IE39927L - Substituted indanones. - Google Patents

Substituted indanones.

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Publication number
IE39927L
IE39927L IE742046A IE204674A IE39927L IE 39927 L IE39927 L IE 39927L IE 742046 A IE742046 A IE 742046A IE 204674 A IE204674 A IE 204674A IE 39927 L IE39927 L IE 39927L
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IE
Ireland
Prior art keywords
dichloro
methyl
compound
formula
oxo
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IE742046A
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IE39927B1 (en
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Merck & Co Inc
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Publication date
Application filed by Merck & Co Inc filed Critical Merck & Co Inc
Priority to IE1620/77A priority Critical patent/IE39928B1/en
Publication of IE39927L publication Critical patent/IE39927L/en
Publication of IE39927B1 publication Critical patent/IE39927B1/en

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Abstract

[1-oxo-2-aryl- or -thienyl-2-subst.-5-indanyloxy-(or -thio)]- alkanecarboxylic acids and their derivatives of the formula I <IMAGE> in which the substituents are defined in Claim 1, are prepared. Appropriate 2-aryl- or 2-thienyl-2-subst.-5-hydroxy-(or -mercapto)-1-indanones are reacted with a haloalkanoic acid or an ester thereof. The said compounds are present as the free acid or as alkyl esters, and they can be converted, if they are an acid, into the corresponding esters, salts and amides. The said compounds and also their salts, esters and amides are useful diuretic and saluretic agents and can be used in medicaments, preferably for the treatment of hypertension. [GB1474459A]

Description

399 27 This invention provides 2-aryl or thienyl substituted indanones having the following formulae: X' O and H N N 9 >-CH2 N II in which R is or f~K' NX where Y is alkylene or haloalkylene containing from 1 to 4 carbon atoms, X"* is hydrogen, halogen, viz. chlorine, bromine, fluorine or iodine, alkyl, e.g. methyl, ethyl, 10 n-propyl, n-butyl, tertiary butyl or n-pentyl, cycloalkyl, e.g. cyclopentyl or cyclohexyl, alkoxy, e.g. methoxy, nitro, hydroxy, amino, cyano, sulfamoyl, methanesulfonyl, aminomethyl, chlorosulfonyl, acylamino or acylaminoethyl, - 2 - 39927 7 X is hydrogen, aminomcthyl, Cj_5 such as methyl or V" O halogen# viz. .chlorine, bromine, fluorine or iodine; X is hydrogen or alkyl such .as methyl; A is oxygen or sulfur; R is alkyl, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or pentyl, cyclo-alkyl, preferably C^_g cycloalkyl, e.g. cyclopentyl or cyclohexyl, cycloalkyl-(C^_g alkyl), e.g. cyclopropylmethyl or cyclopentylmethyl, alkenyl, e.g. allyl, (1,2 or 3)- butenyl or (1,2,3 or 4)-pentenyl, phenyl-(C1_j alkyl), e.g. benzyl, phenethyl or phenylpropyl, phenyl-(C^.^ alkenyl) e.g. cinnamyl, aryl, e.g. phenyl or thienyl, or substituted aryl, e.g. haloaryl, (C^^ alkyl)-aryl, or (C^_^ alkoxy)-aryl; and R1 is hydrogen, C1-5 alkyl or aryl, e.g. phenyl; or R and R* are joined to form a bivalent hydrocarbon chain; and X* is hydrogen, methyl or halo, e.g. chlorine, 2 bromine or fluorine and X is methyl, trihalomethyl or halo, 1 2 e.g. chlorine, bromine or fluorine or X and X are joined to form a bivalent hydrocarbon chain containing 3 or 4 carbon atoms, for example, trimethylene, tetramethylene or 1,3-butadienylene; and the non-toxic pharmacologically acceptable salts, amides, anhydrides and esters thereof.
The preferred compounds of this invention are those compounds in which A is oxygen and R, R°, R^, R2, x\ X2, 3 7 8 X , X and X are as defined above.
Particularly preferred compounds of this invention are l-oxo-2-aryl-2-substituted-6,7-disubstituted-5-indanyloxy- acetic acids having the following formulae: hoccii2o . / and U f ♦ ) hocch2o where R and alkyl, viz. methyl, ethyl, n-propyl or isopropyl, or C3_g cycloalkyl, e.g. cyclopropyl, cyclo- 4 5 pentyl or cyclohexyl; each of X and X , which are the same or different, is methyl or chlorine; and X® is hydrogen, methyl, chlorine or fluorine, and their non-toxic pharmaceutically acceptable salts.
Pharmacological studies have shown that the compounds falling within the above definition are effective diuretic and saluretic agents and so can be used in the treatment of conditions associated with electrolyte and fluid retention. Such compounds are also useful in the treatment of hypertension, and are able to maintain the uric acid .concentration in the body at pretreatment levels or to even effect a decrease in the uric acid concentration when administered in therapeutic dosages in conventional vehicles.
Many currently available diuretics and saluretics have a tendency upon administration to induce hyperuricemia. This may precipitate uric acid and/or sodium urate in the body, which may cause from mild to severe cases of gout. 39927 This invention now provides effective compounds to treat those patients requiring diuretic and saluretic treatment without incurring the risk of inducing gout. Zn fact, when used in appropriate doses, compounds of this invention 5 can function as uricosuric agents.
Compounds in the foregoing class have been found to exhibit particularly good diuretic/saluretic activity.
Such compounds also either maintain the uric acid concentration of the body at pretreatment levels or even cause a lO decrease in uric acid concentration.
Several methods may be used to prepare the substituted indanones of this invention. One method comprises 2-alkyl-ation of a fl-oxo-2-aryl or 2-thienyl-5-indanyl (oxy or thio)*|-alkanoic acid or ester of structure III (infra) with an lb alkylating agent of the formula RZ where Z is halo. This reaction is conducted by first treating the p.-oxo-2-aryl or 2-thienyl-5-indanyl(oxy or thio)]alkanoic acid or ester with a suitable base, for example an alkali metal hydride such as sodium hydride, an alkali metal alkoxide such as potassium 20 tertiary butoxide or sodium methoxide, or an alkali metal amide such as sodium amide or lithium amide. The resulting carbanion is then treated with the alkylating agent, RZ. Any solvent that is inert or substantially inert to the reactants may be used. Suitable solvents include for 25 example, 1,2-dimethoxyethane, tertiary butanol, benzene and dimethylformamide. The reaction may be conducted at a temperature in the range of from 0°C to 150°C. In general, the reaction is conducted at a temperature in the range of from 0-50°C. The following equation illustrates this 30 process: - 5 - 399 27 r3ocya hocya III X O when R = lower alkyl,-hydrolysis when R = t-butyl, pyrolysis 10 where A, R, R°, R1, X1, X2, X3, X7, X8, Z and Y are as defined above and R3 is hydrogen or alkyl.
A second method for preparing the |l-oxo-2-aryl-2-substituted-5-indanyl-oxy(or thio)|alkanoic acids of this invention comprises reacting a halo alkanoic acid or ester thereof, 0 3 'I R OCYZ with a suitable 2-aryl or 2-thienyl-2-substituted-5-hydroxy-(or mercapto)-1-indanone (IV): - 6 - 399 27 when R = lower alkyl,..hydrolysis when R = t-butyl, pyrolysis 10 15 where all substituents are as defined above.
In general, the reaction is conducted in the presence of a base such as an alkali metal carbonate, hydroxide or alkoxide such as potassium carbonate, sodiuin carbonate, potassium hydroxide, sodium hydroxide or sodium methoxide. Any solvent that is inert or substantially inert to the reactants and in which the reagents are reasonably soluble may be used. Acetone, ethanol and dimethylformamide for example have proven to be particularly advantageous solvents. The reaction may be conducted at a temperature in the range of from 25°C. to the reflux temperature of the solvent.
If the haloalkanoic acid ester is used, the ester obtained may be hydrolysed to the free acid by well-known methods. 3 When R is the tert-butyl group, the acid may be obtained by acid-catalysed pyrolysis, such as by heating the tert-butyl ester in the presence of a strong acid, for example, - 7 - 39927 10 in the presence of £-toluene-sulfonic acid, sulfuric acid or gaseous hydrogen chloride. In general, pyrolysis is effected by heating at a temperature in the range from 70° to 140°C., preferably 80°-100°C. Also, the pyrolysis may be conducted without a solvent or in the presence of a suitable non-aqueous medium in which the reactants are reasonably soluble, for example, in the presence of benzene, toluene or xylene.
Two additional processes for preparing compounds of Vormula I are as illustrated by the following flow diagram: r11o2c r11o2c (r11o2c)2cho IVc Ifr The first process shown involves reacting a 5-hydroxy (or mercapto) compound (IVa supra) with halonitro ethane to form a 2-nitroethane, (Formula IVb) which upon hydrolysis yields the end product (I). The preparation of the - 8 - 399 27 compound of Formula IVb is shown in Patent Specification No. 35361.
In the other process shown,the 5-hydroxy (or mercapto) compound (IVa) is reacted with a malonic ester (where R*' is 5 Cl-5 a3-ky1» preferably ethyl) to form a malonic ester (IVc); this is hydrolysed to form another intermediate compound (Formula IVd) which is then decarboxylated to form the end product I.
Those 2-aryl or 2-thienyl substituted indanones of 10 this invention in which the alkylene chain, Y, contains two linear carbon atoms between the carboxy and oxy or thio groups are prepared from the corresponding 5-(hydroxy or mercapto) compounds (IV) by the reaction of the latter with propiolactone or with an appropriately substituted propio-15 lactone in the presence of a base such as an aqueous solution of sodium hydroxide, preferably while heating the solution at reflux temperatures followed by the acidification of the carboxylate thus formed to the desired acid. The following equation illustrates the reaction: - 9 - 39927 X iia 1 + c(r3)2-c(r3)2 o c=o n; MOH X 2 O 1101 < R where all substituents are as defined above and M is an alkali metal cation, which may be derived from an alkali metal hydroxide or alkali metal carbonate, such as sodium or potassium cation.
The 2-aryl or 2-thienyl-2-substituted-5-hydroxy(or mercapto)-1-indanones (IV, supra) are novel compounds. They are claimed in, and their preparation is described and claimed in Patent Specification No. 3'/*] 25*- Those compounds of the invention in which R and R^" are joined to form a cyclopropyl ring (XIII, infra) are prepared by treating a (l-oxo-2-indene-5-yloxy)alkanoic acid (XII) with an alkali metal base such as sodium hydride followed by treatment with a mothylating agent, for example trimethylsulfoxonium iodide. The (l-oxo-2- indene-5-yl-yloxy) alkanoic acids are ,iescrihej in u>s. i»atent " 10 3 9 9 2 7 3,668,241. The following equation illustrates this process: 2 2 X* 0 xz O where all substituents are as defined above.
The nuclear alkoxy precursors of those compounds of the invention in which R and R^ are joined to form a cyclohexyl ring are prepared according to the procedure described and claimed in British Patent Specification 1,427,090: - 11 - :»9 »:i 7 Frledel ^ -crafts R A — cycl alkylation dehydro-halogenation lO where the substituents are as defined above.
Those compounds of formula I in which R° is aryl and the X3 substituents are cyano, chlorosulfonyl, sulfamoyl, nitro, amino or aminomethyi are generally prepared from the compounds of formula I or an intermediate compound such as a compound of formula IV where R° is ur:substituted aryl or thienyl or from a compound of formula IV or 1 when R° is substituted aryl when the substituents can be converted to the jesired substituent by well known methods. For example, when R° is unsubstituted aryl the compounds of formula I can be reacted with chloro--sulfonic acid to yield a compound in which is chlorosulfonyl and the latter compound reacted with ammonia to yield a compound of formula I in which X3 is 3ulfamoyl. - 12 - 399 27 112 in which A, R, R , Y, X and X are as defined above, are conveniently prepared in accordance with the present invention by treating a compound of the formula: OCH, or H N N I N OCH- with an ether-cleaving reagent, e.g. hydrogen bromide in *0 acetic acid.
Compounds of the formula: - 13 - 39927 112 In which A, R, R i Y, X and X are as defined above, are conveniently prepared by reducing a compound of the formula: Other conversions are shown in the examples (see for instance Examples 21, 22 and 31).
Also included within the scope of this invention are the esters and amides of the acids which are prepared by known methods. Thus, for example, the esters may be prepared by the reaction of the Ql-oxo-2-aryl or 2-thienyl-substituted-5-indanyl(oxy or thio)] -alkanoic acid of this invention with an alcohol, for example, with a C^_5 alkanol. - 14 - 39927 The amides may be prepared by converting a Ql-oxo-2-aryl or 2-thienyl-2-substituted-5-indanyloxy(or thio)J -alkanoic acid to its corresponding acid chloride by treatment with thionyl chloride followed by treating said acid chloride 5 with ammonia, an appropriate mono-(C1_5 alkyl)amine, di- (Cl~5 alkyl)amine or a hetero amine, such as piperidine or morpholine, to produce the corresponding amide. To the extent that the esters and amides are both non-toxic and pharmacologically acceptable they are the functional 10 equivalent of the corresponding free acids.
In addition to the salts, esters and amides being functionally equivalent to the carboxyllc products, those compounds in which the carboxyl group is replaced by a 5-tetrazolyl radical are also functionally equivalent to 15 the carboxyllc acids. These tetrazole analogues are prepared as depicted in the following equation: - 15 - 399 27 (Formula I where Y is methylene) where all substituents are as defined above.
The 5-hydroxy (or thio)-1-lndanone (IV above) is 5 treated with a haloacetonitrile such as chloroacetonitrile, bromoacetonitrile or iodoacetonitrile in the presence of a base such as potassium carbonate in a suitable solvent such as acetone, dimethylformamide or dimethoxyethane at a temperature in the range of from 25° to 100°C. to afford the 10 corresponding nitrile (XIV) which upon treatment with sodium azide and ammonium chloride in dimethylformamide at a temperature in the range of from 25° to 100°C, affords the 5-fl-oxo-2-aryl or 2-thlenyl-2-substituted-5-indanyloxy (or thio)methylJtetrazole. 15 A still further process for preparing compounds of Formula I (the end product) in which Y is methylene involves hydrolysis of the nitrile compound shown in Formula XIV 390 27 above. This is a typical and well-known hydrolysis.
Many of the compounds of the invention contain an asymmetric carbon atom in the 2-position of the indanyl ring. When this situation exists, the optical antipodes may be separated by methods described below. This invention embraces, therefore, not only the racemic [l-oxo-2-aryl or 2-thienyl-2-substituted-5-indanyloxy(or thio)]alkanoic acids but also their optically active antipodes.
