US3097243A - Indane compounds - Google Patents

Description

United States Patent Office 3,097,243 Patented July 9, 1963 3,097,243 (TERTIARY AMINO-LOWER ALKOXY)INDANE COMPOUNDS Royal A. Cutler, Sand Lake, N.Y., assignor to Sterling Drug Inc., New York, N.Y., a corporation of Delaware No Drawing. Filed July 16, 1959, Ser. No. 827,439 2 Claims. (*Cl. 260--570.9)

This invention relates to basic ethers of ar-indanols and salts of said others, to intermediates for the same, and to preparation thereof.

More particularly, my new bases and their salts are ar- (tertiary amino-lower alkoxy)indane compounds having the structural formula K O-lower alkyleneZ- Formula I wherein X X and X, which can be the same or different, are members of the group consisting of hydrogen, lower alkyl, chlorine, bromine, and fluorine, Z represents a member of the group consisting of -N=B and where N=B contains 212 carbon atoms and is a member of the class consisting of di-( lower alkyD-amino, l-piperidyl, lower alkylated-l-piperidyl, 4-morph0linyl, 4-thiomorpholinyl, l-pyrrolidyl, lower alkylated-l-pyrrolidyl, l-hexamethyleniminyl, and l-heptamethyleniminyl, Y is a member of the group consisting of hydrogen, alkyl, lower alkenyl, and lower (monocarbocyclic aryl)methyl, and An is an anion.

As will be appreciated, the new ar-tertiary aminolower alkoxy)indanes of my invention are the 4-(tertiary amino-lower alkoxy)indanes having the structural formula O-lower alkyiene-Z Formula II and the S-(tertiary amino-lower alkoxy)indanes having the structural formula Formula III divalent saturated hydrocarbon bridge which joins the oxygen and nitrogen atoms of the compounds and intervenes two to five carbon atoms between the oxygen and nitrogen atoms, and contains a total of two to six carbon atoms. The lower alkylene thus includes such radicals as -CH CH -CH(CH )CH=, CH CH CH and the like.

The radicals X X and X in Formulas I, II, and III above represent the same or different members of the group consisting of: hydrogen; lower alkyl, that is, alkyl having 1-4 carbon atoms, for example, methyl, ethyl, npropyl, isopropyl, n-butyl, and the like; and chlorine, bromine, and fluorine.

The radical -N=B in Formulas I, II, and III above is a basic, aliphatic-type disubstituted amino radical which contains 2l2 carbon atoms and includes: (Ii-(lower alkyUamino wherein the two lower alkyl radicals are the same or different, and each lower alkyl contains from one to six carbon atoms, for example dirnethylamino, diethylamino, ethylmethylamino, isopropylrnethylamino, diisopropylamino, ethyl-n-propylamino, di-(n-butyl)amino, di-(n-hexyl)amino, and the like; l-piperidyl; lower alkylated-l-piperidyl, that is l-piperidyl bearing methyl and/or ethyl substituted on the carbon atoms thereof, for example 2-methyl-l-piperidyl, 3-ethyl-l-piperidyl, 4- methyl-l-piperidyl, 2-methyl-4-ethyl-l-piperidyl, 2,6-dimethyl-I-piperidyl, and the like; 4-morpholinyl; 4-thiomorpholinyl; l-pyrrolidyl; lower alkylated-l-pyrrolidyl, that is l-pyrrolidyl bearing methyl and/or ethyl substitut-ed on the carbon atoms thereof, for example Z-methyll-pyrrolidyl, 3-ethyl-l-pyrrolidyl, 3-methyl-4-ethyl-l-pyrrolidyl, 2,S-dimethyl-l-pyrrolidyl, and the like; l-hexamethyleniminyl; and l-heptamethyleniminyl.

It will be understood of course that when the radical Z in Formula I above is -N=B, the resulting structural formula O-lower alkylene-N=B Formula V represents the acid-addition salts of my new bases when Y is hydrogen, and the quaternary ammonium salts of my new bases when Y is other than hydrogen, that is, alkyl, lower alkenyl, or lower (monocarbocyclic aryl)- methyl. As is readily apparent, the acid-addition salts and the quaternary ammonium compounds possess the same structural nucleus as the bases, and the structure of 3 the bases thus constitutes the common characteristic feature of the three forms of the 4- and 5-(tertiary aminolower a1koxy)indane compounds of my invention.

The acid-addition salts (Formula V: Y=hydrogen) are conveniently prepared by interacting the free base with an approximately equivalent amount of the appropriate acid, H--An, in a suitable inert organic solvent medium. The resulting acid-addition salt is isolated in the usual manner, that is by cooling the solution to cause separation of the salt, after concentrating the solution if necessary, or the solvent is evaporated to leave the salt as a residue.

The acids used in forming the acid-addition salts (Formula V: Y:hydrogen) can be either organic or inorganic, weak or strong; and all of the resulting salts are useful. The choice of acid to be used will of course be dependent on the specific need involved. For example, some acid-addition salts are adapted to purposes of characterization, identification, or purification, and each is useful to regenerate the corresponding base if the acidaddition salt itself is found unsuited for some purposes. Pharmacodynamically acceptable acid-addition salts are of course prepared when a pharmaceutical use is contemplated; among such salts are those derived from hydrochloric acid, hydrobromic acid, hydriodic acid, phosphoric acid, sulfuric acid, sulfonic acid, ethanesulfonic acid, tartaric acid, citric acid, succinic acid, acetic acid, benzoic acid, quinic acid, oleic acid, tannic acid, and the like. If the particular acid-addition salt (Formula V: Y:I-I) at hand does not have the appropriate toxicity or solubility characteristics for the desired purpose, the base (Formula I) is regenerated in the usual manner by treating the acid-addition salt with a strong alkali, and the base can then be converted to a suitable acid-addition salt.

The hydrochlorides are the preferred acid-addition salts for most uses.

In the quaternary ammonium salts (Formula V: Y=other than H), alkyl preferably contains about 1-18 carbon atoms, lower alkenyl preferably contains about 1-6 carbon atoms, and lower (monocarbocylic aryl)methyl preferably contains about 7-12 carbon atoms. When An represents the anion of a strong inorganic acid or of a strong organic sulfonic acid, the quaternary ammonium salts are obtained by the addition of an alkyl, lower alkenyl or lower (monocarbocyclic aryl)methyl ester of the strong acid to the free base form (Formula IV) of my new compounds. The quaternizing esters, which form a well-known class in the quaternary ammonium art, include such compounds as methyl chloride, methyl bromide, methyl iodide, ethyl bromide, propyl chloride, n-hexyl chloride, isooctyl iodide, stearyl bromide, lauryl chloride, allyl chloride, allyl bromide, methyl sulfate, methyl benzenesulfonate, methyl ptoluenesulfonate, benzyl chloride, benzyl bromide, and substituted benzyl halides, such as p-chlorobenzyl chloride, p-nitrobenzyl chloride, p-methoxybenzyl chloride, p-isopropylbenzyl chloride, o-chlorobenzyl chloride, and the like. The quaternization reaction is carried out in conventional fashion by interacting the free base and the quaternizing ester in an inert solvent. Heating may be used to facilitate the reaction, but the quaternary salt formation usually takes place readily when the reactants are mixed at room temperature. The quaternary ammonium salt separates directly or can be obtained by suitable concentration of the reaction solution or removal of the solvent. When An in a desired quaternary ammonium salt is the anion of a weak acid, and it is not ordinarily possible to employ direct quatemization, conversion of one quaternary ammonium salt to another in which the anion is dilferent is carried out in the usual general fashion. Thus, a quaternary ammonium salt containing an anion which forms a water-insoluble silver salt is obtained by direct quaternization and then reacted with silver hydroxide (aqueous suspension of silver oxide) in aqueous medium to form the corresponding quaternary ammonium bydroxide, the original anion being removed as a precipitate. For instance, a quaternary ammonium chloride (Formula V: Yzother than H; An:Cl) can be used for this purpose of conversion, in which case the precipitate obtained is silver chloride. The quaternary ammonium hydroxide solution produced in this fashion is then neutralized with the appropriate acid, either weak or strong, to produce the desired new quaternary ammonium salt in which the anion is different from that of the original salt.

The compounds of my invention in free base form (Formula IV) are produced by interacting a suitable metal salt, such as an alkali metal salt, or an air-indanol having the structural formula Formula V1 with a tertiary amino-lower alkyl halide, halogen-lower alkylene N:B, wherein X X and X lower alkylene, and -N:B have the same significance set forth hereinabove. The formation of the alkali metal salt of the indanol is conveniently carried out by interacting the indanol (Formula VI) and an alkali metal base, for instance an alkali metal or an alkali metal hydride, lower alkoxide, or hydroxide, such as sodium, potassium, lithium, sodium hydride, potassium hydride, lithium hydride, sodium ethoxide, sodium isopropoxide, sodium hydroxide, potassium hydroxide, and the like. The resulting salt, without isolation if desired, is then treated with an approximately equivalent amount of the tertiary amino-lower alkyl halide, thereby producing the 4- or S-(tertiary amino-lower alkoxy)indane (Formula IV). This latter reaction is carried out at room temperature or, if preferred, at higher temperatures such as -150" C., or conveniently at the reflux temperature of the reaction mixture when a solvent is used. Advantageously, these reactions are carried out in the presence of a suitable inert liquid solvent, such as a lower alkanol, for eX- ample methyl alcohol, isopropyl alcohol, and ethyl alcohol, or N,N-dimethylformamide.

The structures of the compounds of my invention are established by the mode of their preparation and by chemical analysis establishing the percentage composition of carbon, hydrogen, and nitrogen, the percentage oxygen content being obtained by difference. The presence of a single basic nitrogen atom is confirmed by analysis of the bases and the salts obtained therefrom.

