FI61866C - PROCEDURE FOR FRAMSTATING OF DIURETICAL ELLER SALURETISK (1-OXO-2-PHENYL-ELLER-THENYL-2-SUBSTITUTE-5-INDANYLOXY) AETTIKSYRA ELLER DESS DERIVAT - Google Patents

Description

I- Γβ. .... NOTICE OF PUBLICATION, '0,, ^ ΙΪα ^ (11) UTLÄGGNINGSSKRIFT 61866 C / 451 Patent granted II ΙΟ 1932' Patent re? 3Jelat ^ (51) KY.ik.Vci.3 C 07 c 59/90, C 07 D 353/10 FINLAND —FINLAND (21) Pw * nttlh »k * mui - PttMtKweknlng 2789/71 + (22) H« k «mltpilv · - An * eknlnf» di | 25.09 * 7 ^ (23) AlkupUvt — GIMghMsd «(25.09.71+ (41) Tullut] ulklMk« l - Bllvlt off * ntll | 12 .OU.75

Patent and registry held. NU.avlk.lpwo, j. kuaLiuHclwn p * m—

Patent- och ragisterstyralaan '' Ansakin ucbgd och utMkrlton published 30.06.82 (32) (33) (31) Fyy4 «** y« uotkuu.— fegird prlorltut n. Χο. 73 3O.O7.7U, 30.07-71 *, 30.07.7 ^ USA (US) I + O5736 I + 9265I, I + 92652, I + 92653 (71) Merck & Co., Inc., 12β E. Lincoln Avenue , Rahway, New Jersey, USA (72) Edward Jethro Cragoe, Jr., Lansdale, Penn., Otto William Woltersdorf,

Jr., Chalfont, Penn., Warren Kenneth Russ, Jr., Piscataway, New Jersey, George Gustave Hazen, Westfield, New Jersey, Earl Martin Chamberlin, Westfield, New Jersey, USA (71+) Oy Kolster Ab ( 5I +) Process for the preparation of a diuretic and a saluretic 1-oxo-2-phenyl- or thienyl-2-substituted-5-indanyloxy-acetic acid or a derivative thereof -thienyl-2-substituents-5-indanyloxy / acetic acid or derivatives

The invention relates to a process for the preparation of N-oxo-2-phenyl- or thienyl-2-substituted-5-indanyloxy / acetic acid or a derivative thereof having diuretic and saluretic activity and having the formula

Cl O

,, YtV

R 0CCH 2 O-J-L

R 1 X 3 wherein R 0 is or ^ ίβηΧΥϋ · wherein X 3 is hydrogen, halogen, 2,61866 3 methoxy, nitro, amino or cyano, R is hydrogen or lower alkyl, • j R is methyl, ethyl, phenyl or cyclopentyl, and R is hydrogen or phenyl or R and R together form a 6-membered ring.

Pharmacological studies show that the novel compounds of the invention are effective diuretic and saluretic agents that can be used to treat conditions associated with electrolyte and fluid retention. They can also be used to treat high blood pressure. In addition, these compounds can maintain the concentration of uric acid in the body at pretreatment concentrations or even reduce the concentration of uric acid when administered at therapeutic doses in conventional media.

Many currently available diuretics and saluretics tend to cause urinary hypersecretion after administration, which may precipitate uric acid or sodium urate or both in the body, which can lead to a mild to severe gout. The new compounds have provided an effective means of treating patients in need of diuretic and saluretic therapy without the risk of developing gout. In fact, when used in appropriate doses, the new compounds are uricosuric agents.

Thus, when comparing the compounds prepared according to the application with structurally related compounds, for example according to DE application publications 2 351 412 and 2 365 379, they have two basic advantages. First, the compounds have higher diuretic and saluretic activity than the known compounds. Second, the compounds also have uricosuric activity, i. the compounds cause the excretion of uric acid together with water and electrolytes during urinary excretion. This uricosuric activity is desirable because it prevents the formation of a hyperuricemic condition, which is almost always the result of the administration of potent diuretics. Thus, urate (uric acid salt) retention, hyperuricemia, and possibly gout may result. In addition, hyperuricemia itself may be a risk factor for the development of cardiovascular disease, carbohydrate resistance, and urate-induced kidney disease.

The process according to the invention for the preparation of said compounds is characterized in that 3 61866 (a) is treated with a compound of formula:

Cl O

civMks °

I R

HO-- | wherein R 0, R 2 and R 2 are as defined above, with a reagent of formula: O ZCH 2 -C-OR 3, 3 wherein R is as defined above and Z is halogen, in the presence of base 3, and when R is a lower alkyl ester obtained if desired, hydrolyzed; or (b) for the preparation of a compound of formula I wherein R 0 is phenyl and R 1 is hydrogen, treating a compound of formula:

Cl 0 cOyV '° 0 I 1 "n 1 R 0CCH 2 O- alkylating agent of formula: R 2, wherein R 0, R 1, R 3 and R are as defined above and 3 Z is halogen, and if desired when R is lower the alkyl ester obtained is hydrolysed, or (c) to prepare a compound of formula I wherein R 3 is hydrogen, treating a compound of formula: 61866

Cl O

4

"VyVT

H0 - ^ / - wherein R0, R and R1 are as defined above, with 1-halo-2-nitroethane to form a compound of formula

Cl 0 is C1 M, O 2 NCH 2 CH 2 O 2 S 2; or (d) for the preparation of a compound of formula I wherein R 3 is hydrogen, treating a compound of formula: wherein R 0, R and R are as defined above with a malonic acid ester of formula R, , 2 ° C, CH 2, wherein R "is lower alkyl, to form a compound of formula R" O 2 Cl 2 of formula

Cl o 5 61866 - Ml R °

^^ * R

(r "° 2C) ^ hct * 5 ^ wherein R °, R, R1 and R" are as defined above, the resulting compound is hydrolyzed to form a compound of formula:

Cl 0 (HO 2 O 2 CHO 1 x 2 O 1 wherein R, R, R are as defined above and the latter compound is decarboxylated to form the desired product; or (e) to prepare a compound of formula I wherein R 0 is phenyl, R is methyl, R 1 is hydrogen and R 1 is hydrogen, is treated with a compound of formula:

Cl 0

R

H0 -v J-k \ r1 o 1 wherein R, R and R are as defined above, with haloacetonitrile in the presence of a base, and the resulting nitrile is hydrolyzed; or (f) for the preparation of a compound of formula:

Cl 0; "Lav».

H0CCH2O - 1 J

wherein R 0 is phenyl, halophenyl or thienyl; a compound of formula: 6 61866

Cl CHCH, R 4 ° - 4 2 2 2 wherein R is Cl 2 COOH, R or Cl 2 COOR where R is methyl is reacted with formaldehyde in the presence of an acid; 3 and that if the substituent X in the final product of formula I is a nitro group, this nitro group may be reduced to an amino group if desired.

Process alternative (a) is illustrated by the following reaction scheme:

Cl O

^ R Base \ + R OCCH2Z

IV

Cl o. C'VW; r3o1ch2o— ^ J 1-3 when R = lower alkyl: hydrolysis, 3 when R = t-butyl, pyrolysis

'V

Cl 0 csAA <"° ° | * hocch2o - L ^ · 1 where the substituents have the same meaning as above.

7 61866

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 inert or substantially inert solvent may be used. Acetone, ethanol and dimethylformamide, for example, have been found to be particularly preferred solvents. The reaction can be carried out at a temperature in the range of about 25 ° C to the reflux temperature of the solvent used. When a haloalkanoic acid ester is used, the ester obtained can be hydrolyzed to the free acid in a manner known per se. When there is a tert-butyl group, the acid can be obtained by acid-catalyzed pyrolysis, such as by heating the tert-butyl ester in the presence of a strong acid, e.g. p-toluenesulfonic acid, sulfuric acid, hydrogen chloride gas and the like. In general, the pyrolysis is carried out by heating at a temperature in the range of about 70 to 140 ° C, preferably 80 to 100 ° C. Pyrolysis can be performed using a solvent or in the presence of a suitable non-aqueous medium in which the reaction components are moderately soluble, e.g., in the presence of benzene, toluene, xylene, and the like.

In process variant (b), the reaction is carried out by first treating 1-oxo-2-phenyl- or -2-thienyl-5-indanyloxy-7-acetic acid or ester with a suitable base, e.g. an alkali metal hydride such as sodium hydride and the like, or an alkali metal alkoxide such as potassium tert-butoxide, sodium methoxide and the like, or an alkali metal amide such as sodium amide, lithium amide and the like. The resulting carbanion is then treated with an alkylating agent RZ. Any inert or substantially inert solvent may be used. Suitable solvents include, for example, 1,2-dimethoxyethane, tert-butanol, benzene, dimethylformamide and the like. The reaction can be carried out at a temperature in the range of about 0 to 150 ° C. In general, the reaction is carried out in the range of about 0 to 50 ° C. The following reaction scheme illustrates this method:

Cl O

8 618 6 6

VyV °,! ,

R OCCH O - 1-R

\ Base 111 RZ \

Cl o

"YyV

o I

R30CCH-O-VN,} -1

2 N / ^ R

3 when R = lower alkyl = hydrolysis, when R 3 = t-butyl, pyrolysis

V

Cl o

IyVV

hocch o - k,

1 R

wherein R, R 0, R 1 and Z are as defined above and R 3 is hydrogen or lower alkyl.

Process variant (c) is described by the following reaction: 9 61866 γΥ ^ ς no2ch2ch2ci ^

Si1 o2nch2ch2o - ^ R1 IVa yS ivb yr hydrolysis οι o If “JX '°

o II

H0CCH20 -R1

According to the method, the 5-hydroxy compound (IVa) is reacted with halonitroethane to form the 2-nitroethane intermediate (IVb), which hydrolyses the final product (I).

The preparation of an intermediate of formula IVb is described in British Patent 1,325,528.

Execution of method variant (d) is described in detail in Embodiment 16.

Method alternative (e) is illustrated by the following reaction scheme: ί1 n o Cl 0 aJX 'C1_JJUR °

| Γ '·. R ZCH2CN / base -L Ni | p ~ R

HO — ky R1 -> NCCH2 ° --k R1

IV XIV

hydrolysis

Cl O

10 61 866 wherein all substituents have the same meaning as above.

5-Hydroxyindanone (IV) is treated with a haloacetonitrile such as chloroacetonitrile, bromoacetonitrile or iodoacetonitrile in the presence of a base such as potassium carbonate or the like in a suitable solvent such as acetone, dimethylformamide, ) which is hydrolysed to give compounds of formula I.

This is a typical hydrolysis of the nitrile reaction and is well known in the art.

Process variant (f) is illustrated by the following reaction scheme: C1 Cl i R ° 1 0 R °

. CHCOCl Step 1 I C

R40_k J I - ^ R4o — L J I CH3

Ch3 / ^ H

yr Step 2 / paraformaldehyde / acid - Cl _ X ° f 0 \ —- / y γ — I isolated intermediates II C products / I— ch2x _ |

V

Cl o I! /

Cl-Step 3 CTL · Lewish acid

4 v 1 J I

ro ---- - o 4 wherein R is phenyl, halophenyl or thienyl and R is CH 2 COOH, 2 2 2 ^ R or CH 2 COOR where R is methyl and X is OH or halogen.

According to the scheme, 2-phenyl, halophenyl or thienylpropionyl halide or its anhydride and 2,3-dichlorophenol ether (such as 2,3-dichloroanisole) or 2,3-dichlorophenoxyacetic acid or its ester are reacted (step 1) under Friedel-Crafts conditions in the presence of a suitable catalyst such as aluminum trichloride and the like in a solvent such as methylene chloride or the like to give the corresponding propiophenone which is reacted (step 2) with formaldehyde (paraformaldehyde) in the presence of an acid to give an intermediate.

In describing Step 1 in more detail, suitable catalysts include a Friedel-Crafts catalyst such as aluminum trichloride, SnCl 2, AlBr 2, BF 2 and the like. The reaction solvent and reaction temperature are not critical to this synthesis if a solvent that is inert or substantially inert to the reaction components and products is used. In this regard, it has been found that solvents such as methylene chloride, 1,2-dichloroethane, carbon disulfide, synthetochloroethane and the like are particularly preferable. The reaction temperature may range from about 0 to 50 ° C and is preferably from about 0-10 ° C. In Step 1, the molar ratio of dichlorophenoxy compound to 2-substituted-propionyl halide may range from about 2: 1 to 1: 4. The amount of catalyst may range from about 25 to 200 mol% based on the dichlorophenoxy compounds; a range of 35 to 60 mole% is preferred.