Separation of the optical isomers of the racemic acids may be accomplished by forming a salt of the racemic mixture with an optically active base such as (+) or (-) amphetimine, {-)-cinchonidine, dehydroabietylamine, (+) or (-)-a-methylbenzylamine, (+) or (-)-a-(1-naphthyl)ethyl-amine, brucine or strychnine in a suitable solvent such as methanol, ethanol, 2-propanol, benzene, acetonitrile, nitromethane or acetone. There is thus formed in the solution two diastereoisomerlc salts one of which is usually more soluble in the solvent than the other. Repetitive recrystallization of the crystalline salt generally affords a pure diastereoisomer. The optically pure 2-aryl or 2-thienyl indane acid is obtained by acidification of the salt with a mineral acid, extraction into ether, evaporation of the solvent and recrystallization of the optically pure antipode.
The other optically pure antipode may generally be obtained by using a different base to form the diastereoisomerlc salt. It is of advantage to isolate the partially resolved acid from the filtrates of the purification of the one diastereoisomerlc salt and to further - 17 - 39927 purify this substance through the use of another optically active base.
The examples which follow illustrate some of the 2-aryl and 2-thienyl indane products of the invention and 5 the methods by which they are prepared. In the examples, proportions of recrystallization solvents are on a volume basis, and the screen and capsule sizes are U.S. standards.
EXAMPLE 1.
Preparation of (l-Oxo-2-methyl-2-phenyl-6,7-10 dichloro-5-indanyloxy)acetic acid Step A: 2,3-Dichloro-4-phenylacetylanisole To a stirred mixture of 2,3-dichloroanisole (62 g., 0.35 mole), phenylacetyl chloride (54 g., 0.35 mole) and carbon disulfide (250 ml.) is added portionwise aluminium 15 chloride (47 g., 0.35 mole) with cooling at 0-5°C. The reaction mixture is left at 25°C for 17 hours, the carbon disulfide removed, and the residue treated with ice-water and concentrated hydrochloric acid (50 ml.) to give 68.8 g. of 2,3-dichloro-4-phenylacetylanisole, which melts 20 at 126-129°C. on crystallization from benzene:cyclohexane, 2:1.
Elemental analysis for ci5H12cl202: Calc.: C, 61.04; H, 4.10; Found: C, 61.46; H, 4.11. 25 Step B: 2,3-Dichloro-4-(2-phenylacryloyl)anisole Acetic anhydride (100 ml.) is added dropwise to a suspension of 2,3-dichloro-4-phenylacetylanisole (29.5 g., 0.01 mole) in bis(dimethylamino)methane (100 ml.) under nitrogen with cooling to maintain the reaction mixture at 30 a temperature below 60°C. The reaction mixture is stirred - 18 - 39927 at 25°C. for 2 hours, and poured into ice water (1500 ml.) to precipitate 7.4 g. of 2,3-dichloro-4-(2-phenylacryloyl)-anisole which melts at 87-89°C.
Elemental analysis for C16H12C12°25 5 Calc.: C, 62.56; H, 3.94; Found : C, 62.67; H, 4.04.
Step C: 2-Phenyl-5-methoxy-6,7-dichloro-l-indanone 2,3-Dichloro-4-(2-phenylacryloyl)anisole (7.4 g., 0.024 mole) is added portionwise to cold, concentrated 10 sulfuric acid (150 ml.) with stirring. The reaction mixture is stirred in an ice bath for 2 hours, then added dropwise to ice-water to precipitate 3.91 g. of 2-phenyl-5-methoxy-6,7-dichloro-l-indanone, which melts at 193-195°C. upon crystallization from benzene:cyclohexane, 1:2. 15 Elemental analysis for cigH12Cl202: Calc.: C, 62.56; H, 3.94; Found : C, 62.84; H, 4.00.
Step D: 2-Phenyl-5-hydroxy-6,7-dichloro-l-indanone A stirred mixture of 2-phenyl-5-methoxy-6,7-dichloro-20 1-indanone (3.91 g., 0.0127 mole) and pyridine hydrochloride (40 g.) is heated at 190°C. for one hour, then poured into water (600 ml.). The 2-phenyl-5-hydroxy-6,7-dichloro-l-indanone, which separates (2.48 g.), melt9 at 250-252°C. after recrystallization from ethanol:water, 2:1. 25 Elemental analysis for ci5HioCl202: Calc.: C, 61.46; H, 3.44; Found : C, 60.94; H, 3.66.
Step E: (l-Oxo-2-phenyl-6,7-dichloro-5-indanyloxy)-acetic acid 30 2-Phenyl-5-hydroxy-6,7-dichloro-l-indanone (5.86 g., - 19 - 39927 0.023 mole), iodoacetlc acid (4.28 g., 0.023 mole), potassium carbonate (3.04 g., 0.022 mole) and acetone (250 ml.) are heated at reflux for 48 hours. The reaction mixture is cooled to 25°C. and concentrated in vacuo to 5 give a solid product which is dissolved in water and acidified with 6N hydrochloric acid to precipitate 6.8 g. of a mixture of (l-oxo-2-phenyl-6,7-dichloro-5-indanyloxy)-acetic acid and 2-phenyl-5-hydroxy-6,7-dichloro-l-indanone. The phenol is removed by crystallisation with nitromethane. 10 Concentrating the filtrate to dryness in vacuo and triturating with toluene gives 470 mg. of (l-oxo-2-phenyl-6,7-dichloro-5-indanyloxy)acetic acid which melts at 181-185°C. Elemental analysis for ci7Hi2C12°4: Calc.: C, 58.14; H, 3.45; CI, 20.19; 15 Found : C, 58.17; H, 3.54; CI, 19.94.
Step F: (l-oxo-2-phenyl-2-methyl-6,7-dichloro-5-indanyloxy)acetic acid A stirred solution of (l-oxo-2-phenyl-6,7-dichloro-5-indanyloxy)acetic acid (0.351 gm., O.OOl mole) in 20 dimethylformamide (7 ml.) is cooled in an ice bath, treated with sodium hydride (0.084 g. of a 57% oil dispersion, 0.002 mole) and stirred for two hours. Methyl iodide (1 ml.) is added and the reaction mixture is stirred at 25°C. for two hours, poured into ice water, 25 and acidified with dilute aqueous hydrochloric acid affording (l-oxo-2-phenyl-2-methyl-6,7-dichloro-5-indanyloxy)-acetic acid, which melts at 168-169°C.
EXAMPLE 2.
Where in Example 1, Step A, there is substituted for 30 the 2,3-dichloroanisole an equivalent amount of 2-chloro-3- - 20 - 39927 methylanisole, 2,3-dimethylanisole, 3-methylanisole, or 2-methyl-3-chloroanisole, respectively, and Steps B to F are carried out as described, there is obtained: {l-oxo-2-phenyl-2,7-dimethyl-6-chloro-5-5 indanyloxy)acetic acid, (l-oxo-2-phenyl-2,6,7-trimethyl-5-indanyloxy)- acetic acid, (l-oxo-2-phenyl-2,7-dimethyl-5-indanyloxy)-acetic acid, or lO (l-oxo-2-phenyl-2,6-dimethyl-7-chloro-5- indanyloxy)acetic acid.
EXAMPLE 3.
Where in Example 1, there is substituted for the phenylacetyl chloride of Step A an equivalent amount of 15 £-methylphenylacetyl chloride, m-methylphenylacetyl chloride, o-chlorophenylacetyl chloride or £-fluorophenyl-acetyl chloride, and Steps B to F are carried out as described, there is obtained respectively: [l-oxo-2-methyl-2-(4-methylphenyl)-6,7-dichloro-20 5-indanyloxy3acetic acid, [l-oxo-2-methyl-2-(3-methylphenyl)-6,7-dichloro- 5-indanyloxy]acetic acid, £l-oxo-2-(2-chlorophenyl)-2-methyl-6,7-dichloro-5-indanyloxy]acetic acid, or 25 [l-oxo-2-(4-fluorophenyl)-2-methyl-6,7-dichloro-5- indanyloxy]ace'-ic acid.
EXAMPLE 4.
Where in Example 1, the 2-alkylating agent, methyl iodide, of Step F is replaced by an equivalent amount of 30 ethyl iodide, allyl bromide, benzyl bromide, or cinnamyl - 21 - 39927 bromide, respectively, there is obtained, respectively: (l-oxo-2-ethyl-2-phenyl-6,7-dichloro-S- indanyloxy) acetic acid, (l-oxo-2-allyl-2-phenyl-6,7-dichloro-S- indanyloxy) acetic acid, (l-oxo-2-benzyl-2-phenyl-6,7-d'lchloro- 5- indanyloxy)acetic acid, or (l-oxo-2-cinnamyl-2-phenyl-6,7-dichloro-S-indanyloxy )acetic acid.
EXAMPLE S. (l-0xo-2-methy1-2-pheny1-6,7-dichloro-S-indanyloxy) acetic acid Step A: 2',3'-Dichloro-4 *-methoxyisobutyrophenone A stirred mixture of 2,3-dichloroanisole (I) (100 g., 0.565 mole) and isobutyryl chloride (II) (66 g., 0.62 mole) in methylene chloride (400 ml.) is cooled to 5°C. and treated with aluminium chloride (83 g., 0.62 mole) during a one-hour period. The reaction mixture is allowed to warm to 2S°C. and after 24 hours is poured into ice water (400 ml.) and hydrochloric acid (30 ml.). The organic phase is washed with 5% sodium hydroxide and water, dried over magnesium sulfate and distilled at reduced pressure affording 68 g. of 2*,3'-dichloro-4■-methoxyisobutyrophenone (III) , which distils at 120°-130°C/ 0.5 mm.
Elemental analysis for C11H12C12°2: Calc.: C, 53.46; H, 4.89; Found : C, 54.25; H, 5.07. - 22 - 309 27 Step D: 2-Bromo-2',3'-dichloro-4'-methoxyisobutyrophenone A stirred solution of 2',3'-dichloro-4'-methoxyisobutyrophenone (45 g., 0.183 mole) in acetic acid (150 ml.) is treated during one-half hour with bromine (30 g., 0.187 5 mole). The reaction mixture is stirred for 10 minutes, then poured into ice water (600 ml.) containing sodium bisulfite (2 g.). The 2-bromo-2',3*-dichloro-4'-methoxyisobutyrophenone (IV), which separates (48 g.), melts at 72°-73°C. after recrystallization from hexane. 10 Elemental analysis for Cj^Hj^BrClj^' Calc.: C, 40.52; H, 3.40; Found : C, 40.68; H, 3.38.
Step C: 2-Methylene-2*,3'-dichloro-4*-methoxypropio-phenone 15 A solution of 2-bromo-2',3'-dichloro-4'-methoxyiso butyrophenone (32 g., 0.1 mole) and anhydrous lithium bromide (17.4 g., 0.2 mole) in DMF (200 ml.) is stirred at 95°C. in an inert atmosphere for three hours and poured into ice water (500 ml.). The 2-methylene-2',3'-dichloro-20 4'-methoxypropiophenone (V), which separates, melts at 59°C. after recrystallization from petroleum ether. Elemental analysis for ci^H^oCl203; Calc.: C, 53.90; H, 4.11; Found : C, 53.72; H, 4.11. 25 Step D: 2-Methyl-5-methoxy-6,7-dichloro-l-indanone A solution of 2-methylene-2',3'-dichloro-4'-methoxypropiophenone (40 g., 0.163 mole) in concentrated sulfuric acid (75 ml.) is allowed to stand at 25°C. for 24 hours and is then slowly poured into vigorously stirred ice water 30 (500 ml.). The 2-methyl-5-methoxy-6,7-dichloro-l-indanone, - 23 - which separates (40 g.), melts at 129°C. after recrystallization from methylcyclohexane.
Elemental analysis for cilH10C^202: Calc. : C, 53.90; H, 4.11; Found : C, 53,84; H, 4.00.
Step E: 2-Methyl-2-phenyl-5-methoxy-6,7-dichloro-l-indanone Potassium tert-butoxide (8.42 g., 0.075 mole) dissolved in tert-butanol (300 ml.) is added to a refluxing solution of 2-methyl-5-methoxy-6,7-dichloro-l-indanone (12.26 g., 0.05 mole). Refluxing is continued for 2 hrs., then a suspension of dlphenyliodonixim chloride (19.0 g., 0.06 mole) in tert-butanol (1 1.) is added and refluxing is continued for a further 2 hrs. The reaction mixture is cooled to 25°C., 300 ml. of water added, and the mixture concentrated to dryness iji vacuo to give 4.97 g. of 2-methyl-2-phenyl-5-methoxy-6,7-dichloro-l-indanone, which melts at 161-163°C. after crystallization from benzene: cyclohexane, 1:2.
Elemental analysis for C17H^4C12°2: Calc.: C, 63.57; H, 4.39; Found : C, 63.24; H, 4.68.
Step F: 2-Methyl-2-phenyl-5-hydroxy-6,7-dichloro-l-indanone A stirred mixture of 2-methyl-2-phenyl-5-methoxy-6,7-dichloro-l-indanone (4.94 g., 0.015 mole) and pyridine hydrochloride (50 g.) is heated at 175°C. for one hour, then poured into water (500 ml.). The 2-methyl-2-phenyl-5-hydroxy-6,7-dichloro-l-indanone, which separates (2.05 g.) melts at 194-196°C. after recrystallization from ethanol: water, 2:1. 399 27 Elemental analysis for ci6,,i2t*l202s Calc.: C, 62.56; H, 3.94; Found : C, 62.60; H, 4.11.
Step G: (l-0xo-2-methyl-2-phenyl-6,7-dichloro-5-5 indanyloxy)acetic acid a stirred mixture of 2-methyl-2-phenyl-5-hydroxy-6,7-dichloro-l-indanone (2.05 g., 0.0067 mole), potassium carbonate (1.85 g., 0.0134 mole) and ethyl bromoacetate (2.23 g., 0.0134 mole) in dimethylformamide (30 ml.) is 10 warmed at 55-60°C. for 3 hours, then treated with potassium hydroxide (0.97 g., 0.0147 mole) dissolved in a minimum amount of water in methanol (30 ml.) and heated on a steam bath for 2\ hours. The reaction mixture is poured into water (500 ml.) and acidified with 6N hydrochloric acid, 15 and the precipitate is collected after trituration with mixtures of ether and petroleum ether and dried to oive 1.31 g. of (l-oxo-2-methyl-2-phenyl-6,7-dichloro-S-indanyloxy) acetic acid, which melts at 168-169°C. on crystallization from acetic-acid:water, 1:1. 20 Elemental analysis for cigHi4C12°4! Calc.: C, 59.20; H, 3.86; Found : C, 58.94; H, 4.20.
