JPS5939415B2 - Process for producing [1-oxo-2-aryl or thienyl-2-substituted-5-indanyloxy (or thio)]alkanoic acid - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention generally relates to [1-oxo-2-aryl or thienyl-2-substituted (and 2-aryl-2,3-disubstituted)
The present invention relates to a process for the preparation of a novel class of compounds that can be described as -J-substituted (and 6,7-disubstituted)-5-indanyloxy (or) thio]alkanoic acids.

These compounds are collectively referred to as ゛ゞ[1-oxo-2-
Pharmacological studies have shown that the products of the present invention are The products of the invention are also useful in the treatment of hypertension. Furthermore, the products of the invention are also useful in the treatment of hypertension.
These compounds are also capable of maintaining uric acid concentrations in the body at predetermined levels when administered in therapeutic doses in common vehicles. Or even reduce uric acid levels. Many currently available diuretics and salt excreters, when administered, have a tendency to induce hyperuricemia, precipitate uric acid and/or sodium urate in the body, and cause mild to severe gout. are doing.

The compounds of the present invention provide an effective means of treating patients in need of diuresis and salt excretion treatment without the risk of inducing gout. In fact, when used in appropriate amounts, the compounds of the present invention can be used as UricOsurica
gent). Thus, an object of the present invention is to provide a method for producing the above-mentioned 2-aryl or thienyl substituted indanones. 2- of the present invention
Aryl or thienyl substituted indanones have the following structural formula.

of [In the formula, RO is ;[-3)-)TAO→Otsu].

X3 is hydrogen, halogen such as chlorine, bromine, fluorine or iodine, lower alkyl such as methyl, ethyl, n-propyl, n-butyl, tert-butyl, n-pentyl etc., cycloalkyl such as cyclopentyl or cyclohexyl, lower alkoxy such as methoxy , nitro, hydroxy, amino, cyano, aminomethyl, sulfamoyl, methanesulfonyl or chlorosulfonyl, acylamino such as acetamide, acylaminomethyl such as chloroacetylaminomethyl. X7 is hydrogen, lower alkyl such as methyl, halogen such as chlorine, bromine, fluorine or iodine or aminomethyl. X8 is hydrogen or lower alkyl such as methyl. A is oxygen or sulfur. R is lower alkyl containing 1 to 5 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, etc.; cycloalkyl, such as cyclopentyl and cyclohexyl; cycloalkyl, cycloalkyl lower alkyl containing ~6 carbon atoms, such as cyclopropylmethyl, cyclopentylmethyl, etc., 3 to 5
lower alkenyl containing 4 carbon atoms, e.g. allyl,
Phenyl lower alkyl (the alkyl moiety contains 1 to 3 carbon atoms) such as 1,2 or 3-butenyl, 1,2,3- or 4-pentenyl, such as benzyl, phenethyl, phenylpropyl, etc. Alkenyl such as cinnamyl, aryl or substituted aryl such as phenyl, haloaryl, lower alkylaryl or lower alkoxyaryl or thienyl. R1 is hydrogen, lower alkyl or aryl such as phenyl. R and R1 together with the carbon atoms to which they are attached may form a hydrocarpylene ring containing 3 to 6 carbon atoms. X1 is hydrogen, methyl or halogen such as chlorine, bromine, fluorine and the like. X2 is methyl,
Trihalomethyl or halogens such as chlorine, bromine, fluorine, etc. X1 and X2 may be taken together to form a hydrocarpylene chain containing 3 to 4 carbon atoms, such as trimethylene, tetramethylene, 1,3-butadienylene, and the like. Y is an alkylene or haloalkylene group having from 1 to about 4 carbon atoms between the oxy (or thio) and carpoxy groups, such as methylene, ethylene, propylidene, isopropylidene, isobutylidene, fluoromethylene, and the like. ] The above-mentioned indanone also includes its non-toxic pharmaceutically usable salts, amides, anhydrides and ester derivatives. Preferred compounds of the invention are those in which A is oxygen, Y is methylene, and R. RO, R1,
X1, X2, X3, X7 and X8 are the formulas (
This is the compound of 1).

Particularly preferred compounds of the invention have the following structural formula: 1-oxo-2-aryl-2-monosubstituted-6,7-disubstituted-5-
Indanyloxyacetic acid and its non-toxic pharmacologically usable salts.

where R2 is lower alkyl containing 1 to 3 carbon atoms, such as methyl, ethyl, n-propyl or isopropyl, or cycloalkyl containing 3 to 6 carbon atoms, such as cyclopropyl, cyclopentyl or cyclohexyl. .

X4 and R5 are the same or different groups selected from methyl or chlorine. X6 is hydrogen, methyl, chlorine or fluorine. Compounds of the aforementioned class are particularly good diuretics/
Shows salt excretion activity.

Such compounds also maintain a predetermined degree of uric acid concentration in the body or even cause a decrease in uric acid concentration. Several methods can be used to make the 2-aryl or 2-thienyl substituted indanones of the present invention.

One method is to use the formula RZ, where z is halogen.

) with the alkylating agent of structural formula () [1-oxo-2
Consists of 2-alkylation of -aryl or 2-thienyl-5-indanyloxy (or thio)]alkanoic acids or esters. This reaction is carried out by first treating a [1-oxo-2-aryl or 2-thienyl-5-indanyloxy (or thio)]alkanoic acid or ester with a suitable base, such as an alkali metal hydride such as sodium hydride, potassium This is carried out by treatment with an alkali metal alkoxide such as tertiary butoxide, sodium methoxide, etc. or an alkali metal amide such as sodium amide, lithium amide, etc. The resulting carbanion is then treated with an alkylating agent RZ. Any solvent that is inert or substantially inert to the reactants may be used. Suitable solvents include, for example, 1,2-dimethoxyethane, tertiary butanol, benzene, dimethylformamide, and the like. The reaction is about 0-150
It may be carried out at temperatures in the range of °C. Generally, the reaction is about 0-5
It is carried out at a temperature of 0°C. The following equation illustrates this method. During the ceremony,
A. R. RO, R1, X1, X2, X3, X7, X8,
z and Y are as described above.

R3 is hydrogen or lower alkyl. [1] of the present invention
-Oxo-2-aryl-2-mono-substituted-5-indanyloxy(or thio)]alkanoic acid is prepared using the appropriate 2-ary*cur or 2-thienyl-2-monosubstituted- It consists of reacting 5-hydroxy (or mercapto)-intason () with a haloalkanoic acid of formula R3OCYZ or an ester thereof.

In the formula, all substituents are as described above.

Generally, the reaction is carried out in the presence of a base such as an alkali metal carbonate, hydroxide or alkoxide such as potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, sodium methoxide and the like. Any solvent that is inert or substantially inert toward the reactants and in which the reagents are reasonably soluble may be used. For example, acetone, ethanol and dimethyl formamide have been found to be particularly advantageous solvents. The reaction may be carried out at a temperature ranging from about 25°C to the reflux temperature of the particular solvent used. If you use a haloalkanoic acid ester,
The resulting ester is hydrolyzed to the free acid by methods well known in the art. When R3 is a tertiary butyl group, the tertiary butyl ester may be subjected to acid catalytic pyrolysis such as heating in the presence of a strong acid, e.g. p-toluenesulfonic acid, sulfuric acid, gaseous hydrogen chloride, etc. Thus, acid can be obtained. Generally, pyrolysis is carried out by heating at a temperature of about 70-140°C, preferably 80-100°C. Thermal decomposition may also be carried out without a solvent or in the presence of a suitable non-aqueous medium in which the reactants are reasonably soluble, such as benzene, toluene, xylene, and the like. Two further methods of preparing compounds of formula (1) are illustrated by the following schemes.

The first method involves reacting a 5-hydroxy (or mercapto) compound [(a) above] with nitroethane to form a 2-nitroethane intermediate [(b) above], which then to obtain the final product (1).

The preparation of intermediates of formula (b) is described in British Patent No. 1325528
No.

In another method, a 5-hydroxy (or mercapto) compound [(a) above] is combined with a malonic ester (R7
7 is lower alkyl, preferably ethyl.

) to form a malonic acid ester intermediate (c), which is then hydrolyzed to form another intermediate [formula (a)].
and then decarboxylation of the latter compound to form the final product (1). The 2-aryl- or 2-thienyl-substituted indanones of the invention in which the alkylene chain Y contains 2 linear carbon atoms between carboxy and oxy (or thio) are preferably prepared by heating the solution at reflux temperature. The corresponding 5-hydroxy (or mercapto) compound [() below] is reacted with propiolactone or a suitably substituted propiolactone in the presence of a base such as an aqueous solution of sodium hydroxide and then as follows. is prepared by acidifying the carboxylate intermediate formed to the desired acid.

The following equation shows this reaction. All substitutions are as described above. M is a cation derived from an alkali metal hydroxide or carbonate, such as a sodium or potassium cation. 2-aryl or 2-thienyl-2-substituted 5-hydroxy (or mercapto)-
1-Indanone [above ()] also exhibits diuretic, salt excretion and UricOsuric activities and is itself a novel compound and it is a substituted compound of the corresponding substituted 2-aryl or 2-thienyl-
5-lower alkoxy or aralkoxy (or lower alkyl or aralkylthio)-1-intason is obtained by treatment with an ether cleaving agent such as aluminum chloride, pyridine hydrochloride, sodium in aqueous solution, etc.

When using aluminum chloride, the solvent is heptane,
Carbon disulfide, methylene chloride, etc. When using pyridine hydrochloride, it is not necessary to use a solvent. 2- of the present invention in which the aryl substituent X3 is hydroxy
The aryl-substituted indanone has the corresponding acid [formula (1) above] in which the aryl substituent X3 is methoxy and the formula (in the formula,
All substituents are as described above.

) with hydrogen bromide in acetic acid. A preferred method of preparing 5-hydroxy or 5-mercapto compounds of formula () in which the aryl substituent X3 is a lower alkoxy group consists of hydrogenolysis of the corresponding 5-aralkoxy (or thio) compound.

The hydrogenolysis reaction is carried out in a hydrogenation apparatus in a liquid agent such as methanol, ethanol, acetic acid, etc. in the presence of a catalyst such as 5% palladium on carbon or platinized carbon under a pressure of about 1,0 to 40 atmospheres. done advantageously. 2- to obtain 5-lower alkoxy or 5-aralkoxy (or lower alkylthio or aralkylthio) compounds () (described below) that exhibit diuretic, salt excretion and uricosuric activity.
Arylation or 2-thienylation involves converting the corresponding 2-monosubstituted compound () into a diphenyl iodonium salt of the formula [RO]21Z (where RO, ) or by treatment with a suitable reagent such as a thienyl compound.

This reaction is carried out by first treating the monosubstituted compound (2) with a suitable base such as an alkali metal hydride such as sodium hydride, an alkali metal alkoxide such as sodium methoxide, potassium tert-butoxide, etc. or sodium amide, lithium amide, etc. This is done by treatment with an alkali metal amide such as. Next, the obtained carbanion is treated with an arylating agent. Any solvent that is inert or substantially inert to the reactants used may be used. Suitable solvents include, for example, 1.2 dimethoxyethane, tertiary butanol benzene, dimethyl formamide, and the like. The reaction is carried out at a temperature in the range of about 25-150°C. The following equation illustrates this method. During the ceremony,
All substitutions are as described above.

R4 is lower alkyl or aralkyl. The t-lower alkoxy or aralkoxy (or lower alkylthio or aralkylthio) reagents [(a) above] used in this particular method are known compounds and are described in U.S. Pat. Nos. 3,668,241 and 3,704,314. The corresponding 5-hydroxy (or mercapto) intason is obtained by known etherification methods.

A second method for preparing ethers of formula ( ) (above) involves converting the corresponding 2-aryl or 2-thienyl compound ( ) (below) into the appropriate formula RZ, where R and Z are as previously described.

) with an alkylating agent. This reaction is carried out by first treating the 2-aryl or 2-thienyl compound (2) with a suitable base, such as an alkali metal hydride such as sodium hydride, an alkali metal alkoxide such as sodium methoxide, potassium tert-butoxide, etc., or a sodium amide. , by treatment with an alkali metal amide such as lithium amide and the like. The resulting carbanion is then treated with an alkylating agent RZ. Any solvent that is inert or substantially inert to the reactants may be used. Suitable solvents include, for example, 1
- Includes 2-dimethoxyethane, tertiary butanol, benzene, dimethyl formamide, etc. The reaction is about 0
It may be carried out at temperatures of -150<0>C. The following equation illustrates this method. In the formula, all substituted components are as described above.

One method for producing the intasone intermediate [(a) below] useful in producing the 2-aryl substituted intasones of the present invention is by treatment with an acid acid such as concentrated sulfuric acid, polyphosphoric acid, boron trifluoride, etc. Cycloalkylation of 4-lower alkoxy (or lower alkylthio) substituted [2-alkylidenealkanoyl (or 2-alkylidenealkanoyl)]benzene
tiOn). The reaction takes place at approximately 0°C to 60°C.
It can be carried out at a temperature of The following equation illustrates this method. In the formula, R
5 is a substituted phenyl group of formula (1) or R as described above.

All other substitutions are as described above. The 4-lower alkoxy (and lower alkylthio) monosubstituted [(2
-Alkylidenealkanoyl (or 2-alkylidenealkanoyl)]benzene (described above) can be produced by several methods.

