogenatomet 15 er substitueret med en alkylgruppe, og der kan således ikke ved denne kendte fremgangsmåde, som ved den omhandlede fremgangsmåde, opnås slutforbindelser med formlen I, hvis 11-stilling er tilgængelig for yderligere omsætninger.From DE Publication No. 1,695,903, it is known to prepare at the 11-position alkyl-substituted 5,11-dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepine-6-ones by reaction of an isatoic anhydride with a 2-halogen-3-aminopyridine. However, this known process is only feasible if the isatoic anhydride used as the starting material at the ring nitrogen atom 15 is substituted by an alkyl group, and thus no known compounds of the formula I, whose 11-position is at the 11-position, cannot be obtained by this known process. available for additional revenue.
20 Endvidere er udbytterne ved den kendte omsætning af 2-halogen-3-aminopyridin med isatosyreanhydrid lavere end ved omsætningen af 2-halogen-3-amincpyridin med an-thranilsyreester ifølge den foreliggende opfindelse, f.eks. 50-60% mod næsten 90%.Furthermore, the yields of the known reaction of 2-halo-3-aminopyridine with isatoic anhydride are lower than in the reaction of 2-halo-3-aminopyridine with anthranilic acid ester of the present invention, e.g. 50-60% versus almost 90%.
25 I dansk patentansøgning nr. 2744/80 er beskrevet en fremgangsmåde til fremstilling af pirenzepin, der som mellemproduktforbindelse anvender 5,11-dihydro-6H-pyri-do[2,3-b][1,4]benzodiazepin-6-on. Denne mellemproduktforbindelse skulle ifølge nævnte ansøgnings beskrivelse 30 kunne opnås i et udbytte på mindst 70% ved omsætning af anthranilsyremethylester med 3-aminopyridin. Gennemførligheden af denne sidstnævnte omsætning har imidlertid ikke kunnet eftervises i praksis, der synes at vise, at uden halogen ved 2-stillingen i pyridinringen, som fore-35 skrevet ved fremgangsmåden ifølge den foreliggende opfindelse, finder der ingen ringslutning sted.Danish Patent Application No. 2744/80 discloses a process for the preparation of pirenzepine using as an intermediate compound 5,11-dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one . This intermediate compound should, according to the description of said application 30, be obtained in a yield of at least 70% by reaction of anthranilic acid methyl ester with 3-aminopyridine. However, the feasibility of this latter reaction has not been demonstrated in practice, which seems to show that without halogen at the 2-position of the pyridine ring, as prescribed by the process of the present invention, no cyclization occurs.
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Det er overraskende, at der ved omsætningen af forbindelser med den almene formel II med forbindelser med den almene formel III i nærværelse af stærke baser opnås de ønskede forbindelser med formlen IV, da det 5 er kendt, at pyridiner med halogenatomer i 2- eller 4-stilling, navnlig i alkalisk medium, omdannes meget hurtigt til de tilsvarende pyridinoler, for eksempel i en alkoholisk natriumhydroxidopløsning eller en vandig kaliumhydroxidopløsning og ved temperaturer på ca. 90°C.Surprisingly, in the reaction of compounds of general formula II with compounds of general formula III in the presence of strong bases, the desired compounds of formula IV are obtained, since it is known that pyridines having halogen atoms in 2- or 4 position, especially in alkaline medium, is very rapidly converted to the corresponding pyridinols, for example in an alcoholic sodium hydroxide solution or an aqueous potassium hydroxide solution, and at temperatures of ca. 90 ° C.
10 Sådanne reaktioner er også kendt fra litteraturen, for eksempel beskriver 0. von Schickh et al. i Ber.Dtsch.Chem. Ges. 1936, Nr.12, side 2594, 2600 og 2602 reaktionen af 2-chlor-3-aminopyridin med en natriummethylatopløsning til 2-methoxy-3-aminopy-ridin. Det er derfor af de ovennævnte grunde særligt 15 overraskende, at der ved omsætningen ifølge opfindelsen ikke blot ikke sker en udveksling af halogenatomet i forbindelsen med formlen II med den anioniske rest af det basiske kondensationsmiddel, men at forbindelserne med de almene formler IV og I opnås i et meget højt udbytte.Such reactions are also known from the literature, for example 0. von Schickh et al. in Ber.Dtsch.Chem. Ges. 1936, No. 12, pages 2594, 2600 and 2602 the reaction of 2-chloro-3-aminopyridine with a sodium methylate solution to 2-methoxy-3-aminopyridine. It is therefore particularly surprising, for the above reasons, that not only does the exchange of the halogen atom in the compound of formula II with the anionic residue of the basic condensing agent be exchanged, but that the compounds of the general formulas IV and I are obtained in a very high yield.
