CA1038396A - Process for the preparation of (1-oxo-2-phenyl, halophenyl or thienyl-2-methyl-6,7-dichloro-5-indanyloxy)acetic acid - Google Patents
Process for the preparation of (1-oxo-2-phenyl, halophenyl or thienyl-2-methyl-6,7-dichloro-5-indanyloxy)acetic acidInfo
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- CA1038396A CA1038396A CA210,646A CA210646A CA1038396A CA 1038396 A CA1038396 A CA 1038396A CA 210646 A CA210646 A CA 210646A CA 1038396 A CA1038396 A CA 1038396A
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- methyl
- dichloro
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/22—Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
- C07C45/46—Friedel-Crafts reactions
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/673—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by change of size of the carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
- C07C49/703—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups
- C07C49/747—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups containing six-membered aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
- C07C49/753—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups
- C07C49/755—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups a keto group being part of a condensed ring system with two or three rings, at least one ring being a six-membered aromatic ring
Abstract
ABSTRACT OF THE DISCLOSURE
(1-Oxo-2-phenyl, halophenyl or thienyl-2-methyl 6,7-dichloro-5-indanyloxy)-acetic acid is prepared by reacting a 2,3-dichloroanisole or 2 3-dichlorophenoxy-acetic acid or ester with a suitable .alpha.-haloacylhalide or .beta.-haloacylhalide under Friedel-Crafts conditions to form an intermediate acylation product which undergoes dehydro-halogenation in the side chain followed by ring closure to give an intermediate or the desired 2-substituted indanone.
This latter compound is alkylated with a methylating or arylating agent to give the desired indanone. Several novel intermediates are also claimed.
(1-Oxo-2-phenyl, halophenyl or thienyl-2-methyl 6,7-dichloro-5-indanyloxy)-acetic acid is prepared by reacting a 2,3-dichloroanisole or 2 3-dichlorophenoxy-acetic acid or ester with a suitable .alpha.-haloacylhalide or .beta.-haloacylhalide under Friedel-Crafts conditions to form an intermediate acylation product which undergoes dehydro-halogenation in the side chain followed by ring closure to give an intermediate or the desired 2-substituted indanone.
This latter compound is alkylated with a methylating or arylating agent to give the desired indanone. Several novel intermediates are also claimed.
Description
~,03~i 13 This invention relates to a new process for the .. . .
14 preparation of [1-oxo-(2-phenyl, halophenyl or thienyl~-2-methyl-6,7-dichloro-5-indanyloxy]-acetic acid. Pharmaccutical 16 studies show that the above-mentioned products are effective 17 diuretic and saluretic agents which can be used in the 18 treatment of conditions associated with electrolyte and 19 fluid retention. The above-mentioned compounds are also used in the treatment of hypertension. In addition, these 21 compounds are able to maintain the uric acid concentration 22 in the body at pretreatment levels and to even effect a 23 decrease in the uric acid concentration.
24 When administered in therapeutic dosages, in conventional vehicles, the compounds effectively reduce 26 the amount of sodium and chloride ions in the body, lower 27 dangerous excesses of fluid levels to acceptable lcvcls
14 preparation of [1-oxo-(2-phenyl, halophenyl or thienyl~-2-methyl-6,7-dichloro-5-indanyloxy]-acetic acid. Pharmaccutical 16 studies show that the above-mentioned products are effective 17 diuretic and saluretic agents which can be used in the 18 treatment of conditions associated with electrolyte and 19 fluid retention. The above-mentioned compounds are also used in the treatment of hypertension. In addition, these 21 compounds are able to maintain the uric acid concentration 22 in the body at pretreatment levels and to even effect a 23 decrease in the uric acid concentration.
24 When administered in therapeutic dosages, in conventional vehicles, the compounds effectively reduce 26 the amount of sodium and chloride ions in the body, lower 27 dangerous excesses of fluid levels to acceptable lcvcls
2~ and, in ~cneral, alleviate conditions usually associated ' 1038396 1 with edema. In addition, the compounds overcome a major 2 problem associated with many of the presently available
3 diuretics and saluretics. For example, many of the
4 presently available diuretics and saluretics have a tendency upon administration to induce hyperuricemia 6 which may precipitate uric acid or sodium urate, or both, 7 in the body which may cause from mild to severe cases of 8 gout. The instant compounds now provide an effective tool 9 to treat those patients, both human and animal, requiring diuretic and saluretic treatment without incurring the 11 risk of inducing gout.
12 Thus, it is an object of the present invention 13 to provide a specific, highly efficient unified process 14 for the preparation of [1-oxo-(2-phenyl, halophenyl or thienyl~2-methyl-6,7-dichloro-5-indanyloxy]-acetic acid 16 and its non-toxic pharmaceutically acceptable salt, ester 17 and amide derivatives. It is also an object of the present 18 invention to provide useful intermediates (II, above) which 19 are involved in the process of this invention. One advan-tage of the instant process is that it allows one to use 21 relatively cheaper starting materials than previous processes.
22 The process of this invention can be shown 23 chemically by the following reaction sequence~
Cl ` 1~83~
Cl_ ~ + CH2=C-COX
RO_ ~ (a) or I R Step A
CH3-CXCOX Lewis (b) Acid or ,R
z (c) II
Cl ~ R Step E
RO_ Z if Z is hydrogen III \
\ - if Z is methyl ~<CH3 Ether Cleavage >~30 ~\CRH3 V VI
StepOD
~XCH2COR"
Cl O Cl CH3 Cl - ~ ~ CH3hydrolysis Cl_ ~ R' C-CH2 - ~ R' ~if R" is not H O
VIII VII
; 1038396 1 In the above reaction sequence 2 R = lower alkyl having up to 5 carbon atoms, 3 preferably methyl; H or CH2CO2R", wherein 4 R" is lower alkyl or hydrogen;
X = Cl, Br or I;
6 R = phenyl, methyl, halophenyl, preferably p-7 chloro or p-fluorophenyl and thienyl, 8 preferably z-thienyl;
9 R' = phenyl, halophenyl, preferably p-chloro or p-fluorophenyl and thienyl, preferably 2- thienyl;
11 R" = lower alkyl or H;
12 Z = H or methyl but is not methyl when R is 13 methyl, i.e. Z and R cannot be methyl at 14 the same time;
Y = phenyl, halophenyl, thienyl, diphenyliodo, 16 dihalophenyliodo, dithienyliodo.
17 More specifically, Step A of this invention 18 involves a reaction of 2,3-dichloroanisol or a related lower 19 alkyl ether or 2,3-dichlorophenoxyacetic acid or a related lower alkyl ester and a suitable substituted or unsubstituted 21 acyl halide of the formulae shown in the reaction sequence.
22 These compounds are reacted under Friedel-Crafts reaction 23 conditions with an appropriate catalyst to produce an 24 intermediate 2-substituted indanone shown as Formula III.
If an a,a-disubstituted acyl halide is used in Formula II(c) 26 such as for example a-methyl-a-phenyl-~-bromopropionyl 27 chloride and R is CH2CO2H, then the desired indanone V is 28 formed directly. This reaction proceeds through a dehydro-29 halogenation introducing a side chain followed by a ring 1 closure to give intermediate Formula III. Typical substi-2 tuted or unsaturated acyl halides are acrylyl chloride-, 3 a-halo isobutyryl chloride, or ~-halo isobutyryl chloride.
4 The Friedel-Crafts reaction conditions under which Step A
of the reaction is carried out are the use of a catalyst 6 such as Lewis acid particularly aluminum chloride or tin 7 chloride and use of a solvent particularly an inert organic 8 solvent which does not react appreciably with the reactants.
9 Typical of such inert solvents are methylene chloride, tetrachloroethane, hexane, carbon disulfide or nitrobenzene.
11 Step A of the reaction is carried out at a temperature from 12 about 0 to the reflux temperature of the solvent, but 13 20-50 is preferred for a length of time sufficient to 14 substantially complete the reaction but generally from about 4 to 6 hours at about 40C.
16 The a,c-disubstituted-~-halo propionyl halide of 17 Formula II(c) can be prepared by the general method of 18 Nicolaus, Mariani and Testa, "A New General Synthesis for 19 ~-Substituted Propionic Acid and its Derivatives", Bruno J.R.
Nicolaus, Luigi r~ariani and Emilio Testa (Lepetit Spa, Milan) 21 Chem. Abst. 55 27271d (1961).