As for Step 2, the molar ratio of propiophenone from Form 1 to formaldehyde is in the range of about 1: 1 to 1:10. The acid used in Step 2 is not critical and any strong organic or inorganic acid such as trifluoroacetic acid, methanesulfonic acid, boron trifluoride, 1H-SO 2, HF, phosphoric acid and the like can be used. The most preferred acids are trifluoroacetic acid, BF 4, and H 2 SO 4. The molar ratio of acid to propiophenonic acid is in the range of about 0.05 to 0.99 when the acid acts as a solvent, which is most preferred. However, other solvents may be used and the solvents may be methylene chloride, benzyl, toluene and the like. The temperature of step 2 is in the range of about 25 to 150 ° C; preferably the reaction is carried out at the reflux temperature of the solvent, normally at 80 to 120 ° C. The reaction of step 2 is complete in about 3-18 hours.

Propiophenone quantitative conversion to the desired Inda-noniksi can be seen metyyni proton and the aromatic protons in the disappearance of half the amount of using nuclear magnetic resonance techniques (NMR).

Alternatively, step 2 may be interrupted to isolate the intermediate for their cyclic alkylation to the corresponding inda 2 61 866 none according to step 3. Quantitative conversion to intermediates is detected by the nmr technique, with the methyl proton of the starting material disappearing. The intermediate, hydroxymethyl compound or acid ester obtained in Step 2 may be converted to the final indanone or may be converted to a halide or other ester such as tosylate, acetate or trifluoroacetate or the like before ring closure according to Step 3. The ring sealants used in Step 3 are generally Lewis acids such as trifluoroacetic acid, concentrated sulfuric acid, BF 3, HF, phosphonic acid and the like. Generally, no solvent is required because the acid also acts as a solvent, but suitable solvents include any non-polar, inert solvents such as methylene chloride, benzene, toluene, and the like. The reaction temperature may be about 0 to 100 ° C, and preferably about 0 to 25 ° C. The reaction requires about 1 to 5 hours and can be closely monitored, as in Step 2, by the nmr technique.

If the phenyl product (R 0) in the final product of formula I has a NO 1 group as a substituent (X 2), it can be reduced to an N 1 group if desired, for example as described in Example 11.

The 5-hydroxy derivative "JLL ·" used as starting material in process alternatives (a), (c), (d) and (e)

I R

-R 1 is prepared by treating the correspondingly substituted 2-phenyl or 2-thienyl-2-substituted-5-lower alkoxy or aralkoxy-1-indanone with an ether cleaving agent such as aluminum chloride, pyridine hydrochloride, sodium in liquid ammonia and the like, respectively. . When aluminum chloride is used, the solvent may be heptane, carbon sulfide, methylene chloride and the like. When using pyridine hydrochloride, it is not necessary to use a solvent.

A preferred process for the preparation of 5-hydroxy compounds in which the phenyl substituent X is methoxy comprises hydrogenolysis of the corresponding 5-aralkoxy compound. The hydrogenolysis reaction is carried out in a hydrogenation apparatus in a solvent such as raethanol, ethanol, acetic acid and the like in the presence of a catalyst such as 5% palladium on carbon or platinum on carbon at a pressure of about 1.0 to 40 atmospheres.

2-Arylation or 2-thienylation to give the above-mentioned 5-lower alkoxy or 5-aralkoxy compounds is carried out by treating the corresponding 2-substituted compound VI with a suitable substance such as diphenyl iodonium salt (when R 0 is phenyl or substituted phenyl) or thienyl, having the formula:

iR ° ajz

where R °, and Z have the same meaning as above.

This reaction is carried out by first treating the 2-substituted compound VI with a suitable base, e.g. an alkali metal hydride such as sodium hydride and the like, an alkali metal alkoxide, e.g. sodium methoxide, potassium tert-butoxide and the like or an alkali metal amide such as sodium amide. The resulting carbanion is then treated with an arylating agent. Any inert or substantially inert solvent may be used; suitable solvents include, for example, 1,2-dimethoxyethane, tert-butanol, benzene, dimethylformamide and the like. The reaction can be carried out at a temperature in the range of about 25 to 150 ° C. The following equation describes this method:

Cl 0

-R

i ♦ RO-- base

VI

V

Cl o “yULf r4 ° —1 ^ \ ^ R1

V

14 61 8 6 6 wherein all substituents have the same meaning as above and R 4 is lower alkyl or aralkyl. The t-lower alkoxy or 5-aralkoxy reaction components (VI) used in this process can be obtained by well-known etherification methods of the corresponding 5-hydroxyindanones, which compounds are known compounds and are described in U.S. Patents 3,668,241 and 3,704,314.

Another process for the preparation of ethers of formula V comprises the preparation of the corresponding 2-phenyl or 2-thienyl compound VII

2-alkylation with a suitable alkylating agent of formula RZ, wherein R and Z are as defined above. This reaction is carried out by first treating the 2-phenyl or 2-thienyl compound (VII) with a suitable base, e.g. an alkyl metal hydride such as sodium hydride and the like, an alkali metal alkoxide, e.g. sodium methoxide, potassium tert-butoxide and the like, or an alkali metal amide such as alkali metal amide. -amide and the like. The resulting carbanion is then treated with an alkylating agent RZ. Any inert or substantially inert solvent may be used. Suitable solvents include, for example, 1,2-dimethoxyethane, tert-butanol, benzene, dimethylformamide and the like. The reaction can be carried out at a temperature in the range of about 0 to 150 ° C. The following equation describes this method:

Cl O

ciVyVr ° * r * 4 1

RO --- R

base VH ,, "Cl c’XL: ·

r4o —L ^ —L

^ R1

V

15 61 866 wherein all substituents have the same meaning as above.

The following reaction scheme shows a highly efficient synthesis of the preferred compounds. ):

Cl

C1 R ° R ° R ° Step A

C1 - f ^. , Lewis

+ CH 2 = C-COX or CH 2 -CXCOX or CH-XC-COX - S

R ^ O - \ S / Z acid X / (a) (b) z (c)

XX

Cl o XXI

J. 1 Step B

^ H + yx Difference ____ r6q_1 X_ Z if Z is hydrogen "^ XXII \ V- if Z is methyl

Cl phase C C! JyYCH3 R60-iy- C ”3 Raisu1” 1 ”10" - "XXIV xxv

Step D

O

11 XCH2COR "C1 o C1 o a-ijsfC <-rVV" ·

C-CH_0 — L ^ - if R "is not H π I

2 v - o R "0-C-CH.O ^ H XXVII z

H XXVI

16 61 866 In this synthesis, which also describes the preparation of starting materials, step D comprises process option (a).

In the above reaction scheme, R is alkyl having up to 5 carbon atoms, preferably methyl; H or CH 2 CO 2 R 2, wherein R "is lower alkyl or hydrogen; X is Cl, Br or J; R 0 is phenyl, methyl, halophenyl, preferably p-chloro or p-fluorophenyl or thienyl, preferably z-thienyl; R 'is phenyl, halophenyl, preferably p-chloro or p-fluorophenyl or thienyl, preferably 2-thienyl; R "is lower alkyl or H; Z is H or methyl but is not methyl when R 0 is methyl, i.e. Z and R 0 cannot be simultaneously methyl; Y is phenyl, halophenyl, thienyl, diphenyl iodine, dihalophenyl iodine, dithienyl -iodine.

More specifically, in Step A, 2,3-dichloroanisole or a related lower alkyl ether or 2,3-dichlorophenoxyacetic acid or a related lower alkyl ester is reacted with an appropriately substituted or unsubstituted acyl halide of the formula shown in the reaction equation. These compounds are reacted under Friedel-Crafts reaction conditions with the appropriate catalyst to form the 2-substituted indanone of formula XXII. If cK. The N-disubstituted acyl halide is used as a compound of formula XXI (c), such as o (methyl-p (phenyl) / t-bromopropionyl chloride and R 2 is CH 2 Cl 2> 2H, then the desired indanone XXIV is directly formed. through which a side chain is attached, followed by ring closure to form intermediate XXII Typical substituted or unsubstituted acyl halides include acrylic chloride, o (halo-isobutyryl chloride) or β-halo-isobutyryl chloride, in step-reaction with Friedel-Crafts. Lewis acid is used as the catalyst, especially aluminum chloride or tin chloride, and the solvent is especially inert organic solvent which does not react with the reaction components. to the reflux temperature of the solvent, but 20 -50 ° C is preferred in terms of reaction time, with the reaction substantially complete in about 4-6 hours at about 40 ° C.

17 61 8 6 6 o {^ -Disubstituted - ^ - halopropionyl halide of formula XXI (c) can be prepared according to the method described by Nicolaus, Mariani and Testa: Ά New General Synthesis for * <- Substituted Propionic Acid and its Derivatives ", Bruno JR Nicolaus, Luigi Mariani and Emilio Testa (Lepetit Spa, Milan)

Chem. Abst. 55 27271d (1961).

In step B of the process, the intermediate 2-methylindanone, formula XXII, is alkylated if the reaction component, formula XXI, is not a C 1-4 (disubstituted propionyl halide), using an alkylating agent YX, wherein Y and X are as defined above, especially a diphenyl iodium halide or a methyl halide. The alkylation reaction is carried out in the presence of a suitable basic catalyst such as sodium tert-butoxide, sodium hydride, sodium amide, sodium methoxide or the like in a suitable solvent such as an inert non-aqueous organic solvent or toluene, especially in benzene. sufficient time to complete the reaction, and preferably at a temperature ranging from room temperature to the reflux temperature of the solvent used.If in the compound of formula XXIV, g formed, R 'is phenyl, halophenyl or thienyl and R is CH 2 CO 2 H, then the desired indanone. It can be separated from the reaction mixture in a manner known per se, such as by extracting the desired compound from its reaction mixture as a solvent, boiling said solvent and then crystallizing the desired indanone from acetone or another suitable solvent.

If R 1 in the compound of formula XXIV is lower alkyl, this compound must be subjected to ether cleavage in which the compound of formula V is treated with an ether cleaving agent and the resulting 5-hydroxy product of formula XXV is treated with haloacetic or pseudohaloacetic acid or with its ester of formula 9 wherein X is xch2c-or "

Cl, Br, J, mesyl or tosyl and R "is hydrogen or lower alkyl.

Finally, if R "in the haloacetic acid ester is lower alkyl, the resulting product of formula XXVI is hydrolyzed to form the desired indanone. When haloacetic acid is used as a reaction component, then the compound of formula XXVI is the desired indanone.

ie 618 6 6

Reaction step C, namely ether cleavage, is performed using ether cleavage agents such as aluminum chloride, pyridine hydrochloride, hydrogen bromide, sodium in liquid ammonia and the like. When using aluminum chloride, the solvent may be heptane, carbon disulfide, methylene chloride and the like, and when using pyridine hydrochloride, it is not necessary to use a solvent.

In general, this ether cleavage is performed at room temperature to the reflux temperature of the solvent at a temperature ranging for the time required for complete formation of the intermediate of formula XXV.

The reaction in which the compound of formula XXV is reacted with a haloacetic acid or an ester thereof is generally 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 inert or substantially inert solvent may be used. Ethanol, dimethylformamide, benzene and toluene are particularly preferred solvents. The reaction can be carried out at a temperature in the range of about 25 ° C to the reflux temperature of the solvent used. The reaction of the haloacetic acid or ester thereof is generally completed within about 10 to 60 minutes. When a haloacetic acid ester is used, the ester obtained can be hydrolyzed to the free acid in a manner known per se.

Several of the compounds described above contain an asymmetric carbon atom in the 2-position of the indanyl ring. In such a case, the optical antipodes can be separated as described below. Thus, the invention also encompasses not only racemic [1-oxo-2-phenyl- or -2-thienyl-2-substituted-5-indanyloxy] alkanonic acids but also their optically active antipodes.

Separation of optical isomers of racemic acids can be accomplished by forming a salt from the racemic mixture with an optically active base such as (+) - or (-) - amphetimine, (-) - cinchonidine, dehydroabietylamine, (+) - or (-) - cK-methylbenzylamine, with (+) - or (-) -? - (1-naphthyl) ethylamine, brucine or strychnine and the like in a suitable solvent such as methanol, ethanol, 2-propanol, benzene, acetonitrile, nitromethane, acetone and the like. In this case, two diastereomeric salts are formed in the solution, one of which is usually more soluble in the solvent than the other. Repeated recrystallization of the crystalline salt usually gives the pure diastereomer. Optically pure 2-phenyl or 2-thienylindanoic acid is obtained by acidifying the salt with mineral acid, extracting into ether, evaporating the solvent and recrystallizing the optically pure antipode.