Nuclear lower alkoxy (and lower alkylthio)-4-(2
- methylenealkanoyl (and 2methylenealkanoyl)benzene (one method limited to (a) below is the nuclear lower alkoxy mono(or lower alkylthio)-4
- treatment of the alkanoylbenzene (or 4-alkanoylbenzene) () with dimethylamine hydrochloride and paraformaldehyde and then heating or heating the Mannitz compound (a) thus obtained; treatment with aqueous sodium bicarbonate or anhydrous dimethylformamide to obtain the desired compound (a). The following equation illustrates this method. In the formula, all substituents are as described above.

4-lower alkoxy (and lower alkylthio) substitution (2
-alkylidenealkanoyl)benzene (R1-methyl), all of the substituents in 4-lower alkoxy (or lower alkylthio)-substituted 2-bromo-2-methylpropionylbenzene are as described above.

[4-mono-lower alkoxy (and lower alkylthio) substitution]
Alkanoyl and aralkanoylbenzenes (b) are known compounds or alkanoyl halides or aralkanoyl halides in the presence of Friedel-Crafts catalysts such as aluminum chloride and nuclear lower alkoxy (or lower alkylthio) substituted benzenes (
M) ★★ [(X) below] consists of treating with a dehydrobromating agent such as lithium bromide, lithium chloride, etc.

Suitable solvents for this reaction include dimethyl formamide and the like. This reaction is advantageously carried out at a temperature in the range of about 50-120<0>C. The following equation shows this reaction. 4
The third method for producing mono-lower alkoxy (and lower alkylthio) [2-alkylidenealkanoyl (or alkylidenealkanoyl)]benzene (c) is
It consists of treating a mono-lower alkoxy (or lower alkylthio) substituted alkanoyl or aralkanoylbenzene (b) with a methylene insertion reagent such as bisdimethylaminomethane in the presence of an alkanoic anhydride such as acetic anhydride.

The reaction is carried out at a temperature of about 25-50°C. Any solvent that is inert or substantially inert to the reactants used may be used. However, methylene insertion reagents such as bis-dimethylaminomethane generally serve as solvent media. The following equation illustrates this method. The compound of the present invention [the following (X]I[)] in which R and R1 are taken together to form a cyclopropyl ring is (1-oxo-2-indene-5
-yloxy)-alkanoic acids () with an alkali metal base such as sodium hydride, followed by treatment with a methylating agent such as trimethersulfoxonium iodide and the like.

The (1-oxo-2-inden-5-yloxy)alkanoic acids used are described in US Pat. No. 3,668,241. The following equation illustrates this method. All substitutions are as described above.

The core lower alkoxy precursor of the compounds of the present invention, in which R and R1 are taken together to form a cyclohexyl ring, is described in patent application Ser. Manufactured by a method.

All substitutions are as described above.

Compounds of formula (I) where RO is aryl and the X3 substituent is cyano, chlorosulfonyl, sulfamoyl, nitro, amino or aminomethyl generally have RO
from a compound of formula (I) or an intermediate thereto such as a compound of formula () in which R° is unsubstituted aryl or thienyl, or where R° is substituted aryl (the substituents being substituted by methods well known in the art). It can be converted to the desired substitution amount.

). Manufactured from compounds of formula () or (I). For example, when RO is unsubstituted aryl, formula (I
) can be reacted with chlorosulfonic acid to give compounds in which X3 is chlorosulfonyl, and the latter compounds can be reacted with ammonia to give compounds of formula () in which X3 is sulfamoyl. Other transformations are specifically illustrated in the examples, such as in Examples 21, 22 and 31. Also included within the scope of the present invention are the ester and amide derivatives of the present invention.

These derivatives are prepared by conventional methods well known in the art. Thus, for example, an ester derivative can be prepared by combining an inventive [1-oxo-2-aryl or 2-thienyl-2-monosubstituted-5-indanyloxy (or thio)]alkanoic acid with an alcohol such as a lower alkanol. It can be produced by reaction. Amide derivatives are
The [1-oxo-2-aryl or 12-thienyl-2-substituted-5-indanyloxy (or thio)]alkanoic acid is converted to the corresponding acid chloride by treatment with thionyl chloride, which is then treated with ammonia , a suitable mono-lower alkyl amine, di-lower alkyl amine or heterocyclic amine such as piperidine, morpholine, etc. to form the corresponding amide compound. These and other equivalent methods of preparing ester and amide derivatives of the products of the invention will be apparent to those skilled in the art and will be readily apparent to those skilled in the art, and will be appreciated if the derivatives are non-toxic and can be used pharmacologically. Insofar, the derivatives are functionally equivalent to the corresponding [1-oxo-2-aryl or 2-thienyl-2-substituted-5-indanyloxy (or thio)]alkanoic acids.
In addition to salts, esters and amides which are functionally equivalent to carboxylic acid products, compounds in which the carboxy group is replaced by a 5-tetrazolyl group are also functionally equivalent to carboxylic acids.

These tetrazole analogs are prepared as shown below. In the formula, all substituents are as described above.

5-Hydroxy(or thio)-1-indanone [(a) above] is dissolved in a base such as potassium carbonate, etc. in a suitable solvent such as acetone, dimethylformamide, dimethoxyethane, etc. at a temperature in the range of 25-100°C. Treatment with a haloacetonitrile such as chloroacetonitrile, bromoacetonitrile or iodoacetonitrile in the presence of
5-[1-oxo-2-aryl or 2-thienyl-2-monosubstituted-5-indanyloxy( or thio)
] Obtain tetrazole.

Another method for producing compounds of formula (1) (final product) in which Y is methylene consists of hydrolyzing a nitrile compound of formula (XIV') above. This is a typical hydrolysis of nitriles and is well known to those skilled in the art. Many of the compounds of the invention described herein contain an asymmetric carbon atom at the 21-position of the indanyl ring.

If this condition exists, the optical antipodes can be separated by the method described below. Therefore, the present invention provides racemic [1-oxo-2-aryl or 2-thienyl-2-monosubstituted-5-indanyloxy (or thio)]
] includes not only alkanoic acids but also their optically active enantiomers. The separation of optical isomers of racemic acids is carried out in suitable solvents such as methanol, ethanol, 2-propanol, benzene, acetonitrile, nitromethane, acetone, etc. abiethylamine, (10) or (1) monoα-methylbenzylamine,
This may be achieved by forming a salt of the racemic mixture with an optically active base such as (+) or (-)-α-(1-naphthyl)ethylamine, brucine or strichynine.

In this way, two diastereomeric monosalts are formed in solution. One of these salts is usually more soluble in the solvent than the other salt. Generally, repeated recrystallization of a crystalline salt provides a pure diastereomer. Optically pure 2-aryl or 2-thienyl indanic acid is prepared by acidifying the salt with mineral acid, extracting with ether, evaporating the solvent and recrystallizing the optically pure enantiomer. You can get it. Other optically pure enantiomers are generally
Obtained by forming diastereomeric monosalts using different bases.

It is advantageous to isolate the partially resolved acid from the aqueous solution of the purification of one diastereomeric monosalt and to further purify this material by the use of another optically active base.

The following examples illustrate the 2-aryl and 2-thienyl indica 7 products of the present invention and methods of making them. As noted above, non-toxic pharmacologically usable salts of acids of Formulas 1 and 1a are within the scope of this invention. These salts include alkali metal salts, alkaline earth metal salts, and amine salts, such as salts of ammonia, primary and secondary amines, and quaternary ammonium hydroxides. Particularly suitable metal cations are those derived from alkali metals such as sodium, potassium, lithium etc.; alkaline earth metals such as calcium, magnesium etc. and other metals such as aluminum, iron and zinc. These salts are prepared by conventional methods well known in the art. Thus, when reacting with alkali metal and alkaline earth metal hydroxides, carbonates, bicarbonates, amines or quaternary ammonium hydroxides, the acid reacts with the corresponding alkali metal, alkaline earth metal, amine or quaternary ammonium salt, Form. Pharmaceutically usable salts are ammonia,
, secondary or tertiary amines, or quaternary ammonium hydroxides, such as methylamine, dimethylamine, trimethylamine, ethylamine, N-methylhexylamine, benzylamine, α-phenethylamine, ethylenediamine, piperidine, 1-methylpiperazine, morpholine , pyrrolidine, 1,4-dimethylpiperazine, ethanolamine, diethanolamine, triethanolamine, tris(hydroxymethyl)aminomethane, N
-Methylglucamine, N-methylglucosamine, efuedrine, procaine, tetramethylammonium hydroxide, tetraethylammonium hydroxide, benzyltrimethylammonium, etc.

The aforementioned salts are particularly useful as parenteral solutions since they are highly soluble in pharmaceutical carriers such as water or alcohols.

However, the following examples are for illustrative purposes only, and as will be apparent to those skilled in the art, by substituting suitable starting materials for those described in the examples, All products included in formula (1) above can be produced in a similar manner. Among the following Examples, Examples 9, 10, 11, 18, 22, and 32 to 40 are reference examples. Example 1 (1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy)acetic acid production process A:2
・3-Dichloro-5-phenylacetinoleanisole 2,3-dichloroanisole (627, 0.35 mol)
, phenylacetyl chloride (547,0,35 mol) and carbon disulfide (0 to 5 mol in a stirred mixture of 250 mol)
While cooling at 0.degree. C., aluminum chloride (477, 0.35 mol) is added in portions.

The reaction mixture was left at 25 °C for 17 hours to remove carbon disulfide, and the residue was then treated with ice water and concentrated hydrochloric acid (50 ml) to give 126-129 after crystallization from benzenelicyclohexane (2:1). 2,3-dichloro- with a melting point of °C
68.8 tons of 5-phenylacetylanisole are obtained. C
Elemental analysis value for l5Hl2Cl2O2: Calculated value: C
6l. O4, H4. 1O experimental value: C6l. 46, H4.
11 Step B: 2,3-dichloro-4-(2-phenylacryloyl)anisole The reaction mixture was reacted with bis(dimethylamino)methane (2 in 1007n0) under nitrogen while cooling to maintain the temperature below 60°C.・3-dichloro-4
Acetic anhydride (100 m0) is added dropwise to a suspension of phenylacetylanisole (29.57, 0.01 mol).

The reaction mixture was stirred at 25°C for 2 hours, then poured into ice water (150°C
2,3-dichloro-4-(2-phenylacryloyl)-anisole 7 with a melting point of 87-89°C when added to 0 m0
．． 47 is precipitated. Elemental analysis values for Cl6Hl2Cl2O2: Calculated values: C62.56, H3.94 Experimental values: C62.67, H4. O4 Step C: 2-phenyl-5-methoxy-6,7-dichloro-1-indanone2.・3-dichloro-4-(2-phenylacryloyl)anisole (7.47, 0.02
4 mol) is added little by little to the cooled concentrated sulfuric acid (150 mol) with stirring.

The reaction mixture was stirred in an ice bath for 2 hours and then added dropwise to ice water to give 2-phenyl-5-methoxy-6,7-dichloro-1.
- Precipitate indanone 3.917. It has a melting point of 193-195°C after crystallization from benzene-cyclohexane (1:2). Cl6Hl2Cl
Elemental analysis value for 2O2: Calculated value: C62.56, H
3.94 experimental value: C62.84, H4. OO Step D: 2-phenyl-5-hydroxy-6,7-dichloro-1-indanone 2-phenyl-5-methoxy-6
・7-dichloro-1-indanone (3,91y10,0
A stirred mixture of 127 mol) and pyridine hydrochloride (401) is heated at 190° C. for 1 hour and then poured into water (600 mol).

2-phenyl-5-hydroxy-6,7-dichloro-1
-Indanone (2.48f) is precipitated.

This after recrystallization from ethanol:water (2:1)
It has a melting point of 50-252°C. Cl5HlOCl2O2
Elemental analysis value for: Calculated value: C6l. 46, H3.4
4 Experimental value: C6O. 94, H3.66 Step E: (1-oxo-2-phenyl-6,7-dichloro-5-indanyloxy) 2-phenyl acetate-5-hydroxy-6,7-dichloro-1-intason (5.86
7,0.023 mol), iodoacetic acid (4,287,0.
023 mol), potassium carbonate (3.047, 0.022
mol) and acetone (250Tn1) are heated under reflux for 48 hours.

The reaction mixture was cooled to 25°C and concentrated in vacuo to give a solid product, which was dissolved in water and then acidified with 6N hydrochloric acid (1
-oxo-2-phenyl-6,7-dichloro-5-indanyloxy)acetic acid and 2-phenyl-5-hydroxy-
6.87 of a mixture of 6,7-dichloro-1-indanone is precipitated. The phenol is removed by crystallization with nitromethane. The slurry is concentrated to dryness in vacuo, and then triturated with toluene to obtain 470rn9 of (1-oxo-12-phenyl-6,7-dichloro-5-indanyloxy)acetic acid having a melting point of 181-185°C. Cl7Hl2Cl2
Elemental analysis value for O4: Calculated value: C58. l4, H3
．． 45, Cl2O. l9 Experimental value: C58. l7, H3.
54, Cl9.94 Step F: (1-oxo-2-phenyl-2-methyl-6,7-dichloro-5-indanyl-6) in dimethyl acetate formamide (7 ml) A stirred solution of 7-dichloro-15-indanyloxy)acetic acid (0.3517, 0.001 mol) was cooled in an ice bath and then dissolved in sodium hydride (
57% oil dispersion (0.0847, 0.002 mol) and then stirred for 2 hours.

