USRE30809E - Method of preparation of 3-(3-carboxy-4-hydroxyphenyl)-4,5-dihydro-2-phenylbenz [e]indole and valuable intermediates related thereto - Google Patents
Method of preparation of 3-(3-carboxy-4-hydroxyphenyl)-4,5-dihydro-2-phenylbenz [e]indole and valuable intermediates related thereto Download PDFInfo
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- USRE30809E USRE30809E US06/065,873 US6587379A USRE30809E US RE30809 E USRE30809 E US RE30809E US 6587379 A US6587379 A US 6587379A US RE30809 E USRE30809 E US RE30809E
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- 238000000034 method Methods 0.000 title claims abstract description 56
- HAWWPSYXSLJRBO-UHFFFAOYSA-N fendosal Chemical compound C1=C(O)C(C(=O)O)=CC(N2C(=CC=3C4=CC=CC=C4CCC=32)C=2C=CC=CC=2)=C1 HAWWPSYXSLJRBO-UHFFFAOYSA-N 0.000 title claims abstract description 13
- 239000000543 intermediate Substances 0.000 title abstract description 7
- 238000002360 preparation method Methods 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 22
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 35
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 239000002904 solvent Substances 0.000 claims description 17
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 15
- 229960000583 acetic acid Drugs 0.000 claims description 14
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 9
- 238000006243 chemical reaction Methods 0.000 claims description 9
- KBOPZPXVLCULAV-UHFFFAOYSA-N mesalamine Chemical compound NC1=CC=C(O)C(C(O)=O)=C1 KBOPZPXVLCULAV-UHFFFAOYSA-N 0.000 claims description 8
- 229960004963 mesalazine Drugs 0.000 claims description 8
- WYJDRDMLKVLOFR-UHFFFAOYSA-N 2-[2-(dimethylamino)-3,4-dihydronaphthalen-1-yl]-1-phenylethanone;hydrobromide Chemical group Br.C12=CC=CC=C2CCC(N(C)C)=C1CC(=O)C1=CC=CC=C1 WYJDRDMLKVLOFR-UHFFFAOYSA-N 0.000 claims description 7
- 239000012362 glacial acetic acid Substances 0.000 claims description 7
- SHLHKLFIKRKJRV-UHFFFAOYSA-M 1-phenyl-2-(2-pyrrolidin-1-ium-1-ylidene-3,4-dihydro-1h-naphthalen-1-yl)ethanone;bromide Chemical compound [Br-].C=1C=CC=CC=1C(=O)CC(C1=CC=CC=C1CC1)C1=[N+]1CCCC1 SHLHKLFIKRKJRV-UHFFFAOYSA-M 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 5
- UCGVRRXOEFAKFW-UHFFFAOYSA-N 2-[2-(dibutylamino)-3,4-dihydronaphthalen-1-yl]-1-phenylethanone;hydrobromide Chemical compound Br.C12=CC=CC=C2CCC(N(CCCC)CCCC)=C1CC(=O)C1=CC=CC=C1 UCGVRRXOEFAKFW-UHFFFAOYSA-N 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 238000009835 boiling Methods 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- HMUQIUZPAYOZGT-UHFFFAOYSA-M dibutyl-(1-phenacyl-3,4-dihydro-1h-naphthalen-2-ylidene)azanium;bromide Chemical compound [Br-].CCCC[N+](CCCC)=C1CCC2=CC=CC=C2C1CC(=O)C1=CC=CC=C1 HMUQIUZPAYOZGT-UHFFFAOYSA-M 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- VXZZQJSYMFAJRL-UHFFFAOYSA-M 1-phenyl-2-(2-piperidin-1-ium-1-ylidene-3,4-dihydro-1h-naphthalen-1-yl)ethanone;bromide Chemical compound [Br-].C=1C=CC=CC=1C(=O)CC(C1=CC=CC=C1CC1)C1=[N+]1CCCCC1 VXZZQJSYMFAJRL-UHFFFAOYSA-M 0.000 claims description 3
- ZHNDHRRQWDSRCE-UHFFFAOYSA-N 2-[2-(dipentylamino)-3,4-dihydronaphthalen-1-yl]-1-phenylethanone;hydrobromide Chemical compound Br.C12=CC=CC=C2CCC(N(CCCCC)CCCCC)=C1CC(=O)C1=CC=CC=C1 ZHNDHRRQWDSRCE-UHFFFAOYSA-N 0.000 claims description 3
- GMDHZXTVMFIZNC-UHFFFAOYSA-M dimethyl-(1-phenacyl-3,4-dihydro-1h-naphthalen-2-ylidene)azanium;bromide Chemical compound [Br-].C[N+](C)=C1CCC2=CC=CC=C2C1CC(=O)C1=CC=CC=C1 GMDHZXTVMFIZNC-UHFFFAOYSA-M 0.000 claims description 3