The second optically pure antipode can generally be obtained by using a different base to form a diastereomeric salt. It is preferred to separate the partially redissolved acid from the purification filtrates of the second diastereomeric salt and purify this material using a second optically active base.

The following examples illustrate processes for the preparation of the 2-phenyl and 2-thienylindan products of the invention.

Example 1 Preparation of (1-oxy-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy) -acetic acid

Step A: 2,3-Dichloro-5-phenylacetylanisole

To a stirred mixture of 2,3-dichloroanisole (62 g, 0.35 mol), phenylacetyl chloride (54 g, 0.35 mol) and carbon disulfide (250 mL) is added portionwise aluminum chloride (47 g, 0.35 mol). ) while cooling at 0-5 ° C. The reaction mixture is allowed to stand at a further 25 ° C for 17 hours, the carbon disulphide is removed and the residue is treated with ice water and concentrated hydrochloric acid (50 ml) to give 68.8 g of 2,3-dichloro-5-phenylacetylanisole, m.p. 126-129 ° C when crystallized from benzene / cyclohexane 2: 1.

Elemental analysis for ci5Hi2C ^ 2 ° 2:

Calculated: C, 61.04; H, 4.10; Found: C, 61.46; H, 4.11.

Step B: 2,3-Dichloro-4- (2-phenylacryloyl) -anisole

Acetic anhydride (100 mL) is added dropwise to a suspension of 2,3-dichloro-4-phenylacetylanisole (29.5 g, 0.01 mol) in bis (dimethylamino) methane (100 mL) under nitrogen while cooling to keep the reaction mixture below 60 ° C. C. The reaction mixture is stirred at 25 ° C for 2 hours and poured into ice water (1500 ml) to precipitate 7.4 g of 2,3-dichloro-4- (2-phenylacryloyl) anisole, m.p. 87-89 ° C.

Elemental analysis for c 18 H 12 Cl 2 2 2 2 20 6 6 6 6

Calculated: C, 62.56; H, 3.94; Found: C, 62.67; H, 4.04.

Step C: 2-Phenyl-5-methoxy-6,7-dichloro-1-indanone 2,3-Dichloro-4- (2-phenylacryloyl) anisole (7.4 g, 0.024 mol) is added portionwise to cold concentrated sulfuric acid (150 ml) while stirring. The reaction mixture is stirred in an ice bath for 2 hours, then added dropwise to ice water to precipitate 3.91 g of 2-phenyl-5-methoxy-6,7-dichloro-1-indanone, m.p. 193-195 ° C after crystallization from benzene / cyclohexane 1: 2.

Elemental analysis for C Calculated: C, 62.56; H, 3.94; Found: C, 62.84; H, 4.00.

Step D: 2-Phenyl-5-hydroxy-6,7-dichloro-1-indanone A stirred mixture of 2-phenyl-5-methoxy-6,7-dichloro-1-indanone (3.91 g, 0.0127 mol) and pyridine hydrochloride (40 g), heated at 190 ° C for 1 hour and then poured into water (600 ml). 2.48 g of 2-phenyl-5-hydroxy-6,7-dichloro-1-indanone are obtained, m.p. 250-252 ° C after recrystallization from ethanol / water 2: 1.

Elemental analysis for the compound Calculated: C, 61.46; H, 3.44; Found: C, 60.94; H, 3.66.

Step E: (1-Oxo-2-phenyl-6,7-dichloro-5-indanyloxy) -acetic acid 2-phenyl-5-hydroxy-6,7-dichloro-1-indanone (5.86 g, 0.023 mol) , iodoacetic acid (4.28 g, 0.023 mol), potassium carbonate (3.04 g, 0.022 mol) and acetone (250 ml) are heated at reflux for 48 hours. The reaction mixture is cooled to 25 ° C and concentrated in vacuo to give a solid which is dissolved in water and acidified with 6N hydrochloric acid to precipitate 6.8 g of (1-oxo-2-phenyl-6,7-dichloro-5-indanyloxy) a mixture of acetic acid and 2-phenyl-5-hydroxy-6,7-dichloro-1-indanone. The phenol is removed by crystallization with nitromethane. Concentration of the filtrate to dryness in vacuo and stirring with toluene gives 470 mg of (1-oxo-2-phenyl-6,7-dichloro-5-indanyloxy) acetic acid, m.p. 181-185 ° C.

Elemental analysis for compound 21 618 6 6

Calculated: C, 58.14; H, 3.45; Cl, 20.19; Found: C, 58.17; H, 3.54; Cl, 19.94.

Step F: (1-Oxo-2-phenyl-2-methyl-6,7-dichloro-5-indanyloxy) acetic acid_

A stirred solution of (1-oxo-2-phenyl-6,7-dichloro-5-indanyloxy) acetic acid (0.351 g, 0.001 mol) in dimethylformamide (7 ml) was cooled in an ice bath, then treated with sodium hydride (0.084 g, 57 % oil dispersion, 0.002 mol) and stirred for 2 hours. Methyl iodide (1 ml) is added and the reaction mixture is stirred at 25 ° C for 2 hours, poured into ice water and acidified with dilute aqueous hydrochloric acid to give (1-oxo-2-phenyl-2-methyl-6,7-dichloro-5 -indanyloxy) -acetic acid, m.p. 168-169 ° C.

Example 2 (1-Oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy) -acetic acid_

Step A: 2 ', 3'-Dichloro-41-methoxy-isobutyrophenone

A stirred mixture of 2,3-dichloroanisole (I) (100 g, 0.565 mol) and isobutyryl chloride (II) (66 g, 0.62 mol) in methylene chloride (400 ml) is cooled to 5 ° C and treated with aluminum chloride ( 83 g, 0.62 mol) for 1 hour. The reaction mixture is allowed to warm to 25 ° C and after 24 hours is poured into ice water (400 ml) and hydrochloric acid (30 ml). The organic phase is washed with 5% sodium hydroxide, water, dried over magnesium sulphate and distilled under reduced pressure to give 68 g of 2 ', 3'-dichloro-4'-methoxyisobutyrophenone (III), which distills at 120-130 ° C. ° C / 0.5 mm.

Elemental analysis for C. 2C1202:

Calculated: C, 53.46; H, 4.89; Found: C, 54.25; H, 5.07.

Step B: 2-Bromo-2 ', 3'-dichloro-4'-methoxy-isobutyrophenone

A stirred solution of 2 ', 3'-dichloro-4'-methoxyisobutyrophenone (45 g, 0.183 mol) in acetic acid (150 mL) is treated with bromine (30 g, 0.187 mol) over 1/2 hour. The reaction mixture is stirred for 10 minutes, then poured into ice water (600 ml) containing sodium bisulphite (2 g). 48 g of 2-bromo-2 ', 3'-dichloro-4'-methoxyisobutyrophenone (IV), m.p.

72-73 ° C after crystallization from hexane.

22 618 6 6

Elemental analysis for the compound, jBrCl2O2:

Calculated: C, 40.52; H, 3.40; Found: C, 40.68; H, 3.38.

Step C: 2-Methylene-2 ', 31-dichloro-4'-methoxypropionophenone A solution of 2-bromo-2', 3'-dichloro-4'-methoxy-iso-butyrophenone (32 g, 0.1 mol) ) and anhydrous lithium bromide (17.4 g, 0.2 mol) in dimethylformamide (200 ml), stirred at 95 ° C under an inert atmosphere for 3 hours and poured into ice water (500 ml). 2-Methylene-2 ', 3'-dichloro-41-methoxypropiophenone (V) separates and melts at 59 ° C after crystallization from petroleum ether.

Elemental analysis for C.j, jH

Calculated: C, 53.90; H, 4.11; Found: C, 53.72; H, 4.11.

Step D: 2-Methyl-5-methoxy-6,7-dichloro-1-indanone To a solution of 2-methylene-2 ', 3'-dichloro-41-methoxy-propiophenone (40 g, 0.163 mol) in concentrated sulfuric acid (75 ml), allow to stand at 25 ° C for 24 hours and then slowly pour into vigorously stirred ice water (500 ml). 40 g of 2-methyl-5-methoxy-6,7-dichloro-1-indanone are obtained, m.p. 129 ° C after crystallization from methylcyclohexane.

Elemental analysis for C ^ H ^ C ^ O:

Calculated: C, 53.90; H, 4.11; Found: C, 53.84; H, 4.00.

Step E: 2-Methyl-2-phenyl-5-methoxy-6,7-dichloro-1-indanone______

Potassium tert-butoxide (8.42 g, 0.075 mol) dissolved in tert-butanol (300 ml) is added to a refluxing solution of 2-methyl-5-methoxy-6,7-dichloro-1-indanone (12, 26 g, 0.05 mol), refluxing is continued for 2 hours, then a suspension of diphenyl iodochloride (19.0 g, 0.06 mol) in tert-butanol (1 L) is added and refluxing is continued for 2 hours. The reaction mixture is cooled to 25 ° C, 300 ml of water are added and the mixture is concentrated to dryness in vacuo to give 4.97 g of 2-methyl-2-phenyl-5-methoxy-6,7-dichloro-1-indanone, m.p. 161-163 ° C after crystallization from benzene / cyclohexane 1: 2.

Elemental analysis for C17H14Cl22:

Calculated: C, 63.57; H, 4.39: Found: C, 63.24; H, 4.68.

61 866 23

Step F: 2-Methyl-2-phenyl-5-hydroxy-6,7-dichloro-1-indanone-2-methyl-2-phenyl-5-methoxy-6,7-dichloro-1-indanone (4.94 g , 0.015 mol) and a stirred mixture of pyridine hydrochloride (50 g) is heated at 175 ° C for 1 hour and then poured into water (500 ml). 2.05 g of 2-methyl-2-phenyl-5-hydroxy-6,7-dichloro-1-indanone are obtained, m.p. 194-196 ° C after crystallization from ethanol / water 2: 1.

Elemental analysis for ^ 2 ^ 12 ^ 2:

Calculated: C, 62.56; H, 3.94; Found; C, 62.60; H, 4.11.

Step G: (1-Oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy) acetic acid_

A stirred mixture of 2-methyl-2-phenyl-5-hydroxy-6,7-dichloro-1-indanone (2.05 g, 0.0067 mol), potassium carbonate (1.85 g, 0.0134 mol) and ethyl bromoacetate (2.23 g, 0.0134 mol) in dimethylformamide (30 ml), heated at 55-60 ° C for 3 hours, then treated with potassium hydroxide (0.97 g, 0.0147 mol) dissolved in as little water as possible in methanol. -sa (30 ml) and heat on a steam bath for 2 1/2 hours. The reaction mixture is poured into water (500 ml), acidified with 6N hydrochloric acid and the precipitate is collected after stirring with ether / petroleum ether and dried to give 1.31 g of (1-oxo-2-methyl-2-phenyl-6 , 7-dichloro-5-indanyloxy) acetic acid, m.p. 168-169 ° C after crystallization from acetic acid / water 1: 1. Elemental analysis for C

Calculated: C, 59.20; H, 3.86; Found: C, 58.94; H, 4.20.

Example 3 Preparation of (1-oxo-2- (4-chlorophenyl) -2-methyl-6,7-dichloro-5-indanyloxy) acetic acid hemihydrate

Step A: 2- (4-Chloro-phenyl) -2-methyl-5-methoxy-6,7-dichloro-1-indanone_

Potassium tert-butoxide (2.81 g, 0.025 mol) dissolved in tert-butanol (150 ml) is added to a refluxing solution of 2-methyl-5-methoxy-6,7-dichloro-1-indanone (4, 90 g, 0.02 mol) in tert-butanol (100 ml) and benzene (200 ml), heating is continued for 3 hours, then 4,4'-dichlorophenyl iodochloride (11.55 g, 0, 03 moles) and refluxing is continued for 2 hours. The reaction mixture is cooled to 25 ° C, 100 ml of water are added and the mixture is concentrated to dryness to give 4.30 g of 2- (4-chlorophenyl) -2-methyl-5-methoxy-6,7-dichloro-1-indanone, m.p. . 176-178 ° C after crystallization from cyclohexane / Bentene 5: 1.

Step B: 2- (4-Chlorophenyl) -2-methyl-5-hydroxy-6,7-dichloro-1-indanone-2- (4-chlorophenyl) -2-methyl-5-methoxy-6,7 A stirred mixture of -dichloro-1-indanone (4.15 g, 0.012 mol) and pyridine hydrochloride (40 g) is heated at 180 ° C for 1 hour and then poured into water (500 ml). 3.11 g of 2- (4-chlorophenyl) -2-methyl-5-hydroxy-6,7-dichloro-1-indanone, m.p. 211-213 ° C after crystallization from ethanol / water 1: 1.