Methyl iodide (1 m0) was added and the reaction mixture was stirred for 2 hours at 25°C, poured into ice water and then acidified with dilute aqueous hydrochloric acid to give (1-oxo-12- phenyl-2-methyl-6,7-dichloro-5-indanyloxy)acetic acid is obtained.jl Example 2 In step A of Example 1, instead of 2,3-dichloroanisole, a corresponding amount of 2-chloro-3- methyl anisole,
Using 2,3-dimethylanisole, 3-methylanisole or 2-methyl-3-chloroanisole and using steps B-F (1-oxo-2-phenyl-2
・7-dimethyl-6-chloro-5-indanyloxy)
Acetic acid (1-oxo-2-phenyl-2,6,7-trimethyl-5-indanyloxy)acetic acid (1-oxo-2-
phenyl-2,7-dimethyl-5-indanyloxy)
Acetic acid (1-oxo-2-phenyl-2,6-dimethyl-
J-[chloro-5-indanyloxy)acetic acid is obtained.

Example 3 In Example 1, corresponding amounts of p-methylphenylacetyl chloride, m-methylphenylacetyl chloride, o-chlorophenylacetyl chloride, p-fluorophenylacetyl chloride were used instead of phenylacetyl chloride in Step A. [1-oxo-2-methyl-
2-(4-methylphenyl)-6,7-dichloro-5-
indanyloxy]acetic acid[1-oxo-2-methyl-2
-(3-methylphenyl)-6,7-dichloro-5-indanyloxy]acetic acid[1-oxo-2-(2-chlorophenyl)-2-methyl-6,7-dichloro-5-indanyloxy]acetic acid[1 -oxo-2-(4-fluorophenyl)-2-methyl-6,7-dichloro-5-indanyloxy]acetic acid is obtained.

Example 4 In Example 1, the 2-alkylating agent methyl iodide in Step F was replaced with corresponding amounts of ethyl iodide, allyl bromide, benzene bromide and cinnamyl bromide, respectively (1-oxo-2-ethyl -2-phenyl-6,7-dichloro-5-indanyloxy)acetic acid (1-oxo-2-allyluphenyl-6,7-dichloro-5-indanyloxy)acetic acid, (1
-oxo-2-benzyl-2-phenyl-6,7-dichloro-5-indanyloxy)acetic acid (1-oxo-2-
Cinnamyl-2-phenyl-6,7-dichloro-5-indanyloxy)acetic acid is obtained.

Example 5 (1-oxo-2-phenyl-6,7-dichloro-5-
(indanyloxy)acetic acid step A: 21,3'-dichloro-4'-methoxyisobutyro-phenonemethylene chloride (
2,3-dichloroanisole (1) (1
A stirred mixture of aluminum chloride (007, 0,565 mol) and isobutyryl chloride (10.62 mol) (66t10.
．． 62 mol).

The reaction mixture was warmed to 25°C and then cooled after 24 hours with ice water (4
00ml) and hydrochloric acid (30ml). The organic phase was washed with 5% sodium hydroxide, water, dried over magnesium sulfate and then distilled under reduced pressure to 120-130°C/0.5
2'.37-dichloro-4/-methoxyisobutylophenone (2') is obtained by distillation. CllHl2Cl2O2
Elemental analysis value: Calculated value: C53.46, H4.8
9 Experimental values: C54.25, H5. O7 Step B: 2-bromo-21,3'-dichloro-4/-methoxyisobutylophenoneacetic acid (2ζ3 in 150m0
″-dichloro-4′methoxyisobutylphenone (45
A stirred solution of bromine (7, 0.183 mol) was heated for 30 minutes with bromine (3
0f, 0.187 mol).

The reaction mixture is stirred for 10 minutes and then poured into ice water (600 ml) containing sodium acid sulfite (27).
2-bromo-2! -31-dichloro-4'-methoxyisobutylophenone () (487) is precipitated.

It has a melting point of 72-73°C after recrystallization from hexane. Elemental analysis value for CllHllBrcl2O2: Calculated value: C4O. 52, H3.4O experimental value: C4
O. 68, H3.38 Step C: 2-methylene-2',3'-dichloro-4'-methoxypropiophenone DMF (2-methylene in 200m0
A solution of bromo-2',3'cyclo-4'-methoxyisobutylophenone (327, 0.1 mol) and anhydrous lithium bromide (17.47, 0.2 mol) was heated at 95°C in an inert atmosphere. Stir for 3 hours, then add ice water (500 m
Add to 0.

2-methylene-2ζ3'-dichloro-4'-methoxypropiophenone () is precipitated.

It has a melting point of 59° C. after recrystallization from petroleum ether. Elemental analysis value for CllHlOCl2O3: Calculated value: C53.9O. ．． H4. ll Experimental value: C53.7
2.H4. ll Step D: 2-methyl-5-methoxy-6,7-dichloro-1-indanone concentrated sulfuric acid (2-methylene-
A solution of 2',3'cyclo-4'-methoxypropiophenone (40y10.163 mol) is allowed to stand at 25 DEG C. for 24 hours and then slowly poured into vigorously stirred ice water (500 ml).

2-Methyl-5-methoxy-6,7-dichloro-1-indanone (40y) is precipitated.

This is 129°C after recrystallization from methylcyclohexane.
It has a melting point of Elemental analysis value for CllHlOCl2O2: Calculated value: C53.9O. H4. ll Experimental value: C5
3.84, H4. OO Step E: 2-methyl-2-phenyl-5-methoxy-6
・7-dichloro-1-intason tertiary butanol (3
Potassium tert-butoxide (8.4
27, 0.075 mol) to 2-methyl-5-methoxy-
6,7-dichloro-1-interson (12.267, 0
．． 05 mol) and continued refluxing for 2 hours, then added a suspension of diphenyliodonium chloride (19.0V 10.06 mol) in tert-butanol (1f?.), then refluxed for 2 hours. Continue time.

The reaction mixture is cooled to 25° C., 300 ml of water are added and the mixture is concentrated to dryness in vacuo. Thereby, 2-methyl-2-phenyl-5-methoxy-6,7-dichloro-1-
Obtain Indanone 4.97f. This after crystallization from benzenelicyclohexane (1:2)
It has a melting point of 3°C. Elemental analysis value for Cl7Hl4Cl2O2: Calculated value: C63.57, H4.39 Experimental value:
C63.24, H4.68 Step F: 2-methyl-2-phenyl-5-hydroxy-
A stirred mixture of 6,7-dichloro-1-indanone 2-methyl-2-phenyl-5-methoxy-6,7-dichloro-1-1-indanone (4.947, 0.015 mol) and pyridine hydrochloride (507) was added to 175 Heat at ℃ for 1 hour,
Then add water (500 m0).

2-Methyl-2-phenyl-5-hydroxy-6,7-dichloro-111 intason (2.05y) is precipitated.

It has a melting point of 194-196°C after recrystallization from ethanol:water (2:1). Cl6Hl2Cl2O
Elemental analysis value for 2: Calculated value: C62.56, H3.
94 experimental value: C62.6O,. H4. ll Step G: (1-oxo-2-methyl-2-phenyl-6
-7-dichloro-5-indanyloxy)acetic acid dimethyl formamide (2-methyl-2-phenyl-5-hydroxy-6,7-dichloro-1-1-intason (2.05V10.0067 mol) in 30 m0, potassium carbonate (
1.857, 0.0134 mol) and ethyl bromoacetate (2.23y10.0134 mol).
Warm at ~60°C for 3 hours, then add methanol (30r11
1) Potassium hydroxide (0,9
7y, 0.0147 mol) and then treated with 2
Heat for 1/2 hour.

The reaction mixture was poured into water (500 me), acidified with 6N hydrochloric acid, then the precipitate was collected after trituration with ether-petroleum ether and dried (1-oxo-2-methyl-2-phenyl-6 - 1.31y of 7-dichloro-5-indanyloxy)acetic acid is obtained. This is acetic acid: water (
1:1) with a melting point of 168-169°C. Elemental analysis value for Cl8Hl4Cl2O4: Calculated value: C59.2O, H3.86 Experimental value: C58.94, H
4.2O Example 6 In Example 5, instead of 2,3-dichloroanisole in step A, corresponding amounts of 2-chloro-3-methylanisole, 2,3-dimethylanisole and 2-methyl-3-chloroanisole were used. When used, the following compounds of the invention are obtained respectively.

(1-oxo-2,7-dimethyl-2-phenyl-6-
Chloro-5-indanyloxy)acetic acid (1-oxo-2
・6,7-Trimethyl-121-phenyl-5-indanyloxy)acetic acid (1-oxo-2,6-dimethyl-2-phenyl-[chloro-5-indanyloxy)acetic acid Example 7
Production process A of [1-oxo-2-(4-chlorophenyl)-2-methyl-6,7-dichloro-5-indanyloxy]acetic acid hemihydrate: 2-(4-chlorophenyl)-2
-Methyl-5-methoxy-6,7-dichloro-1-indanone tert-butanol (potassium tertiary in 150 mO
Butoxide (2.817, 0.025 mol) was dissolved in tert-butanol (100 mO-benzene (2.817, 0.025 mol) in 200 mO
-Methyl-5-methoxy-6,7-dichloro-1-indanone (4.907, 0.02 mol) was added to the refluxing solution and reflux was continued for 3 hours, then 4,4'-dichlorodiphenyliodonium chloride ( 11.55y.0.03
mol) is added and then refluxing is continued for 2 hours.

The reaction mixture was cooled to 25°C, 100 ml of water was added, and the mixture was then concentrated to dryness in vacuo to give 2-(4-chlorophenyl)-2-methyl-5-methoxy-6,7-dichloro-1.
- Obtain Internson 4,307. This after crystallization from cyclohexane-benzene (5:1)
It has a melting point of 78°C. Step B: 2-(4-chlorophenyl)-2-methyl-5-hydroxy-6,7-dichloro-11-indanone 2-(4-chlorophenyl)-2-methyl-5-methoxy-16,7-dichloro-1- A stirred mixture of Intason (4.15y, .0.012 mol) and pyridine hydrochloride (407) was heated at 180°C for 1 hour,
Then add water (500 m0).

2-(4-chlorophenyl)-2-methyl-5-hydroxy-6,7-dichloro-1-indanone (3.117
) is precipitated.

It has a melting point of 211-213°C after crystallization from ethanol:water (1:1). Cl6HllCl3O
Elemental analysis value for 2: Calculated value: C56.25, H3.
25 experimental value: C55.53, H3.23 Step C: [1-oxo-2-(4-chlorophenyl)-
2-Methyl-6,7-dichloro-5-indanyloxy]acetic acid hemihydrate dimethyl formamide (2(4-chlorophenyl)-2-methyl-5-hydroxy-6,7-dichloro-1-indanone( 2.957,
0.00863 mol), potassium carbonate (2.26y,.
0.0163 mol) and ethyl bromoacetate (2.
72y10.0163 mol) in a stirred mixture of 55 to 60
C. for 2 hours, treated with water (50 mO-10 N sodium hydroxide solution (2.5 ml, 0.025 mol)) and then heated at 80.degree. C. for 1 hour.

The reaction mixture was gradually dissolved in water (500ml) and 12N hydrochloric acid (10ml).
In addition to m0, 1.37 y of [1-oxo-2-(4-chlorophenyl)-2-methyl-6,7-dichloro-5-indanyloxy]acetic acid hemihydrate is precipitated. 141-142 after crystallization from acetic acid:water (1:1).
It has a melting point of °C. Cl8Hl3Cl3O4・1/2H2
Elemental analysis value for 0: Calculated value: C52.9O,. H3
．． 45, Cl26. O3 experimental value: C52.47, H3,
45, Cl26. Example 8 [1-oxo-2-(4-methoxyphenyl)2-methyl-6,7-dichloro-5-
Production process A of indanyloxy]acetic acid: 2-methyl-5
-Hydroxy-6,7-dichloro-1-indanone-2-
A stirred mixture of methyl-5-methoxy-6,7-dichloro 1-intason (30.07, 0.123 mol) and pyridine hydrochloride (2707) was heated at 180° C. for 1 hour,
Then pour into water (1500ml).

2-Methyl-5-hydroxy-6,7-dichloro-1-
Indanone (27.6y) is precipitated.

It has a melting point of 224-230°C and is used without further purification. Step B: 2-methyl-5
-benzyloxy-6,7-dichloro-1-indanone dimethyl formamide (2 methyl-5 in 100 m0
-Hydroxy-6,7-dichloro-11-indanone (2
7.67, 0.12 mol), potassium carbonate (24.97
, 0.18 mol) and benzyl bromide (21.4 m110
．． A stirred mixture of 18 mol) of
Precipitate t.

It has a melting point of 153-155°C after crystallization from benzene-hexane (3:2). C17H14C1
Elemental analysis value for 202: Calculated value: C63.57, H
4.39 Experimental value: C64.28, H4.61 Step C: 2-(4-methoxyphenyl)-2-methyl-
5-benzyloxy-6,7-dichloro-1-indanone tert-butanol (potassium tert-butoxide (8.427, 0.075 mol) dissolved at 450 mO)
2-methyl-5-benzyloxy-6,7-dichloro-1-intason (16.17, 0.05 mol) in benzene (600 mO) was added to a refluxing solution of 4,4'-dimethoxydiphenyliodonium chloride (37.66
y. ．． O. 10 mol) is added and then refluxing is continued for 3 hours.

The reaction mixture is cooled to 25° C., 500 ml of water is added and the mixture is concentrated in vacuo to give a brown oil. This was extracted with ether and dried over anhydrous magnesium sulfate to remove the ether, and the residue was then chromatographed on silica gel earth using chloroform to 2-(4-methoxyphenyl)-2- Methyl-5-benzyloxy-6.
3.447 of 7-dichloro-1-interson is obtained. It has a melting point of 115-119°C and is used without further purification. Step D: 2-(4-methoxyphenyl)-2-methyl-5-hydroxy-6,7-dichloro-1-indanone 2-(4-methoxyphenyl)
-2-Methyl-5-benzyloxy-6,7-dichloro-1-intason (3.447, 0.008 mol) was dissolved in anhydrous ethanol (5 in 300 mO) in a Parr apparatus.
% palladium on carbon (500 η) at 25° C. for 4 hours.

The reaction mixture was filtered and then concentrated in vacuo to give 2-(4-methoxyphenyl)-2-methyl-5-hydroxy-6.7
-Dichloro-1-indanone 2.6y is obtained. It has a melting point of 149-156°C and is used without further purification. Step E: [1-oxo-2-(4
-methoxyphenyl)-2-methyl-6,7-dichloro-5-indanyloxy]acetic acid dimethyl formamide (2(4-methoxyphenyl)-2-methyl-5-hydroxy-6,7 in 60 mO) -dichloro-1-indanone (2.67, O.0077 mol), potassium carbonate (2
．． 147, 0.0154 mol) and ethyl bromoacetate (
2.58y10.0154mol) of a stirred mixture of 55~
Warm at 60° C. for 2.5 hours, treat with water (60 ml) and 10N sodium hydroxide solution (3 ml..O.O.3 moles) and then heat at 100° C. for 1 hour.

The reaction mixture was mixed with crushed ice, water (600 mO-12N hydrochloric acid (2
0 m0 to obtain 1.697 of [1-oxo-2-(4-methoxyphenyl)-2-methyl-6,7-dichloro-5-indanyloxy]acetic acid. It has a melting point of 173-175°C after crystallization from nitromethane. Elemental analysis value for C19H16C1205: Calculated value: C57.74, H4.08 Experimental value: C57.35, H
4.31 Example 9 [1-oxo-2-(4-hydroxyphenyl)-2-
Methyl-6,7-dichloro-5-indanyloxy]acetic acid [1-oxo-2-(4-methoxyphenyl)-2-methyl-6,7-dichloro-5-indanyl in Step E of Example 8] oxy]acetic acid (1,807, 0.0046 mol),
A stirred mixture of 48% hydrobromic acid (50 ml) and acetic acid (50 mO) was heated to reflux for 1 hour, then cooled with crushed ice and water (800 mO
ml) to precipitate 900 η of [1-oxo-2-(4-hydroxyphenyl)2-methyl-6,7-dichloro-5-indanyloxy]monoacetic acid.

It has a melting point of 220-222°C after crystallization from acetic acid:water (1:1) and nitromethane. C18H1
Elemental analysis values for 4C1205・1/3CH3NO2: Calculated values: C54.84, H3.77, N1.16 Experimental values: C54.38, H3.93, NO. 94 Examples 10 Ethyl (1-oxo-2-methyl-2-phenyl-6,7-
(1-oxo-2- obtained from Example 5 in dichloro-5-indanyloxy)acetate ethanol (10d)
Boron trifluoride etherate (1.0 mO) is added to a solution of methyl-2-phenyl-6,7-dichloro-5-indanyloxy)acetic acid (1.07).

The reaction mixture is refluxed for 1/2 hour, treated with water, and then cooled to yield ethyl (1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy) acetate. Example 11 N-ethyl-(1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy)acetamidobenzene (1-oxo-2-methyl- 2-phenyl-6.
7-dichloro-5-indanyloxy)acetic acid (1.0y
) and thionyl chloride (a solution of 0.5 mO is refluxed for 1 hour.

The solvent is removed under reduced pressure and the residue is then treated with benzene (10 m0) and ethylamine (1 m0). After 2 hours at 25°C the reaction mixture is poured into water and then extracted with ether.

The ether extract was washed first with dilute hydrochloric acid and then with aqueous sodium bicarbonate. The ether solution is dried over magnesium sulfate and evaporated under reduced pressure to yield the desired N-ethyl-(1-oxo-2methyl-2-phenyl-6,7-dichloro-15-indanyloxy)acetamide. Example 12 [1-oxo-2-(4-fluorophenyl)2-methyl-6.
Production process A of 7-dichloro-5-indanyloxy]acetic acid: 2-(4-fluorophenyl)-2-methyl-5-
Methoxy-6,7-dichloro-1-indanone Tert-butanol (50 mO of potassium tert-butoxide (3.387, 0.03 mol) dissolved in 150 mO -5
-Methoxy-6,7-dichloro-1-intason (4.
Add 4,4'-difluorodiphenyliodonium chloride (10.587, 0.03 mol) to a refluxing solution of 907, 0.02 mol) and continue refluxing for 3 hours, then add 4,4'-difluorodiphenyliodonium chloride (10.587, 0.03 mol) and then continue refluxing for 21/2 hours. .

The reaction mixture was cooled to 25° C., 100 ml of water was added, and the mixture was then concentrated to dryness in vacuo to give 2-(4-fluorophenyl)-2-methyl-5-methoxy-6,7-dichloro-1
- Obtains an internson of 1.247. This thing is ether-
After treatment with hexane it has a melting point of 163-170°C and is used without further purification. Process B: 2-
(4-fluorophenyl)-2-methyl-5-hydroxy-6,7-dichloro-11-indanone 2-(4-fluorophenyl)-2-methyl-5-methoxy-6,7-dichloro-1-indanone (1.2f.0.00354
1 mole) and pyridine hydrochloride (127).
Heat at 80° C. for 1 hour and then pour into water (500 ml).

2-(4-fluorophenyl)-2-methyl-5-hydroxy-6,7-dichloro-1-indanone is 193-
It has a melting point of 200°C and is used without further purification.

Step C: [1-oxo-2-(4-fluorophenyl)
-2-Methyl-6,7-dichloro-5-indanyloxy]acetic acid dimethyl formamide (2-( in 30 m0)
4-fluorophenyl)-2-methyl-5-hydroxy-6,7-dichloro-1-indanone (1,047,0
．． 0032 mol), potassium carbonate (0.8857, 0.0032 mol), potassium carbonate (0.8857, 0.
0064 mol) and ethyl bromoacetate (1.077, 0
．． A stirred mixture of 0.0064 mol) was heated at 55-60°C for 3 hours, treated with water (30ml) - 10N sodium monohydroxide solution (1ml, 0.01mol), then heated at 80°C for 1 hour.
Heat for an hour.

The reaction mixture was gradually diluted with water (500 mO-12N hydrochloric acid (10
In addition to m0, 450 η of [1-oxo-2-(4-fluorophenyl)-2-methyl-6,7-dichloro-5-indanyloxy]acetic acid are precipitated. This after crystallization from ethyllihexane acetate (1:3)
It has a melting point of 56°C. Elemental analysis values for Cl8H, 3Cl2FO4: Calculated values: C56.42, H3.42, C
ll8,5O Experimental value: C56.3O. H3.65, Cl
l8.57 Example 13 (1-oxo-2,2-diphenyl-6,7-dichloro-5-indanyloxy)acetic acid production process A: 2,2-diphenyl-5-methoxy-6,7-dichloro-1- Indanone tert-butanol (500m
Potassium tert-butoxide (7.07,0
．． 0624 mol) was converted into 2-phenyl-5-methoxy-6,7-dichloro-1-indanone (2-phenyl-5-methoxy-6,7-dichloro-1-indanone (
9.59y,. 0.0312 mol), diphenyliodonium chloride (39.6y.0.125 mol), tert-butanonyl (1500 ml) and benzene (500 ml).
m0 mixture and then stirred at 70° C. for 2 hours.

The reaction mixture was concentrated in vacuo to 1/4 volume to remove unreacted iodonium salt, and the remaining liquid was concentrated to dryness to give 2.
2-diphenyl-5-methoxy-6,7-dichloro-1
- Obtain 5.717 indanone. It has a melting point of 172-174°C after crystallization from cyclohexane.
Elemental analysis value for C22Hl6Cl2O2: Calculated value:
C68.94, H4, 2l Experimental value: C68.99, H4
．． 34 Step B: 2,2-diphenyl-5-hydroxy-6,7
-dichloro-1-indanone-2,2-diphenyl-5-
Methoxy-6,7 dichloro-1-interson (5.57
, 0.014 mol) and pyridine hydrochloride (557) was heated at 175°C for 30 minutes, then water (500 m
Add to 0.

2,2-diphenyl-5-hydroxy-6,7-dichloro-1-indanone (4.94
7) is obtained. Elemental analysis value for C2lH, 4Cl2O2: Calculated value: C68.3l, H3,82 Experimental value: C67
．． 86, H3.88 Step C: (1-oxo-2,2-diphenyl-6,7-dichloro-5-indanyloxy)acetic acid dimethyl formamide (2,2-diphenyl-5-hydroxy-6,・7-dichloro-1-interson (4.
9y,. 0.0133 mol) potassium carbonate (3.687
, 0.0266 mol) and ethyl bromoacetate (4.45 mol)
7, 0.0266 mol) at 55-60'C.
Heat for 3.5 hours.

This was then treated with water (150 mO - 10 N sodium hydroxide solution (7.5 m1, .0.075 mol), then 9
Heat at 0°C for 1.5 hours.

The reaction mixture was gradually mixed with water (11)-12N hydrochloric acid (30m0
In addition to ((1nioxo-2,2-diphenyl-6,7
-dichloro-5-indanyloxy)acetic acid 3.607 is obtained. It has a melting point of 251 DEG -252 DEG C. after crystallization first from acetic acid and then from nitromethane. C23H
Elemental analysis value for l6Cl2O4: Calculated value: C64.
65, H3.77, Cll6.59 Experimental value: C64.6
9, H3,94, Cl6.73 Example 14 (1-oxo-2,3-diphenyl-2-methyl-6,7-dichloro-5-indanyloxy)acetic acid production process A: 2', 3'
-dichloro-4'-methoxypropionphenonemethylene chloride (2,3-dichloroanisole in 600 mO)
177.07, 1.0 mol) and propionyl chloride (1
A stirred mixture of aluminum chloride (146.0, 1.1 mol) was cooled to 5° C. and then added over a period of 21/2 hours.
77, 1.1 mol).

The reaction mixture was warmed to 25°C and after 16 hours was added to ice water (21
) and concentrated hydrochloric acid (poured into 200 mO. The organic phase was reduced to 10%
Wash with sodium hydroxide solution and saturated salt solution and then dry over magnesium sulfate. After evaporation of the solvent, the product was crystallized from hexane to give 2',3'-dichloro-
l-Methoxypropiophenone 124.57 (53%)
get. It has a melting point of 51-54°C. Process B
:2,3-dichloro-4-(2-benzylidenemethyl)
2ζ3'- dissolved in anisole ethanol (1f?)
Dichloro-4! -Methoxypropiophenone (124.
5y, 0.53 mol) and benzaldehyde (54.4
A 20% sodium hydroxide solution (117.0 ml, 0.59 mol) is added dropwise to a mixture of 117.0 ml, 0.53 mol).

After adding 3/4 of the base the product begins to precipitate. 25
After 2 hours at <0>C, the solid product is collected by suction P filtration to yield 163.27 (95%) of 2,3-dichloro-4-(2-benzylidenemethyl)anisole.

This after crystallization from ethanol 137.5~1
It has a melting point of 39°C. Elemental analysis values for C,7Hl4Cl2O2: Calculated values: C63.57, H4.39 Experimental values: C63.69, H4.49 Step C: 2-Methyl-3-phenyl-5-methoxy-6
・7-dichloro-1-indanone 2,3-dichloro-4
-(2-benzylidenemethyl)anisole (1007,
0.32 mol) and trifluoroacetic acid (400 mol to 6
Reflux gently for 7 hours.

The trifluoroacetic acid is removed and the oily residue is triturated with ether to give 2-methyl 3-phenyl-5-methoxy-6,7-dichloro-1-indanone 80.07. This product is 155-157℃ after crystallization from benzene.
It has a melting point of Elemental analysis value for Cl7Hl4Cl2O2: Calculated value: C63.57, H4.39 Experimental value: C6
3. 17, H4.59 Step D: 2,3-diphenyl-2-methyl-5-methoxy-6,7-dichloro-1-intason sodium methoxide (2.47, 0.045 mol) was heated at 70°C under nitrogen. 2-methyl-3-phenyl-5-methoxy-6
・7-dichloro-1-interson (6.447, 0.0
2 mol), diphenyliodonium chloride (31.
6y,. 0.1 mol), dry dimethyl formamide (
Add portionwise to a stirred mixture of 200 m0 and benzene (200 m1) and then continue heating at 70° C. for 2 hours.

The reaction mixture is poured into water (1.51), the benzene phase is separated, dried over anhydrous magnesium sulfate, then concentrated in vacuo and after trituration with hexane gives 2,3-diphenyl-2-methyl- 5-methoxy-6,7 dichloro-1
- Obtain 2.487 indanone. This material, which has a melting point of 197-207°C, is used without further purification.

Step E: 2,3-diphenyl-2-methyl-5hydroxy-6,7-dichloro-1-indanone 2,3-diphenyl-2-methyl-5-methoxy-6,7-dichloro-1-intanone (2.487 , 0.0065 mol) and pyridine hydrochloride (257) at 175°C.
Heat for an hour and then pour into water (500 ml).

The precipitated 2,3-diphenyl-2-methyl-5-hydroxy-6,7-dichloro-1-interson (2.247
) has a melting point of 238-244°C and is used without further purification. Step F: (1-oxo-2, 3
-diphenyl-2-methyl-6,7-dichloro-5-indanyloxy)acetic acid dimethyl formamide (100
2,3-diphenyl-2-methyl-5-hydroxy-6,7-dichloro-1-intason (2.247
, 0.00585 mol), potassium carbonate (1.627,
0.0117 mol) and ethyl bromoacetate (1.967 mol)
, 0.0117 mol) at 55-60°C.
Warmed for 1 hour and treated with water (100 m 0 - 10 N sodium hydroxide solution (5 ml 1 10.05 mol), then heated at 90 °C for 1
．． Heat for 5 hours.

The reaction mixture was gradually dissolved in water (11)-12N hydrochloric acid (10 mO
plus crystallization from nitromethane melting point 203-205
1.147 of (1-oxo-2,3-diphenyl-2-methyl-6,7-dichloro-5-indanyloxy)acetic acid having a temperature of 1.147 °C is obtained. Elemental analysis value for C24Hl8Cl2O4: Calculated value: C65.32, H4. ll Experimental value:
C65.3O, H4. 19 Example 15 Production process of (1-oxo-2-ethyl-2-phenyl-6,7-dichloro-5-indanyloxy)acetic acid A:2
-ethyl-2-phenyl-5-methoxy-6,7-dichloro-1-indanone sodium methoxide (1.24
y,. 0.023 mol), 2-phenyl-5-methoxy-6,7-dichloro-1-intason (4.61y, .0.015 mol), iodoethane (
15.5 m/, 0.15 mol), benzene (60 m0) and dimethyl formamide (60 m0) in small portions.

The reaction mixture was brought to ambient temperature for 1 hour and water (1
1? ), the benzene phase was separated, dried over anhydrous magnesium sulfate, and then concentrated in vacuo to give 2-ethyl-2
-Phenyl-5-methoxy-6,7-dichloro-1-interson 3.237 is obtained. It has a melting point of 139-141° C. after crystallization from benzenelihexane (1:1). Elemental analysis values for Cl8Hl6Cl2O2: Calculated value: C64.49, H4.8l Experimental value: C64.
73, H4.99 Step B: 2-ethyl-2-phenyl-5-hydroxy-
A stirred mixture of 6,7-dichloro-1-intason-2-ethyl-2-phenyl-5-methoxy-6,7-dichloro-1-indanone (3.017, 0.009 mol) and pyridine hydrochloride (35y) was added to 175 ml of Heat for 30 minutes at °C and then pour into water (350 ml).

Precipitated 2-ethyl-2-phenyl-5-hydroxy-6
・7-dichloro-1-interson (2.64y) is 17
It has a melting point of 7-179. Elemental analysis values for Cl7Hl4Cl2O2: Calculated values: C63.57, H4.39 Experimental values: C63.73, H4.8l Step C: (1-oxo-2-ethyl-2-phenyl-6
7-dichloro-5-indanyloxy)acetic acid dimethyl formamide (2-ethyl-2-phenyl-5-hydroxy-6,7-dichloro-1-intason (2.67, 0.008 mol) in 40 mO, carbonic acid Potassium (2.
247, 0.016 mol) and ethyl bromoacetate (2.
717, 0.016 mol) at 55-60°C.
for 2.5 hours, treated with water (40 mO-10N sodium hydroxide solution (3 ml, 0.03 mol), then 1
Heat at 00'C for 1 hour.

The reaction mixture was gradually diluted with water (600 mO-12N hydrochloric acid (10
In addition to m1) a gummy residue is obtained. This was extracted with ether, dried and then concentrated in vacuo to a melting point of 187-189.
(1-oxo-2-ethyl-2-phenyl-6.7
-dichloro-5-indanyloxy)acetic acid 2.167 is obtained. Elemental analysis value for Cl9Hl6Cl2O4: Calculated value: C6O. l8, H4.25 experimental value: C59.76,
H4.24 Example 16 (1-oxo-2-cyclopentyl-2-phenyl-6
・Production process A of 7-dichloro-5-indanyloxy)acetic acid: 2-cyclopentyl-2-phenyl-5-methoxy-6,7-dichloro-1-indanone sodium methoxide (1.637, 0.03 mol) 2-phenyl-5-methoxy-6,7-dichloro-1-indanone (4.617, 0.015 mol) at 25°C under nitrogen;
Add portionwise to a stirred mixture of cyclopentyl bromide (167711.0.15 mol), benzene (60 ml) and dimethyl formamide (60 ml).

The reaction mixture was stirred at 25 °C for 16 h, poured into water (11), the benzene phase was separated, dried over anhydrous magnesium sulfate, and then concentrated in vacuo to give a red-brown oily residue. obtain. This was chromatographed on silica gel using chloroform to give a melting point of 105-10.
1.427 of 2-cyclopentyl-2phenyl-5-methoxy-6,7-dichloro-1-intason is obtained at 8°C.
Elemental analysis value for C2lH2OCl2O2: Calculated value:
C67.2l, H5.37 Experimental value: C66.88, H5
．． 53 Step B: 2-cyclopentyl-2-phenyl-5-hydroxy-6,7-dichloro-1-indanone 2-cyclopentyl-2-phenyl-5-methoxy-6,7-dichloro-1-indanone (1.407,0 0.0037 mol) and pyridine hydrochloride (147).
Heat at ℃ for 30 minutes and then pour into water (400 ml).

2-Cyclopentyl- with a melting point of 161-170 °C after crystallization from butyl chloride dichloroform (5:1)
2-phenyl-5-hydroxy-6,7-dichloro-1
- obtain indanone (1.17). C2OHl8Cl2
Elemental analysis value for O2: Calculated value: C66.49, H5
．． O2 experimental value: C65.52, H5. O3 Step C: (1-oxo-2-cyclopentyl-2-phenyl-6,7-dichloro-5-indanyloxy)acetic acid dimethylformamide (2-cyclopentyl-2-phenyl-5-hydroxy6,7-dichloro in 20 m0 A stirred mixture of 1-1-intason (1.107, 0.003 mol), potassium carbonate (0.857, 0.006 mol) and ethyl bromoacetate (1.027, 0.006 mol) at 55-60°C. Heat for 3 hours and add water (20m0-10N
Sodium hydroxide solution (1.2ml 1.0.012mol)
and then heated at 100° C. for 1 hour.

The reaction mixture was gradually mixed with water (300ml) and 12N hydrochloric acid (5ml).
m0 plus 184-18 after crystallization from nitromethane
680% of (1-oxo-2-cyclopentyl-2-phenyl-6,7-dichloro-5-indanyloxy)acetic acid having a melting point of 6 DEG C. is obtained. Elemental analysis value for C22H2OCl2O4: Calculated value: C63. O2, H4.8l
Experimental values: C62.59, H4.86 Example 17 [1-oxo-2-methyl-2-(4-nitrophenyl)-6,7-dichloro-5-indanyloxy]acetic acid production process A: 2-methyl- 2-(4-nitrophenyl)
5-methoxy-6,7-dichloro-1-indadanone amyl nitrate (2-methyl-2-phenyl-5-methoxy-6,7-dichloro-1) in polyphosphoric acid (1507) at 50-60°C with stirring. 11 Indanone (9.36
y10.03 mol) in 10 ml portions at 2 hour intervals.

The total heating time is 8 hours. The reaction mixture was treated with crushed ice water to give 2-methyl-2-(4-nitrophenyl)-
5-Methoxy-6,7-dichloro-1-indanone4.
82y is precipitated. It has a melting point of 179-180°C after crystallization from butyl chloride. Cl7Hl3C
Elemental analysis value for l2NO4: Calculated value: C55.76
, H3.58, N3.82 Experimental value: C55.83, H3
．． 66, N3.85l Step B: 2-methyl-2-(4-
2-Methyl-2-(4-nitrophenyl)-5-methoxy-6,7-dichloro-1-indanone 2 (4.827, 0.013 mol) and pyridine hydrochloride (507) is heated at 175° C. for 30 minutes and then poured into crushed ice water (11).

2-Methyl-2-(4-nitrophenyl)-5-hydroxy-6,7-dichloro-1-interson (4.422
7) is precipitated.

This after crystallization from ethanol 268-270
It has a melting point of °C. Elemental analysis values for Cl6Hl, Cl2NO4: Calculated values: C54.57, H3. l5, N3.
98 experimental value: C54. 18, H3.27, N4.66 Step C: [1-oxo-2-methyl-2-(4nitrophenyl)-6,7-dichloro-5-indanyloxy]acetic acid dimethylformamide (2-methyl- 2-(4-nitrophenyl)-5-human 30xy-6,7-dichloro-1-indanone (4.47, 0.0
126 mol), potassium carbonate (3.497, 0.025
2 mol) and ethyl bromoacetate (4.217, 0.02
A stirred mixture of 52 mol) was heated at 55-60°C for 3 hours, water (150 ml) and 10N sodium hydroxide solution (7.5
Tn1, 0.075 mol) and then 100°C at 100°C.
．． Heat for 5 hours.

The reaction mixture was gradually mixed with water (11?)-12N hydrochloric acid (15 m
1) plus 202-20 after crystallization from nitromethane
[1-oxo-2-methyl-2-(
2.44 y of 4-nitrophenyl)-6,7-dichloro-5-indanyloxy]acetic acid are precipitated. Cl8Hl
Elemental analysis value for 3Cl2NO6: Calculated value: C52.
7O. H3. l9, N3.4l Experimental value: C52.72,
H3. l6, N3.3O Example 18 [1-oxo-2-(4
-Aminophenyl)-2-methyl-6,7-dichloro-5-indanyloxy]Production of acetic acid Absolute ethanol (2-methyl-6,7-dichloro-5-indanyloxy)
50ml)-36N sulfuric acid ([1-oxo-2 in 2ml)
-Methyl-2-(4nitrophenyl)-6,7-dichloro-5-indanyloxy]acetic acid (6.11f10.
015 mol) is catalytically hydrogenated over 5% palladium on carbon (500 m') in a Parr apparatus.

The reaction mixture is filtered and then concentrated in vacuo to 50 ml. Add water (200 m0 to precipitate the ethyl ester,
This was mixed with ethanol (200ml), 110N sodium hydroxide solution (4.5ml, 0.045mol) and water (100ml).
Hydrolyze by refluxing for 1.5 hours in m0. The reaction mixture was cooled, concentrated to 1/3 volume, filtered, and then neutralized with 6N hydrochloric acid to give a solution with a melting point of 235-236°C (decomposed).
1-oxo-2-(4-aminophenyl)-2-methyl-6,7-dichloro-5-indanyloxy]acetic acid 1.
09y is precipitated. Elemental analysis values for Cl8Hl5Cl2NO4: Calculated values: C56.86, H3.98, N
3.68 Experimental value: C56.46, H4. O4, N3.6
Example 2 20 [1-oxo-2-(4-promophenyl)-
2-Methyl-6,7-dichloro-5-indanyloxy]acetic acid Step A: 2,3-dichloro-4-(4-bromophenyl)acetylanisole 2,3-dichloroanisole (73.5y10.414 mol), Add aluminum chloride (6.09y, 0.456 mol) in small portions to a stirred mixture of 4-promophenyl acetyl chloride (105y, 0.456mol) and carbon disulfide (360m0) while cooling at 0 to 5°C. .

The reaction mixture was kept at 25°C for 17 hours, flushed with nitrogen, and the solid residue was then washed with crushed ice and 12N hydrochloric acid (80 m
Treatment with O gives 2,3-dichloro-4-(4-bromophenyl)acetylanisole 147.77. This after crystallization from benzene:hexane (1:1)
It has a melting point of 3-164.5°C. c15H1! Brcl
Elemental analysis value for 202: Calculated value: C48.16, H
2.96 Experimental value: C48.38, H3.10 Process B: 2ζ3! -dichloro-4'-methoxy-2-(
4-bromophenyl)acrylophenone Bis-dimethylaminomethane (2,3- in 325 mO) under nitrogen
To a suspension of dichloro-4-(4-bromophenyl)acetylanisole (142,57, 0.38 mol) was added dropwise acetic anhydride (325 mol) while cooling to maintain the reaction mixture temperature below 40°C. do.

The reaction mixture was stirred at 25°C for 1 hour, then poured with crushed ice and water (
41) and added to 2ζ31-dichloro-4'-methoxy-2-(4-bromophenyl)acrylophenone 143
7 is precipitated. This is benzene-hexane (1
:5) has a melting point of 110-116°C.
Elemental analysis values for c16H11Brcl202: Calculated value: C49.78, H2.87 experimental value ZC49.73,
H2.88 Step C: 2-(4-bromophenyl)-5-methoxy-
6,7-dichloro-1-indanone dichloromethane (2
f! ) 2/・3′-dichloro-4′-methoxy-2-(4-bromophenyl)acrylophenone (1
43y10.37 mol) is added dropwise over 4 hours into cold 36N sulfuric acid (1f!)-dichloromethane (1 l) in an ice bath.

After stirring for a further 30 minutes, the reaction mixture was gradually added to crushed ice, the dichloromethane phase was separated, washed with saturated salt solution and concentrated in vacuo to give 2-(4-bromophenyl)-5-methoxy-6,7- Dichloro-1-Intason 134.87
get. This stuff is benzene in the following mash with water:
It has a melting point of 202-203°C after crystallization from hexane (1:1). Elemental analysis value for c16H11Brcl202: Calculated value: C49.78, H2.87 Experimental value: C
50.46, H3. O7 Step D: 2-(4-bromophenyl)-2-methyl-5
-Methoxy-6,7-dichloro-1-indanone sodium methoxide (28.4y10.522 mol) was added to 2-(4-bromophenyl)-5-
Methoxy-6,7-dichloro-1-interson (134
．． 6y. O. 348 mol), iodomethane (217 ml)
13.48 mol), dry benzene (1700 ml) and dry dimethylformamide (1700 ml).

The reaction mixture was brought to ambient temperature for 2 hours and then water (
81) to give 2-(4-bromophenyl)-2-methyl-5-methoxy-6,7- with a melting point of 200 to 203°C.
Dichloro-1-indanone 92.27 is precipitated. It is not soluble in the benzene present. c17H1
Elemental analysis value for 3Brc1202: Calculated value: C51
．． 03, H3.28 Experimental value: C50.71, H3.24 Step E: 2-(4-bromophenyl)-2-methyl-5
-Hydroxy-6,7-dichloro-1-indanone 2-
(4-bromophenyl)-2-methyl-5-methoxy-
6,7-dichloro-1-indanone (5.07, O.0
A stirred mixture of pyridine hydrochloride (507) and pyridine hydrochloride (507
m? Add to l).

2-(4-bromophenyl)-2-methyl-5-hydroxy-6,7-dichloro-1-indanone (4.6
87) is obtained. Elemental analysis values for C16H, 1BrCl202: Calculated values: C49.78, H2.87 Experimental values:
C49.18, H2.87 Step F: [1-oxo-2-(4-bromophenyl)-
2-Methyl-6,7-dichloro-5-indanyloxy]acetic acid in dimethyl formamide (100 ml).
4-bromophenyl)-2-methyl-5-hydroxy-
6,7-dichloro-1-indanone (4.48f..O
．． 0116 mol), potassium carbonate (3.88y10.O
232 mol) and ethyl bromoacetate (3,217, O.
A stirred mixture of 0.0232 mol) was heated at 55-60° C. for 3 hours and diluted with water (100 mO 10 N sodium hydroxide solution (5
ml, 0.05 mol) and then heated at 100° C. for 2 hours.

The reaction mixture was gradually added to crushed ice, water (1,500 m), 2 N hydrochloric acid (50 m), and 3.247 m of [1-oxo-121(4-promophenyl)-2-methyl-6,7-dichloro-5-indanyloxy]acetic acid. This is precipitated by acetic acid:water (3:2) following crystallization from nitromethane.
It has a melting point of 171-172°C after crystallization from. Cl8
Elemental analysis value for Hl3Brcl2O4: Calculated value: C
48.68, H2.95 Experimental value: C48.64, H2.
l93 Example 21 [1-oxo-2-(4-cyanophenyl)-2-methyl-6,7-dichloro-5-indanyloxy]acetic acid production process A: 2-(4-cyanophenyl)-2-methyl-5 -Methoxy-6,7-dichloro-1-indanone 2
-(4-bromophenyl)-2-methyl-5methoxy-
6,7-dichloro-1-indanone (8.00y.0.
02 mol), cuprous cyanide (3.947, 0.04 mol) and dimethylformamide (100 mol) were heated under reflux for 8 hours, and heated to a warm sodium cyanide solution (400 ml of water).
3y) and extraction with benzene, drying the benzene solution over anhydrous magnesium sulfate and then concentrating in vacuo to give an oily residue.

This was chromatographed on silica gel using chloroform and benzenelihexane (2:1).
1.13 of 2-(4-cyanophenyl)2-methyl-5-methoxy-6,7-dichloro-1-indanone with a melting point of 161-163 DEG C. is obtained. Cl8Hl3Cl
Elemental analysis value for 2NO2: Calculated value: C62.45,
H3.78, N4. O5 experimental value: C6l. 37, H3.
68, N3.73 Step B: 2-(4-cyanophenyl)
-2-methyl-5-hydroxy-6,7-dichloro-1
-indanone 2-(4-cyanophenyl)-2-methyl-5-methoxy-6,7-dichloro-1-isodanone (
2.087, 0.006 mol) and pyridine hydrochloride (2
The stirred mixture of 0y) is heated at 185° C. for 2 hours and then poured into ice water (300TI11).

2-(4-cyanophenyl)- with a melting point of 189-196°C
2-Methyl-5-hydroxy-6,7-dichloro-1-
Indanone (1.897) is obtained. This is used without further purification. Step C: [1-oxo-2-
(4-cyanophenyl)-2-methyl-6,7-dichloro-5-indanyloxy]acetic acid dimethylformamide (2(4-cyanophenyl)-2-methyl-5-hydroxy-6,7-dichloro-1 in 60 mO - indanone (1.87, 0.0054 mol), potassium carbonate (1
．． 5y,. 0.0109 mol) and ethyl bromoacetate (
1.87, 0.0109 mol) in a stirred mixture of 55 to 6
Warmed at 0 °C for 3 hours, treated with water (60 ml) and 10N sodium hydroxide solution (3 ml, 0.03 mol), then 1
Heat at 00°C for 1.5 hours.

The reaction mixture was gradually mixed with ice water (300 ml) and 12N hydrochloric acid (
In addition to 5 Tne), 160 W of [1-oxo-2-(4-cyanophenyl)-2-methyl-6,7-dichloro-5-indanyloxy]acetic acid was obtained. It has a melting point of 184-185°C after crystallization from acetic acid:water (1:1). Elemental analysis values for Cl, Hl3Cl2NO4・H2O: Calculated value: C55.9O,. H3,7O, N3.4
3 experimental values: C55.77, H3.53, N4. OO example 2
2 [1-oxo-2-methyl-2-(4-sulfamoylphenyl)-6,7-dichloro-5-indanyloxy]acetic acid production process A: [1-oxo-2-(4-chloro sulfonylphenyl)-2-methyl-6,7-dichloro-5-indanyloxy]acetic acid (1-oxo-2-
Methyl-2-phenyl-6,7-dichloro-5-indanyloxy)acetic acid (0.507, 0.0014 mol) is added portionwise to chlorosulfonic acid (5 ml) in an ice-water bath with stirring.

The reaction mixture was stirred at 0° C. for 2 hours, brought to ambient temperature for 2 hours, and then slowly added to crushed ice to form [1oxo-2-(4-
0.517 chlorosulfonylphenyl)-2-methyl-6,7-dichloro-5-indanyloxy]acetic acid is precipitated. It has a melting point of 209-210°C after crystallization from acetic acid:water (3:2). Cl8Hl3Cl
Elemental analysis value for 3O4S: Calculated value: C46.62,
H2.83, Cl22.94 Experimental value: C46.67, H
2.97, Cl22.59 Step B: [1-oxo-2-
Methyl-2-(4-sulfamoylphenyl)-6,7
-dichloro-5-indanyloxy]acetic acid [1-oxo-2-(4-chlorosulfonylphenyl)-2-methyl-6,7-dichloro-5-indanyloxy]acetic acid (
2.07, 0.0043 mol) is added in small portions to the liquid ammonia with stirring.

Evaporate the ammonia (3 hours). Dilute the residue with water (40
Dissolve to 0m0, filter, and acidify with 12N hydrochloric acid [
1-oxo-2-methyl-2-(4-sulfamoylphenyl)-6,7-dichloro-5-indanyloxy]
780 watts of acetic acid is precipitated. It has a melting point of 258-260°C after crystallization from acetic acid. Cl8Hl5C
Elemental analysis values for l2NO6S・1/4CH3C02H: Calculated values: C48.38, H3.5l, N3. O5 experimental value: C48. l5, H3.52, N2.86 Example 23 (
Process for producing 1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy)acetic acid (see GB 1328528).

)1-(1-oxo-2-methyl-2-phenyl-6.
A mixture of 7-dichloro-5-indanyloxy)-2-nitroethane (37) and 6N hydrochloric acid (100ml) was added to
Reflux for 6 hours, cool and then extract with ether.

The ethereal phase was washed with water and then extracted with dilute aqueous sodium bicarbonate, which was acidified to give (
2.07 g of 1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy)acetic acid are obtained. Example 24 (1-oxo-2-methyl-2-phenyl-6,7
-dichloro-5-indanyloxy)acetic acid production method 1 and 2
-dimethoxyethane (sodium hydride in 10 m0)
0.247, 0.01 mol) in 1,2-dimethoxyethane (10 ml) over 15 minutes. A solution of indanone (3,077, 0.01 mol) is added.

When hydrogen evolution ceases, diethyl-2-promomalonate (2.397, 0.01 mol) is added and the mixture is refluxed for 1 hour. Distill the solvent under reduced pressure. The remaining diethyl-2-(1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy) malonate was dissolved in ethanol (50 ml) and water (50 ml).
) and sodium bicarbonate (2.57) are added and the mixture is then refluxed for 4 hours, cooled, acidified, extracted with ether, washed with water and then dried over magnesium sulfate. The ether was evaporated under reduced pressure to obtain crude 2-(1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy)malonic acid, which was heated at 150°C until the evolution of carbon dioxide ceased. (1-oxo-2-methyl-2
-Phenyl-6,7-dichloro-5-indanyloxy)acetic acid is obtained.

This after recrystallization from nitromethane is 168-1
It has a melting point of 69°C. Example 25 Process for producing (1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy)acetic acid Step A: (
1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy)acetonitrile 2-methyl-2-phenyl-5-hydroxy-6,7-dichloro-1-indanone (4,617,0 .0015 mol),
Chloroacetonitrile (1.137, 0.015 mol)
, potassium carbonate (2.087, 0.015 mol), potassium iodide (0.257, 0.0015 mol) and acetone (757 n1) are heated under reflux for 23 hours.

The reaction mixture is cooled to 25° C. and then concentrated to dryness in vacuo to give an oily residue. This is triturated with water to obtain 5.127 g of (1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy)acetonitrile. It has a melting point of 163-165°C after crystallization from cyclohexanebenzene (5:1). Cl8H
Elemental analysis value for l8Cl2NO2: Calculated value: C62
．． 45, H3.78, N4. O5 experimental value: C63. O
6, H4. O3, N4. O3 step B: (1-oxo-2
-Methyl-2-phenyl-6,7-dichloro-5-indanyloxy)acetic acid Step A (1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy)acetonitrile (3. 0y) acetic acid (20ml),
A mixture of water (5 m0 and concentrated sulfuric acid (5 m0) was refluxed for 2 hours, then poured into ice water (100 m1) and (1-oxo-12
2.57 -methyl-2-phenyl-6,7-dichloro-5-indanyloxy)acetic acid are obtained.

It has a ridge of 168-169°C after recrystallization from acetic acid. Example 26 (1,2-dichloro-5a,5,6,7,8,8a-hexahythro8a-phenyl-9-oxofluoren-3-yloxy)acetic acid Step A: Cyclohexyl (2,3
-dichloro-4-methoxyphenyl)ketone 2,3-dichloroanisole (8 ml) in methylene chloride (400 ml)
8.5y10.5 mol) and cyclohexanecarbonyl chloride (817, 0.55 mol).
Cool to 74°C and then add aluminum chloride (74°C) for 1/2 hour.
7, 0.55 mol).

The reaction mixture is warmed to 25° C. and after 16 hours poured into ice water (11) and hydrochloric acid (200 mO). The organic phase is washed with 10% sodium hydroxide and saturated salt solution and then poured over magnesium sulfate. Drying. After evaporation of the solvent, the product is crystallized from hexane to give cyclohexyl (2,3-dichloro-4-methoxyphenyl)ketone 42.3y, melting point 97-98°C. Cl4Hl6Cl2O2
Elemental analysis value: Calculated value: C58.55, H5.6
2 Experimental values: C58.92, H5.64 Step B: 1-bromocyclohexyl (2,3-dichloro-4-methoxyphenyl) ketone acetic acid (bromine (22.4y, 0.14 mol) in 50 m0 was converted into acetic acid (cyclohexyl(2,3-dichloro-4-methoxyphenyl)ketone (407, 0.14 mol) in 400 mO and 30% hydrobromic acid (0.5 mO) in a stirred solution for 1.5 h at 25 °C. drip in between.

The mixture was dissolved in water (1.51) and sodium acid sulfite (1.51)
0y). The precipitated product is crystallized from cyclohexane to give 47.37 ml of 1-bromocyclohexyl (2,3-dichloro-4-methoxyphenyl)ketone, melting point 94-95°C. Elemental analysis values for Cl4Hl5Brcl2O2: Calculated values: C45.93, H4, l3 Experimental values: C45.77, H4. ll Step C: 1-cyclohexenyl (2,3-dichloro-4
-methoxyphenyl)ketone 1-bromocyclohexyl(2,3-dichloro4-methoxyphenyl)ketone (4
7.3V10.13 mol), lithium chloride (16.57
, 0.39 mol) and dimethyl formamide (200
Heating m0 at 90° C. for 2 hours and then pouring into water (11) yields 36.5 of 1-cyclohexenyl (2,3-dichloro-4-methoxyphenyl) ketone.

After vacuum drying at 60℃ for 16 hours,
It has a melting point of 129°C. Elemental analysis values for Cl4Hl4Cl2O2: Calculated values: C58.96, H4.95 Experimental values: C58.87, H5. lO Step D: 1a, 1, 2, 3, 4, 4a-hexahythro-6-methoxy 7, 8-dichlorofluoren-9-one 1-cyclohexenyl (2, 3-dichloro-4 methoxyphenyl) ketone (347, 0.12 mol) and polyphosphoric acid (340y) in a resin pot at 90'C.
Heat for 17 hours.

The product is precipitated by adding crushed ice (1k9). This was crystallized from benzenelicyclohexane (1:1) and the melting point was 1a, 1, 2, 3, 4, 4a with a melting point of 169-171°C.
18.4 of -hexahythro6-methoxy7,8-dichlorofluoren-9-one are obtained. Cl4Hl4Cl2
Elemental analysis value for O2: Calculated value: C58.96, 4.
95 experimental value: C59.35, H5.43 Process E: 1a-phenyl-1a, 1, 2, 3, 4, 4a
- Hexahythro 6-methoxy 7,8 dichlorofluoren-9-one Potassium tert-butoxide (1.697, 0.015 mol) in tert-butanol (40 ml)
1a, 1, 2, 3, 4, 4a in benzene (50 ml) and tert-butanol (10 ml) dried under nitrogen.
Add to the refluxing solution of 9-one (2.857, 0.01 mol) and continue refluxing for 0.5 hour.

The reaction mixture is cooled to 25° C. and diphenyliodonium chloride (4.757, 0.015 mol) is added, then reflux is continued for 2 hours. The reaction mixture was cooled to 25°C, 50 ml of water was added, and the mixture was then concentrated to dryness in vacuo to 1.
a-phenyl-1a,1,2,3,4,4a-hexahythro6-methoxy7,8-dichlorofluorene-9
- Get on 3.0f. This one is 136-142℃
and is used without further purification. Step F: 1a-Phenyl-1a, 1, 2, 3, 4.
4a-Hexahythro6-hydroxy-7,8dichlorofluoren-9-one 1a-phenyl-1a,1,2.
3.4.4a A stirred mixture of hexahythro 6-methoxy 7,8-dichlorofluoren-9-one (30y.0.0083 mol) and pyridine hydrochloride (307) was added to 18
Heat at 0° C. for 2 hours, then pour in water (800 m0).

1a-phenyl 1a, 1, 2, 3, 4-4a with a melting point of 213-215 °C after crystallization from absolute ethanol
-hexahydro 6-hydroxy-7,8-dichlorofluoren-9-one (1.717) is obtained. Cl9Hl6C
Elemental analysis value for l2O2: Calculated value: C65.72,
H4.64 experimental value: C66.27, H4.78 Step G: (1,2-dichloro-5a, 5, 6, 78, 8
a-hexahythro8a-phenyl-9oxofluoren-3-yloxy)acetic acid dimethyl formamide (
1a phenyl-1a, 1, 2, 3, 4, in 50 m1)
4a-hexahythro6-hydroxy-7,8-dichlorofluoren-9-one (1.77, 0.0049 mol), potassium carbonate (1.367, 0.0098 mol) and ethyl bromoacetate (1.647, 0. 0098 mol)
The stirred mixture of was heated at 55-60°C for 3 hours and water (50
m0-10N sodium hydroxide solution (2.5me10.
025 mol) and then heated at 80° C. for 1.5 hours.

The reaction mixture was gradually diluted with water (500 m
0 plus (1,2-dichloro-5a,5,6,7,8
1.517 of 8a-hexahydro8a-phenyl-9-oxofluoren-3-yloxy)acetic acid is obtained.
This after crystallization from acetic acid:water (1:1)
It has a melting point of ~196°C. Elemental analysis values for Cl2Hl8Cl2O4: Calculated values: C62.24, H4.48 Experimental values: C62.27, H4.56 Example 27 (1-oxo-2-methyl-2-phenyl-67-dichloro-5-indanyloxy ) Acetic acid manufacturing process A: 3rd
Butyl (1-oxo-2-methyl-2-phenyl-6
・7-dichloro-5-indanyloxy)acetate dimethyl formamide (2-methyl-2- in 30 m0
phenyl-5-hydroxy-6,7-dichloro-1-intason (9.27, 0.03 mol), potassium carbonate (8
．． 297, 0.06 mol) and tert-butyl bromoacetate (6.447, 0.033 mol) at 25°C.
Stir for an hour.

The reaction mixture was poured into cold water (150 mO) and the precipitated tertiary butyl (1-oxo-2-methyl-2-phenyl 6
-7-dichloro-5-indanyloxy)acetate is filtered off, rinsed with water and dried. Step B: (1-oxo-2-methyl-2-phenyl-6,7-dichloro-5
Tertiary-butyl (1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy) acetate (1.0 V, .0.00237 in benzene (25 ml)) mol) with methanesulfonic acid (2 drops) and then refluxed for 1/2 hour.

The reaction mixture was treated with cyclohexane (20 mO) and cooled to give (1-oxo-2-methyl-2-phenyl-6
- 7-dichloro-5-indanyloxy)acetic acid is obtained, which is filtered and then dried. Example 28 [1-oxo-2-methyl-2-(2-thienyl)-6,7-dichloro-5-
Production process A of indanyloxy] acetic acid: 2.Z-dithienyl iodonium chloride at 20°C and acetic anhydride (70
To m0, with stirring, fuming nitric acid (27 m0) is added dropwise, followed by iodine (257, 0.1 mol) and trifluoroacetic acid (47 ml, 0.61 mol).

The mixture is brought to ambient temperature for 3 hours while the iodine is dissolved. The solvent is removed by vacuum distillation. At this time, the pot temperature should not exceed 50°C. The residue was dissolved in acetic anhydride (150 mO, the solution was cooled to 10 °C,
Then a mixture of thiophene (63 ml, 0.08 mol), acetic anhydride (350 ml) and trifluoroacetic acid (50 ml) is added dropwise over 1 hour. After cooling to 5° C. for 17 hours, the mixture is distilled under vacuum.

At this time, the pot temperature should not exceed 50°C.
Water (500ml) was added to the residue, the solution was filtered and then ammonium chloride (21.36y
After crystallization from methanol by adding 10.4 mol)
2.Z-dithienyl iodonium chloride 26,67 is obtained with a melting point of 5-236°C. C8H6CHS2
Elemental analysis value for: Calculated value: C29.24, Hl. 84 Experimental values: C28.9O, Hl. 92 Step B: 2-Methyl-2-(2-thienyl)-5methoxy-6,7-dichloro-1-indanone Potassium tert-butoxide (5.06y10.045 mol) dissolved in tert-butanol (100 ml) tertiary butanol (
150 mO-benzene (Step A of Example 5 in 150 mO
2-Methyl-5-methoxy6,7-dichloro-1-interson (7.35y
, 0.03 mol) of the reflux solution and the reflux was reduced to 3
The mixture was then allowed to cool slightly and the solid dithienyl iodonium chloride (16.57,0.
05 mol) at once.

Continue heating at reflux for 2 hours. The reaction mixture was cooled to 25°C, 100ml of water was added, and the mixture was then concentrated to dryness in vacuo to give 2-methyl-2-(2-thienyl)-5methoxy-6.
- 7-dichloro-1-indanone 3.857 is obtained.

After trituration with ether and crystallization from benzenelihexane (1:4), the
It has a melting point of 6.5°C. Elemental analysis value for Cl5Hl2Cl2O2S: Calculated value: C55. O6, H3.7O Experimental value: C55.24, H3.77 Wang Cheng C: 2-methyl-2-(2-thienyl)-5hydroxy-6,7-dichloro-1-indanone 2-methyl-
2-(2-thienyl)-5-methoxy-6,7-dichloro-1-indanone (3.65y10.0112 mol)
and pyridine hydrochloride (367) at 175°C.
Heat for 30 minutes, then add crushed ice water (500 mO).

224-226 after crystallization from ethanol:water (2:1)
2-Methyl-2-(2-thienyl)- with a melting point of °C
5-hydroxy-6,7-dichloro-1-indanone (
3.37y) is obtained. Elemental analysis values for Cl4HlOCl2O2S: Calculated values: C53.69, H3.22 Experimental values: C53.27, H3.36 Step D: [1-oxo-2-methyl-2-(2-thienyl)-6,7-dichloro- 5-Indanyloxy]2-methyl-2 in dimethyl acetate formamide (40ml)
-(2-thienyl)-5-hydroxy 6,7-dichloro-1-indanone (3.137, 0.01 mol), potassium carbonate (2.777, 0.02 mol) and ethyl bromoacetate (3.34V10. 02 mol) of a stirred mixture of 5
Warm at 5-60° C. for 2 hours, treat with water (40 ml)-10N sodium hydroxide solution (4 ml, 0.04 mol), then heat to 100° C. for 1 hour.

The reaction mixture was gradually added to crushed ice water (700 ml) and 12N hydrochloric acid (10 ml).
1.787 -(2-thienyl)6,7-dichloro-5-indanyloxy]acetic acid is precipitated. It has a melting point of 161-162°C after crystallization from nitromethane. Elemental analysis values for Cl6Hl2Cl2O4S: Calculated values: C5l, 78, H3.24, Cl9. 1O experimental value: C5l. 66, H3.34, Cll9.2l Example 29
In step A of Example 5, instead of 2.3-dichloroanisole, a corresponding amount of 2-chloro-3-methylanisole, 2.3-dimethylanisole, 3-methylanisole or 2-methyl-3-chloroanisole was added. and using Steps B-D of Example 5 and Steps A-D of Example 28 as described above, [1-oxo-2-(2-thienyl)-2.7dimethyl-6-chloro-5 -indanyloxy]acetic acid[1-oxo-2-(2-thienyl)-2.
6゜7-trimethyl-5-indanyloxy]acetic acid [1
-oxo-2-(2-thienyl)2,7dimethyl-5-
Indanyloxy]acetic acid.

[1-oxo-2-(2-thienyl)-2,6-dimethyl-J-[chloro-5-indanyloxy]acetic acid is obtained.

Example 30 In step A of Example 28, instead of thiophene, the respective corresponding amounts of 2-methylthiophene, 2-promothiophene, 2-chlorothiophene or 2..5-dimethylthiophene
JAG is used and steps B through D are used as described above. Oxy]acetic acid[1-oxo-2-methyl-2-(5-bromo2-thienyl)-6,7-dichloro-5-indanyloxy]acetic acid[1-oxo-2-methyl-2-(5-
Chloro-2-thienyl)-6,7-dichloro-5-indanyloxy]acetic acid [1-oxo-2-methyl-2-(2
・5-dinimethyl-3-thienyl)-6,7-dichloro-5-indanyloxy]acetic acid is obtained.

Example 31 [1-oxo-2-(4-aminomethylphenyl)
-2-Methyl-6,7-dichloro-5-indanyloxy]acetic acid production process A: {1-oxo-2-[4-(2
Stir well-pulverized N-hydroxymethyl-2-chloroacetamide (3.377, 0.0274 mol) However, 36N sulfuric acid (100 m
(1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy)acetic acid (10.07, 0.0274 mol) in 100 mO.

Furthermore, N-hydroxymethyl-2-chloroacetamide (
1.687, 0.014 mol) over 4 hours until no starting material remains. After stirring at 25 °C for 16 h, the reaction mixture was added to crushed ice (21)
11.97 ml of 1-oxo-2-[4-(2chloroacetamidomethyl)phenyl-2-methyl-6,7-dichloro-5-indanyloxy}acetic acid is precipitated.

It has a melting point of 138-141°C and is used without further purification. Step B: Ethyl [1-
Oxo)-2-(4-aminomethylphenyl)-2-methyl-6,7-dichloro-5-indanyloxy]acetate hydrochloride {1-oxo-2-[4-(2-chloroacetamidomethyl)phenyl ]-2-methyl-6,7dichloro-5-indanyloxy}acetic acid (2.07, 0.
004 mol), anhydrous ethanol (20 ml) and 12N hydrochloric acid (7 ml) are combined and heated to reflux for 3 hours.

Cool to 5°C and add ethyl [1-oxo2-(4-aminomethylphenyl)-2-methyl-6,7-dichloro-5-
Indanyloxy]acetate hydrochloride is precipitated.

This after crystallization from ethanol 211-213
It has a melting point of °C. Elemental analysis values for C2lH2, Cl2NO4/HCl: Calculated values: C54.98, H4.83
, N3. O5 experimental value: C54.39, H4.72, N2
．． 76 Step C: [1-oxo-2-(4-aminomethylphenyl)-2-methyl-6,7-dichloro-5-indanyloxy]acetic acid sodium salt ethyl [1-oxo-2-(4-aminomethylphenyl)-2-methyl-6,7-dichloro5-indanyloxy]
-(4-aminomethylphenyl)-2-methyl-6,7
-dichloro-15-indanyloxy]acetate hydrochloride (1.577, 0.0034 mol), sodium bicarbonate (1.157, 0.0136 mol), absolute ethanol (
50 mO and water (50 mO) are combined and then heated under reflux for 1.5 hours.

The solution was filtered and then 1N hydrochloric acid (10.26ml 110.0
1026 mol) to precipitate the sodium salt of [1-oxo-2-(2-methyl-6,7-dichloro-5-indanyloxy]acetate, 900% of 4-aminomethylphenol). , has a melting point of 270-271°C after drying. Elemental analysis values for Cl, Hl7cl2NO4Na: Calculated values: C54.83, H3.87, N3.3
7 Experimental value: C55. O7, H4.27, N3.2O example 3
2. Process for resolving optical isomers of (1-oxo-2-methyl-2-JG-6,7-dichloro-5-indanyloxy)acetic acid A. (+) monoisomeric racemic (1-oxo-2-methyl-2-phenyl-6.
7-dichloro-5-indanyloxy)acetic acid (267,
A mixture of 0.071 mol) and L-(-)-α-methylbenzylamine (8.6f7, 04071 mol) was dissolved in hot acetonitrile (250 mol) and heated at 25°C for 18
Leave it for a while.

The salt obtained from acetonitrile (13.

27) and this salt was recrystallized three times from a minimum amount of propanol to obtain the pure (+) enantiomer salt 1.9
Get 7.

This is converted to the acid by treatment of the salt with dilute hydrochloric acid and ether. The ether phase is washed with water and dried over magnesium sulfate, then the ether is distilled under reduced pressure. The (+) monoisomer has a melting point of 163° C. after crystallization from toluene.
[α]=+88 crystals (C, 2, acetone). Process B: (-
) partially resolved (1-oxo-2-methyl-2-phenyl6,7-dichloro-5-indanyloxy)acetic acid (15.57,0,
042 mol) (obtained from the acetonitrile mother liquor of step A) and D-(+)-α-methylbenzylamine (5,
15y (10.042 mol) as a reactant and the resulting salt was recrystallized three times from a minimum amount of 2-propanol--substantially by the method described in step A. -) monoenantiomer salt 2.27 is obtained.

The (-) monoisomer has a melting point of 164° C. after crystallization from toluene. [α] Blue 1188 crystal (C, 2, acetone).
The novel compounds of this invention are diuretics and salt excretion agents.

Furthermore, these compounds can also maintain the uric acid concentration in the blood at a predetermined level. or even cause a decrease in uric acid concentration. The compounds of the invention can be administered for therapeutic use in a wide variety of common vehicles, such as by oral administration in tablet form or by intravenous injection.

Also, the daily dosage of the product may be eg 2.5 of the active ingredient while adjusting the dosage symptomatically for the patient being treated.
, 1, 5, 10, 25, 501100, 1501200
The form of tablets containing 1250 and 500η can vary over a wide range. These usage amounts are far below toxic or lethal amounts of product. Suitable unit usage forms of the products of the invention include the [1-oxo-2-aryl or 2-thienyl-2-monosubstituted-5-indanyloxy (or thio)]alkanoic acids (1) or their appropriate forms. 50 salts, esters, amide derivatives, 5-tetrazolyl analogues are mixed with 149 mg of lactose and 1 η of magnesium stearate, and this mixture is mixed with A6. 1 by placing it in a gelatin capsule.

Similarly, other use forms can be incorporated into Taki 1 gelatin capsules by using larger amounts of active ingredient and smaller amounts of lactose. If desired, compressed tablets, pills or other desired unit dosage forms can be prepared and incorporated with the compounds of the invention by conventional methods. If necessary, they can be made into elixirs or injectable solutions by methods well known to the pharmaceutical industry. The effective amount of the drug is usually about 0.00 kg/kg body weight.
Applicable at a dosage of 0.025-20. The preferred range is approximately 0.06 to 7 kg/k9 body weight. Combining two or more compounds of the invention in one unit dosage form or combining one or more compounds of the invention in one unit dosage form with other known diuretic and salt excretion agents or other It is also within the scope of this invention to combine with desired therapeutic and/or nutritional agents. For example, a compound of the invention can be combined with a treatment agent such as an anti-hypertensive compound, particularly methyldopa or reserpine. Also,
Especially when one compound has a large diuretic activity and the other compound has a large uricosuric activity.
Mixtures of different intersons of formula (1) are advantageous. The following examples illustrate the manufacture of typical usage configurations.

Example 33 Preparation of dry-filled capsules containing 10 η of active ingredient per capsule (1-oxo-12-methyl-2-phenyl-6,7-dichloro-5-indanyloxy) washed with acetic acid 6
0 powder, then lactose and magnesium stearate/1f). 60 through a sieve cloth and mix the combined ingredients, then Al). 1 Fill into dry gelatin capsules.

Similar dry-filled capsules may be prepared by replacing the active ingredients of the above examples with molar equivalent amounts of other novel compounds of the invention.

Example 34 Parenteral solution of sodium (1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy) acetate (1-oxo-2-methyl-2-phenyl-6,7-dichloro-1) 5-indanyloxy)acetic acid (1
7) in water (10 mO) with sodium bicarbonate (0.25 V
) and then the mixture is stirred and heated to form a solution.

This solution was diluted with water to make 50ml and then heated to 120°C.
Sterilize by autoclaying for 1 hour. Example 35 10 to 10 active ingredients and 0.1 reserpine per capsule
Dry-filled capsules (1-oxo-2-
Combine methyl-2-phenyl-6,7-dichloro-5-indanyloxy)acetic acid and reserpine and wash 60
powder, then lactose and magnesium stearate were mixed with the powder through a 60-sieve sieve cloth, the combined ingredients were mixed for 10 minutes, and then S). 1 Fill into dry gelatin capsules.

Similar dry-filled capsules can be made by replacing the indanyloxyacetic acid component of the above examples with any of the compounds of the present invention.

Example 36 Dry-filled capsules containing 10~ of the active ingredient and 250~ of levo-3-(3,4-dihydroxyphenyl)-2-methylalanine (1-oxo-2-methyl-2-phenyl-6,7-dichloro -5-indanyloxy)acetic acid and levo-3-(
3,4-dihydroxyphenyl)2-alanine and. 4660 powder, then lactose and magnesium stearate are mixed with the above powder through a 60 sieve cloth, the combined ingredients are mixed for 10 minutes and then filled into rotary 0 dry gelatin capsules.

As is clear from the above explanation, 1-oxo-2
- The 2-disubstituted-5-indanyloxyalkanoic acid products (1) constitute a valuable class of compounds that have not been produced hitherto.

As those skilled in the art will appreciate, the methods illustrated in the examples above are for illustrative purposes only and a wide range of changes and modifications may be made without departing from the spirit of the invention. Example 37 Dry-filled capsules containing 50 mg of active ingredient per capsule (1-oxo-2-methyl-2-(2-thienyl)
-6,7-dichloro-5-indanyloxy)acetic acid as Tiger 60 powder, then lactose and magnesium stearate were mixed with the above powder through a waste 60 sieve cloth, the combined ingredients were mixed for 10 minutes, then Fill into 1 dry gelatin capsule.

Similar dry-filled capsules can be prepared by replacing the active ingredients of the above examples with molar equivalents of other novel compounds of the invention. Example 38 Parenteral solution of sodium (1-oxo-2-methyl-2(2-thienyl)-6,7-dichloro-5-indanyloxy)acetate (1-oxo-2-methyl-2-
thienyl-6,7-dichloro-5-indanyloxy)
Acetic acid (1V) was dissolved in sodium bicarbonate (0
．． 25y) and then stir and heat the mixture to form a solution.

The solution was diluted to 50 ml with water, then diluted to 120 ml at 120°C.
Sterilize by autoclaving for an hour. Example 39 1 capsule 25η of active ingredient and 0.125m of reserpine
Dry-filled capsules containing A6
．． 6O powder and then mix lactose and magnesium stearate with the powder through a waterfall 60 sieve cloth,
Mix the combined ingredients for 10 minutes, then A6. Fill into 1 liter dry gelatin capsules.

Similar dry-filled capsules can be made by replacing indanyloxyacetic acid in the above examples with other compounds of the invention.

Example 40 Dry-filled capsules (1-oxo-2-methyl-2-(2-thienyl)-6) containing 10 m of active ingredients and 250 η of levo-3-(3,4-dihydroxyphenyl)-2-methylalanine.
・7-dichloro-5-indanyloxy)acetic acid and levo-3-(3,4-dihydroxyphenyl)-2-alanine are combined, then lactose and magnesium stearate are mixed with the above powder through a washed 60 sieve cloth. The combined ingredients are mixed for 10 minutes and then filled into dry gelatin capsules.

Claims (1)

[Claims] 1. In the presence of a base, the formula ▲ has a mathematical formula, a chemical formula, a table, etc. ▼ (wherein, A, R^0, R, R^1, X^1, X^2, X
^3, X^7 and X^8 are as described below. ) is treated with a reagent of formula ZY-C-OR^3 (where Y is as defined below, Z is halogen, and R^3 is hydrogen or lower alkyl) and R^ 3
If is lower alkyl, the resulting ester is hydrolyzed ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^0 is ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲There are mathematical formulas, chemical formulas, tables, etc.▼. A is oxygen or sulfur. R is lower alkyl, lower alkenyl, phenyl lower alkyl, thienyl, phenyl lower alkenyl, phenyl, cycloalkyl or cycloalkyl lower alkyl. R^1 is hydrogen, lower alkyl or aryl. R^1 and R can be taken together to form cycloalkylene. Y is alkylene or haloalkylene containing 1 to about 4 carbon atoms. X^3 is hydrogen, nitro, lower alkyl, lower alkoxy, cycloalkyl, halogen, amino, cyano, sulfamoyl or methanesulfonyl. X
^7 is hydrogen, lower alkyl or halogen. X^
8 is hydrogen or lower alkyl. X^1 is hydrogen, halogen or methyl. X^2 is halogen, methyl or trihalomethyl. X^1 and X^2 may be taken together to form a hydrocarpylene chain containing from 3 to about 4 carbon atoms. ] method for producing the compound. 2 Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^0, R, X^1, X^2, X^3, X^7
and X^8 are as described below. ) is treated with a reagent of the formula ▲ (mathematical formula, chemical formula, table, etc.) (where Z is halogen. R^3 is t-butyl) in the presence of a base, then t - Formulas characterized by thermal decomposition of butyl esters to form desired products ▲ Numerical formulas, chemical formulas, tables, etc. ▼ [In the formula, R
^0 is ▲There are mathematical formulas, chemical formulas, tables, etc.▼ or ▲There are mathematical formulas, chemical formulas, tables, etc.▼. R is lower alkyl. X^1 and X^2 are selected from the group consisting of chlorine and methyl. X^3
is hydrogen, nitro, lower alkyl, lower alkoxy, cycloalkyl, halogen, amino, cyano, sulfamoyl or methanesulfonyl. X^7 is hydrogen, lower alkyl, or halogen. X^8 is hydrogen or lower alkyl. ] method for producing the compound. 3 Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, X^1, X^2, R^0, R and R^1 are as described below). React with to form a compound with the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (wherein, X^1, X^2, R^0, R and R^1 are as described below) A formula characterized by hydrolyzing the latter compound to obtain the desired product ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^0 is ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲There are mathematical formulas, chemical formulas, tables, etc.▼. R is lower alkyl, lower alkenyl, phenyl lower alkyl, thienyl, phenyl lower alkenyl, thienyl,
Cycloalkyl or cycloalkyl lower alkyl. R^1 is hydrogen, lower alkyl or aryl R^
1 and R may be taken together to form cycloalkylene. X^3 is hydrogen, nitro, lower alkyl, lower alkoxy, cycloalkyl, halogen, amino, cyano, sulfamoyl or methanesulfonyl. X^7
is hydrogen, lower alkyl or halogen. X^8 is hydrogen or lower alkyl. X^1 is hydrogen, halogen or methyl. X^2 is halogen, methyl or trihalomethyl. Or X^1 and X^2 can be taken together to form a hydrocarpylene chain containing from 3 to about 4 carbon atoms. ] method for producing the compound. 4 Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, X^1, X^3, R^0, R and R^1 are as described above.) There are tables, etc. ▼ (In the formula, R'' is lower alkyl.) Reacted with malonic acid ester ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (In the formula, X^1, X^2, R ＾0, R and R＾1 are as described below. R″ is as described above.)), and the latter compound is hydrolyzed to form the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (wherein X^1, Formulas characterized by obtaining ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^0 is ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼. R is lower alkyl, lower alkenyl, phenyl lower alkyl, thienyl, phenyl lower alkenyl, phenyl,
Cycloalkyl or cycloalkyl lower alkyl. R^1 is hydrogen, lower alkyl or aryl. R^1 and R can be taken together to form cycloalkylene. X^3 is hydrogen, nitro, lower alkyl, lower alkoxy, cycloalkyl, halogen, amino, cyano, sulfamoyl or methanesulfonyl.
X^7 is hydrogen, lower alkyl or halogen. X
^8 is hydrogen or lower alkyl. X^1 is hydrogen,
Halogen or methyl. X^2 is halogen, methyl or trihalomethyl. or X^1 and X
^2 can be taken together to form a hydrocarpylene chain containing from 3 to about 4 carbon atoms. ] method for producing the compound. 5 Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, A, R^0, R, R^1, X^1 and X^2
is as described below. ) is reacted with a haloacetonitrile in the presence of a base, and then the nitrile intermediate is hydrolyzed. There are formulas, chemical formulas, tables, etc., where R^0 is There are chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼. A is oxygen or sulfur. R is lower alkyl, lower alkenyl, phenyl lower alkyl, thienyl, phenyl lower alkenyl, phenyl, cycloalkyl or cycloalkyl lower alkyl. R^1 is hydrogen, lower alkyl or aryl. R^1 and R can be taken together to form cycloalkylene. X^3 is hydrogen, nitro, lower alkyl, lower alkoxy, cycloalkyl, halogen, amino, cyano, sulfamoyl or methanesulfonyl. X^7 is hydrogen, lower alkyl or halogen. X^8 is hydrogen or lower alkyl. X_1 is hydrogen, halogen or methyl. X^2 is halogen, methyl or trihalomethyl. Or X^1 and X^2 can be taken together to form a hydrocarpylene chain containing from 3 to about 4 carbon atoms. ] method for producing the compound.