Jan- 26, 1971
`
`-
`
`A. SALLMANN ETAL
`.-AN_ILINOPHENYLACBT
`‘ SUBSTITUTED DERIVATIVES OF 2
`IC
`ACIDS AND A PROCESS
`0F‘ PREPARATION
`Filed Sept. 29, 1969
`
`3,558,690
`
`r
`
`
`
`3.5 Euzmdzi
`
`
`
`MW, 1 wbm ‘
`
`
`
`
`
`r ‘ . z ,
`
`$5 3H6 \ I .,
`‘ / / u , .. ..
`,. Ill IM .
`
`I
`
`.
`
`\ ‘
`
`fl 9
`T;
`a ‘
`.mvsmons
`LMMI
`ALFREDSAL
`“RLDOLFP
`FISTER
`
`-
`
`Page 1
`
`LUPIN EX. 1033
`Lupin v. iCeutica
`US Patent No. 9,017,721
`
`

`
`United States Patent Office
`
`3,558,690
`
`Patented Jan. 26, 1971
`
`1
`
`'
`
`3,558,690
`SUBSTITUTED DERIVATIVES ‘0F 'Z-ANILINO- .
`PHENYLACETIC ACIDS AND A PROCESS OF
`
`PREPARATION
`
`‘
`
`,
`
`'
`
`-
`
`Alfred Sallmann, Bottmingen, and Rudolf P?ster, Basel,
`Switzerland, assignors to Geigy Chemical Corporation,
`Ardsley, N.Y., a corporation of New York
`Continuation-impart of applications Ser. No. 782,206,
`and Ser. No. 782,473, both Dec. 9, 1,968, and Ser. No.
`. 625,326, Mar. 23, 1967. Said Ser.‘ No.‘ 782,206, being
`a continuation-in-part of said application Ser. No.
`, 625,326, and Ser. No. ‘539,829, Apr. 4, 1966. This ap
`' plication Sept. 29, 1969, Ser. No. 861,571
`Claims priority, application Switzerland, Apr. 8, 1965,
`4,961/65; Feb. 25, 1966, 2,770/66; Mar. 30, 1966,
`. 4,626/66; Dec. 20, 19677, 17,891/67, 17,892/67,
`17 ,893/ 67
`Int._ Cl. C07c 101/44
`US. Cl. 260—471
`
`27 Claims
`
`2
`cut, designated by R1, is a (lowerjlalkyl, (lower)alkoxy,
`chloro or ?uoro group, preferably methyl or chloro.
`In a second embodiment, the present invention pertains
`to 2-(S-tri?uoromethylanilino)phenylacetic acids and -ace
`tates of the formula:
`
`I(B)
`
`15
`
`20
`
`wherein :
`each of R4, R5, R6 and R7 is as de?ned above for Formula
`I(A);
`R8 is hydrogen or tri?uoromethyl; and
`R is hydrogen or chloro.
`
`ABSTRACT OF THE DISCLOSURE
`‘ Substituted 2-‘anilinophenylacetic ' acids, their esters
`and salts have’desirable absorption patterns for protecting
`the skin against the irritating e?‘ect of ultraviolet light.
`The compounds are also antiin?a'mmatory agents. Typical
`embodiments are 2 - (2,6 - dichloroanilino)-phenylacetic
`acid, the sodium salt thereof and the methyl ester thereof.
`
`CROSS REFERENCE
`This is a continuation-in-part of copending applications
`Serial Nos. 782,206, 782,473 and 625,326 ?led Dec. 9,
`1968, Dec. 9, 1968 and Mar. 23, 1967 respectively, Ser.
`No. 782,206 itself being a continuation~in-part of‘ said
`.Ser. No. 625,326 and of Ser. No. 539,829, ?led Apr; 4,
`1966 and now abandoned. All of the above listed applica
`tions are now abandoned.
`DETAILED DESCRIPTION
`The present invention pertains to substituted 2-anilino
`phenylacetic acids, to saltsand esters thereof, to methods
`of treating in?ammatory conditions and of protecting skin
`against irritating ultraviolet light, to compositions adapted
`for these methods, and to novel synthetic methods for the
`preparation of these compounds.
`.
`In, a ?rst embodiment, the present invention pertains
`to 2-(2-substituted anilino)phenylacetic acids and -ace-‘
`tates of the formula:
`
`»
`
`I(A)
`
`wherein:
`
`_
`
`,
`
`~
`
`.
`
`.
