CA1056821A - Indoline derivatives - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
This invention relates to a process for the preparation of a compound of the following formula:
A
wherein R1 is selected from the group consisting of hydrogen, chloro, bromo, lower alkoxy, nitro, amino, acetamido and dimethylamino; R2 is selected from the group consisting of hydrogen, lower alkoxy and nitro, or R1 and R2 together form a methylenedioxy group; R3 is selected from the group consist-ing of hydrogen and methyl; Y is selected from the group consisting of hydroxy, chloro, bromo, methanesulfonyloxy and p-toluenesulfonyloxy, which comprises either;- (a) lower alkanoylating or bensoylating a compound of the formula where R1 , R2, R3 and Z are as defined above; or (b) reducing an acid of the formula:
or a lower ethyl ester or anhydride thereof, wherein R1, R2, R3 and Y are as defined above, to produce a compound of formula I in which Z is hydroxy;
or (c) partially hydrolyzing a compound of the formula:

Description

This application is a divisional of our copending Canadian Patent Application Serial No. 140,989 filed May 1, 1972, now Patent No. 1,041,154.
Patent No. 1~041,154 relates to new organic compounds and, more par-ticularly, is concerned with novel substituted 3-[2-(4-phenyl-1-pipera~inyl)-ethyl] indolines and novel methods for the preparation of these compounds.
The novel substituted 3-[2-(4-phenyl-1-piperazinyl)ethyl] indolines of Patent No. 1,0413154 may be represented by the following general formula:

H (I) wherein ~ is hydrogen, chloro, bromo, lower alkoxy, nitro, amino, acetamido or dimethylamino; R2 is hydrogen, lower alkoxy or nitro and Rl and R2 taken together is methylenedioxy; R3 is hydrogen or methylj R4 is hydrogen or me-thyl; and R5 is hydrogen, chloro, methoxy, methyl or trifluoromethyl.
This application is conce~ned with novel intermediates useful~in the preparation of the compounds of Patent No. 1~041,154. The novel Inter- ~ -mediates of the present invention are represented by the follo~ing general formula

2 ~ N 3 (~) ' ': ' where m Y is benzoyl or lower alkanoyl; Z is hydroxy~ chloro, bromo, methane-sulfonyloxy or p-toluenesulfonyloxy; and ~ , R2 and R3 are as hereinabove ' defined. Suitable lower alkoxy groups contemplated by the present invention are those ha~ing up to four carbon atoms such as, for example~ methoxy~

.

1' ' ' ' `

~ .'' ,. ' .
, - la -,, ':

,, , .... , ,. , .~ , : ; .. . . . , .: , ethoxy~ isopropo.Yy, sec-butoxy, etc. Suit.lble lowcr alkLnoyl gr~ups contcm-platcd by thc present :invctlt:ion arc thosc lulving flom ~ to ~ eilrbon .Itom, such as acetyl, propionyl, n-butyryl and isobutyryl.
Furthermore, according ~o the prcscnt invcntion, there is provided a process for the preparation of a compound of the following formula:

Rl ~ ~ 2 2 , ,~ ~

wherein Rl is selected from the group consisting of hydrogcn, chloro, bromo, lower alkoxy, nitro~ amino, acetamido and dimethylamino; R2 is selected from the group consisting of hydrogen, lower ~ilkoxy and nitro, or ~1 and R2 together form a methylenedioxy group; R3 is sclected from the group consist-ing of hydrogen and methyl; Y is selected from the group consisting of lower --alkanoyl and ben~oyl; and Z is selected from the group consisting of hydroxy~
chloro, bromo, methanesulYonyloxy and p-toluenesulfonylo.~y~ which comprises either:- (a~ lower alkanoylating or benzoylating a compound ofthe formllla: -H

wher~ Rl, R2, R3 and ~ are as dcfined above; or (b) reducing an acid of the formulà:

, .

, . .

H~cH2C

y or a lower alkyl ester or anhydride thereof, wherein R1, R2, R3 asld Y are as defined above, to produce a compound of formula I in which Z is hydroxy, or ~
(c) partially hydroly~ing a compound of the formula: -' '` ~"

1 ~ CH2CH20-ACYl ;

I
;' in which "Acyl" reprcsents an acyl group and Rl, R2, R3 and Y arc as - pre~iously defined; when a compound of formula I is required in which R1 is chloro, bromo or nitro, chlorinating, brominating or nitrating a correspond-.
ing compound of formula I in which Rl is a hydrogen atom; when a compound ~
:
of formula I is required in which R2 is nitro nitrating a~ corresponding , .
compound of formula I in which R2 is a hydrogen atom; when a compound of ~
.
formula I is required in which R1 is amino reducing a corresponding compound of formula I in which Rl is nitro; asld when a compound of formula I is ~ ; -rcquirod in which Z is chloro, bromo, mcthaslesulfonyloxy or p-toluencsulfonyl-oxy, ch].orinating, brominating~ methanesulfonylating or p-toLuonesulfonyla_ ting a corresponding compound of formula I in which Z is hydro.Yy.
The substituted 3-~2-~4-phenyl-1-piperazinyl)etllylJ-indolinos which are obtained from the intermediates of the present invetltion are obtainable as crystalline material~ ha~ing chas~actcristic melting points and

-3-absorption spectra. They are appreciably soluble in many organic solvents such as lower alkanols, acetone, ethyl acetate, and the like but are generally insoluble in water. These compounds are organic bases and thus are capable of forming acid-addition and quaternary ammonium salts with a variety of organic and inorganic salt-forming reagents. Thus, acid-addition salts, formed by admixture of the organic free base ~ith up to three equivalents of an acid, suitably in a neutral solvent, are formed with such acids as sul-furic, phosphoric, hydrochloric, hydrobromic, sulfamic, citric, maleic, fumaric, tartaric, acetic, benzoic, gluconic, ascorbic, and related acids.
In like manner, quaternary ammonium salts may be formed by reaction of the free bases with a variety of organic esters of sulfuric, hydrohalic and aromatic sulfonic acids. The organic reagents employed for quaternary ammonium salt formation are preférably lower alkyl halides. However, other organic reagents are suitable for quaternary ammonium salt formation and may be selected from among a diverse class of compounds including benzyl chloride, phenethyl chloride, naphthylmethyl bromide, dimethyl sulfate, methyl ben-zenesulfonate, ethyl toluenesulfonate, allyl chloride, methallyl bromide and , crotyl bromide. The acid-addition and quaternary ammonium salts of the substituted 3-~2-~4-phenyl-1-piperazinyl)ethyl~indolines are, in general, crystalline solids relatively soluble in water, methanol and ethanol but relatively insoluble in non-polar organic solvents such as diethyl ether, benzene, toluene, and the like. For purposes of this invention, the free bases are equivalent to their non-toxic acid-addition and quaternary ammonium salts.
Certain of the substituted 3-~2-(4-phenyl-1-piperazinyl)ethyl~
indolines are prepared by the series of reactions set forth in the following reaceion scheme:

. ~ .

~ . -4-~, .

6 ~ 1 2 2 ~ 3 (III) / (IV) 6 ~I Y R

~ Y ,~

6 ~ 2CN2 ~ y N~

R2 f 3 H (VI) ;:' wherein R2, R3, R4~ R5 and Y are as hereinabove defined; R6 is hydrogen~ :
chloro~ bromo, lower alkoxy~ nitro~ acetamido or methylenedioxy when taken together with R2, and R7 is chloro, bromo, mekhanesulfonyloxy or p-toluene-sulfonyloxy. In acoordance with this reaction scheme, treatment of a 1-acyl-3-indoline ethanol (III) with phosphorus trichloride or phosphorus tribromide is productive of a l-acyl-3-indoline ethyl chloride or bromide (IV, R7-Cl or Br) 7 respectively. Alternatively, treatment of the 1-acyl-3-indoline ~hanol ~-(III) with methanesulfonyl chloride or p-toluenesulfonyl chloride in a solvent such as pyridine or collidine gives the sulfonyl ester (IV, R7-CH3S03 or E~CH3C6~4so3)- Reaction of the intermediates (IV) with a 4-phenylpipera-zine of the ~ormula:

. ~ ..
~ '~

H-N N ~/ \~ (VII) R

wherein R4 and R5 are as hereinabove defined~ gives the 1-acyl-3-amino-ethyleneindolines (V). This reaction is preferably conducted in an inert medium such as benzene, toluene, ~ylene, dioxane, and the like at tempera-tures of 50 -140 C. However, temperatures of 100 -110 C. are preferable.
The conversion of the 1-acyl-3-aminoethyleneindolines (V) to the substituted 3-~2-(4-phenyl-1-piperazinyl)ethylJindolines (VI) may be effected by acidic or basic hydrolysis. Mineral add hydrolysis is particularly useful for this conversion. The preferred conditions consist of treating (V) with boiling --6N hydrochloric acid solution for one-fifth to one-half hour.
Other compounds of formula (I? are prepared as indicated in the following reaction sequence:

O N CH CH -N N_ 2 2 y R2 ~ N A R3 R4 R5 (VIII) t Y

~ J , - ~ , 2 ~ N R3 ~ R5 (I~

~ \ ~

R2~ 5 (y) B

g~
1 ~

H2N ~ y R5 (XI) (CR3)2N ~ I CR~H2N N
H
(XII) wherein R2, R3, R4, R5 and Y are as hereinabove defined. Thus~ in accordance with this reaction scheme~ redu~tion of a 1-acyl-5-nitroindoline ethylamine (VIII) affords the 1-acyl-5-aminoindoline ethylamine (IX). This reduction may be performed using a metal in mineral acid or catalytically. The latter process is particu~arly advantageous. Methylation of (IX) with formaldehyde and formic acid~ according to the Eschweiler-Clarke procedure, gives the 1-acyl 5-dimethylamino derivatives (X~. Mineral acid hydrolysis of the 1-acyl derivatives (IX) and (X) then gives the 5-aminoindoline ethylamine (XI) and the 5-di=ethylamino derivatives (XII), respectively.
The novel 1-acyl-3-indoline ethanols (III) which serve as starting materials for the substituted 3-r2-(4-phenyl-1-piperazinyl)ethyl~indolines (VI) are prepared by several procedures. In those instances when R3 is hydro-gen in (III), the appropriate 1-acyl-3-indoline ethanol is prepared as set forth in the following reaction scheme:
. ' ' ' :' .

- 6a-~7 ' ' ~ > ~1~C-C0 n? ~ N O R2 ~ I
(XIII) H / (XIV~ 1~

~H2C02-R~/ R~ cH2co2H
R2 ~ / ~2 N 0 ( ~ ) I /
/ ' . .
, .
Re~CH2cH20H R~CH2CH20H
151 1~ < ' ~ .
R2~ ~ ~ R2~/ ~ N~ ~
(XVII) H \ (XV~ ) H
. .
', ~' ` ~ .

3 ~ _~CH2cH20-y ~ CHzCH20H

2~ N .~ - RZ~N
(XIX) ~(XX) Y
.:
whereln R2, R~ ~nd Y are as hereinabove defined and R3 i9 lower alkyl Or from 1 to 4 car~on atoms or phenyl lower alkyl such a~
benzyl, a-phenethyl and p-phenethyl. In accordance with this reactlon schemel condensatlon o~ an oxindole (XIII1 with an oxa-late ester (~uch as dlmethyl oxalnte, di~propyl oxalate, di-benzyl oxalate, etc.) affords the corresponding i3atylidene ester (XIV). The la~t:substance may be converted into the l-~cyl--3-i.ndolinc ethnnols (XX) by 3evcral route3. Clemmen~cn reduc~
tion Or th~ tylidcne ester ~XIV) ~ives thc oxlndoleacctlc 7 ~

:
,, ' .
.

e.ster (XV) D.l.borar)e reduct;lon Or ~XV) then ~i.ves the in~lol:lrle ethanol (XVII). ~lternat:lvcly9 thc i.satylit3cne es~er (XIV) may be converted direckly into the incloline ethanol (XVII) by reduc-tion with excess dlborane. When the ester-ifyin~ group (R~) is benzyl, catalytic hydrog,enation of the isatylidene ester (XIV) using a palladium-on-carbon catalyst affords the oxindoleacetic acid (XVI) mis last substance may be converted into the indo~ :~
line ethanols (XVII). Thus, treatment of (XVI) with a lower alkyl chloroformate produces a mixed carbonic anhydride. Reduc-10 tion of this carbonic anhydride with sodium borohydride gives ~.
the oxindolylethanol (XVIII). Treatment of (XVIII) with diborane then affords the indoline ethanol (XVII). The conversion of :-(XVII) into the useful l-acyl-3-indoline ethanols (XX) may be accornplished by either of two procedures. Thus, treatment of (XVII) with an acyl halide (YCl or ~Br) or an acyl anhydride (Y20) under Schotten-Bauman conditions affords the l-acyl-3-indo-line ethanol (XX) directly. Alternatively, treatment of the in-doline ethanol (XVII) with an acyl halide or an acyl anhydride in pyridine produces the O,N-diacyl derivative (XIX). m e O-acyl group may be removed selectlvely to give the 1-acyl-3-indoline ethanol (XX). Sodium methoxide in methanol is particularly use-ful for this de-O-acylation. Solutions of ammonia or triethyl-amine in methanol may also be used for this selective deacylation.
Other l-acylindoline ethanols may be prepared from the known 1-acetyl-3-indolineacetic acids (XXI) as set forth in the following reaction scheme: .
.
.1 ~ .' .
.,",.

~ 30 ` ' . .

~ \ ~ Cl~2C02~1 R9 ~ ~ C~l2CO2~I

I~2 N R2 N
COC~13 COC~I3 (XXI) (XXII~
~ , ~ , 2 ~ ~ CH2CH20lI R~ ~ J CH2CH20H

R I -> R

~XXIII) (XXIV) wherein Rg is chlorog bromo or nitro and R2 is as hereinabove defined. Thus~ the l-acetyl-3-indolineacetic acids (XXI) react with electrophilic agents to give the 5-substituted derivatives (XXII). Examples of such electrophilic agents are chlorine J bro-mine and nitric acid, m ese reagents react with (XXI) to give the 5-chloro, 5-bromo and 5-nitro derivatives (XXII), respectively.
The reactions may be carried out in acetic acid at room tempera-ture, The l-acetyl-3-indolineacetic acids (XXI and XXII) may be reduced to give the l-acetylindoline ethanols (XXIII and XXIV)g respectively. Diborane is particularly e~fective for this trans-formation, Alternatively7 the acids may be converted into mixed carbonic anhydrides by reaction with a lower alkyl chlorofor- ~
mate. Treatment of these mixed anhydrides with sodium borohy- -dride then gives the l-acetylindoline ethanols (XXIII and XXIV).
m e l-acetyl-3-indoline ethanols (XXIII) can also serve as pre-cursors for the alcohols (XXIV). Thus, treatment of (XXIII) with chlorine, bromine or nltric acid affords the 5-chloro, 5-bromo and 5~nitro derivatives (XXIV)J respectively, The 1 acetyl-5--nltro-3-indollne ethanols (XXIV~ Rg=NO2) also serve as precur-sors ~or other 1-acetyl-3-indoline ethanols. Thus, hydro~ena-tLon in the presence o~ a noble metal catalyst a~fords the cor-; resI)ondln~ 6-substitute(l-1-acetyl-5-amino-3 1ndoline ethanolsJ
_ 9 _ .:

ace~ylation of which gives the corresponding S-acetamido deriva-tives.
Other important l-acyl-3-lndoline ethanols may be ob-t~ined in accordance with the followin~ reactlon scheme:

10 ~ H2C02 R8 Rlo ~\ CH2C02-R8 ( ) H H

.~ .
Rlo / \ ~ CH2CU20U ~ ~ R R3 (X~VIII) \ (XXVII) Rlo / ~ ~ ~ CH2cH2GH

: ' `
wherein Rl~ is lower alkoxy and R3,R8 and Y are as hereinabove def$ned~ Thus, reduction of a 3~indoleacetic ester (XXV) gives the corresponding 3-lndolineacetic ester (XXVI). This reduction may be performed in several ways~ Ihe utilization of metallir . ~. ~, .
tin and hydrochloric acid is particularly advantageous when the 3~indoleacetic ester (XXV) has a methyl group at the 2-position, since these conditions lead to a great degree of stereoselec~
. ~ .
tivity. O~her reductive procedures that have been used with a degree of success for ~he conversion of (XXV) to (XXVI) are ~-ata~
lytic hydrogenation in the presence of a noble metal catalyst under neutral or acidic conditions. Suitable catalysts are platinum, palladium, ruthenium, and the like~ Appropriate sol-.' . ~ ~ ! .

~11; 156~Z~

vents are those selected fr~m the lower alkanols and mixtures of the lower alkanols with hydrochloric or fluoroboric acid. Treat=
ment of the 3~indolineacetic ester (XXVI) with a metal hydride such as lithium aluminum hydride is productive of the indoline ethanol (XXVII~ e resulting indoline ethanol (XXVII) may be acylated with an acyl chloride (YCl) or anhydride (Y20) to give the l~acyl derivative (XXVIII). Treatment of the l-acyl deriva-tlve (XXVIII) with nitric acid in acetic acid gives the l-acyl-6--nitro-3~indoline ethanol (XXIX).
Other important l-acyl-3-indoline ethanols may be ob-tained in accordance with the following reaction scheme:

Rlo ~ CH2C02-R0 Rl~ C02co2-R8 ~ ~ ~

H H
(XXX) (XXXI ) -' ' ~ ~ Rlo~_,j- CH2cH2oH :

11 '` R R'Ll ~ ~ ~ R3 ~ ~
(XXXIII) \ / (XXXII~ .

Rlo~\ ~ CH2CH20~ ~

ll ~ ~ 3 (XXXIV) .: " ' wherein Rll is lower alko~y~ Rlo and Rll taken together is methy-lenedioxy and R3~ R8 ~10 and Y are as hereinabove definedO Thereduction Df the 3-indoleacetic esters (XXX) to the correspond-ing 3-indolineacetic esters (XXXI) is carried out in a manner .
analogous to the reduction of (XXV) to ~XXVI)~ Reduction of the ' , ., . , ~ . . .

~L~56~
3-indolineacetic esters (XXXI) with a met~l hydride reagent, such as lithium aluminum hydride, is productive of ~he 3-indoline ethanols (XXXII). This last substance may be converted directly into the useful l-acyl-3-indoline ethanol (XXXIY) by acylation under Schotten Bauman conditions with the appropriate acyl halide (YCl or YBr) or acyl anhydride ~Y20). Alternatively~ treatment of (XXXII) with an acyl halide or acyl anhydride in a solvent such as pyridine, lutidine~ collidine, and the like gives the O,N-diacgl derivative (XXXIII). Treatment of (XXXIII) ~ith sodium methoxide in methanol then gives the important 1-acyl-3-indoline ethanol (XXXIV3.
The compounds of general formula (I) of the present invention are physiologically active on the central nervous sys-tem and show high activity as tranquilizers at non-toxic doses.
A useful test for tranquilizer ac~ivity consists of measuring ~he reduc~icn of spontaneous motor activity in animals by means of an actophotometer ~a photoelectric device for quantitatively measur-ing locomotor activity). Graded doses of the active compounds prepa~ed by the prooesses of this invention are administered to groups of mice~ and the effecti~e dosage ran~e for a significant reduction o~ motor activity (a measure of tranquili~ation) com-pared to control groupa is es~ablished. The use of reduced motor acti~ity as a measure of tranquilizing actlvity has been des-crlbed by W.D. Gray~ A.C. Osterberg and C.E. Rauh, Archives Internationales et de Therapie~ Vol. 134~ p. 198 (1961) and W.J.
Kinnard and C.J. Carr, Journal of ~harmacology and Experimental Therapeutics~ Vol. 121~ p. 354 (1957).
The effective dose that caused a 50% reduction in motor ac~ivity (MDD50~, exp~essed in milligrsms per kilogram of body ~Jeight, of some typicsl compounds of the present invention i5 set forth in Table I below~

TABLE I

Compound MDD50 ~mg./kg-) 3-[2- (~phenyl-l-pipera~inyl)ethyl]indoline dimaleate 13 3-~2-[~(o-methoxyphenyl~-1-piperazinyl]ethyl3-indoline trihydrochloride 7 5,6-dimethoxy-2-methyl-3-[2-(4-phenyl-1--piperazinyl )ethyl]indoline 0.2 6~7-dihydro-7-~ 2-[4-(o -methoxyphenyl)-l--piperazinyl]ethyl}-5H-1,3-dioxolo[4~5-I]-indole difumarate 1.1 5-methoxy-2-methyl-~[2-(4-phenyl-1-pipera-~inyl)ethyl]indoline 12 5-me~hoxy-2-methyl-3-~2-[4- ~o-methoxyphenyl)--l-pipera3inyl]ethyl}indoline 25 5-methoxy-3-~2-[4-(o-metho~Tphenyl)-l-pipera-zinyl]ethyl}-2-methyl-~nitroindoline 19 3-{ 2-[4- ~-methoxyphenyl)-l-piperazinyl]ethyl}--5-nitroindoline dihydrochloride 6 5,6-dimethoxy-3-{2-[4- (~-methoxyphenyl)-l- pipera-~inyl]~thyl}indoline trihydrochloride 9 , _ ...... ..
The Invention will be described in greater detail in conj~mctionwith the ~ollowing specific examples~ OI the examples, Ez~amples 3, 4, 9, 19, 23 to 28, 31, 32, 37, 40 to 45 and 49 to 52 illustrate ~he preparation of compounds within formula A in claim 1. Examples 79 to 95 and 97 to 103 il~
lustrate the preparation of compounds of formula I in Patent No. lgO41~154 from which this applioation is divided.
EX~IPLE 1 ~ ,~ ' . ',:
To a solution of 2.35 gr of oxindole-3-acetic acid CJ Am. Chem.
Soc. 75, 5305 (1953)~ in 18 ml. of tetrahydrofuran at -5 C. in an argon at-mosphere is added 1.71 ml. of triethylamine and then 1053 ml. of ethyl chloro--: :.

carbonate. The mixture is stirred at -5 C. ~or 30 minutes and then filtered, The filtrate is added drop~ise to a cold solution of 1.16 g. of sodium boro-hydride in 18 ml. of water, and the solution is then stirred at ambient tem-perature for 2 hours. The reaction mixture is rendered strongly acid with hydrochloric acid and extracted with ethyl acetate. The organic extracts are washed successively with - 13a -. .. ,J, ., ~ .

saturlt;cd ~odlum chlorlde solution, sot3iuln hydroxlde solution and wit;h saturated sodLum chloride solution. The organic extract ls dried wjth magnesium sulfate and evaporated under reduced pressure leaving a clear gum which is crystallized from ether and , recrystallized from acetone-petroleum ether (30-60C.) afrording 3-(2-hydroxyethyl)-2-indolinone, m.p. 111-112C.
EX~MPLE 2 Preparation of 3-indolineethanol -~
A solution of 531 mg, of 3-(2-hydroxyethyl)~2-indolinone in 35 ml~ of tetrahydrofuran is purged with argon and 6.5 ml. of lM borane in tetrahydrofuran is added, The solution is heated under reflux for 18 hours, then the solvent is removed under re-duced pressure. The residual glass is dissolved in 35 ml. of methanol and heated under reflux for 4 hours. The methanol is removed under reduced pressure and the residual gum is dissolved ln 25 ml. of ethyl acetate. The organic solution is extracted with two 15 ml. portions of lN hydrochloric acid, The acid ex-tract is rendered alkaline with sodium hydroxide and extracted with ethyl acetate. The organic extract is washed with saturated sodium chioride solution, dried with magnesium sulfate and eva-porated under reduced pressure affording 3-indolineethanol as an oil.

Preparakion of l--acet,yl-3-indolineethanol --To a ~uspension of 11.3 g. of 1-acetyl-3-indoline ace-tic acid [J. Org. Chem. 28, 2794 (1963)] in 90 ml. of tetrahydro-furan at 0C. is added 9.0 ml. triethylamine, The resultant ~olution is stlrred at -5C. and 6~3 ml. of ekhyl chlorocarbonate ~s added dropwise. The reaction mixture 1s allowed to rise to 28C. over a period of 30 minutes and then filtered free of tri-ethylamine hydrochloride. The clear filtrate is added dropwlse to ~ ~olution of 5.95 g. o~ sodium borohydride in 90 ml, of water stlrred in ~n ice-bath and stirring i~ contlnued for t~o hours a~

- ~ . , . , ,, ,, ~

)~ ~` \ j ~ ;$~
room temperature. The reaction mixture is again stirred in an lce-bath and acidified with lN hydrochloric acid, The acid solu-tion ls extracted with ethyl acetate and the organic extract is washed with saturated sodium bicarbonate solution, dried ~ith magnesium sulfate and concentrated under reduced pressure leaving a clear gum weighing 5,2 g. The crude product is dissolved in methylene chloride and passed thru a column of synthetic magnesium silicate collecting that fraction eluted by 2:8-acetone:methylene chloride. The resulting gum is ~rystallized from ethyl ether affording 2.5 g, of l~acetyl 3-indolineethanol, m.p, 49-52~C.

Preparation_of 1 acetyl-3-indolineethanol To a suspension of 4,38 g, o~ 1-acetyl-3-indoline ace-tic acid in 45 ml. of tetrahydrofuran at 19C. is added dropwise 25 m~. of lM borane in tetrahydrofuran. The solution is stirred for o~e hour~ then diluted with 20 ml, of water and 30 ml, Or saturated sodium chlor-lde solution, The mixture is extracted with ether and the organic extract is washed with ~aturated sodium bicarbonate solu-tion and saturated sodium chloride solution, then extracted with 6N hydrochloric acid solution, The acid extract is rendered alkaline with lON sodium hydroxide solution and ex-tracted with ether, The ether extract is washed with saturated sodium chloride solution, dried with magnesium sulfate and eva-porated under reduced pressure affording 3,02 g, of 1-acetyl-3--indolineethanol as a gum of sufficient purity for subsequent reactions, EXAMPLE_5 Preparation of ethyl 5,6-dimethoxy-2-oxo- ~3'a-indoline~lycolate To a solution of 4,82 g. of 5,6-dimethoxyoxindole [J.
Am, Chem, Soc, 77, 3844 (1955) ] in 50 ml, of dimethylformamide stirred in an lce-b~th in an argon atmosphere is ~dded 1025 g, of ~ sodlum hydride in oil dispersion (60,2~ concentration~, The mixture is ~tirred for 30 minutes and then a solu-tion of , ~ 15 -~ i3~
5.~5 g, of diethyl oxalate in 25 m:L, of dlmethyl~ormamide is added dropwi~e, The solution is stirred at ambient temperature for 18 hours, then diluted with 150 ml. of waterO The aqueous solutlon i~ stirred in an ice-bath and acidified with hydrochloric !
acid, The resultant red solid is collected and recrystallized from acetone affording ethyl 5g6-dimethoxy-2-oxo- ~3~a-indoline-glycolate, m.p, 18~-185~C. dec.

Pre aration of ethyl 5 6-dimethoxy-2-oxo-~-indolineacetate P . ~ , To a suspension of 0.73 g. of ethyl 5~6-dimethoxy-2-o~o- ~ -indolineglycolate in 50 ml. of acetic acid is added freshly prepared zinc amalgam (from 11 g. zinc and lo 1 g~ mercuric chloride). The mixture is stirred under reflux for 16 hours.
The mlxture is cooled and filtered and the filtrate is reduced in volume to 10 ml. under reduced pressure, The residue is di-luted with 50 ml, of water and extracted with ether. m e ether extract is washed with saturated sodium carbonate solution and saturated sodium chloride solutionj then dried with magnesium - sulfate and evaporated to dryness under reduced pressure. The resultant solid mass crystallizes from acetone-petroleum ether (30-60Co) affording ethyl 5,6-dimethoxy-2-oxo-3-indolineacetate, m,p. 123-124C.

Pre aration of 5,6-dimethoxy-3-indolineethanol p ~
~o a ~olutio~ of 1.95 g, o~ cthyl 5,6-dimethoxy-2-oxindolinacetate in 100 ml. o~ tetrahydro~uran stirred in an ice-bath in an argon atmosphere is added 40 ml. of lM borane in tetrahydrofuran. m e mixture is stirred for 15 ho~rs at ambient temperature and then heated under reflux for ~0 18 hoursO The solvent is removed under reduced pressure and the residue is heated at 100C. with 100 ml. lN hydrochloric acld, The acid solution is cooled and washed with ethyl acetate, then cooled in an lce-bath and made allc~line wlth aqueous sodium hydroxlde solution. The alkaline solution 1~ extracted w-lth ethyl ace~ate. The org~nic extract 1~ washed with saturated sodium chlorlde, dried with magnesium sulfate and evaporated under reduced pressure affording 1.23 g. o~ 5,6-dimethoxy-3-indoline-ethanol as a gum.

Preparation of 5,6-dimethoxy-3-indolineethanol To a partial solution of 2093 g. of ethyl 5,6-dimethoxy--2-oxo-~ 3'a~indolineglycolate in 150 ml. of tetrahydrofuran stirred at -5C. in an atmosphere of argon is added 80 ml. of a lM solution of borane in tetrahydrofuran. The solution is stirred at -5C. for one hour, stirred at ambient temperature for three hours and finally heated at re~lux temperature for eighteen hour~.
The solvent is removed under reduced pressure and the residue is heated with 100 ml. of lN sodium hydroxide on the steam bath for one hour. The cooled alkaline solution is extracted with ethyl acetate. The ethyl acetate solution is extracted with lN hydro-chloric acid. m e hydrochloric acid extract is rendered alkaline with 5N sodium hydroxide, extracted with ethyl acetate and the extract evaporated under reduced pressure a~fording 0.82 g. of 596-dimethoxy-3-indolineethanol.

Preparation of l-acetyl-5,6-dimethoxy-3-indolineethanol A solution of 1,2~ g, of 5,6-dimethoxyindoline~
-ethanol in 60 ml. of 0.5N hydrochloric acid is rendered alkaline with lON sodium hydroxide. The mlxture is stirred in an ice-bath and 12 ml. of acetic anhydride is added dropwise. The mixture is skirred at ambient temperature for 15 minutes maintaining alkalinity by addition of sodium hydroxide solution An addi tional 12 ml. of acetic anhydride is added and the mixture is stirred for one hour. The solution is extracted with ethyl ace-tate and the extracts are washed with saturated sodium chloride ~olution~ drled with m~ene~ium sulfate and evaporated ~ 17 -., . , ,, , .. , , ~ :

z~
undzr reduced pressure~ The residual gum is crystallized from acetone-petroleum ether (30;60C.) affording l-acetyl-5~6~dlmeth-oxy-3-indolineethanol~ m,p. 148-150C.

Preparation of 4,5-_ethylenedioxy-2_nitrophenylacetic acid A suspension of 25 g. of 4,5-methylenedioxyphenyl ace-tic acid ~J. Org. Chem~ 17~ 568 (1952)~in llO ml. of acetic acid is stirred at 15 C. while 40.5 ml. of concentrated nitric acid is added in portions maintaining the tempera~ure at ~iOC. The mix~
ture is stirred for an additional 40 minO~ then added to 800 ml~
of ice water. The 4,5-methylenedioxy-2-nitrophenylacetic acid ls collected as 24.5 g. of yellow crystals, m,pO 185-188C.

A solution of 25 g. of 4~5~methylenedioxy~2-nitrophenyl~
acetic acid and 1 ml. concentrated sulfuric acid in 500 ml. meth-anol is heated at reflux temperature for 18 hours. The solution is cooled and 5 g~ of anhydrous sodium acetate is added. The result2nt precipitate is collected and washed with water affording 17.8 g. of methyl 495~methylenedioxy-2-nitrophenylacetate, m.p.
106-108 C. Dilution of the filtrate with water affords an addi-tional 5.8 g~ of product, m.p..106-108C.

A mixture of 11 g. of methyl 2-nitro-4~5-methylene~
dioxyphenylacetate and 1.1 g. of 10 per cent palladium-on-char-coal catalyst in 200 ml. of ethanol is shaken with hydrogen until the theoretical amount of hydrogen is absorbed. The reaction mixture is filtered free of catalyst and evaporated under reduced pressure affording mzthyl 2-amino-4~5-methylenedioxyphenylacetate as a white solid~

.

-18_ ' . : . :
.

Preparation of 5,7-dihydro-6H-173-dioxolo~4,5-f~indol~6-one A soLution of 1.0 gO of methyl 2-amino 4,5-methylene-dioxyphenylacetate in 5 ml. of acetic acid is purged with argon and heated under reflux for 1 hour. The hot acetic acid solution is stirred and diluted with water until crystaLs form. The mix-ture is cooled and 660 mg~ of 5~7-dihydro-6H-1J3-dioxoloC4,5-f~-indol-6~one~ m.p. 222-225C., is collected by filtration.
EXA~PLE 14 10 ,~
indole-,~ 7'a-glycolate A solution of 5031 g. of 5~7-dihydro 6H-1~3-dioxolo-C4~5-f~indol~6-one in 50 ~1. of dimethylformamide is stirred in an ice-bath in an argon atmosphere with 1.45 g. of sodium hydride--in-oil dispersion (60~2 per cent concentration) for 30 minutes.
To the reaction mixture is added a solution of 6.07 ml. of diethyl oxalate in 25 ml. of dimethylformamide. The reaction solution is stirred at ambient temperature for lR hours, then added to 150 ml.
of water and acidified with concentrated hydrochloric acid. The resultant red precipitate is collected by filtration and recrys-tallized from acetone affording ethyl 5~6-dihyclro-6-o~o-7H-1~3~--dioxoloL4~5~f~indole ~ 7'a-glycolate~ m.p. 246_248C.
~XAU~L= 15 indole-7-acetate A suspenslon of 1.39 g. of ethyl 5,6-dihydro~6-oxo~7H--1~3-dioxolo~4~5-f~indole-~ 7~a-glycolate and 1.39 g. of 10 per -cent palladium~on-charcoal catalyst in 50 ml~ of acetic acid con-taining 0.25 ml. concentrated sulfuric acid is shaken with hydro-gen until two mole equivalents of hydrogen are absorbed. The re-action mixture is filtered directly onto 1.0 g. of anhydrous sodium acetate and the filtrate is evaporated under reduced pres sure. The residue is partitioned between water and ethyl acetateO

The e~hyl acet~lte solutlon la ev~porated :Ln vacuo and thc reslr~ue cryst~llized frorn acetone-petroleum ether (30~60C.) affording ethyl 5,6-dihydro-6-oxo-7H~1,3-dioxolo[l~,5-f]lndole 7-acetate, m.p. 151-152C.
EX~MPLE 16 Preparation of e-thyl 5,6-dihydro-6-_xo-7H-1,3-dioxolo~ll,5-fl- $
indole-7 acetate To a suspension of 1.39 g. of ethyl 5,6-dihydro~6-oxo--7H-lJ3-dioxolor4,5-f]indole-~ 7J~-glycolate in 50 ml~ of acetic acid is added zinc amalgam prepared from 11 g~ o~ zinc and 1.1 g.
mercuric chloride. The mixture is stirred and heated at reflux for 18 hours, then cooled and filtered. m e filtrate is evapor-ated under reduced pressure to a volume of 10 mlO and diluted with 100 ml. of water. The solution is extracted with ethyl ace-tate and the extracts washed successively with saline solution,sodium bicarbonate solution and with saline solution The ethyl acetate is evaporated under reduced pressure and the residue crystallized from acetone-petroleum ether (~o-600c.) affording ethyl 5,6-dihydro~6-oxo-7~ dioxolo[4j5-f~indole-7-acetate, m~p. 150-151C.
EhAMPLE 17 Preparation of 6,7-dih~dro-5H-lJ3-dioxolo[4,5-f]indole-7-ethanol , To a solution of 1.0 g. of ethyl 5,6-dihydro-6-oxo-7H- ' -193-dioxolo~495-~indole-7-acetate in 50 ml. of tetrahydro~uran stirred at -5C. in-an atmosphere of argon is added 21.8 ml. of a lM solution of borane in tetrahydro~uran. The solution is stirred' ' at 0C. for 15 minutes, at ambient temperature for 90 minu-tes and ~
finalJy heated at reflux for 18 hours. m e solvent is removed - '-under reduced pres~ure and the residue is heated on the steam '' -bath with 50 ml. of lN hydrochloric acid for one hour The solu-tlon ls washed with ethyl acetate, rendered alkaline with lON ' '' sodlum hydr~xlde and extracted with ethyL acetate The solven-t .~,.. ..... ... .
is removcd under reduce~ pressure leavin~ o.6 e. of 6,7-dihydro--5II-1,3-dioxolo~)l,5-r~in(lole-7-et~ano:l. a~3 an amber o:Ll.
]~X/~MI'I,I?, 1~3 Pre~arat~on Or 5-ac~tyl-6,7-dlh~dro-5II-1,3-d-Loxolo~ r~in 7-ethyl acetate A solutlon of o.6 g. OI 6,7-dihydro-5I-I-1,3-clioxolo-[4,5-flindole-7-ethanol in 10 ml. of pyridine and 0 9 ml. of ace-tic anhydr-Lde is heated on the steam bath for two hours The solutlon is cooled, d-lluted with water and extracted with ethyl acetate. The extract is washed with lN hydrochloric acid and saline solution and evaporated under reduced pressure. The resi-due is crystallized from acetone-petroleum ether (30-60C.) affording 5-acetyl-697-dihydro-5H-1,3-dioxolo[4,5-f]indole-7--ethylacetate, m.p. 93-94C.

Preparation_of 5-acet~1-6,7-dihydro-5H-1,3-dioxolo~4,5-f~indole-~7~ethanol --_ A solution of 200 mg. of 5-acetyl-6,7-dihydro-5H-1,3--dioxolo~4,5-f]indole-7-ethylacetate and 40 mg~ of sodium meth-oxide in 10 ml of methanol is heated at reflux for 2 hours, then evaporated under reduced pressure me residue is partitioned between ethyl acetate and water. The ethyl acetate solution is separated and evaporated under reduced pressure. The residue is crystalliæed from acetone-petroleum ether (30-60C ) affording 5-acetyl-6,7-dihydro-5H-1,3-dioxolo[4,5-f~indole 7-ethanol, m.p.
140-141C.
E~{AMPLE 20 Preparation of l-acetyl-5 nitro~3-indoline acetic acid ~ ~ -To a stirred mixture of 34.21 g. (0.16 mol) of l-ace~
tyl-3-indoline acetic acid ~J. Org. Chem., 2~3, 2794 (1963)] and 450 ml. oî glacial acetic acid is added dropwise at 15C. 233 ml.
of 90~, fuming nitric acld The resul~ing solutlon ig st;irred at room temperature for one hour and then poured onto 1100 g of craclccd Jce. The 501i(3 i.S collected by filtration to ~ive . . ~ . .

32.25 ~. Or brJ~ht; yellow cry~tals, m.p ~0~-211C.
EXAMP1~ ?1 Preparation Or l-acetyl-5-bromo-3-indolineacetic acid A solution o~ l~ oo g. (25 mmol, 1 3 ml ) of bromine in 12.5 ml. of acetic acid is added dropwise to a stirred mixture of 5.10 g. (22.5 mmol) Or l-acetyl-3-indolineacetic acid in 25 ml~
of glacial acetic acid. The resulting solution is stirred at ambient temperature for 90 min. and is then poured into 150 ml.
of water. The precipitated solid is recrystallized from isopro-pyl alcohol to give white crystals, m.p~ 195-197C.
EXAMPI,E 22 Preparation of l-acetyl-5-chloro-3-indolineacetic acid A solution of 1 55 g. (22 mmol) of chlorine in 15 ml of glacial acetic acid is added to a stirred mixture of 4.40 g.
(20 mmol) of 1-acetyl~3-indolineacetic acid in 20 ml. of acetic acid The mixture is stirred at ambient temperature for one hour, during which the solid dissolved. m e solution is diluted with water, and the precipitated solid is recrystallized from isopropyl alcohol to give white crystals, m.p l90-19~C.
EXAMPLE_23 Pre aration of l-acetyl-5-nitro-3~indolineethanol P ~
- To a stirred mixture of 29.43 g. (0.118 mol3 of l-ace~
tyl-5-nitro-~-indolineacetic acid in 500 ml of tetrahydrofuran is added dropwise over 45 minutes 120 ml. of lM borane in tetra-hydrofuran solution. The resulting solution is stirred at room ternperature for 90 minutes, whereafter 25-ml. of water is added dropwise. The solvents are removed under reduced pressure, and the residue i~ distributed between ethyl acetate and sodium car-bonate solution. The organic layer i5 washed with additlona1 sodium carbonate solution, dried and concentrated under reduced pressure untll a mas~ Or yellow crystal~ separate. The solid is recrystallized from ethyl acetate-heptane to give yellow crys- ~ -tal~, m.p 13~ l1C.

~ ~, E~xl\MpT~E 2 1~
Preparation of l-acetyl-5~b~romo-7-indolLneethanol In the m~nner de~cribed in Example 2~ treatment of 6,07 g, (20.4 mmol) of 1-acetyl-5-bromo-3-indolineacetic acid in 50 ml, of tetrahydrofuran with 20 ml. of lM borane in tetrahydro-furan solution gives white crystals.

Preparation of l-acetyl-5-chloro-~-indolineethanol In the manner described in Example 23 treatment of 3,29 g~ (13 mmol) of 1-acetyl-5-chloro-3~-indolineacetic acid in 50 ml. of tetrahydrofuran with 13 ml, of lM borane in tetrahydro-furan solution affords white crystals, m,p. 103-106C, Recrys-tallization several times from acetone-hexane raises the m.p. to 118-119C.

Preparation of l-acetyl-5-amino-3-indolineethanol A mixture of 3.0 g. (0,012 mole) of 1-acetyl-5-nitro--3-indolineethanol and 300 mg. of 83~ platinum oxide in 200 ml, of ethanol is shaken under 40 p.s.i, of hydrogen for 30 min. The catalyst is separated by ~iltration and the filtrate is dried over magnesium sulfate and concentrated to yield l-acetyl-5-~amino-3-indolineethanol as a yellow oil.

Preparation of N~ acetyl~3-(2-acetoxyethyl) 5-indolinyllacet-amide A solution of ~,1 g. (0.01l~ mole) of 1-acetyl 5-amino--3-indolineethanol in 40 ml, of pyridine and 5 ml. of acetic an~
hydride is warmed on a ~team bath for 30 min, After dilution with water the mixture is extracted with ethyl acetate, The ex-tract is washed with lN hydrochloric acid~ dried over magnesium sulfate, and concentrated. The residue is crystallized from acetone to yield N-~l-acetyl-~ (2 acetoxyethyl)-5-indolinyll--acetamide, m.p. 163-164~C.

" . ... .. . . . . . ........... ... . . . ... ... . .. ..
.... , , , . . . . : .:, . . : .

Preparation of N~ acetyl-3 (2-hydroxy ~ h amide A mixturs of 104 g. (0,0046 mole~ of N~ acetyl-3-(2--acetoxyethyl)~5~indolinyl~acetamide~ and 0.50 g~ (0~0093 mole) of sodium methoxide in 40 ml. of methanol is stirred under ~ -reflux for 30 minO The methanol is removed by dis~illation and the residual oil is dissolved in water and extracted with ethyl acetate. The extract is dried o~er magnesium sulfate and con-centratedO The residue is recrystallized from acetone~ether to yield N~ acetyl-3-(2-hydroxyethyl)-5-indolinyl~aretamide, m.p.
181-182C~

~y~ ineacetate A mixture of 25 g. (0.11 mole) of 5-methoxy-2-methyl -3-indoleacetic acid, 260 ml. of hydrochloric acid~ 260 ml. of ethanol and 104 g, of tin is heated under reflux three days and filtered~ The filtrate is concentrated and the residual oil is dissolved in ethanol previously saturated with hydrogen chloride.
This mixture is stirred under reflux for 16 hours and then con- -centrated. The concentrate is rendered alkaline with saturated sodium bicarbonate solution. The mixture is filtered and the filtrate is ~x~racted ~ith ehter. The ether extract is washed with saturated sodium bicarbonate and satura~ed sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated to yield ethyl 5-methoxy-2-methyl-3-indolineacetate a lightly colored oil.

To a stirred suspension of 7.5 g. ~0.20 mol~ of lithium aluminum hydride in 1.5 1. tetrahydrofuran is added 27 g. (0.11 mol) of ethyl 2-methyl-5-methoxy-3-iadolineacetate. The mix-ture is stirred at reflux for 18 hours, cooled and an aqueous .

~56~
solution of sodium potassium ta~trate is added. The reaction mixture is filtered and the filter cake is washed with ethyl ace-tate. T&e filtrate is concentrated to an oil which is dissolved in benzene, treated with activated carbon, dried over magnesium sulfate9 filtered through diatomaceous earth and evaporated under reduced pressure. The resulting oil is cooled in the refrigera-tor to afford 2-methyl-5-methoxy-3_indolineethanol as gray white crystals, m.p. 79~1 C.

10 ~
To a stirred suspension of 10 g. (0.05 mole) of 2-_methyl-5-methoxy-3-indolineethanol in 0.5 1. of lON sodium hy-droxide is added 9.9 gO (0.10 mole) acetic anhydride. Ater being allowed to stir overnight the reaction mixture is extracted with ethyl acetate. The organic layer is washed with lN hydro-chloric acid and saturated aqueous sodium chloride. The organic layer is dried over magnesium sulfate1 filtered and the filtrate concentrated to a clear oil. The oil is suspended in 1 1. of 2N
sodium hydroxide solution and ailowed to stir overnight. The re-action mixture is filtered and the filter cak~ washed with etherand petroleum ether to afford 1acetyl-2-methyl~S-meth~xy-3--indolineethanol as o~f-white crystals, m.p. 71 73C.

~ .
ethanol A solution of 1.00 g. of 1-acetyl-2-methyl-5-methoxy-~3-indolineethanol in 25 mlO of glacial acetic acid is stirred in an ~ce bath and treated with 1 ml. of fuming nitric acid.

The solution is stirred at room temperature for one hour and poured onto cracked ice to give orange crystals of 1-acetyl-2 _methyl-5-methoxy-6-nitro~3-indolineethanol.

-25~

' ' ,: , . . .

~L~S6~3Zl :
EX~MPLE 33 A mixture of 3.~ g. tO. 019mole) oE 3,4-dimethoxyphenylY
hydrazine hydrochloride~ 2~4 ml. (0.017 mole) of e-thyl levulinate, and 40 ml. of ethanolic hydrogen chloride is stirred under reflux for 30 minutes. The ethanol is evaporated under reduced pressure and the residue is diluted with water and extracted with ether.
The extract is washed with aqueous sodium bicarbonate solution, dried over magnesium sulfate, and concentrated under reduced pressure. Crystalli~ation from ether-petroleum ether affords ethyl 5,6~dimethoxy-2-methyl-3-indole acetate, m.p. 78-79C.

Preparation of ethyl 5~6-dimethox~ methyl-3-indoline a~etate A mixture of 3.0 gO (0.011 mole) of ethyl 5,6-dimethoxy--2-methyl-3-indole acetate~ 7.0 g. (Q.059 mole) of tin, 35 mlr of ..... .... .. .
ethanol~ and 35 ml. of concentrated hydrochloric acid is heated under reflux for one hour. An additional 7O0 gO (0~059 mole) of tin is added and the mix~ure is heated under reflux for six hours.
Excess tin is separated by filtration and ~he filtrate is eva-porated ullder reduced pressure. The residue is diluted withwater3 rendered alkaline with aqueous sodium hydroxide solution~
and extracted with ethyl acetateO The extract is dried over mag-nesium sulfate and concentrated under reduced pressure to yield ethyl 536-dimethoxy-2-methyl~3-indoline acetate as a yellow oilO

Prep_ration of 5?6-dimethoxy~2-methyl-3-indolineeth_nol A suspension of 10 g. tOr26 mole) of lithium aluminum hydride in 300 ml. of tetrahydrofuran is stirred under an argon atmosphere while a solution of 20 g. (0.072 mole) of ethyl 5,6 _dimethoxy-2-methyl-3-indolineaceta~e in 100 ml. of tetrahydro-furan is added. The mixture is stirred under reflux for two hours and ~hen treated with aqueous sodium potassium ~artrate solution. The precipitate is separated by filtration and washed . .

~5~2~.
with ethyl acetate The filtrate is dried over magnesium sulfate~ -and concentrated under reduced pressure to yi~ld 5~6-dimethoxy -2-methyl-3-indolineethanol as a yellow oil~
EXANPL~ 36 Preparation of l-benzoyl~5~6-dl _ hoxy-2-methy1~3-indolineethyl benzoate A solution of 16 g. (0.069 mole) of 5,6-dimethoxy-2--methyl-3-indolineethanol in 100 ml. of pyridine is stirred whlle 16 g. (0014 mole) of benzoyl chloride is added dropwise. The mixture is heated on a steam bath or 30 minutes and then parti tioned between water and methylene chloride. The organic layer is separated, washed with aqueous sodium hydroxide solution and dilute hydrochloric acid, dried over magnesium sulfate, and con-centrated under reduced pressure. The residual oil is crystal-lized from ether and recrystallized from methanol to yield l-ben-zoyl~5~6-dimethoxy-2-methyl-3-indolineethyl benzoate, m.p. 135-136C.

~ L-3_indolineethanol To a suspension of 3.0 g. (0.0068 mole) of l-benzoyl--5,6-dime~hoxy-2~methyl~3-lndolineethyl benzoate in 20 mlO of metha~ol is added l~S g~ (0~028 mole) of sodium methoxide. The mixture is s~irred under reflux for one hour and then evaporated .: ~
under reduced p~essure. The residue is diluted with water and extracted with ethyl acetate. The extract is dried over magne~
sium sulfate and concentrated in vacuo to yield l-benzoyl-5,6--dimetho~y-2-methyl~3-indolineethanol as a yellow oil.
EXAK~L3 38 -indoline-,-' ethanol A solution of 415 mg, (2~0 mmol) of 5-methoxy-2-methyl--3-lndolineethanol in 5 ml~ of methylene chloride is trea~ed with 200 mg. (S.0 mmol) of sodium hydroxide in 5 ml. of water. The .~ .... . . . .
,, , :. , .

~5~32~
mi~ture is treated with a solution of 375 mg. (2~0 ~mol) of p--nitrobenzoyl chloride in 5 ml. of methylene chloride and stirred at room temperature for 16 hours~ The mixture is separated, and the organic layer is washed with water and saline7 dried and evaporated to give a yellow oil which crystallizes from ether--hexane to give yellow prisms~ m.p~ 135-138C~
EEA~PLE 39 Preparation of 5-methoxy~2-methyl-1-(p-chlorobenzoyl)-3-indoline-ethanol A solution of 415 mg. (2.0 mmol) of 5-methoxy-2-methyl--3-indolineethanol in 10 mlO of methylene chloride is treated with 365 mg. (2.05 mmol~ of p-chlorobenzoyl chloride in methylene chloride. The resulting mixture is stirred at ambient tempera-ture for 16 hours. The organic layer is separated, washed with water and evaporated to give a white glass.

Pre~aration of l-acet~ -3-(2-bromoethyl)indoline To a solution of 410 mg. of 1-acetyl-3-indolineethanol in 25 ml. of benzene in an argon atmosphere is added 0.117 ml.
of phosphorous tribromide and one drop of pyridine. The resul-tant mixture is heated under reflux for 18 hours. The reacti~n mixture is cooled and the benzene solution decanted into 20 ml.
of ice-water and 10 ml. saturated sodium bicarbonate solution.
The organic soluti~n is separated, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution and dried with magnesium sulfate. The solvent is removed under reduced pressure and the resulting gum is crystallized from an acetone-hexane mixture affording l-acetyl-3-(2-bromo- ~
ethyl)indoline, m.p. 80-82C. ~ -To a partial solution of 254 mg~ of 1-acetyl-5,6~di-methoxy-3-indolineethanol in 25 ml. of benzene in an argon atmos-.
. .

phere is added one drop of pyridine and 0.056 mlO of phosphorous tribromide. The mixture is stirred and heated under reflux for 18 hours. The reaction mixture is cooled and the benzene solu-tion is decanted into 20 ml~ of ice-wa~er and 5 ml. of saturated sodium bicarbonate solution. The organic solution is separated, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic extract is dried with mag-nesium sulfate, evaporated to dryness under reduced pressure and the residual gum crystallized from acetone-petroleum ether (30-10 60C.) affording l-acetyl-3-(2-bromoethyl)5,6-dimethoxyindoline, m.p. 103-105Co olo~4 5-flindole-L . - _ :

To a partial solution of 1.5 g. of 5-acetyl-6,7-dihydro--5H-1,3-dioxolo~4,5-~indole~7 ethanol in 150 ml~ of benzene purged with argon is added 10 drops of pyridinle, and 0O35 mlO of phosphorus tribromide. The mixture is stirrèd and heated at re-flu~ for 18 hours. The mixture is oooled and the supernatant 20 liquid 1~ poured into 120 ml, o~ stirred ice-water and 70 ml. of ; saturated sod~um bicarbonate solutionO The or~anic phase is separated and ev~porated under reduced pressure. The residual solid is crystallized from acetone-petroleum ether (b.po 30-60C.) aford~ng 5-acetyl-697-dihydro-5H-1~3-dioxolo ~4,5-f~indole-7--ethyl bromide~ m.p. 147-148~C.

,'j ~ ~ .
fonate A solution of 1.0 g. (0.0040 mole) of 1-acetyl-5-nitro-30 -3-indolineethanol and 1.5 80 (0.0080 mole) of ~toluenesulfonyl chloride in 20 ml. of pyridlne is maintained at 0C. for 18 hours. The mixture is poured into ice wa~er and extracted with ~; ethyl acetate. The extract is washed with lN hydrochloric acid~

:; :

.. . . . .. : ... : .

~;6~2 Iried over magnesium sulfate, and concentrated. The residue is crystallized from e~her-petroleum ether to yield l-acetyl-5--nitro-3-indoline ethyl ~toluenesulfonate~ m.p. 118-120C.

Preparation of l-acetyl-3~(2-bromoethyl~-5-chloroindoline A mixture of 1.19 g. t5 mmol) of l-acetyl-5wchloro-3--indolineethanol, 0.29 ml. of phosphorus tribromide and 3 drops of pyridine in 50 ml. of benzene is heated at reflu~ temperature for 16 hours~ The supernatant solution is decanted from an orange sludge onto cracked ice-water. The organic layer is washed with sodium carbonate solut1on, dried over magnesium sulfate and eva-porated~ Trituration of the residue with petroleum ether (b.p.
30-60 C~) gives white crystals~ m~p. 115~ C. Recrystalliza- -tion from acetone~hexane raises the m.p. to 120-121C.

line In the manner described in Example 40 from 430 mg.
(0.0017 mol) 1-acetyl-2-methyl-5-methoxy-3-indolineethanol and 44~ mg. (0.0017 mole) of phosphorous tribromide there is obtained l-acetyl-3 (2-bromoethyl)-2-methyl-5-methoxyindoline as a cream colored solidg m.p. 108-110C.

~ .
.

A mixture of 356 mg. (1.0 mmol) of 5~methoxy-2-methyl-nitrobenzoyl)~3~indolineethanol and 135 mg. (0.5 mmol~ of phosphorus tribormide in 20 ml. of benzene containing a drop of pyridlne is heated at reflux temperature for 16 hoursO The organic solution is washed with a 5% sodium hydroxide solution and then with saline. The dried solution is evaporated to give j an oil that is ohromatographed on silicic acid. After removal of an impurity by elution with hexane-methylene chloride (1~
'~ ~

'~

:. : ~ . . . . ;

~5~
the product is eluted with methylene chloride. This material crystallizes from acetone-hexane to give yellow crystals~ m.p~
156-158C.

Preparation of l-(p-cblorobenzoyl)-3-(2-chloroethyl)-5 methoxy-. ~_~

A solution of 500 mg. (2.0 mmol) of 5-methoxy-2-methyl-p-chlorobenzoyl)-3 indolineethanol and 240 mg. (2.0 mmol) of thionyl chloride in 25 ml. of benzene is heated at reflux tem-10 perature for 2 hours. An additional 2~0 mg. (2.0 mmol) of ~hionyl chloride is added and the reaction is continued for one hour.
Thin layer chromatography now shows the reaction to be complete.
The solution is diluted with benzene, and washed successively with water~ sodium bicarbonate solution and water~ dried, and -evaporated to give an oil.

Preparation of 3-(2-chloroethyl)-S-me~hoxy-2-me ~
A solution of 1.45 g. (7.0 mmol) of 5_methoxy-2-methyl--3-indolineethanol in 50 ml. of benzene is treated with ~30 mg, (7.0 mmol) of thionyl chloride. The solution is heated~at reflux temperature for one hour and then cooled. Additional benzene is added, and this solution is washed with a 2% sodium hydroxide ~ -solution and water. Remuval of the sol~ent gives the product as : . , .
a mobile liquid.

.
indoline A solution of 2.6 g. (0O0075 mole) of 1-benzoyl-5,6--dimethoxy-~-methyl-3~indolineethanol in 25 ml. of benzene is stirred under an argon atmosphere while two drops of pyridine, and 0.40 ml~ (0.0042 mole) of phosphorus tribromide are added.
The mixture is stirred under reflux for two hours and ~hen poured into an ice-cold aqueous sodium bicarbonate solution. The ether ,., ' ~31-' ~` / ' extract o~ t;hi~ mlxl;llre is washed wJt;l) sntur~tcd ~queous ~odlum chlorldc solution, drled over magnesium sulfate, ~nd concentr~ted under reduced pressure. Crystalllzation o~ the resldue from ether, affords l-benzoyl-3-(2~bromoethyl)-5,6-dimethoxy-Z-methyl- j indoline, mOp. 125~127C.

Preparation of l-acet~1-3-(2-bromoethyl)-5-methoxy-2-methyl-6--nitroindoline To 50 ml glacial acetic acid is added 2.22 g. (0.00712 10 mole) of 1-acetyl-3-(2-bromoethyl)-2-methyl-5-methoxyindoline at ice bath temperature. To this stirred solution is added drop~Jise with stirring o.448 g. (0.00712 mole) fuming nitric acid. The reaction mixture is stirred at room temperature for one hour, poured onto ice water and extracted with ethyl acetate. The organic extract is washed with saturated sodium chloride solu-tion, dried over magnesium sulfate, clarified with carbon and evaporated to give an oil. Crystallization from heptane affords l-acetyl 3-(2-bromoethyl)-5-methoxy-2-methyl-6-nitroindolineJ
m.p. 148-150C.

. _ _ _ .... . .. ....
Preparation o~ l-acetyl-3-(2-bromoethyl~-5-methox~-2-methyl-6--nitroindoline By the procedure of Example 49 treatment of 1-acetyl-2- ~ `
-methyl-5-methoxy-6 nltro-3-indolineethanol in benzene with phos- ~ `
phorus tribromide give yellow crystals of l~acetyl-3~(2-bromo-ethyl) 5-methoxy-2-methyl-6-nitroindoline, m p. 147-150C.

reparation Or l-acetyl-5-bromo-3-(?-bromoethyl~indoline In the manner described in Example 40 treatment of 1--acetyl-5-bromo~3-indolineethanol with phosphorus tribromide in benzene is productive of l-acetyl-5~bromo~3-(2-bromoethyl)indo-line ' ~

t~ p,3~ 1 ~X~IrJ]-' ~3 Pre~aration ~,r 5-methoxy-2-methyl-1~ n-ltrohenzoyl)-~ indollne-.. . .. . . _ _ ethyl methanei~ulf`on~te A solution of l.00 g. of 5-methoxy-2~methy].~ nitro-benzoyl)-~-indolineethanol and 1 ml. of methanesulfonyl chloride in 20 ml. of pyridine ls malntained at 0C. for 18 hours. The mixture is poured into ice-water and extracted with ethyl acetate. - -The extract is washed with lN hydrochloric acid, dried over mag- !
nesium sulfate and evaporated to give the methanesulfonate, Preparation of N-Ll~acetyl-3-(2~methanesulfonyloxyethyl)-5-indo-inyl]acetamide A ~olution of 2.00 g. of N-[l acet~1-3-(2-hydroxyethyl)--5-indolinyl]acetamide and 2 ml. of methanesulfonyl chloride in 20 ml. of pyridine ~s maintained at 0C. for 18 hours. The mix-ture is poured onto a cracked ice-hydrochloric acid mixture, which is then extracted with methylene chloride. m e dried ex-tract i~ evaporated to give N-[l-acetyl-3-(2-methanesulfonyloxy-ethyl)-5-indolinyl]acetamide.

~ aration of l-acetyl-3-[2-(4-phenyl-1-piperazinyl)ethyl~indo-: , line A solution of 268 mg, o~ l acetyl-3-(2-bromoethyl)in-doline and 340 mg. of l-phenylpiperazine in 20 ml, of toluene is -;~
~25 heated under reflux for 18 hours, The mixture is cooled and the toluene solution is decanted and evaporated under reduced pres-sure. m e residual gum is dissolved in ethyl acetate and the organic solution is washed with water and saturated sodium bi-carbonate solution. The organic solution is dried with magnesium sulfate and evaporated under reduced pressure leaving a gum which i8 crystallized from ether-petroleum ether (30-60C,) to afford -~
.: . .
l-acetyl-3-[2-(4-phenyl-l-pipera~1nyl)ethyl]indoline~ m.p. 107-109 C, . .

,:

, ,.; . . . . ..

!
~3~
MPI,'I~ rjG
Prepar~tlon Or l-aeetyl-3-~2-~4-( o-mcthoxyp}lenyl)-l~plpcra7inyl~-ethyl~indoline In the manner described ln ~xample 55, from 2.5 g~ of 1-acetyl-~-(2-bromoethyl)indoline and 3.5 g. of l-(o-methoxyphen-yl)piperazine there is obtained l-acetyl-3-~2-[4-(o-methoxyphen- ;
yl) l-piperazinyl~ethyl}indolineg m.p. 77~0C.

Preparation of l-acetyl-5,6-dimethoxy-3- &-[4-(o-methoxyphenyl~--l-piperazinyl]ethyl}indoline A solution of 200 mg o.f 1-acetyl-3-(2~bromoethyl)--5,6-dimethoxyindoline and 250 mg. of l-(o-methoxyphenyl)pipera-zine in 20 ml. of toluene is heated under reflux for 18 hours.
The reaction mixture is cooled and filtered, and the filtrate is evaporated under reduced pressure. The residual gum is parti-tioned between ether and water. The organic solution is separated, washed with saturated sodium bicarbonate solution and sodium chloride solution. The ether solution is dried with magnesium sulfate and evaporated under reduced pressure The residual gum is crystallized from ether-petroleum ether a~fording l-acetyl-~596-dimethoxy-3-{2~ (o~methoxyphenyl)-l-piperazinyljethyl3-indolineJ m.p 149-150C.

Pre~aration of l-acetyl-5,6 dimethoxy-3-r2-(4-phenyl-1-pipera-zinyl)ethyl]indoline In the manner described in Example 57 treatment of 2.37 g. (7.24 mmol) o~ 1-acetyl-3 (2-bromoethyl)-5,6-dimethoxyin-doline with 2.35 g. (14.5 mmol) of l-~henylpiperazine in 150 ml of boiling toluene for 17 hour~ produces 1 acetyl~5,6-dimethoxy--3-r2-(4~phenyl-1-plperazlnyl3ethyl]indoline.
.

, .
.

~ i~
Preparation of l-acetyl-5,6-dimethoxy-3~ 2~ methox~yphenyl)--~-methyl-l-piperazinyl~ethyl}indoline In the manner described in Example 57 treatment of 2,~0 g. (7.02 mmol) of l~acetyl-3-(2-bromoethyl)-5,6-dimethoxyin-doline with 2.90 g. (14,1 mmol) of 1-(~-methoxyphenyl3-2-methyl-piperazine in 150 ml. of boiling toluene for 15 hours produces l-acetyl-5 9 6-dime~hoxy-3-{2-[4-(~-methoxyphenyl)-~-methyl-1-~piperazinyl]ethyl}indoline.

Preparation of l-acetyl-3 ~2-[4-(o-methoxyphenyl)-1-piperazinyl]-.
ethyl~-5-nitroindoline -A solution of 1.3 g. (0.0033 mole) of 1-acetyl-5-nitro--3-indolineethyl, ~-toluenesulfonate and 1.3 g. (o.oo68 mole) of 1-(o-methoxyphenyl)piperazine in 25 ml. of toluene is stirred under reflux for 72 hours and then concentrated by distillation.
The residue is diluted with water and extracted with ethyl ace-tate. The organic layer is separated and extracted with lN hy~
drochloric acld and thè acidic solution is rendered alkaline with lON aqueous sodium hydroxide and extracted with ethyl acetate This extract is dried over magnesium sulfate, clarified with activated carbon, and concentrated to a yellow oil. Pure l-ace tyl-3-~2-~4-(o-methoxyphenyl)-1-piperazinyl]ethyl}-5-nitroindo-line, m,p. 141-143C., is obtained by chromatography using a synthetic magnesia-silica column.

Preparation o~ 5~acetyl-6,7-dihydro-7-r2-[3~methyl-4-(~-tolyl)-piperazinyl]ethyl3-5H-1,3-dioxolo[4,5-f]indole In the manner described in Example 57, from 850 mG. of 5-acetyl-6,7-dihydro-5H-1,3-dioxolo[4,5-f]indole-7-ethyl bromide and 1.23 g. of 2-methyl~l-(~tolylpiperazine) is obtained 5-ace-tyl-6,7-dihydro-7-~2~3-methyl~ -tolyl)piperazinyl]ethyl}-5H--1,3-dloxolo[4,5-r]indole, m.p, 156-157C.

EX~MP],l;, G,.' Pre~a;ra~i.on Or 5-acetyl-6,7-~lih~ydro-7-~2~ (o-to]yl)piper~zinyl]-~
.
ethyl~-51I-l,~-dioxolo[l~,5-flindole r In the ~anner de3cribed in Example 57, from 1.0 g. o~
5-acetyl-6,7-dihydro-5H-1,3-dioxolo[4,5-f]indole-7-ethyl bromide and 1023 g. of l-(o-tolylpiperazine) is obtained 5-acetyl-6,7--dihydro-7-~2-[4-(o-tolyl)piperazinyl]ethyl~-5H-15 ~-dioxolo[4,5--f]indole, m,p, 166-168~C.
E~MPLE 6~
Preparation of 5-methoxy-3-{2-[4-(o-methoxyphenyl)-1-piperazinyl]-ethyl3-2-methyl-1-(~-ni.trobenzoyl)indoline In the manner described in Example 57 treatment of 5- ;
-methoxy-2-methyl~ -nitrobenzoyl)-3-indolineethyl methanesul-fonate gives the product as a viscous oil.

.
Preparation of 5-methox~-2-methyl-3-r2-(4-phenyl-l~piperazinyl~-ethyl]-1-(~-nitrobenzoyl)indoline . . .
In the mc:nner described in Example 57 treatment of 3--(2-bromoethyl)-5-methoxy-2-methyl-1-(~-nitrobenzoyl)indoline with l-phenylpiperaz-lne ~ives 5-methoxy-2-methyl-~-[2-(4-phenyl--l-plperazinyl)ethyl~-l-(p-nitrobenzoyl)indoline.

Preparation of 5-acetyl-6~7-dihydro-7-~2-~4-(m-tolyl?piperazinyl]-ethyl}-5H-1,3-dioxolo[~ 5-f]indole In the manner descrlbed in Example 57, from 950 mg. of 5-acetyl 6,7-dihydro-5H~ dioxolo[4~5-f]indole-7-ethyl bromide and 1.2 g. of l-(m-tolyl)piperazine is obtained 5-acetyl-6,7-di-hydro-7-f2-[1l-(m-tolyl)piperazinyl~ethyl~-5H-1,3-dioxoloC4,5-f]-indole, m,p. 98-103C, Preparation o~ 5-acetyl-6,7-dihydro-7-~2-~4-(o~methoxyphenyl)-piperazi.ny].lethyl}-51I-1,3-dioxo]o~4,~-~Jindolè
In the manner dcscribed in Example 57, from 1.25 g. o~

- 3~ -.. . . .

5 acety1-6,7-dihydro-51l-1,3~:loxolo[J~,5-r]:Lndole-7-et;hyl bromlde and 1.51 F,. of ].-(o-mcthoxyphcnyl)piperaz:Lne i5 obta:Lned 5~~cetyl-~
-6,7-dihydro-7-~2-~4-(o-metho~yphenyl)plperazinyl]ethyl~-5H-1,3--d-loxolo[4,5-f]indole, m.p. 159-160~C.

Preparati.on of l-acetyl-5-chloro~3-~2-[J~-(m-tolyl)-3-methyl-1-, . . . .
-piperazinyl~ethyl}indoline In the manner described in Example 57 treatment of 1.00 g (3.32 mmol) of 1-acetyl-3-(2-bromoethyl)-5-chloroindoline with 1026 g. (6.64 mmol) of 1-(m-tolyl)-2-methylpiperazine gives 1,~1 g. of an oil that crystallizes from ether~petroleum ether (b.p. 30-60C.) to give white crystals~ m.p. 105-110C. Recrys-tallization from acetone-hexane raises the m.p. to 1~0-132C~

Preparation of l-acetyl-5~methoxy-3-~2-~4-(o methoxyphenyl)-1~ ~ --p_perazinyl~_th~1~-2-methylindoline In the manner described in Example 57 treatment of 780 mg. (2.5 mmol) of 1-acetyl-3-(2-bromoethyl)-2-methyl-5-meth-oxyindoline with 1.83 g~ (9,5 mmol) of l-(o-methoxyphenyl)pipera-zine gives the product as white crystals, m,p. 87-89C.

Preparation of N-~l-acetyl-3-[2 (4 o-methoxyphenyl-l-pipera~.inyl)-In the manner described in Example 57 treatment of N~
~ acetyl-3-(2-m~:thanesulfonyloxyethyl)-5-indolinylJacetamide with l-(o~methoxyphenyl)piperazine provides N-{l-acetyl-3-[2-(4--o~methoxyphenyl)-l-piperazi.nyl)ethyl~-5-indolinyl}acetamide Preparati.on of l-acetyl-5-methoxy-2-rne-thyl-3-[2-(4-phenyl~
-i-piperazinyl)ethylJindoli.ne .-', By the procedure of Example 57 treatment of 2.00 g.
(10 mmol) of 1 acetyl-3 (2-bromoethyl)-2-methyl-5-methoxyindoline with 3.10 g. (20 mmol) of l-phenylpiperaæine furnishe~ the pro-- 37 ~

:

.. ,; I .. . . .

~ t duct a~ oI`i`~white cry~,tals, m.p. 12'7-129C, )!
~MPLI~'71 Pre~aration of l-acetyl-3-~2-~li-(o-chloropllenyl)-1-piperaæin,yl]-ethy:l.}-5-rnethoxy-2-mctllyl:Lndollne In the manner described in Example 57 from 400 mg, (0,0013 mole) 1-acetyl~3~(2-bromoethyl)-2-methyl-5-methoxyindo-line and 1,12 g, (0.0057 mole) of l-(o-chlorophenyl)piperazine there is obtained l-ace-tyl ~-~2~[4-(o-chlorophenyl)~l-piperazin-yl]ethyl}~5-methoxy-Z-methylindoline as a cream colored solid, m,p, 125-127C, EXAMP~E 72 Preparation of l-(~chlorobenzoyl)-5-methoxy-2-methyl-3-[2-(4-_ -phenyl-l-piperazinyl)e-thyl]indoline A solution of 400 mg, of crude 1-(~chlorobenzoyl)-3- --(2-chloroethyl)-5-methoxy 2-methylindoline in 15 ml. of dry benzene is treated with 5 ml, of l-phenylpiperazine and heated at reflux temperature for 16 hours, The solution is evaporated, and the residue is distributed between benzene and sodium bicar-bonate solution. m e organic layer is washed with saline, dried and evaporated, The residue is crystallized from'ether-hexane and then recrystallized from acetone-hexane to give crystals, -Preparation of l-acetyl-5-methoxy-3-~2-[4-(o-methoxyphenyl)-1--plperazinyl]ethyl3-2-methyl 6-nitroindoline '~
To 75 ml. toluene is added 2,0 g, (0.01 mol) of l-(o--methoxyphenyl)piperazine and 1.31~ g. (3.76 mmol) of 1-acetyl~3--(2-bromoethyl)-5-methoxy-2-methyl-6-nitroindoline. The reaction mixture is stirred under re'flux overnight and then filtered. The filtrate is concentrated and then extracted with ethyl acetate, The organic layer i~ washed with water, dried over magnesium sul-fate~ clariried with activated carbon and concentrated to yield a dark amber oil. Puri~ica~tion by chromatography on a ~ynthetic magne~i.a-~tlica adsorbent afrord~ l-acetyl 5-methoxy-3-~2 [4-(o-_ 3~ _ ~ . :
,.. , ,: ~ , ,. , . .. .. ,. ~ .. . .. . ... .. . . . ...

~s~

-methoxyphenyl)-l-piperaziny]~ethyl~-2~methyl-6-nitroindoline~
m.p. 146-149C.

~ _~ .....

~L~
A solution of 0.70 g. (O.OOt7 mole) of 1-benzoyl-3-(2 -bromoethyl~-5~6-dimethoxy~2-methylindoline and 1.1 g. (0.0069 mole) of N~phenylpiperazine in 20 mlO of toluene is stirred under reflux for 65 hours. The precipltate which forms is separated by filtration and the filtrate concentrated. The residue is partitioned between water and ethyl acetate and the organic layer is separated, dried over magnesium sulfate and concentrated to a yellow oil. Purification of the oil by chromatography on a syn~
thetic magnesia-silica adsorbent affords l-benzoyl-5~6~dimethoxy-~2_rnethyl-3~ (4-phenyl-1-piperazinyl)ethyl~indoline as a yellow glass.
E _ -~3~ 4-(o-methoxy-.... ..... ... .
~enyl)-l-piperazinyl~ethyl~indoline A solution of 1.5 g. (0.0037 mole~ of 1-benzoyl-3-(2--br~moe~hyl~-5,6-dimethoxy-2-methylindoline and 2.2 g. (0.011 mole~ of l-(o-methoxyphenyl)pipera~ine in S0 mlO of ben~ene is stlrrPd unter reflux for 70 hours. The precipitate which forms is separated by filtration and the filerate is washed with water, dried over magnesium sulfate~ and concen~ra~ed to a yellow oil.
The oil is purified by chromatography on a synthetic magnesia--silica adsorbent to yield l-benzoyl-5~6-dimethoxy-2-methyl-3-~2-~4-(o-methoxyphenyl)-1-piperaæinyl~ethyl~indoline as a yellow glass~ This substance gives a dlhydrochloride monohydrate upon treatment with ethereal hydrogen ¢hloride. This salt is obtained from ethanol-ether as white crystals7 m.p~ 199~ 200C. (decomp.) :', ' , .

. -- .

.. : . . .: . . .

F.u ~ ~
.. . .
~r~s~
~:XAMPI,]~ 76 Prepnr~tlon of l-benzoyl-~,6-(1-lmethox~-2-methyl-3-~2~ -(m-chloro-_ ~henyl~-]~~lnerazLnyllethyl~-Lndol~ne ~ . . J J , . . .
A solutlon of lc5 g (0.0037 mole) of 1-benzoyl~3-(2--bromoethyl)-5,6-dimethoxy-2-methyllndoline and 2.1 g. (0.011 mole) Or l-(m-chlorophenyl)piperazine in 50 ml of benzene is stirred under reflux for 70 hours. The precipitate which forms is separated by filtration and the filtrate is washed with waterJ
dried over magnesium sulfate, and concentrated to a yellow oil.
Purification of the oil by chromatography using a synthetic mag-- nesia-silica adsorbent affords l-benzoyl-5,6-dimethoxy-2-methyl--3-~2-~4-(m-chlorophenyl)-1-piperazinyl]ethyl}indoline as a yellow glass~

Prepara-tion of l~acetyl-5-bromo-3~2-~4 (o-methoxyphenyl)-l-~ erazinyl]ethyl~indoline In the manner described in Example 55 treatment of 1 -acetyl-5-bromo-3-(2-bromoethyl)indoline with l-(o-methoxyphenyl)-piperazine in refluxing toluene is productive of l-acetyl-5--bromo-~-~2-[4-(o-methoxyphenyl)-1-piperazinyl]ethyl~indoline.

Preparation of l-benzoyl-5,6-dimethoxy-2-methyl-~-~2-r4-(m-tri-fluoromethylphenyl)-l-piperazinyl]ethyl}indoline In the manner described in Example 76 treatment of 3.0 g. (0.0074 mole) of 1-benzoyl-3-(2-bromoethyl) 5,6-dimethoxy--2-methylindoline with 3.45 g. (0.015 mol3 of l-(m-trifluoro-methylphenyl)piperazine gives l-benzoyl-5,6-dimethoxy-2-methyl--3-~2-[4-(m-trifluoromethylphenyl)-1-piperazinyl]ethyl}indoline -An ethereal solution Or the ~ast substance ls treated with hydro-gen chlorldeJ and the solid which re5ults is recrystallized from acetonitrile to give the monohydrochloride as white crystals, m,p. 232-233C. dec, .:

~ 40 ', . ' . .. ..

~5~8Z~

A solution of 4.4 g. of 1-acetyl~3{i2-(4-phenyl~l--piperazinyl)ethylJindoline and 80 mlO of 6N hydrochloric acid is heated under reflux for 30 minutes~ The solution is concentrated under reduced pressure to 10 ml~g diluted with water and rendered alkaline with sodium hydroxide solution The alkaline solution is extracted with ether. The ether extract is washed with satur_ ated sodium chloride solution~ dried wlth magnesium sulfate and evaporated under reduced pressure affording 3.4 g. of 3-~2-(4--phenyl-l~piperazinyl)ethylJindoline. The dimaleate salt has m.p. 139-141C.

,~ . .... . . .
Preparation of_3- ~ o-me~ y~_enyl)-~
indoline .
According to ~he manner described in Example 79~ 1.20 g.
of l-acetyl-3-~2-4-(o-methoxyphenyl)-l-pipera7inylJethyl~indo-line and 25 ml. of 6N hydrochloric acid gives 3-~2-~4-(o-methoxy-phenyl)~l-piperazinyl~ethyl~indoline trihydrochloride~ m.p. 248-250C.

Preparation of 697-dihydro-7-~2_L4-(o_methoxyphenyl?piperazinyl~-~ _ .
A solution of 500 mg. of 5-acetyl-697~dihydro-7-~2-~4--~o-methoxyphenyl)piperazinyl~ethyl~-5H-1~3-dioxolo ~5~f~indole and 10 ml. of 6N hydrochloric acid ls heated at reflux for 15 minutesO The solution is treated with activated charcoal~ ;
filtered and evaporated under reduced pressure. The residual gum is evaporated several times with ethanol. The resulting glass is dissolved in ethanol~ treated with activated ~harcoal and the solvent removed under reduced pressureO The residual glass is dissolved in water. The aqueous solution is rendered alkaline with 10N sodium hydr~xide~ and extracted with ethyl ': '' _41- ~

: , , . . . .. ;; .. . ...

acetate The ethyl ace~ate soluti.on is evaporated under reduced prcssure affordirlg 6,7-d:Lhydro-7~ [l~ (o-methoxypherlyl)plpcra-zinyl]ethyl~-5II-1,3-dioxolo[llJ5-r]i.n(]ole, the difumarate of ~rhich has m p 193~195C.
EX~MPI,~ ~2 Preparati.on of G,7-dihydro-7-~2-[3-methyl-4~ tolyl)piperazinyl]-;
ethyl~-5H-l,~-dio,;olo[4,5-f]indole A soluti.on of 530 mg. Or 5-acetyl-637-dihydro-7-~2-[3--methyl~4-(~-tolyl)piperazinyl]ethyl}-5H-1,3-dioxolo[4,5-f]indole and 10 ml. of 6N hydrochloric acid is heated under reflux for 15 minutes, The solution is treated with activated charcoal, filtered and evaporated under reduced pressure~ The residual gum is evaporated several times with ethanol. The resulting glass is dissolved in ethanol, treated with activated charcoal and the solvent removed under reduced pressure affording 6,7-dihydro-7 -~2 ~3-methyl-4-(~-tolyl)piperazinyl]ethyl~-5H-1,3-dioxolo~4,5-f~
indole trihydrochloride, m,p. 219-224C, Preparation of 6,7-dihydro-7-~2-[4--(m-tolyl)piperazinyl]ethyl~
-5H-1,3-dioxolo[4,5-flindole In the manner described in Example 82, from 500 mg of .
5-acetyl-6,7-dihydro~7-{2-[1~-(m-tolyl)piperazinyl]ethyl~-5H-1"3 -dioxolo[4,5-r]indole and 10 ml, 6N hydrochloric acid is obtained 6,7-dihydro-7-~2--r4-(m-tolyl)piperazinyl]ethyl,~5H-1,3-dioxolo~
25 [4,5-f]indoline trihydrochloride, :
` EXAMPLE 84 ..
Preparation of 5-bromo-3-~2-[4-(o-methoxyphenyl)-1-piperazinyl]- -.
.
ethyl}irldoline In the manner described in Example ~2 a solution.of 1--acetyl-5-bromo-3-~2-[4-(o-methoxyphenyl)-l~piperazinyl]e~hyl}- .
indoli.ne in 6N hydrochlorlc acid is heated at reflux temperature for 15 mlnutes. Removal of the solvent furnishes the hydrochlo-ride ~alt of 5-bromo~ -(o-methoxyphenyl)~l-piperazinyl]~
, - ll2 ' .. . . . ~
.
. ~. ; :. ' . : ,'' . ' .

ethyl~lndol~nc, ~JXIIMI'I~r~ n5 Prepar~tlon Or G,7-dlhy(~ro-7-~2-~l-(o-tolyl)plpc~azlnyl~cthyl}-..
5~ 3~dioxoln[l1,5-r]lndolc In the manner described ln Example 82, from 500 mG. ~
5-acetyl-5,7-dlhydro-7-~2-[4-~o-tolyl)piperazinyl]ethyl~-5H-1,3--dloxolo[4,5-f~indoline and 10 ml. of 6N hydrochloric acid is ob t~ined 6~7-dihydro-7-~2-r4-(o-tolyl)piperazinyl]ethyl~-5H-1,3-~dioxolo[4,5-fJindole trihydrochloride.

Pre~aration of 5-methoxy-2-methyl-3-r2-(4-~henyl-1-piperazinyl)-ethyl 3 indoline In the malmer described in Example 79, ~rom 1.86 g.
(~.7 mmol) Or l acetyl-5-methoxy-2-methyl-3-[?-(4-phenyl-1-pipera-zinyl)ethyl]indoline ~nd 60 ml. of 6N hydrochloric acid i5 ob-tained 5-methoxy-2-methyl-3-[2-(4 phenyl-l-piperazinyl)ethyl]in-doline as white crystals, m.p. 64-67C.

Preparation o~ 5-methoxy~3-{2-[4-(o-methoxyphenyl)-1-piperazinyl]-ethyl ~ ethylindoline ~ -In the manner described in Example 79, from 2.52 g.
(5.9 mmol) o~ 1-acetyl-5-methoxy~ 2-t4-(o-methoxyphenyl)-1--plperazinyl~ethyl}-2-methylindoline and 75 ml. Or 6N hydrochloric acld 1~ obtained 5 methoxy 7~2-[4(o~methoxyphenyl)~l-plpera-zlnyl]ethyl}-2-methylindoline a~ white crystals, m.p. 92-93CC.

~_ . . .. . ._ .
- Preparation of 3-~2-[4-~o-chlorophenyl)-1-piperazinyl]ethyl3-5--methoxy-2~methylindoline ~ In the manner described ln ~xample 79, from 1.25 e.
(2.9 mmol) Or 1-acetyl-3-{2-~4-to-chlorophenyl)-1-piper~zlnyl]-; ethyl}~5-methoxy-2-methylln~ollne ~nd 50 ml, Or 6N hydrochlorlc ~c1d ls obt~lned 3-~2~4-(o-chlorophenyl)-1-piperazlnyl]ethyl~
-5-mcthoxy-2-methylin~ole Q~ ofr-white crystala, m.p, 109-110C, d - 3l~
', .' ~.

.. . . . . . . ..

$
]~:XAMI~TJI~ ~9 l'reparul; 1 on Or r~,6-(l;mc-t;hoxy-~ mcth~-3-[2~ plleny]~ pcra-z-lnyl)el;hyl J i ndo] i ne A solution of 0.32 g. (o.ooo66 mole) of 1-benzoyl-5,6-dimethoxy-2-methyl-3-[2~ -phenyl-1-piperazinyl)ethyl]indoline in 10 ml. of 6N hydrochloric acid is stirred under reflux for 30 minutes and then poured into 50 ml. of ice-cold aqueous sodium bicarbonate solution. The mixture is rendered alkaline with lON
sodium hydroxide solution and extracted with methylene chloride The extract is dried over magnesium sulfate and concentrated to a yellow oil Crystallizatlon from ether affords 5,6-dimethoxy--2-methyl-3-~2-(4-phenyl-1-piperazinyl)ethyl]indoline, mOp. 112-113~C.

Preparation of 5-methoxy-2-methyl-3-~2-(4-phenyl-1-piperazinyl~-ethyl~indoline ;-In the manner described in Example 79 a solution of 5--methoxy-2-methyl-3~[2-(4-phenyl-1-piperazinyl)ethyl]-1~ nitro-benzoyl)indoline in 6N hydrochloric acid is heate~ at re~lux temperature for 15 minutes. Removal of the solvent furnishes 5-methoxy 2-methyl-~-[2-(4-phenyl-1-piperazinyl)ethyl]indoline as white crystals, m.p. 64-67C.

Preparation o~ 5~methoxy-~-~2-[4-(o-methoxyphenyl)-1-piperazinyl]-.
ethyl~-?-methylindoline ;~

In the manner described in Example 79 a solution of 5- ~--me~hoxy-3-~2-~4-(o-methoxyphenyl~-1-piperazinyl~ethyl}~2-methyl--l-(p-nltrobenzoyl)indoline in 6N hydrochloric acid i5 heated at reflux temperature for 15 mlnutes. Removal of the solvent fur- ~-nishes 5-methoxy-3-~2-~4-(o-methox~phenyl)-1-piperazlnyl]ethyl}--2-methyllndoline as white crystals, m.p~ 90-93C.

_ J~

., , . , ., . ... .. ... , . i - ..

EXAMI'T,~
.
Prcp~ration o~ 3-{2-~4-(o-mct}~oxyphen~yl)-1-plperazlnyl~e~;hyl~--5-nitroindolJne dihydroch]ori~e A m-Lxture of 1.0 g. (0.0024 mole) of 1-acetyl-3-{2 ~4--(o-methoxyphenyl)-1-p-lperazinyl]ethyl3-5-nitroindoline and 20 ml.
of 6N hydrochloric acid is stirred under reflux for 15 minutes.
Concentratlon affords a yellow oil which is crystallized from methanol-ethanol to yield 3-~2 [4-(o~methoxyphenyl)-1-piperazin-yl]ethyl}-5-nitroindoline dihydrochloride, m.p 243-246C. dec Preparation of l-acetyl ~-~2-~4-(o-methoxyphenyl)-1-piperazinyl]-ethy~ -5-aminoindoline A mixture of 1 0 g. (0.0024 mole) of 1-acetyl-3-~2-[4--(o-methoxyphenyl)-l-piperazinyl]ethyl~-5-nitroindoline, 0.20 g.
of 83~ platinum oxide, 20 ml. of 6N hydrochloric acid, and 50 ml.
of ethanol is shaken under hydrogen pressure for one hour. The catalyst is separated by filtration and the solvent removed by concentration. The residue is partitioned between water and methylene chloride and the aqueous layer is separated and rendered alkaline using aqueous sodium hydroxide solution, and extracted with methylene chloride. The extract is dried over anhydrous magnesium sul~ate, clarified using activated carbon~ and concen- ;
tr~ted to yield l-acetyl-3-~2-[4-(o-methoxyphenyl)-1-piperazinyl]-ethyl~-5-aminoindoline as a yellow oil.

Preparation of 3-~2 ~4-(o-methoxyphenyl)-1 piperazinyl]ethyl}-5 -aminoindoline hydrochloride A solution of 0.90 g. (0.0023 mole) of 1-acetyl-3-{2--r4~(o-methoxyphenyl) 1-piperazinyl]ethyl}-5-amlnoindoline ln 20 ml. of 6N hydrochloric acid is heated on a steam bath for 30 minutes The solution is clarifled wlth activated carbon and concentrated Dilution of the resldue witll ether followed by flltratJon a~ords 3-~2 ~4-(o-methoxyphenyl)-1-piperazlnyl]ethyl}-1~ r;

i6~
-5~aminoindolinc hydrochloride, m.pO 185-195 C. dec.

EY~MPLE_95 Preparation of 5 amino-3_52-L4-(o-methox ~henyl)-l-piperaziny t , , .. . Y ~ ~
ethyl~indoline hydrochloride In the manner d~scribed in Example 82 a solution of N~ acetyl-3-L2-(4-o-methoxyphenyl-1-piperazinyl)ethylJ-5 indo-linyl~acetamide in 6N hydrochloric ac;d is heated at reflux tem-perature for 15 minutesO Removal of the solvent furnishes a gray powder, m.p. 183~190C. dec.

Pre aration of l-acet 1-3-~2-4-(o-methox hen 1)-1- i erazin 17-P . __ _ _ _ _ .... , Y~P _Y _ ~, P y ~
~ ne A mixture of 0.39 ~. {0.0010 mole) of 1-acetyl-3-~2 -(o-methoxyphenyl)-l-piperazinyl~ethyl~-5-aminoindolineg 2.2 ml~
formic acidg and 0.23 ml. of 37% aqueous formaldehyde is stirred ~nder reflux for 5 hours. The solution is diluted with lN hydro- -chloric acid and extracted with ether-ethyl acetate. The aqueous layer is separated~ rendered alkaline using aqueous sodium hydrox- ' ide solution~ and extrac'ted with ethyl ace~ate. The extract is '' dried over anhydrous magnesium sulfate and concentrated to yield' l~acetyl-3_~2_~4~to~methoxyphenyl~-l-piperazinyl~ethyl~ 5-dimethyl aminoindoline as a yellow g~m. ~ ' -n of 3-~2-~4 ~o-methox hen l)~l-piperaæin l~eth 1~-5- ' ' -~, _ .. ~,. . . YP . Y - - ~ - - - ~V . -~ . .

In the manner deseribed in Example B2~ 1-acetyl-3-~2- -

4-(o-methoxyphenyl)-1-piperazinyl ethyl~5~dimethylaminoindo-line is hydrolyzed to 3~ L4-(o-methoxyphenyl)-1-piperazinyl~- ;
ethyl~-5-dfmethylaminoindoline.

-' ' '''''' EXAMPLE 98 ~---------Preparation of 5~6-dimethoxy-3-~2_~h_(o_methoxyphenyl)_1_pipera_ '' ~ ~ ~ in~
In the rnanner described in Example 82 a solu~ion of -46- ' : -

5 Eil~

2.57 g. (5.85 mol) of 1-acetyl-5,6-diMethoxy-3-~2-~4-(o-methoxy-phenyl)~l~piperaæiny~ethylJindoline in 50 ml~ of 6N hydrochloric acid is heated at reflux temperature for 15 minutesO Removal of the solvent furnishes the hydrochloride salt of 5,6-dimethoxy-3--~2 L4 (o methoxyphenyl)-l-piperazinylJethyl~indoline as a glass.

_~ : ',.

In the manner described in Example 82 a solution of l--benzoyl-5~6-dimethoxy-2-methyl-3_~2-~4_(m_trifluoromethylphenyl)_ -l-piperazinyl~ethyl~indoline in 6N hydrochloric acid is heated at reflux temperature for 15 minu~es. Removal of the solvent fur nishes a hydrochloride salt of 5,6-dimethoxy-2-methyl-3-~2-~4--(m-trifluoromethylphenyl)-l-piperazinyl~ethyl~indoline.
EXA~LE 100 h~l l-piperazinylJ -~ .' In the manner described in Example 82 a solution of 1--acetyl~5-chloro-3-~2-¦4-(m-tolyl)-3-methyl-1-piperazinyl~ethyl~
indoline in 6N hydrochloric acid is heated at reflux temperature for 15 ~inutes~ Removal of the~solvent furnishes the hydrochlo-rlde salt of the product4 ~XAMPLE 101 Preparation of 5 6-dimetho -3-~2-r4 ( -methoxyphen 1)-3-methyl--l-piperazinyl1ethy~ i~doline __ .
In ~he manner described in Example 82 a solution of 1--acetyl-596-dimethoxy-3-~2-~4~ methoxyphenyl)-3~methyl-l-pipera- -~inyl~ethyl~lndoline in 6N hydrochloric acid is heated at reflux ~ -ternperature for 15 minutes. Removal of the solvent furnishes the hydrochloride salt of 5~6-dimethoxy~3-t2_~4~ methoxyphenyl)--3-methyl~l~piperazinyl~ethyl~indoline.

_47_ ' ': ,' ,, . ~ :

Pr~aration of 5~6-dimethoxy-3 ~2-(4-phenyl-1-piperazinyl)ethyl~-indoline In the manner described in Example 82 a solution of 1--acetgl 5,6-dimethoxy-3-L2-(4 phenyl 1-piperazinyl)ethyl3indoline in 6N hydrochloric acid is heated at reflux temperature for 15 minutesO Removal of the solvent furnishes 5,6-dimethoxy-3-~ -(4-Ophenyl-l-piperazinyl)ethyl indoline trihydrochloride.
3X~MPLE 103 Prepa~ation of 5-methox~-2-methyl~3-C2-(4-phenyl-l-pi~ azinyl)-ethyl~in_oline In the manner described in Example 79 a solution of 1-chloroben~oyl)-5~methoxy-2-methoxy~3~ 2-(4-phenyl~l-pipera_ zinyl)ethyl~indoline in 6N hydrochloric acid is heated at reflux temperature for 15 minutes. The produc~ is obtained as white crystals~ m.pO 64-67C.

-~8-: , . . - . ~.: . . , : , : ., ,

Claims (12)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the preparation of a compound of the following formula:

wherein R1 is selected from the group consisting of hydrogen, chloro, bromo, lower alkoxy, nitro, amino, acetamido and dimethylamino; R2 is selected from the group consisting of hydrogen, lower alkoxy and nitro, or R1 and R2 together form a methylenedioxy group; R3 is selected from the group consisting of hydrogen and methyl; Y is selected from the group consisting of lower alkanoyl and benzoyl; and Z is selected from the group consisting of hydroxy, chloro, bromo, methanesulfonyloxy and p-toluenesulfonyloxy, which comprises either:- (a) lower alkanoylating or benzoylating a compound of the formula:

where R1, R2, R3 and Z are as defined above; or (b) reducing an acid of the formula:

or a lower ethyl ester or anhydride thereof, wherein R1, R2, R3 and Y are as defined above, to produce a compound of formula I in which Z is hydroxy; or (c) partially hydrolyzing a compound of the formula:

in which "Acyl" represents an acyl group and R1, R2, R3 and Y are as previously defined; when a compound of formula I is required in which R1 is chloro, bromo or nitro, chlorinating, brominating or nitrating a correspon-ding compound of formula I in which R1 is a hydrogen atom; when a compound of formula I is required in which R2 is nitro nitrating a corresponing compound of formula I in which R2 is a hydro ton atom; when a compound of formula I is required in which R1 is amino reducing a corresponding compound of formula I
in which R1 is nitro; and when a compound of formula I is required in which Z is chloro, bromo, methanesulfonyloxy or p-toluenesulfonloxy, chlorinating, brominating, methanesulfonylating or p-toluenesulfonylating a corresponding compound of formula I in which Z is hydroxy.

2. A process according to claim 1(b) in which the reduction is effect-od by reaction with a complex metal hydride or diborone.

3. A process according to claim 1(a) in which the acylation is effected by reaction with a lower alkanoyl or benzoyl halide or a correspond-ing anhydride.

4. A compound of the formula:

wherein R1 is selected from the group consisting of hydrogen, chloro, bromo, lower alkoxy, nitro, amino, acetamido and dimethylamino; R2 is selected from the group consisting of hydrogen, lower alkoxy and nitro with the proviso that R1 and R2 taken together is methylenedioxy; R3 is selected from the group consisting of hydrogen and methyl; Y is selected from the group consisting of lower alkanoyl and benzoyl; and Z is selected from the group consisting of hydroxy, chloro, bromo, methanesulfonyloxy and p-toluenesulfonyloxy whenever prepared according to the process of Claim 1 or an obvious chemical equiva-lent thereof.

5. A process according to Claim 1 for the preparation of 1-benzoyl-3(2-bromoethyl)-5,6-dimethoxy-2-methylindoline by benzoylating 5,6-dimethoxy-2-methyl-3-indolineethanol and partially hydrolyzing the compound so obtained.

6. The compound 1-benzoyl-3(2-bromoethyl)-5,6-dimethoxy-2-methyl-indoline whenever prepared according to the process of claim 5 or an obvious chemical equivalent thereof.

7. A process according to Claim 1 for the preparation of 5-acetyl-6,7-dihydro-5H-1,3-dioxolo[4,5-f]indole-7-ethyl bromide by reacting 5-acetyl-6,6-dihydro-5H-1,3-dioxolo-[4,5-f]indole-7-ethanoll with phosphorus tribromide.

8. The compound 5-acetyl-6,7-dihydro-5H-1,3-dioxolo-[4,5-f]indole-7-ethyl bromide whenever prepared according to the process of claim 7 or by an obvious chemical equivalent thereof.

9. A process according to claim 1 for the preparation of 1-acetyl-3-(2-bromoethyl)-5,6-dimethoxyindoline by reacting 1-acetyl-5,6-dimethoxy-3-indolineethanol with phosphorus tribromide.

10. The compound 1-acetyl-3-(2-bromoethyl)-5,6-dimethoxyindoline whenever prepared according to the process of claim 9 or by an obvious chemi-cal equivalent thereof.

11. A process according to claim 1 for the preparation of 1-acetyl-5-nitro-3-indolineethyl p-toluenesulfonate by reacting 1-acetyl-5-nitro-3-indolineethanol with p-toluenesulfonyl chloride in the presence of pyridine.

12. The compound 1-acetyl-5-nitro-3-indoleneethyl p-toluenesulfo-nate whenever prepared according to the process of claim 11 or by an obvious chemical equivalent thereof.