20 Overføringen af en forbindelse med den almene for mel I i det ovennævnte pirenzepin eller i pirenzepin-lignende forbindelser er beskrevet i DE patentskrift nr. 1.795.183.The transfer of a compound with the general one of flour I into the above-mentioned pirenzepine or in pirenzepine-like compounds is disclosed in DE Patent No. 1,795,183.
Fremgangsmåden ifølge opfindelsen beskrives nærme-25 re gennem følgende eksempler.The process of the invention is described in greater detail by the following examples.
A. Eksempler på fremstilling af: 2-Chlor-3-(2-aminobenzoylj ^aminopyridin 30 Eksempel 1 51,4 g (0,4 mol) 2-Chlor-3^aminopyridin blev suspenderet i 160 ml xylen. Hertil blev sat 58,4 g (0,52 mol) kalium-tert.-butylat og i løbet af ca. 25 minutter 78,6 g (0,52 mol) 2^aminobenzoesyremethylester. Derefter 35 blev der opvarmet 1 time ved 120°C, reaktions- 6A. Examples of Preparation of: 2-Chloro-3- (2-aminobenzoyl) aminopyridine Example 1 51.4 g (0.4 mole) of 2-Chloro-3'-aminopyridine were suspended in 160 ml of xylene. 4 g (0.52 mole) of potassium tert.-butylate and in about 25 minutes 78.6 g (0.52 mole) of 2-aminobenzoic acid methyl ester, then heated for 1 hour at 120 ° C. - 6
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blandingen blev afkølet til ca. 20°C, og der blev tilsat 100 ml vand. Krystalsuspensionen blev med koncentreret saltsyre indstillet på pH 6, krystallerne blev frasuget, vasket med vand og tørret·til konstant vægt i vakuum ved 80°C.the mixture was cooled to ca. 20 ° C and 100 ml of water were added. The crystal suspension was adjusted to pH 6 with concentrated hydrochloric acid, the crystals were aspirated, washed with water and dried to constant weight in vacuo at 80 ° C.
5 Udbytte: 94,3 g (95,2% af det teor.).Yield: 94.3 g (95.2% of theory).
Smp.; 169-171°C.m.p .; 169-171 ° C.
Yderligere fremstillingsmuligheder under lignende reaktionsbetingelser: 1° Opløsnings- I ~ Tempe- I 1 * mlddel ratur teoretiskeFurther preparation possibilities under similar reaction conditions: 1 ° Solution I ~ Temp I 1 * average theoretical
Dimethyl- Kalium-tert.- 50°C 98,0 sulfoxid butylatDimethyl potassium tert.-50 ° C 98.0 sulfoxide butylate
Sulfolan Kalium-tert.- 60°C 97,4 I 5 butylatSulfolane Potassium tert.- 60 ° C 97.4 l of butylate
Toluen Kalium-tert.- 90°C 91,9 butylatToluene Potassium tert.- 90 ° C 91.9 butylate
Dimethyl- Natrium- 50°C 98,0 sulfoxid isopropylat 20 Eksempel 2 12,85 g (0,1 mol) 2-Chlor-3-aminopyridin blev opløst i 65 ml dimethylsulfoxid, og ved stuetemperatur blev der tilsat 10,9 g 50%’s natriumamidsuspension i toluen (=5,45 g natriumamid, 0,14 mol). Derefter lod man 25 i løbet af 10 minutter tilflyde 19,7 g (0,13 mol) 2-aminobenzoesyre-methylester, og der blev omrørt 30 mi- * nutter ved 50°C. Derefter blev der 'afkølet til 20 C og under en nitrogenatmosfære tilsat 100 ml vand og 30 koncentreret saltsyre indtil pH 6. De danncyfe krystaller blev frasuget, vasket med vand og tørret til konstant vægt ved 50°C.Dimethyl Sodium 50 ° C 98.0 Sulfoxide Isopropylate Example 2 12.85 g (0.1 mole) of 2-Chloro-3-aminopyridine was dissolved in 65 ml of dimethyl sulfoxide and at room temperature 10.9 g was added. % sodium amide suspension in toluene (= 5.45 g sodium amide, 0.14 mol). Then, over 10 minutes, 19.7 g (0.13 mole) of 2-aminobenzoic acid methyl ester was charged and 30 minutes were stirred at 50 ° C. Then, it was cooled to 20 ° C and, under a nitrogen atmosphere, 100 ml of water and 30 concentrated hydrochloric acid were added to pH 6. The crystals formed were suctioned off, washed with water and dried to constant weight at 50 ° C.
