US3784602A - Aryloxy-and arylthioalkanoic acids and esters and salts thereof - Google Patents

Aryloxy-and arylthioalkanoic acids and esters and salts thereof Download PDF

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US3784602A
US3784602A US00125823A US3784602DA US3784602A US 3784602 A US3784602 A US 3784602A US 00125823 A US00125823 A US 00125823A US 3784602D A US3784602D A US 3784602DA US 3784602 A US3784602 A US 3784602A
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tetrahydrodibenzofuran
mmol
acid
yloxy
tetrahydrodibenzothiophen
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J Frei
C Morel
O Wacker
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Novartis Corp
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Ciba Geigy Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/91—Dibenzofurans; Hydrogenated dibenzofurans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/70—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/753—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/76—Dibenzothiophenes
    • H—ELECTRICITY
    • H01—ELECTRIC ELEMENTS
    • H01L—SEMICONDUCTOR DEVICES NOT COVERED BY CLASS H10
    • H01L24/00—Arrangements for connecting or disconnecting semiconductor or solid-state bodies; Methods or apparatus related thereto
    • H01L24/01—Means for bonding being attached to, or being formed on, the surface to be connected, e.g. chip-to-package, die-attach, "first-level" interconnects; Manufacturing methods related thereto
    • H01L24/02—Bonding areas ; Manufacturing methods related thereto
    • H01L24/04—Structure, shape, material or disposition of the bonding areas prior to the connecting process
    • H01L24/05—Structure, shape, material or disposition of the bonding areas prior to the connecting process of an individual bonding area

Definitions

  • the present invention relates to new aryloxyand arylthioalkanoic acids, their salts and functional derivatives, to processes for the production of the new compounds, to medicaments containing the new compounds, and to the use thereof.
  • R represents hydrogen or the methyl group
  • R represents the hydroxyl group, wherein the hydrogen atom can be replaced by an alkali metal atom or an alkaline-earth metal atom, an alkyloxy group having at most 3 carbon atoms, or the amino group, and
  • X and Y represent, independently of each other, oxygen or sulphur.
  • hypolipaemic activity which can be shown, e.g. by the lowering of the level of cholesterol and triglyceride in the blood and liver on repeated administration, in dosages of 2 times 10 mg./kg. per day to male rats, according to standard methods.
  • the total cholesterol is determined according to R. Richterich and K. Lauber [cp. Klin. Wienschrift 40, 1252-1256 (1962)] direct in the serum.
  • serumas well as liver-lipids are extracted according to J. Folch et a1. [cp. J. Biol. Chem.
  • the new compounds are distinguished by a, in comparison with the hypolipaemic activity, only slight hepatomegal activity.
  • R is, e.g. the methyl, ethyl, propyl, butyl, isobutyl, pentyl, isopentyl, 2,2-dimethylpropyl, hexyl, isohexyl, 3,3-dimethylbutyl, heptyl, nonyl, decyl, undecyl, dodecyl, tridecyl or tetradecyl group; and as a cycloalkyl group having 5-7 carbon atoms R, is, e.g. the cyclopentyl, cyclohexyl, or cycloheptyl group.
  • the new compounds of the General Formula I are produced according to the invention by reacting an alkali metal salt of a phenol or thiophenol of the General Formula H:
  • R R and R have the meaning given under the General Formula I, and A represents halogen, an alkylsulphonyloxy group or an arylsulphonyloxy group.
  • the reaction is preferably performed in a solvent or diluent.
  • solvents or diluents are, e.g. lower alkanols such as ethanol, or solvents free of hydroxyl groups, such as N,N-dimethylformamide, N,Nrdimethylacetamide, or N,N,N',N,N", "-hexamethylphosphoric acid triamide.
  • the reaction temperatures are between 50 and preferably at the boiling point of the applied solvent.
  • the boiling temperature of the solvent attainable under normal conditions can, if required, be raised by the reaction being performed in a closed vessel.
  • the formation of the alkali salts of phenols or thiophenols of the General Formula II which are used as starting material, and of the alkali salts of the carboxylic acids embraced by the General Formula HI is preferably efiected in situ, e.g. with the aid of an alkali metal alcoholate, alkali metal hydroxide, or alkali metal hydride, depending on whether an anhydrous alkanol or a solvent free of hydroxyl groups is used as the reaction medium.
  • an alkali metal hydride it is also possible to use a corresponding amide, e.g. sodium amide.
  • 6,7,8,9-tetrahydrodibenzofuran-2-ol can be produced in a simple manner by reaction of l-morpholinocyclohexene- (l) and p-benzoquinone at room temperature in methylene chloride, and splitting the initially obtained 5a,6,7,8, 9,9a-hexahydro-5a-morpholinodibenzofuran-2ol by boiling in aqueous hydrochloric acid to give 6,7,8,9-tetrahydrodibenzofuran-Z-ol and morpholine hydrochloride [cp. G. Domschke, J. Prakt. Chem. 32, 144-157 (1966)].
  • a further possibility for the production of 6,7,8,9-tetrahydrodibenzofuran-Z-ol which includes at the same time the production of 6,7,8,9-tetrahydrodibenzofuran-Ol, consists in reacting 2-chlorocyclohexanone or 2-bromocyclohexanone with an alkali metal salt of hydroquinonemonomethyl ether or resorcinmonomethyl ether, and then converting the firstly obtained 2-(4-methoxyphenoxy)cyclohexanone or 2-(3-methoxyphenoxy)-cyclohexanone in the presence of an acid catalyst such as, e.g.
  • methyl group can be split off, e.g. by boiling the substance in a mixture of concentrated hydrobromic acid and glacial acetic acid, or by heating with pyridine hydrochloride.
  • 6,7,8,9-tetrahydrodibenzofuran-Z-thiol, as well as 6,7, 8,9-tetrahydrodibenzofuran-3-thiol can be obtained in a simple manner, starting with the corresponding 2- or 3- hydroxy compounds, by reacting these with an N,N-dialkylthiocarbamic acid chloride, and rearranging the N,N- dialkylthiocarbamoyloxy group present in the 2- or 3- position to give the N,N-dialkylcarbamoylthio group, and subsequently hydrolyzing this.
  • the rearrangement is advantageously effected by the substance being heated for several hours to temperatures of 250-300 [cp. also M. S. Newman and H. A. Karnes, J. Org. Chem. 31, 3980- 3984 (1966)].
  • 6,7,8,9-tetrahydrodibenzothiophen-Z-ol and 6,7,8,9-tetrahydrodibenzothiophen-3-ol are produced by reacting e.g. 2-chloro or 2-bromocyclohexanone with an alkali salt of 4-methoxyand 3-methoxythiophenol to give 2-(4- methoxyphenylthio)-cyclohexanone and 2-(3-meth0xyphenylthio)-cyclohexanone, respectively, and converting these compounds by subsequent ring closure with phosphoric acid, and ether-splitting with pyridine hydrochloride, into 6,7,8,9-tetrahydrodibenzothiophen-2- or -3-ol.