`
`R1,isr(lower)alkyl, i(lower)alkoxy, ?uoro or‘ chloro; '
`each of R2 and Rauis hydrogen, (lower)a1kyl, chloro or
`
`?uoro;':
`
`, “ ‘
`
`'0
`
`‘
`
`I
`
`I‘
`
`'
`
`7 '
`
`,
`
`R4 is, hydrogen, (lower)'alkyl,' (lower)alkoxy, chloro,
`
`.?uoroorbromo; . r
`" “
`R5 is hydrogen or (.lower)alkyl;‘ ‘
`'
`i‘
`g
`R is ‘hydrogen, (lower)alkyl'or wheri‘R? is hydrogen,
`
`‘
`
`‘
`
`- benzyl;and‘
`
`‘
`
`'
`
`v
`
`'
`
`'
`
`"
`
`‘
`
`R’1 is hydrogen, (lower)alkyl or benzyl.
`The j2-(substituted anilino)phenylacetic acids and -ace-.
`tatcs of this ?rst embodiment will necessarily have asub
`stituent ‘in the2-position of ‘the anilino ring} This substitu+
`
`In the compounds of Formula I(A) and (B) and in
`the present speci?cation, the term (lower)alkyl means a
`straight or branched monovalent hydrocarbon chain of
`from 1 to 5 carbon atoms. The term (lower)alkoxy is
`de?ned as a (lower)alkyl connected through an ether oxy
`gen link. Thus alkyl includes for example, methyl, ethyl,
`n-propyl, isopropyl, n-butyl, sec. butyl, and tert. butyl,
`preferably methyl or ethyl, ‘while (lower)alkoxy includes
`for example, methoxy, ethoxy, n-propoxy, isopropoxy, n
`butoxy, and isobutoxy, perferably methyl or ethyl.
`The compounds of Formulas I(A) and I(B) absorb
`the irritating rays of ultraviolet light which are primarily
`responsible for vsunburn, those of a wavelength of about
`290 to about 300—315 millimicrons, while at the same
`time they do not absorb the desirable so-called “tanning”
`rays of over 315 millimicrons wavelength. These com
`pounds are, therefore, especially useful as ultraviolet ab
`sorbers for cosmetic purposes, e.g., in sun-tan creams or
`lotions. The corresponding anthranilic acid derivatives, on
`the contrary, show a distinct and pronounced absorption
`of the desired “tanning” radiation. The diagram shown
`in the accompanying drawing illustrates the absorption of
`ultraviolet light of wavelengths in the “sunburn-causing”
`and “tanning” ranges of two preferred compounds accord
`ing to the invention, on the one hand, and to structurally
`similar anthranilic acid derivatives, on, the other hand.
`The compounds advantageously also possess antiin?am
`matory, analgesic and antipyretic activity combined with
`a favorable therapeutic index. This activity can be ob
`served in various standard pharmacological tests, as for
`example in the bolus alba test in rats, the UV-erythema
`test ,in guinear pigs, the cotton pellet test in rats, the
`phenylquinone stretch test in mice, etc. These properties
`render the compounds of the invention additionally suit
`able for the treatment of rheumatic, arthritic and other
`in?ammatory conditions.
`As an example of the anti-in?ammatory activity of the
`compounds, the sodium salt of 2-(2,6-dichloroanilino)
`phenylacetic acid demonstrates a signi?cant inhibitory
`effect in bolus alba induced edema in the rat paw, de
`scribed by G. Wilhelmi, Jap. Journ. Pharmac. 15, 190
`( 1965 ).
`- Topical sun-tan compositions according to the inven
`tion contain at least one compound of Formulas I(A) or
`I(B) or a pharmaceutically acceptable salt thereof with
`, a-base, in an amount which absorbs‘a su?icient amount of'
`ultraviolet radiation having a wavelength in the range
`of from 290 to 315 millimicrons, as well as a carrier
`compatible with the compound or salt, the carrier being
`of a creamy to highly ?uid consistency so as to provide
`an ointment, cream or oil.
`
`30
`
`40
`
`65
`
`70
`
`Page 2
`
`

`
`3,558,690
`3
`When utilized primarily for their anti-in?ammatory
`pounds of Formulas I(A) or I(B) or pharmaceutically
`activity, the compounds of the present invention can also
`acceptable salts thereof with a base, for the treatment of
`be administered orally, rectally or parenterally, in par
`rheumatic, arthritic and other in?ammatory conditions
`ticular intramuscularly. The 2-(substituted anilino)phenyl
`is from about 50 to about 1500‘ mg. for adult patients,
`although the amounts administered depend upon the
`acetate esters falling under Formulas I(A) and I(B) are
`principally administered orally or rectally. Suitable phar
`species, age and Weight of the subject under treatment,
`maceutical forms include solid and liquid unit oral dosage
`as well as the particular condition to be treated and the
`forms such as tablets, capsules, powders, suspensions,
`mode of administration. Dosage units such as dragees,
`solutions, syrups and the like, including sustained release
`tablets or suppositories, preferably contain from about
`preparations, and ?uid injectable forms such as sterile
`25 to about 300 mg. of a compound of Formulas I(A)
`solutions and suspensions. The term dosage form as
`or I(B) or a pharmaceutically acceptable salt thereof.
`used in this speci?cation and the claims refer to phys
`Unit dosages for oral administration preferably contain
`ically discrete units to be administered in single or multi
`from 1% to 90% of an active ingredient of Formula
`ple dosage to animals, each unit containing a prede
`I(A) or I(B).
`iPharmaceutically acceptable salts of the acids falling
`termined quantity of active material in association with
`the required diluent, carrier or vehicle. The quantity of
`under Formulas I(A) or I(B) are obtained either in
`active material is that calculated to produce the desired
`the courses of the production of the acids as described
`therapeutic effect upon administration of one or more of
`hereafter, or via conventional methods, such as the mix
`ing of preferably equimolar amounts of the free acid
`such units.
`Powders are prepared by comminuting the compound
`and the base in a suitable solvent, such as water, methanol,
`to a suitably ?ne size and mixing with a similarly com
`ethanol, diethyl ether, chloroform, methylene chloride or
`minuted diluent pharmaceutical carrier such as an edible
`the like. Salts, which in certain solvents have an ap
`carbohydrate material as for example, starch. Sweetening,
`preciably lower solubility than the alkali salts, can also
`?avoring, preservative, dispersing and coloring agents
`be produced from the latter by double reaction. Phar
`maceutically acceptable salts of the acids falling under
`can also be present.
`Capsules are made by preparing a powder mixture as
`Formulas I(A) and I(B) are such as derived from non
`described above and ?lling formed gelatin sheaths. A
`toxic inorganic or organic bases. Examplesof such salts
`lubricant such as talc, magnesium stearate and calcium
`are the sodium, potassium, lithium, magnesium, calcium
`stearate can be added to the powder mixture as an ad
`and ammonium salts, as well as salts with ethylarnine, tri
`juvant before the ?lling operation; a glidant such as
`ethylamine, Z-aminoethanol, 2,2-iminodiethanol, Z-di
`colloidal silica may be added to improve ?ow properties;
`methylamino-ethanol, 2 - diethylamino-ethanol, ethylene
`diamine, benzylamine, p-aminobenzoic acid, Z-diethyl
`a disintegrating or solubilizing agent may be added to
`aminoethyl ester, pyrrolidine, piperidine, morpholine, l
`improve the availability of the medicament when the
`capsule is ingested.
`ethylpiperidine or 2-piperidino-ethanol, and the like. A
`Tablets are made by preparing a powder mixture, gran
`particular advantage of the salts is that they tend to
`ulating or slugging, adding a lubricant and disintegrant
`stabilize the acids falling under ‘Formulas I(iA) and I(B).
`and pressing into tablets. A powder mixture is prepared
`The compounds of the present invention can be pre
`by mixing the compound, suitably comminuted, with a
`pared in a number of ways.
`,
`,
`.
`diluent or base such as starch, sucrose, kaolin, dicalcium
`_ In a ?rst process, a 2-(substituted anilino)phenyl
`phosphate and the like. The powder mixture can be
`acetonitrile of the formula:
`granulated by wetting with a binder such as syrup, starch
`34
`paste, acacia mucilage or solutions of cellulosic or poly
`meric materials and forcing through a screen. As an
`alternative to granulating, the powder mixture can be run
`through the tablet machine and the resulting imperfectly
`formed slugs broken into granules. The granules can be
`lubricated to prevent sticking to the tablet forming dies
`by means of the addition of stearic acid, a stearate salt,
`talc or mineral oil. The lubricated mixture is then com
`pressed into tablets. The medicaments can also be com
`bined with free ?owing inert carriers and compressed
`into tablets directly without going through the granulat
`ing or slugging steps. A protective coating consisting of
`a sealing coat of shellac, a coating of sugar or polymeric
`material and a polish coating of wax can be provided.
`Dyestuffs can be added to these coatings to distinguish
`different unit dosages.
`Oral fluids such as syrups and elixirs can be prepared
`in unit dosage form so that a given quantity, e.g., a tea
`spoonful, contains a predetermined amount of the com
`pound. Syrups can be prepared by dissolving the
`compound in a suitably ?avored aqueous sucrose solution
`while elixirs are prepared through the use of a non-toxic
`alcoholic vehicle. Suspensions can be formulated by dis
`persing the medicament in a non-toxic vehicle in which it
`is insoluble.
`For parenteral administration, ?uid unit dosage forms
`can be prepared by suspending or dissolving a measured
`amount of the compound in a non-toxic liquid vehicle
`suitable for injection such as an aqueous or oleaginous
`medium. Alternatively a measured amount of the com
`pound is placed in a vial and the vial and its contents
`are sterilized and sealed. An accomlpanying vial or
`vehicle can be provided for mixing prior to administration.
`The daily dosages, to be taken internally, of com
`
`"
`II(B)
`wherein R1, R2, R3, R4, R5, R6, R'’, R8 and R9 are as de
`?ned above and A is hydrogen or a (lower) alkanoyl group,
`is treated with an alkali metal hydroxide
`an aqueous
`solvent. Suitable solvents include aqueous lower- alkanols
`such as ethanol, methanol or n-butanol, polyolssuch as
`ethylene glycol or dimethylformamide. The hydrolysis is
`' performed at or slightly below the boiling temperature
`of the solvent, using at least two equivalents. of an alkali
`metal hydroxide, in particular sodium or potassium ,hy.-'
`
`15
`
`20
`
`30
`
`40
`
`50
`
`55
`
`60
`
`65
`
`70
`
`R5
`|
`
`R”
`
`l
`
`@114»:
`1II—A
`__Rl
`
`R
`
`or of the formula:
`
`_R2
`
`II(A)
`
`R6
`
`R“
`
`I @me I
`Iii-A
`
`R4
`
`R0;
`
`R8—
`
`—o F‘:
`
`droxide.
`
`,
`
`1
`
`i'
`
`‘I
`
`.
`
`The 2-(substituted anilino)phenylacetonitriles of For
`mulas II(A) and II(B) where A is (lower)alkanoyl can
`also be converted into the corresponding phenylacetates
`wherein R7 is (lower)alkyl through treatment of ‘the ni~v
`
`Page 3
`
`

`
`trile with a (lower)alkanol in the presence of an acid
`catalyst. (Lower)alkyl and ‘benzyl Z-(substituted anilino)
`phenylacetates can also be obtained from the correspond
`ing free acids through standard esteri?cation techniques.
`Conversely the (lower)alkyl 2 - (substituted anilino)
`phenylacetates can be saponi?ed and the benzyl 2-(substi
`tuted anilino)phenylacetates hydrogenolysized with cata
`lytically activated hydrogen to yield in both cases the
`corresponding 2-(substituted anilino)pheny1acetic acids.
`The starting materials of Formulas II(A) and II(B)
`are obtained from the corresponding 2-(substituted ani
`lino)anthranilic acids or their (lower)alkyl esters through
`reduction with lithium aluminum hydride in ether or tetra
`hydrofuran, sodium borohydride in methanol, or sodium
`borohydride and lithium bromide in diglyme (diethylene
`glycol dimethyl ether). The resultantZ-t substituted ani
`lino)benzylalcohols are then converted to the correspond
`ing benzyl chlorides through treatment with acetyl chlo
`ride, with dry ethereal hydrogen chloride, or with thionyl
`chloride and dry pyridine in ether. These Z-(Substituted
`anilino)benzyl chlorides are then treated with sodium or
`potassium cyanide to yield the requisite 2-(substituted
`anilino)phenylacetonitriles of Formulas II(A) or II(B).
`The groups R5 or R6 can be introduced into a 2-(substi
`tuted anilino)phenylacetonitrile of Formula II(A) 0r
`II(B) wherein A is a (lower)alkanoyl group and R5 and
`R6 are hydrogen or into the corresponding 2-(substituted
`anilino)phenylacetic acid bearing an N-alkanoyl group,
`through conventional alkylation techniques, with the N
`alkanoyl group‘ subsequently being removed by alkaline
`hydrolysis.
`.
`In a second process an indolinone of the formula:
`
`20
`
`25
`
`_R2
`
`40
`
`III(A)
`
`is treated with at least one equivalent of an alkali metal
`hydroxide, alkali metal carbonate or alkaline earth metal
`hydroxide with heating and, if desired, the acid is liber
`ated from the alkali or alkaline earth salt thus obtained.
`This acid can be converted into another salt with, an or
`ganic or inorganic base if desired. Suitable solvents for
`this second process are, in particular, aqueous lower a1
`kanols such as ethanol, methanoljor n-‘butanol; ethylene
`glycol; or dimethylformamide. The hydrolysis is performed
`at or slightly under the boiling point of the solvent. ,
`The indolinones of Formula III(A) are obtained from
`substituted N-phenylanilines (obtained for example from
`optionally substituted o-chloro- or o-bromo- benzoic acids r
`and substituted .anilines followed by. decarboxylation of
`the o-anilino-benzoic acids formed, or by heating N,O-di
`aryl-iminoesters and hydrolysing the N,N-diarylamides
`formed by rearrangement, or, by, reacting an optionally
`substituted-acetanilide with a bromo‘benzene substituted
`by a group corresponding to R4) through the reaction of
`the substituted N-phenyl aniline with an uq-chloroalkanoic
`acid chloride, e.g., chloroacetyl chloride, ‘2-chloropro
`pionyl chloride and the like, to yield an NI-(OL-ChIQI‘OaI
`kanoyl) (N-substituted phenyl) aniline; This is ‘then heated
`with aluminum chloride as a melt at temperatures of
`
`69
`
`about160°4C.
`
`_
`
`f
`
`_
`
`‘
`
`_
`
`.
`
`a
`
`.
`
`The substituents ‘R5 and R6 ‘can also be directlytintro?
`duced into an indolinone of Formula III(A). Thus an
`indolinone of formula III(A) wherein R5 and R6 are‘ hy}
`drogen is treated with an alkyl halide or dialkyl' sulfate
`in the presence of sodium hydride or’sodium amide in di~
`methylformamide, or with an aralkyl halide, such as ben
`zyl chloride. A benzyl radical is also introduced, into such
`an indolinone by reacting the latter withbenzaldehyde
`
`70
`
`3,558,690
`
`6
`and then reducing the l-aryl-3-benzal-2-indolinone formed;
`e.g., with activated hydrogen.
`In a third process an N-substituted indol-2,3-dione of
`the formula:
`
`R4-
`
`= o
`
`\Nlo
`
`|
`
`R3
`
`_._R1
`
`_R2
`
`IV(A)
`
`_ or of the formula:
`
`R4— —~=o Jzo
`
`N
`I
`
`Rs__
`
`R8—
`
`on
`
`IV(B)
`wherein R1, R2, R3, R4, R8 and R9 are as previously de
`?ned, is treated ?rst with hydrazine or a semicarbazide
`and then with an alkali hydroxide or alkali metal al
`coholate. This process is carried out by either ?rst con
`verting the substituted indole-2,3-dione with hydrazine,
`which can also be used in the form of the hydrate, or
`with semicarbazide to the corresponding 3-(hydrazone)
`or 3-(semicarbazone), respectively, and decomposing
`this intermediate with an alkali metal hydroxide or alkali
`metal alkoxides or by mixing and reacting all three re
`action components simultaneously. The temperature for
`the main reaction, the action of the alkali metal hydroxide
`or alkali metal alkoxide, is in the range of 100-220",
`preferably from 140-200°. The optional prior and‘ sepa
`rate formation of the hydrazone can be carried out at
`considerably lower temperatures, e.g., at room tempera
`ture; it can however also be conducted at higher tem
`peratures. Water which may be introduced when the hy-.
`drazine hydrate is used or that which is liberated by the
`reaction, can be removed by distillation. A higher boiling
`organic solvent can be used as reaction medium. Such
`solvents include ethylene glycol (or mono- and di- ethers
`thereof such as diethylene glycol, diethylene glycol mono
`methylether) or triethylene glycol, higher boiling alcohols
`such as benzyl alcohol, octyl alcohol or nitrilotriethanol,
`or when the reaction is carried out in a closed vessel, a
`>(lower)alkanol. It is ‘also possible when employing a
`(lower)alkanol solvent such as ethanol or butanol as the
`initial reaction medium, to remove this solvent during
`the reaction together with excess hydrazine and liberated
`water until the reaction mixture gradually solidi?es, reach
`ing a temperature between 150° and 200°. The alkali
`metal hydroxides which can be used in this third process
`are, in particular, potassium or sodium hydroxide. The
`alkali metal alkoxides include‘ sodium alkoxide and are
`either derivatives of (lower)alkanol solvent or of the
`higher boiling hydroxy compounds used as reaction media.
`The alkali metal salts of substituted phenylacetic acids
`of Formula I(A) or I(B) that are ?rst obtained accord
`ing to this process are optionally ‘converted into the free
`acid in the usual manner‘using strong acids, e.g., hydro‘
`'c'hloric‘acid. If ‘desiredythe acid obtainedjis converted in
`to another salt,rpreferably‘ a pharmaceutically acceptable
`‘salt, with an“ inorganic or organic base, according to proc
`esses‘mentioned hereinhefore.
`p
`_
`._ In converting the ring-substituted indol-2,3-diones of
`Formula IY_(A) or IV(B) into the corresponding phenyl~
`acetic acids, the process can be carried out through an
`additional intermediate stage, namely-the production of
`the'Z-(substitut‘ed anilino)phenylg1yoxylic acid‘of Formu
`
`las V(A) and‘V(B).
`
`‘
`
`V
`
`s
`
`.
`
`.
`
`.v v
`
`i
`
`Page 4
`
`

`
`7
`
`NH
`
`R4
`|
`
`O 0
`
`gm...
`
`§H
`
`3,558,690
`use of conventional techniques. These includes the use of
`a lower diazoalkane, such as diazomethane, in an inert
`organic solvent such as ether, methylene chloride, benzene,
`acetals of N,N-dimethylformamide, i.e., 1,1-diethoxy
`trimethylamines or 1,1-diaralkoxytrimethylamines, etc.;
`the use of benzyl alcohol or (lower)alkanols in the pres
`ence of N,N-dimethyl formaldehyde dineopentyl acetal,
`i.e., l,l-dineopentyloxytrimethylamine; the raction of an
`alkali salt of an acid falling under Formulas I(A) or I(B)
`and a reactive ester of a (lower)alkanol or benzyl alcohol,
`e.g., with dimethylsulfate, diethylsulfate, methyl iodide,
`ethyl iodide, propyl bromide, butyl bromide, benzyl
`chloride, benzyl bromide or p-toluenesulfonic acid methyl
`ester in a suitable reaction medium; and the reaction of an
`acid falling under Formulas I(A) or I(B) with a mixture
`consisting of the alcohol desired as ester component and
`thionyl chloride. In this last method, the maintenance of
`low temperatures, e.g., below about —5 °, is advantageous.
`The following examples set forth the manner and
`process of making typical embodiments of the invention,
`without being a limitation thereof, and include the best
`mode contemplated by the inventors for carrying out the
`invention. In these examples, temperatures are expressed
`on the centigrade scale.
`
`V(A)
`
`15
`
`V(B)
`
`wherein R1, R2, R3, R4, R8 and R9 are as previously de
`?ned and R10 is hydrogen or a cation.
`‘
`Thus a compound of Formula IV(A) or IV(B) is
`initially subjected to hydrolysis and 2-(substituted anilino)
`phenylglyoxylic acid or its salt is then reduced with
`hydrazine or semicarbazide and with an alkali metal hy
`droxide or alkali metal alkoxide as previously described.
`The third method is especially advantageous both in
`terms of its yield and of its application. Thus in the
`second method described above, the relatively high tem
`peratures utilized in the aluminum chloride ring closure
`can lead to a number of undesirable side reactions, in
`cluding loss or exchange of fluoro in tri?uoromethyl
`groups, migration of alkyl groups and splitting of alkoxy
`groups. Such are avoided in the preparation of the indol
`2,3-diones of Formulas IV(A) and IV(B) as can be seen
`in the following description of these starting materials.
`Thus a substituted N-phenylaniline, obtained for example
`as previously described, is treated with oxalyl chloride to
`yield a substituted N-phenyl oxanilic acid of the formula:
`
`40
`
`or of the formula
`
`R:
`
`o
`
`VI(A)
`
`VICB)
`
`65
`
`wherein R1, R2, R3, R4, R8 and R9 are as previously de
`?ned.
`These oxanilic acid chlorides can then be converted into
`the corresponding indol-2,3-diones of Formulas IV(A)
`and IV(B) respectively, through the use of aluminum
`chloride, the reaction being conducted however at room
`temperature.
`Yields-are further improved if the indol-2,3-dione is
`puri?ed, as through recrystallization, prior to treatment
`with hydrazine or a semicarbazide.
`As previously described, the Z-(substituted anilino)
`phenylacetic acids of Formula I(A) and I(B) can be
`esteri?ed to yield the corresponding acetates through the
`
`EXAMPLE 1
`
`2-(2,6-dichloro-B-methylanilino) phenylacetic acid
`(A) N-phenyl-2,6-dichloro ~ 3 - methylaniline: Seven
`grams of 2-(2,6-dichloro-3-methylanilino)benzoic acid [al
`ternatively named as N-(2,6-dichloro-m-tolyl)-anthranilic
`acid] are heated for 2 hours at 280°. The cooled melt is
`dissolved in 30 ml. of benzene and the bnzene solution is
`extracted with 5 m1. of 2 N sodium carbonate and 5 ml. of
`water. The solution is dried ‘with sodium sulfate and con
`centrated. The residue is distilled whereupon N-phenyl
`2,6-dichloro-3-methylaniline (alternatively named as 2,6
`dichloro-N-phenyl-m-toluidine) is obtained as a yellow
`oil, B.P. 1l5-120°/0.001 torr.
`The following are obtained in a similar fashion from
`the corresponding anthranilic acids:
`(a) N-phenyl-2,6-dichloroaniline, B.‘P. 109—l11°/ 0.003
`torr.
`(b) N~phenyl-2-chloro-6-methylaniline, B.P. 88°/ 0.005
`torr.
`Alternatively, these substituted N-phenylanilines can‘be
`prepared according to the following procedures:
`Forty milliliters of acetyl chloride are slowly added
`dropwise to a solution of 81 g. of 2,6-dichloraniline in 30
`ml. of glacial acetic acid. The solution is then heated in a
`Water bath ‘until the development of hydrogen chloride
`has been completed. It is then cooled to room tempera
`ture and the mixture is poured into ice. The crystals
`which separate are ?ltered off and recrystallised from
`glacial acetic acid to yield 'N-acetyl-2,6-dichloraniline,
`M.P. 180-181". The yield is 70% of the theoretical.