Udbytte: 23,9 g (96,4% af det teor.).Yield: 23.9 g (96.4% of theory).
Smp.: 170-172°C.Mp: 170-172 ° C.
35 I stedet for natriumamid kan der anvendes for eks empel også lithiumamid. Udbytte 68,4% af det teoretiske.35 Instead of sodium amide, for example, lithium amide can also be used. Yield 68.4% of theory.
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Eksempel 3 25,7 g (0,2 mol) 2rChlor-3-raminopyridin og 16,2 g (0,3 mol) natriummethylat blev 1 160 ml toluen opvarmet 5 til kogning, og 30 ml opløsningsmiddel blev afdestille-ret indtil en temperatur på 100°C. Der blev tilsat 30 ml frisk toluen til reaktionsblandingen, og derefter lod man, begyndende ved 70°C, i løbet af 20 minutter tilflyede 39,6 g (0,26 mol) 2~aminobenzoesyremethylester. Der-10 efter blev der omrørt 4 timer ved 90^95°C. Eventuelt kan der efter dette tidsrum tilsættes yderligere 5,4 g (0,1 mol) natriummethylat og reageres videre ved 90-95°C.Example 3 25.7 g (0.2 mole) of 2-Chloro-3-raminopyridine and 16.2 g (0.3 mole) of sodium methylate were heated to boiling in 160 ml of toluene and 30 ml of solvent were distilled off to a temperature. at 100 ° C. 30 ml of fresh toluene was added to the reaction mixture and then, starting at 70 ° C, 39.6 g (0.26 mol) of 2-aminobenzoic acid methyl ester was added over 20 minutes. Then, it was stirred for 4 hours at 90 ° 95 ° C. Optionally, after this time, an additional 5.4 g (0.1 mole) of sodium methylate may be added and further reacted at 90-95 ° C.
Efter endt omsætning blev der afkølet til ca. 15¾ frasuget og vasket med ca. 200 ml petroleumsether. Den 15 godt tørsugede filterrest blev suspenderet i 250 ml vand og indstillet på pH 6 med kone.saltsyre. Krystallerne blev frasuget, vasket med vand og tørret til konstant vægt ved 50°C.After the turnover was cooled to approx. 15¾ extracted and washed with approx. 200 ml of petroleum ether. The 15 well-dried suction filter residue was suspended in 250 ml of water and adjusted to pH 6 with hydrochloric acid. The crystals were aspirated, washed with water and dried to constant weight at 50 ° C.
Udbytte: 37,7 g (76,1% af det teor.).Yield: 37.7 g (76.1% of theory).
20 Smp.: 168-170°C.Mp: 168-170 ° C.
Yderligere fremstillingsmuligheder under lignende reaktionsbetingelser: 8Additional manufacturing possibilities under similar reaction conditions: 8
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Opløsnings- Tempe- Bemærk- mlddel__ratur »*Qr< nlngerResolution Temp-Notice__rature »* Qr <nlnger
Xylen Natrium- 95°C 76,3 methylat 5 Dimethyl- Natrium- 45°C 97,4 Udfæld- sulfoxid methylat ning med vand og saltsyreXylene Sodium 95 ° C 76.3 Methylate Dimethyl Sodium 45 ° C 97.4 Precipitated Sulfoxide Methylation with Water and Hydrochloric Acid
Sulfolan Natrium- 70°C 72,6 Udfæld- methylat ning med vand og 10 saltsyreSulfolane Sodium 70 ° C 72.6 Precipitation methylation with water and 10 hydrochloric acid
Ethanol, Natrium- 75°C 52,4 Udfæld- abs. methylat ning med vand og saltsyreEthanol, Sodium 75 ° C 52.4 Precipitation Abs. methylation with water and hydrochloric acid
Anthranil- Natrium- 75°C 68,5 Udfæld- -]5 syremethyl- methylat ning med ester vand og saltsyreAnthranil-Sodium 75 ° C 68.5 Precipitate - 5 acid methyl methylation with ester water and hydrochloric acid