  • 2-chloro or 2-bromocyclohexanone with an alkali salt of 4-methoxyand 3-methoxythiophenol to give 2-(4- methoxyphenylthio)-cyclohex
  • the starting materials of the General Formula III which embraces chlorides and bromides derived from 2- hydroxyalkanoic acids, -alkanoic acid esters and -alkanoic acid amides can be produced in a manner analogous to that for producing 2-bromopropionic acid ethyl ester [cp. Ann. 197, 13 (1879)].
  • the alkylor arylsulphonic acid esters likewise embraced by the General Formula III can be obtained, starting with the thus produced bromides, by reaction with corresponding sulphonic acid salts, or by reaction of 2-hydroxya1kanoic acids, -esters or -amides with an alkylor arylsulphonic acid chloride in the presence of alkali.
  • a-Halogenocarboxylic acids can moreover be produced by the generally known a-halogenation of carboxylic acids. Starting with these, the corresponding lower alkyl esters, and the amides likewise embraced by the General Formula HI are readily accessible in a manner known per se.
  • R R X and Y have the meanings given under the General Formula I, and their salts with alkali metals and alkaline-earth metals, can be produced using a second process according to the invention by hydrolyzing a functional derivative of such an acid.
  • Suitable functional derivatives of aryloxyand arylthioalkanoic acids of the General Formula Ia are esters thereof, e.g. lower alkyl esters, or the cyclohexyl, phenyl or benzyl ester, as well as nitriles, amides and lower imidoalkyl esters.
  • These functional derivatives or carboxylic acids of the General Formula Ia can be hydrolyzed by heating in an aqueous mineral acid, e.g. by boiling in 60-70% sulphuric acid, or in a mixture of, e.g. 6-n. hydrochloric acid and glacial acetic acid.
  • the free carboxylic acids of the General Formula Ia obtained by this procedure can optionally be converted into an alkali metal salt or alkaline-earth metal salt.
  • a solubility-promoting agent Suitable as such are water-miscible organic solvents such as, e.g. lower alkanols, tetrahydrofuran or, as already mentioned, glacial acetic acid.
  • the hydrolysis may, however, also be carried out in an alkaline medium, e.g.
  • alkanolic or aqueous-alkanolic alkali hydroxide solutions to temperatures between about 50 and the boiling temperature of the applied reaction medium.
  • alkali metal salts obtained direct with this procedure it is possible to obtain, if required, the free acids of the General Formula Ia by dissolving for example, the alkali salts in water and adding mineral acid.
  • the functional derivatives of alkanoic acids of the General Formula Ia required as starting materials can be obtained analogously to the first process by reacting an alkali metal salt of a phenol or thiophenol of the General Formula II with corresponding 2-brom0alkanoic acid esters, -am.ides and -nitri1es.
  • a further method of production of functional derivatives of carboxylic acids of the General Formula Ia consists in decarboxylating monoesters or monoamides of corresponding substituted aryloxyor arylthiomalonic acids, or corresponding substituted aryloxyor arylthiocyanoamtic acids.
  • R1 X--Z1 H 2 (IV) wherein R X and Y have the meanings given under the General Formula I, and Z and Z represent, independently of each other, lower alkoxycarbonyl groups or nitrile groups, until one of the groups Z or Z; is completely hydrolyzed and hydrogen is present in place of the other.
  • compounds of the General Formula IV are heated in an aqueous mineral acid, e.g. in 60-70% sulphuric acid or come. hydrochloric acid, and, optionally, the obtained carboxylic acid of the General Formula Ib is converted into an alkali metal salt or alkaline-earth metal salt.
  • the reaction is performed in the presence of an inert, water-miscible organic solvent which serves as solubility-promoting agent for the starting materials difiicultly soluble in water.
  • solvents it is possible to use, e.g. lower alkanols, tetrahydrofuran, glacial acetic acid, etc.
  • compounds of the General Formula IV are heated with alkanolic alkali hydroxide, e.g. with methanolic potassium hydroxide solution, or in aqueousalkanolic alkali hydroxide, and the alkali metal salts of carboxylic acids of the General Formula I-b obtained in this manner are optionally converted into the free acids.
  • alkanolic alkali hydroxide e.g. with methanolic potassium hydroxide solution
  • aqueousalkanolic alkali hydroxide e.g. with methanolic potassium hydroxide solution
  • the alkali metal salts of carboxylic acids of the General Formula I-b obtained in this manner are optionally converted into the free acids.
  • R R X and Y have the meanings given under the General Formula I until the equimolar amount of carbon dioxide is split off.
  • the compounds of the General Formula V can be heated either in sub stance or in an inert solvent, e.g. toluene or xylene, to temperatures of -150.
  • the compounds of the General Formula V can, for example, be produced by completely or partially saponifying esters of malonic acid or of malonamic acid. Malonamic acid can be obtained by addition of water to the nitrile group of the corresponding cyanoacetic acid esters and, immediately afterwards, sapo ni-fication of the ester group.
  • Alkali metal salts of carboxylic acids of the General Formula Ic are preferably produced by starting with acid salts of the malonic acids embraced by the General Formula V, heating these until the equimolar amount of carbon dioxide is split off and, optionally, liberating from the obtained salt the carboxylic acid embraced by the General Formula Ic.
  • reaction according to the invention is preferably performed by dissolving a compound of the General Formula VI in an inert solvent, and then introducing ammonia.
  • the acid halides thereby react already at room temperature, whereas aminolysis of the esters requires, as a rule, higher temperatures.
  • Suitable as solvents for the reaction of the acid halides embraced by the General Formula VI with ammonia are ethereal liquids such as, e.g. diethyl ether, tetrahydrofuran, or hydrocarbons such as, e.g.
  • benzene, toluene, and so forth, or chlorinated hydrocarbons such as chloroform and methylene chloride.
  • Suitable as solvent for the reaction of the esters likewise embraced by the General Formula V1 with ammonia are, besides the already stated higher ethers and hydrocarbons, also lower alkanols such as, e.g. methanol or ethanol.
  • the reaction is performed, e.g. by refluxing the ammonia-saturated solutions of the esters in the stated solvents, or, if necessaryy, it is performed under pressure in a closed vessel.
  • the acid halides of the General Formula VI which are used as starting materials can be obtained, starting with the corresponding carboxylic acids, by reaction with thionyl chloride or phosphorus pentachloride, phosphorus trichloride or phosphorus oxychloride.