Elemental analysis for C.j.ClCl2:

Calculated: C, 56.25; H, 3.25; Found: C, 55.53; H, 3.23.

Step C! 1-Oxo-2- (4-chlorophenyl) -2-methyl-6,7-dichloro-5-indanyloxy-acetic acid hemihydrate

A stirred mixture of 2- (4-chlorophenyl) -2-methyl-5-hydroxy-6,7-dichloro-1-indanone (2.95 g, 0.00863 mol), potassium carbonate (2.26 g, 0 .0163 mol) and ethyl bromoacetate (2.72 g, 0.0163 mol) in dimethylformamide (50 ml), heated at 55-60 ° C for 2 hours, then treated with 10N aqueous sodium hydroxide (2.5 ml, 0.025 mol) (50 ml). ml) and heated at 80 ° C for 1 hour. The reaction mixture is slowly added to an aqueous solution of 500N hydrochloric acid (10 ml) (500 ml), whereupon 1.37 g of oxo-2- (4-chlorophenyl) -2-methyl-6,7-dichloro-5-indanyloxy) -acetic acid hemihydrate, m.p. 141-142 ° C after crystallization from acetic acid / water 1: 1.

Elemental analysis for C, j gH.j ^ Cl ^ O ^. 1/21 ^ 0:

Calculated: C, 52.90; H, 3.45; Cl, 26.03; Found: C, 52.47; H, 3.45; Cl, 26.11.

Example 4 Preparation of N-oxo-2- (4-methoxyphenyl) -2-methyl-6,7-dichloro-5-indanyloxy-acetic acid

Step A: 2-Methyl-5-hydroxy-6,7-dichloro-1-indanone 25 61 866

A stirred mixture of 2-methyl-5-methoxy-6,7-dichloro-1-indanone (30.0 g, 0.123 mol) and pyridine hydrochloride (270 g) was heated at 180 ° C for 1 hour and then then poured into water (1500 ml). The separated 2-methyl-5-hydroxy-6,7-dichloro-1-indanone (27.6 g) melts at 224-230 ° C and is used without further purification.

Step B: 2-Methyl-5-benzyloxy-6,7-dichloro-1-indanone

A stirred mixture of 2-methyl-5-hydroxy-6,7-dichloro-1-indanone (27.6 g, 0.12 mol), potassium carbonate 24.9 g, 0.18 mol) and benzyl bromide ( 21.4 ml, 0.18 mol) in dimethylformamide (100 ml), heated at 55-60 ° C for 2 hours and then poured into water (1 L) to precipitate 35.5 g of 2-methyl-5-benzyloxy- 6,7-dichloro-1-indanone, m.p. 153-155 ° C after crystallization from benzene / hexane 3: 2.

Elemental analysis for C.j 7H.j:

Calculated: C, 63.57; H, 4.39; Found: C, 64.28; H, 4.61.

Step C: 2- (4-Methoxyphenyl) -2-methyl-5-benzyloxy-6,7-dichloro-1-indanone_

Potassium tert-butoxide (8.42 g, 0.075 mol) dissolved in tert-butanol (450 ml) is added to a solution of 2-methyl-5-benzyloxy-6,7-dichloro-1-indanone (16.1 g, 0.05 mol) in tert-butanol (150 ml) and benzene (600 ml), refluxing is continued for 2.5 hours, then 4,4'-dimethoxydiphenyl iodochloride (37.66 g, 0.10 moles) reflux is continued for 3 hours. The reaction mixture is cooled to 25 ° C, 500 ml of water are added and the mixture is concentrated in vacuo to a brown oil which, after extraction with ether, drying over anhydrous magnesium sulphate, removal of ether and chromatography of the residue on silica gel using chloroform, gives 3.44 g of 2- (4-methoxy). ) -2-methyl-5-benzyloxy-6,7-dichloro-1-indanone, melting at -115-119 ° C and 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-Indanone (3.44 g, 0.008 mol) is catalytically hydrogenated in absolute ethanol (300 mL) using 5% palladium on carbon 26 61 866 on carbon (500 rag) in a Parr apparatus at 25 ° C for 4 hours. The reaction mixture is filtered and concentrated in vacuo to give 2.6 g of 2- (4-methoxyphenyl) -2-methyl-5-hydroxy-6,7-dichloro-1-indanone, m.p.

149-156 ° C, which is used without further purification.

Step E: E, 1-Oxo-2- (4-methoxyphenyl) -2-methyl-6,7-dichloro-5S-indanyloxy-acetic acid___

A stirred mixture of 2- (4-methoxyphenyl) -2-methyl-5-hydroxy-6,7-dichloro-1-indanone (2.6 g, 0.0077 mol), potassium carbonate (2.14 g , 0.0154 mol) and ethyl bromoacetate (2.58 g, 0.0154 mol) in dimethylformamide (60 ml), heated at 55-60 ° C for 2.5 hours, then treated with 10N sodium hydroxide (3 ml, 0.03 mol). ) with aqueous solution (60 ml) and heated at 100 ° C for 1 hour. The reaction mixture is slowly added to crushed ice water (600 ml) with 12N hydrochloric acid (20 ml), precipitating 1.69 g of E-oxo-2- (4-methoxyphenyl) -2-methyl-6,7-dichloro-5- indanyloxy) acetic acid, melting at 173-175 ° C after crystallization from nitromethane.

Elemental analysis for C.j gH ^ gC ^ O,.:

Calculated: C, 57.74; H, 4.08; Found: C, 57.35; H, 4.31.

Example 5 1-Oxo-2- (4-fluorophenyl) -2-methyl-6,7-dichloro-5-indanyloxy-acetic acid__

Step A: 2- (4-Fluorophenyl) -2-methyl-5-methoxy-6,7-dichloro-1-indanone__

Potassium tert-butoxide (3.38 g, 0.03 mol) dissolved in tert-butanol (150 ml) is added to a refluxing solution of 2-methyl-5-methoxy-6,7-dichloro-1-indanone ( 4.90 g, 0.02 mol) in tert-butanol (50 ml) and benzene (200 ml), refluxing is continued for 3 hours, then 4,4'-trifluorodiphenyl iodochloride (10.58 g, 0.03 mol) is added. ) and refluxing is continued for 2 1/2 hours. The reaction mixture is cooled to 25 ° C, 100 ml of water are added and the mixture is concentrated to dryness in vacuo to give 1.24 g of 2- (4-fluorophenyl) -2-methyl-5-methoxy-6,7-dichloro-1- indanone, which melts at 163-170 ° C when treated with ether / hexane and is used without further purification.

Step B: 2- (4-Fluorophenyl) -2-methyl-5-hydroxy-6,7-dichloro-1-indanone ______ 27 β 1 8 6 6

A stirred mixture of 2- (4-fluorophenyl) -2-methyl-5-methoxy-6,7-dichloro-1-indanone (1.2 g, 0.00354 mol) and pyridine hydrochloride (12 g), heated at 180 ° C for 1 hour and then poured into water (500 ml). 2- (4-fluorophenyl) -2-methyl-5-hydroxy-6,7-dichloro-1-indanone melts at 193-200 ° C and is used without further purification.

Step C: 1H-Oxo-4- (4-fluoro-phenyl) -2-methyl-6,7-dichloro-1-indanyloxy) -acetic acid

A stirred mixture of 2- (4-fluorophenyl) -2-methyl-5-hydroxy-6,7-dichloro-1-indanone (1.04 g, 0.0032 mol), potassium carbonate (0.885 g, 0.0064 moles) and ethyl bromoacetate (1.07 g, 0.064 moles) in dimethylformamide (30 mL), heated at 55-60 ° C for 3 h, then treated with an aqueous solution of 10N sodium hydroxide (1 mL), 0.01 mole). (30 ml) and heated at 80 ° C for 1 hour. The reaction mixture is slowly added to an aqueous solution of 500N hydrochloric acid (10 ml) (500 ml), precipitating 450 mg of N-oxo-2- (4-fluorophenyl) -2-methyl-6,7-dichloro-1-indanyloxyO-acetic acid, mp. After crystallization from 150-156 ° C from ethyl acetate / hexane 1: 3.

Elemental analysis for gH 2:

Calculated: C, 56.42; H, 3.42; Cl, 18.50; Found: C, 56.30; H, 3.65; Cl, 18.57.

Example 6 Preparation of (1-oxo-2,2-diphenyl-6,7-dichloro-5-indanyloxy) acetic acid

Step A: 2,2-Diphenyl-5-methoxy-6,7-dichloro-1-Indanone

Potassium tert-butoxide (7.0 g, 0.0624 mol) dissolved in tert-butanol (500 mL) is added to a mixture of 2-phenyl-5-methoxy-6,7-dichloro-1-indanone (9 , 59 g, 0.0312 mol), diphenyl iodonium chloride (39.6 g, 0.125 mol), tert-butanol (1500 ml) and benzene (500 ml) at 70 ° C for 1 hour and then stirred At 70 ° C for 2 hours. The reaction mixture is concentrated in vacuo to 1/4 volume, the unreacted iodonium salt is filtered off and the remaining liquid is concentrated to dryness to give 5.71 g of 2,2-diphenyl-5-methoxy-6,7-dichloro-1-indanone, m.p. 172-174 ° C after crystallization from cyclohexane.

Elemental analysis for ^ 2 ^ 16 ^ 2 ^ 21

Calculated: C, 68.94; H, 4.21; Found: C, 68.99; H, 4.34.

28 61 866

Step B; 2,2-Diphenyl-5-hydroxy-6,7-dichloro-1-indanone A stirred mixture of 2,2-diphenyl-5-methoxy-6,7-dichloro-1-indanone (5.5 g, 0.014 moles) and pyridine hydrochloride (55 g), heated at 175 ° C for 1/2 hour and then poured into water (500 ml). 4.94 g of 2,2-diphenyl-5-hydroxy-6,7-dichloro-1-indanone are obtained, m.p. 207-213 ° C.

Elemental analysis for C

Calculated: C, 68.31; H, 3.82; Found: C, 67.86; H, 3.88.

Step C: (1-Oxo-2,2-diphenyl-6,7-dichloro-5-indanyloxy) -acetic acid___

A stirred solution of 2,2-diphenyl-5-hydroxy-6,7-dichloro-1-indanone (4.9 g, 0.0133 mol), potassium carbonate (3.68 g, 0.0266 mol) and ethyl bromoacetate (4.45 g, 0.0266 mol) in dimethylformamide (150 ml), heated at 55-60 ° C for 3.5 hours, then treated with 10N aqueous sodium hydroxide solution (7.5 ml, 0.075 mol) (150 ml) and heated to 90 ° C. At 1.5 ° C. The reaction mixture is slowly added to an aqueous solution (1 L) of 12N hydrochloric acid (30 ml), whereupon 3.60 g of (1-oxo-2,2-diphenyl-6,7-dichloro-5-indanyloxy) acetic acid precipitates, m.p. 251-252 ° C after crystallization first from acetic acid and then from nitromethane.

Elemental analysis for C-OH., Clo0 .: Ίθ Z 4

Calculated: C, 64.65; H, 3.77; Cl, 16.59; Found: C, 64.69; H, 3.94; Cl, 16.73.

Example 7 Preparation of (1-oxo-2,3-diphenyl-2-methyl-6,7-dichloro-5-indanyloxy) acetic acid__

Step A: 21,3'-Dichloro-41-methoxypropiophenone A stirred mixture of 2,3-dichloroanisole (177.0 g, 1.0 mol) and propionyl chloride (101.8 g, 1.1 mol) in methylene chloride. (600 mL), cooled to 5 ° C and treated with Aluminum Chloride (146.7 g, 1.1 mol) over 1 1/2 hours. The reaction mixture is allowed to warm to 25 ° C and after 16 hours is poured into ice water (2 liters) of concentrated hydrochloric acid (200 ml). The organic phase is washed with 10% sodium hydroxide solution and saturated brine and dried over magnesium sulfate. After evaporation of the solvent, the product is crystallized from hexane to give 124.5 g (53%) of 2 ', 3'-dichloro-4'-methoxypropiophenone, m.p. 51-54 ° C.

29 61 8 6 6

Step B; 2,3-dichloro-4- (2-benzylidenemethyl) anlsole

To a mixture of 2 ', 3'-dichloro-4'-methoxypropiophenone (124.5 g, 0.53 mol) and benzaldehyde (54.4 ml, 0.53 mol) dissolved in ethanol (1 L) is added dropwise 20 % sodium hydroxide solution (117.0 mL, 0.59 mol). The product begins to precipitate after one third of the base has been added. After 2 hours at 25 ° C, the solid product is collected by suction filtration to give 163.2 g (95%) of 2,3-dichloro-4- (2-benzylidenemethyl) anisole, m.p. 137.5-139 ° C after crystallization from ethanol.