The new compounds (Formula I) of my invention have been found to have biocidal and biostatic activities, and they are useful for combatting deleterious bacteria and fungi present on surface areas of widely varying types, including surfaces which are either living or of inanimate nature, such as mucous membrane, skin, hair, fur, cloth, walls, floors, glassware, and the like. In such use, my new compounds are applied topically in any appropriate fashion, as by spraying, swabbing, immersing, or similar treatment of the surface on which the antibacterial or antifungal effect is desired. As will be appreciated, the particular mode of application in any given instance is chosen so as best to meet the requirements involved. For certain purposes, for example in disinfection of nonliving objects of wood or metal, the 4- or S-(tertiary aminoalkoxyfindane, or preferably an acid-addition or quaternary ammonium salt thereof, can be applied per so if desired. Generally speaking, however, it has been found preferable to apply the compounds, in a concentration of at least 0.1 percent by weight, in admixture with a suitable carrier; the carrier can be biologically inert, or on the other hand can have biological activity, for example antibacterial or antifungal activity, or can contain other biologically active ingredients,

For application of compositions containing the compounds (Formula I) to living tissue, it is of course de sirable and usually necessary that the carrier be innocuous and pharmaceutically acceptable; that is to say, the carrier should be substantially non-irritating, free of objectionable odor, and of low toxicity. Pharmaceutically acceptable carriers are of course well known in the pharmaceutical art and include, for example, powders such as talc, precpitated calcium carbonate, starches, and gums; ointments such as petrolatum, hydrogenated oils, soft fats and waxes, intermediately polymerized ethylene oxide and monoor di-glycerides of fatty acids; creams such as cetyl alcohol, stearic acid, oleic acid, and lanolin; jellies such as starch, tragacanth, agar-agar, and gelatin; liquid diluents, as for example water, liquid petrolatum, ethyl alcohol, vegetable oils, polyethylene glycol, acetone, glycerol, and syrups; and the like.

When applied by the above mentioned methods, the new compounds (Formula I) have useful bactericidal and bacteriostatic activity against a number of bacterial species. The following species are illustrative: Staphylococcus aureus, 209; Eberthella typhi, Hopkins; Clostridium welchii, M; and M ycobacterium tuberculosis, H37Rv; against these species the minimum bacteriostatic and bactericidal concentration by weight of the compounds of the examples described below were found to fall generally in the range from about 1:1000 to about 1:l20,000 as measured by conventional serial dilution techniques. The following fungi are illustrative of the species against which my compounds (Formula I) have useful 'fungistatic and fungicidal activity: Trichopkyton menmgrophytes, Aspergilllrs niger, and Monilia albicans; against these species the minimum fungistatic and fungicidal concentrations by weight of my compounds of the following examples were found to fall gen-erally in the range from about 1:1000 to about l:l35,000 as measured by conventional serial dilution techniques.

The indanols (Formula VI) used as starting materials for the preparation of my new compounds (Formula I) are old as a general class, and are readily prepared by known general procedures. For instance, a method of general applicability which can be employed involves interacting a phenol, X X X C H OH, in which the 3-position and at least one of the 2- and 4-positions of the phenol are unsubstituted, with beta-chloropropionyl chloride, thereby forming the beta-chloropropionate ester of the phenol. On heating this ester with aluminum chloride at 95-120 C. it rearranges to form the ortho-(beta chloropropionyl) phenol, and/or the para-(beta-chloropropionyl) phenol, depending on whether an ortho or the para-position, or both, of the starting ester is unsubstituted. This rearranged product is cyclized by heating with aluminum chloride at 165170 C. to produce a 4hydroxyl-indanone from an ortho-(beta-propionyl)phenol or a S-hydroxy-l-indanone from a para-(beta-propionyl)- phenol. Reduction of these indanones with zinc and hydrochloric acid yields an indanol (Formula VI) with the hydroxyl at the 4-position or the 5-position, respectively. The reaction conditions in the cyclization step can be readily adjusted to favor the production of either the 4- or the S-indanol compound, if both are possible, as desired. As will be obvious, when X is other than hydrogen and occupies the para position in the starting phenol, only a 4-indanol derivative is possible and is produced. This procedure is illustrated below in Example D.

Monoand dichloro-4- and S-indanols, which are also preparable by the above general procedure, can be obtained by chlorination of 4- and 5-indanols, as shown in Canadian Patent 557,116, granted May 6, 1958, and British Patent 770,593, published March 20, 1957.

My invention is illustrated by the following examples without, however, being limited thereto.

6 EXAMPLE 1 5 -(3-Diethylaminopropoxy)Indane A. A solution of sodium isopropoxide was prepared by adding 4.8 g. of sodium hydride in small portions to 200 m1. of anhydrous isopropyl alcohol. To this solution in a 500 ml. round-bottom flask fitted with a stirrer, dropping funnel, and reflux condenser with drying tube attached there was added 26.8 g. of S-indanol, and the resulting solution was heated to reflux temperature. The stirrer was then started, and 30 g. of 3-diethylarninopropyl chloride was added dropwise to the refluxing solution over a period of one hour. After this addition was completed, refluxing was continued for fifteen minutes more, and then the isopropyl alcohol was removed from the reaction mixture by distillation under reduced pressure. The residue in the distillation flask was diluted with 500 ml. of water and the oily layer which formed was dissolved in about 500 ml. of ethyl ether. The ethereal layer, which contained the desired product, 5-(3-diethylarninopropoxy)indane, was separated from the aqueous layer. The ethereal layer was then extracted with a solution of 18 ml. of concentrated hydrochloric acid in 300 ml. of water and the acidic aqueous extract was separated and mixed with 50 ml. of 35 percent aqueous sodium hydroxide solution, thus causing the separation of an oil. This oil was dissolved in ethyl ether, the solution was dried over anhydrous calcium sulfate, and then the ethyl ether Was removed by distillation under reduced pressure. There was obtained as a residue 43 g. of a pale yellow oil, which was then distilled under reduced pressure. The fraction distilling at l24l25 C. (0.2 mm.) was a colorless oil, n =l.5l03, which weighed 36 g.; it consisted of 5-(3-diethylaminopropoxy)- indane, having the structural formula OH: 01H, o-cmomcmrv our5 Analysis.-Calcd. for C H NO: N, 5.66. N, 5.72.

B. In the foregoing procedure, equivalent amounts of, metallic sodium, potassium hydride and lithium hydride, respectively, can be substituted for the sodium hydride with similar satisfactory results.

C. The hydrochloride of the above base was prepared by dissolving 16 g. of 5-(3-diethylaminopropoxy)indane in 50 ml. of isopropyl alcohol and adding 14 ml. of 5.6 N alcoholic hydrogen chloride solution. When the solution was chilled, the desired hydrochloride separated as a white flufly solid. This solid was collected on a filter and was washed first with cold isopropyl alcohol and then with ethyl ether, and the product was then dried for two hours at 70 C. There was thus obtained 12.5 g. of 5-(3-diethylaminopropoxy)indane hydrochloride as a white crystalline solid which melted at 106-109 C. Analysis.Calcd. for C ,;H NOl-ICl: C, 67.70; H, 9.23; Cl, 12.49. Found: C, 67.80; H, 8.75; CI, 12.49.

D. The methiodide of the base was prepared in the folling manner. 10 g. of 5-(3 diethylaminopropoxy)indanc and 8.5 g. of methyl iodide were dissolved at room temperature (about 26 C.) in 50 ml. of acetonitrile in a ml. round-bottom flask. Immediately after the reactants were mixed the temperature of the reaction mixture rose rapidly to about 49 C. The reaction mixture was allowed to stand overnight at room temperature, and carbon tetrachloride was then added to the solution until a slight cloudiness persisted. The mixture was then chilled and after several hours the white platelets which had separated from solution were collected on a filter and washed with carbon tetrachloride. On standing in air, the product became yellow. It was purified by dis- Found:

solving the crystals in hot benzene, decanting the hot benzene solution from a small amount of undissolved oil, and then cooling the benzene solution. The white crystals which separated from solution were collected on a filter. There was thus obtained 3.1 g. of 5-(3-diethylaminopropoxyfindane methiodide having the structural formula on, I

This product melted at 105-107 C. AnaIysis.-Calcd. for C H INO: C, 52.46; H, 7.25; I, 32.61. Found: C, 52.32; H, 6.82; I, 32.5.

E. Silver hydroxide is mixed with 5-(3-diethylaminopropoxy)-indane methiodide in aqueous solution, and the silver iodide which precipitates from the reaction mixture is collected on a filter. By evaporating the water from the filtrate, there is obtained N,N-diethyl-N-methyl-N- [3-(indan-S-yloxypropyl) -arnmonium hydroxide, having the structural formula This product is a strong base which reacts readily with acids to yield the corresponding quaternary ammonium salts. For instance it reacts with lactic acid to yield 5- (3-diethylaminopropoxy)indane methyl lactate having the structural formula CH: (EH5 4 -CHICH2CHz-N C\2 CgH 0 co ouon on.

F. The 2-chlorobenzyl chloride salt of the base was prepared as follows. A mixture of g. of 5 -(3-diethylaminopropoxyfindane and 6.5 g. of 2-chlorobenzyl chloride was placed in a 50 ml. one-neck flask and warmed on a steam bath for one and one-half hours. After the resulting oily reaction product had been allowed to stand at room temperature for one week it crystallized spontaneously. The solid thus obtained was recrystallized twice from benzene and then dried at 70 C. There was thus obtained 7.2 g. of S-(S-diethylaminopropoxy)indane 2-ohlorobenzyl chloride, having the structural formula as a white crystalline solid which melted at 139-142 C. Analysis.-Calcd. for C H Cl NO: Cl, 17.34; N, 3.43. Found: Cl, 17.36; N, 3.33.

EXAMPLE 2 4-(S-Dimethylaminopropoxy)Indane Proceeding in accordance with the mani ulative procedure of part A of Example 1, but substituting 26.8 g.

of 4-indanol for the 5 indanol, and substituting 33.2 g. of 3-dimcthylaminopropyl bromide for the 3-diethylaminopropyl chloride, the product obtained is 4-(3-dimethylaminopropoxy)indane, having the structural formula This base reacts with one equivalent of hydrogen chloride to yield 4-(3-dimethylaminopropoxy)indane hydrochloride; and treatment of the base with one equivalent of methyl iodide yields 4-(3-dimethylaminopropoxy)indane methiodide, having the structural formula CH3 CH3 EXAMPLE 3 4-(3-Diethylamin0pr0p0xy )Indane A. Proceeding in the manner described above in part A of Example 1, but using 26.8 g. of 4-indanol instead of S-indano], there was obtained as the reaction product a pale yellow oil which was distilled under reduced pressure. The fraction distilling at ll21l5 C. (0.15 mm.) was a colorless oil which weighed 32.9 g. and had n =l.5l39. This product was 4-(3-diethylaminopropoxy)indane, having the structural formula OCH2CHzCHr-N K C1115 Analysis.Calcd. for C H NOz C, 77.68; H, 10.19. Found: C, 76.57; H, 9.96.