Dimethyl- Kalium- 50°C 52,0 Udfæld- sulfoxid methylat ning med vand og saltsyre 20 -Dimethyl Potassium 50 ° C 52.0 Precipitation Sulfoxide Methylation with Water and Hydrochloric Acid 20 -
Eksempel 4 51,4 g (0,4 mol) 2-Chlor-3-aminopyridin blev opløst i 160 ml dimethylsulfoxid, og der blev tilsat 24,0 g (0,6 mol) natriumhydroxid-pulver. Blandingen blev under 2 5 qExample 4 51.4 g (0.4 mole) of 2-Chloro-3-aminopyridine was dissolved in 160 ml of dimethyl sulfoxide and 24.0 g (0.6 mole) of sodium hydroxide powder was added. The mixture became below 25 q
påføring af vandstrålevakuum opvarmet 1 time ved ca.80 Qapplication of water jet vacuum heated for 1 hour at about 80 ° C
hvorved små mængder overdestillerede. Kolbeindholdet blev derefter afkølet til 50°C. I løbet af ca. 30 minutter lod man tilflyde 78,6 g (0,52 mol) 2r-aminobenzoesyreme-^ thylester, der blev omrørt 30 minutter ved 50°C og tilsat yderligere 11,7 g (0,077 mol) ester. Efter yderligere 2^ time blev der tilsat yderligere 11,7 g 2-amino-benzoesyremethylester (0,077 mol) og 5,0 g natriumhydroxid-pulver (0,125 mol) til reaktionsblandingen og omrørt 30 minutter ved den anførte temperatur. Der blev afkølet 35 ø til ca. 20 C, tilsat 190 ml vand og koncentreret saltsyre indtil pH 6. Krystallerne blev frasuget, vasket med 9thereby overstating small quantities. The flask contents were then cooled to 50 ° C. Over approx. For 30 minutes, 78.6 g (0.52 mole) of 2β-aminobenzoic acid methyl ester were allowed to stir, which was stirred for 30 minutes at 50 ° C and added an additional 11.7 g (0.077 mole) of ester. After an additional 2 hours, an additional 11.7 g of 2-amino-benzoic acid methyl ester (0.077 mol) and 5.0 g of sodium hydroxide powder (0.125 mol) were added to the reaction mixture and stirred for 30 minutes at the indicated temperature. 35 islands were cooled to approx. 20 C, added 190 ml of water and concentrated hydrochloric acid until pH 6. The crystals were aspirated, washed with 9
DK 157999 BDK 157999 B
vand og tørret til konstant vægt ved 50°G.water and dried to constant weight at 50 ° G.
Udbytte: 30,7 g (31,0% af det teor.)..Yield: 30.7 g (31.0% of theory).
Smp.: 168-170°C.Mp: 168-170 ° C.
5 Eksempel 5 25,7 g (0,2 mol) 2-Chlor^3-aminopyridin blev suspenderet i 160 ml toluen, og der blev tilsat 11,2 g natriumhydroxidsuspension (ca. 60%' s, 0,28 mol), og 39,6 g (0,26 mol) 2-aminobenzoesyremethylester. Der blev omrørt 10 i yderligere 4 timer ved 90°C, afkølet til stuetemperatur, og under en nitrogenatmosfære lod man tilflyde 100 ml vand. Krystalgrøden blev med kone.saltsyre indstillet på pH 6, krystallerne blev frasuget, vasket med vand og tørret til konstant vSgt ved 50°C.Example 5 25.7 g (0.2 mole) of 2-Chloro 3-aminopyridine were suspended in 160 ml of toluene and 11.2 g of sodium hydroxide suspension (about 60%, 0.28 mole) was added, and 39.6 g (0.26 mol) of 2-aminobenzoic acid methyl ester. The mixture was stirred for an additional 4 hours at 90 ° C, cooled to room temperature and 100 ml of water was allowed to flow under a nitrogen atmosphere. The crystal crop was adjusted with pH hydrochloric acid to pH 6, the crystals were aspirated, washed with water and dried to constant vSgt at 50 ° C.
15 Udbytte: 36,8 g (74,3% af det teor.).Yield: 36.8 g (74.3% of theory).
Smp.: 168-170°C.Mp: 168-170 ° C.