Elemental analysis for C.j:

Calculated: C, 63.57; H, 4.39; Found: C, 63.69; H, 4.49.

Step C: 2-Methyl-3-phenyl-5-methoxy-6,7-dichloro-1-indanone-2,3-dichloro-4- (2-benzylidenemethyl) anisole (100 g, 0.32 mol) and trifluoroacetic acid ( 400 ml) is heated gently under reflux for 67 hours. The trifluoroacetic acid is removed and the oily residue is treated with ether to give 80.0 g of 2-methyl-3-phenyl-5-methoxy-6,7-dichloro-1-indanone, m.p. 155-157 ° C after crystallization from benzene.

Elemental analysis for C 1 H 2 Cl 2 Cl 2:

Calculated: C, 63.57; H, 4.39; Found: C, 63.17; H, 4.59.

Step D: 2,3-Diphenyl-2-methyl-5-methoxy-6,7-dichloro-1-indanone

Sodium methoxide (2.4 g, 0.045 mol) is added portionwise to a stirred mixture of 2-methyl-3-phenyl-5-methoxy-6,7-dichloro-1-indanone (6.44 g, 0.02 mol), diphenyl iodonium chloride (31.6 g, 0.1 mol), dry dimethylformamide (200 ml) and benzene (200 ml) at 70 ° C under nitrogen and heating at 70 ° C is continued for 2 hours. The reaction mixture is poured into water (1.5 L), the benzene layer is separated, dried over anhydrous magnesium sulfate and concentrated in vacuo to give 2.48 g of 2,3-diphenyl-2-methyl-5-methoxy-6,7-dichloro-1- indanone after mixing with hexane. This material, which melts at 197-207 ° C, is used without further purification.

30 61 8 6 6

Step E: 2,3-Diphenyl-2-methyl-5-hydroxy-6,7-dichloro-1-indanone

A stirred mixture of 2,3-diphenyl-2-methyl-5-methoxy-6,7-dichloro-1-indanone (2.48 g, 0.0065 mol) and pyridine hydrochloride (25 g) is heated to 175 At 1 ° C and then poured into water (500 ml). 2.24 g of 2,3-diphenyl-2-methyl-5-hydroxy-6,7-dichloro-1-indanone are obtained, m.p. 238-244 ° C and is used without further purification.

Step F: (1-Oxy-2,3-diphenyl-2-methyl-6,7-dichloro-5-indanyloxy) -acetic acid_

A stirred mixture of 2,3-diphenyl-2-methyl-5-hydroxy-6,7-dichloro-1-indanone (2.24 g, 0.00585 mol), potassium carbonate (1.62 g, 0.0117 moles) and ethyl bromoacetate (1.96 g, 0.0117 moles) in dimethylformamide (100 mL), heated at 55-60 ° C for 3 h and then treated with aqueous 10N sodium hydroxide (5 mL, 0.05 mole) ( 100 ml) and heated at 90 ° C for 1.5 hours. The reaction mixture is slowly added to a solution of water (1 L) and 12N hydrochloric acid (10 mL) to precipitate 1.14 g of (1-oxo-2,3-diphenyl-2-methyl-6,7-dichloro-5-indanyloxy) acetic acid, melting at 203-205 ° C after crystallization from nitromethane.

Elemental analysis for C24H18Cl2 ° 4:

Calculated: C, 65.32; H, 4.11; Found: C, 65.30; H, 4.19.

Example 8 Preparation of (1-oxo-2-ethyl-2-phenyl-6,7-dichloro-5-indanyloxy) -acetic acid

Step A: 2-Ethyl-2-phenyl-5-methoxy-6,7-dichloro-1-indanone

Sodium methoxide (1.24 g, 0.023 mol) is added portionwise to a stirred mixture of 2-phenyl-5-methoxy-6,7-dichloro-1-indanone (4.61 g, 0.015 mol), iodoethane (15, 5 ml, 0.15 mol), benzene (60 ml) and dimethylformamide (60 ml), under nitrogen in an ice-water bath. The reaction mixture is allowed to warm to room temperature over 1 hour, then poured into water (1 L), the benzene layer is separated, dried over anhydrous magnesium sulfate and concentrated in vacuo to give 3.23 g of 2-ethyl-2-phenyl-5-methoxy-6,7-dichloro- 1-indanone, m.p. 139-141 ° C after crystallization from benzene / hexane 1: 1.

31 61866

Elemental analysis for 5 ^ 2 ^ 2:

Calculated: C, 64.49; H, 4.81; Found: C, 64.73; H, 4.99.

Step B: 2-Ethyl-2-phenyl-5-hydroxy-6,7-dichloro-1-indanone_

A stirred mixture of 2-ethyl-2-phenyl-5-methoxy-6,7-dichloro-1-indanone (3.01 g, 0.009 mol) and pyridine hydrochloride (35 g) is heated at 175 ° C for 1 / 2 hours and then poured into water (350 ml). 2.64 g of 2-ethyl-2-phenyl-5-hydroxy-6,7-dichloro-1-indanone are obtained, m.p. 177-179 ° C.

Elemental analysis for the compound Calculated: C, 63.57; H, 4.39; Found: C, 63.73; H, 4.81.

Step C: (1-Oxo-2-ethyl-2-phenyl-6,7-dichloro-5-indanyloxy) acetic acid_

A stirred mixture of 2-ethyl-2-phenyl-5-hydroxy-6,7-dichloro-1-indanone (2.6 g, 0.008 mol), potassium carbonate (2.71 g, 0.016 mol) and ethyl bromoacetate (2.71 mol). g, 0.016 mol) in dimethylformamide (40 ml), heated at 55-60 ° C for 2.5 hours, then treated with a solution of water (40 ml) and 10N sodium hydroxide (3 ml, 0.03 mol) and heated to 100 ° C: in 1 hour. The reaction mixture is then slowly added to a solution of water (600 ml) and 12N hydrochloric acid (10 ml) to give a resinous residue which is extracted with ether, dried and concentrated in vacuo to give 2.16 g of (1-oxo-2-ethyl-2 -phenyl-6,7-dichloro-5-indanyloxy) acetic acid, m.p. 187-189 ° C.

Elemental analysis for C 18 H 19 Cl 2 O 2:

Calculated: C, 60.18; H, 4.25; Found: C, 59.76; H, 4.24.

Example 9 Preparation of (1-oxo-2-cyclopentyl-2-phenyl-6,7-dichloro-5-indanyloxy) acetic acid

Step A: 2-Cyclopentyl-2-phenyl-5-methoxy-6,7-dichloro-N-indanone__

Sodium methoxide (1.63 g, 0.03 mol) is added portionwise or to a stirred mixture of 2-phenyl-5-methoxy-6,7-32 61 8 6 6

dichloro-1-indanone (4.61 g, 0.015 mol), cyclopentyl bromide (16 ml, 0.15 mol), benzene (60 ml) and dimethylformamide (60 ml) under nitrogen at 25 ° C. The reaction mixture was stirred at 25 ° C for 16 hours, then poured into water (1 L), the benzene layer separated, dried over anhydrous magnesium sulfate and concentrated in vacuo to leave a red-brown oil which was chromatographed on silica gel using chloroform to give 1.42 g. 2-cyclopentyl-2-phenyl-5-methoxy-6,7-dichloro-1-indanone, m.p. 105-108 ° C

Elemental analysis for C21H20Cl2O2:

Calculated: C, 67.21; H, 5.37; Found: C, 66.88; H, 5.53.

Step B: 2-Cyclopentyl-2-phenyl-5-hydroxy-6,7-dichloro-1-indanone

A stirred mixture of 2-cyclopentyl-2-phenyl-5-methoxy-6,7-dichloro-1-indanone (1.40 g, 0.0037 mol) and pyridine hydrochloride (14 g) is heated to 175 ° C. at 1/2 hour and then poured into water (400 mL). 1.1 g of 2-cyclopentyl-2-phenyl-5-hydroxy-6,7-dichloro-1-indanone are obtained, m.p. 161-170 ° C after crystallization from butyl chloride / chloroform 5: 1.

Elemental analysis for C2qH, jClCl2>:

Calculated: C, 66.49; H, 5.02; Found: C, 65.52; H, 5.03.

Step C: (1-Oxo-2-cyclopentyl-2-phenyl-6,7-dichloro-5-indanyloxy) -acetic acid_

A stirred mixture of 2-cyclopentyl-2-phenyl-5-hydroxy-6,7-dichloro-1-indanone (1.10 g, 0.003 mol), potassium carbonate (0.85 g, 0.006 mol) and ethyl bromoacetate (1.02 g, 0.006 mol) in dimethylformamide (20 ml), heated at 55-60 ° C for 3 hours, then treated with a solution of water (20 ml) and 10N sodium hydroxide (1.2 ml, 0.012 mol) and heated for 10 hours. At 1 ° C for 1 hour. The reaction mixture is slowly added to a solution of water (300 ml) and 12N hydrochloric acid (5 ml) to precipitate 680 mg of (1-oxo-2-cyclopentyl-2-phenyl-6,7-dichloro-5-indanyloxy) acetic acid, which melts After crystallization at 184-186 ° C from nitromethane.

Elemental analysis for C 22 H 20 Cl 2 · 2 ° 4: 33 61 866

Calculated: C, 63.02; H, 4.81; Found: C, 59.59; H, 4.86.

Example 10 Preparation of N-oxo-2-methyl-2- (4-nitrophenyl) -6,7-dichloro-5-indanyloxy-acetic acid___

Step A: 2-Methyl-2- (4-nitrophenyl) -5-methoxy-6,7-dichloro-1-indanone ______

Amyl nitrate (40 mL) is added in 10 mL portions every 2 hours to 2-methyl-2-phenyl-5-methoxy-6,7-dichloro-1-indanone (9.36 g, 0.03 mol) in polyphosphoric acid (150 g). ) At 50-60 ° C with stirring. The total heating time is 8 hours. The reaction mixture is treated with crushed ice water to precipitate 4.82 g of 2-methyl-2- (4-nitrophenyl) -5-methoxy-6,7-dichloro-1-indanone, which melts at 179-180 ° C after crystallization. butyl chloride. Elemental analysis for C.j ^ H.j:

Calculated: C, 55.76; H, 3.58; N, 3.82; Found: C, 55.83; H, 3.66; N, 3.85.

Step B: 2-Methyl-2- (4-nitrophenyl) -5-hydroxy-6,7-dichloro-1-indanone

A stirred mixture of 2-methyl-2- (4-nitrophenyl) -5-methoxy-6,7-dichloro-1-indanone (4.82 g, 0.013 mol) in pyridine hydrochloride (50 g) is heated to 175 ° At C for 1/2 hour and then poured into crushed ice water (1 L). 4.42 g of 2-methyl-2- (4-nitrophenyl) -5-hydroxy-6,7-dichloro-1-indanone are obtained, m.p. 268-270 ° C after crystallization from ethanol.

Elemental analysis for compound C. | g H ^ NO ^ C ^:

Calculated: C, 54.57; H, 3.15; N, 3.98; Found: C, 54.18; H, 3.27; N, 4.66.

Step C: E-1-Oxo-2-methyl-2- (4-nitro-phenyl) -6,7-dichloro-5-indanyloxy} -acetic acid_

A stirred mixture of 2-methyl-2- (4-nitrophenyl) -5-hydroxy-6,7-dichloro-1-indanone (4.4 g, 0.0126 mol), potassium carbonate (3.49 g , 0.0252 moles) and ethyl bromoacetate (4.21 g, 0.0252 moles) in dimethylformamide (150 ml), heated at 55-60 ° C for 3 hours, then treated with water (150 ml) and 10N sodium hydroxide (7, 5 ml, 0.075 mol) and heated at 100 ° C for 1.5 hours. The reaction mixture is slowly added to a solution of water (1 L) and 12N hydrochloric acid (15 mL) to precipitate 2.44 g of N-oxo-2-methyl-2- (4-nitrophenyl) -6,7-dichloro-5-inda nyloxy} acetic acid, m.p. 202-205 ° C after crystallization from nitromethane.

Elemental analysis for c- qH- | 3 ^ 2 ^ 6:

Calculated: C, 52.70; H, 3.19; N, 3.41; Found: C, 52.72; H, 3.16; N, 3.30.