B. The hydrochloride of the above base was prepared as follows. To a solution of 5 g. of 4-(3-diethylaminopropoxy)-indane in 1 00 ml. of anhydrous ethyl other there was added 4 ml. of 6 N alcoholic hydrogen chloride solution. When the resulting solution was allowed to stand at room temperature, a white crystalline solid separated from solution. This product was collected on a filter and then was recrystallized from isopropyl alcohol. There was thus obtained 4.1 g. of 4-(3-diethylaminopropoxyfindane hydrochloride as white crystals which melted at l44146 C. Analysis.Calcd. for C H NO.HCl: C, 67.71; H, 9.24; Cl, 12.49. Found: C, 67.40; H, 9.21;Cl, 12.24.

C. 4-(3-diethylarninopropoxy)indane reacts with one equivalent of benzyl bromide to yield 4-(3-diet-hylarninopropoxy)indane benzyl bromide, having the structural formula 9 10 EXAMPLE 4 EXAMPLE 6 4-(2-Dimethylaminoethoxy)Indcme 4-(Z-Diethylaminoethoxy)Indane Proceeding as described above in part A of Example 1, Employing the procedure described in part A of Exambut substituting 26.8 g. of 4-indanol for the S-indanol ple l, but substituting 26.8 g. of 4-indano1 for the 5-inand substituting 30.5 g. of 2-dimethylaminoethyl bromide danol and substituting 27.2 g. of 2-d1ethy1am1noethyl for the 3-diethylarninopropyl chloride, the product obchloride for the 3-diethy p py chlofidei the P Q tained is 4-(2-dirnethylaminoethoxy)indane, having the uct obtamed 1S 4-(2-diethylamlnoethoxy)indane, having structural formula the structural formula CH; CIHE OCH2CH:-N\ CH: CH; CH: C2135 CH: CH:

CH1 CH2 This base reacts with one equivalent of hydrogen chlorine This ase reads with ne equivalent of hydrogen chloto form 4-(Z-dlmethylaminoethoxy)indane hydrochloride. ride to form 4-(Z-chethylammoethoxy)rndane hydro- The base reacts with one equivalent of methyl iodide to ChlOflde- The base reacts Wlth 0116 eqlllvalfim of methyl yield 4-(2-dimethylaminoethoxy)indane methiodide, haviodide U0 form 4-(z-dlethylammoethoxy)illdane methioing h structural fg la dide, which is chemically identical with the compound designated by the alternative nomenclature 4-(2-ethyl- (3113 methylaminoethoxyfindane ethiodide in Example 5. O' CH2CHI N EXAMPLE 7 i ori 4 4-[2-(N-Isopropyl-N-Methylamino)Ethoxfllndane C 2 Proceeding in the manner described above in part A of Example 1, but substituting 26.8 g. of 4-indanol for CH: the S-indanol and substituting 27.2 g. of Z-(N-isopropyl- N-methylamino)ethyl chloride for the S-diethylamino- EXAMPLE 5 propyl chloride, there is obtained as the reaction product 4 [2 (N Ethyl N Melhyiamino)Ethoxyundane 4-[2-(N-isopropyl-N-methylamino)ethoxy]indane, having th struct 1 form 1 By substituting 26.8 g. of 4-indanol for the S-indanol 5 e um u a and by substituting 24.2 g. Z-(N-ethyl-N-methylamino)-ethyl chloride for the B-diethylaminopropyl chlo- 0H; ride in the procedure of part A of Example 1, there is obtained as the reaction product 4-[2-(N-ethyl-N-methylamino)ethoxy]indane, having the structural formula CH3 CH2 O-CH2CH:N/ CH/ on 2 i g This base reacts with one equivalent of methyl iodide to C 2 yield 4 [2 N isopropyl N methylamino)ethoxylindane methiodide, having the structural formula CH; CH: This base reacts with one equivalent of hydrogen bromide 5 to yield 4-[2-(N-ethyl-N-rnethylarnino)ethoxylindane hy- 0 OCHzCHz-N drobromide. The base reacts with one equivalent of 0H, (HUGH) ethyl iodide to yield 4-[2-(N-ethyl-N-methylarnino)eth oxy]indane ethiodide, having the structural formula. CH2 x CgH CH;

o-oniom-iir 1 and reacts with one equivalent of benzyl bromide to yield OH 4- 2-( N-isopropyl-N-methylamino )ethoxy] indane benzyl bromide, having the structural formula CHa CHQCQHQ and melting at approximately 100104 C. and reacts with one equivalent of allyl chloride to yield 4-[2-(N- ethyl-N-methylamino)ethoxy]indane allyl chloride, hav- 2 mg the structural formula 5 Br Caronon, C

CH3 CHz OCH:CH2- CH, H EXAMPLE 8 2 6 I 5-[2-(N-Isopropyl-N-Merhyl'am no)EthoxyJIIzdane Proceeding as in part A of Example 1, but using 27.2 g. of 2-(N-isopropyl-N-methylamino)ethyl chloride in place of the 3-diethylaminopropyl chloride, the product 1 1 obtained is -[2-(N-isopropyl-N-methylamino)ethoxy]- indane, having the structural formula CHa CH3 O-CH2CH2N CH1 This base reacts with one equivalent of methyl iodide to yield 5- 2- (N-isopropyl-N-methylamino ethoxy indane methiodide, having the structural formula CH. g -0c1non,-s 1 2 I 011mm EXAMPLE 9 S-(Z-Diethylaminoethoxy)Indane Analysis.-Calcd. for C H NO: N, 6.00. Found:

B. The hydrochloride of the above base Was prepared by dissolving 1g. of 5-(2diethylaminoethoxy)indane prepared in accordance with the method of part A above in 70 ml. of isopropyl alcohol and bubbling gaseous hydrogen chloride into the solution until the solution was slightly acidic. The reaction mixture was diluted with 800 ml. of ethyl ether and chilled at 6 C. overnight. The crystalline solid which had separated from the solution was then collected on a filter. This product, which weighed 29.6 g. and melted at 137-139 C., was 5-(2' diethylaminoethoxy)indane hydrochloride. Analysis. Calcd. for C H NOHCl: C, 66.76; H, 8.96; Cl, 13.14. Found: C, 66.65; H, 8.93; Cl, 13.16.

C. The above base reacts with one equivalent of methallyl bromide to yield 5-(Z-diethylaminoethoxy)indane methallyl bromide, having the structural formula and with one equivalent of stearyl chloride to yield 5-(2- diethylaminoethoxy)indane stearyl chloride, having the structural formula oestrous cm 4 OCH;OH -N C I C2115 EXAMPLE 1'0 5-(3-Dimethylaminopropoxy)Indane Proceeding as in part A of Example 1, except that 12 24.2 g. of 3-dimethylaminopropyl chloride is substituted for the 3-diethylaminopropyl chloride, the product obtained is 5-(3-dimethylaminopropoxy)indane having the structural formula CH2 /CH3 -0C HzCHzCHzN on,

This base reacts with one equivalent of methyl iodide to yield 5 (3 dimethylaminopropoxy)indane methiodide, having the structural formula and reacts with one equivalent of p-methylbenzyl chloride to yield 5-(S-dimethylaminopropoxy)indane p-methylbenzyl chloride, having the structural formula on, CH3 o-cmomoupzv a... 1 CH, 6112/ (:1

EXAMPLE 11 5,7-Dimcthyl-4-(3-Diethylamin0pr0poxy)Indane A. To an ice-cooled solution of 50 g. of 4-indanol in 50 m1. of isopropyl alcohol there was added an ice-cooled solution of 60 g. of dimethylamine in 200 ml. of water. The resulting solution was then further cooled to about 0 C. and 93 ml. of formalin was added dropwise, the temperature of the reaction mixture not being allowed to rise above 7 C. After this addition was completed, ml. of isopropyl alcohol was added, and the mixture was refluxed for three hours. The solvent and excess volatile reactants were removed by distillation under reduced pressure (water-pump), and the residual oil was distilled under reduced pressure. The fraction distilling at 137-l4l C. (0.3 mm.) was a colorless oil, 11 1.5340, which weighed 56.5 g.; this product was 5,7- bis(dirnethylaminomethyl)-4-indanol, having the structural formula OH 011. l

Analysis.Calcd. for C H N O: N, 11.28. Found: N, 11.25.

B. 56.5 g. of 5,7-bis(dimethylaminomethyl)-4-indanol was catalytically reduced with hydrogen in the presence of 7 g. of copper chromite catalyst in a bomb at a pressure of 2900 pounds per square inch and l15l20 C. The reduction product was isolated as follows. The bomb contents were cooled, and then mixed with 400 ml. of ethyl ether, and the mixture was filtered to remove the catalyst. The ethereal filtrate was washed twice with 400 ml. portions of 1.25 N aqueous hydrochloric acid and then twice with water. The ether layer was dried over anhydrous calcium sulfate, the drying agent was then removed, and the ethereal solution was distilled to remove the ether. The residual oil, which weighed 30.1 g., solidified on cooling; this solid, which was white.

13 melted at 7076 C. After crystallizations from petroleum ether, this product weighed 19.8 g. and melted at 102-109 C.; it consisted of 5,7-dimethyl--indanol, having the structural formula C. 1.5 g. of sodium hydride was dissolved in 55 ml. of isopropyl alcohol and the resulting solution was mixed with 8.5 g. of 5,7-dimethyl-4-i11danol and heated. To this hot mixture there was slowly added 8.4 g. B-diethylaminopropyl chloride. The resulting product was a red oil. Attempted distillation of this oil at 145 C. (0.2 mm.) gave indications of decomposition, so the distillation was discontinued. The oil was then dissolved in ethyl ether and the solution was extracted with 17 ml. of 3 N hydrochloric acid. The acidic aqueous extract was separated and was made strongly alkaline by addition of 35 percent aqueous sodium hydroxide solution. The desired 5,7-dimethyl 4 (3-diethylarninopropoxy)indane having the structural formula C5115 (IJCHgCH CHglN CH n separated from solution as an oil.