  • the free carboxylic acids forming the basis of the compounds of the General Formula VI, as well as the esters embraced by this formula, can be produced, for their part, analogously to the first process by reaction of alkali metal salts of the corresponding phenols or thiophenols with a-halides of corresponding alkanoic acids or their lower alkyl esters.
  • R R X and Y have the meanings given under the General Formula I.
  • This process can be carried out by dissolving the nitrile of the General Formula VII used as starting material in a strong mineral acid, e.g. sulphuric acid, containing an amount of water sufficient for the formation of the amide, and subsequently stirring the solution for half an hour to one hour at temperatures between 20 and 60.
  • this reaction may also be carried out in the presence of a solvent, e.g. ether or tetrahydrofuran.
  • a further possibility of carrying out the reaction according to the invention consists in dissolving a nitrile of the General Formula VII in hydrous ether and feeding in gaseous hydrogen chloride.
  • a nitrile of the General Formula VII is reacted in an alkaline medium in the presence of hydrogen peroxide.
  • the reaction is performed in aqueous medium, whereby it is necessary to ensure, of course, that the medium contains a suflicient amount of water-miscible organic solvent, e.g. a lower alkanol, which will render certain the solubility of a nitrile of the General Formula VII.
  • a nitrile of the General Formula VII is first converted, by dissolving in an anhydrous lower (VII) alkanol and feeding in hydrogen chloride, into the imidoalkyl ester hydrochloride, and subsequently splitting this, by heating to temperatures of -130, preferably to into an amide of the General Formula Id and alkyl chloride.
  • the nitrile of the General Formula VII can be firstly converted into the imido ester hydrochloride by reaction with a lower alkanol in the presence of hydrogen chloride, and the imido ester hydrochloride then hydrolyzed to an ester of the General Formula Ie.
  • the conversion of the nitrile into the imido ester hydrochloride is advantageously performed in a solvent.
  • the solvent it is possible to use, e.g. excess alkanol, ether or chloroform.
  • the water-addition to the nitrile is advantageously carried out in 80-95% sulphuric acid, and to the obtained solution of the amide in sulphuric acid is added an excess of alkanol, and the mixture refluxed.
  • the isolation of the final product is performed most simply by dilution of the reaction mixture with water, whereby the desired ester precipitates as crude product.
  • the nitrile of the General Formula VH used as starting material can likewise be produced analogously to the first process by reaction of an alkali metal salt of a corresponding phenol or thiophenol with an a-halogenalkanoic acid nitrile.
  • aryloxyand arylthioalkanoic acids (likewise embraced by the General Formula I) of the above given General Formula Ia wherein R R X and Y have the meanings given under the General Formula I, and their salts with alkali metals and alkaline-earth metals, are produced according to an eighth process by reacting a bisalkali metal compound or bis-halogenmagnesium compound of a carboxylic acid of the General Formula VIII:
  • R A (IX) wherein R has the meaning given under Formula I, and A represents halogen, an alkylsulphonyloxy group or an arylsulphonyloxy group; optionally liberating from the obtained salt of a carboxylic acid of the General Formula Ia the carboxylic acid and, optionally, again converting it into an alkali metal salt or alkaline-earth metal salt.
  • Suitable bis-alkali metal compounds are, in particular, the hislithium compounds, also bis-sodium compounds.
  • the lithium-diisopropylamide is initially formed at ca.
  • hexamethylphosphoric acid triamide may optionally be omitted, especially with the use of starting materials having a methyl group as R
  • starting materials having a methyl group as R According to a further embodiment of the process are formed from sodium amide suspensions in liquid ammonia (which, for their part, have been obtained in situ from solutions of sodium in ammonia by addition of catalytic amounts of iron(III)-nitrate and stirring until the blue color of the metal solution has disappeared) and carboxylic acids of the General Formula VIII the bis-sodium compounds of the latter, and these then reacted with compounds of the General Formula IX, which are added dissolved in ether or tetrahydrofuran.
  • Bis-halogenmagnesium compounds of carboxylic acids of the General Formula VIlI are obtained, e.g. by reaction of these acids with the double-molar amount of isopropyl magnesium bromide or isopropyl magnesium chloride in ethereal solution at room temperature and a reac tion duration of ca. 4-15 hours.
  • the reaction is subsequently performed with the compounds of the General Formula IX likewise in ether, or in another ethereal solvent such as, e.g. tetrahydrofuran, at room temperature to boiling temperature of the reaction medium.
  • H Y (VIIIa) wherein X and Y have the meaning given under Formula I are likewise new materials. They are produced by reacting, e.g. analogously to the first process, an alkali metal salt of a compound of the General Formula II with a halogenated acetic acid, or a lower halogenated acetic acid alkyl ester; and hydrolyzing the alkyl ester firstly obtained in the last-mentioned case, analogously to the second process.
  • A is preferably bromine, but also iodine or chlorine, as an alkylsulphonyloxy group A is, e.g. the methanesulphonyloxy group, and as an arylsulphonyloxy group A is, e.g. the p-toluenesulphonyloxy group.
  • R has the meaning given under Formula I, or with the reaction product of the last two mentioned components, i.e. a compound of the General Formula XI:
  • the last-mentioned is preferably acetone, whereas a suitable halogen-substituted methane derivative is preferably chloroform, a suitable compound of Formula XI is preferably l,1,1-trichloro-2-methyl-2-propanol, and a suitable strong base is an alkali metal hydroxide such as sodium or potassium hydroxide.
  • Suitable alkali metal salts and alkaline-earth metal salts of carboxylic acids embraced by the General Formula I are, e.g. their sodium, potassium, lithium, magnesium, and calcium salts. These salts are produced, e.g. by the combining of acid and base in a suitable solvent such as, e.g. methanol, ethanol, or acetone/water. Formed salts which are relatively difficultly soluble can be isolated by filtration, and readily soluble sats by concentration by evaporation of the sovent. Furthermore, salts which are relatively difficultly soluble in the applied solvent may also be produced by double reaction of another salt of the acid with the base or with a suitable salt thereof.
  • the compounds of the General Formula I and the alkali salts and alkaline-earth metal salts of the free carboxylic acids embraced by this formula are administered, as previously mentioned, orally or parenterally.
  • the daily dosages vary between 0.5 and 10 mg./kg. for warm-blooded animals.
  • Suitable dosage units such as drages, tablets, suppositories, and capsules preferably contain as active substance 10-250 mg., e.g. 50 or 100 mg. of a compound of the General Formula I, or of an alkali metal salt or alkaline-earth metal salt of one of the free carboxylic acids embraced by the Genera Formula I.
  • Dosage units for oral administration contain as active substance preferably between 10 and of a compound of the General Formula I.
  • the said dosage units are produced by a combination of the active substance, e.g. with solid pulverulent carriers such as lactose, saccharose, sorbitol, mannitol; starches such as potato starch, maize starch or amylopectin, also laminaria powder or citrus pulp powder; cellulose derivatives or gelatine, optionally with the addition of lubricants such as magnesium or calcium stearate, or polyethylene glycols, to form tablets or drage cores.
  • the drage cores are coated, e.g. with concentrated sugar solutions which can also contain, e.g.
  • gum arabic, talcum and/or titanium dioxide are coated with a lacquer dissolved in readily volatile organic solvents or mixtures of solvents.
  • Dyestuffs may be added to these coatings, e.g. for identification of the various dosages of active substance.
  • suitable dosage units for oral administration are hard gelatine capsules, as well as as soft closed capsules made from gelatine and a softener such as glycerin.
  • the hard capsules contain the active substance preferably as a granulate, e.g. in admixture with fillers such as maize starch, and/or lubricants such as talcum or magnesium stearate, and optionally stabilizers such as sodium metadisulphite (Na S O or ascorbic caid.
  • the active substance is preferably dissolved or suspended in suitable liquids, such as liquid polyethylene glycols.
  • the granulate is dried for about 14 hours, and is then put through a sieve II-IIIa.
  • the granulate is thereupon mixed together with 16 g. of maize starch, 16 g. of talcum and 2 g. of magnesium stearate; the obtained mixture is then pressed to form 1000 drage cores.
  • These are coated with a concentrated syrup of 2 g. of lacca, 7.5 g. of gum arabic, 0.15 g. of dyestuffs, 2 g. of highly-dispersed silicon dioxide, 25 g. of talcum and 53.35 g. of sugar; the coated drage cores are then dried.
  • the obtained drages each weigh 260 mg. and each contain 100 mg. of active substance.
  • Example 1 In a round-bottomed flask fitted with reflux condenser, dropping funnel, stirrer, gas-inlet tube, and drying-tube containing potassium hydroxide, 4.0 g. (21.0 mMol) of 6,7,8,9-tetrahydrodibenzofuran-2-ol are added, under nitrogen, to a solution of 0.48 g. (21.0 mMol) of sodium in 50 ml. of absolute ethanol. To the thus obtained solution of sodium-6,7,8,9-tetrahydrodibenzofuran-Z-olate are added dropwise, with stirring, 4.98 g.
  • the 6,7,8,9-tetrahydrodibenzofuran-Z-ol used as starting material can be produced as follows:
  • Example 2 In a round-bottomed flask fitted with reflux condenser, dropping funnel, stirrer, gas-inlet tube, and drying tube containing potassium hydroxide, 3.76 g. (20.0 mMol) of 6,7,8,9-tetrahydrodibenzofuran-3-ol are added under nitrogen to a solution of 0.46 g. (20.0 mMol) of sodium in ml. of absolute ethanol. To the thus obtained solution of sodium 6,7,8,9 tetrahydrodibenzofuran-3-olate are added dropwise, with stirring, 5.02 g.
  • the 6,7,8,9 tetrahydrodibenzofuran-3-ol used as starting material can be produced as follows:
  • Example 3 In a round-bottomed flask fitted with reflux condenser, dropping funnel, stirrer, gas-inlet tube, and drying tube containing potassium hydroxide, 1.0 g. (4.9 mMol) of 6,7,8,9 tetrahydrodibenzofuran 2 thiol is added, under nitrogen, to a solution of 0.112 g. (4.9 mMol) of sodium in 10 ml. of absolute ethanol.
  • the 6,7,8,9-tetrahydrodibenzofuran-Z-thiol used as starting material can be produced as follows:
  • the ether phase is repeatedly washed with cold dilute sodium hydroxide solution and water, dried over magnesium sulphate, and concentrated by evaporation, whereby crude dimethylthiocarbamic acid-O-(6,7,8,9-tetrahydrodibenzofuran-2-yl)-ester remains behind as yellow-brown oil, which is then purified by column-chromatography [silicagel 0.05-O.2 mm., Merck, solvent: benzene/ethyl acetate (9:1)]. After concentration by evaporation of the pure fractions, these are recrystallized twice from aqueous methanol with the addition of active charcoal. Thus obtained is pure dimethylthiocarbamic acid-O-(6,7,8,9-tetrahydrodibenzofuran-Z-yl)ester, M.P. 129131.
  • Example 4 In a round-bottomed flask provided with reflux condenser, dropping funnel, stirrer, gas-inlet tube, and drying tube containing potassium hydroxide, 4.08 g. (20 mMol) of 6,7,8,9 tetrahydrodibenzofuran-3-thiol are added under nitrogen to a solution of 0.46 g. (20 mMol) of sodium in 100 ml. of absolute ethanol.
  • the 6,7,8,9-tetrahydrodibenzofuran-3-thiol used as starting material can be produced as follows:
  • Example 3(a) Analogously to Example 3(a) is obtained from 22.6 g. (0.12 mol) of 6,7,8,9-tetrahydrodibenzofuran- 3-01 and 19.8 g. (0.16 mol) of dimethylthiocarbamic acid chloride: dimethylthiocarbarnic acid--(6,7,8,9- tetrahydrodibenzofuran 3 yl)-ester, M.P. 158-159 (from ethyl acetate);
  • Example 3(b) Analogously to Example 3(b) is obtained from 19.0 g. (69.0 mMol) of dimethylthiocarbamic acid- O-(6,7,8,9-tetrahydrodibenzofuran-3-yl)-ester: dimethylthiocarbamic acid-S-(6,7,8,9-tetrahydrodibenzofuran- 3-yl)-ester, M.P. l02-103 (from ethanol/water).
  • Example 3(c) Analogously to Example 3(c) is obtained from 11.75 g. (42.0 mMol) of dimethylthiocarbamic acid- S-(6,7,8,9-tetrahydrodibenzofuran-3-yl)-ester: 6,7,8,9- tetrahydrodibenzofuran-3-thiol, M.P. 7374 (from methanol/ water).
  • the 6,7,8,9 tetrahydrodibenzothiophen-Z-ol used as starting material can be produced as follows:
  • Example 6 Analogously to Example are obtained from 4.08 g. (20.0 mMol) of 6,7,8,9-tetrahydrodibenzothiophen-3-ol and 5.02 g. (20.0 mMol) of 2-bromooctanoic acid ethyl ester: 2-(6,7,8,9-tetrahydrodibenzothiophen-3-yloxy)-octanoie acid ethyl ester; n 1.5482;
  • the crystalline crude product obtained after extraction with ether/methylene chloride (3:1), washing of the organic phase with water, drying over sodium sulphate, and concentration in vacuo, is filtered through silica gel [Merck, 0.05-0.2 mm., elution with benzene/ethyl acetate (9:1)], and recrystallized from methylene chlo h x ne- Th s 20 tained is 6,7,8,9-tetrahydrodibenzothiophen-3-0l, M.P. 117-118" (from methanol).