- SXCMYIPMFYMQOU-UHFFFAOYSA-M dipentyl-(1-phenacyl-3,4-dihydro-1h-naphthalen-2-ylidene)azanium;bromide Chemical compound [Br-].CCCCC[N+](CCCCC)=C1CCC2=CC=CC=C2C1CC(=O)C1=CC=CC=C1 SXCMYIPMFYMQOU-UHFFFAOYSA-M 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 3
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 125000001246 bromo group Chemical group Br* 0.000 claims description 2
- 229910052801 chlorine Chemical group 0.000 claims description 2
- 239000000460 chlorine Chemical group 0.000 claims description 2
- 150000001649 bromium compounds Chemical group 0.000 claims 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical group [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims 1
- 101150108015 STR6 gene Proteins 0.000 claims 1
- 230000000202 analgesic effect Effects 0.000 abstract description 2
- 230000003110 anti-inflammatory effect Effects 0.000 abstract description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 239000007787 solid Substances 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 6
- KCKZIWSINLBROE-UHFFFAOYSA-N 3,4-dihydro-1h-naphthalen-2-one Chemical compound C1=CC=C2CC(=O)CCC2=C1 KCKZIWSINLBROE-UHFFFAOYSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- AZUYLZMQTIKGSC-UHFFFAOYSA-N 1-[6-[4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methylindazol-5-yl)pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl]prop-2-en-1-one Chemical compound ClC=1C(=C2C=NNC2=CC=1C)C=1C(=NN(C=1C)C1CC2(CN(C2)C(C=C)=O)C1)C=1C=C2C=NN(C2=CC=1)C AZUYLZMQTIKGSC-UHFFFAOYSA-N 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- LIGACIXOYTUXAW-UHFFFAOYSA-N phenacyl bromide Chemical compound BrCC(=O)C1=CC=CC=C1 LIGACIXOYTUXAW-UHFFFAOYSA-N 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- 150000002081 enamines Chemical class 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- ZUMAGUBZZXWNRS-UHFFFAOYSA-N n,n-dibutyl-3,4-dihydronaphthalen-2-amine Chemical compound C1=CC=C2CCC(N(CCCC)CCCC)=CC2=C1 ZUMAGUBZZXWNRS-UHFFFAOYSA-N 0.000 description 2
- ZFOQAJYJFVWBKU-UHFFFAOYSA-N n,n-dipentyl-3,4-dihydronaphthalen-2-amine Chemical compound C1=CC=C2CCC(N(CCCCC)CCCCC)=CC2=C1 ZFOQAJYJFVWBKU-UHFFFAOYSA-N 0.000 description 2
- -1 naphthalene compound Chemical class 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 101100386054 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) CYS3 gene Proteins 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- QUSLRVPVUZMBTO-UHFFFAOYSA-N n,n-dimethyl-3,4-dihydronaphthalen-2-amine Chemical compound C1=CC=C2CCC(N(C)C)=CC2=C1 QUSLRVPVUZMBTO-UHFFFAOYSA-N 0.000 description 1
- UFWIBTONFRDIAS-UHFFFAOYSA-N naphthalene-acid Natural products C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- ROFVJSWBDQUQGW-UHFFFAOYSA-N piperidin-1-ium;bromide Chemical compound Br.C1CCNCC1 ROFVJSWBDQUQGW-UHFFFAOYSA-N 0.000 description 1
- 150000003233 pyrroles Chemical class 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 101150035983 str1 gene Proteins 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
- C07D295/112—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/58—[b]- or [c]-condensed
- C07D209/60—Naphtho [b] pyrroles; Hydrogenated naphtho [b] pyrroles
Definitions
- This invention relates to a method of preparation of 3-(3-carboxy-4-hydroxyphenyl)-4,5-dihydro-2-phenylbenz[e]indole, said compound being useful due to its antiinflammatory and analgesic activity.
- This invention further relates to the novel intermediates of the aforesaid method.
- the aforesaid patent describes the condensing of enamines with ⁇ -haloketones or aldehydes in a solvent such as dimethylformamide or toluene at a temperature of from 0° to 120° C., followed by hydrolysis to produce ⁇ -diketones or ⁇ -ketoaldehydes which can be further reacted to produce various pyrroles including 3-(3-carboxy-4-hydroxyphenyl)-2-phenyl-4,5-dihydrobenz[e]indole.
- 3-(3-carboxy-4-hydroxyphenyl)-4,5-dihydro-2-phenylbenz[e]indole can be prepared by reacting 5-aminosalicylic acid with an enammonium salt which, in .[.one of the possible.]. .Iadd.its .Iaddend.tautomeric forms, is represented by the .[.formula.]. .Iadd.following formulae and equilibrium, .Iaddend.
- R 1 and R 2 are the same or different and each represents alkyl of from 1 to 6 carbon atoms or, together with the nitrogen atom to which they are attached, form a pyrrolidino, or piperidino ring and X is bromine or chlorine.
- the reaction is carried out in a solvent such as glacial acetic acid, 2-propanol or methanol and at a temperature of from about ambient to the boiling point of the solvent.
- the enammonium salt is prepared by reacting a naphthalene compound of the formula ##STR2## in which R 1 and R 2 are as previously defined with phenacyl halide. This reaction can be carried out in dimethylformamide or toluene as a solvent at a temperature from about ambient to the boiling point of the solvent.
- b. 304 g of 5-aminosalicylic acid are added to 3800 ml of acetic acid while stirring.
- the stirred suspension is heated to 60° C. and 791 g of .Iadd.tautomeric 1-[3,4-dihydro-1-(2-oxo-2-phenylethyl)-2(1H)-naphthalenylidene]pyrrolidinium bromide in equilibrium with .Iaddend.1-phenacyl-2-(1-pyrrolidino)-3,4-dihydronaphthalene hydrobromide are added.
- An additional 150 ml of acetic acid are added to the reaction mixture, which is stirred at 70° C. for 3 to 4 hours and then cooled to ambient temperature.
- reaction mixture is then cooled to 20° C., filtered and the precipitate collected, washed successively with one 20 ml portion of acetic acid and five 20 ml portions of hexane and then dried for 20 hours under vacuum to give 3-(3-carboxy-4-hydroxyphenyl)-4,5-dihydro-2-phenylbenz[e]indole.
- 3-(3-carboxy-4-hydroxyphenyl)-4,5-dihydro-2-phenylbenz[e]indole can be prepared from .Iadd.tautomeric N-[3,4-dihydro-1-(2-oxo-2-phenylethyl)-2-(1H)-naphthalenylidene]-N-butyl-butanaminium bromide in equilibrium with .Iaddend.1-phenacyl-2-di-n-butylamino-3,4-dihydronaphthalene hydrobromide.Iadd.; .Iaddend.or .Iadd.tautomeric 1-[3,4-dihydro-1-(2-oxo-2-phenylethyl)-2(1H)-naphthalenylidene]-piperidinium bromide in equilibrium with .Iaddend.1-phenacyl-2-(1-piperidino)-3,4
- ⁇ -tetralone can be reacted with an amine to produce the naphthaleno compounds from which the corresponding enammonium salt is prepared.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
Abstract
A novel method of preparing the valuable compound 3-(3-carboxy-4-hydroxyphenyl)-4,5-dihydro-2-phenylbenz[e]indole is described, said compound possessing antiinflammatory and analgetic activity. Also described are novel intermediates useful in the disclosed method.
Description
This invention relates to a method of preparation of 3-(3-carboxy-4-hydroxyphenyl)-4,5-dihydro-2-phenylbenz[e]indole, said compound being useful due to its antiinflammatory and analgesic activity. This invention further relates to the novel intermediates of the aforesaid method.
To the best of my knowledge the method and the intermediates thereof described herein have not heretofore been described or suggested. While several synthetic routes for the preparation of 3-(3-carboxy-4-hydroxyphenyl)-4,5-dihydro-2-phenylbenz[e]indole are described by Allen et al., U.S. Pat. No. 3,878,225, none relate to the method of the present invention. Furthermore, the facile reaction of a poorly nucleophilic amino group such as that of 5-aminosalicylic acid with an .[.enamine.]. .Iadd.enammonium salt .Iaddend.is rather unexpected. The method described herein represents a preferred method inasmuch as it is a more economical way to produce the valuable 3-(3-carboxy-4-hydroxyphenyl)-4,5-dihydro-2-phenylbenz[e]indole.
The aforesaid patent describes the condensing of enamines with α-haloketones or aldehydes in a solvent such as dimethylformamide or toluene at a temperature of from 0° to 120° C., followed by hydrolysis to produce γ-diketones or γ-ketoaldehydes which can be further reacted to produce various pyrroles including 3-(3-carboxy-4-hydroxyphenyl)-2-phenyl-4,5-dihydrobenz[e]indole. While the above partially describes a general procedure whereby the novel intermediates of this method can be made, the patent does not teach or describe the presence or isolation of such intermediates or, even more importantly, their presently disclosed utility in my new method. As the prior art only describes a condensation reaction to prepare a third compound, there is no suggestion of any isolable or useful intermediate being produced in that procedure. Accordingly, the enammonium salts have now been effectively prepared, recognized, isolated and characterized for the first time and found especially suitable in a novel, preferred method for preparing valuable compounds.
I have now discovered that 3-(3-carboxy-4-hydroxyphenyl)-4,5-dihydro-2-phenylbenz[e]indole can be prepared by reacting 5-aminosalicylic acid with an enammonium salt which, in .[.one of the possible.]. .Iadd.its .Iaddend.tautomeric forms, is represented by the .[.formula.]. .Iadd.following formulae and equilibrium, .Iaddend. ##STR1## wherein R1 and R2 are the same or different and each represents alkyl of from 1 to 6 carbon atoms or, together with the nitrogen atom to which they are attached, form a pyrrolidino, or piperidino ring and X is bromine or chlorine. The reaction is carried out in a solvent such as glacial acetic acid, 2-propanol or methanol and at a temperature of from about ambient to the boiling point of the solvent.
The enammonium salt is prepared by reacting a naphthalene compound of the formula ##STR2## in which R1 and R2 are as previously defined with phenacyl halide. This reaction can be carried out in dimethylformamide or toluene as a solvent at a temperature from about ambient to the boiling point of the solvent.
The method of this invention is further illustrated in greater detail in the examples below.
a. A solution of 500 g of phenacyl bromide in 700 ml of dimethylformamide is added dropwise to a stirring solution of 505 g of 2-(1-pyrrolidino)-3,4-dihydronaphthalene in 1300 ml of dimethylformamide. After total addition the reaction mixture is stirred for an additional 4.5 hours and then 1280 ml of ether are added. The precipitate is removed by suction filtration and washed successively with a dimethylformamide-ether (1:2) mixture and ether, leaving a white solid. The solid is dried under a vacuum to give tautomeric 1-[3,4-dihydro-1-(2-oxo-2-phenylethyl-2(1H)-naphthalenylidene]-pyrrolidinium bromide in equilibrium with 1-phenacyl-2-(1-pyrrolidino)-3,4-dihydronaphthalene hydrobromide, .Iadd.having the .Iaddend.mp 217°-219° C.
b. 304 g of 5-aminosalicylic acid are added to 3800 ml of acetic acid while stirring. The stirred suspension is heated to 60° C. and 791 g of .Iadd.tautomeric 1-[3,4-dihydro-1-(2-oxo-2-phenylethyl)-2(1H)-naphthalenylidene]pyrrolidinium bromide in equilibrium with .Iaddend.1-phenacyl-2-(1-pyrrolidino)-3,4-dihydronaphthalene hydrobromide are added. An additional 150 ml of acetic acid are added to the reaction mixture, which is stirred at 70° C. for 3 to 4 hours and then cooled to ambient temperature. A solid appears and is collected by filtration, washed successively with acetic acid and petroleum ether and dried for 16 hours under vacuum to give 3-(3-carboxy-4-hydroxyphenyl)-4,5-dihydro-2-phenylbenz[e]indole.