D. The base obtained in the above described manner was converted to the hydrochloride salt as follows. The oil was dissolved in ethyl ether and the ethereal solution Was dried over anhydrous colcium sulfate and then filtered with decolorizing charcoal. To the filtrate, which was almost colorless, there was added sufiicient alcoholic hydrogen chloride solution to make the filtrate slightly acidic. The slightly yellow solid which precipitated from solution was collected on a filter and dried in a desiccator. The dry solid was slurried in anhydrous ethyl ether, collected on a filter, and then recrystallized twice from toluene. There was thus obtained 2 g. of 5,7-dimethyl 4 (3-diethylaminopropoxy)indane hydrochloride as a white crystalline solid which melted at 124- 127 C. Analysis.-Ca lcd. for C H NQHCI: Cl, 11.37; N, 4.49. Found: Cl, 11.43; N, 4.42. The base also interacts with acetic acid, boric acid. citric acid, p-toluenesulfonic acid, nitric acid, sulfuric acid, and phosphoric acid to form the corresponding acetate, borate, citrate, p-toluenesulfonate, nitrate, sulfate, and phosphate acid addition salts of 5,7-dimethyl-4-(3-diethylaminopropoxy indane.

E. Interaction of 5,7-dimethyl 4-(B-diethylaminopropoxy)indane with one equivalent of n-hexyl bromide yields 5,7-dimethyl 4 (3 diethylaminopropoxy)inclane n-hexyl iodide, having the structural formula EXAMPLE 12 6-]llethyI-4-(3 -Dieth ylaminopropoxy I ndane Proceeding as in part C of Example 11, except that 14 7.7 g. of 6-rnethyl4-indanol is substituted for the 5,7- dimethyl-4-indanol, there is obtained 6-rnethyl-4-(3-diethylaminopropoxy)indane, having the structural formula CH2 czHi This base reacts with hydrogen bromide to yield 6-methyl- 4-(3-diethylaminopropoxy)indane hydrobromide, and reacts with one equivalent of benzyl chloride to yield 6- methyl-4-(3-diethylaminopropoxy)indane benzyl bromide, having the structural formula CaHs CI)-CH2CHzC HgN CzHs CH2 I Br EXAMPLE 13 4,6-Dimcthyl-5-(Z-Diethylaminoetlzoxy lndaize A. Proceeding in the manner described in part A of Example 11, and using the following reactants: g. of S-indanol; a solution of g. of dimethylarnine in 400 ml. of water; 186 ml. of formalin; and 100 ml. of isopropyl alcohol, followed by a 300 ml. portion of this compound after the formalin addition step. the reaction product obtained was an oil, which was distilled under reduced pressure. The fraction distilling at l37 C. (0.2 mm.) was a colorless oil, n =1.5356, which weighed 148.6 g.; this product was 4,6-bis(dimethylaminomethyl)-5-indanol, having the structural formula Analysis.Calcd. for C H N O: N, 11.28. Found: N, 11.20. This base in isopropyl alcohol reacted with hydrogen chloride in ethyl alcohol to yield the base dihydrochloride, M.P. 2l5218 C. Analysis.Cal-cd. for C15H24N20-2HC1I C, H, Cl, Found: C, 55.95; H, 8.06; Cl, 21.94.

B. 58 g. of 4,6bis(dimethylaminomethyl)-5-indanol was catalytically reduced for one hour with hydrogen in the presence of 6 g. of copper chromite catalyst, in a bomb at a pressure of 3600 pounds per square inch and at 131-135 C. The bomb contents were then cooled and diluted with 400 ml. of ethyl ether, and the resulting solution was filtered to remove the hydrogenation catalyst. The purple ethereal filtrate was washed twice with 400 ml. portions of 1.25 N aqueous hydrochloric acid, which removed the purple color, and then was washed twice with water. The ether layer was dried over anhydrous calcium sulfate, the drying agent was removed by filtration, and the filtrate was distilled to remove the ether. The residual pale yellow oil, which weighed 35.4 g., solidified on cooling. After two recrystallization-ls from petroleum ether, this product melted at 7980 C.; it was 4,6-dimethyl-5-indanol, having the structural formula CH3 CH3 Analysis.--Calcd. for C H O: C, 81.45; H, 8.70; O, 9.86. Found: C, 81.02; H, 9.00; O, 9.60. This compound was found to have antibacterial and antifungal properties. For instance, the minimum bacteriostatic concentrations against Staphylococcus aureus 209 and Eberthella typhi Hopkins were 1:100,000 and 1:1000, respectively; and the minimum bactericidal concentration against the same species was 1:1000 in each case, as measured by conventional serial dilution techniques. The minimum fungistatic concentration against Trichophyton mcntagrophytes, Aspergillus niger, and Monilia albicans was l:10,000 in each instance; and the minimum fungicidal concentrations were 1:10,000 against the first species and less than 1: 0.000 against the latter two species, using conventional serial dilution techniques.

EXAMPLE 14 4,6-Dimetl1y[-5-(3-Diethylamin0pr0p0xy)Indane A. To a solution prepared by dissolving 2 g. of sodium hydride in 75 ml. of isopropyl alcohol there was added 11.5 g. of 4,6-dimethyl-5-indanol. The resulting mixture was heated, and 11 g. of S-diethylaminopropyl chloride was gradually added thereto. The reaction product was isolated as a pale yellow oil which was then distilled under reduced pressure. The fraction distilling at 136- 137 C. was a colorless oil, n :1.5096, which weighed 11.5 g.', it consisted of 4,6-dimethyl-5-(3-diethylaminopropoxy)indane, having the structural formula CH2 can Analysis.-Calcd. for C H NO: N, 5.09. N, 5.09.

B. 13.5 g. of 4,6-dimethyl-5-(3-diethylaminopropoxy)- indane was dissolved in 90 ml. of anhydrous ethyl ether and then 10 ml. of 6 N alcoholic hydrogen chloride solution was added. After chilling the reaction mixture in a refrigerator for three days, the dense white crystalline solid which had separated from solution was collected on a filter. This product, which was 4,6-dimethyl-5-(3-diethylaminopropoxy)indane hydrochloride, melted at 128- 131 C. AnaIysis.-Calcd. for C H NOHCI: C, 69.31; H, 9.70; C1, 11.37. Found: C, 69.32; H, 9.25; Cl, 11.50. The base reacts with hydrofluoric acid, formic acid, picric acid, succinic acid, and stearic acid to yield the corresponding hydrofluoride, formate, picrate, succinate, and stearate acid-addition salts of 4,6-dimethyl-5-(3-diethylaminopropoxyfindane.

C. Treatment of 4,6-dimethyl-5-(3-diethylaminopropoxy)indane with one equivalent of m-nitrobenzyl bromide yields 4,6-dimethyl-5-(3-diethylaminopropoxy)indane m-nitrobenzyl bromide, having the structural formula Found 2 16 EXAMPLE 15 7-ChI0r0-4-(3-Diethyl'aminopr0poxy)Indane A. 7 g. of sodium hydride was dissolved in 255 ml. of isopropyl alcohol, and to this solution there was added 40 g. of 7-chlor0-4-indanol. The resulting mixture was heated and 36 g. of 3-diethylaminopropyl chloride was added gradually. The reaction product was isolated as an oil which was then distilled. The fraction distilling at 168173 C. was a colorless oil, n =1.5242, which weighed 22.4 g.; this product was 7-chloro-4-(3-diethylaminopropoxy)indane, having the structural formula AnaJysis.-Calcd. for C H ClNO: N, 4.97. Found: N, 4.97.

B. 19.4 g. of 7-chloro-4-(3 diethylaminopropoxy)indane was dissolved in 65 ml. of isopropyl alcohol and to this solution there was added 12.5 ml. of 6.14 N alcoholic hydrogen chloride solution. Ethyl ether was added to the reaction mixture to a point just short of permanent turbidity, and the mixture was allowed to stand at room temperature. The white crystalline solid which separated from solution was collected on a filter. This product, which was 7-chloro-4-(3-diethylaminopropoxy)indane hydrochloride, weighed 11.2 g. and melted at -147 C. Analysis.Calcd. for C H ClNO.HCl: Cl, 22.28. Found: Cl, 22.05. The base reacts with p-nitrobenzoic acid and oleic acid to yield the corresponding p-nitrobenzoate and oleate acid-addition salts of 7-chloro-4-(3-diethylaminopropoxy)indane.

C. Interaction of 7-chloro-4-(B-diethylaminopropoxy)- indane with one equivalent of dimethyl sulfate yields 7-chloro-4-(3-diethylaminopropoxy)indane methosulfate, having the structural formula CzHs (SO CHa) D. The 7-chloro-4-indanol used as a starting material in part A above can be prepared in the following manner. Molten p-chlorophenol was stirred and treated dropwise with an equimolecular amount of ti-chloropropionyl chloride. After the addition was completed, the reaction mixture was allowed to stir for three hours at room temperature and then was heated for one hour on a steam bath. Distillation of the resulting oil gave a 90% yield of p-chlorophenyl beta-chloropropionate which boiled at 152-156 C. (11 mm.) and had 11 :1.5306. Analysis.Calcd. for C H CI O Cl, 32.38. Found: Cl, 32.4.

A mixture of g. of p-chlorophenyl beta-chloropropionate with 350 g. of anhydrous aluminum chloride was heated for five hours at 95 C. and then for one hour at -170 C. The reaction mixture was quenched with ice and water. The solid which separated was collected on a filter and washed well with water. Recrystallization of this solid from isopropyl alcohol, including treatment 17 with charcoal, yielded 45 g. of 4-chloro-7-hydroXy-lindanone, having the structural formula which melted at ll8122 C. From the mother liquors, the intermediate 5,beta-dichloro-2-hydroxypropiophenone was recovered; by increasing the heating time at 165-170 in a subsequent run to two hours, the yield of crude indanone was raised to 70% and none of the intermediate was recovered.

The 4-chloro-7-hydroxy-l-indanone was purified by recrystallization from ethyl acetate to yield a product melting at 120-122 C. AnaIysis.-Caled. for CgHqClOgi C, 59.20; H, 3.86; Cl, 19.42. Found: C, 59.16; H, 3.99; Cl, 19.50. A mixture of 450 g. of 4-chloro-7-hydroxy-1- indanone in 2 liters of toluene with 2 liters of acetic acid and 1500 g. of freshly amalgamated zinc mesh) was heated with strong mechanical stirring under reflux at 90 C., and 5 liters of hydrochloric acid was added to the mixture over a four hour period. After addition of the acid was completed, the heating and stirring were continued for four hours with occasional additions of hydrochloric acid to a total of 7 liters. The reaction mixture was cooled and separated from undissolved zinc. The Water layer was separated and washed with one liter of toluene in several portions. The combined toluene extracts were concentrated under reduced pressure, and the residue thus obtained was crystallized from 1 liter of petroleum ether after decolorizing the crystallization solution with charcoal. A 300 g. first crop of 7-chloro-4- indanol, M.P. 90-92 C. was collected; and by concentration and cooling of the filtrate from the first crop, and recrystallization of the second crop obtained thereby, another 35 g. of 7-chloro 4-indanol, M.P. 9092 C. resulted. After recrystallization of the 335 g. of product from 1.5 liters of ethylene dichloride, there was obtained 310 g. of 7-chloro-4-indanol melting at 9193 C. Analysis.Calcd. for C H CIO: Cl, 21.03. Found: Cl, 21.0.

EXAMPLE 16 5-Chl0r0-4- Z-Diethylmninoethmy I ndane A. 4.8 g. of sodium hydride was dissolved in 185 ml. of isopropyl alcohol, and to this solution there was added 29 g. of 5-chloro-4-indanol. The resulting mixture was heated and 23.8 g. of Z-diethylarninoethyl chloride was gradually added thereto. The reaction product was isolated as an oil which was then distilled. The fraction distilling at 115 C. (0.2 mm.) was a colorless oil, 11 1.5235, which weighed 14.6 g.; this product was S-chloro- 4-(2-diethylaminoethoxy)indane, having the structural formula O-CHrCHs-N CH2\ C1 2 a Analysis.Calcd. for C H ClNO: N, 5.23. Found: N, 5.17.

B. 14 g. of 5-chloro-4-(Z-diethylaminoethoxy)indane was dissolved in 50 ml. of isopropyl alcohol and 9.5 ml. of 6.14 N alcoholic hydrogen chloride solution was added. The salt failed to separate on cooling, so the isopropyl alcohol was distilled from the reaction mixture and ethyl ether was added. The white crystals which separated from solution were collected on a filter. This product, which was 5-chloro-4-(Z-diethylaminoethoxy)indane hydrochloride, weighed 11.5 g. and melted at 121-123 C.

AnaIysz's.-Calcd. for C H ClN0.HCl: Cl, 23.30. Found: Cl, 23.02. When a solution of the hydrochloride in water is made strongly alkaline by addition of aqueous sodium hydroxide solution, the free base, 5-chloro-4-(2- diethylaminoethoxyfindane, is regenerated as a water-insoluble oil; and separation and treatment of the base thus obtained with lactic acid yields the lactate acid-addition salt of 5-ch1oro-4-(Z-diethylaminoethoxy)indane.

C. Treatment of 5-chloro-4(Z-diethylaminoethoxy)indane with one equivalent of isobutyl chloride yields 5-chloro-4-(Z-diethylarninoethoxy)indane isobutyl chloride, having the structural formula CHHCH(CH3)| OCH2CH; CH2 H 2 I CH I EXAMPLE l7 5-ChIor0-4-(3-Diethylaminopropoxy)Indane A. 4.8 g. of sodium hydride was dissolved in ml. of isopropyl alcohol, and to the resulting solution there was added 30 g. of 5-chloro-4-indanol. This mixture was heated and 27 g. of 3-diethylaminopropyl chloride was gradually added thereto. The reaction product was isolated as a yellow oil, which was then distilled under reduced pressure. The fraction distilling at l26-131 C. (0.05 mm.) was a colorless oil, n =l.52l3, which weighed 11.4 g.; this product was 5-chloro-4-(3-diethylaminopropoxy)indane, having the structural formula 0 CH2CHZCHi CH2 CaHi CHI AnaIysis.-Calcd. for C H CINO: N, 4.97. Found: N, 4.97.

B. 16 g. of 5-chloro-4-(3-diethylaminopropoxy)indane was dissolved in 60 ml. of isopropyl alcohol, and 12 ml. of 6.14 N alcoholic hydrogen chloride solution was added. Since very little solid separated from the reaction mixture, the isoporpyl alcohol was removed by distillation and the oily residue was dissolved in ethyl ether, and the solution was allowed to stand. The white crystalline solid which separated from solution was collected on a filter. This product, which weighed 14.4 g. and melted at 134- 139 C., was 5-chloro-4-(3-diethylaminopropoxy)indane hydrochloride. AnaIysis.-Calcd. for C H ClNO.HCl: Cl, 22.28. Found: Cl, 22.22. The base reacts with hydrocyanic acid and with arsenic acid to yield the corresponding hydrocyanide and arsenate acid-addition salts of 5-ch1oro-4- 3-diethylaminopropoxy) indane.

C. Treatment of 5-chloro-4-(3-diethylaminopropoxy)- indane with one equivalent of m-methoxybenzyl chloride yields 5-chloro-4-(3-diethylaminopropoxy)indane m-methoxybenzyl chloride, having the structural formula 19 EXAMPLE 1% 7-Chl0r0-4-(Z-Diethylaminoethoxy)lndane A. 7 g. of sodium hydride was dissolved in 255 ml. of isopropyl alcohol, and to the resulting solution there was added 40 g. of 7-chloro-4-indanol. This mixture was heated and 32.6 g. of Z-diethylaminoethyl chloride was gradually added thereto. The reaction product was isolated as a pale yellow oil, which was then distilled under reduced pressure. The fraction distilling at 140-142 C. (0.2 mm.) was a colorless oil, n =1.5308, which weighed 14 g.; this product was 7-chloro-4-(2-diethylaminoethoxy)indane, having the structural formula O C likens-N CH2 CEHB Analysis.Calcd. for C H CINO: N, 5.23. Found: N, 5.06.

B. 12.5 g. of 7-chloro-4-(Z-diethylaminoethoxy)indane was dissolved in 45 ml. of isopropyl alcohol, and then 8.5 ml. of 6.14 N alcoholic hydrogen chloride solution was added. On cooling the reaction mixture, a white crystalline solid separated from solution. This solid was collected on a filter. This product, which weighed 11.1 g. and melted at 165-17 1 C., was 7-chloro-4-(2-diethylaminoethoxy)indane hydrochloride. Analysis.Calcd. for C H N0.HC1: C1, 23.30. Found; Cl, 23.37. The base reacts with adipic acid and maleic acid to yield the corresponding adipate and maleate acid-addition salts of 7-chloro-4-(Z-diethylaminoethoxy)indane.

C. Interaction of '7-ch1oro-4-(2-diethylaminoethoxy)- indane with one equivalent of 2-chloro-4-methoxybenzyl chloride yields 7-chloro-4-(Z-diethylaminoethoxy)indane 2-chloro-4-methoxybenzyl chloride, having the structural formula CHg- -OCH3 OCHrCHr-N or can .4.

EXAMPLE 19 6-Chl0r0-5-(3-Diethylaminopr0poxy)lndane A. 7.7 g. of sodium hydride was dissolved in 325 ml. of isopnopyl alcohol, and to this solution there was added 50 g. of 6-chloro-5-indanol. The resulting mixture was heated, and 45 g. of 3-diethylaminopropyl chloride was gradually added thereto. The reaction product was isolatcd as an oil, which was then distilled under reduced pressure. The fraction distilling at 166170 C. was a colorless oi], n =1.5252, which weighed 24.7 g.; this product was 6-ch1oro-5-(S-diethylaminopropoxy)indane, having the structural formula Analysis.-Calcd. for C H ClNOz N. 4.97. Found:

B. 24 g. of 6-chloro-5-(3-diethylarninopropoxy)indane was dissolved in ml. of isopropyl alcohol and to this solution there was added 23.5 ml. of 4.16 N alcoholic hydrogen chloride solution. Ethyl ether was added to the reaction mixture to a point just short of permanent turbidity and the mixture was then allowed to stand. The white crystalline solid which separated from solution was collected on a filter. There was thus obtained 16.3 g. of 6- chloro-5-(3 diethylaminopropoxy)indane hydrochloride, which melted at 125127 C. Analysis.Calcd. for C H ClNO-flclz C1 (ionic), 11.14. Found: C1 (ionic) 11.27. The base reacts with cholic acid to yield the cholate acid-addition salt of 6-chloro-5-(3-diethylarninopr-opoxy)indane.

C. Interaction of 6-chloro-5-(3-diethylaminopropoxy) in-dane with one equivalent of methyl p-toluenesulfonate yields 6-chloro-5-(B-diethylaminopropoxy)indane methop-to-luenesulfonate, having the structural formula 5,7-Dz'cIzl0r0-4- (2-Diethylamin0ethoxy Indane A. 10.3 g. of sodium hydride was dissolved in 370 ml. of isopropyl alcohol, and 71.1 g. of 5,7-dichloro-4-indanol was added thereto. This mixture was heated, and 49.5 g. of Z-diethylaminoethyl chloride was gradually added. The reaction product was isolated as a yellow oil, which was then distilled under reduced pressure. The fraction distilling at 144148 C. was a colorless oil, n =1.532S, which weighed 61 g; this product was 5,7-diehloro-4-(2- diethylaminoethoxy)indane, having the structural formula Analysis.-Calcd. for C H Cl NO: N, 4.64. Found: N, 4.72.

B. 36 g. of 5,7-dichloro-4-(2-diethylaminoethoxy)in dane was dissolved in ml. of isopropyl alcohol, and to this solution there was added 21.8 ml. of 6.14 N alcoholic hydrogen chloride solution and the mixture was allowed to stand. The white crystalline solid which separated from solution was collected on a filter. The collected solid, which weighed 18.3 g., was recrystallized from isopropyl alcohol. There was thus obtained 9.6 g. of 5,7- dichloro-4-(Z-diethylaminoethoxy)indane hydrochloride as a white crystalline solid which melted at l60169 C. Analysis.-Calcd. for C H Cl NO.HCl: C, 53.19; H, 6.55; C], 31.41. Found: C, 53.05; H, 6.23; Cl, 31.50. The base reacts with lactic acid and trifluoroacetic acid to yield the corresponding lactate and trifiuoroacetate acidaddition salts of 5,7-dichloro-4-(Z-diethylaminoethoxy)indane.

C. Interaction of 5,7dichloro-4-(2 diethylaminoethoxy)indane with one equivalent of di-n-butyl sulfate yields 21 5,7-dichloro-4-(2 diethylaminoethoxy)indane n-butosulfate, having the structural formula MCH;

o-omoH- H Cl 2 i CH SOt(CH2)aCH EXAMPLE 21 5,7 -Dich I0r0-4- (3-Diethylaminopropoxy)Indane A. 5.3 g. of sodium hydride was dissolved in 210 ml. of isopropyl alcohol, and the resulting solution was mixed with 40 g. of 5,7-dichloro-4-indanol. The mixture thus obtained was heated, and 30 g. of 3-diethylaminopropyl chloride was gradually added thereto. The reaction product was isolated as an oil, which was then distilled under reduced pressure. The fraction distilling at 145452 C. (0.1 mm.) was a colorless oil, n =1.5301, which weighed 17.2 g. this product was 5,7-dichioro-4-(3-diethylaminopropoxy)indane, having the structural formula Analysis..Calcd. for C H Cl NO; N, 4.43. Found: N, 4.39. V B. 16 g. of 5,7-dichlor-o-4-(3-diethylaminopropoxy)in dame was dissolved in 45 ml. of isopropyl alcohol, and to this solution there was added 9.4 mi. of 6.14 N alcoholic hydrogen chloride solution. The reaction mixture was diluted with ethyl ether to a point just short of permanent turbidity and then allowed to stand. The white crystalline solid which separated from solution was collected on a filter. The product thus obtained, which weighed 11 1g. and melted at 117-136 0., was 5,7-dichloro-4-(3-diethylaminopropoxy)indane hydrochloride. Analysis.-Calcd. for C H CI NQHCI: Cl (ionic), 10.05; Cl (total) 30.16. Found: Cl (ionic), 9.98; Cl (total) 29.70.

C. Interaction of S,7dichloro-4( 3 diethylaminopropoxy)indane with one equivalent of ethyl iodide yields 5,7- dichloro-4-(3diethylaminopropoxy)indane ethiodide, having the structural formula CH; i

D. Interaction of 5,7dichloro-4-(3 diethylaminopropoxy)=indane ethiodide in aqueous solution with silver hydroxide yields the corresponding ammonium hydroxide, a strong base which reacts with benzoic acid to yield 5,7-di- 22 chloro-4-(3-diethylaminopropoxy)indane ethyl benzoate, having the structural formula EXAMPLE 22 5 ,7 -Dich!or0-4- S-Dimetlzylaminopropoxy)Indane A. A solution of sodium methoxide was prepared by adding 2.3 g. of sodium to 70 ml. of anhydrous methyl alcohol in a 500 ml. three-neck flask fitted with a thermometer, stirrer, dropping funel, and a distillation con denser. Benzene was slowly added with stirring until the temporary localized turbidity in the solution caused by the addition was just short of becgmipg permanent, and then 20.3 g. 'Of 5,7-dichloro-4-indangi was added. The resulting orange-yellow solution waeheated on a steam bath and the methyl alcohol was distilled from the reaction mixture under reduced pressure. When most of the methyl alcohol had been removed the sodium salt of 5.7-dichloro-4-indanol separated as a solid from the solution. Two portions of benzene were added to the residue during the latter stage of the distillation to aid in evaporation of thelast traces of methyl alcohol. Then ml. of benzene and 50 ml. of anhydrous dioxane were added to the distillation residue, the condenggpwas fitted with a drying tube'a'nd set in upright POSitiOtlifOt' reflux, and the mixture, in which some of the sodiumsalt remained in undissolved, solid form, was heated to reflux temperature and stirred. Over a period of thirty minutes, 20 g. of 3-dimethylair'rl propyl chloride was added slowly through the dropping iftgnnel. As this addition proceeded, the solid in the reaction mixture disappeared and was gradually replaced by sodium chloride which separated from the solution After addition of the S-dimethyllarninopropyl chloride complemented, refluxing was continued for thirty i 7 es more. After refluxing had been discontinued, about 200 ml. of water wasWstir -ed with the reaction mixture The aqueous layer separated was collected and discarded, and the benzene layer was filtered with decolorizing charcoal. The filtrate thus obtained was extracted with 300 ml. of water containing 9 m1. of concentrated hydrochloric acid. The acidic aqueous extract was made Strongly alkaline by addition of 3 5 percent aqueous sodium hydroxide solution, thereby causing separation of 5,7-dichloro-4-(S-dimethylarninoas an 01'].

B. This base was converted to the hydrochloride by dissolving it in ethyl ether, drying in ethereal solution over anhydrous calcium sulfate, filtering the solution, and then adding to the filtrate a solution of hydrogen chloride in ethyl other until the filtrate became slightly acidic. The white solid which separated from the solution was collected on a filter. This crude product Weighed Z9 g. and melted at -172 C. It was recrystallized from 200 m1. of isopropyl alcohol. There was thus obtained 7.8 g. of 5.7-dichloro-4-(3-dimethylaminopropoxy)indane hydrochloride as a white crystalline solid which melted at 23 202-205" C. Analysis.Calcd. for C H Cl NOHCI: C, 51.79; H, 6.21; Cl, 32.76. Found: C, 51.48; H, 6.24; Cl, 33.00.

C. Interaction of 5,7-dichloro-4(3-dirnethylaminopropoxy)indane with one equivalent of allyl bromide yields 5,7-dichloro-4(3-dimethylaminopropoxy)indane allyl bromide, having the structural formula CH2C1I3GH z-N CH: I

EXAMPLE Z3 5 ,7-Dich lore-4 [2-(1 -Piperidyl) Ethoxy] I ndane A. In a 500 ml. three-neck flask with a thermometer insert and fitted with a thermometer, stirrer, dropping funnel, and drying tube, 40.6 g. of 5,7-dichloro-4-indanol was dissolved in 250 ml. of N,N-dimethylformamide which had been dried over calcium hydride. The stirrer was started, the flask was cooled with an ice-bath, and 9.6 g. of a 50 percent (by weight) suspension of sodium hydride in oil was added to the flask contents. Hydrogen was evolved, causing foaming, and the temperature of the reaction mixture rose to 45 C. despite the cooling. The reaction mixture was cooled to C., after which the ice-bath was removed, and then g. of 2-(l-piperidyl) ethyl chloride was added dropwise over a period of thirty minutes. After this addition was completed, the reaction mixture was allowed to stand for about twenty hours, and then was diluted with approximately one liter of water. The resulting solution was extracted with four 200 ml. portions of ethyl ether. These ether extracts were combined and washed with water to remove some of the N,N- dimethylformamide. The ether layer was then extracted with a mixture of 500 ml. of water and 17 ml. of concentrated hydrochloric acid. The acidic extract was made strongly alkaline by addition of percent aqueous sodium hydroxide solution, and the oily base which separated from solution was collected and dissolved in ethyl ether. The ether solution was dried over anhydrous calcium sulfate and treated with decolorizing charcoal. The mixture was filtered to remove the drying agent and the charcoal, and the filtrate, which was almost colorless, was distilled under reduced pressure to remove the ethyl ether. There was obtained as a residue a pale orange oil which weighed 39 g.', this product was 5 ,7-dichloro-4[2(1-piperidyl)ethoxy]indane, having the structural formula (when.

CHz-CHg B. The above base was converted to the hydrochloride by dissolving it in 200 ml. of isopropyl alcohol, and adding 5 N alcoholic hydrogen chloride solution thereto until the mixture was acidic to Congo red paper. The white crystalline solid which separated from solution was collected on a filter. This product, which weighed 34 g. and melted at 216-217" (3., was 5,7-dichloro-4-[2 (1-piperidyl) ethoxylindane hydrochloride. Analysis.Calcd. for c H Cl NQHcl: C, 54.79; H, 6.32; Cl, 30.33. Found: C, 55.05; H, 6.53; Cl, 30.05.

C. Interaction of 5,7-dichloro-4-[2-( l-piperidy1)ethoxy] indane with one equivalent of ethyl iodide yields 5,7-di- 24 chloro-4-[2-(l-piperidyl)ethoxylindane ethiodide, having the structural formula OCIIICIIQAN CH1 Cut 1 CH:-CH -01 CH2 1 EXAMPLE24 This base reacts with one molecular equivalent of methyl iodide to yield 4-[2-(1-piperidyl)ethoxy]indane methiodide, having the structural formula /CH3 CH2-CH3 4- [3-(1-Piperidyl)Propoxyflndane Following the procedure described in part A of Example 23, but substituting 26.8 g. of 4-indanol for the 5,7-dichloro-4-indanol and substituting 32.4 g. of 3-(1- piperidyl)propyl chloride for the 2-(l-piperidyl)ethyl chloride, there is obtained as the product 4-[3-(l-piperidyl)propoxy]indane, having the structural formula This base reacts with one equivalent of methyl iodide to yield 4-[3-(l-piperidyl)propoxy]indane methiodide, having the structural formula EXAMPLE 26 4- [2-(l-Hexamethyleniminyl) Ethoxyflndane Following the procedure described in part A of Example 23, but substituting 26.8 g. of 4-indanol for the 5,7-dichloro4-indanol and substituting 32.4 g. of 2-(1- 25 V hexamethylenirninynethyl chloride for the Z-(I-piperidyl)ethyl chloride, there is obtained as the reaction prod net 4- [2-( l-hexamethylenirninyl)ethoxy1indane, having the structural formula CHi-CHQ CH OCH2CH2N i 7 CH2 10 CH -CH; C n

This base reacts with one equivalent of methyl iodide to yield 4-[2-(1-hcxamethyleniminyl)ethoxy]indane methiodide, having the structural formula This base reacts with one equivalent of methyl iodide to yield 5-[2-( l-piperidyhethoxyjindane methiodide, having the structural formula CH, CH2 0H2 moment-n CH2 0 {Y 1 our-oh,

EXAMPLE 28 5 [2-( 1 -H examethyleniminyl )Eth oxy I ndane 30 Following the procedure described in part A of Example 23, but substituting 26.8 g. of S-indanol for the 5,7-dichloro-4-indanol and substituting 32.8 g. of 2-(1- hexamethyleniminyD-ethyl chloride for the 2-(1-piperidyDethyl chloride, there is obtained 5-[2-( l-hexamethyleniminyl)ethoxy]indane, having the structural formula 011743112 CH2\ CH2 -oomc1nN I CH2 on,

onrcn, CH3

This base reacts with one equivalent of methyl iodide to yieldS-[2-(1-hexamethyleniminyl)ethoxy]indane methiodide, having the structural formula CHg-CH: CHI 1 O-CH:CH:-N 1 CH1 CHz-CHz CH;

EXAMPLE 29 5- [3-(1-Piperz'dyl PropoxyJInddne Following the procedure described in part A of Example 23, but substituting 26.8 g. of S-indanol for the 5,7-dichloro-4-indanol and substituting 32.8 g. of 3-(1- piperidyDpropyl chloride for the 2-(1-piperidyl)ethyl chloride, there is obtained 5-[3-(l-piperidyl)propoxy]indane, having the structural formula CHa CH2 CHQ O-CHgCH:CHgN /CH2 0 1 onronr This base reacts with one equivalent of methyl iodide to yield 5-[3-(l-piperidyUpropoxy]indane methiodide, having the structural formula CH3 CHz-CHK o-oH2crnom-1 v 0H, I om-orn EXAMPLE 30 5-{2-(I-Heptamethyleniminyl)EthoxyHndane When 35.7 g. of 2-(1- eptamethyleniminyhethyl chloride is substituted for the 2-( l-hexamethyleniminyUethyl chloride in the procedure of Example 28, there is obtained 5-{2-(l-heptamethyleniminyl)ethoxyJindane, having the structural formula CH1CH3CH:

CHPCH2C 2 O-GHgCHrN CH3 1 This base reacts with hydrogen chloride to yield S-[Z-(lheptamethyleniminyl)ethoxylindane hydrochloride. The base reacts with one equivalent of methyl bromide to yield 5-[2-( l-heptamethyleniminyl)ethoxyJindane methobromide, having the structural formula 0H, CH: CHr-CHg-CHK OCHrCH N 0111 om-cm-om EXAMPLE 31 5,7-Dich lor0-4- [3- (4 -M orpholinyl Propoxy] Indane A. Proceeding in accordance with the manipulative procedure described above in part A of Example 23, the following we cuts were employed: 20.3 g. of 5,7-dichloro-4-indanol; ml. of N,N-dimethylformamide which had been dried over calcium hydride; 4.8 g. of a 50 percent (by Weight) suspension of sodium hydride in mineral oil; and 17 g. of 3-(4-morpholinyl)propyl chloride. The reaction product thus obtained, which was 7 5,7 dichloro 4 [3 (4 morpholinyl)propyl]indane, having the structural formula O -CHZCIDCHr-N /O our-on2 was isolated as an orange-yellow oil which weighed 12.5 g.

B. The above base was dissolved in 50 ml. of isopropyl alcohol, and to this solution there was added alcoholic hydrogen chloride solution until the mixture was acidic to Congo Red paper. The finely divided white solid which separated from solution was collected on a filter. This product, which weighed 9.3 g. and melted at 160-174 C., was recrystallized from isopropyl alcohol. thus obtained 5 g. of 5,7-dichloro-4-[3-(4-morpholinyl)- propoxylindane hydrochloride as 12. white crystalline solid.

C. Interaction of 5,7-dichloro-4-[3-(4-morpholinyl)- propoxylindane with one equivalent of n-propyl iodide yields 5,7 dichloro 4 [3 (4 morpholinyl)propoxylindane n-propiodide, having the structural formula 1 cutout EXAMPLE 32 4-[2-(4-M0rph0linyl) Ethxy1lndane Proceeding in the manner described in part A of Example 23, but substituting 13.4 g. of 4-indanol for the 5,7dichloro-4-indanol and substituting 15.5 g. of 2-(4- morpholinyl)ethyl chloride for the 2-(1-piperidyl)ethyl chloride, the product obtained is 4-[2-(4-morpholinyl)- ethoxy]indane, having the structural formula This base reacts with one equivalent of methyl iodide to yield 4 [2 (4 morpholinyl)ethoxy]indane methiodide, having the structural formula 5-[2-(4-M0rpholinyl)Ethoxy]Indane Proceeding in the manner described above in part A of Example 23, but substituting 13.4 g. of S-indanol for the 5,7-dichloro-4-indanol and substituting 15.5 g. of 2-(4-morpholinyl)-ethyl chloride for the 2-(1-piperidy1)- There was ethyl chloride, there is obtained 5-[2-(4-morpholinyl)- ethoxy]indane, having the structural formula CH2 1 /crncrn \V -o-cmom N out i om oni This base reacts with one equivalent of methyl iodide to yield 5 [2 (4 morpholinyl)ethoxy]indane methiodide, having the structural formula Cm /cnl-on= O CHsCHZ N 0 on 1\ 1 I Gin-on,

EXAMPLE 34 5,7-Dichl r0-4- [Z-(J-Pyrrolidyl)Ethoxy Indane was obtained as a colorless oil which weighed 33 g.

B. The above base was dissolved in 200 ml. of isopropyl alcohol, and the solution was then acidified by addition of a solution of hydrogen chloride in ethyl ether. After the reaction mixture had stood for four hours at room temperature, the white crystalline solid which had separated from solution was collected on a filter. This product, which weighed 18.5 g. and melted at 178-179 C., was 5,7-dichloro-4[2-(1-pyrrolidyl)ethoxy]indane hydrochloride. Analysis.-Calcd. for C H Cl NOHCl: C, 53.51; H, 5.99; Cl, 31.59. Found: C, 53.58; H, 6.12; Cl, 31.40. The base reacts with hydriodic acid to yield 5,7-dichloro-4-[2-( l-pyrrolidyl ethoxyl indane hydrioditle.

C. Interaction of 5,7-dichloro-4-[2-(1-pyrrolidyl)ethoxy]indane with one equivalent of n-arnyl iodide yields 5,7-dichloro-4-[2-(l-pyrrolidyl)ethoxy]indane n-amyl iodide, having the structural formula EXAMPLE 4-[2-(I-PyrroIidyl)Et/z0xy}Indane Proceeding in the manner described in part A of Example 1, but substituting 26.8 g. of 4-indanol for the S-indanol and substituting 27 g. of 2-(l-pyrrolidyl)ethyl chloride for the 3-diethylaminopropyl chloride, the prod uct obtained is 4-[2-(1-pyrrolidyl)ethoxy]indane, having the structural formula GHQ-CH1 o-crncm-N cutout This base reacts with hydrogen chloride to yield the 4-[2-(l-pyrrolidyl)ethoxy1indane hydrochloride. The base reacts with one equivalent of lauryl bromide to yield 4-[2-(1-pyrrolidyl)ethoxy]indane lauryl bromide, having the structural formula rton-cm CH2H -CH1CH9- CH: Bl CH2CH] .4

EXAMPLE 36 Proceeding in accordance with the manipulative pro cedure described above in part A of Example 23, but using the fiollowing reagents: 26.8 g. of S-indanol; 250 ml. of anhydrous N,N-dimethylformamide; 9.6 g. of a 50 percent (by weight) suspension of sodium hydride in mineral oil; and 27 g. of 2-(pyrrolidyl)ethyl chloride, the reaction product obtained is 5-[2-(1-pyrrolidyl)ethoxy]indane, having the structural formula CH: ou -cu. OCHzCH;-N CHr-CH;

This base reacts with one equivalent of methyl iodide to yield 5-[2-(l-pyrrolidyl)ethoxylindane, having the structural formula 5,7-Dz'chIor0-4-(2-Diisopropylaminoethoxy )Indane A. Following the manipulative procedure of part A of Example 23, the following reagents were employed: 40.6 g. of 5,7-dichloro-4-indanol; 250 ml. of anhydrous N,N-dimethylforrnamide; 9.6 g. of a 50 percent (by weight) suspension of sodium hydride in minenal oil, and 33 g. of 2-diisopropylaminoethyl chloride. The reaction product was isolated as an orange oil which weighed 58 g. This oil was distilled under reduced pressure. The fraction distilling at 159163 C. was a colorless oil, n =l.5263, which weighed 47.1 g.; this product 30 was 5,7-dichloro 4 (Z-diisopropylaminoethoxy)indane, having the structural formula CH CEH,

CH(CH )2 EXAMPLE 38 7 -Brom 0-4- (Z-Dieth ylaminoethoxy Indane cumin A. Following the manipulative procedure of part A of Example 23, the following reagents were employed: 15 g. of 7-bromo-4-indanol; ml. of anhydrous N,N-dimethylformamide; 3.4 g. of a 50 percent (by Weight) suspension of sodium hydride in mineral oil; and 9.5 g. of Z-diethylaminoethyl chloride. The reaction product, which was 7-bromo 4 (2-diethylarninoethoxy)indane, having the structural formula was isolated as a pale yellow oil weighing 19.8 g.

B. The above base was dissolved in 70 ml. of isopropyl alcohol, and the solution was acidified with 12 m1. of 5.9 N alcoholic hydrogen chloride solution. The white solid which separated from the solution was collected on a filter. There was thus obtained 16 g. of 7-bromo-4-(2- diethylaminoethoxyfindane which melted at -176 C. Analyris.-Calcd. for C H BrNOHCl: C, 51.66; H, 6.65; Br, 22.9; Cl, 10.17. Found: C, 51.62; H, 6.62; Br, 22.7; CI, 10.22.

C. Interaction of 7-bromo-4-(Z-diethylaminoethoxy)- indane with one equivalent of diethyl sulfate yields 7- brorno-4-(Z-diethylarninoethoxy)indane ethosulfate, having the structural formula Cam O--CH:CH2N /orn i Cam CH1 I somiui 31 EXAMPLE 39 7-Fluor0-4-(Z-Diethylaminoethoxy )Indane Proceeding as in part A of Example 38 with the exception of substituting 10.6 g. of 7-iluoro-4-indanol for the 7-bromo-4-indanol, there is produced 7-fluoro-4-(2-diethylaminoethoxy)indane, having the structural formula O-CHzCHz-N CIT-2 a (1H5 CHI 50 0 11 EXAMPLE 40 4- (Z-Dimethylamino-l-Methylcthoxy)Indane Following the procedure described in part A of Example 23, but substituting 26.8 g. of 4-indanol for the 5,7-dichloro-4-indanol and substituting 24.2 g. of 2-dimethylaminopropyl chloride for the 2-(l-piperidyl)ethyl chloride, the reaction product obtained is 4-(2-dimethylamino- 1-methylethoxy)indane, having the structural formula This base reacts with hydrogen bromide to yield 4-(2-dimethylamino-l-methylethoxy)indane hydrobromide. The U base reacts with one equivalent of methyl iodide to yield 4- (Z-dimethylamino- 1 -rnethylethoxy) indane methiodide,

having the structural formula EXAMPLE 41 5-(Z-Dimethylamina-1-Methyleth0xy)Indane This base reacts with glutamic acid to yield 5-(2-dimethylamino-l-methylethoxy)indane glutamate. The base reacts with one equivalent of methyl iodide to yield S-(Z-dimethylamino-l-methylethoxy)lndane methiodide, having the structural formula Oil EXAMPLE 42 5,7-Dichl0r0-4-(2-Dimethylaminopropoxy)Indane and 5,- 7-Dz'chl0r0-4-(Z-Dimethylamino-I -Metlrylethoxy)Indane A. Following the manipulative procedure of part A of Example 16, the following reagents were employed; 20 g. of 5,7-dichloro-4-indanol; ml. of anhydrous N,N-dimethylformamide; 4.8 g. of a 50 percent (by weight) suspension of sodium hydride in mineral oil; and 10.5 g. of a mixture of Z-dimethylarninopropyl chloride and 2-dimethylamino-Z-methylethyl chloride obtained by treating Z-dimethylaminopropyl chloride hydrochloride with sodium hydroxide solution. The reaction product was isolated as a colorless oil weighing 13.5 g. which consisted of a mixture of 5,7-dichloro-4-(Z-dimethylaminopropoxy) indane, having the structural formula Cl and 5,7-dichloro-4-(Z-dimethylamino-l-methylethoxy)indane, having the structural formula This mixture was distilled under reduced pressure. The three major fractions were as follows: 1.9 g., distilling at 124137 C., n =1.5384; 1.8 g., distilling at 137-142 C., n :l.5385; and 7.5 g., distilling at 142-146" C., n =1.5394.

Analysis.--Calcd. for C H Cl NOz N, 4.86. Found: N, Fraction 1:4.82, Fraction 2:4.80, Fraction 3:4.77.

EXAMPLE 43 5,7-Dichl0ro-4-(3-Dimethylaminopropoxy)Indane A. Following the manipulative procedure of part A of Example 23, the following reagents were employed: 20.3 g. of 5,7-dichloro-4-indanol; ml. of anhydrous N,N- dimet hylformamide; 4.8 g. of a 50 percent (by weight) suspension of sodium hydride in mineral oil; and 20 g. of 3-dimethylaminopropy1 chloride. The reaction product, which was 5,7-dichloro-4-(3-dimethylaminopropoxy)indane, was isolated as a yellow oil which Weighed 18 g., representing a considerably better yield of this base by this procedure than by the method of part A of Example 22.

B. The above base Was dissolved in 100 ml. of isopropyl alcohol and the solution was made acidic to Congo red paper by addition of an ethyl ether solution of hydrogen chloride. The white solid which separated immediately from solution was collected on a filter. There was thus obtained 18 g. of 5,7 dichloro-4-(3-dimethylaminopropoxy)indane hydrochloride which melted at 209-210 33 C. Analysis-Calcd. for C l-l Cl NQHClz Cl, 32.76. Found: Cl, 32.90.

EXAMPLE 44 7-Chl0r0-6-Methyl-4-[2-(2,6-DimethyI-1-Piperidyl) Ethoxy]lndane A. A commercial grade of 6-methyl-4-indanol (Carbide and Carbon, M.P. 82-84 C., was recrystallized with charcoaling from petroleum ether to obtain flufr'y white needles. 25 g. of this product was dissolved in 35 ml. of glacial acetic acid and a small crystal of iodine was added as a chlorination catalyst. The resulting solution was stirred, and 23 g. of sulfuryl chloride was added dropwise while keeping the temperature of the reaction mixture below 45 C. by external cooling when necessary. After all of the sulfuryl chloride had been added, the reaction mixture was stirred for a few minutes and then a solid separated from solution. This solid was collected on a filter, was washed with acetic acid, and then was dried. This product, which weighed 17.5 g. was recrystallized twice from petroleum ether. There was thus obtained 11.5 g. of fluffy white needles which melted at 120-122" (1.; this product was 7-chloro-6-methyl-4-indanol, having the structural formula CH 5 C 2 Analysis.-Calcd. for C H ClO: C, 65.75; H, 6.07; Cl, 19.42. Found: C, 66.07; H, 6.39; Cl, 19.11.

B. Proceeding as described in part A of Example 23, but substituting 36.4 g. of 7-chloro-6-methyl-4-indanol for the 5,7-dichloro-4-indanol and substituting 35.7 g. of 2-(2,6-dimethyl-1-piperidyl)ethyl chloride for the 2-(1- piperidyl)-ethyl chloride, there is obtained 7-chloro-6- methyl-4-[2-(2,6 dimethyl 1 piperidyl)ethoxy]indane, having the structural formula CH2 oruoHa-cm on ons-org C42 Br EXAMPLE 45 5,7-Dichlor0-6-Methyl-4-[2-(3-MethyZ-I -Pyrr0lidyl Ethoxy] I ndane A. 30 g. of 6-methyl-4-indanol was slurried in 50 ml. of glacial acetic acid and a small crystal of iodine was added as a chlorination catalyst. The slurry was stirred and 58 g. of sulfuryl chloride was added dropwise at such rate that the temperature of the reaction mixture remained 34 below 55 C. without application of external cooling. After this addition was completed, the reaction mixture was stirred for one hour longer, during which period a solid separated from solution. This solid was collected on a filter, and was washed with acetic acid and then dried. There was thus obtained 35 g". of white solid; this was recrystallized from 300 ml. of petroleum ether. There was thus obtained 28 g. of silky white needles which melted at 99102 C. This product was 5,7-dichloro-6- methyl-4-indanol, having the structural formula OH CH: I

Anaiysis.--Calcd. for c d-1 C1 0: C, 55.31; H, 4.64; Cl, 32.66. Found: C, 55.16; H, 4.70; Cl, 32.19.

B. Following the procedure of part A of Example 1, but substituting 40.6 g. of 5,7-dichIoro-6-methyl-4-indanol for the S-indanol and substituting 29.6 g. of 2-(3- methyl-l pyrrolidynethyl chloride for the 3-diethylaminoethyl chloride, there is obtained 5,7-dichloro-6-methyl-4- [2-(3 methyl l -pyrrolidyl)ethoxy]indane, having the structural formula CHr -CHCHg O-CH:OH2N our-on.

CH; CH,

This base reacts with methanesulfonic acid to yield 5,7- dichloro-6amethyl-4-[2-(B-methyl-l pyrrolidyl)ethoxy}- indane methanesulfonate. The base reacts with u-propyl iodide to yield 5,7-dichloro-6-methyl-4-[2-(3-methyl-lpyrrolidyl)ethoxy]indane propiodide, having the structural formula CHzCHgCHs OHz-CH(CH&) o-mmom-rq Q 01 I our- H, C I

OH; OH

EXAMPLE 46 5 7-Dichi0r0-4- [1-Methyl-5( l-Pr'peridyl) Pentoxy] Indane Proceeding in the manner described in part A of Example 23, but substituting 37.8 g. of I-methyl-S-(l-piperidyl)pentyl chloride for the 3-(1-piperidyl) propyl chloride, there is obtained 5,7-dichloro-4-[l-methyl-S-(lpiperidyl)pentoxy]indane, having the structural formula This base reacts with Z-naphthoic acid to yield 5,7-dichloro-4-[l-methyl 5 (1 piperidyDpentoxylindane 2- naphthoate. The base reacts with dimethyl sulfate to 35 yield 5,7-dichloro-4-[l-methyl-S-(l piperidyl)pentoxy]- indane methosulfate, having the structural formula 6-Chloro-5-(Z-Diethylaminoethoxy)Indane A. 10 g. of sodium hydride was added to 400 ml. of isopropyl alcohol in a one liter three-neck flask fitted with a refiux condenser, drying tube, stirrer, and dropping funnel. The resulting solution was heated to reflux and stirred, and 50 g. of Z-diethyIaminoethyl chloride was added to the refluxing solution dropwise over a period of fifteen minutes. After this addition was completed, the reaction mixture was refluxed for one hour more, and then the excess isopropyl alcohol was distilled off. The distillation residue was diluted with water and extracted with ethyl ether. The ether layer, was separated and extracted with a mixture of 960 ml. of water and 75 ml. of concentrated hydrochloric acid. The acid aqueous extract was made alkaline by addition of excess 35 percent aqueous sodium hydroxide solution. The oily base which separated was dissolved in ether, and the ether solution was dried over anhydrous calcium sulfate. After removal of the drying agent, the ether was removed from the solution by distillation, and the residual oil was distilled under reduced pressure. The fraction distilling at 145-180 C. (0.05 mm.) was a colorless oil, n 1.5277, which weighed 40.7 g. This product was 6- chloro-S-(Z-diethylaminoethoxy)indane, having the structural formula .4. i CH B. 40 g. of 6-chloro-5-(2-diethylarninoethoxy)indane, 125 ml. of isopropyl alcohol, and 41.3 ml. of 4.16 N ethanolic hydrogen chloride solution were mixed and the mixture was then cooled. Ethyl ether was added to the cooled solution, just short of turbidity. The solid which separated from solution on standing was collected on a filter. This product, which weighed 23.3 g. was recrystallized from isopropyl alcohol, using decolorizing charcoal, to yield 10 g. of 6-chloro-5-(Z-diethylaminoethoxy) indane hydrochloride which melted at 150-152 C.

Analysis.Calcd. for C H CI NO: Cl (total, 23.30; Cl (ionic), 11.65. Found: Cl (total), 23.03; Cl (ionic), 11.69.

36 C. 6chloro-5-(2 diethylarninoethoxy)indane reacts with one equivalent of p-ethoxybenzyl chloride to yield 6-chloro-5(2 diethylaminoethoxy)indane p-ethoxybenzyl chloride, having the structural formula.

CH2 CZH5 O-CHzCHq-N 01 can EXAMPLE 48 5, 7-Dich I0r0-4- [2- (4-Thi0m0rph0linyl )EthoxyJIndane ethoxy]indane methiodide, having the structural formula on, om\ 0o1noHI I 1 orb-cm I claim: 1. 5,7-Bis(dimethylaminomethyl)-4-indanol. 2. 4,6-Bis(dimethylaminomethyl)-5-indanol.

References Cited in the file of this patent UNITED STATES PATENTS Sam Jan. 21, 1958 Huebner Jan. 31, 1961 OTHER REFERENCES Fieser et al.: J. Am. Chem. Soc., volume 58, pages 20502054 (1936).

Claims (1)

1. 5,7-BIS(DIMETHYLAMINOMETHYL)-4-INDANOL. 2. 4,6-BOS(DIMETHYLAMINOMETHYL)-5-INDANOL.