Example 11 N, N-Oxo-2- (4-aminophenyl) -2-methyl-6,7-dichloro-5-indanyloxy-acetic acid

1-oxo-2-methyl-2- (4-nitrophenyl) -6,7-dichloro-5-indanyl

solution / acetic acid (6.11 g, 0.015 mol) in absolute ethanol (250 ml) containing 36N sulfuric acid (2 ml) is catalytically hydrogenated using 5% palladium on carbon (500 mg) in a Parr apparatus. After 1 hour, the reaction mixture is filtered and concentrated in vacuo to a volume of 50 ml. Water (200 ml) is added to precipitate the ethyl ester, which is hydrolysed under reflux in ethanol (200 ml), 10N sodium hydroxide solution (4.5 ml, 0.045 mol) and water (100 ml) for 1.5 hours. The reaction mixture is cooled, concentrated to 1/3 volume, filtered and neutralized with 6N hydrochloric acid to precipitate 1.09 g of t-oxo-2- (4-aminophenyl) -2-methyl-6,7-dichloro-5-indanyloxy. acetic acid, which melts at 235-236 ° C with decomposition.

Elemental analysis for C 18 H 19 Cl 2 NO 2:

Calculated: C, 56.86; H, 3.98; N, 3.68; Found: C, 56.46; H, 4.04; N, 3.62.

Example 12

Process for the preparation of (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 (4.61 g, 0.015 mol), chloroacetonitrile (1.13 g, 0.015 mol), potassium carbonate (2.08 g, 0.015 mol), potassium iodide (0.25 g, 0.0015 mol) and acetone (75 ml). heated to reflux for 23 hours. The reaction mixture is cooled to 25 ° C and concentrated to dryness in vacuo to give an oily residue which, when mixed with water, gives 5.12 g of (1-oxo-2-methyl-2-phenyl-6,7-dichloro- 5-indanyloxy) -acetonitrile, melting at 163-165 ° C after crystallization from cyclohexane / benzene 5: 1. Elemental analysis for gH ^ gC ^ NC ^:

Calculated: C, 62.45; H, 3.78; N, 4.05; Found: C, 63.06; H, 4.03; N, 4.03.

Step B: (1-Oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanynyloxy) -acetic acid_

A mixture of (1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy) acetonitrile (3.0 g), acetic acid (20 ml), water (5 ml) and concentrated sulfuric acid ( 5 ml), refluxed for 2 hours and then poured into ice water (100 ml) to give 2.5 g of (1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy) acetic acid, m.p. 168-169 ° C after crystallization from acetic acid.

Example 13 Preparation of N-oxo-2- (4-bromophenyl) -2-methyl-6,7-dichloro-5-indanyloxy-acetic acid

Step A: 2,3-Dichloro-4- (4-bromophenyl) acetylanisole To a stirred mixture of 2,3-dichloroanisole (73.5 g, 0.414 mol), 4-bromophenylacetyl chloride (105 g, 0.456 mol) and carbon disulfide ( 300 ml), aluminum chloride (60.9 g, 0.456 mol) is added portionwise while cooling at 0-5 ° C. The reaction mixture is allowed to stand at 25 ° C for 17 hours, then purged with nitrogen and the solid residue is treated with crushed ice and 12N hydrochloric acid (80 ml) to give 147.7 g of 2,3-dichloro-4- (4-bromophenyl) acetylanisole which melts at 163-164.5 ° C after crystallization from benzene / hexane 1: 1.

Elemental analysis for ^ H.j.rBrC ^ t ^:

Calculated: C, 48.16; H, 2.96; Found: C, 48.38; H, 3.10.

Step B: 2 ', 31-Dichloro-4'-methoxy-2- (4-bromophenyl) -acryloxyphenone___

A suspension of 2,3-dichloro-4- (4-bromophenyl) -acetylanisole (142.5 g, 0.38 mol) in bis-dimethylaminomethane (325 ml) under nitrogen gas was added dropwise to acetic anhydride (325 ml) while cooling the reaction mixture. to keep 36 6 1 8 6 6 below 40 ° C. The reaction mixture is stirred at 25 ° C for 1 hour and then poured into crushed ice water (4 liters) to precipitate 143 g of 2 ', 3'-dichloro-4'-methoxy-2- (4-bromophenyl) -acrylophenone, m.p. After crystallization from 110-116 ° C from benzene / hexane 1: 5.

Elemental analysis for gH.j. ^ BrC ^ C ^:

Calculated: C, 49.78; H, 2.87; Found: C, 49.73; H, 2.88.

Step C: 2- (4-Bromophenyl) -5-methoxy-6,7-dichloro-1-indanone-2 ', 3'-dichloro-4'-methoxy-2- (4-bromophenyl) acrylophenone (143 g, 0 .37 moles) · dissolved in dichloromethane (2 liters) is stirred in cold 36N sulfuric acid (1 liter) containing dichloromethane (1 L) in an ice bath for 4 hours. After stirring for an additional 1/2 hour, the reaction mixture is slowly added to the crushed ice, the dichloromethane layer is separated, washed with brine, concentrated in vacuo to give 134.8 g of 2- (4-bromophenyl) -5-methoxy-6,7-dichloro- 1-indanone, melting at 202-203 ° C after mixing with water and after crystallization from benzene / hexane 1: 1.

Step D: 2- (4-Bromophenyl) -2-methyl-5-methoxy-6,7-dichloro-1-indanone

Sodium methoxide (28.4 g, 0.522 mol) is added to a stirred mixture of 2- (4-bromophenyl) -5-methoxy-6,7-dichloro-1-indanone (134.6 g, 0.348 mol), iodomethane (217 ml, 3.48 mol), dry benzene (1700 ml) and dry dimethylformamide (1700 ml), under nitrogen gas in an ice - water bath. The reaction mixture is allowed to come to ambient temperature over 2 hours and poured into water (8 liters) to precipitate 92.2 g of 2- (4-bromophenyl) -2-methyl-5-methoxy-6,7-dichloro-1-indanone, m.p. 200-203 ° C, insoluble in benzene present.

Elemental analysis for 7Η ^ 3BrCl2O2:

Calculated: C, 51.03; H, 3.28; Found: C, 50.71; H, 3.24.

Step E: 2- (4-Bromophenyl) -2-methyl-5-hydroxy-6,7-dichloro-1-indanone

A stirred mixture of 2- (4-bromophenyl) -2-methyl-5-methoxy-6,7-dichloro-1-indanone (5.0 g, 0.0125 mol) and pyridine hydrochloride (50 g), heated at 185 ° C for 1 hour and then poured into crushed ice water (500 mL). 4.68 g of 2- (4-bromophenyl) -2-methyl-5-hydroxy-6,7-dichloro-1-indanone are obtained, m.p. 221-223 ° C after crystallization from ethanol.

Elemental analysis for gH.j ^ BrC ^ C ^:

Calculated: C, 49.79; H, 2.87; Found: C, 49.18; H, 2.87.

Step F: 1-Oxo-2- (4-bromophenyl) -2-methyl-6,7-dichloro-

^ N

_5-indanyloxy / etikkahappo_

A stirred mixture of 2- (4-bromophenyl) -2-methyl-5-hydroxy-6,7-dichloro-1-indanone (4.48 g, 0.0116 mol), potassium carbonate (3.88 g, 0 , 0232 moles) and ethyl bromoacetate (3.21 g, 0.0232 moles) in dimethylformamide (100 mL), heated at 55-60 ° C for 3 h, then treated with water (100 mL) and 10N sodium hydroxide (5 mL, 0 mL). 05 moles) and heated at 100 ° C for 2 hours. The reaction mixture is slowly added to crushed ice water (1500 ml) with 12N hydrochloric acid (50 ml), precipitating 3.24 g of N-oxo-2- (4-bromophenyl) -2-methyl-6,7-dichloro-5- indanyloxy-acetic acid, m.p. 171-172 ° C after crystallization from nitromethane followed by acetic acid / water 3: 2.

Elemental analysis for C1 gH13BrCl2C> 4:

Calculated: C, 48.68; H, 2.95; Found: C, 48.64; H, 2.93.

Example 14 Preparation of trans-oxo-2- (4-cyanophenyl) -2-methyl-6,7-dichloro-5-indanyloxy-acetic acid

Step A: 2- (4-Cyanophenyl) -2-methyl-5-methoxy-6,7-dichloro-1-indanone-2- (4-bromophenyl) -2-methyl-5-methoxy-6,7-dichloro- 1-Indanone (8.00 g, 0.02 mol), cuprocyanide (3.94 g, 0.04 mol) and dimethylformamide (100 ml) are heated under reflux for 8 hours, added to warm sodium cyanide solution (3 g in 400 ml of water) , extracted with benzene, the benzene solution is dried over anhydrous magnesium sulfate and concentrated in vacuo to give an oily residue. Chromatography on silica gel using chloroform gives 1.13 g of 2- (4-cyanophenyl) -2-methyl-5-methoxy-6,7-dichloro-1-indanone, m.p. 161-163 ° C after crystallization from benzene / hexane 2: 1.

38 61 8 6 6

Elemental analysis for gH 2 Cl 2 NO 2:

Calculated: C, 62.45; H, 3.78; N, 4.05; Found: C, 61.37; H, 3.68; N, 3.73.

Step B: 2- (4-Cyanophenyl) -2-methyl-5-hydroxy-6,7-dichloro-1-indanone

A stirred mixture of 2- (4-cyanophenyl) -2-methyl-5-methoxy-6,7-dichloro-1-indanone (2.08 g, 0.006 mol) in pyridine hydrochloride (20 g) is heated to 185 °. At C for 2 hours and then poured into ice water (300 ml). 1.89 g of 2- (4-cyanophenyl) -2-methyl-5-hydroxy-6,7-dichloro-1-indanone are obtained, m.p. 189- 196 C and is used without further purification.

Step C: N, N-Oxo-2- (4-cyanophenyl) -2-methyl-6,7-dichloro-5S-indanyloxy] acetic acid

A stirred mixture of 2- (4-cyanophenyl) -2-methyl-5-hydroxy-6,7-dichloro-1-indanone (1.8 g, 0.0054 mol), potassium carbonate (1.5 g , 0.0109 mol) and ethyl bromoacetate (1.8 g, 0.0109 mol) in dimethylformamide (60 ml), heated at 55-60 ° C for 3 hours, then treated with water (60 ml) containing 10N sodium hydroxide ( 3 ml, 0.03 mol) and heated at 100 ° C for 1.5 hours. The reaction mixture is slowly added to ice water (300 ml) containing 12N hydrochloric acid (5 ml), precipitating 160 mg of 1-oxo-2- (4-cyanophenyl) -2-methyl-6,7-dichloro-5-indanyloxy ^ acetic acid, m.p. 184-185 ° C after crystallization from acetic acid / water 1: 1.

Elemental analysis for the compound Calculated: C, 55.90; H, 3.70; N, 3.43; Found: C, 55.77; H, 3.53; N, 4.00.

Example 15

Process for the preparation of (1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy) acetic acid_

A mixture of 1- (1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy) -2-nitroethane (3 g) prepared by the method described in British Patent 1,328,528 and 6N hydrochloric acid , refluxed for 16 hours, cooled and extracted with ether. The ether layer is washed with water and extracted with dilute sodium bicarbonate and acidified to give 2.0 g of (1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy) acetic acid, m.p. 168-169 ° C.

39 61 866

Example 16

Process for the preparation of (1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy) acetic acid_

To a suspension of sodium hydride (0.24 g, 0.01 mol) in 1,2-dimethoxyethane (10 mL) is added a solution of 2-methyl-2-phenyl-5-hydroxy-6,7-dichloro-1-indanone (3.07 g, 0.01 mol) in 1,2-dimethoxyethane (10 mL) over 15 minutes. When the evolution of hydrogen ceases, diethyl 2-bromomalonate (2.39 g, 0.01 mol) is added and the mixture is heated under reflux for 1 hour.

The solvent is distilled off under reduced pressure. The remaining diethyl 2- (1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy) malonate is dissolved in ethanol (50 ml), then water (50 ml) and sodium bicarbonate (2 ml) are added. , 5 g) and the mixture is heated under reflux for 4 hours, cooled, acidified, extracted with ether, washed with water and dried over magnesium sulphate.

The ether is evaporated under reduced pressure to give crude 2- (1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy) -malonic acid, which is heated until the evolution of carbon dioxide ceases to give (1- oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy) acetic acid, m.p. 168-169 ° C after crystallization from nitromethane.