A well stirred mixture of 3.98 g of .Iadd.tautomeric 1-[3,4-dihydro-1-(2-oxo-2-phenylethyl)-2(1H)-naphthalenylidene]pyrrolidinium bromide in equilibrium with .Iaddend.1-phenacyl-2-(1-pyrrolidino)-3,4-dihydronaphthalene hydrobromide (Example 1a), 1.53 g of 5-aminosalicylic acid and 10 ml of acetic acid is heated at reflux for 15 minutes. The reaction mixture is allowed to stand at ambient temperature and then diluted with 10 ml of acetic acid. The resulting solid is collected by suction filtration, washed with 50 ml of petroleum ether and then dried under high vacuum for 72 hours to give 3-(3-carboxy-4-hydroxyphenyl)-4,5-dihydro-2-phenylbenz[e]indole.
A mixture of 1.92 g of 5-aminosalicylic acid and 5.0 g of .Iadd.tautomeric 1-[3,4-dihydro-1-(2-oxo-2-phenylethyl)-2(1H)-naphthalenylidene]pyrrolidinium bromide in equilibrium with .Iaddend. 1-phenacyl-2-(1-pyrrolidino)-3,4-dihydronaphthalene hydrobromide (Example 1a), in 75 ml of methanol is refluxed under nitrogen for 9 hours. The solution is allowed to reach ambient temperature before being filtered. The methanol is removed under a vacuum to give a viscous oil which is dissolved in acetonitrile. This solution immediately crystallizes to give a yellow crystalline solid which is collected by filtration and washed with acetonitrile to give 3-(3-carboxy-4-hydroxyphenyl)-4,5-dihydro-2-phenylbenz[e]indole.
a. A mixture of 25 g of β-tetralone, 100 g of 4.[.a.]..Iadd.A .Iaddend.molecular sieves in 400 ml of toluene is ice-bath cooled and then saturated with dimethylamine. The reaction mixture is stirred at 100° C. for 4 hours, permitted to cool and then filtered. The toluene is evaporated off leaving a red oil which is vacuum distilled to give the yellow oil of .[.3,4-dihydro-2-naphthyl)-dimethylamine.]. .Iadd.2-dimethylamino-3,4-dihydronaphthalene.Iaddend..
b. A solution of 22 g of phenacyl bromide in 50 ml of dimethylformamide is added dropwise to a stirring solution of 2-dimethylamino-3,4-dihydronaphthalene in 70 ml of dimethylformamide. After total addition the reaction mixture is stirred for an additional 5 hours and then 400 ml of ether are added. The white precipitate is collected, washed with ether and then dried. Recrystallization from acetonitrile gives .[.the white solid, mp 145°-147° C., of.]. .Iadd.tautomeric N-[3,4-dihydro-1-(2-oxo-2-phenylethyl)-2(1H)-naphthalenylidene]-N-methylmethanaminium bromide in equilibrium with .Iaddend.1-phenacyl-2-dimethylamino-3,4-dihydronaphthalene hydrobromide .Iadd.as a white solid, mp 145°-147° C.Iaddend..
c. A mixture of 10.0 g of .Iadd.tautomeric N-[3,4-dihydro-1-(2-oxo-2-phenylethyl)-2(1H)-naphthalenylidene]-N-methylmethanaminium bromide in equilibrium with .Iaddend.1-phenacyl-2-dimethylamino-3,4-dihydronaphthalene hydrobromide and 4.1 g of 5-aminosalicylic acid in 50 ml of acetic acid is vigorously stirred at 75° C. for 4.5 hours. The reaction mixture is then cooled to 20° C., filtered and the precipitate collected, washed successively with one 20 ml portion of acetic acid and five 20 ml portions of hexane and then dried for 20 hours under vacuum to give 3-(3-carboxy-4-hydroxyphenyl)-4,5-dihydro-2-phenylbenz[e]indole.
By following the method of Example 1a the treatment of .Badd..[.2-di-n-butylamino-3,4-dihydro-naphthalene,2-diamylamino-3,4-dihydronaphthalene, .]..Baddend..Iadd.2-di-n-butylamino-3,4-dihydronaphthalene, 2-diamylamino-3,4-dihydronaphthalene, and .Iaddend.2-(1-piperidino)-3,4-dihydronaphthalene with phenacylbromide produces .Iadd.tautomeric N-[3,4-dihydro-1-(2-oxo-2-phenylethyl)-2(1H)-naphthalenylidene]-N-butyl-butanaminium bromide in equilibrium .Iaddend.with 1-phenacyl-2-di-n-butylamino-3,4-dihydronaphthalene hydrobromide, .Iadd.tautomeric N-[3,4-dihydro-1-(2-oxo-2-phenylethyl)-2(1H)-naphthalenylidene]-N-pentyl-pentanaminium bromide in equilibrium with .Iaddend.1-phenacyl-2-diamylamino-3,4-dihydronaphthalene hydrobromide, and .Iadd.tautomeric 1-[3,4-dihydro-1-(2-oxo-2-phenylethyl-2(1H)-naphthalenylidene]piperidinium bromide in equilibrium with .Iaddend.1-phenacyl-2-(1-piperidino)-3,4-dihydronaphthalene hydrobromide, respectively.
By following any of the methods of Examples 1b, 2, 3 or 4, 3-(3-carboxy-4-hydroxyphenyl)-4,5-dihydro-2-phenylbenz[e]indole can be prepared from .Iadd.tautomeric N-[3,4-dihydro-1-(2-oxo-2-phenylethyl)-2-(1H)-naphthalenylidene]-N-butyl-butanaminium bromide in equilibrium with .Iaddend.1-phenacyl-2-di-n-butylamino-3,4-dihydronaphthalene hydrobromide.Iadd.; .Iaddend.or .Iadd.tautomeric 1-[3,4-dihydro-1-(2-oxo-2-phenylethyl)-2(1H)-naphthalenylidene]-piperidinium bromide in equilibrium with .Iaddend.1-phenacyl-2-(1-piperidino)-3,4-dihydronaphthalene hydrobromide.
By following the method of Example 4a, β-tetralone can be reacted with an amine to produce the naphthaleno compounds from which the corresponding enammonium salt is prepared.
Claims (5)
1. A method of preparing 3-(3-carboxy-4-hydroxyphenyl)-4,5-dihydro-2-phenylbenz[e]indole which comprises reacting an enammonium salt which, in one of the possible tautomeric forms, is represented by the formula ##STR3## wherein R1 and R2 are the same or different and each represents alkyl of from 1 to 6 carbon atoms or, together with the nitrogen atom to which they are attached, form a pyrrolidino, or piperidino ring and X is bromine or chlorine with 5-aminosalicylic acid in a solvent and at a temperature of from about ambient to the boiling point of the solvent..]. .[.
