DK161324B - METHOD FOR PREPARING 4- (1-SUBSTITUTED-4-PIPERIDYLIDE) -4H-BENZO (4,5) CYCLOHEPTA (1,2-B) THIOPHEN-10 (9H) -ONDERIVATIVES - Google Patents
METHOD FOR PREPARING 4- (1-SUBSTITUTED-4-PIPERIDYLIDE) -4H-BENZO (4,5) CYCLOHEPTA (1,2-B) THIOPHEN-10 (9H) -ONDERIVATIVES Download PDFInfo
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Description
DK 161324 BDK 161324 B
Den foreliggende opfindelse angår en særlig fremgangsmåde til fremstilling af 4-(l-substituerede-4-piperidyliden)-4H-benzo[4,5]cyclo-hepta[l,2-b]thiophen-10(9H)-onderivater med den almene formel IThe present invention relates to a particular process for the preparation of 4- (1-substituted-4-piperidylidene) -4H-benzo [4,5] cyclohepta [1,2-b] thiophene-10 (9H) -one derivatives with the general formula I
00
Rl-\XXiR¹ \ XXI
5 X5 X
ku Jku J
I 2 hvor R1 betegner hydrogen eller i 6- eller 7-stillingen siddende halogen eller lavere alkoxy, og R2 betegner lavere alkyl, eller syre-additionssalte deraf.In 2 wherein R 1 represents hydrogen or in the 6- or 7-position halogen or lower alkoxy and R 2 represents lower alkyl, or acid addition salts thereof.
10 Såfremt R^· er halogen, er dette især chlor eller brom, fortrinsvis chlor.If R 2 is halogen, this is especially chlorine or bromine, preferably chlorine.
Såfremt R1 er en lavere alkoxygruppe, kan denne indeholde 1-4 carbon-atomer, og er især methoxy.If R 1 is a lower alkoxy group, it may contain 1-4 carbon atoms and is especially methoxy.
Symbolet R2 betegner lavere alkyl med 1-4 carbonatomer, fortrinsvis 15 methyl.The symbol R2 represents lower alkyl of 1-4 carbon atoms, preferably 15 methyl.
Fremgangsmåden ifølge opfindelsen er ejendommelig ved, at en forbindelse med formlen VIIIThe process according to the invention is characterized in that a compound of formula VIII
r1 —^vm yC oh vN ^ 12r1 - ^ vm yC oh vN ^ 12
RR
22
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hvor og R2 har de ovenfor i forbindelsen med formlen I anførte betydninger, dehydratiseres, og at den resulterende forbindelse med formlen I vindes i form af en base eller i form af et syre-additionssalt deraf.wherein and R 2 have the meanings set forth above in the compound of formula I, are dehydrated and that the resulting compound of formula I is obtained in the form of a base or in the form of an acid addition salt thereof.
5 Forbindelserne med formlen Vildsom er hidtil ukendte, vindes ved, at man omsætter forbindelser med den almene formel IIThe compounds of the formula Wild which are novel, are obtained by reacting compounds of the general formula II
i is iii is ii
H -- I I IH - I I I
10 hvor R^· har den ovenfor anførte betydning, og X betegner chlor eller brom, med alkanoler med den almene formel IIIWherein R 2 is as defined above and X represents chlorine or bromine with alkanols of the general formula III
R30H IIIR30H III
hvor R3 betegner lavere alkyl, og derefter omdanner de vundne forbindelser med formlen IV 15 X OR3 0wherein R 3 represents lower alkyl and then the compounds of formula IV which are converted convert 15 X OR 30
hvor r1, R3 og X har de ovenfor anførte betydninger, ved HX-fraspalt-ning, hvor X har den ovenfor anførte betydning, til forbindelser med 20 den almene formel Vwherein R 1, R 3 and X have the above meanings, by HX cleavage, where X has the meaning given above, for compounds of general formula V
33
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OR3 <ip )OR3 <ip)
hvor R-* og rA har de ovenfor anførte betydninger, og derefter om-5 sætter forbindelserne med formlen V under Grignard-reaktionsbetingel-ser med forbindelser med den almene formel VIwherein R- and RA have the meanings set forth above, and then the compounds of formula V react under Grignard reaction conditions with compounds of general formula VI
MgHal vi 10 hvor har den ovenfor anførte betydning, og Hal betegner chlor, brom eller iod, til dannelse af forbindelser med den almene formel VII, - OR^ i r^V=V SniMgHal we 10 where has the meaning given above, and Hal represents chlorine, bromine or iodine to form compounds of general formula VII, - OR ^ in r ^ V = V Sni
» ui] P I»Ui] P I
vilwill
0H0H
l2L2
RR
15 hvor r1, R^ og har de ovenfor anførte betydninger, hvorefter forbindelserne med formlen VII hydrolyseres til dannelse af forbindelser med formlen VIII.15 and R1 have the meanings set forth above, after which the compounds of formula VII are hydrolyzed to form compounds of formula VIII.
R^ betegner i formlerne III, IV og V lavere alkyl med 1-4 carbonato-mer, fortrinsvis methyl.R ^ in formulas III, IV and V represents lower alkyl of 1-4 carbon atoms, preferably methyl.
20 Fremgangsmåden, ved hvilken forbindelserne med formlen I syntetiseres i udmærkede udbytter, beskrives nedenfor i enkeltheder.The process by which the compounds of formula I are synthesized in excellent yields is described below in detail.
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Til indføring af ethergruppen i forbindelserne med formlen II omsættes disse med forbindelserne med formlen III, hensigtsmæssigt under opvarmning, fortrinsvis under tilbagesvalingstemperatur.For introduction of the ether group into the compounds of formula II, these are reacted with the compounds of formula III, conveniently under heating, preferably under reflux temperature.
Ved omsætningen dannes som eneste reaktionsprodukt forbindelser med 5 formlen IV: Ethergruppen indføres overraskende nok praktisk taget kvantitativt i 10-stillingen i tricyclen.By reaction, as the only reaction product, compounds of formula IV are formed: surprisingly, the ether group is introduced, practically, quantitatively at the 10-position of the tricycle.
Ved omdannelse af forbindelserne med formlen IV til enoletheme med formlen V fraspaltes syren HX tinder alkaliske betingelser, fx ved behandling af forbindelserne med formlen IV med en opløsning af 10 kaliumhydroxid i et under de herskende betingelserne inert organisk opløsningsmiddel såsom methanol.By converting the compounds of formula IV into the enol ethers of formula V, the acid HX is cleaved off by alkaline conditions, for example by treating the compounds of formula IV with a solution of 10 potassium hydroxide in an inert organic solvent such as methanol.
Indføringen af en tert.alkoholfunktion i keto-enoletheren med formlen V er i princippet en Grignard-reaktion og kan foretages under de for fremstillingen af denne type forbindelser analoge betingelser.The introduction of a tert-alcohol function into the keto-enol ether of formula V is in principle a Grignard reaction and can be made under the conditions analogous to the preparation of this type of compound.
15 Til den praktiske udførelse af dette fremgangsmådetrin gås der fx frem på den måde, at en opløsning af en forbindelse med formlen V i et egnet organisk opløsningsmiddel dryppes til en opløsning af en forbindelse med formlen VI i et egnet organisk opløsningsmiddel, hvorefter reaktionsproduktet lades henstå i nogen tid ved stuetempe-20 ratur og derefter eventuelt opvarmes, hvorefter forbindelserne med formlen VII isoleres fra opløsningen på i og for sig kendt måde og oprenses.For the practical embodiment of this process step, for example, it is proceeded by dropping a solution of a compound of formula V in a suitable organic solvent to a solution of a compound of formula VI in a suitable organic solvent, after which the reaction product is allowed to stand. for some time at room temperature and then optionally heated, after which the compounds of formula VII are isolated from the solution in a manner known per se and purified.
Ved behandling af forbindelser med formlen VII med svage syrer såsom eddikesyre hydrolyseres kun enolethergruppen, hvorved der dannes 25 forbindelserne med formlen VIII.In treating compounds of formula VII with weak acids such as acetic acid, only the enol ether group is hydrolyzed to form the compounds of formula VIII.
Forbindelserne med formlen I, som er kendt fra DK-fremlæggelsesskrift nr. 134404, udmærker sig ved histaminolytiske egenskaber, som det fremgår af resultaterne i histamin-toxicitetsforsøg på marsvin, og de kan på grund af disse egenskaber anvendes ved allergiske lidelser af 30 forskellig oprindelse. Den histaminolytiske virkning hos disse forbindelser er specifik, da der ved hjælp af serotonin-toxicitetsforsøg 5The compounds of formula I, which are known from DK disclosure no. 134404, are distinguished by histaminolytic properties as evidenced by the results in histamine toxicity experiments on guinea pigs, and because of these properties they can be used for allergic disorders of 30 different origins . The histaminolytic effect of these compounds is specific, as by serotonin toxicity experiments 5
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og acetylcholin-toxicitetsforsog på marsvin ikke kunne fastslås signifikante serotoninantagonistiske og anticholinerge egenskaber.and acetylcholine toxicity tests on guinea pigs could not establish significant serotonin antagonistic and anticholinergic properties.
Særlig interessante repræsentanter for denne forbindelsesklasse er 4-(l-methyl-4-piperidyliden)-4H-benzo[4,5]cyclohepta[l,2-b]thiophen-5 10(9H)-on, 6-chlor- og 7-chlor-4-(l-methyl-4-piperidyliden)-4H-ben- zo[4,5]cyclohepta[1, 2 -b ]thiophen-10(9H)-on.Particularly interesting representatives of this class of compounds are 4- (1-methyl-4-piperidylidene) -4H-benzo [4,5] cyclohepta [1,2-b] thiophene-5 (9H) -one, 6-chloro- and 7-Chloro-4- (1-methyl-4-piperidylidene) -4H-benzo [4,5] cyclohepta [1,2-b] thiophen-10 (9H) -one.
Ved en fra DK-fremlæggelsesskrift nr. 134404 kendt fremgangsmåde til fremstilling af forbindelser med formlen I omsættes forbindelser med formlen VI med forbindelser med den almene formel IXIn a process known for the preparation of compounds of formula I known from DK-presenting publication No. 134404, compounds of formula VI are reacted with compounds of general formula IX
1010
XX
WJ-J ixWJ-J ix
IIII
o hvor R^· og X har de ovenfor anførte betydninger, de vundne reaktionsprodukter med formlen X,wherein R 2 and X have the above meanings, the reaction products obtained of formula X,
XX
15 I15 I
O OHO OH
I 2I 2
FTFT
hvor R·'-, og X har de ovenfor anførte betydninger, omdannes til forbindelser med den almene formel XIwherein R · and X have the meanings set forth above are converted into compounds of general formula XI
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66
XX
Rl-Ønul JL xi lRl-Enul JL xi l
RR
hvor R*·, R^ og X har de ovenfor anførte betydninger, forbindelserne med formlen XI omsættes med kaliumalkoholater til dannelse af forbindelser med den almene formel XII 5wherein R 1, R 2 and X have the meanings set forth above, the compounds of formula XI are reacted with potassium alcoholates to form compounds of general formula XII
YY
r1~{Qr pLil m '2r1 ~ {Qr pLil m '2
RR
hvor R^· og har de ovenfor anførte betydninger, og Y betegner alkoxy, denne forbindelse hydrolyseres, og den vundne blanding af 9-10 ketoner og 10-ketoner (2:1) adskilles. Denne adskillelse af isomere ketoner foretages ved fraktioneret krystallisation af deres fumara-ter.and R is the alkoxy, this compound is hydrolyzed and the resulting mixture of 9-10 ketones and 10-ketones (2: 1) is separated. This separation of isomeric ketones is accomplished by fractional crystallization of their fumarates.
Det kritiske trin ved den kendte fremgangsmåde er omsætningen af forbindelserne med formlen XI med alkoholater, som intermediært 15 forløber over en tredobbeltbinding, hvorved der hovedsagelig dannes 9-enolether, udover en mindre andel af de ønskede 10-enolethere.The critical step of the known process is the reaction of the compounds of formula XI with alcoholates, which intermediate proceeds over a triple bond, thereby forming mainly 9-enol ether, in addition to a minor proportion of the desired 10-enol ethers.
Denne type bireaktioner kan ikke konstateres ved anvendelse af forbindelserne med formlerne IV og V til fremstilling af forbindelserne med formlen I.This type of side reactions cannot be ascertained using the compounds of formulas IV and V to prepare the compounds of formula I.
20 Især forløber Grignard-reaktionen mellem forbindelserne med formlen V og forbindelserne med formlen VI glat og giver mindre anledning til bireaktioner end den tilsvarende omsætning af forbindelserne med 7In particular, the Grignard reaction between the compounds of formula V and the compounds of formula VI runs smoothly and gives less cause for side reactions than the corresponding reaction of the compounds with 7
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formlen VI med forbindelserne med formlen IX ifølge fremgangsmåden i DK-fremlæggelsesskrift nr. 134404.Formula VI having the compounds of Formula IX according to the method of DK Patent Specification No. 134404.