Example 17 (1,2-Dichloro-5,5,5,7,7,8,8e-hexahydro-8 * (- phenyl-9-oxofluoren-3-yloxy) acetic acid)

Step A: Cyclohexyl- (2,3-dichloro-5-methoxyphenyl) -ketone A stirred mixture of 2,3-dichloroanisole (88.5 g, 0.5 mol) and cyclohexanecarbonyl chloride (81 g, 0.55 mol) in methylene chloride (400 mL), cooled to 5 ° C and treated with aluminum chloride (74 g, 0.55 mol) over 1/2 hour. The reaction mixture is allowed to warm to 25 ° C and after 16 hours is poured into ice water (1 L) and hydrochloric acid (200 ml). The organic phase is washed with 10% sodium hydroxide and saturated brine and dried over magnesium sulfate. After evaporation of the solvent, the product is crystallized from hexane to give 42.3 g of o cyclohexyl- (2,3-dichloro-4-methoxyphenyl) ketone, m.p. 97-98 C. Elemental analysis for C 18 H 19 Cl 2 O 2:

Calculated: C, 58.55; H, 5.62; Found: C, 58.92; H, 5.64.

40 618 6 6

Step B: 1-Bromocyclohexyl- (2,3-dichloro-4-methoxy-phenyl) -ketone_

Bromine (22.4 g, 0.14 mol) in acetic acid (50 ml) is added dropwise to a stirred solution of cyclohexyl- (2,3-dichloro-4-methoxyphenyl) ketone (40 g, 0.14 mol) and 30% from hydrobromic acid (0.5 ml) in acetic acid (400 ml) over 11/2 hours at 25 ° C. The mixture is poured into water (1.5 L) and sodium bisulfite (10 g). The precipitated product is crystallized from cyclohexane to give 47.3 g of 1-bromocyclohexyl- (2,3-dichloro-4-methoxyphenyl) ketone, melting at 94-95 ° C.

Elemental analysis for 4H 2 Br-CH 2 Cl 2:

Calculated: C, 45.93; H, 4.13; Found: C, 45.77; H, 4.11.

Step C: 1-Cyclohexenyl- (2,3-dichloro-4-methoxy-phenyl) -_-ketone-1-bromo-cyclohexyl- (2,3-dichloro-4-methoxy-phenyl) -ketone (47.3 g, 0.13 mol), lithium chloride (16.5 g, 0.39 mol) and dimethylformamide (200 ml) are heated at 90 ° C for 2 hours and poured into water (1 L) to give 36.5 g of 1-cyclohexenyl- (2,3- dichloro-4-methoxyphenyl) ketone, which melts after drying at 126-129 ° C at 60 ° C under vacuum for 16 hours.

Elemental analysis for c 14 H 14 Cl 2 O 2:

Calculated: C, 58.96; H, 4.95; Found: C, 58.87; H, 5.10.

Step D: 1 * (1,2,3,4,4,4-hexahydro-6-methoxy-7,8-dichloro-fluoren-9-one)

A stirred mixture of 1-cyclohexenyl (2,3-dichloro-4-methoxyphenyl) ketone (34 g, 0.12 mol) and polyphosphoric acid (340 g) is heated at 90 ° C for 17 hours in a resin vessel. Crushed ice (1 kg) is added to precipitate the product to give 18.4 g of 1, 1,2,3,4,4-hexahydro-6-methoxy-7,8-dichlorofluorene-9 when crystallized from benzene / cyclohexane 1: 1. -onia, sp. 169-171 ° C. Elemental analysis for C14H14Cl2C> 2:

Calculated: C, 58.96; H, 4.95; Found: C, 59.35; H, 5.43.

Step E: N, N-Phenyl-N, 2,3,4,4e (hexahydro-6-methoxy-7,8-dichlorofluoren-9-one) 41,618 6 6

Potassium tert-butoxide (1.69 g, 0.015 mol) in tert-butanol (40 ml) is added to a refluxing solution of 1 - ((1,2,3,4,4) -hexahydro-6- Methoxy-7,8-dichlorophenloren-9-one, (2.85 g, 0.01 mol) in dry benzene (50 ml) and tert-butanol (10 ml) under nitrogen, and refluxing is continued. The reaction mixture is cooled to 25 ° C, diphenyl iodonium chloride (4.75 g, 0.015 mol) is added and refluxing is continued for 2 hours, the reaction mixture is cooled to 25 ° C, 50 ml of water are added and the mixture is concentrated to dryness in vacuo to give , 3.0 g of N-phenyl-N, 1,2,3,4,4 * {- hexahydro-6-methoxy-7,8-dichlorofluoren-9-one, melting at 136-142 ° C, and it is used without further purification.

Step F: 1H-Phenyl-1,2,3,4,4-hexahydro-6-hydroxy-7,8-dichlorofluoren-9-one

A stirred mixture of 1 H -phenyl-1H, 1,2,3,4,6-hexahydro-6-methoxy-7,8-dichlorofluoren-9-one (3.0 g, 0.0083 moles) and pyridine hydrochloride (30 g), heated at 180 ° C for 2 hours, then poured into 800 ml of water to give 1.71 g of M-phenyl-1 H, 1,2,3,4,4 Z- hexahydro-6-hydroxy-7,8-dichlorofluoren-9-one, melting at 213-215 ° C after crystallization from absolute ethanol.

Elemental analysis for C „nH„, .C1_0 „:

1: JO AA

Calculated: C, 65.72; H, 4.64; Found: C, 66.27; H, 4.78.

Step G: (1,2-Dichloro-5H, 5,6,7,8,8) -hexahydro-f - [(phenyl-9-oxo-fluoren-3-yloxy) -acetic acid_

A stirred mixture of 1H-phenyl-1,1,2,3,4,4-hexahydro-6-hydroxy-7,8-dichlorofluoren-9-one (1.7 g, 0, 0049 mol), potassium carbonate (1.36 g, 0.0098 mol) and ethyl bromoacetate (1.64 g, 0.0098 mol) in dimethylformamide (50 ml), Λ heated at 55-60 ° C for 3 hours, then treated with water (50 mL) containing 10N sodium hydroxide (2.5 mL, 0.025 mol) and heated at 80 ° C for 1.5 h. The reaction mixture is slowly added to water (500 ml) containing 12N hydrochloric acid (10 ml), precipitating 1.51 g of (1,2-dichloro-5H, 5,6,7,8,8), hexahydro- 8H-phenyl-9-oxo-fluoren-3-yloxy) acetic acid, melting at 194-196 ° C after crystallization from acetic acid / water 1: 1.

42 61 8 6 6

Elemental analysis for gC 2 O 2:

Calculated: C, 62.24; H, 4.48; Found: C, 62.27; H, 4.56.

Example 18 (1-Oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy) -acetic acid ___

Step A: Tert-butyl (1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy) acetate_

A mixture of 2-methyl-2-phenyl-5-hydroxy-6,7-dichloro-1-indanone (9.2 g, 0.03 mol), potassium carbonate (8.29 g, 0.06 mol) ) and tert-butyl bromoacetate (6.44 g, 0.033 mol) in dimethylformamide (30 ml) are stirred at 25 ° C for 2 hours. The reaction mixture is poured into cold water (150 ml) and the separated tert-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-indanyloxy) -acetic acid___

A solution of tert-butyl (1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy) acetate (1.0 g, 0.00237 mol) in benzene (25 ml), treated with 2 drops of methanesulfonic acid and heated to reflux for 1/2 hour. The reaction mixture is treated with cyclohexane (20 ml) and cooled to give (1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy) acetic acid, which is filtered off and dried.

Example 19 1-Oxo-2-methyl-2- (2-thienyl) -6,7-dichloro-5-indanyloxy) acetic acid

Step A: 2,21-Dithienyl iodonium chloride

To acetic anhydride (70 mL) at -20 ° C is added dropwise with stirring fuming nitric acid (27 mL), then iodine (25 g, 0.1 mol) and trifluoroacetic acid (47 mL, 0.61 mol). The mixture is allowed to warm to ambient temperature while the iodine dissolves over 3 hours. The solvent is removed by distillation in vacuo so that the temperature does not exceed 500 ° C. The residue is dissolved in acetic anhydride (150 ml), the solution is cooled to -10 ° C and a mixture of thiophene (63 ml, 0.08 mol), acetic anhydride (350 ml) and trifluoroacetic acid is added dropwise over 1 hour. acid (50 ml). After cooling to 5 ° C, the mixture is distilled in vacuo over 17 hours, at which point the temperature must never exceed 50 ° C. To the residue is added 500 ml of water, the solution is filtered and ammonium chloride (21.36 g, 0.4 mol) in 100 ml of water is added, precipitating 26.6 g of 2,2'-dithienyl iodonium chloride, m.p. 235-236 ° C after crystallization from methanol.

Elemental analysis for CQH-C1IS_:

o o Z

Calculated: C, 29.24; H, 1.84; Found: C, 28.90; H, 1.92.

Step B: 2-Methyl-2- (2-thienyl) -5-methoxy-6,7-dichloro-1-indanone_

Potassium tert-butoxide (5.06 g, 0.045 mol) dissolved in tert-butanol (100 ml) is added to a refluxing solution of 2-methyl-5-methoxy-6,7-dichloro-1-indanone which is prepared according to steps AD of Example 5 (7.35 g, 0.03 mol) in tert-butanol (150 ml) and benzene (150 ml), refluxing is continued for 3 hours under nitrogen, then the mixture is cooled slightly and solid dithienyl iodonium chloride (16.5 g, 0.05 mol) is added in one portion. Heating under reflux is continued for 2 hours. The reaction mixture is cooled to 25 ° C, 100 ml of water are added and the mixture is concentrated to dryness in vacuo to give 3.85 g of 2-methyl-2- (2-thienyl) -5-methoxy-6,7-dichloro-1-indanone, mp.

145-146.5 ° C after mixing with ether and after crystallization from benzene / hexane 1: 4.

Elemental analysis for c- 5H-2C ^ 2 ° 2 ^:

Calculated: C, 55.06; H, 3.70; Found: C, 55.24; H, 3.77.

Step C: 2-Methyl-2- (2-thienyl) -5-hydroxy-6,7-dichloro-1-indanone_______

A stirred mixture of 2-methyl-2- (2-thienyl) -5-methoxy-6,7-dichloro-1-indanone (3.65 g, 0.0112 mol) and pyridine hydrochloride (36 g), heated at 175 ° C for 1/2 hour and then poured into crushed ice water (500 mL). 3.37 g of 2-methyl-2- (2-thienyl) -5-hydroxy-6,7-dichloro-1-indanone are obtained, m.p. 224-226 ° C after crystallization from ethanol / water: 2: 1.

Elemental analysis for C

Calculated: C, 53.69; H, 3.22; Found: C, 53.27; H, 3.36.

44 61866

Step D: N-oxo-2-methyl-2- (2-thienyl) -6,7-dichloro-5-indanyloxy-acetic acid__

A stirred mixture of 2-methyl-2- (2-thienyl-5-hydroxy-6,7-dichloro-1-indanone (3.13 g, 0.01 mol), potassium carbonate (2.77 g, 0.02 moles) and ethyl bromoacetate (3.34 g, 0.02 moles) in dimethylformamide (40 mL), heated at 55-60 ° C for 2 h, then treated with water (40 mL) with 10N sodium hydroxide ( 4 ml, 0.04 mol) and heated at 100 [deg.] C. for 1 hour The reaction mixture is slowly added to crushed ice water (700 ml) containing 12N hydrochloric acid (10 ml), whereupon 1.78 g / l-oxo-2 -methyl-2- (2-thienyl) -6,7-dichloro-5-indanyloxy-acetic acid, mp 161-162 ° C after crystallization from nitromethane.

Elemental analysis for compound:

Calculated: C, 51.78; H, 3.24; Cl, 19.10; Found: C, 51.66; H, 3.34; Cl, 19.21.

Example 20 Separation of optical isomers of (1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy) -acetic acid_

Step A: (+) - isomer

Racemic (1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy) acetic acid (26 g, 0.071 mol) and L - (-) - N-methylbenzylamine (8.6 g, 0.071 mol) is dissolved in hot acetonitrile (50 ml) and allowed to stand at 25 ° C for 18 hours.

The acetonitrile is decanted off from the resulting salt (13.2 g), which is recrystallized twice from the smallest possible volume of 2-propanol to give 1.9 g of the salt of the pure (+) - enantiomer, which is converted to the acid by treatment with dilute hydrochloric acid and ether. The ether phase is washed with water, dried over magnesium sulfate and the ether is distilled off under reduced pressure. The (+) - isomer melts at 163 ° C after crystallization from toluene.

(<k) ^ - + 88 °. (C, 2, acetone)

Step B: (-) - isomer

Substantially following the procedure described in Step A and using partially decomposed (1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy) acetic acid 618 6 6 45 (15.5 g, 0.042 mol) as the reaction components (obtained from the acetonitrile mother liquor of step A) and D- (+) - .beta.-methylbenzylamine (5.15 g, 0.042 mol) in acetonitrile (150 ml) and recrystallization of the salt twice from the smallest possible volume of 2-propanol gives 2.2 g of the salt of the pure (-) enantiomer. The (-) isomer melts at 164 ° C after crystallization from toluene.