  • Example 7 To a solution of 0.11 g. (4.78 mMol) of sodium in 20 ml. of absolute ethanol is added 1.0 g. (4.54 mMol) of 6,7,8,9-tetrahydrodibenzothiophen-2-thiol. With stirring and whilst nitrogen is being introduced, 0.86 g. (4.78 mMol) of 2-bromopropionic acid ethyl ester are rapidly added dropwise to the above solution. The reaction mixture is refluxed for 3 hours. After cooling, the ethanol is evaporated off in vacuo, and the residue distributed between water and ether.
  • the 6,7,8,9-tetrahydrodibenzothiophene-Z-thiol used as starting material can be produced as follows:
  • Example 8 Analogously to Example 7 are obtained from 1.30 g. (5.90 mMol) of 6,7,8,9-tetrahydrodibenzothiophene-3-thiol and 1.48 g.
  • the 6,7,8,9-tetrahydrodibenzothiophene-3-thio1 used as starting material can be produced by a reaction sequence analogous to that described in Examples 7(a), (b) and (c):
  • Example 7(a) Analogously to Example 7(a) is obtained from 16.0 g. (78.3 mMol) of 6,7,8,9 tetrahydrodibenzothiophen-3-ol and 12.95 g. (104.9 mMol) of dimethylthiocarbamic acid chloride: dimethylthiocarbamic acid-O-( 6,7,8, 9-tetrahydrodibenzothiophen-3-yl)-ester, M.P. 139.5-140" (from methanol).
  • Example 7(c) Analogously to Example 7(c) is obtained from 8.74 g. (30.0 mMol) of dimethylthiocarbamic acid-S-(6, 7,8,9-tetrahydrodibenzothiophen 3 yl) ester: 6,7,8,9- tetrahydrodibenzothiophene-3-thiol, M.P. 36-365 (from hexane).
  • Example 9 In a round-bottomed flask fitted with reflux condenser, dropping funnel, stirrer, gas-inlet tube, and drying tube containing potassium hydroxide, 2.82 g. (15 mMol) of 6,7,8,9-tetrahydrodibenzofuran-Z-ol are added, under nitrogen, to a solution of 0.345 g. (15 mMol) of sodium in 25 ml. of absolute ethanol. To the thus obtained solution of sodium-6,7,8,9-tetrahydrodibenzofuran-Z-olate is added, with stirring, an ethanolic' solution (prepared in the same manner) of the sodium salt of 2-bromoheptanoic acid [from 3.14 g.
  • Example 10 To a solution of 2.3 g. (100 mMol) of sodium in 100 m1. of absolute ethanol are added 10.20 g. (50 mMol) of 6,7,8,9 -tetrahydrodibenzothiophen-Z-ol. With stirring and whilst nitrogen is being introduced, a solution of 11.15 g. (50 mMol) of 2-bromooctanoic acid in 60 ml. of absolute ethanol is quickly added dropwise. The reaction mixture is refluxed for 4 hours, then concentrated in vacuo, and the residue taken up in water. After acidification with concentrated hydrochloric acid, extraction is performed with ether.
  • Example 11 In a round-bottomed flask fitted with reflux condenser, dropping funnel, stirrer, gas-inlet tube, and drying tube containing potassium hdyroxide, 4.0 g. (21 mMol) of 6,7,8,9-tetrahydrodibenzofuran 2 01 are added, under nitrogen, to a solution of 0.48 g. (21 mMol) of sodium in 50 ml. of absolute ethanol, To the thus obtained solution of sodium-6,7,8,9-tetrahydrodibenzofuran-2-olate is added, with stirring, a solution of 3.43 g. (21 mMol) of 2-chloroheptaneamide in 50 ml.
  • Example 12 In a round-bottomed flask fitted with reflux condenser, 6.2 g. (18 mMol) of 2-(6,7,8,9-tetrahydrodibenzofuran- 2-yloxy)-heptanoic acid ethyl ester are refluxed in a solution of 2.02 g. (36 mMol) of potassium hdyroxide, 60 ml. of methanol and 6 ml. of water for 4 hours. After cooling, the reaction mixture is concentrated in vacuo, the residue distributed between dilute hydrochloric acid and ether, and extracted with ether.
  • Example 13 In a round-bottomed flask fitted with reflux condenser, 5.7 g. (16 mMol) of 2-(6,7,8,9-tetrahydrodibenzofuran- 2-yloxy)-octanoic acid ethyl ester are refluxed in a solution of 2.0 g. (35 mMol) of potassium hydroxide in 50 ml. of methanol and 5 ml. of water for 3 hours. After cooling, the reaction mixture is concentrated in vacuo, the residue distributed between dilute hydrochloric acid and ether, and extracted with ether.
  • Example 14 In a round-bottomed flask provided with a reflux condenser, 1.4 g. (3.73 mMol) of 2-(6,7,8,9-tetrahydrodibenzofuran-2-ylthio)-octan0ic acid ethyl ester are refluxed in a solution of 0.414 g. (7.4 mMol) of potassium hydroxide in 20 ml. of methanol and 1 ml. of water for 5 /2 hours. After cooling, the reaction mixture is concentrated in vacuo, the residue distributed between water and ether, the aqueous phase acidified with 2-n. hydrochloric acid, and extracted with ether.
  • Example 15 In a round-bottomed flask fitted with reflux condenser, 6.35 g. (17 mMol) of 2-(6,7,8,9-tetrahydrodibenzofuran- 3-ylthio)-octanoic acid ethyl ester are refluxed in a solution of 2.6 g. (46 mMol) of potassium hydroxide in 60 ml. of ethanol and 6 ml. of water for 4 hours. After cooling, the reaction mixture is concentrated in vacuo, the oily residue suspended in Water, the suspension aciditied with dilute hydrochloric acid, and repeatedly extracted with ether.
  • Example 16 To a solution of 2.1 g. (5.607 mMol) of 2-(6,7,8,9- tetrahydrodibenzothiophen-Z-yloxy)-octanoic acid ethyl ester in 25 ml. of methanol is added a solution of 0.65 g. (9.96 mMol) of potassium hydroxide (86%) in 5 ml. of water. The mixture is refluxed for 1. /2 hours, and is then concentrated in vacuo. The residue is distributed between dilute hydrochloric acid and ether, and the crude precipitated carboxylic acid extracted with ether. The ether extract, washed until neutral with water, is dried over sodium sulphate, and concentrated in vacuo.
  • Example 17 Analogously to Example 16 are obtained:
  • Example 18 An amount of 1.0 g. (3.12 mMol) of 2-(6,7,8,9-tetrahydrodibenzothiophen-Z-ylthio)-propionic acid ethyl ester is dissolved in 20 ml. of methanol; to the solution are added 0.75 g. of potassium hydroxide and 2 ml. of water, and the whole is refluxed, whilst nitrogen is fed in, for 1% hours. After cooling, the reaction mixture is concentrated in vacuo, and the residue distributed between dilute hydrochloric acid and ether. The ether phase is separated, washed with water until neutral, dried over sodium sulphate, and concentrated by evaporation.
  • Example 20 An amount of 1.60 g. (4.60 mMol) of 2-(6,7,8,9-tetrahydrodibenzothiophen 2 ylthio)-heptaneamide is dissolved in 40 ml. of ethanol; to this solution is then added a solution of 2.3 g. (41 mMol) of potassium hydroxide in 40 ml. of water, and the reaction mixture refluxed for 45 hours. After the ethanol has been evaporated off in vacuo, the residue is distributed between l-n. hydrochloric acid and ether.
  • Example 21 In a round-bottomed flask fitted with reflux condenser and stirrer, 2.4 g. (7 mMol) of 2-(6,7,8,9-tetrahydrodibenzofuran-Z-yloxy)-octaneamide are refluxed in a mixture of 30 ml. of 6-n. hydrochloric acid and 50 ml. of glacial acetic acid for 5 hours. After cooling, the reaction mixture is concentrated in vacuo, and the residue remaining taken up in ether. The ethereal solution is firstly washed with water; it is then extracted with 2-n. sodium hydroxide solution, the alkaline extract separated, and washed with ether.
  • Example 22 In a round-bottomed flask fitted with reflux condenser, 0.3 g. (1 mMol) of 2-(6,7,8,9-tetrahydrodibenzofuran-Z- yloxy)-heptanoic acid nitrile are refluxed in a solution of 0.3 g. (5 mMol) of potassium hydroxide in 20 ml. of ethanol and 2 ml. of water for 20 hours. After cooling, the reaction solution is acidified with 2-n. hydrochloric acid, the ethanol evaporated off in vacuo, the aqueous phase remaining behind extracted with ether, and the ether solution Washed twice with water.
  • the 2-(6,7,8,9-tetrahydrodibenzofuran-Z-yloxy)heptanoic acid nitrile used as starting material can be produced as follows:
  • Example 23 To 3.28 g. mMol) of 2-(6,7,8,9-tetrahydrodibenzothiophen-Z-yloxy)-octanoic acid nitrile in 70 ml. of ethanol is added a solution of 5.0 g. (89 mMol) of potassium hydroxide in ml. of water, and the mixture is refluxed for 24 hours. The ethanol is then evaporated ofl? in vacuo, the residue acidified with 2-n. hydrochloric acid, and extracted with ether. The extract, washed with Water until neutral and dried over sodium sulphate, is concentrated in vacuo. The crude hydrolysis product remaining behind is recrystallized from hexane. Thus obtained is 2-(6,7,8,9-
  • the 2 (6,7,8,9-tetrahydrodibenzothiophen-Z-yloxy)- octanoic acid nitrile used as starting material can be produced as follows:
  • Example 24 A solution of 3.11 g. (10.0 mMol) of 2-(6,7,8,9-tetrahydrodibenzofuran 2 yloxy)-octanoic acid nitrile in 50 ml. of absolute chloroform and 5 ml. of absolute ethanol is saturated at 0 to 5 with dry hydrogen chloride gas; the solution is then stirred for 20 hours at room temperature, and subsequently concentrated in vacuo at 30. The crude 2 (6,7,8,9-tetrahydrodibenzofuran-2-y1oxy)-octanoic acid imidoethyl ester hydrochloride is refluxed with a solution of 2.0 g. (ca.
  • Example 25 In a round-bottomed flask fitted with reflux condenser and stirrer, 4.0 g. (9.3 mMol) of 2-(6,7,8,9-tetrahydrodibenzofuran-Z-yloxy)-2-hexylmalonic acid diethyl ester are refluxed in a mixture of ml. of 5-n. sulphuric acid and 50 ml. of glacial acetic acid for 20 hours. After cooling, the reaction mixture is concentrated in vacuo, and the oily residue remaining is distributed between ether and water. After the ether phase has been separated, it is first washed with water and then extracted with 100 m1. of 2% potassium hydroxide solution.
  • the thus obtained ethereal solution is washed with water until neutral, dried with magnesium sulphate, and concentrated in vacuo, whereby crude 2-(6, 7,8,9 tetrahydrodibenzofuran-Z-yloxy)-octanoic acid is obtained as yellow oil.
  • After recrystallization twice from hexane is obtained the pure acid in the form of white crystals, M.P. 99-100".
  • Example 26 In a round-bottomed flask fitted with reflux condenser and stirrer, 3.0 g. (6.9 mMol) of 2-(6,7,8,9-tetrahydrodibenzofuran-2-yloxy)-2-hexylmalonic acid diethyl ester are refluxed in 30 ml. of l-n. sodium hydroxide solution for 20 hours. After cooling, the reaction mixture is acidified with 1-n. hydrochloric acid, and extracted with ether. The ethereal solution is Washed with water until neutral, dried over magnesium sulphate, and concentrated by evaporation.
  • Example 27 To a solution of 1.34 g. (3.0 mMol) of 2-(6,7,8,9- tetrahydrodibenzothiophen-Z-yloxy)-2-hexylmalonic acid diethyl ester in 15 ml. of glacial acetic acid are added 3 ml. of 5-n. sulphuric acid, and the whole is then refluxed for 24 hours in a nitrogen atmosphere. The reaction mixture is afterwards concentrated in vacuo, and the oily residue distributed between water and ether.
  • Example 28 To 2.68 g. (6.0 mMol) of 2-(6,7,8,9-tetrahydrodibenzothiophen-2-yloxy)-2-hexylmalonic acid diethyl ester in 20 ml. of methanol is added a solution of 0.92 g. of potassium hydroxide in 3 ml. of water. With stirring and while nitrogen is being fed in, the mixture is then refluxed for 24 hours. After the solvent has been evaporated off, the residue is distributed between ether and l-n. hydrochloric acid. The ether phase is washed with water, dried over sodium sulphate, and concentrated in vacuo.
  • Example 29 In a round-bottomed flask fitted with reflux condenser and stirrer, 3.0 g. (7.8 mMol) of 2-(6,7,8,9-tetrahydrodibenzofuran 2 yloxy)-2-hexylcyanoacetic acid ethyl ester are refluxed in a solution of 50 ml. of glacial acetic acid and 10 ml. of 5-n. sulphuric acid for 20 hours. After cooling, the reaction mixture is concentrated in vacuo, and the residue remaining distributed between ether and water. The ether phase is separated, washed with water until neutral, dried with magnesium sulphate, and then concentrated in vacuo.
  • the 2-(6,7,8,9-tetrahydrodibenzofuran 2 yloXy)-2- hexylcyanoacetic acid ethyl ester used as starting material can be produced as follows:
  • Example 30 In a round-bottomed flask fitted with reflux condenser and stirrer, 2.11 g. mMol) of 2-(6,7,8,9-tetrahydrodibenzofuran-Z-yloxy)-2-hexylcyanoacetic acid ethyl ester are refluxed in a solution of 1.0 g. of potassium hydroxide in 25 ml. of ethanol and 2.5 ml. of water for hours. After cooling, the reaction mixture is concentrated in vacuo, the residue suspended in ca. 30 ml. of water, acidified with concentrated hydrochloric acid, and the thereby precipitating solid substance exhaustively extracted with ether, whereby only a small part goes into solution.
  • Example 31 In a round-bottomed flask fitted with reflux condenser and stirrer, 1.0 g. (2.6 mMol) of 2-(6,7,8,9-tetrahydrodibenzofuran-Z-yloxy)-2-hexylcyanoacetic acid ethyl ester is refluxed in 20 ml. of 1-n. sodium hydroxide solution for 22 hours. After cooling, the reaction mixture is acidified with concentrated hydrochloric acid, and extracted with ether. The ethereal solutions are washed with water until neutral, dried over magnesium sulphate, and concentrated by evaporation.
  • the thus obtained solid residue contains only very little 2-(6,7,8,9-tetrahydrodibenzofuran-2-yloxy)-octanoic acid.
  • the residue is extracted with hot hexane, whereby only a small part of the residue goes into solution. After concentration by evaporation of the hexane extract, the thereby obtained residue is recrystallized from hexane.
  • 2-(6,7,8,9- tetrahydrodibenzofuran 2 yloxy)-0ctanoic acid M.P. 99100.
  • Example 32 With stirring and while nitrogen is being fed in, 2.31 g. (6.0 mMol) of 2-(6,7,8,9-tetrahydrodibenzothiophen-3- yloxy)-2-pentylcyanoacetic acid ethyl ester are refluxed in a solution of 35 ml. of glacial acetic acid and 7 ml. of 5-n. sulphuric acid for 48 hours. The reaction mixture is then concentrated by evaporation in vacuo, and the residue distributed between water and ether.
  • reaction mixture is refluxed for 2 /2 hours; it is then cooled, concentrated in vacuo, and the residue distributed between water and ether.
  • the ether phase Washed with Water and dried over sodium sulphate, is again concentrated by evaporation.
  • the crude product remaining behind is purified by chromatography on silica gel [elution with benzene/hexane (2:1)], whereby pure 2-(6,7,8,9 tetrahydrodibenzothiophen-3-yloxy)-2-pentylcyanoacetic acid ethyl ester, n 1.5504, is obtained.
  • Example 33 An amount of 3.4 g. (9.0 mMol) of 2-(6,7,8,9-tetrahydrodibenzofuran-Z-yloxy)-2-hexylma10nic acid is refluxed in 34 ml. of xylene for half an hour. After cooling, the reaction mixture is completely concentrated in vacuo. The thus obtained oily residue is recrystallized twice from hexane. Thus obtained is pure 2-(6,7,8,9-tetrahydrodibenzofuran-Z-yloxy)-octan0ic acid in the form of white needles, M.P. 99100.
  • the 2-(6,7,8,9-tetrahydrodibenzofuran 3 yloxy)-2- hexylmalonic acid used as starting material can be ob-' tained as follows:
  • Example 34 Analogously to Example 33 are obtained from 0.80 g. (ca. 2 mMol) of crude 2-(6,7,8,9-tetrahydrodibenzothiophen-Z-ylthio)-2-hexylmalonic acid: 2-(6,7, 8,9-tetrahydrodibenzothiophen-Z-ylthio)-octanoic acid, M.P. 91-92 (from hexane);
  • the starting materials are obtained analogously to Example 33(a), but with only two hours boiling, from 0.924 g. (2.0 mMol) of 2-(6,7,8,9-tetrahydrodibenzothiophen-Z-ylthio)-2-hexylmalonic acid diethyl ester, or 1,386 g. (3.0 mMol) of 2-(6,7,8,9-tetrahydrodibenzothiophen-3-ylthio)-2-hexylmalonic acid diethyl ester.
  • Example 35 An amount of 0.78 g. (ca. 2 mMol) of crude 2-(6,7, 8,9 tetrahydrodibenzothiophen-Z-yloxy)-2-hexylmalonic acid is heated under nitrogen for half an hour at 150.
  • the decarboxylated crude product is purified by chromatography on silica gel [elution with benzene and benzene/glacial acetic acid (19:1)]. After recrystallization of the pure iractions from hexane is obtained 2-(6,7,8,9- tetrahydrodibenzothiophen-Z-yloxy)-octanoic acid, M.P. 90-91".
  • the starting materials are obtained analogously to Example 33(a), but with only two hours boiling, from 0.892 g. (2.0 mMol) of 2-(6,7,8,9-tetrahydrodibenzothiophen-2-yloxy)-2-hexy1malonic acid diethyl ester, or 0.892 g. (2.0 mMol) of 2-(6,7,8,9-tetrahydrodibenzothiophen- 3-yloxy)-2-hexylmalonic acid diethyl ester.
  • Example 36 In a round-bottomed flask fitted with reflux condenser, stirrer, gas-inlet tube, and drying tube containing potas sium hydroxide are placed ml. of absolute benzene, 12.0 g. (99 mMol) of thionyl chloride and 0.5 ml. of dimethylformamide; to these are then added 9.4 g. (28 mMol) of 2- (6,7,8,9-tetrahydrodibenzofuran-Z-yloxy)- octanoic acid. After all acid is dissolved, refluxing is carried out for a further 2 hours.
  • the ether phase is dried with magnesium sulphate, and concentrated by evaporation, whereby is obtained in solid form crude 2-(6,7,8,9-tetrahydrodibenzofuran-Z-yloxy)-octaneamide. From ethanol/water crystallizes the pure amide, M.P. -13l.
  • Example 37 A solution of 3 g. (7.24 mMol) of 2-(6,7,8,9-tet-rahydrodibenzofuran-3-yloxy)-dodecanoic acid ethyl ester in 10 ml. of ethanol is heated with 20 g. of ammonia, at a maximum pressure of 45 bar, for 40 hours to 100. After concentration by evaporation and recrystallization of the thus obtained residue is obtained pure 2-(6,7,8,9-tetrahydrodibenzofuran-3-yloxy)-dodecaneamide, M.P. 131.5-
  • Example 38 While stirring is maintained, 1.19 g. (10.0 mMol) of thionyl chloride are added dropwise to a solution of 1.73 g. (5.0 mMol) of 2-(6,7,8,9-tetrahydrodibenzothiophen-3- yloxy)-octanoic acid in 25 ml. of absolute benzene and 0.1 ml. of dimethylforrnamide. The reaction mixture is refluxed for 1 /2 hours, and subsequently concentrated in vacuo. Excess thionyl chloride is removed by repeated addition of absolute benzene, and concentration in vacuo.