`N-acetyl-2,6-dichloro-3-methylaniline M.P. 179—18l°
`from glacial acetic acid/water, is prepared analogously.
`Fifteen grams of N-acetyl-2,v6-dichloroaniline (alterna
`tively named as 2,6-dichlor-acetanilide) are dissolved in
`150 ml. of bromobenzene. Five and a half grams of cal
`cinated potassium carbonate and 0.5 g. of copper powder
`are added. The mixture is re?uxed for 4 days, the water
`formed being removed by a water separator, cooled and
`subjected to steam distillation. The residue is extracted
`with 200 ml. of ether. The ether solution is ?ltered through
`Hyflo and the residue is concentrated to dryness under 11
`torr. The residue is dissolved in 60 ml. of 10% ethanolic
`potassium hydroxide solution and the solution is re?uxed
`for 3 hours. The solution is then concentrated to dryness
`at 40” under 11 torr. Ten milliliters of water are added to
`the residue which is then extracted with 100 ml. of ether.
`The ether solution is removed and extracted With 20 ml. of
`water. The ether solution is then dried with sodium sulfate
`and concentrated to dryness under 11 torr. The residue is
`
`Page 5
`
`

`
`10
`
`20
`
`25
`
`30
`
`3,558,690
`distilled under high vacuum to yield N-pheny1-2,6-di
`tral aluminum oxide column, melts at 184-187°; yield
`chloroaniline as a yellow oil, at 115°/ 0.01 torr. The yield
`60% of the theoretical.
`In a similar fashion is obtained 1-(2,6~dichlorophenyl)
`is 43 % of the theoretical.
`'
`.
`Similarly prepared are:
`S-hydroxy-Z-indolinone, M.P. 204-205° from methanol
`(c) N-(4-chlorophenyl)-2,6-dichloraniline, B.P. 123
`benzene.
`125 °/0.00l torr.
`, A solution of 8.1 g. of this crude l-(2,6-dichloro-3
`(d) N-(4-chlorophenyl)-2,6-dichloro-B-methylaniline,
`methylphenyl)-5~hydroxy-2-indolinone in 26.3 ml. of l N
`.B.P. 135-145°/0.005 torr.
`sodium hydroxide solution is combined with 3.7 g. of di
`(e) N-(4~methoxyphenyl)-2,6-dich1oro-3-methy1aniline
`methyl sulfate and the whole is re?uxed for half an hour.
`B.P. 115~130°/ 0.001 torr.
`After cooling, the reaction solution is extracted with 400
`(f) N-(4-methoxyphenyl) - 2,6- dichloroaniline, M.P.
`ml. of ethyl acetate. The organic phase is ?ltered, the
`75-77 ° from chloroform.
`?ltrate is washed once with water and once with saturated
`(B) N-chloroacetyl-N-phenyl - 2,6 - dichloro-3-methyl
`sodium chloride solution, dried over sodium sulfate and
`aniline: Four grams of N-phenyl-2,6-dichloro-3-met_hy1
`concentrated to dryness under 11 torr. The residue is puri
`aniline and 40 ml. of freshly distilled chloroacetyl chloride
`?ed by chromatography on an aluminum oxide column.
`are re?uxed for 1 hour. The dark solution is then con
`1-(2,6-dichloro-3-methylphenyl)-5-rnethoxy - 2 - indoli
`centrated at a bath temperature of 50° under 11 torr. The
`none, after recrystallization from ether/petroleum ether,
`residue is dissolved in 70 ml. of 1:1 ethyl acetate/ether.
`melts at 135-136°; yield 20% of the theoretical.
`This solution is extracted with 10 ml. of 2 N potassium
`Similarly prepared is 1-(2,6-dichlorphenyl)-5-methoxy
`bicarbonate solution and 10 ml. of water, dried over
`2-indolinone, M.P. 144-1450 from ether/petroleum
`sodium sulfate and concentrated. under 11 torr. The prod
`ether.
`not, which is alternatively named as phenyl-2,2’-6'-trichlor
`These l-(substitnted phenyl)-2-indolinones can be
`arietoiifi-toluidide, is crystallized from cyclohexane, M.P.
`brominated, as exempli?ed by the following procedure:
`A solution of 11.2 g. of 1-(2,6-dichlorophenyl)-2
`indolinone in 700 ml. of ethanol is added to a solution of
`8 g. of potassium bromide and 2.08 g. of bromine in
`160 ml. of water; The mixture is vigorously shaken and
`then left to stand for 3 hours at 0°. The alcohol is then
`evaporated off and the insoluble precipitate is ?ltered
`off from the remaining aqueous solution. The latter is
`then taken up in methylene chloride. The methylene chlo
`ride solution is dried over sodium sulfate and concentrated
`to dryness under 11 torr. The residue consists of a mix
`ture, 60% of which is 1-(2,6-dichlorophenyl)-5-bromo-2
`indolinone. This is puri?ed by repeatedly chromatograph—
`35
`ing on a silica gel column and, after having been crystal
`lized several times from ether/petroleum ether, it melts
`at 188-190".
`.
`(D) 2 - (2,6 - dichloro - 3-methylanilino)phenylacetic
`acid: A solution of 40 g. of 1-(2,6-dichloro-3-methyl
`phenyl)-2-indolinone in 280 ml. of 1 N sodium hydroxide
`solution and 420 ml. of ethanol is re?uxed for 2 hours.
`The clear solution is cooled and the ethanol is distilled
`off at a bath temperature of 40° under 11 torr. The
`aqueous residue is extracted with 100‘ ml. of ether and
`cooled to 5° by the addition of ice (about 50 g.) and
`external cooling. 2 N hydrochloric acid is then added
`while stirring until the pH of the solution is about 6. The
`precipitated acid is taken up in 400 ml. of ether, the ether
`solution is separated and the aqueous solution is again
`extracted with 200 ml. of ether. The ether solutions are
`washed with 50 ml. of water, combined, dried over sodium
`sulfate and concentrated under 11 torr without heating.
`After adding petroleum ether to the concentrated ethereal
`' solution, 2 - (2,6-dichloro-3-methylanilino)phenylacetic
`acid crystallizes out. After recrystallization from ether/
`petroleum ether, it melts at 146-449".
`1 In a similar manner there are obtained:
`(a) 2 - (2,6 - dichloroanilino)phenylacetic acid, M.P.
`156-158“;
`(b) 2-(2 - chloro-6 - methylanilino)phenylacetic acid,
`M.P. 140-l47° from ether;
`(c) 2-(2,6-dichloroanilino)-5-chlorophenylacetic acid,
`M.P. 181—l83° from methanol;
`((1) 2 - (2,6 - dichloro - 3 - methylanilino)-5-chloro
`phenylacetic acid, M.P. 152-l56° from ethyl ether/petro
`leum ether; »
`'
`"
`(e) 2 - (2,6 - dichloro - 3-methylani1ino)~5-methoxy
`phenylacetic acid, M.P. 120—122° from ethyl ether/petro
`leum ether;
`(f) 2 - (2,6 - dichloroanilino)damethoxyphenylacetic
`acid, M.P. 134~136° from ethyl ether/petroleum ether;
`(g)2 - (2,6 - dichloroanilino) - 5 - bromophenylacetic
`acid, M.P. 161'’ from ether.
`
`Similarly prepared are:
`.
`.
`(a) N-chloroacetyl-N-phenyl-Z,6-dichloroaniline, M.P.
`143—144° from methanol;
`(b) N-chloroacetyl-N-phenyl-2~chloro-6-methylaniline,
`‘M.P. 11'0—1 12 ° from ether;
`‘
`(c) N-chloroacetyl~N-(4-chlorophenyl) - 2,6 - dichloro
`aniline M.P. 130-431° from ethanol/water;
`(d) N-chloroacetyl-N-(4-chlorophenyl)-2,6 - dichloro
`3-methylaniline, M.P. l06—107° from ethyl ether/petro
`leum ether;
`,
`(e) N-chloroacetyl-N - (4 - methoxyphenyl) - 2,6 - di
`chloro-B-methylaniline, as a yellow oil; and
`‘
`(f) N - chloroacetyl - N - (4~methoxyphenyl) -2,6-di
`chloroaniline M.P. 127-128° from methanol.
`(C) 1 - (2,6 - dichloro-3-methylphenyl)-2-ind0linone:
`Four grams of N-chloroacetyl-N-phenyl-Z,6-dichloro-3
`methylaniline and 4 g. of aluminum chloride was well
`mixed together and heated for 2 hours at 160°. The melt
`is cooled and poured onto about 50l g. of ice while it is
`still warm. The oil which separates is dissolved in 50 ml.
`of chloroform, the chloroform solution is washed with
`10 ml. of water, dried over sodium sulfate and concen
`trated under 11 torr. The residue is distilled. The 1-(2,6~
`dichloro-3-methylphenyl)-2-indolinone boils at 128-130°/
`0.001 torr. The oil obtained crystallizes on standing, these
`crystals melting at 129-132”.
`In a similar fashion are obtained:
`(a) l-(2,6-dichlorophenyl)~2