= -88 ° (C, 2, acetone).

Example 21 Preparation of (1-oxo-2-phenyl-2-methyl-6,7-dichloro-5-indanyloxy) acetic acid______

Step A: Preparation of 2,3-dichloro-4-methoxy-4-phenyl-propiophenone

To a 2-liter round bottom 4-neck flask equipped with a stirrer, reflux condenser with drying tube, thermometer, and aluminum chloride funnel is charged 2,3-dichloroanisole (137.0 g, 0.774 mol), 2-phenylpropionyl chloride (mole), mg and methylene chloride (600 mL). The mixture is stirred, cooled to 5 ° C and Aluminum trichloride (114 g) is added portionwise over 1 hour while maintaining the temperature at 5 ° C. The mixture is heated and kept at 25 ° C for 16 hours.

The resulting mixture is added to 1 liter of 1.5 molar HCl. The lower organic layer is separated, the aqueous phase is extracted with methylene chloride and the combined extracts are washed with saturated aqueous sodium chloride solution, 10% strength by weight aqueous sodium hydroxide solution and re-saturated sodium chloride solution, dried over magnesium sulphate and evaporated under reduced pressure. The resulting green oil is dissolved in hot hexane (200 mL) and upon cooling, 2,3-dichloro-4-methoxy-N, {-phenyl-propiophenone is separated.

Step B: 2-Phenyl-2-methyl-5-methoxy-6,7-dichloro-1-indanone 1-mole of 2,3-dichloro-4-methoxy-β-phenyl-porpiophenone and 1.3 moles of formaldehyde (paraformaldehyde) and 1 1 of trifluoroacetic acid is heated to reflux and metyyni proton loss and finally the amount of aromatic protons half the loss is monitored by analyzing samples of the reaction mixture by nMR technique excess trifluoroacetic acid is removed under vacuum at 25 ° C. and at the raw product obtained is released from yet remaineth trifluorietikkahapos-of dissolving ether and washed with saturated sodium bicarbonate solution until neutral, then the ether solution is dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give 2-phenyl-2-methyl-5-methoxy-6,7-dichloro-1-indanone.

Step C: 1-Oxo-2-phenyl-2-methyl-6,7-dichloro-5-indanyloxy-acetic acid 250 g of 2-phenyl-2-methyl-5-methoxy-6,7-dichloro-1- heating the indanone for 7 hours at 85 ° C in 100 g of pyridine hydrochloride to give the 5-hydroxy compound; then 200 ml of dimethylformamide, 100 g of sodium carbonate and 0.105 mol of chloroacetic acid are added. The product obtained is extracted with methylene chloride, separated and recrystallized from glacial acetic acid to give 1-oxo-2-phenyl-2-methyl-6,7-dichloro-5-indanyloxyacetic acid, m.p.

168-169 ° C.

Example 22 Preparation of 2-methyl-2-phenyl-5-methoxy-6,7-dichloro-1-indanone starting material

Step A; 2-Methyl-5-methoxy-6,7-dichloro-1-indanone 2,3-dichloroanisole (177 g, 1.0 mol), anhydrous Aluminum chloride (280 g, 2.10 mol) and 545 ml of carbon sulfide are mixed in a nitrogen atmosphere. The mixture is stirred at 25-30 ° C while 110 mL of N-bromo-2-methylpropionyl bromide (209 g, 0.91 mol) is added over 1 1/2 hours. The reaction mixture is kept at 25-30 ° C for 1 hour and then at 43-45 ° C for 4 hours. After stirring overnight at 25 ° C, the batch is carefully cooled in a mixture of 2.72 liters of ice and water. The temperature rises to 28 ° C during freezing and the batch is allowed to stand for 10 minutes. The layers are separated and the aqueous phase is extracted with 2 x 250 ml of toluene. The combined organic phase is washed with 275 ml of 10% sodium bicarbonate solution, dried over magnesium sulphate and concentrated to dryness in vacuo to give 207 g (93%) of 2-methyl-5-methoxy-6,7-dichloro-1-indanone.

Step B: 2-Methyl-2-phenyl-5-methoxy-6,7-dichloro-1-indanone 2-methyl-5-methoxy-6,7-dichloro-1-indanone (245 g, 1.0 mol) , 2.19 liters of t-butanol (sieve-dried) and 1.74 liters of Bent-mushene (azeotropically dried) are stirred under a nitrogen atmosphere and heated at 50 ° C. A solution of 47 61 8 6 6 potassium t-butoxide (190 g, 1.7 mol) in 1.74 liters of t-butanol (sieve-dried) is added in one portion. The charge is heated to reflux (78 ° C) for 30 minutes. Cool to 30 ° C and add bromobenzene (372.5 g, 2.5 moles) over 15 minutes (initial temperature rises). The mixture is heated to reflux (71 ° C) for 10 minutes and re-cooled to 30 ° C. 903 ml of water are gradually added at 30-40 ° C and the batch is concentrated in vacuo to a volume of 887 ml.

The solid is collected by filtration. The filter cake is washed with 3 x 350 ml of water and dried in vacuo at 45 ° C to give 200 g (60%) of 2-methyl-2-phenyl-5-methoxy-6,7-dichloro-1-indanone in crude yield.

The crude material is crystallized from 1.37 liters of boiling ethanol, cooled to 0-5 ° C and filtered. The solid is washed with cold ethanol and dried in vacuo at 45 ° C to give 100 g (50%) of 2-methyl-2-phenyl-5-methoxy-6,7-dichloro-1-indanone.

Example 23 Preparation of 2-methyl-2-phenyl-5-methoxy-6,7-dichloro-1-indanone starting material

Step A; 2-Phenyl-5-methoxy-6,7-dichloro-1-indanone This compound was prepared as in Example 22, but using 266 g (0.91 mol) of bromo-2-phenylpropionyl bromide. instead of propionyl bromide. The crude yield is 285 g (93%) of 2-phenyl-5-methoxy-6,7-dichloro-1-indanone, m.p. 193-195 ° C after crystallization from benzene / cyclohexane 2: 1.

Step B: 2-Methyl-2-phenyl-5-methoxy-6,7-dichloro-1-indanone____ Dissolve 50.84 g of 2-phenyl-5-methoxy-6,7-dichloro-1-indanone in 700 ml. dry dimethylformamide and 700 ml of dry benzene in a 3-liter flask equipped with a nitrogen inlet, an air condenser and a sodium methoxide hopper. 103 ml of iodomethane in nitrogen gas are added to the solution while cooling in an ice-water bath, and 13.5 g of sodium methoxide are added portionwise from a funnel through a Gooch tube over a period of 3/4 hour. During the addition, the reaction mixture turns bright red, after which the color slowly disappears and a solid precipitate forms. After stirring for 1/2 hour in an ice-water bath, the reaction mixture is added to water (about 4 liters) and extracted with benzene. After the benzene solution is dried on a molecular sieve and concentrated to dryness, a pale yellow substance is formed; yield 45.6 g, m.p. 161-165 ° C (86%). A recrystallized sample of benzene / cyclohexane (1: 2) melts at 164-165 ° C.

Claims (5)

61 8 6 6 48 A process for the preparation of a diuretic and a saluretic (* -1-oxo-2-phenyl- or thienyl-2-substituted-5-indanyloxy-acetic acid or a derivative thereof) of the formula I: C1r R OCCH-O -KX JL 2 X / R 1 X 1 wherein R 0 is - or thienyl, wherein X 1 is hydrogen, halogen, 3 methoxy, nitro, amino or cyano, R is hydrogen or lower alkyl, R is methyl, ethyl, phenyl or cyclopentyl, and R 1 is hydrogen or phenyl or R and R 1 together form a 6-membered ring, characterized in that (a) a compound of formula: is treated with the formula: Cl 0 '' VyV '' HO-o 1 wherein R, R and R are as defined above , with a reagent of formula: O zch2-c-or1, wherein R is as defined above and Z is halogen, in the presence of base 3, and when R is lower alkyl the ester obtained is optionally hydrolyzed, or (b) to prepare a compound of formula I, wherein R 0 is phenyl and R 1 is hydrogen, treating a compound of formula: 49 613 6 6 Cl o cOjL- * ° * s I Pi R 0CHCH 2 O - with an alkylating agent of formula: R 2, wherein R 0, R 1, R 3 and R 2 are as defined above and 3 Z is halogen, and if desired, the ester obtained when R is lower alkyl is hydrolysed, or 3 (c) the formula I to prepare a compound of formula wherein R is hydrogen, treating a compound of formula: Cl 0 wherein R, R and R are as defined above with 1-halo-2-nitroethane to form a compound of formula Cl 0 O 2 NCH 2 CH 2 O - R wherein R 0, R and R 1 are as defined above, and the resulting compound is hydrolyzed to form the desired product; or (d) for the preparation of a compound of formula I wherein R 3 is hydrogen, treating a compound of formula: 618 6 6 50 i1 ° csAA <r ° R «0-ν- ^ Εΐ o 1 wherein R, R and R are the same as above, with a malonic acid ester of formula R "O 2c CH 2, wherein R" is lower alkyl, to give a compound of formula R "O 2 (r of formula of formula C 0" yYV · "(r" O 2 O 2 CH 2 O 2 ' Wherein R 0, R, R 1 and R "are as defined above, the resulting compound is hydrolyzed to form a compound of formula: Cl O (ho 2 c) 2 CH 2 R 1 wherein R 0, R, R 1 are as defined above, and the latter compound is decarboxylated to form the desired product, or (e) to prepare a compound of formula I wherein R 0 is 1 phenyl, R is methyl, R is hydrogen and R is hydrogen, treating a compound of formula: 51 618 6 6 ci o kR1 wherein R 0, R and R 1 are as defined above, with haloacetonitrile in the presence of a base, and the resulting nitrile is hydrolysed, or (f) to prepare a compound of the formula: wherein R 0 is phenyl, halophenyl or thienyl; reacting a compound of formula: Cl c 1 -C 6 -A 2 -O 2 CHCH 4 2 2 2 wherein R is CH 2 COOH, R or Cl 2 COOR where R is methyl in the presence of an acid; 3 and that if in the final product of formula I the substituent X is a nitro group, this nitro group can be reduced to an amino group if desired. Process for the preparation of (1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy) acetic acid according to Claim 1, characterized in that in the formula IR 0 is phenyl, 13 R is methyl and R and R is hydrogen. 52 618 6 6 A process for the preparation of diuretics and saluretics of 1-oxo-2-phenyl- or thienyl-2-substituents-5-indanyloxy. , o 3 color R is — C or thienyl, colors X is a derivative, halogen, 3 methoxy, nitro, amino or cyano, R is a derivative or a light alkyl, R is methyl, ethyl, phenyl or cyclopentyl, and R is a derivative or phenyl or R and R are the same as in the 6-ring ring, as shown in Figure 1 (a) to give the following formula: Cl O HO-1 color R °, R and R1 -c-or3 3 color R betyder decamma som ovan and Z is halogen, i is a nerve from 3 to bas, and if R is a alkyl alkyl of a hydrogen ester, or (b) a framställning av en förening enligt formuleln I, color o 1 R ° är phenyl and R är väte, behandlar man en förening med formuleln V 53 61866 Cl o VyV ”o I 3" · D "IR OCCH20 ---- K med ett alkyleringsmedel med formuleln: R 2, i and R form, R 1, R 1, and R betyder decamma som ovan and Z 3 are halogen, and when R is an alkyl hydrolyser, which is an alkyl ester; or (c) for the preparation of the formulation with formula I, color 3 R is used, the method of preparation of the formulation: Cl O color R °, R and R1 betyder decamma som ovan, with 1-halo-2-nitro-ethane for the formulation of the formulation with the color R °, R and R ^ butyder decamma som ovan, och den erh & llna föreningen hydrolyseras for the formulation of the product itself; or (d) for the production of formula I, color 3 R är väte, behandlar man en förening med Formeln: 54 6 1 8 6 6 i1 ° “VW; R ° I 'r HO-J-1 R color R °, R and R1 betyder decamma som ovan, med en malonsyraester med formeIn R "° 2C ^ ^^ CH2 / color R" Sr lSgre alkyl, för bildande av R ”02C ^ 0 in the case of the formula: Cl 0 (R "02C) o 1 color R, R, R and R" in the form of a solid which has been hydrolysed for the formulation: Cl 0 (H02O 2CHO ^ R1 color) R °, R, R 2 are selected from the group consisting of the same or more than the system of decarboxylation to give the same product, or (e) from the group consisting of 13 R Sr phenyl, R Sr methyl, R Sr vSte och R Sr vSte, behandlar man en förening med formeln: