Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
  • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
  • C07D211/12—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with only hydrogen atoms attached to the ring nitrogen atom
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
  • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
  • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
  • C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/62—Oxygen or sulfur atoms
  • C07D213/70—Sulfur atoms

Definitions

• the alkyl radical may be substituted, for example, with a hydroxy, a mesyloxy or an amino group.
• the presence of either a single bond or a double bond between the 10 and 11 carbon atoms is indicated by the dotted line.
• the numbering of the dibenzocycloheptatriene ring system conforms to the Ring Index, number 2077.
• the radicals X and X may be hydrogen or a halogen which particularly is chlorine, bromine or fluorine, but X and X may as well be radicals such as trifluoromethyl, lower alkyl having up to four carbon atoms, lower alkoxy having up to four carbon atoms, or a mononuclear aryl radical such as phenyl.
• the radicals X and X may be similar or may be dissimilar and each benzene ring may have one or two of the aforementioned radicals attached to it.
• One or more of the hydrogens in positions 2, 3, 5, and 6 of the piperidine ring may be replaced by alkyl groups so long as the total number of carbon atoms in all such substituent alkyl groups does not exceed four.
• the invention also contemplates the N-oxides of compound I, which may be prepared from the bases by known methods.
• the compounds represented by the structure I are useful as intermediates and may be sold commercially for making the compounds of structure II.
• the compounds of structure II possess antiserotonin and antihistamine activity. They may be administered to persons in any of the usual pharmaceutical oral forms such as powders, capsules, tablets, elixirs and aqueous suspensions, in the amount of from l to 250 milligrams per dose taken 2 to 4 times a day. For sterile solutions, for injection, from 0.1 to 50 milligrams would be injected per dose 2 to 4 times a day.
• the compound II may most easily be administered as a salt and any convenient, nontoxic acidsuch as hydrochloric acid may be used for this purpose and these salts are considered to be equivalent to the bases.
• dibenzo[a,e]cycloheptatrien-S-one and its 10,11-dihydro derivative are used as starting materials and they are hereinafter referred to generically as dibenzo[a,e]cycloheptatrien-S-ones. They may be prepared by using the process described by -A. C. Cope et al., entitled Cyclic Polyolefins, [XV. 1-methylene- 2,3,6,7-dibenzo-cycloheptatriene, appearing in I. Am.
• the selected dibenzo[a,e]cycloheptatrien-S one (III) is condensed with a 1-alkyl-4-piperidylmagnesium halide (IV) employing tetrahydrofuran as the solvent, the precautions usually taken to exclude air and moisture from the apparatus during Grignard reactions being observed. (See Step B hereinafter.)
• This 1-alkyl-4- piperidylmagnesium halide may be either the bromide or the chloride but is preferably the chloride.
• the Grignard reagent may be prepared as follows: The selected 1-alkyl-4-piperidone is reduced to the carbinol by the method described by S. M. McElvain and K. Rorig, J. Am. Chem. Soc. 70, 1826 (1948). The l-alkyl-4-piperidinol then may be converted to the l-alkyl- 4-chloropiperidine as described by these authors or to the 1-alkyl-4-bromopiperidine by the method employed by A. Einhorn, Ber. der Deutschen Chemischenmaschine 23, 2891 (1890) for the conversion of tropine to 3-bromotropane. The Grignard reagent is then prepared by combining the -1-alkyl-4-halopiperidine with magnesium, preferably using tetrahydrofuran as the solvent. The usual maintenance of dry conditions should be observed. This may be represented as follows:
• StepB The condensation reaction of StepB is preferably initially carried out at low temperature for example cooling by means of an ice bath and finally may, continue at room temperature. It has been found that tetrahydrofuran is an. excellent solvent for carrying out the reaction of Step B and the source of this may be the solution obtained in Step- A.
• the dibenzo[a,e]cycloheptatrien-S-one can be added directly to the reaction mixture in which the Grignard reagent IV was prepared. However, any inert solvent for the reactants of Step B may be employed.
• Compound I is dehydrated to produce Compound 11, as is represented by the following:
• EXAMPLE la methy l-4- 5 -di benzo ⁇ a,e*] cycloh eptaltrierzy Z id cne -p iperidine hydrochloride hydrate 1 methyl-4-(5-dibenzo[a,e] cycloheptatrienylidene) -piperidine (0.400 g., 0.00139 mole) as obtained in Example I, was dissolved in 55 ml. of 1 N hydrochloric acid at the boiling point. The solution was allowed to cool to room temperature and to stand for 24 hours. The crystalline product was collected and dried in a vacuum desiccator over concentrated sulfuric acid and soda lime for 6 hours.
• the product then was pulverized and dried over calcium chloride and soda lime at 0.1 mm. for approximately 65 hours.
• the yield of dried product was 0.420 g.
• this substance sintered at 190 C. and melted at 214216 C. when heated at a rate of 6 per minute from 180 C.
• Step A and omitting the final period of heating.
• the 3 chlorodibenzo[a,e]cycloheptatrien 5 one employed in step B was prepared by the following sequence.
• 3-(p-chlorobenzylidene)-phthalide was prepared from pchlorophenylacetic acid and phthalic anhydride following essentially the method for the preparation of benzalpthalide described in Organic Syntheses Collective Volume II, page 61 (John Wiley and Sons, 1948).
• the 3-(pchlorobenzylidene)-phthalide was reduced to 2-(p-chlorophenethyl)-benzoic acid with phosphorus and hydriodic acid, essentially as described by A. C. Cope and S. W.
• EXAMPLE VII 4-(5-dibenz0 [a,e,] cycloheptatrienylidene) -piperidine STEP A.PREPARATION OF l-CYANOd-(zS-DIBENZO 11,13] -CYCLOHEPTATRIENYLIDENE) -PIPERIDINE A solution of 1-methyl-4-(5-dibenzo[a,e]cycloheptatrienylidene)-piperidene (8.9 g., 0.031 mole) in 20 ml.
• EXAMPLE VIII 1 -eIhyl-4-(5-dibenz0 [cw] cycloheptatrienylidene) -piperidine hydrogen maleate 4 (5 dibenzo[a,e]cycloheptatrienylidene) piperidine (1.093 g., 0.004 mole) was dissolved in 25 ml. of dry t-butyl alcohol. Potassium t-butoxide (4.5 m1. of a 0.97 molar solution in t-butyl alcohol) was added followed by 0.624 g. (0.004 mole) of ethyl iodide. The solution was allowed to stand at room temperature for 20 hours then heated on the steam-bath for 2 hours.
• EXAMPPLE XI 1 (Z-hydroxyethyl) 4 (5 dibenz0[a,e]cycloheptatri enylidene) -piperidine 4 (5 dibenzo[a,e]cycloheptatrienylidene)-piperidine (5.47 g., 0.02 mole) was dissolved in 109 ml. of ethanol. The solution was cooled to 0 C. and ethylene oxide was passed in until the gain in weight was 1.76 g. The container then was stoppered and heated to 65-70 C. in an autoclave for 1 hour. The solvent then was distilled and the last traces of alcohol and water removed by azeotropic distillation with benzene. The crystalline residue was extracted with boiling hexane and recrystallized from a mixture of benzene and hexane. Further recrystallization from mixtures of alcohol and water gave product, MP. 158-159 C.