EXAMPLE 6.
Where in Example 5, there Is substituted for the 25 2,3-dichloroanisole of Step A an equivalent amount of 2-chloro-3-methylanisole, 2,3-dimethylanisole and 2-methyl- 3-chloroanisole, respectively, the following compounds of this invention are obtained, respectively: (l-oxo-2,7-dimethyl-2-phenyl-6-chloro-5-30 indanyloxy)acetic acid, - 25 - 39927 (l-oxo-2,6,7-trimethyl-2-phenyl-5-indanyloxy)- acetic acid, (l-oxo-2,6-dimethyl-2-phenyl-7-chloro-5-indanyloxy)acetic acid. 5 EXAMPLE 7. preparation of [l-0xo-2-(4-chlorophenyl)-2-methyl-6,7-dichloro-5-indanyloxyJ acetic acid hemihydrate Step A: 2-(4-chlorophenyl)-2-methyl-5-methoxy-6,7-lO dichloro-l-indanone Potassium tert-butoxide (2.81 g., 0.025 mole) dissolved in tert-butanol (150 ml.) is added to a refluxing solution of 2-methyl-5-methoxy-6,7-dichloro-l-indanone (4.90 g., 0.02 mole) in a mixture of tert-butanol (100 ml.) 15 and benzene (200 ml.), refluxing is continued for 3 hours, then 4,4'-dichlorodiphenyliodonl'Tr chloride (11.55 g., 0.03 mole) is added and refluxing is continued for a further 2 hours. The reaction mixture is cooled to 25°C., lOO ml. of water added, and the mixture concentrated to 20 dryness jln vacuo to give 4.30 g. of 2-(4-chlorophenyl)-2-methyl-5-methoxy-6,7-dichloro-i-indanone, which melts at 176-178°C. after crystallization from cyclohexane:benzene, 5:1.
Step B: 2-(4-Chlorophenyl)-2-methyl-5-hydroxy-6,7-25 dichloro-l-indanone A stirred mixture of 2-(4-chlorophenyl)-2-methyl-5-methoxy-6,7-dichloro-l-indanone (4.15 g., 0.012 mole) and pyridine hydrochloride (40 g.) is heated at 180°C. for one hour, then poured into water (500 ml.). The 2-(4-chloro-30 phenyl)-2-methyl-5-hydroxy-6,7-dichloro-l-indanone, which - 26 - 39927 separates (3.11 g.), melts at 211-213°C. after crystallization from ethanol:water, 1:1.
Elemental analysis for ci6Hllcl3°2! Calc.: C, 56.25; H, 3.25; Found : C, 55.53; H, 3.23.
Step C: [l-oxo-2-(4-chlorophenyl)-2-methyl-6,7- dlchloro-5-lndanyloxy]acetic acid hemlhydrate A stirred mixture of 2-(4-chlorophenyl)-2-methyl-5-hydroxy-6,7-dichloro-l-indanone (2.95 g., 0.00863 mole), potassium carbonate (2.26 g., 0.0163 mole) and ethylbromo-acetate (2.72 g., 0.0163 mole) in dimethylformamide (50 ml.) is warmed at 55-60°C. for two hours, then treated with water (50 ml.) and ION sodium hydroxide solution (2.5 ml., 0.025 mole) and heated at 80°C. for one hour. The reaction mixture is added slowly to water (500 nil.) and 1?N hydrochloric acid (10 ml.) to precipitate 1.37 g. of p.-oxo-2-(4-chlorophenyl)-2-methy1-6,7-dichloro-S-indanyloxy) acetic acid hemlhydrate, which melts at 141-142°C. after crystallization from acetic-acid:water, 1:1. Elemental analysis for ci8H13C13°4:1/2H20: Calc.: C, 52.90; H, 3.45; Cl, 26.03; Found : C, 52.47; H, 3.45; Cl, 26.11.
EXAMPLE 8.
Preparation of [l-0xo-2-(4-methoxyphenyl)-2-methyl-6,7-dichloro-S-indanyloxy]acetic acid Step A: 2-Methyl-5-hydroxy-6,7-dichloro-l-indanone A stirred mixture of 2-methyl-5-methoxy-6,7-dichloro-l-indanone (30.0 g., 0.123 mole) and pyridine hydrochloride (270 g.) is heated at 180°C. for one hour, then poured into water (1500 ml.). The 2-methyl-5-hydroxy-6,7-dichloro-l- - 27 - 399 27 indanonc, which separates (27.6 g.), melts at 224-230°C. and is used without further purification.
Stop H: 2-Mothy 1 -fi-ben/.y I oxy-6,7—*i 1 rh 1 oro-l -1 ml.mnno A stirred mixture of 2-methyl-5-hydroxy-6,7-dlcliloro 1-indanone (27.6 g., 0.12 mole), potassium carbonate (24.9 g., 0.18 mole) and benzyl bromide (21.4 ml., 0.18 mole) in dimethylformamide (100 ml.) is warmed at 55-60°C. for 2 hrs., then poured into water (1 1.) to precipitate 35.5 g. of 2-methyl-5-benzyloxy-6,7-dichloro-l-indanone, which melts at 153-155°C. after crystallization from benzenerhexane, 3:2.
Elemental analysis for C17H14C12°2: Calc.: C, 63.57; H, 4.39; Found : C, 64.28; H, 4.61.
Step C: 2-(4-Methoxyphenyl)-2-methyl-5-benzyloxy-6,7-dichloro-l-indanone Potassium tert-butoxide (8.42 g., 0.075 mole) dissolved in tert-butanol (450 ml.) is added to a refluxing solution of 2-methyl-5-benzyloxy-6,7-dichloro-l-indanone (16.1 g., 0.05 mole) in tert-butanol (150 ml.)-benzene (600 ml.) and refluxing is continued for 2.5 hours. Then 4,4'-dimethoxydiphenyliodonium chloride (37.66 g., 0.10 mole) is added and refluxing is continued for a further 3 hrs. The reaction mixture is cooled to 25°C., 500 ml. water added, and the mixture concentrated in vacuo to give a brown oil which on ether extraction, drying over anhydrous magnesium sulfate, removal of the ether and chromatography of the residue on silica gel with chloroform gives 3.44 g. of 2-(4-methoxyphenyl)-2-methyl-5 benzyloxy-6,7-dichloro-l-indanone, which melts at 115-119° - 28 - 39927 and is used without further purification.
Step Dt 2-(4-Methoxyphenyl)-2-methyl-5-hydroxy-6,7-dichloro-l-indanone 2-(4-Methoxyphenyl)-2-methyl-5-benzyloxy-6,7-5 dichloro-l-indanone (3.44 g., 0.008 mole) is catalytically hydrogenated in absolute ethanol (300 ml.) over 5% palladium on carbon (500 mg.) .in a Parr apparatus at 25°C. for 4 hrs. The reaction mixture is filtered and concentrated _in vacuo to give 2.6 g. of 2-(4-methoxyphenyl)-10 2-methyl-5-hydroxy-6,7-dichloro-l-indanone, which melts at 149-156°C. and is used without further purification.
Step E: [l-Oxo-2-(4-methoxyphenyl)-2-methyl-6,7-dichloro-5-indanyloxy]acetic acid A stirred mixture of 2-(4-methoxyphenyl)-2-methyl-5-15 hydroxy-6,7-dichloro-l-indanone (2.6 g., 0.0077 mole), potassium carbonate (2.14 g., 0.0154 mole) and ethyl bromo-acetate (2.58 g., 0.0154 mole) in dimethylformamide (60 ml.) is warmed at 55-60°C. for 2.5 hrs., then treated with water (60 ml.) and ION sodium hydroxide solution (3 ml., 20 0.03 mole) and heated at 100°C. for one hour. The reaction mixture is added slowly to crushed ice-water (600 ml.) and 12N hydrochloric acid (20 ml.) to precipitate 1.69 g. of [l-oxo-2-(4-methoxyphenyl)-2-methyl-6,7-dichloro-S-indanyloxy] acetic acid, which melts at 173-175°C. after 25 crystallization from nitromethane.
Elemental analysis for ci9Hi6cl2°5: Calc.: C, 57.74; H, 4.08; Found : C, 57.35; H, 4.31. - 29 - 39927 EXAMPLE 9.
Preparation of [l-0xo-2-(4-hydroxyphenyl)-2-methy1-6,7-dichloro-5-indanyloxy]acetic acid A stirred mixture of j[l-oxo-2-(4-methoxyphenyl)-2-5 methyl-6,7-dichloro-5-indanyloxy]acetic acid (1.80 g., 0.0046 mole). Example 8, Step E, 48% hydrobromic acid (50 ml.) and acetic acid (50 ml.) is heated at reflux for i one hour, then poured into crushed ice-water (800 ml) to precipitate 900 mg. of Ql-oxo-2-(4-hydroxyphenyl)-2-methyl-lO 6,7-dichloro-S-indanyloxy]-acetic acid, which melts at 220-222°C. after crystallization from acetic-acid:water, 1:1, and nitromethane.
Elemental analysis for ci8H14C12°5*1/3CH3N02: Calc.: C, 54.84; H, 3.77; N, 1.16; 15 Found : C, 54.38; H, 3.93; N, 0.94.
EXAMPLE 10.
Ethyl (l-0xo-2-methyl-2-phenyl-6,7-dichloro-S-indanyloxy) acetate To a solution of (l-oxo-2-methyl-2-phenyl-6,7-dichloro-20 5-indanyloxy)acetic acid (1.0 g.), obtained from Example 5, in ethanol (lO ml.) is added boron trifluoride etherate (1.0 ml.). The reaction mixture is refluxed for half an hour, treated with water and cooled to afford the ethyl (l-oxo-2-methyl-2-phenyl-6,7-dichloro-S-indanyloxy)acetate. 25 EXAMPLE 11.
N-Ethyl-(l-oxo-2-methyl-2-phenyl-6,7-dichloro- indanylox" ->cetamide A solution of (l-oxo-2 -iu>,yl-2-phenyl-6,7-dichloro-S-indanyloxy) acetic acid (1.0 g obtained from Example 5 30 and thionyl chloride (0.5 ml.) in benzene (20 ml.) is - 30 - 39927 refluxed for one hour. The solvent 1s distilled at reduced pressure and the residue is treated with benzene (10 ml.) and ethylamine (1 ml.). After two hours at 25°C. the reaction mixture is poured into water and 5 extracted with ether; the ethereal extract is washed first with diluted hydrochloric acid then with aqueous sodium bicarbonate. The ethereal solution is dried over magnesium sulfate and evaporated at reduced pressure to afford N-ethyl-(l-oxo-2-methyl-2-phenyl-6,7-dichloro-5-10 indanyloxy)acetamlde.
EXAMPLE 12.
Preparation of [i-0xo-2-(4-fluorophenyl)-2-methyl-6,7-dichloro-S-indanyloxy]acetic acid Step A: 2-(4-Pluorophenyl)-2-methyl-5-methoxy-6,7-15 dichloro-l-indanone Potassium tert-butoxide (3.38 g., 0.03 mole) dissolved in tert-butanol (150 ml.) is added to a refluxing solution of 2-methyl-5-methoxy-6,7-dichloro-l-indanone (4.90 g., 0.02 mole) in tert-butanol (50 ml.) and benzene 20 (200 ml.). Refluxing is continued for 3 hours, then 4,4'-difluorodiphenyliodonium chloride (10.58 g., 0.03 mole) is added and refluxing is continued for a further 2\ hours. The reaction mixture is cooled to 25°C., 100 ml. of water added, and the mixture concentrated to dryness 25 in vacuo to give 1.24 g. of 2-(4-fluorophenyl)-2-methyl-5-methoxy-6,7-dichloro-l-indanone, which melts at 163-170°C. on treatment with ether-hexane and is used without further purification.
Step B: 2-(4-Fluorophenyl)-2-methyl-5-hydroxy-6,7-30 dichloro-l-indanone - 31 - 39927 A stirred mixture of 2-(4-fluorophenyl)-2-methyl-5-methoxy-6,7-dichloro-l-indanone (1.2 g., 0.00354 mole) and pyridine hydrochloride (12 g.) is heated at 180°C. for one hour, then poured into water (500 ml.). The 2-(4-5 fluorophenyl)-2-methyl-5-hydroxy-6,7-dichloro-l-indanone melts at 193-200°C. and is used without further purification.
Step C: £l-Oxo-2-(4-fluorophenyl)-2-methyl-6,7-dichloro-5-indanyloxy]acetic acid A stirred mixture of 2-(4-fluorophenyl)-2-methyl-5-10 hydroxy-6,7-dichloro-l-indanone (1.04 g., 0.0032 mole), potassium carbonate (0.885 g., 0.0064 mole) and ethyl bromoacetate (1.07 g., 0.0064 mole) in dimethylformamide (30 ml.) is wanned at 55-60°C. for 3 hours, then treated with water (30 ml.) and ION sodium hydroxide solution 15 (1 ml., 0.01 mole), and heated at 80°C. for one hour.
The reaction mixture is added slowly to water (500 ml.) and 12N hydrochloric acid (lO ml.) to precipitate 450 mg. of [l-oxo-2-(4-fluorophenyl)-2-methyl-6,7-dichloro-S-indanyloxy] acetic acid, which melts at 150-156°C. after 20 crystallization from ethyl-acetate:hexane, 1:3.
Elemental analysis tor C18H13C12F04: Calc.: C, 56.42; H, 3.42; Cl, 18.50; Found : C, 56.30; H, 3.65; Cl, 18.57.
EXAMPLE 13. 25 Preparation of (l-Oxo-2,2-diphenyl-6,7-dichloro- S-indanyloxy) acetic acid Step A: 2,2-Diphenyl-5-methoxy-6,7-dichloro-l-indanone Potassium tert-butoxide (7.0 g., 0.0624 mole) dissolved in tert-butanol (500 ml.) is added to a mixture of 30 2-phenyl-5-methoxy-6,7-dichloro-l-indanone (9.59 g., 0.0312 - 32 - 39927 mole), diphenyliodonium chloride (39.6 g., 0.125 mole), tert-butanol (1500 ml.) and benzene (500 ml.) at 70°C. during one hour, then stirred at 70°C. for 2 hours. The reaction mixture is concentrated in vacuo to of its 5 volume, unreacted lodonium salt filtered off, and the remaining liquid concentrated to dryness to give 5.71 g. of 2,2-diphenyl-5-methoxy-6,7-dichloro-l-indanone, which melts at 172-174°C. after crystallization from cyclohexane.