Eksempel 6 25,95 g (0,1 mol) Tetrabutylammoniumhydroxid (opnå-20 et ved inddampning af kommerciel tetrabutylammoniumhy-droxidopløsning) blev opløst i 30 ml dimethylsulfoxid, og der blev tilsat 9,2 g (0,072 mol) 2-chlor-3-aminopyri-din. Begyndende ved ca. 30°C blev der i løbet af ca. 20 minutter tilsat 14,0 g (0,092 mol) 2-aminobenzoesyreme-25 thylester, idet der blev opereret med vandstrålevakuum.Example 6 25.95 g (0.1 mole) of Tetrabutylammonium hydroxide (obtained by evaporation of commercial tetrabutylammonium hydroxide solution) was dissolved in 30 ml of dimethylsulfoxide and 9.2 g (0.072 mole) of 2-chloro-3 was added. -aminopyri-din. Starting at approx. At about 30 ° C, about For 20 minutes, 14.0 g (0.092 mol) of 2-aminobenzoic acid methyl ester was added, operating with water jet vacuum.
Efter endt tilflydning blev der omrørt først 50 minutter ved 50°C og derefter 30 minutter ved 70°C. Efter afkøling til stuetemperatur blev der tilsat 30 ml vand og kone.saltsyre indtil pH 6. Krystallerne blev frasuget, 30 vasket med vand og tørret til konstant vægt ved 50°C.After flowing, stirring was first stirred for 50 minutes at 50 ° C and then 30 minutes at 70 ° C. After cooling to room temperature, 30 ml of water and hydrochloric acid were added until pH 6. The crystals were aspirated, washed with water and dried to constant weight at 50 ° C.
Udbytte: 10,3 g (58,1% af det teor.).Yield: 10.3 g (58.1% of theory).
Smp.: 168-170°C.Mp: 168-170 ° C.
1010
DK 157999 BDK 157999 B
B. Eksempler på fremstilling af: 5,ll-Dihydro-6H-pyrldo[2,3-b][1,4]benzodiazepin-6-on.B. Examples of Preparation of: 5,11-Dihydro-6H-pyrldo [2,3-b] [1,4] benzodiazepin-6-one.
Eksempel 7 5 51,4 g (0,4 mol) 2^Chlor-3-aminopyridin blev sus penderet i 160 ml l,2,4i-trichlorben2en, og der blev tilsat 58,4 g (0,52 mol) kalium-tert.-butylat. I løbet af 30 minutter blev der tildryppet 78,6 g (0,52 mol) 2-ami-nobenzoesyremethylester og omrørt 1 time ved 50 C. Der-10 efter blev reaktionsblandingen fortyndet med 220 ml 1,2, 4-trichlorbenzen, der blev tilsat 22,8 ml kone.svovlsyre (pH< 1.) og tert.-butanolen blev af destilleret under anvendelse af vakuum. Der blev omrørt 24 timer ved 115°C cg derefter yderligere 2 timer ved 160°C. Derefter blev 15 (jer afkølet til stuetemperatur, de dannede krystaller blev frasuget og eftervasket med 300 ml petroleums-ether. Den godt tørsugede filterkage blev suspenderet i 670 ml 50%'s vandig acetone ved ca. 50°C, der blev tilsat 60 ml kone. ammoniak og omrørt 1 time ved ca. 50°C.Example 7 51.4 g (0.4 mole) of 2 3 Chloro-3-aminopyridine was suspended in 160 ml of 1,2,4-trichlorobenzene and 58.4 g (0.52 mole) of potassium was added. tert-butylate. Over 30 minutes, 78.6 g (0.52 mol) of 2-ami-nobenzoic acid methyl ester was added dropwise and stirred for 1 hour at 50 ° C. The reaction mixture was then diluted with 220 ml of 1,2,4-trichlorobenzene which 22.8 ml of hydrochloric acid (pH <1) was added and the tert-butanol was distilled off using vacuum. It was stirred for 24 hours at 115 ° C and then an additional 2 hours at 160 ° C. Then 15 (you were cooled to room temperature, the crystals formed were aspirated and washed with 300 ml of petroleum ether. The well-dried suction filter cake was suspended in 670 ml of 50% aqueous acetone at about 50 ° C, added 60 ml The mixture was stirred for about 1 hour at about 50 ° C.
20 Derefter blev der frasuget, eftervasket med vand og tørret natten over ved 80°C. Stoffet blev findelt, udrørt i 500 ml petroleumsether, frasuget og eftervasket med petroleumsether. Den godt tørsugede filterkage blev til slut vasket chlorid- og sulfatfri med deioniseret 2 5 vand og tørret til konstant vægt ved 80°C.Then, it was aspirated, washed with water and dried overnight at 80 ° C. The substance was triturated, stirred in 500 ml of petroleum ether, extracted and washed with petroleum ether. The well-dried suction filter cake was finally washed chloride- and sulfate-free with deionized water and dried to constant weight at 80 ° C.
Udbytte: 58,7 g (69,5% af det teor.).Yield: 58.7 g (69.5% of theory).
Smp.: 279-281°C (dek.).Mp: 279-281 ° C (dec.).
I stedet for 1,2,4-trichlorbenzen kan der som opløsningsmiddel for eksempel anvendes sulfolan. Udbytte: 87,4% af det teoretiske.Instead of 1,2,4-trichlorobenzene, for example, solvent may be used as sulfolane. Yield: 87.4% of theory.
Claims (4)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3127849 | 1981-07-15 | ||
| DE3127849 | 1981-07-15 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK311982A DK311982A (en) | 1983-01-16 |
| DK157999B true DK157999B (en) | 1990-03-12 |
| DK157999C DK157999C (en) | 1990-08-13 |
Family
ID=6136912
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK311982A DK157999C (en) | 1981-07-15 | 1982-07-12 | METHOD FOR PREPARING 5,11-DIHYDRO-6H-PYRIDOOE2,3-BAAOE1,4AABENZODIAZEPIN-6-ONER |
Country Status (16)
| Country | Link |
|---|---|
| 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) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0737698A1 (en) * | 1994-10-27 | 1996-10-16 | Polyplastics Co. Ltd. | Modified polyacetal and process for production |
| KR100358667B1 (en) * | 1995-04-27 | 2003-04-16 | 폴리플라스틱스 가부시키가이샤 | Thermoplastic Composition and Manufacturing Method thereof |
-
1982
- 1982-05-26 NL NL8202145A patent/NL8202145A/en not_active Application Discontinuation
- 1982-06-21 ES ES513293A patent/ES8307248A1/en not_active Expired
- 1982-06-28 NO NO822182A patent/NO160140C/en unknown
- 1982-07-06 FI FI822391A patent/FI77860C/en not_active IP Right Cessation
- 1982-07-07 AT AT0263482A patent/AT379394B/en not_active IP Right Cessation
- 1982-07-12 YU YU1519/82A patent/YU43724B/en unknown
- 1982-07-12 CH CH4227/82A patent/CH649085A5/en not_active IP Right Cessation
- 1982-07-12 GR GR68721A patent/GR76198B/el unknown
- 1982-07-12 DK DK311982A patent/DK157999C/en not_active IP Right Cessation
- 1982-07-13 DD DD82241618A patent/DD202571A5/en unknown
- 1982-07-14 JP JP57122800A patent/JPS5818383A/en active Granted
- 1982-07-14 HU HU822292A patent/HU186090B/en not_active IP Right Cessation
- 1982-07-14 PL PL23747182A patent/PL237471A1/en unknown
- 1982-07-14 CS CS825387A patent/CS226745B2/en unknown
- 1982-07-14 SE SE8204330A patent/SE449102B/en not_active IP Right Cessation
- 1982-07-14 PT PT75244A patent/PT75244B/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| ES513293A0 (en) | 1983-06-16 |
| PT75244B (en) | 1985-10-04 |
| YU43724B (en) | 1989-10-31 |
| FI77860C (en) | 1989-05-10 |
| FI77860B (en) | 1989-01-31 |
| FI822391L (en) | 1983-01-16 |
| ATA263482A (en) | 1985-05-15 |
| YU151982A (en) | 1986-04-30 |
| PL237471A1 (en) | 1983-01-17 |
| NO160140B (en) | 1988-12-05 |
| NO160140C (en) | 1989-03-15 |
| NO822182L (en) | 1983-01-17 |
| AT379394B (en) | 1985-12-27 |
| NL8202145A (en) | 1983-02-01 |
| CH649085A5 (en) | 1985-04-30 |
| HU186090B (en) | 1985-05-28 |
| SE8204330L (en) | 1983-01-16 |
| DK157999C (en) | 1990-08-13 |
| SE449102B (en) | 1987-04-06 |
| CS226745B2 (en) | 1984-04-16 |
| SE8204330D0 (en) | 1982-07-14 |
| PT75244A (en) | 1982-08-01 |
| GR76198B (en) | 1984-08-03 |
| DD202571A5 (en) | 1983-09-21 |
| DK311982A (en) | 1983-01-16 |
| FI822391A0 (en) | 1982-07-06 |
| ES8307248A1 (en) | 1983-06-16 |
| JPH0330596B2 (en) | 1991-04-30 |
| JPS5818383A (en) | 1983-02-02 |
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