• EXAMPLE XII 1 (2 methane snlfonyloxyethyl) 4 (5 dibenzo[a,e]- cycloheptatrienylidene)-piperidine hydrochloride 1 (2 hydroxyethyl) 4 (5 dibenzo[a,e]cycloheptatrienylidene)-piperdine (2.10 g., 0.00662 mole) was dissolved in ml. of. dry acetonitrile. A solution of methanesulfo-nic anhydride (1.22 g., 0.007 mole) in 4 ml. of acetonitrile was added and the solution allowed to stand at room temperature for 48 hours.
• the reaction mixture then was filtered and the solvent evaporated on the steam-bath under reduced pressure.
• the residue contained a white crystalline solid. It was taken up in ether and shaken with water till the solid dissolved. The ether layer then was separated, washed with water and evaporated.
• the residue, a clear dark brown resin weighed 6.31 g. It was dissolved in benzene, 25 m1. and treated with a solution of 4.70 g. (0.05 mole) of maleic anhydride in 50 ml. of benzene. The dark brown solution was refluxed on the steam-bath for 20 minutes. The Warm mixture then was treated with ml. of absolute methanol. The dark brown solution was decanted from a black tarry solid that had separated.
• the 3-methoxydibenzo[a,e]cycloheptatrien-S-one is obtained by the sequence employed for the preparation of 3- chlorodibenzo[a,e]cycloheptatrien-5-one except that 3 (p methoxybenzylidene)-phthalide is reduced to 2-(p-methoxyphenethyl)-benzoic acid by the three step method of W.Deutschs and H. Klinkhammer [Chemische Berichte, 84,671 (1951)] instead of employing the hydriodic acid method. 1
• the 3,7 dichlorodibenzo ⁇ a,e]cycloheptatrien-S-one is prepared from 3,7-dinitrodibenzo[a,e]cycloheptatrien-5- one by reducing the nitro groups to amino and replacing the amino groups by chlorine, employing the Sandmeyer reaction.
• the dinitrodibenzocycloheptatrienone is prepared by the method of T. W. Campbell, R. Ginsig and H. Schmid, Helv. Acta 36, 1489 (1953).
• the 4 methyl 10,11 dihydro 5 dibenzo[a,e]- cyclohept-atrien-5one is prepared by the cyclization of 2-methyl-6-phenethylbenzoic acid with polyphosphoric acid under the conditions for the cyclization of Z-phenethylbenzoic acid described by T. W. Campbell, R. Ginsig and H. Schmid, Helv. Chim. Acta 36, 1489 (1953).
• the 10,11 dihydro 2,3 dimethyl 7 isopropyl-dibenzoIa,e]cycloheptatrien-S-one is prepared by the following sequence.
• 4,5-dimethylphthalic anhydride is condensed with p-isopropylphenylacetic acid to give 3-(p-isopropylbenzylidene)-phthalide.
• Reduction with phosphorus and hydriodic acid gives 2- (p-isopropylphenethyl)-4,5- dimethylbenzoic acid.
• the acid is cyclized to the desired ketone by the action of polyphosphoric acid as described by T. W. Campbell, R. Ginzig and H. Schmid, Helv. Chim. Acta 36, 1489 (1953).
• the 10,11 dihydro 2,3 dichloro 7 methyldibenzo[a,e]cycloheptatrien-S-one is prepared by the sequence of reactions employed for the preparation of 10, 11 dihydro 2,3 dimethyl 7 isopropyldibenzo[a,e]- cycloheptatrien-S-one, described in Example XIX, employing 4,5-dichlorophtha1ic anhydride and p-methylphenylacetic acid as starting materials.

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Citations (6)

• 1959
  • 1959-07-13 US US826493A patent/US3014911A/en not_active Expired - Lifetime
  • 1959-08-28 GB GB7308/63A patent/GB931556A/en not_active Expired
  • 1959-08-28 GB GB29490/59A patent/GB931555A/en not_active Expired
  • 1959-09-01 BE BE582220A patent/BE582220A/fr unknown
  • 1959-09-03 DE DE1420072A patent/DE1420072C3/de not_active Expired
  • 1959-09-29 CH CH7878959A patent/CH387037A/de unknown
• 1960
  • 1960-08-30 FR FR837257A patent/FR490M/fr active Active
• 1964
  • 1964-12-29 OA OA51101A patent/OA00998A/xx unknown
  • 1964-12-30 MY MY51/64A patent/MY6400051A/xx unknown

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