Elemental analysis for C22H16C12°2: 10 Calc.1 C, 68.94; H, 4.21; Found : C, 68.99; H, 4.34.
Step B: 2,2-Diphenyl-5-hydroxy-6,7-dichloro-l-indanone A stirred mixture of 2,2-diphenyl-5-methoxy-6,7-dichloro-l-indanone (5.5 g., 0.014 mole) and pyridine 15 hydrochloride (55 g.) is heated at 175°C. for half an hour, then poured into water (500 ml.). The 2,2-diphenyl-5-hydroxy-6,7-dichloro-l-indanone, which separates (4.94 g.), melts at 207-213°C.
Elemental analysis for C21H14C12°2: 20 Calc.: C, 68.31; H, 3.82; Pound : C, 67.86; H, 3.88.
Step C: (l-Oxo-2,2-diphenyl-6,7-dichloro-S-indanyloxy) acetic acid A stirred mixture of 2,2-diphenyl-5-hydroxy-6,7-25 dichloro-l-lndanone (4.9 g., 0.0133 mole), potassium carbonate (3.68 g., 0.0266 mole) and ethyl bromoacetate (4.45 g., 0.0266 mole) in dimethylformamide (150 ml.) is warmed at 55-60°C. for 3.5 hours, then treated with water (150 ml.) and ION sodium hydroxide solution (7.5 ml., 30 0.075 mole) and heated at 90°C. for 1.5 hrs. The reaction - 33 - 39 9 27 mixture is added slowly to water (1 1.) and 12N hydrochloric acid (30 ml.) to precipitate 3.60 g. of (1-oxo-2,2-dipheny1-6,7-dichloro-5-indanyloxy)acetic acid, which welts at 251-252°C. after crystallization first from 5 acetic acid and then from nitromethane.
Elemental analysis for C23H16C12°4: Calc.: C, 64.65; H, 3.77; Cl, 16.59; Found : C, 64.69; H, 3.94; Cl, 16.73.
EXAMPLE 14. 10 Preparation of (l-Oxo-2,3-diphenyl-2-methyl- 6,7-dichloro-5-indanyloxy)acetic acid Step A: 2',3*-Dichloro-4'-methoxypropiophenone A stirred mixture of 2,3-dichloroanisole (177.0 g., 1.0 mole) and propionyl chloride (101.8 g., 1.1 mole) in 15 methylene chloride (600 ml.) is cooled to 5°C. and treated with aluminum chloride (146.7 g., 1.1 mole) during a 1% hour period. The reaction mixture is allowed to warm to 25°C. and after 16 hours is poured into ice-water (2 1.) and concentrated hydrochloric acid (200 ml.). 20 The organic phase is washed with 10% sodium hydroxide solution and saturated salt solution, and dried over magnesium sulfate. After evaporation of the solvent, the product is crystallized from hexane to give 124.5 g. (53%) of 2',3'-dichloro-4'-methoxypropiophenone, which 25 melts at 51-54°C.
Step B: 2,3-Dichloro-4-(2-benzylidenepropionyl)anisole To a mixture of 2',3'-dichloro-4'-methoxypropiophenone (124.5 g., 0.53 mole) and benzaldehyde (54.4 ml., 0.53 mole) dissolved in ethanol (1 1.) is added dropwise 30 20% sodium hydroxide solution (117.0 ml., 0.59 mole). - 34 - 39927 The product begins to precipitate after three quarters of the base has been added. After two hours at 25°C. the solid product is collected by suction filtration to give 1 163.2 g. (95%) of 2#3-dichloro-4-(2-benzylldenepropionyl)-anisole, which melts at 137.5-139°C. after crystallization from ethanol.
Blemental analysis for C17H14C12°2: Calc.: C, 63.57; H, 4.39; Found : C, 63.69; Hr 4.49.
Step C: 2-Methyl-3-phenyi-5-meth;xy-t»,7-dichlor:>-l-indanone 2,3-Dichloro-4-(2-benzylidenepropionyl)anisole (100 g., 0.32 mole) and trifluoroacetic acid (400 ml.) are heated at gentle reflux for 67 hours. The trifluoroacetic acid is removed, the oily residue triturated with ether to give 80.0 g. of 2-methyl-3-phenyl-5-methoxy-6,7-dichloro-l-indanone, which on crystallization from benzene melts at 155-157°C.
Elemental analysis for C17H14C12°2: Calc.: C, 63.57; H, 4.39; Found : C, 63.17; H, 4.59.
Step D: 2,3-Dipheny1-2-mathyl-5-methoxy-6,7-dichloro-l-indanone Sodium methoxide (2.4 g., 0.045 mole) is added portionwise to a stirred mixture of 2-methyl-3-phenyl-5-methoxy-6,7-dichloro-l-indanone (6.44 g., 0.02 mole), diphenyliodonium chloride (31.6 g., 0.1 mole), dry dimethyl-formamide (200 ml.) and benzene (200 ml.) at 70°C. under nitrogen, and heating at 70°c. is continued for 2 hours. The reaction mixture is poured into water (1.5 1.) and the benzene layer separated, dried over anhydrous magnesium - 35 - 39927 sulfate and concentrated in vacuo to give 2.48 g. of 2,3-diphenyl-2-methyl-5-methoxy-6,7-dichloro-l-indanone after trituration with hexane. This material, which melts at 197-207°C., is used without further purification. 5 Step E: 2,3-Diphenyl-2-methyl-5-hydroxy-6,7-dichloro-l- indanone A stirred mixture of 2,3-diphenyl-2-methyl-5-methoxy-6,7-dichloro-l-indanone (2.48 g., 0.0065 mole) and pyridine hydrochloride (25 g.) is heated at 175°C. for one hour, 10 then poured into water (500 ml.). The 2,3-diphenyl-2-methyl-5-hydroxy-6,7-dichloro-l-indanone, which separates (2.24 g.), melts at 238-244°C. and is used without further purification.
Step F: (l-0xo-2,3-diphenyl-2-methyl-6,7-dichloro-6-indanyloxy)acetic acid 15 A stirred mixture of 2,3-diphenyl-2-methyl-5-hydroxy- 6,7-dichloro-l-indanone (2.24 g., 0.00585 mole), potassium carbonate (1.62 g., 0.0117 mole) and ethyl bromoacetate (1.96 g., 0.0117 mole) in dimethylformamide (100 ml.) is warmed at 55-60°C. for 3 hours, then treated with water 20 (100 ml.) and ION sodium hydroxide solution (5 ml., 0.05 mole) and heated at 90°C. for 1.5 hours. The reaction mixture is added slowly to water (1 1.) and 12N hydrochloric acid (10 ml.) to precipitate 1.14 g. of (l-oxo-2,3-diphenyl-2-methyl-6,7-dichloro-S-indanyloxy)acetic acid, 25 which melts at 203-205°C. after crystallization from nitromethane.
Elemental analysis for C24Hi8C*2°4: Calc.: C, 65.32; H, 4.11; Found : C, 65.30; H, 4.19. - 36 - I 399 27 EXAMPLE 15.
Preparation of (l-Oxo-2-ethyl-2-phenyl-6,7-dichloro-5-indanyloxy)acetic acid Step At 2-Ethyl-2-phenyl-5-methoxy-6,7-dichloro-l-5 indanone Sodium methoxide (1.24 g., 0.023 mole) is added portlonwlse to a stirred mixture of 2-phenyl-5-methoxy-6/7-dichloro-l-indanone (4.61 g., 0.015 mole), indoethane (15.5 ml., 0.15 mole), benzene (60 ml.) and dimethylform-10 amide (60 ml.) under nitrogen in ar. ice-water bath. The reaction mixture is left to come to ambient temperature over one hour, then poured into water (1 1.), and the benzene layer is separated, dried over anhydrous magnesium sulfate and concentrated in vacuo to give 3.23 g. of 2-15 ethyl-2-phenyl-5-methoxy-6,7-dichloro-l-indanone, which melts at 139-141°C. on crystallization from benzene: hexane, 1:1.
Elemental analysis for c^gH^gc^2°2: Calc. : C, 64.49; H, 4.81; 20 Found : C, 64.73; H, 4.99 Step B: 2-Ethyl-2-phenyl-5-hydroxy-6,7-dichloro-l-indanone A stirred mixture of 2-ethyl-2-phenyl-5-methoxy-6,7-dichloro-l-indanone (3.01 g., 0.009 mole) and pyridine 25 hydrochloride (35 g.) is heated at 175°C. for half-an-hour, then poured into water (350 ml.). The 2-ethyl-2-phenyl-5-hydroxy-6,7-dichloro-l-indanone, which separates (2.64 g.), melts at 177-179°C.
Elemental analysis for C17H14C12°2: 30 Calc. : C, 63.57; H, 4.39; Found : C, 63.73; H, 4.81. - 37 - 39927 Step C: (l-Oxo-2-ethyl-2-pheny1-6,7-dichloro-S-indanyloxy) acetic acid A stirred mixture of 2-ethyl-2-phenyl-5-hydroxy-6,7-dichloro-l-indanone (2.6 g., 0.008 mole), potassium carbonate (2.24 g., 0.016 mole) and ethyl bromoacetate (2.71 g., 0.016 mole) in dimethylforroamide (40 ml.) is warmed at 55-60°C. for 2.5 hours, then treated with water (40 ml.) and ION sodium hydroxide solution (3 ml., 0.03 mole) and heated at 100°C. for one hour. The reaction mixture is added slowly to water (600 ml.) and 12N hydrochloric acid (lO ml.) to give a gummy residue which, on ether extraction, drying and concentrating in vacuo gives 2.16 g. of (1-oxo-2-ethyl-2-phenyl-6,7-dichloro-S-indanyloxy)acetic acid, which melts at 187-189°C.
Elemental analysis for C19H16C12°4= Calc.: C, 60.18; H, 4.25; Found : C, 59.76; H, 4.24.
EXAMPLE 16.
Preparation of (l-Oxo-2-cyclopentyl-2-phenyl-6,7-dichloro-5-indanyloxy)acetic acid Step A: 2-Cyclopentyl-2-phenyl-5-methoxy-6,7-dichloro-l-indanone Sodium methoxide (1.63 g., 0.03 mole) is added portlonwlse to a stirred mixture of 2-phenyl-5-methoxy-6,7-dichloro-l-indanone (4.61 g., 0.015 mole), cyclopentyl bromide (16 ml., 0.15 mole), benzene (60 ml.) and dimethyl-formamide (60 ml.) under nitrogen at 25°C. The reaction mixture is stirred at 25°C. for 16 hours, then poured into water (1 1.) and the benzene layer is separated, dried over anhydrous magnesium sulfate and concentrated in vacuo - 38 - 399 27 leaving a red-brown oily residue, which is chromatographed with chloroform on silica gel to give 1.42 g. of 2-cyclo-penty1-2-phenyl-5-methoxy-6,7-dichloro-l-indanone, which melts at 105-108°C. 5 Elemental analysis for C2^H20^2°2: Calc.: Ci 67.21; H, 5.37; Found : C, 66.88) H, 5.53.
Step B: 2-Cyclopenty1-2-phenyl-5-hydroxy-6,7-dichloro-l-indanone 10 A stirred mixture of 2-cyclopentyl-2-phenyl-5-methoxy 6,7-dichloro-l-indanone (1.40 g., 0.0037 mole) and pyridine hydrochloride (14 g.) is heated at 175°C. for half an hour, then poured into water (400 ml.). The 2-cyclopentyl-2-phenyl-5-hydroxy-6,7-dichloro-l-indanone, which separates 15 (1.1 g.), melts at 161-170°C. on crystallization from butyl chloride:chloroform, 5:1.
Elemental analysis for C2oHl8C*2°2: Calc.: C, 66.49; H, 5.02; Found : C, 65.52; H, 5.03. 20 Step C: (l-Oxo-2-cyclopentyl-2-phenyl-6,7-dichloro-S-indanyloxy) acetic acid A stirred mixture of 2-cyclopentyl-2-phenyl-5-hydroxy 6,7-dichloro-l-indanone (1.10 g., 0.003 mole), potassium carbonate (0.85 g., 0.006 mole) and ethyl bromoacetate 25 (1.02 g., 0.006 mole) in dimethylformamide (20 ml.) is warmed at 55-60°C. for 3 hours, then treated with water (20 ml.) and ION sodium hydroxide solution (1.2 ml., 0.012 mole) and heated at 100°C. for one hour. The reaction mixture is added slowly to water (300 ml.) and 12N hydro-30 chloric acid (5 ml.) to precipitate 680 mg. of (l-oxo-2- - 39 - 39927 eyelopenty1-2-pheny1-6,7-dichloro-S-indanyloxy)acetic acid, which melts at 184-186°C. after crystallization from nitrome thane.
Elemental analysis for C22H20C^2°4: 5 Calc.: C, 63.02; H, 4.81; Found : C, 62.59; H, 4.86.
EXAMPLE 17.
Preparation of [l-Oxo-2-methyl-2-(4-nitrophenyl)-6,7-dichloro-5-indanyloxy3 acetic acid 10 Step A: 2-Methyl-2-(4-nitrophenyl)-5-methoxy-6,7-dichloro-l-indanone Amyl nitrate (40 ml.) is added in 10-rol. increments at two-hour intervals to 2-methy1-2-phenyl-5-methoxy-6,7-dichloro-l-indanone (9.36 g., 0.03 mole) in polyphosphoric 15 acid (150 g.) at 50-60°C. with stirring. The total heating period is 8 hours. The reaction mixture is treated with crushed icc-water to precipitate 4.82 g. of 2-methyl-2-(4-nitrophcnyl)-5-mcthoxy-6,7-dichloro-l-indanone, which melts at 179-180°C. after crystallization 20 from butyl chloride.
Elemental analysis for C17H13C12N04: Calc.: C, 55.76; H, 3.58; N, 3.82; Found : C, 55.83; H, 3.66; N, 3.85.
Step B: 2-Methyl-2-(4-nitrophenyl)-5-hydroxy-6,7-25 dichloro-J.-indanone A stirred mixture of 2-methyl-2-(4-nitrophenyl-5-methoxy-6,7-dichloro-l-indanone (4.82 g., 0.013 mole) and pyridine hydrochloride (50 g.) is heated at 175°C. for half an hour, then poured into crushed ice-water 30 (1 1.). The 2-methyl-2-(4-nitrophenyl)-5-hydroxy-6,7- - 40 - 39927 dichloro-l-indanone, which separates (4.42 g.), melts at 268-270°C. after crystallization from ethanol.
Elemental analysis for C16H11C12NV Calc.i C, 54.57) H, 3.15; N, 3.98; Found t C, 54.18) H, 3.27) N, 4.66.
Step Ci [l-Oxo-2-methyl-2-(4-nitrophenyl)-6,7-dichloro-5-indanyloxy]acetic acid A stirred mixture of 2-methyl-2-(4-nitrophenyl)-5-hydroxy-6,7-dichloro-l-indanone (4.4 g., 0.0126 mole), potassium carbonate (3.49 g.. 0.0252 mole) and ethyl bromoacetate (4.21 g., 0.0252 mole) in dlmethylformamide (150 ml.) is warmed at 55-60°C. for 3 hours, then treated with water (150 ml.) and ION sodium hydroxide solution (7.5 ml., 0.075 mole) and heated at 100°C. for 1.5 hours. The reaction mixture is added slowly to water (1 1.) and 12N hydrochloric acid (15 ml.) to precipitate 2.44 g. of p.-oxo-2-methyl-2-(4-nitrophenyl)-6,7-dichloro-5-indanyloxy]-acetic acid, which melts at 202-205°C. after crystallization from nitromethane.
Elemental analysis for ci8H13cl2N06! Calc.: C, 52.70; H, 3.19; N, 3.41; Found : C, 52.72; H, 3.16; N, 3.30.
EXAMPLE 18. preparation of [l-0xo-2-(4-aminophenyl)-2-methyl- 6,7-dichloro-5-indanyloxy]acetic acid [l-Oxo-2-methyl-2-(4-nitrophenyl)-6,7-dichloro-S-indanyloxy] acetic acid (6.11 g., 0.015 mole) in absolute ethanol (250 ml.) and 36N sulfuric acid (2 ml.) is catal-ytically hydrogenated over 5% palladium on carbon (500 mg.) in a Parr apparatus. After one hour, the reaction 39927 mixture Is filtered, then concentrated in vacuo to a 50 ml. volume. Water (200 ml.) Is added to precipitate the ethyl ester, which is hydrolysed by refluxing in ethanol (200 ml.), ION sodium hydroxide solution (4.5 ml., 0.045 5 mole) and water (100 ml.) for 1.5 hours. The reaction mixture is cooled, concentrated to 1/3 its volume, filtered, and then neutralized with 6N hydrochloric acid to precipitate 1.09 g. of [l-oxo-2-(4-amlnophenyl)-2-methyl-6,7-dichloro-S-indanyloxy]acetic acid, which melts at 235-10 236°C. dec.
Elemental analysis for C18H15C12N04: Calc.: C, 56.86; H, 3.98; N, 3.68; Found : C, 56.46; H, 4.04; N, 3.62.
EXAMPLE 19. 15 preparation of 5-(l-Oxo-2-methy1-2-pheny1-6,7- dichloro-5-indanyloxy-methyl)tetrazole Step A: (l-Oxo-2-methyl-2-phenyl-6,7-dichloro-S-indanyloxy) acetonltrile 2-Methyl-2-phenyl-5-hydroxy-6,7-dichloro-l-indanone 20 (4.61 g., 0.015 mole), chloroacetonitrile (1.13 g., 0.015 mole), potassium carbonate (2.08 g., 0.015 mole), potassium iodide (0.25 g., 0.0015 mole) and acetone (75 ml.) are heated at reflux for 23 hours. The reaction mixture is cooled to 25°C. and concentrated to dryness in vacuo to 25 give an oily residue which, on trituration with water, gives 5.12 g. of (l-oxo-2-methyl-2-phenyl-6,7-dichloro-S-indanyloxy) acetonltrile, which melts at 163-165°C. on crystallization from cyclohexane:benzene, 5:1.
Elemental analysis for C18 H13C12N02: 30 Calc.: C, 62.45; H, 3.78; N, 4.05; Found : C, 63.06; H, 4.03; N, 4.03. - 42 - 39927 Step B: 5-(l-Oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxymethyl)tetrazole (l-Oxo-2-methyl-2-phenyl-6,7-dichloro-S-indanyloxy)-acetonltrile (4.87 g., 0.014 mole), sodium azide (1.09 g., 5 0.0168 mole), ammonium chloride (0.90 g., 0.0168 mole) and dimethylformamide (30 ml.) are heated at 80°c. for 2^ hrs. The reaction mixture is poured into water (500 ml.) and the solution is filtered and acidified with 6N hydrochloric acid to precipitate 2.60 g. of 5-(l-oxo-2-methy1-2-phenyl-10 6,7-dichloro-5-indanyloxymethyl)tetrazole, which melts at 227-229°C. after crystallization from ethanol.
Elemental analysis for C18H14C12N4°25 Calc.: C, 55.54; H, 3.63; N, 14.39; Found : C, 55.29; H, 3.90; N, 14.40. 15 EXAMPLE 20.
Preparation of [l-0xo-2-(4-bromophenyl)-2-methyl-6,7-dichloro-S-indanyloxy]acetic acid Step As 2,3-Dichloro-4-(4-bromophenyl)-acetylanisole To a stirred mixture of 2,3-dichloroanisole (73.5 g., 20 0.414 mole), and 4-bromophenylacetyl chloride (105 g., 0.456 mole) and carbon disulfide (300 ml.) is added portion-wise aluminium chloride (60.9 g., 0.456 mole) with cooling at 0-5°C. The reaction mixture is left at 25°C. for 17 hours, then flushed with nitrogen, and the solid residue 25 treated with crushed ice and 12N hydrochloric acid (80 ml.) to give 147.7 g. of 2,3-dichloro-4-(4-bromophenyl)acetyl-anisole, which melts at 163-164.5°C. after crystallization from benzene:hexane, 1:1.
Elemental analysis for C^5H11BrCl202: 30 Calc.: C, 48.16; H, 2.96; Found : C, 48.38; H, 3.10. - 43 - 39927 Step B: 2',3'-Dichloro-4'-methoxy-2-(4-bromophenyl)-acrylophenone To a suspension of 2,3-dichloro-4-(4-bromophenyl)-acetyl anisole (142.5 g., 0.38 mole) in bis-dimethylamino-5 methane (325 ml.) under nitrogen is added dropwise acetic anhydride (325 ml.) with cooling to maintain the reaction mixture temperature below 40°C. The reaction mixture is stirred at 25°C. for one hour, then poured into crushed ice-water (4 1.) to precipitate 143 g. of 2',3*-dichloro-4* 10 methoxy-2-(4-bromophenyl)acrylophenone, which melts at 110-116°C. after crystallization from benzene:hexane, 1:5. Elemental analysis for C^gH^^BrCljOj: Calc.: C, 49.78; H, 2.87; Found : C, 49.73; H, 2.88. 15 Step C: 2-(4-Bromophenyl)-5-methoxy-6,7-dichloro-l-indanone 2',3'-Dichloro-4'-methoxy-2-(4-bromophenyl)acrylophenone (143 g., 0.37 mole) dissolved in dichloromethane (2 1.) is dribbled into cold 36N sulfuric acid (1 1.) and 20 dichloromethane (1 1.) in an ice bath over 4 hours.
After being stirred for an additional half hour, the reaction mixture is slowly added to crushed ice and the dichloro methane layer is separated, washed with saturated salt solution and concentrated in vacuo to give 134.8 g. of 25 2-(4-bromophenyl)-5-methoxy-6,7-dichloro-l-indanone, which melts at 202-203°C. after trituration with water followed by crystallization from benzene:hexane, 1:1.
Elemental analysis for 0^11^8^1202: Calc.^ C, 49.78; H, 2.87; 30 Found : C, 50.46; H, 3.07. - 44 - 39927 Step D: 2-(4-Bromophenyl)-2-methyl-5-methoxy-6,7-dichloro-l-indanone Sodium methoxide (28.4 g., 0.522 mole) is added to a stirred mixture of 2-(4-bromophenyl)-5-methoxy-6,7-5 dichloro-l-indanone (134.6 g., 0.348 mole), iodomethane (217 ml., 3.48 mole), dry benzene (1700 ml.) and dry dimethylformamide (1700 ml.) under nitrogen in em ice-water bath. The reaction mixture is left to come to ambient temperature over 2 hours, then poured into water 10 (8 1.) to precipitate 92.2 g. of 2-(4-bromophenyl)-2- methyl-5-methoxy-6,7-dichloro-l-indanone, m.p. 200-203°C., which is not soluble in the benzene present.
Elemental analysis for C^H^BrC^Oj: Calc.: C, 51.03; H, 3.28; 15 Found : C, 50.71; H, 3.24.
Step E: 2-(4-Bromophenyl)-2-methyl-5-hydroxy-6,7-dichloro-l-indanone A stirred mixture of 2-(4-bromophenyl)-2-methyl-5-methoxy-6,7-dichloro-l-indanone (5.0 g., 0.0125 mole) and 20 pyridine hydrochloride (50 g.) is heated at 185°C. for one hour, then poured into crushed ice-water (500 ml.). The 2-(4-bromophenyl)-2-methyl-5-hydroxy-6,7-dichloro-l-indanone, which separates (4.68 g.), melts at 221-223°C. after crystallization from etheuiol. 25 Elemental emalysis for C1gH^^BrCl202: Calc.: C, 49.78; H, 2.87; Found :C, 49.18;H, 2.87.
Step F: [l-0xo-2-(4-bromophenyl)-2-methyl-6,7-dichloro-indanyloxy]acetic acid 30 A stirred mixture of 2-(4-bromophenyl)-2-methy1-5- - 45 - 39927 hydroxy-6,7-dichloro-l-indanone (4.48 g., 0.0116 mole), potassium carbonate (3.88 g., 0.0232 mole) and ethyl bromoacetate (3.21 g., 0.0232 mole) in dimethylformamide (100 ml.) is warmed at 55-60°C. for 3 hours, then treated 5 with water (100 ml.) and ION sodium hydroxide solution (5 ml., 0.05 mole) and heated at 100°C. for 2 hours. The reaction mixture is addeu slowly to crushed ice-water (1500 ml.) and 12N hydrochloric acid (50 ml.) to precipitate 3.24 g. of [l-oxo-2-(4-bromophenyl-2-methyl-6,7-10 dichloro-5-indanyloxyJacetic acid, which melts at 171-172°C. after crystallization from nitromethane followed by acetic-acidswater, 3:2.
Elemental analysis for C^gHjjBrCljO^: Calc.: C, 48.68; H, 2.95; 15 Found : C, 48.64; H, 2.93.
EXAMPLE 21.
Preparation of [l-0xo-2-(4-cyanophenyl)-2-methyl-6,7-dichloro-5-indanyloxy]acetic acid Step A: 2- (4-Cyanopi:enyl)-2-methyl-5-r.ethoxy-6,7-20 dichloro-l-indanone 2-(4-Bromophenyl)-2-methyl-5-methoxy-6,7-dichloro-l-lndanone (8.00 g., 0.02 mole), cuprous cyanide (3.94 g., 0.04 mole) and dimethylformamide (100 ml.) are heated at reflux for 8 hours, added to warm sodium cyanide solution 25 (3 g. in 400 ml. water) and extracted with benzene. The benzene solution is dried over anhydrous magnesium sulfate and concentrated in vacuo to give an oily residue. Chromatographing with chloroform on silica gel givos 1.13 g. of 2-(4-cyanophenyl)-2-methyl-5-methoxy-6,7-dichloro-l-30 indanone, which melts at 161-163°C. after crystallization from benzene:hexane, 2:1. - 46 - 39927 Elemental analysis for C^gHjjCljNOj: Calc.: C, 62.45; H, 3.78; N, 4.05; Found < C, 61.37; H, 3.68; N, 3.73.
Step B: 2-(4-Cyanophenyl)-2-methyl-5-hydroxy-6,7-5 dichloro-l-indanone A stirred mixture of 2-(4-cyanophenyl)-2-methy1-5-methoxy-6,7-dichloro-l-indanone (2.08 g., 0.006 mole) and pyridine hydrochloride (20 9.) Is heated at 185°C. for 2 hours, then poured Into Ice-water (300 ml.). The 2-(4-10 cyanophenyl)-2-methyl-5-hydroxy-6,7-dichloro-l-indanone, which separates (1.89 9.), melts at 189-196°C. and is used without further purification.
Step C: [i-Oxo-2-(4-cyanophenyl)-2-methyl-6,7-dichloro-5-indanyloxy]acetic acid 15 A stirred mixture of 2-(4-cyanophenyl)-2-methyl-5- hydroxy-6,7-dichloro-l-indanone (1.8 g., 0.0054 mole), potassium carbonate (1.5 g., 0.0109 mole) and ethyl bromo-acetate (1.8 g., 0.0109 mole) in dimethylformamide (60 ml.) is warmed at 55-60°C. for 3 hours, then treated with water 20 (60 ml.) and ION sodium hydroxide solution (3 ml., 0.03 mole) and heated at 100°c. for 1.5 hours. The reaction mixture is added slowly to ice-water (300 ml.) and 12N hydrochloric acid (5 ml.) to precipitate 160 mg. of [l-oxo-2-(4-cyanophenyl)-2-methyl-6,7-dichloro-S-indanyloxy]acetic 25 acid which melts at 184-5°C. after crystallization from acetic acid:water, 1:1.
Elemental analysis for C19H13C12N04.H20: Calc. : C, 55.90; H, 3.70; N, 3.43; Found : C, 55.77; H, 3.53; N, 4.00. - 47 - 39927 EXAMPLE 22.
Preparation of [l-0xo-2-methyl-2-(4-sulfamoylphenyl)-6,7-dichloro-S-indanyloxy]acetic acid Step A: [l-0xo-2-(4-chlorosulfonylphenyl)-2-methy1-6,7-5 dichloro-5-indanyloxy]acetic acid (l-Oxo-2-methyl-2-phenyl-6,7-dichloro-S-indanyloxy)-acetic acid (0.50 g., 0.0014 mole) is added portionwise with stirring to chlorosulfonic acid (5 ml.) in an ice-water bath. The reaction mixture is stirred at 0°C. for 2 hours, left to 10 come to ambient temperature for 2 hours, then al.fly added to crushed ice to precipitate 0.51 g. of [l-oxo-2-(4-chloro-sulfonylphenyl)-2-methyl-6,7-dichloro-5-indanyloxy]acetic acid, which melts at 209-210°C. after crystallization from acetic-acid:water, 3:2. 15 Elemental analysis for ci8H13C13°4S: Calc. : C, 46.62; H, 2.83; Cl, 22.94; Found : C, 46.67; H, 2.79; Cl, 22.59.