2. The method defined in claim 1 wherein the solvent is methanol, 2-propanol or glacial acetic acid..]. .[.3. The method defined in claim 2 wherein the solvent is methanol and the reaction is carried out under reflux..]. .[.4. The method defined in claim 3 wherein the enammonium salt is 1-phenacyl-2-(1-pyrrolidino)-3,4-dihydronaphthalene hydrobromide..]. .[.5. The method defined in claim 3 wherein the enammonium salt is 1-phenacyl-2-(1-piperidino)-3,4-dihydronaphthalene hydrobromide..]. .[.6. The method defined in claim 3 wherein the enammonium salt is 1-phenacyl-2-dimethylamino-3,4-dihydronaphthalene hydrobromide..]. .[.7. The method defined in claim 2 wherein the solvent is glacial acetic acid and the reaction is carried out at a temperature of from 70° to 80° C..]. .[.8. The method defined in claim 7 wherein the enammonium salt is 1-phenacyl-2-(1-pyrrolidino)-3,4-dihydronaphthalene hydrobromide..]. .[.9. The method defined in claim 7 wherein the enammonium salt is 1-phenacyl-2-(1-piperidino)-3,4-dihydronaphthalene hydrobromide..]. .[.10. The method defined in claim 7 wherein the enammonium salt is 1-phenacyl-2-dimethylamino-3,4-dihydronaphthalene hydrobromide..]. .[.11. The method defined in claim 2 wherein the solvent is glacial acetic acid and the reaction is carried out at reflux..]. .[.12. The method defined in claim 11 wherein the enammonium salt is 1-phenacyl-2-(1-pyrrolidino)-3,4-dihydronaphthalene hydrobromide..]. .[.13. The method defined in claim 11 wherein the enammonium salt is 1-phenacyl-2-(1-piperidino)-3,4-dihydronaphthalene hydrobromide..]. .[.14. The method defined in claim 11 wherein the enammonium salt is 1-phenacyl-2-dimethylamino-3,4-dihydronaphthalene hydrobromide..]. .Iadd. 15. A method of preparing 3-(3-carboxy-4-hydroxyphenyl-4,5-dihydro-2-phenylbenz[e]indole which comprises reacting a tautomeric compound of the formula ##STR4## wherein R1 and R2 are the same or different and each represents alkyl of from 1 to 6 carbon atoms or, together with the nitrogen atom to which they are attached, form a pyrrolidino or piperidino ring and X is bromide or chloride with 5-aminosalicylic acid in a solvent at a temperature of from about ambient to the boiling point of the solvent.
.Iaddend..Iadd. 16. The method as defined in claim 15 wherein one tautomeric form is represented by the formula ##STR5##
.Iaddend. .Iadd. 17. The method as defined in claim 15 wherein one tautomeric form is represented by the formula ##STR6##
.Iaddend. .Iadd. 18. The method as defined in claim 15 wherein X is bromide. .Iaddend..Iadd. 19. The method as defined in claim 18 wherein R1 and R2 each represent alkyl of from 1 to 6 carbon atoms. .Iaddend..Iadd. 20. The method as defined in claim 18 wherein the tautomeric compound is 1-[3,4-dihydro-1-(2-oxo-2-phenylethyl)-2(1H)-naphthalenylidene]pyrrolidinium bromide in equilibrium with 1-phenacyl-2-(1-pyrrolidino)-3,4-dihydronaphthalene hydrobromide. .Iaddend..Iadd. 21. The method as defined in claim 18 wherein the tautomeric compound is 1-[3,4-dihydro-1-(2-oxo-2-phenylethyl)-2(1H)-naphthalenylidene]piperidinium bromide in equilibrium with 1-phenacyl-2-(1-piperidino)-3,4-dihydronaphthalene hydrobromide. .Iaddend. .Iadd. 22. The method as defined in claim 19 wherein the tautomeric compound is N-[3,4-dihydro-1-(2-oxo-2-phenylethyl)-2(1H)-naphthenylidene]-N-methylmethanaminium bromide in equilibrium with 1-phenacyl-2-dimethylamino-3,4-dihydronaphthalene hydrobromide. .Iaddend..Iadd. 23. The method as defined in claim 19 wherein the tautomeric compound is N-[3,4-dihydro-1-(2-oxo-2-phenylethyl)-2(1H)-naphthalenylidene]-N-butylbutanaminium bromide in equilibrium with 1-phenacyl-2-di-n-butylamino-3,4-dihydronaphthalene hydrobromide. .Iaddend..Iadd. 24. The method defined in claim 19 wherein the tautomeric compound is N-[3,4-dihydro-1-(2-oxo-2-phenylethyl)-2(1H)-naphthalenylidene]-N-pentyl-pentanaminium bromide in equilibrium with 1-phenacyl-2-diamylamino-3,4-dihydronaphthalene hydrobromide. .Iaddend..Iadd. 25. The method