Totaludbyttet af forbindelser med formlen I ved fremgangsmåden ifølge opfindelsen (ud fra forbindelser med formlen II og hvor forbindelsen 5 med formlen V anvendes som mellemprodukt ved fremstilling af forbindelser med formlen VIII), ligger på 45-60%. Totaludbyttet af forbindelser med formlen I (ud fra forbindelser med formlen II) ved den i DK-patentskrift nr. 134404 beskrevne fremgangsmåde ligger på 10-15%.The total yield of compounds of formula I in the process of the invention (from compounds of formula II and wherein compound 5 of formula V is used as an intermediate in the preparation of compounds of formula VIII) is 45-60%. The total yield of compounds of formula I (from compounds of formula II) in the process described in DK Patent No. 134404 is 10-15%.
10 Fremgangsmåden ifølge opfindelsen belyses nærmere ved nedenstående eksempler. Af eksemplerne fremgår således, at en forbindelse med formlen I kan fremstilles ud fra en forbindelse med formlen II i et totaludbytte på 46%, idet en forbindelse med formlen II omsættes med en forbindelse med formlen III i et udbytte på 83% til dannelse af en 15 forbindelse med formlen IV (eksempel 2); denne forbindelse omdannes til en forbindelse med formlen V i et udbytte på 95% (eksempel 3); forbindelsen med formlen V omsættes med en forbindelse med formlen VI i et udbytte på 72% til dannelse af en forbindelse med formlen VII (eksempel la)), der derefter omdannes via en forbindelse med formlen 20 VIII til en forbindelse med formlen I i et udbytte på 81% (eksempel lb)).The process of the invention is illustrated in more detail by the following examples. Thus, it is apparent from the examples that a compound of formula I can be prepared from a compound of formula II in a total yield of 46%, reacting a compound of formula II with a compound of formula III in a yield of 83% to give a Compound of formula IV (Example 2); this compound is converted to a compound of formula V in a yield of 95% (Example 3); the compound of formula V is reacted with a compound of formula VI in a yield of 72% to give a compound of formula VII (Example 1a), which is then converted via a compound of formula 20 VIII to a compound of formula I in a yield of 81% (Example 1b)).
EKSEMPEL 1.EXAMPLE 1.
4-(l-Methyl-4-piperidyliden)-4H-benzo[4,5 cyclohepta[l,2-b]thiophen-10(9H)-on.4- (1-Methyl-4-piperidylidene) -4H-benzo [4,5 cyclohepta [1,2-b] thiophen-10 (9H) -one.
25 a) 3,07 g med iod aktiverede magnesiumspåner overhældes med 25 ml absolut tetrahydrofuran og tilsættes ca. 1/10 af en opløsning af 17,7 g 4-chlor-l-methylpiperidin-base i 70 ml absolut tetrahydrofuran. Ved tilsætning af nogle dråber 1,2-dibromethan sættes Grignard-reaktionen 30 i gang. Den resterende mængde 4-chlor-l-methylpiperidin-opløsning dryppes nu så hurtigt til magnesiumet, at reaktionsblandingen stadig koger under tilbagesvaling uden ydre varmetilførsel. Blandingen koges derefter i yderligere 1. time under tilbagesvaling. Derefter tilsæt- 8A) 3.07 g of iodine activated magnesium shavings are poured with 25 ml of absolute tetrahydrofuran and added to ca. 1/10 of a solution of 17.7 g of 4-chloro-1-methylpiperidine base in 70 ml of absolute tetrahydrofuran. By adding a few drops of 1,2-dibromoethane, Grignard reaction 30 is started. The remaining amount of 4-chloro-1-methylpiperidine solution is now dropped so rapidly to the magnesium that the reaction mixture still boils under reflux without external heat supply. The mixture is then refluxed for an additional 1 hour. Then add- 8
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tes ved 20°C og vinder let afkøling 15,3 g 10-methoxy-4H-benzo[4,5]-cyclohepta[l,2-b]thiophen-4-on (fremstillet som i eks. 3) portionsvis i løbet af 40 minutter. Efter 1 1/2 times omrøring ved 20°C hældes reaktionsopløsningen ud på en blanding af 180 g is og 20 g 5 ammoniumchlorid. Den frie base ekstraheres med chloroform. Chlorofor-mopløsningen inddampes, og remanensen omkrystalliseres af 270 ml absolut ethanol. På denne måde fås den rene 10-methoxy-4-(l-methyl-4-piperidyl)-4H-benzo[4,5]cyclohepta[l,2-b]thiophen-4-ol-base, som smelter ved 194-196°C. Mikroanalysen stemmer overens med formlen 10 C2oH23N02S. Udbytte: 72%.Tests at 20 ° C and gently cools 15.3 g of 10-methoxy-4H-benzo [4,5] -cyclohepta [1,2-b] thiophen-4-one (prepared as in Example 3) portionwise over time. of 40 minutes. After stirring for 1 1/2 hours at 20 ° C, the reaction solution is poured onto a mixture of 180 g of ice and 20 g of 5 ammonium chloride. The free base is extracted with chloroform. The chloroform solution is evaporated and the residue is recrystallized from 270 ml of absolute ethanol. In this way, the pure 10-methoxy-4- (1-methyl-4-piperidyl) -4H-benzo [4,5] cyclohepta [1,2-b] thiophen-4-ol base is obtained, which melts at 194 -196 ° C. The microassay corresponds to the formula 10 C 20 H 23 NO 2 S. Yield: 72%.
b) En blanding af 3,4 g 10-methoxy-4-(l-methyl-4-piperidyl)-4H-benzo-[4,5]cyclohepta-[1,2-b]thiophen-4-ol-base og 40 ml 3N saltsyre holdes i et kogende vandbad i 1 time på 95-100°C. Derpå indstilles blandingen på alkalisk reaktion ved hjælp af koncentreret natriumhydroxidop-15 løsning under afkøling til 20eC, og den frie base ekstraheres med chloroform. Chloroformopløsningen inddampes, og remanensen omkrystalliseres af ethanol/vand 1:1. På denne måde fås den rene 4-(1-methyl- 4-piperidyliden) -4H-benzo [4,5]cyclohepta[l, 2-b] thiophen-10(9H) -on-base, som smelter ved 152-153eC. Mikroanalysen stemmer overens med 20 formlen C^jHj^NOS. Strukturen undersøges ved hjælp af IR-, NMR- og MS-spektrer. Udbytte: 81%.b) A mixture of 3.4 g of 10-methoxy-4- (1-methyl-4-piperidyl) -4H-benzo [4,5] cyclohepta- [1,2-b] thiophen-4-ol base and 40 ml of 3N hydrochloric acid are kept in a boiling water bath for 1 hour at 95-100 ° C. Then, the mixture is adjusted to alkaline reaction by means of concentrated sodium hydroxide solution with cooling to 20 ° C and the free base is extracted with chloroform. The chloroform solution is evaporated and the residue is recrystallized from ethanol / water 1: 1. In this way, the pure 4- (1-methyl-4-piperidylidene) -4H-benzo [4,5] cyclohepta [1,2-b] thiophene-10 (9H) -one base is obtained which melts at 152 ° C. 153eC. The microanalysis corresponds to the formula C ^ jHH ^NOS. The structure is investigated by IR, NMR and MS spectra. Yield: 81%.
Analogt med den i eksempel 1 beskrevne fremgangsmåde fås under anvendelse af: 6- chlor-10-methoxy-4H-benzo[4,5]cyclohepta[l,2-b]thiophen-4-on 25 6-chlor-4-(1-methyl-4-piperidyliden)-4H-benzo[4,5]cyclohepta[1,2-b]- thiophen-10(9H)-on (smeltepunkt 168-169°C); (det intermediært dannede 6-chlor-10-methoxy-4-(l-methyl-4-piperi-dyl) -4H-benzo[4,5]cyclohepta[l,2-b]thiophen-4-ol (forbindelse med formlen VIII) smelter ved 200-202°G); 30 7-chlor-10-methoxy-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-on 7- chlor-4-(l-methyl-4-piperidyliden)-4H-benzo[4,5]cyclohepta[1, 2 -b ] -thiophen-10(9H)-on (smeltepunkt 150-151°C); (det intermediært dannede 7-chlor-10-methoxy-4-(l-methyl-4-piperi-dyl)-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-ol (forbindelse med 35 formlen VIII) smelter ved 223-227°C under sønderdeling);Analogous to the procedure described in Example 1 is obtained using: 6- chloro-10-methoxy-4H-benzo [4,5] cyclohepta [1,2-b] thiophen-4-one 6-chloro-4- ( 1-methyl-4-piperidylidene) -4H-benzo [4,5] cyclohepta [1,2-b] -thiophen-10 (9H) -one (mp 168-169 ° C); (the intermediate formed 6-chloro-10-methoxy-4- (1-methyl-4-piperidyl) -4H-benzo [4,5] cyclohepta [1,2-b] thiophen-4-ol (compound of formula VIII) melts at 200-202 ° G); 7-Chloro-10-methoxy-4H-benzo [4,5] cyclohepta [1,2-b] thiophen-4-one 7- chloro-4- (1-methyl-4-piperidylidene) -4H-benzo [ 4,5] cyclohepta [1,2-b] -thiophen-10 (9H) -one (mp 150-151 ° C); (the intermediate formed 7-chloro-10-methoxy-4- (1-methyl-4-piperidyl) -4H-benzo [4,5] cyclohepta [1,2-b] thiophen-4-ol (compound of Formula VIII) melts at 223-227 ° C with decomposition);
DK 161324BDK 161324B
9 6-brom-10-methoxy-4H-benzo[4,5]cyclohepta[l,2-b]thiophen-4-on 6-brom-4-(l-methyl-4-piperidyliden)-4H-benzo[4,5]cyclohepta[l,2-b]thiophen-10(9H)-on (smeltepunkt 172-173°C); 7,10-dimethoxy-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-on 5 7-methoxy-4-(l-methyl-4-piperidyliden)-4H-benzo[4,5]cyclohepta[1,2- b]thiophen-10(9H)-on (smeltepunkt 157-158°C); 10-butoxy-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-on 4-(1-methyl-4-piperidyliden)-4H-benzo[4,5]cyclohepta[l,2-b]thiophen- 10(9H)-on (smeltepunkt 152-153°C).9 6-Bromo-10-methoxy-4H-benzo [4,5] cyclohepta [1,2-b] thiophen-4-one 6-bromo-4- (1-methyl-4-piperidylidene) -4H-benzo [ 4,5] cyclohepta [1,2-b] thiophen-10 (9H) -one (mp 172-173 ° C); 7,10-dimethoxy-4H-benzo [4,5] cyclohepta [1,2-b] thiophen-4-one 5 7-methoxy-4- (1-methyl-4-piperidylidene) -4H-benzo [4, 5] cyclohepta [1,2- b] thiophen-10 (9H) -one (mp 157-158 ° C); 10-Butoxy-4H-benzo [4,5] cyclohepta [1,2-b] thiophen-4-one 4- (1-methyl-4-piperidylidene) -4H-benzo [4,5] cyclohepta [1,2 -b] thiophene-10 (9H) -one (mp 152-153 ° C).
10 EKSEMPEL 2 9-Brom-9,10-dihydro-10-methoxy-4H-benzo[4,5]cyclohepta[1,2-b]thio-phen-4-on (forbindelse med formlen IV).EXAMPLE 2 9-Bromo-9,10-dihydro-10-methoxy-4H-benzo [4,5] cyclohepta [1,2-b] thiophen-4-one (compound of formula IV).
En suspension af 20 g 9,10-dibrom-9,10-dihydro-4H-benzo[4,5]cyclohep-ta[l,2-b]thiophen-4-on i 400 ml methanol koges i 5 timer under til-15 bagesvaling. Der fås 9-brom-9,10-dihydro-10-methoxy-4H-benzo[4,5]cyc-lohepta[l,2-b]thiophen-4-on (smeltepunkt 103-106eC). Udbytte: 83%.A suspension of 20 g of 9,10-dibromo-9,10-dihydro-4H-benzo [4,5] cyclohepta [1,2-b] thiophen-4-one in 400 ml of methanol is boiled for 5 hours under reflux. -15 baking. 9-Bromo-9,10-dihydro-10-methoxy-4H-benzo [4,5] cyclohepta [1,2-b] thiophen-4-one is obtained (mp 103-106 ° C). Yield: 83%.
Analogt med den i eksempel 2 beskrevne fremgangsmåde fås under anvendelse af de relevante udgangsforbindelser nedenstående forbindelser med den almene forøel IV: 20 9-Brom-6-chlor-9,10-dihydro-10-methoxy-4H-benzo[4,5]cyclohepta- [1,2-b]thiophen-4-on (smeltepunkt 134-136eC); 9-brom-7-chlor-9,10-dihydro-10-methoxy-4H-benzo[4,5]cyclohepta-[1,2-b]thiophen-4-on (smeltepunkt 135-137*0); 6,9-dibrom-9,10-dihydro-10-methoxy-4H-benzo[4,5]cyclohepta-25 [1,2-b]thiophen-4-on; 9-brom-9,10-dihydro-7,10-dimethoxy-4H-benzo[4,5]cyclohepta-[1,2-b]thiophen-4-on; 9-chlor-9,10-dihydro-10-methoxy-4H-benzo[4,5]cyclohepta-[1,2-b]thiophen-4-on; 30 9-brom-10-butoxy-9,10-dihydro-4H-benzo[4,5]cyclohepta[1,2-b]thiophen- 4-on (smeltepunkt 90-91eC); 10Analogous to the procedure described in Example 2, the following compounds are obtained using the general starting compound IV: 20 9-Bromo-6-chloro-9,10-dihydro-10-methoxy-4H-benzo [4,5] cyclohepta- [1,2-b] thiophen-4-one (mp 134-136 ° C); 9-bromo-7-chloro-9,10-dihydro-10-methoxy-4H-benzo [4,5] cyclohepta- [1,2-b] thiophen-4-one (mp 135-137 * 0); 6,9-dibromo-9,10-dihydro-10-methoxy-4H-benzo [4,5] cyclohepta-25 [1,2-b] thiophen-4-one; 9-bromo-9,10-dihydro-7,10-dimethoxy-4H-benzo [4,5] cyclohepta [1,2-b] thiophene-4-one; 9-chloro-9,10-dihydro-10-methoxy-4H-benzo [4,5] cyclohepta [1,2-b] thiophene-4-one; 9-bromo-10-butoxy-9,10-dihydro-4H-benzo [4,5] cyclohepta [1,2-b] thiophen-4-one (m.p. 90-91 ° C); 10
DK 161324 BDK 161324 B
9- brom-10-ethoxy-9,10-dihydro-4H-benzo[4,5]cyclohepta[1,2-b]thiophen- 4-on.9- bromo-10-ethoxy-9,10-dihydro-4H-benzo [4,5] cyclohepta [1,2-b] thiophen-4-one.
EKSEMPEL 3 10- Methoxy-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-on (forbindelse 5 med formlen V).Example 3 10- Methoxy-4H-benzo [4,5] cyclohepta [1,2-b] thiophen-4-one (Compound 5 of Formula V).
Til en opløsning af 17,5 g 9-brom-9,10-dihydro-10-methoxy-4H-benzo-[4,5]cyclohepta[l,2-b]thiophen-4-on i 400 ml methanol sættes 9 g kaliumhydroxid, og blandingen koges under tiLbagesvaling i 6 timer.To a solution of 17.5 g of 9-bromo-9,10-dihydro-10-methoxy-4H-benzo [4,5] cyclohepta [1,2-b] thiophen-4-one in 400 ml of methanol is added 9 g of potassium hydroxide and the mixture is refluxed for 6 hours.
Efter afkøling til 0-5°C frafiltreres det udfældede krystallisat og 10 omkrystalliseres af methanol. På denne måde fås rent 10-methoxy-4H-benzo[4,5]cyclohepta[l,2-b]thiophen-4-on, som smelter ved 164-166eC. Mikroanalysen stemmer overens med formlen C^^H^o°2s· Strukturen undersøges ved hjælp af NMR- og MS-spektrer. Udbytte: 95%.After cooling to 0-5 ° C, the precipitated crystallate is filtered off and recrystallized from methanol. In this way pure 10-methoxy-4H-benzo [4,5] cyclohepta [1,2-b] thiophen-4-one is obtained, which melts at 164-166 ° C. The microanalysis corresponds to the formula C ^^ HH ^ o ° 2s · The structure is investigated by NMR and MS spectra. Yield: 95%.
Analogt med den i eksempel 3 beskrevne fremgangsmåde under anvendelse 15 af de i og under eksempel 2 anførte forbindelser med formlen IV fås de nedenfor anførte forbindelser med formlen V: 6- Chlor-10-methoxy-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-on (smel-tepunkt 220-222°C); 7- chlor-10-methoxy-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-on (smel-20 tepunkt 216-218°C); 6-brom-10-methoxy-4H-benzo [4,5] cyclohepta [1,2-b] thiophen-4-on; 7,10-dimethoxy-4H-benzo[4,5]cyclohepta[l,2-b]thiophen-4-on; 10-butoxy-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-on (smeltepunkt 83-85eC); 25 10-ethoxy-4H-benzo[4,5]cyclohepta[l,2-b]thiophen-4-on (smeltepunkt 127-129eC).By analogy to the procedure described in Example 3 using the compounds of formula IV listed in and under Example 2, the following compounds of formula V: 6- chloro-10-methoxy-4H-benzo [4,5] cyclohepta [ 1,2-b] thiophen-4-one (m.p. 220-222 ° C); 7- chloro-10-methoxy-4H-benzo [4,5] cyclohepta [1,2-b] thiophen-4-one (m.p. 216-218 ° C); 6-bromo-10-methoxy-4H-benzo [4,5] cyclohepta [1,2-b] thiophen-4-one; 7,10-Dimethoxy-4H-benzo [4,5] cyclohepta [l, 2-b] thiophene-4-one; 10-butoxy-4H-benzo [4,5] cyclohepta [1,2-b] thiophen-4-one (mp 83-85 ° C); 10-Ethoxy-4H-benzo [4,5] cyclohepta [1,2-b] thiophen-4-one (mp 127-129 ° C).
Claims (1)
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH98572 | 1972-01-24 | ||
| CH98572A CH568312A5 (en) | 1972-01-24 | 1972-01-24 |
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| Publication Number | Publication Date |
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| DK238090D0 DK238090D0 (en) | 1990-10-02 |
| DK238090A DK238090A (en) | 1990-10-02 |
| DK161324B true DK161324B (en) | 1991-06-24 |
| DK161324C DK161324C (en) | 1991-12-09 |
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| Application Number | Title | Priority Date | Filing Date |
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| DK555680A DK154296C (en) | 1972-01-24 | 1980-12-29 | 4H-BENZOCYCLO (4,5) CYCLOHEPTA (1,2-B) THIOPHEN-4-ONER USED AS INTERMEDIATE PRODUCTS FOR THE PREPARATION OF THERAPEUTIC EFFECTIVE 4-PIPERIDYLIDEEN-4H-BENZO (4,5) CYCLOHEPTA THIOPHEN-10 (9H) -ONER AND A PROCEDURE FOR MANUFACTURING THESE INTERMEDIATES |
| DK238090A DK161324C (en) | 1972-01-24 | 1990-10-02 | METHOD FOR PREPARING 4- (1-SUBSTITUTED-4-PIPERIDYLIDE) -4H-BENZO (4,5) CYCLOHEPTA (1,2-B) THIOPHEN-10 (9H) -ONDERIVATIVES |
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| DK555680A DK154296C (en) | 1972-01-24 | 1980-12-29 | 4H-BENZOCYCLO (4,5) CYCLOHEPTA (1,2-B) THIOPHEN-4-ONER USED AS INTERMEDIATE PRODUCTS FOR THE PREPARATION OF THERAPEUTIC EFFECTIVE 4-PIPERIDYLIDEEN-4H-BENZO (4,5) CYCLOHEPTA THIOPHEN-10 (9H) -ONER AND A PROCEDURE FOR MANUFACTURING THESE INTERMEDIATES |
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| BE (1) | BE794370A (en) |
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| CH (1) | CH568312A5 (en) |
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| BRPI0821909A2 (en) * | 2008-01-30 | 2018-07-17 | Nippon Zoki Pharmaceutical Co., Ltd. | piperidine derivative |
| AU2009277496B2 (en) * | 2008-08-01 | 2013-09-26 | Nippon Zoki Pharmaceutical Co., Ltd. | Aminopropylidene derivative |
| JP5083989B2 (en) * | 2008-11-20 | 2012-11-28 | 日本臓器製薬株式会社 | Medicaments containing piperidine derivatives |
| CN104817532B (en) * | 2015-03-04 | 2017-07-25 | 浙江工业大学 | A kind of preparation method of the ketone of 10 methoxyl group 4H benzos [4,5] cycloheptatriene [1,2 b] thiazole 4 |
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