Step B: [l-0xo-2-methyl-2-(4-sulfamoylphenyl)-6,7- \ dichloro-5-indanyloxy]acetic acid 20 [l-Oxo-2-(4-chlorosulfonylphenyl)-2-methyl-6,7- dichloro-5-indanyloxy]acetic acid (2.0 g., 0.0043 mole) is added portionwise to liquid ammonia with stirring. The ammonia is left to evaporate (3 hours). The residue is dissolved in water (400 ml.), filtered, and acidified with 25 12N hydrochloric acid to precipitate 780 mg. of [l-oxo-2-methyl-2-{4-sulfamoylphenyl)-6,7-dichloro-5-indanyloxy]-acetic acid, which melts at 258-260°C. after crystallization from acetic acid.
Elemental analysis for ClgH15cl2N06S.1/4 CH3C02H: 30 Calc. : C, 48.38; H, 3.51; N, 3.05; Found : C, 48.15; H, 3.52; N, 2.86. - 48 - 39927 EXAMPLE 23.
Process for preparing (l-Oxo-2-methyl-2-phenyl-6,7-dichloro-S-indanyloxy ) acetic acid (See British Pat. 1,328,528) A mixture of 1-(l-oxo-2-methy1-2-pheny1-6,7-dichloro-5-5 indanyloxy)-2-nitroethane (3 g.) and 6N hydrochloric acid (100 ml.) is refluxed for 16 hours, cooled and extracted with ether. The ethereal layer is washed with water and extracted with dilute aqueous sodium bicarbonate which upon acidification affords 2.0 g. of (l-oxo-2-methyl-2-phenyl-10 6,7-dichloro-5-indanyloxy)acetic acid which melts at 168-169°C.
EXAMPLE 24.
Process for preparing (l-oxo-2-methyl-2-phenyl-6,7-dichloro-S-indanyloxy)acetic acid 15 To a suspension of sodium hydride (0.24 g., 0.01 mole) in 1,2-dimethoxyethane (10 ml.) is added a solution of 2-methyl-2-phenyl-5-hydroxy-6,7-dichloro-l-indanone (3.07 g., 0.01 mole) in 1,2-dimeth*->xyethane (10 ml.) over a 15-minute period. When the evolution of hydrogen ceases, diethyl-2-20 bromomalonate (2.39 g., 0.01 mole) is added and the mixture is refluxed for 1 hour. The solvent is distilled at reduced pressure. The residual diethyl-2-(l-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy)malonate is dissolved in ethanol (50 ml.). Water (50 ml.) and sodium bicarbonate 25 (2.5 g.) are added and the mixture is refluxed for four hours, cooled, acidified, extracted with ether, washed with water, and dried over magnesium sulfate.
The ether is evaporated at reduced pressure to give crude 2-(l-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy)-30 malonic acid, which is heated at 150°C. until evolution of - 49 - 39927 carbon dioxide ceases, affording (l-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy)acetic acid, which melts at 168-169°C. after recrystallization from nitromethane.
EXAMPLE 25. 5 Process for preparing (l-oxo-2-methyl-2-phenyl-6,7- dichloro-5-indanyloxy)acetic acid A mixture of (l-oxo-2-methyl-2-phenyl-6,7-dichloro-S-indanyloxy) acetonltrile (3.0 g.), from Example 19, Step A, acetic acid (20 ml.), water (5 ml.) and concentrated 10 sulfuric acid (5 ml.) is refluxed for 2 hours then poured into ice-water (100 ml.) affording 2.5 g. of (l-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy)acetic acid, which melts at 168-169°C. after recrystallization from acetic acid. 15 EXAMPLE 26. (1,2-Dichloro-5a,5,6,7,8,8a-hexahydro-8a-pheny1-9-oxofluoroen-3-yloxy)acetic acid Step A: Cyclohexyl(2,3-dichloro-4-methoxyphenyl)ketone A stirred mixture of 2,3-dichloroanisole (88.5 g., 20 0.5 mole) and cyclohexanecarbonyl chloride (81 g., 0.55 mole) in methylene chloride (400 ml.) is cooled to 5°C. and treated with aluminum chloride (74 g., 0.55 mole) during half an hour. The reaction mixture is allowed to warm to 25°C. and after 16 hours is poured into ice-water 25 (1 1.) and hydrochloric acid (200 ml.). The organic phase is washed with 10% sodium hydroxide and saturated salt solution, and dried over magnesium sulfate. After evaporation of the solvent, the product is crystallized from hexane to give 42.3 g. of cyclohexyl (2,3-dichloro-4-methoxy-30 phenyl) ketone, which melts at 97-98°C. - 50 - Elemental analysis for Gi4Hi6C12°2: Calc. s C, 58.55; H, 5.62; Found : C, 58.92; H, 5.64.
Step B: 1-Bromocyclohexyl(2,3-dlchloro-4-methoxyphenyl) 5 ketone Bromine (22.4 g., 0.14 mole) In acetic acid (50 ml.) Is added dropwlse to a stirred solution of cyclohexyl-(2,3-dlchloro-4-methoxyphenyl) ketone (40 g., 0.14 mole) and 30% hydrobromlc acid (0.5 ml.) In acetic acid (400 ml.) 10 during one and a half hours at 25°C. The mixture Is poured Into water (1.5 1.) and sodium bisulfite (10 g.). The product that precipitates is crystallized from cyclohexane to give 47.3 g. of 1-bromocyclohexyl(2,3-dichloro-4-methoxy-phenyl) ketone, which melts at 94-95°C. 15 Elemental analysis for C14H15BrC12°2: Calc. : C, 45.93; H, 4.13; Found : C, 45.77; H, 4.11.
Step Cs l-Cyclohexenyl(2,3-dlchloro-4-methoxyphenyl) ketone 1-Bromocyclohexyl (2,3-dlchloro-4-methoxyphenyl) 20 ketone (47.3 g., 0.13 mole), lithium chloride (16.5 g., 0.39 mole) and dimethylformamide (200 ml.) are heated at 90°C. for two hours, then poured into water (1 1.) to give 36.5 g. of 1-cyclohexenyl (2,3-dichloro-4-methoxyphenyl) ketone, which melts at 126-129°C. after drying at 60°C. 25 under vacuum for 16 hours.
Elemental analysis for C14H14C12°2: Calc. : C, 58.96; H, 4.95; Found : C, 58.87; H, 5.10. - 51 - <39927 Step Ds la,l,2,3,4,4a-Hexahydro-6-methoxy-7,8-dichloro-fluoren-9-one A stirred mixture of 1-cyclohexenyl (2,3-dichloro-4-methoxyphenyl) ketone (34 g., 0.12 mole) a polyphosphoric 5 acid (340 g.) is heated at 90°C. for 17 hours in a resin pot. Crushed ice (1 kg.) is added to precipitate the product which, on crystallization from benzene:cyclohexane, 1:1, gives 18.4 g. of la,l,2,3,4,4a-hexahydro-6-methoxy-7,8-dichlorofluoren-9-one, which melts at 169-171°C. 10 NElemental analysis for C14H14C^2°2! Calc. : C, 58.96; H, 4.95; Found : C, 59.35; H, 5.43.
Step E: la-phenyl-la,l,2,3,4,4a-hexahydro-6-methoxy-7,8-dichlorofluoren-9-one 15 Potassium tert-butoxide (1.69 g., 0.015 mole) in tert-butanol (40 ml.) is added to a refluxing solution of la,1,2,3,4,4a-hexahydro-6-methoxy-7,8-dichloro-fluoren-9-one (2.85 g., O.Ol mole) in dry benzene (50 ml.) and tert-butanol (lO ml.) under nitrogen, and refluxing is 20 continued for 0.5 hour. The reaction mixture is cooled to 25°C., diphenyliodonium chloride (4.75 g., 0.015 mole) is added and refluxing is continued for 2 hours. The reaction mixture is cooled to 25°C., 50 ml. water is added, and the mixture is concentrated to dryness in vacuo 25 to give 3.0 g. of la-phenyl-la,l,2,3,4,4a-hexahydro-6- methoxy-7,8-dichlorofluoren-9-one, which melts at 136-142°C. and is used without further purification.
Step F: la-Phenyl-la,1,2,3,4,4a-hexahydro-6-hydroxy-7,8-dichlorofluoren-9-one 30 A stirred mixture of la-phenyl-la,l,2,3,4,4a-hexahydro- - 52 - 39927 6-methoxy-7,8-dichlorofluoren-9-one (3.0 g., 0.0083 mole) and pyridine hydrochloride (30 g.) 13 heated at 180°C. for 2 hours, then poured into water (800 ml.). The la-phenyl-la-1,2,3,4,4a-hexahydro-6-hydroxy-7,8-dichlorofluoren-9-one, 5 which separates (1.71 g.), melts at 213-215°C. after crystallization from absolute ethanol.
Elemental analysis for ci<)H^6C*202: Calc. : C, 65.72; H, 4.62; Found : C, 66.27; H, 4.78. 10 Step G: (l,2-Dichloro-5a,5,6,7,8,8a-hexahydro-8a-phenyl-9-oxo-fluoren-3-yloxy)acetic acid A stirred mixture of la-phenyl-la,l,2,3,4,4a-hexahydro-6-hydroxy-7,8-dichlorofluoren-9-one (1.7 g., 0.0049 mole), potassium carbonate (1.36 g., 0.0098 mole) and ethyl bromo-15 acetate (1.64 g., 0.0098 mole) in dimethylformamide (50 ml.) is warmed at 55-60°C. for 3 hours, then treated with water (50 ml.) and ION sodium hydroxide solution (2.5 ml., 0.025 mole) and heated at 80°C. for 1.5 hours. The reaction mixture is added slowly to water (500 ml.) and 12N hydro-20 chloric acid (10 ml.) to precipitate 1.51 g. of (1,2- dichloro-5a,5,6,7,8,8a-hexahydro-8a-phenyl-9*-oxo-fluoren-3-yloxy)acetic acid, which melts at 194-196°C. after crystallization from acetic-acid:water, 1:1.
Elemental analysis for C2iHi8C12°4: 25 Calc. : C, 62.24; H, 4.48; Found : C, 62.27; H, 4.56.
EXAMPLE 27.
Preparation of (l-oxo-2-methyl-2-pheny1-6,7-dichloro-S-indanyloxy) acetic acid 30 Step A: Tert-butyl(l-oxo-2-methyl-2-pheny1-6,7-dichloro-S-indanyloxy) acetate - 53 - 39927 A mixture of 2-methyl-2-phenyl-5-hydroxy-6,7-dichloro-l-indanone (9.2 g., 0.03 mole), potassium carbonate (8.29 9., 0.06 mole) and tert-butyl bromoacetate (6.44 g., 0.033 mole) in dimethylformamide (30 ml.) is stirred at 25°C. for two hours. The reaction mixture is poured into cold water (150 ml.) and the tert-butyl (l-oxo-2-methy1-2-pheny 1-6 ,7-dichloro-5-indany loxy) acetate, which separates, is filtered, rinsed with water and dried.
Step B: (l-Oxo-2-methyl-2-phenyl-6,7-dichloro-S-indanyloxy) acetic acid A solution of tert-butyl (l-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy)acetate (1.0 g., 0.00237 mole) in benzene (25 ml.) is treated with methanesulfonic acid (2 drops) and refluxed for half an hour. The reaction mixture is treated with cyclohexane (20 ml.) and cooled, affording (l-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy) acetic acid, which is filtered and dried.
EXAMPLE 28.
Preparation of [l-Oxo-2-methyl-2-(2-thienyl)-6,7-dichloro-5-indanyloxy] acetic acid Step A: 2,2'-Dithienyl iodonium chloride To acetic anhydride (70 ml.) at -20°c. there is added dropwise with stirring fuming nitric acid (27 ml.), then iodine (25 g., 0.1 mole) and trifluoroacetic acid (47 ml., 0.61 mole). The mixture is left to warm to ambient temperature while the iodine dissolves over 3 hours. The solvent is removed by distillation in vacuo, the pot temperature never exceeding 50°C. The residue is dissolved in acetic anhydride (150 ml.), the solution cooled to -10°C. and a mixture of thiophene (63 ml., 0.08 39927 mole), acetic anhydride (350 ml.) and trifluoroacetic acid (50 ml.) is added dropwise over one hour. After cooling at 5°C. for 17 hours, the mixture is distilled in vacuo, the pot temperature never exceeding 50°C. Water (500 ml.) 5 is added to the residue, the solution is filtered and ammonium chloride (21.36 g., 0.4 mole) in water (100 ml.) is added to precipitate 26.6 g. of 2,2•-dithienyl iodonium chloride, which melts at 235-236°C. after crystallization from methanol. 10 Elemental analysis for CgHgClIS2: Calc. : C, 28.24; H, 1.84; Found : C, 28.90; H, 1.92.
Step B: 2-Methyl-2-(2-thienyl)-5-methoxy-6,7-dichloro-l- indanone 15 Potassium tert-butoxide (5.06 g., 0.045 mole) dissolved in tert-butanol (100 ml.) is added to a refluxing solution of 2-methyl-5-methoxy-6,7-dichloro-l-indanone prepared by the method described in Example 5, Steps A to D, (7.35 g., 0.03 mole) in tert-butanol (150 ml.) and benzene (150 ml.), 20 refluxing is continued for 3 hours under nitrogen, then the mixture is cooled slightly and solid dithienyliodonium chloride (16.5 g., 0.05 mole) is added in one portion.
Heating at reflux is continued for 2 hours. The reaction mixture is cooled to 25°C., 100 ml. water added, and the 25 mixture concentrated to dryness in vacuo to give 3.85 g. of 2-methyl-2-(2-thienyl)-5-methoxy-6,7-dichloro-l-indanone, which melts at 145-146.5°C. after trituration with ether and crystallization from benzene:hexane, 1:4. - 55 - 399 27 Elemental analysis for ci5H^2cl2°2S: Calc. : C, 55.06; H, 3.70; Found : C, 55.24; H, 3.77.
Step C: 2-Methyl-2-(2-thienyl)-5-hydroxy-6,7-dichloro -1- indanone A stirred mixture of 2-methyl-2-(2-thienyl)-5-methoxy-2-(2-thienyl)-5-methoxy-6,7-dichloro-l-indanone (3.65 g., 0.0112 mole) and pyridine hydrochloride (36 g.) is heated at 175°C. for half an hour, then poured into crushed ice-water (500ml.). The 2-methy1-2-(2-thienyl)-5-hydroxy-6,7-dichloro-l-indanone, which separates (3.37 g.), melts at 224-226°C. after crystallization from ethanol:water, 2:1.
Elemental analysis for Cj^H10Cl202S: Calc. : C, 53.69; H, 3.22; Found : C, 53.27; H, 3.36.
Step D: [l-Oxo-2-methyl-2-(2-thienyl)-6,7-dichloro-S-indanyloxy] acetic acid A stirred mixture of 2-methy1-2-(2-thienyl)-5-hydroxy-6,7-dichloro-l-indanone (3.13 g., 0.01 mole), potassium carbonate (2.77 g. , 0.02 mole) and ethyl bromo-acetate (3.34 g., 0.02 mole) in dimethylformamide (40 ml.) is warmed at 55-60°C. for 2 hours, then treated with water (40 ml.) and ION sodium hydroxide solution (4 ml., 0.04 mole), and heated at 100°C. for one hour. The reaction mixture is added slowly to crushed ice-water (700 ml.) and 12N hydrochloric acid (10 ml.) to precipitate 1.78 g. of [l-oxo-2-methyl-2-(2-thienyl)-6,7-dichloro-5-indanyloxy]-acetic acid, which melts at 161-162°C. after crystallization from nitromethane. - 56 - 39927 Elemental analysis for C^Hj^C^O^: Calc. : C, 51.78; H, 3.24; Cl, 19.10; Found : C, 51.66; H,. 3.34; Cl, 19.21.
EXAMPLE 29. 5 Where in Example 5, Step A, there is substituted for the 2,3-dichloroanisole em equivalent amount of 2-chloro-3-methylanisole, 2,3-dimethylanisole, 3-methylemisole, or 2-methy1-3-chloroanisole, respectively, and Steps B to D in Example 5 and Steps A to D in Example 28 are carried out 10 as described, there is obtained: [l-oxo-2-(2-thienyl)-2,7-dimethyl-6-chloro-5- indanyloxy]acetic acid; [l-oxo-2-(2-thienyl)-2,6,7-tr imethy1-5-indanyloxy]-acetic acid; 15 [l-oxo-2-(2-thienyl)-2,7-dimethyl-5-ind5nyloxy]- acetic acid; or [l-oxo-2-(2-thienyl)-2,6-dimethyl-7-chloro-5-indanyloxy]acetic acid.
EXAMPLE 30. 20 Where in Example 28, Step A, there is substituted for the thiophene an equivalent amount of 2-methylthiophene, 2-bromothiophene, 2-chlorothiophene, or 2,5-dimethylthio-phene, respectively, and Steps B to D are employed as described, there is obtained: 25 [l-oxo-2-methyl-2-(5-methyl-2-thienyl)—6,7— dichloro-5-Andanyloxy]acetic acid; [l-oxo-2-methyl-2-(5-bromo-2-thienyl)-6,7- dichloro-5-indanyloxy]acetic acid; [l-oxo-2-methyl-2-(5-chloro-2-thienyl)-6,7- 30 dichloro-5-indanyloxy]acetic acid; or - 57 - 39927 [l-oxo-2-methyl-2- (2,5-diinethy 1-3-thienyl) -6,7-dichloro-5-indanyloxy]acetic acid.
EXAMPLE 31.
Preparation of • [l-Oxo-2-(4-aminomethylphenyl)-2-5 methyl-6,7-dichloro-5-indanyloxy] acetic acid Step A: [l-0xo-2- [4-(2-chloroacetamidomethyl)phenyl]-2-methyl-6,7-dichloro-5-indanyloxy]acetic acid Well-pulverized N-hydroxyxnethyl-2-chloroacetaraide (3.37 g., 0.0274 mole) is added portionwise to (l-oxo-2-10 methyl-2-pheny1-6,7-dichloro-5-indanyloxy)acetic acid (10.0 g., 0.0274 mole) in 36N sulfuric acid (100 ml.) and acetic acid (lOO ml.) with stirring at 40-50°C. over half an hour. Additional N-hydroxymethyl-2-chloroacetamide (1.68 g., 0.014 mole) is added over a four-hour period until no starting 15 material remains. After stirring at 25°C. for 16 hours, the reaction mixture is added to crushed ice-water (2 1.) to precipitate 11.9 g. of [l-oxo-2-[4-(2-chloroacetamidomethyl) phenyl]-2-me thy 1-6 ,7-dichloro-5-indanyloxy]acetic acid, which melts at 138-141°C. and is used in the next 20 step without purification.
Step B: Ethyl[l-oxo-2-(4-aminomethylphenyl)-2-methyl-6,7-dichloro-5-indanyloxy]acetate hydrochloride [l-Oxo-2-[4-(2-chloroacetamidomethyl)phenyl]-2-methyl-6,7-dichloro-S-indanyloxy]acetic acid (2.0 g., 0.004 mole), 25 absolute ethanol (20 ml.) and 12N hydrochloric acid (7 ml.) are combined and heated at reflux for 3 hours. On cooling to 5°C. 1.14 g. of ethyl [l-oxo-2-(4-aminomethylphenyl)-2-methyl-6,7-dichloro-5-indanyloxy]acetate hydrochloride is precipitated, it melts at 211-213°c. after crystallization 30 from ethanol. - 58 - 39927 Elemental analysis for C2jH2^Cl2N04«HCl: Calc. : C, 54.98; H, 4.83; N, 3.05; Found : C, 54.39; H, 4.72; N, 2.76.
Step C: [l-oxo-2-(4-aminomethylphenyl)-2-raethyl-6,7-5 dichloro-5-indanyloxy]acetic acid sodium salt Ethyl [l-oxo-2-(4-aminomethylphenyl)-2-methyl-6,7-dichloro-5-indanyloxy]acetate hydrochloride (1.57 g., 0.0034 mole), sodium bicarbonate (1.15 g., 0.0136 mole), absolute ethanol (50 ml.) and water (50 ml.) are combined 10 and heated at reflux for 1.5 hours leaving a solution which is filtered and then neutralized with IN hydrochloric acid (10.26 ml., 0.01026 mole) to precipitate 900 mg. of [l-oxo-2-(4-aminomethylphenyl)-2-methyl-6,7-dichloro-S-indanyloxy] acetic acid sodium salt, which melts at 270-15 271°C. after drying.
Elemental analysis for C^gH^C^NO^Na: Calc. : C, 54.83; H, 3.87; N, 3.37; Found : C, 55.07; H, 4.27; N, 3.20.
The sodium salt of (l-oxo-2-methyl-2-phenyl-6,7-20 dichloro-5-lndanyloxy)acetic acid may be obtained from the product of Example 1 by a similar procedure.
EXAMPLE 32.
Resolution of the Optical Isomers of (l-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy)acetic 25 acid Step A: (+)-isomer A mixture of racemic (l-oxo-2-methyl-2-phenyl-6,7-dichloro-S-indanyloxy) acetic acid (26 g., 0.071 mole) and L-(-)-a-methylbenzylamine (8.6 g., 0.071 mole) is 30 dissolved in hot acetonitrile (250 ml.) and aged at 25°C. for 18 hours. - 59 - 39927 The acetonltrile is decanted from the resultant salt (13.2 g.) , which is recrystallized three times from a minimum volume of 2-propanol, thus affording 1.9 g. of the salt of the pure (+) enantiomer. This is converted 5 to the acid by treatment of the salt with dilute hydro chloric acid and ether. The ethereal phase is washed with water and dried over magnesium sulfate and the ether is distilled off at reduced pressure. The (+)-isomer melts at 163°C. after crystallization from toluene. 10 [a]D25 = +88°C. (C, 2, acetone) Step'B: (-)-Isomer By following substantially the procedure described in Step A using as the reacta' :s partially resolved (l-oxo-2-methyl-2-phenyl-6,7-dlchloro-5-indanyloxy)acetic 15 acid (15.5 g., 0.041 mole), obtained from the acetonltrile mother liquor of Step A, and D-(+)-methylbenzylamine (5.15 g., 0.042 mole) in acetonltrile (150 ml.) and recrystallizing the resultant salt three times from a minimum volume of 2-propanol, there is obtained 2.2 g. of 20 the salt of the pure (-)-enantiomer.
The (-)-isomer melts at 164°C. after crystallization from toluene. » -88° (C, 2, acetone) The compounds of this invention can be administered 25 in a wide variety of therapeutic dosages in conventional vehicles. The present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I and a pharmaceutically acceptable carrier. For example, the compounds can be administered - 60 - 39927 orally in the form of a tablet or by intravenous injection. The daily dosage of the products may be varied over a wide range, for example, in the form of scored tablets containing 2.5, 1, 5, 10, 25, 50, 100, 150, 200, 250 and 500 milligrams 5 of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. These dosages are well below the toxic or lethal dose of the products.
A suitable unit dosage form of the products of this Invention can be administered by mixing 50 milligrams of a 10 [l-oxo-2-aryl or 2-thienyl-2-substituted-5-indanyloxy (or thio)]alkanoic acid (I) of this invention or a suitable salt, ester, amide or 5-tetrazolyl analogue thereof, with 149 mg. of lactose and 1 mg. of magnesium stearate and placing the mixture into a No. 1 gelatin capsule. 15 Similarly, by using more of the active ingredient and less lactose, other dosage forms can be put up in No. 1 gelatin capsules. Should it be necessary compressed tablets, pills, or other desired unit dosages can be prepared to incorporate the compounds of this invention 20 by conventional methods, and, if desired, can be made up as elixirs or as Injectable solutions by methods well known to pharmacists. An effective amount of the drug is ordinarily supplied at a dosage level of from 0.025 mg. to 20 mg./kg., preferably 0.06 mg. to 7 mg./kg., of body 25 weight.
It is also within the scope of this invention to combine two or more of the compounds of this invention in a unit dosage form or to combine one or more of the compounds of this invention with other known diuretics 30 and saluretics or with other desired therapeutic and/or - 61 - nutritive agents in dosage unit form. For example, the compounds of this invention can be combined with antihypertensive compounds, and particularly with an agent such as mothyl-dopa or reserpine. Also a combination or 5 mixture of different indanones of Formula I with each other can be advantageous particularly where one compound has greater diuretic activity and the other has greater uricosuric activity.
The following examples illustrate the preparation lO of representative dosage forms.
EXAMPLE 33.
Preparation of dry-filled capsules containing lO mg. of active ingredient per capsule Per Capsule 15 (l-Oxo-2-mf»thyl-2-phenyl-6,7- dichloro-5-indar.yloxy) -acetic acid 10 mg.
Lactose 189 mg.
Magnesium stearate 1 mg. 20 Capsule (Size No. 1) 200 mg.
The (l-oxo-2-methy1-2-pheny1-6,7-dichloro-5-indanyloxy) acetic acid is reduced to a No. 60 powder and then lactose and magnesium stearate are passed through a No. 60 bolting cloth onto the powder and the combined ingredients mixed 25 for 10 minutes and then filled into a No. 1 dry gelatin capsule.
Similar dry-filled capsules can be prepared by replacing the active ingredient of the above example by a molar equivalent amount of any of the other novel 30 compounds of this invention. - 62 - 39927 EXAMPLE 34.
Parenteral Solution of Sodium (l-oxo-2-methyl-2-pheny1-6,7-dichloro-S-indanyloxy)acetate (l-Oxo-2-methyl-2-phenyl-6,7-dichloro-5-lndanyloxy)-5 acetic acid (1 gin.) is treated with sodium bicarbonate (0.25 g,.) in water (10 ml.) and the mixture stirred and heated to effect solution. The solution is diluted with water to a volume of 50 ml. and sterilized by autoclaving at 120°C. for one hour. 10 EXAMPLE 35.
Dry-filled capsules containing 10 mg. of active ingredient and 0.125 mg. of reserplne per capsule Per Capsule (l-0xo-2-methyl-2-pheny1-6,7-15 dichloro-5-indanyloxy)- acetic acid lO mg.
Reserplne 0.125 mg.
Lactose 188.875 mg.
Magnesium stearate 1 mg. 20 Capsule (Size No. 1) 200 mg.
The (l-oxo-2-methyl-2-phenyl-6,7-dichloro-S-indanyloxy) acetic acid and reserplne are united and reduced to a No. 60 powder and then lactose and magnesium stearate are passed through a No. 60 bolting cloth onto the powder 25 and the combined ingredients are admixed for ten minutes and then filled into a No. 1 dry gelatin capsule.
Similar dry-filled capsules can be prepared by replacing the indanyloxyacetic acid ingredient of the above example by any of the compounds of this invention. - 63 - M 399 27 EXAMPLE 36.
Dry-filled capsules containing lO mg. of active ingredient and 250 mg. of levo-3-(3,4-dihydroxy-phenyl)-2-methylalanine 5 Per Capsule (l-Oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy)-acetic acid 10 mg.
Levo-3-(3,4-dihydroxyphenyl)-lO 2-methylalanine 265 mg.
Lactose 124 mg.
Magnesium stearate 1 mg.
Capsule (Size No. 0) 400 mg.
The (l-oxo-2-methyl-2-phenyl-6,7-dichloro-5-15 indanyloxy)acetic acid and levo-3-(3,4-dihydroxyphenyl)-2- alanine are united and reduced to a No. 60 powder and then lactose and magnesium stearate are passed through a No. 60 bolting cloth onto the powder and the combined ingredients admixed for ten minutes and then filled into a No. 0 dry 20 gelatin capsule.
EXAMPLE 37.
Dry-filled capsules containing 50 mg. of active ingredient per capsule Per Capsule 25 (l-0xo-2-methyl-2-(2-thienyl)- 6,7-dichloro-5-indanyloxy)-acetic acid 50 mg.
Lactose 149 mg.
Magnesium stearate l mg. 30 Capsule (Size No. 1) 200 mg. - 64 - 39927 • The (l-oxo-2-methyl-2-(2-thienyl)-6,7-dichloro-5-lndanyloxy)acetic acid Is reduced to a No. 60 powder and then lactose and magnesium stearate are passed through a No. 60 bolting cloth onto the powder and the combined ingredients admixed for 10 minutes and then filled into a No. 1 dry gelatin capsule.
Similar dry-filled capsules can be prepared by replacing the active ingredient of the above Example by a molar equivalent amount of any of the other novel compounds of this invention.
Parenteral Solution of sodium(l-oxo-2-methyl-2-(2-thienyl)-6,7-dichloro-5-indanyloxy)acetate (l-Oxo-2-methyl-2-thienyl-6,7-dichloro-S-indanyloxy)-acetic acid (1 gn.) is treated with sodium bicarbonate (0.25 gm.) in water (10 ml.) and the mixture stirred and heated to effect solution. The solution is diluted with water to a volume of 50 ml. and sterilized by autoclaving at 120°C. for one hour.
EXAMPLE 39.