defined in claim 17 wherein the compound is 1-[3,4-dihydro-1-(2-oxo-2-phenylethyl)-2(1H)-naphthalenylidene]pyrrolidinium bromide. .Iaddend..Iadd. 26. The method defined in claim 17 wherein the compound is 1-[3,4-dihydro-1-(2-oxo-2-phenylethyl)-2(1H)-naphthalenylidene]piperidinium bromide. .Iaddend..Iadd. 27. The method defined in claim 17 wherein the compound is N-[3,4-dihydro-1-(2-oxo-2-phenylethyl)-2(1H)-naphthalenylidene]-N-methyl-methanaminium bromide. .Iadd. 28. The method defined in claim 17 wherein the compound is N-[3,4-dihydro-1-(2-oxo-2-phenylethyl)-2(1H)-naphthalenylidene]-N-butyl-butanaminium bromide. .Iaddend..Iadd. 29. The method defined in claim 17 wherein the compound is N-[3,4-dihydro-1-(2-oxo-2-phenylethyl)-2(1H)-naphthalenylidene]-N-pentyl-pentanaminium bromide. .Iaddend..Iadd. 30. The method defined in claim 16 wherein the compound is 1-phenacyl-2-(1-pyrrolidino)-3,4-dihydronaphthalene hydrobromide. .Iaddend..Iadd. 31. The method defined in claim 16 wherein the compound is 1-phenacyl-2-(1-piperidino)-3,4-dihydronaphthalene hydrobromide. .Iaddend..Iadd. 32. The method defined in claim 16 wherein the compound is 1-phenacyl-2-dimethylamino-3,4-dihydronaphthalene hydrobromide. .Iaddend..Iadd. 33. The method defined in claim 16 wherein the compound is 1-phenacyl-2-di-n-butylamino-3,4-dihydronaphthalene hydrobromide. .Iaddend..Iadd. 34. The method defined in claim 16 wherein the compound is 1-phenacyl-2-diamylamino-3,4-dihydronaphthalene hydrobromide. .Iaddend..Iadd. 35. The method defined in claim 15 wherein the solvent is methanol, 2-propanol or glacial acetic acid. .Iaddend..Iadd. 36. The method defined in claim 35 wherein the solvent is methanol and the reaction is carried out under reflux. .Iaddend. .Iadd. 37. The method defined in claim 35 wherein the solvent is glacial acetic acid and the reaction is carried out at a temperature of from 70° to 80° C. .Iaddend..Iadd. 38. The method defined in claim 35 wherein the solvent is glacial acetic acid and the reaction is carried out at reflux. .Iaddend.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US06/065,873 USRE30809E (en) | 1976-06-03 | 1979-08-13 | Method of preparation of 3-(3-carboxy-4-hydroxyphenyl)-4,5-dihydro-2-phenylbenz [e]indole and valuable intermediates related thereto |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US05/692,331 US4066659A (en) | 1976-06-03 | 1976-06-03 | Method of preparation of 3-(3-carboxy-4-hydroxyphenyl)-4,5-dihydro-2-phenylbenz (e) indole and valuable intermediates related thereto |
| US06/065,873 USRE30809E (en) | 1976-06-03 | 1979-08-13 | Method of preparation of 3-(3-carboxy-4-hydroxyphenyl)-4,5-dihydro-2-phenylbenz [e]indole and valuable intermediates related thereto |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US05/692,331 Reissue US4066659A (en) | 1976-06-03 | 1976-06-03 | Method of preparation of 3-(3-carboxy-4-hydroxyphenyl)-4,5-dihydro-2-phenylbenz (e) indole and valuable intermediates related thereto |
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| Publication Number | Publication Date |
|---|---|
| USRE30809E true USRE30809E (en) | 1981-12-01 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US06/065,873 Expired - Lifetime USRE30809E (en) | 1976-06-03 | 1979-08-13 | Method of preparation of 3-(3-carboxy-4-hydroxyphenyl)-4,5-dihydro-2-phenylbenz [e]indole and valuable intermediates related thereto |
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| Country | Link |
|---|---|
| US (1) | USRE30809E (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3845073A (en) * | 1971-06-03 | 1974-10-29 | Wyeth John & Brother Ltd | 2-(halophenyl)-1h-benz(g)indol-3-ylacetic acid derivatives |
-
1979
- 1979-08-13 US US06/065,873 patent/USRE30809E/en not_active Expired - Lifetime
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3845073A (en) * | 1971-06-03 | 1974-10-29 | Wyeth John & Brother Ltd | 2-(halophenyl)-1h-benz(g)indol-3-ylacetic acid derivatives |
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