  • Example 39 In a round-bottomed flask fitted with stirrer, gas-inlet tube, thermometer, and drying tube containing potassium hydroxide, a solution of 1.1 g. (4.0 mMol) of 2-(6,7,8,9- tetrahydrodibenzofuran-2-yloxy)-heptanoic acid nitrile in 40 m1. of absolute chloroform and 2 ml. of absolute methanol is saturated at 5-8", with stirring, for minutes with dry hydrogen chloride, and subsequently stirred for 4 hours at room temperature. The reaction mixture is afterwards concentrated in vacuo, and the oily residue remaining behind heated, to remove the formed methyl chloride, for ca. 3 minutes in vacuo to 90.
  • Example 40 Dry hydrogen chloride gas is passed through the icecold solution of 1.40 g. (4.28 mMol) of 2-(6,7,8,9-tetrahydrodibenzothiophen-Z-yloxy)-octanoic acid nitrile in 80 ml. of absolute chloroform and 4 m1. of absolute meth- 40 anol until saturation is obtained, whereby care is taken to prevent the temperature exceeding 5.
  • the reaction mixture is allowed to stand, whilst being stirred, for a further 4 hours at room temperature; it is then concentrated in vacuo.
  • the oily residue is heated for-a further 10 minutes to in a water-jet vacuum. As frothing up occurs, methyl chloride is split oif.
  • the desired product is obtained direct in crystalline form. After recrystallization from methanol is obtained 2-(6,7,8,9-tetrahydrodibenzothiophen-Z-yloxy)-octaneamide, M.P. 116-117 (from methanol).
  • Example 41 In a round-bottomed flask fitted with stirrer, gas-inlet tube, thermometer, and drying tube containing potassium hydroxide, a solution of 3.11 g. (10 mMol) of 2-(6,7,8,9- tetrahydrodibenzofuran 2 yloxy)-octanoic acid nitrile in 50 ml. of absolute chloroform and 5 ml. of absolute ethanol is saturated at 0-5" with dry hydrogen chloride; the solution is then stirred for 20 hours at room temperature, and subsequently concentrated at 30 in vacuo. The residue is taken up in 40 ml. of dioxane, 4 ml. of water are added, and the thus obtained solution is stirred for 3 hours at 40.

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3846445A (en) * 1971-09-23 1974-11-05 Astra Laekemedel Ab Dibenzofuranyloxy and carbazolyloyx alkanoic acids and esters
US3953601A (en) * 1973-03-16 1976-04-27 Aktiebolaget Astra Dibenzothiophene derivatives as serum lipid lowering agents
US4101668A (en) * 1977-05-10 1978-07-18 Bristol-Myers Company Antiosteoporotic agents
US4185108A (en) * 1977-05-10 1980-01-22 Westwood Pharmaceuticals Inc. Antiosteoporotic agents
EP0050326A3 (en) * 1980-10-20 1982-07-21 Hoechst-Roussel Pharmaceuticals Incorporated Benzo(b)thiophenes
US4528399A (en) * 1981-04-22 1985-07-09 Hoechst-Roussel Pharmaceuticals Inc. Benzo[b]thiophenes intermediates
US4537976A (en) * 1981-04-22 1985-08-27 Hoechst-Roussel Pharmaceuticals Inc. Benzo[b]thiophenes
US6420408B1 (en) * 1998-07-30 2002-07-16 Warner-Lambert Company Tricyclic sulfonamides and their derivatives as inhibitors of matrix metalloproteinases

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US1997744A (en) * 1932-10-05 1935-04-16 Gen Aniline Works Inc Hydroxydiphenylene compound

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3846445A (en) * 1971-09-23 1974-11-05 Astra Laekemedel Ab Dibenzofuranyloxy and carbazolyloyx alkanoic acids and esters
US3953601A (en) * 1973-03-16 1976-04-27 Aktiebolaget Astra Dibenzothiophene derivatives as serum lipid lowering agents
US4101668A (en) * 1977-05-10 1978-07-18 Bristol-Myers Company Antiosteoporotic agents
US4125621A (en) * 1977-05-10 1978-11-14 Bristol-Myers Company Antiosteoporotic agents
US4185108A (en) * 1977-05-10 1980-01-22 Westwood Pharmaceuticals Inc. Antiosteoporotic agents
EP0050326A3 (en) * 1980-10-20 1982-07-21 Hoechst-Roussel Pharmaceuticals Incorporated Benzo(b)thiophenes
US4436748A (en) 1980-10-20 1984-03-13 Hoechst-Roussel Pharmaceuticals Inc. Benzo[b]thiophenes
US4528399A (en) * 1981-04-22 1985-07-09 Hoechst-Roussel Pharmaceuticals Inc. Benzo[b]thiophenes intermediates
US4537976A (en) * 1981-04-22 1985-08-27 Hoechst-Roussel Pharmaceuticals Inc. Benzo[b]thiophenes
US6420408B1 (en) * 1998-07-30 2002-07-16 Warner-Lambert Company Tricyclic sulfonamides and their derivatives as inhibitors of matrix metalloproteinases
US6492422B2 (en) 1998-07-30 2002-12-10 Warner-Lambert Company Tricyclic sulfonamides and their derivatives as inhibitors of matrix metalloproteinases

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DK128003B (da) 1974-02-18
CA948209A (en) 1974-05-28
IE35027B1 (en) 1975-10-29
CH542835A (de) 1973-10-15
CH542836A (de) 1973-10-15
SU404258A3 (enrdf_load_stackoverflow) 1973-10-26
ES389360A1 (es) 1973-06-01
NL7103358A (enrdf_load_stackoverflow) 1971-09-22
OA03697A (fr) 1971-12-24
DE2113455A1 (de) 1971-10-07
AT307407B (de) 1973-05-25
AT307406B (de) 1973-05-25
AT307403B (de) 1973-05-25
BE764536A (fr) 1971-09-20
FR2085725B1 (enrdf_load_stackoverflow) 1974-08-30
CH531501A (de) 1972-12-15
AT307409B (de) 1973-05-25
AT307404B (de) 1973-05-25
NO134655B (enrdf_load_stackoverflow) 1976-08-16
IE35027L (en) 1971-09-20
NO134655C (enrdf_load_stackoverflow) 1976-11-24

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