Dry-filled capsules containing 25 mg. of active ingredient and 0.125 mg. of reserplne per capsule Per Capsule (l-Oxo-2-methyl-2-(2-thlenyl)- EXAMPLE 38. 6,7-dichloro-5-indanyloxy)- acetic acid 25 mg. 0.125 mg. 173.875 mg.
Reserplne Lactose Magnesium stearate 1 mg.
Capsule (Size No. 1) 200 mg. - 65 - 39927 The (l-oxo-2-methy1-2-(2-thienyl)-6,7-dichloro-5-indanyloxy)acetic acid and reserplne are united and reduced to a No. 60 powder and then lactose and magnesium stearate are passed through a No. 60 bolting cloth onto 5 the powder and the combined ingredients are admixed for ten minutes and then filled into a No. 1 dry gelatin capsule.
Similar dry-filled capsules can be prepared by replacing the indanyloxyacetic acid ingredient of the 10 above example by any of the compounds of this invention.
EXAMPLE 40.
Dry-filled capsules containing 10 mg. of active ingredient and 250 mg. of levo-3-(3,4-dihydroxyphenyl) -2-methylalanine 15 Per Capsule (l-0xo-2-methyl-2-(2-thienyl)-6,7-dichloro-S-indanyloxy)-acetic acid 10 mg.
Levo-3-(3,4-dihydroxyphenyl)-2-20 methylalanine 250 mg.
Lactose 139 mg.
Magnesium stearate 1 mg.
Capsule (Size No. 0) 400 mg.
The (l-oxo-2-methyl-2-(2-thienyl)-6,7-dichloro-5-25 indanyloxy)acetic acid and levo-3-(3,4-dihydroxyphenyl)-2- alanine are united and reduced to a No. 60 powder and then lactose and magnesium stearate are passed through a No. 60 bolting cloth onto the powder and the combined ingredients admixed for ten minutes and then filled into a No. 0 dry 30 gelatin capsule. - 66 -

Claims (43)

CLAIMS:-
1. A compound of the formula: 3992? or N II N in which R is o or <5. A is oxygen or sulphur; R is C^_5 alkyl, C3_^ alkenyl, phenyl-(C1-3 alkyl), phenyl-(C3_5 alkenyl), aryl, substituted aryl, cycloalkyl or cycloalkyl-(C1_5 alkyl); R* is hydrogen, C^_^ alkyl or aryl; or R* and R are joined 10 together to form a C^_4 bivalent hydrocarbon chain; Y is alkylene or haloalkylene containing from 1 to 4 carbon atoms; X3 is hydrogen, nitro, hydroxy, C1-5 alkyl, C^_j. alkoxy, cycloalkyl, halo, amino, cyano, sulfamoyl, methanesulfonyl, chlorosulfonyl, aminomethyi, acylamino 15 or acylaminomethyl; X^ is hydrogen, C^_^ alkyl, amino- Q methyl or halogen; X is hydrogen or C^_^ alkyl and 1 2 X is hydrogen, halogen or methyl and X is halogen, 1 2 methyl or trihalomethyl; or X and X are joined together to form a bivalent hydrocarbon chain containing 3 or 4 20 carbon atoms; and the non-toxic, pharmacologically - 67 - acceptable salts, amides, anhydrides and esters thereof.
2. A compound of the formula: X o II hocch2o in which R° is 5 R is C^_5 alkyl; each of X1 and X2, which are similar or dissimilar, is chlorine or methyl; X3 is hydrogen, nitro, hydroxy, alkyl, C^_5 alkoxy, cycloalkyl, halo, amino, cyano, sulfamoyl, methanesulfonyl, chlorosulfonyl or aminomethyi; X7 is hydrogen, alkyl, halogen or aminomethyi; O 10 and X is hydrogen or Cj_^ alkyl; and the non-toxic, pharmacologically acceptable salts thereof.
3. A compound according to Claim 2 in which X3 is hydrogen, methyl, chlorine, fluorine, hydroxy, amino or 7 ft aminomethyi; X is hydrogen; and X is hydrogen. 15
4. (l-Oxo-2-methyl-2-pheny1-6,7-dichloro-S- indanyloxy) acetic acid.
5. {-) (l-Oxo-2-methyl-2-pheny1-6,7-dichloro-S-indanyloxy) acetic acid.
6. (+) (l-Oxo-2-methyl-2-phenyl-6,7-dichloro-5- 20 indanyloxy)acetic acid.
7. The sodium salt of the compound according to Claim 4.
8. [l-0xo-2-(4-chlorophenyl)-2-methy1-6,7-dichloro-S-indanyloxy] acetic acid. - 68 - 39927
9. [l-Oxo-2-(4-fluorophenyl)-2-methy1-6,7-dichloro- 0 5-lndanyloxy]acetic acid.
10. [l-0xo-2-(2-thienyl)-2-raethyl-6,7-dichloro-S-indanyloxy] acetic acid.
11. [l-Oxo-2-(4-aminophenyl)-2-methy1-6,7-dichloro-S-indanyloxy] acetic acid.
12. A compound of the formula: X" 0 10 15 R is alkyl; each of X* and X2 is methyl or chloro; X3 is hydrogen, nitro, hydroxy, Cj_5 alkyl, cl_5 alkoxy, cycloalkyl, halo, amino, cyano, sulfamoyl, methanesulfonyl, chlorosulfonyl or aminomethyi; X7 is O hydrogen, C^_,. alkyl or halogen; and x is hydrogen or Cj_5 alkyl; or a pharmacologically acceptable salt thereof.
13. A compound according to Claim 12 in which R° is v3 ..7 or 2o X3 is hydrogen, methyl, chlorine or fluorine; and X7 and X® are hydrogen. - 69 - * 39927
14. 5-(l-Oxo-2-metny1-2-pheny1-6,7-dichloro-5-lndanyloxymethyltetrazole.
15. A pharmaceutical composition comprising a therapeutically effective amount of a compound as claimed 5 in Claim 1 and a pharmaceutical^ acceptable carrier.
16. A composition as claimed in Claim 15, in which the said compound is a compound as claimed in Claim 2.
17. A composition as claimed in Claim 15, in which, in the formulae R° is X3 is hydrogen, methyl, chlorine or fluorine; X7 is 0 hydrogen and X is hydrogen.
18. A composition as claimed in Claim 16 in which the compound is (l-oxo-2-methy1-2-pheny1-6,7-dichloro-5- 15 indanyloxy)acetic acid.
19. A composition as claimed in Claim 16, in which the compound is a compound as claimed in any one of Claims 3 and 5-14.
20. A composition as claimed in any one of Claims 20 16-19, in orally administrable form.
21. A composition as claimed in any one of Claims 16-19, in parenterally injectable form.
22. A composition as claimed in Claim 20, in the form of a tablet or capsule. 25
23. A composition as claimed in any one of Claims 16-22, that also contains a second pharmaceutically active compound. - 70 - 39927
24. A process for preparing a compound of the formula in which R is
25. A process as claimed in Claim 24, in which, in 1 2 the formulae, Y is methylene, A is oxygen, and R, X , X o o and X are as defined in Claim 2, X is hydrogen, nitro, \ . C^_5 alkyl, C1-5 alkoxy, cycloalkyl, halo, amino, cyano, 7 5 sulfamoyl, methanesulfonyl; and X is hydrogen, C^_^ alkyl or halogen^
26. A modification of the process claimed in Claim 24 and 25 in'whibh, in the second formula 0 B 3 (i.e. ZCH2 —C-ORJ) , 10 Z is halo and R3 is t-butyl and the t-butyl ester produced in the first step is pyrolysed to form the desired product.
27. A process as claimed in Claim 25 in which R° is X3 .X7 - <5 X8 X3 is hydrogen, methyl, chlorine or fluorine; R is C^_5 1 2 15 alkyl; and each of X and X is methyl or chlorine.
28. A process as claimed in Claim 27 in which the starting materials are chosen so that the product is (l-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy)acetic acid, and the base used is potassium carbonate. 20
29. A process as claimed in Claim 26 in which the starting materials are chosen so that the product is (l-oxo-2-methyl-2-phenyl-P,7-dichloro-S-indanyloxy)acetic acid, and the base used is potassium carbonate.
30. A process for preparing a compound of the 25 formula: - 72 - 39927 O 11 a a HO-CC(R°)2C(R°)2A 11 2 In which A, R, R , X and X are as defined in Claim 1, O ft and R is as defined in Claim 24 and each R is hydrogen, Q methyl or ethyl, the four R s together containing O, 1 or 2 carbon atoms, that comprises treating a compound of the formula: 9 with a compound of the formula: C(R8)2— C(R8)2 C« 0 10 in the presence of a base, and acidifying the resulting ester to obtain the desired compound.
31. A process for preparing a compound of the formula: ,2 IS" in which A, r, r1, x1 and X2 are as defined in Claim 1 and R° is as defined in Claim 24 that comprises treating a compound of the formula: - 73 - 3 0 9 27 lo with a haloacetonitrile in the presence of a base and treating the resulting intermediate nitrile with sodium azide and ammonium chloride to produce the desired product.
32. A process according to Claim 31 that comprises reacting 2-methyl-2-phenyl-5-hydroxy-6,7-dichloro-l-indanone with chloroacetonitrile in the presence of potassium carbonate and treating the intezmediate nitrile with sodium azide and ammonium chloride to produce 5-(l-oxo—2-methyl-2—phenyl-6,7-dichloro-S-indanyloxynethyl)-tetrazole.
33. A process for preparing a compound of the formula: 15 rjocch2a that comprises treating a compound of the formula: 0 II r"0cch2a - 74 - 398 27 with an alkylating agent of the formula RZ, where R°, R3 and Z are as defined in Claim,24 and A, R, R1, X1 and X2 are as defined in Claim 1.
34.' A process for preparing a compound of the 5 formulai , in which A, R, R1, Y, X1 and X2 are as defined in Claim 1, that comprises treating a compound of the formula: with an ether-cleaving reagent.
35. A process for preparing a compound of the formula: - 75 - 39927 O II hocya • 2 NH2 ■ Vn N N n_N^-C"2A~^^ 112 in which A, R, R , Y, X and X are as defined in Claim 1, that comprises reducing a compound of the formula: ,2
36. A process for preparing a compound of the formula: so2nh2 or - 76 - 39827 in which A is oxygen or sulphur; R is alkyl, C3_5 alkenyl, cycloalkyl or cycloalkyl (Cj_5 alkyl)? and R* is hydrogen, Cj_j alkyl or aryl, or R* and R are joined together to form a alkylene radical; and X1 is hydrogen, halogen or methyl; and X2 is halogen, methyl or trihalomethyl; or X* and X2 are joined together to form a C3..4 bivalent hydrocarbon chain; that comprises reacting a compound of the formula: 12 1 wherein X , X , A, Y, R and R are as above defined with chlorosulfonic acid to form a compound of the formula: :t!> !»:i7 112 where A, R, R , X , X and Y are as above defined and then reacting the latter compound with ammonia to form the desired product.
37. A process for preparing a compound of the formula: hocch2o In in which R° is as defined in Claim 24 and R, R1, X1 and X2 are as defined in Claim 1, that comprises reacting a compound of the formula: 2 X* 0 J. HO - 78 - 3 9 9 27 10 1 9 /> 1 where X , X , R , R and R are as above defined with 1-halo-2-nitroethane to form a compound of the formula: ,2 y2NCH2CH20 1 « where X » X , R , R and R are as above and then hydrolysing the latter compound to form the desired product.
38. A process for preparing a compound of the formula: ,2 ! H0CCH20 in which R° is as defined in Claim 24 and R, R1, x1 and X2 are as defined in Claim 1, that comprises reacting a compound of the formula: where X , X , R , R and R are as above defined with a malonic ester of the formula: 15 r-o2c ch- r"o2c - 79 - 39 9 37 lo where R" is C1-5 alkyl to form a compound of the formula: 2 xr o ■ xYV CR-02c)2CH0_l^iJ 1^r1 \ 2 o i where X , X , R R, R and R" are as above defined; hydrolysing the latter compound to form a compound of the formula: J2 (h02c)2ch0 where X^# X2, R°, R, R^" are as above defined and decarboxyl-ating the latter compound to form the desired product.
39. A process for preparing a compound of the formula: 2 X 0 hocch2a VW •\)-C in which R° is as defined in Claim 24 and A, R, R1, X1 and 2 X are as defined in Claim 1, that comprises reacting a compound of the formula: - 80 - I 39927 X ,7 O HA X R R R p 1 5 10 with a haloacetonltrlle In the presence of a base followed by hydrolysis of the nitrile Intermediate.
40. A pharmaceutical composition as claimed In Claim 23, In which the second pharmaceutically active agent is an antihypertensive agent.
41. A pharmaceutical composition as claimed in Claim 40 in which the antihypertensive agent is reserplne.
42. A pharmaceutical composition as claimed in Claim 40 in which the antihypertensive agent is levo-3-(3,4-dihydroxyphenyl)-2-methylalanine.
43. A pharmaceutical composition as claimed in any one of Claims 15-22, that comprises a therapeutically effective amount of two or more different compounds as claimed in any one of Claims 1-14. **• V F. R. KELLY & CO. AGENTS FOR THE APPLICANTS - 81 -
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KR870000034B1 (en) 1987-02-07
ATA807874A (en) 1977-07-15
AT342036B (en) 1978-03-10
IL45779A0 (en) 1974-12-31
AR213170A1 (en) 1978-12-29
NL7412829A (en) 1975-04-15
RO71480B (en) 1983-07-30
AR213840A1 (en) 1979-03-30
AR213065A1 (en) 1978-12-15
DE2448454C2 (en) 1985-08-29
GB1474460A (en) 1977-05-25
CH613933A5 (en) 1979-10-31
SU738509A3 (en) 1980-05-30
DE2463215C2 (en) 1986-03-13
GB1474459A (en) 1977-05-25
NL187854C (en) 1992-02-03
AU7391674A (en) 1976-04-08
BG28255A3 (en) 1980-03-25
CH610290A5 (en) 1979-04-12
FR2247218A1 (en) 1975-05-09
IE39927B1 (en) 1979-01-31
EG11741A (en) 1977-12-31
DE2448454A1 (en) 1975-04-24
HU169587B (en) 1976-12-28
MY8100163A (en) 1981-12-31
CA1063125A (en) 1979-09-25
YU272774A (en) 1983-06-30
NL9100396A (en) 1991-06-03
DD118075A5 (en) 1976-02-12
IL45779A (en) 1978-06-15
RO71480A (en) 1983-08-03
CS190439B2 (en) 1979-05-31
CY1074A (en) 1980-10-24

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