22 Step B of the process involves alkyla~ing the 23 intermediate 2-methyl indanone, Formula III, if the ini'-ial 24 reactant Formula II was not an a,a-disubstituted propionyl halide using an alkylating agent, YX wherein Y and X are 26 as defined above, particularly with diaryliodium halide or 27 methyl halide to yield an intermediate indanone, Formula V.
28 The alkylation reaction is carried out in the presence of 29 a suitable basic catalyst such as sodium tertiary butoxide, 1 sodium hydride, sodamide, sodium methoxide or the like 2 in a suitable solvent such as any inert non-aqueous 3 organic solvent, particularly benzene or toluene. The 4 alkylation reaction is carried out for a time sufficient to complete the reaction and preferably at a temperature 6 from about room temperature to a reflux temperature of the 7 particular solvent used. If in the compound Formula V
8 which is formed R' is phenyl, halophenyl or thienyl and 9 R is CH2CO2H, then the desired indanone is already formed.
It can be isolated from the reaction mixture by methods 11 known in the art such as by extracting the desired compound 12 from its reaction mixture with a solvent, boiling off said 13 solvent and then recrystallizing the desired indanone from 14 acetone or other suitable solvent.
If in the compound of Formula V R is lower alkyl, 16 this compound must further undergo an ether cleavage which 17 comprises treating the compound of Formula V with an ether 18 cleavage reagent and then treating the 5-hydroxy product 19 formed, Formula VI, with a haloacetic or ~seudohaloacetic acid or ester thereof of the formula XCH2C-OR" wherein X is 21 Cl, Br, I, mesyl or tosyl and R" is hydrogen or lower alkyl.
22 Finally, if R" in the halo acetic acid ester is 23 lower alkyl, the product formed, Formula VII, must further 24 undergo a hydrolysis to form the desired indanone. If a halo acetic acid is used as the reactant, then Formula VII
26 is the desired indanone.
27 Step C of the reaction scheme, namely, the ether 28 cleavage, is carried out with ether cleaving reagents, such 29 as aluminum chloride, pyridine hydrochloride, hydrogen bromide, 1 sodium in liquid ammonia and the like. When aluminum 2 chloride is employed, the solvent may be heptane, carbon 3 disulfide, methylene chloride and the like and when pyridine 4 hydrochloride is employed, it is not necessary to employ a solvent.
6 Generally, this ether cleavage is carried out 7 at temperatures from room temperature to reflux temperature 8 of any solvent used for any time sufficient to complete 9 substantial formation of the intermediate of Formula VI.
The reaction wherein the product of Formula VI
11 is reacted with a halo acetic acid or ester, the reaction 12 is generally conducted in the presence of a base, such as 13 alkali metal carbonate, hydroxide or alkoxide such as 14 potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, sodium ethoxide and the like. Any solvent 16 which is inert or substantially inert to the reactants and 17 in which the reagents are reasonably soluble may be employed.
18 Ethanol, dimethylformamide, benzene and toluene, for example, 19 have proved to be particularly advantageous solvents. The reaction may be conducted at a temperature in the range of 21 from about 25C. to the reflux temperature of the particular 22 solvent employed. The reaction with the haloacetic acid or 23 ester is generally complete in about 10 to 60 minutes. If 24 the haloacetic acid ester is employed, the ester obtained may be hydrolyzed to the free acid by methods well known 26 to those skilled in the art.
27 The invention herein can be illustrated by the 28 following examples:
. .
2 2-Methyl-2-phenyl-5-methoxy-6,7-dichloro-1-indanone 3 Step A: 2-Methyl-5-methoxy-6,7-dichloro-l-indanone 4 2,3-Dichloroanisole (177 g., 1.0 mole), anhydrous aluminum chloride (280 g., 2.10 mole) and 545 ml. of carbon 6 disulfide are mixed under a nitrogen atmosphere. The 7 mixture is stirred at 25-30 while adding 110 ml. of ~-bromo-8 2-methylpropionyl bromide (209 g., 0.91 mole) over 1-1/2 9 hours. The reaction mixture is aged at 25-30 for one hour, then at 43-45 for 4 hours. After finally stirring 11 overnight at 25 the batch is quenched, carefully, into a 12 mixture of 2.72 liters of ice and water. The temperature 13 increases to 28 during the quench and the batch is aged 14 for 10 minutes. The layers are separated and the aqueous phase is extracted with 2 x 550 ml. of toluene. The combined 16 organic phase is washed with 275 ml. of 10% sodium 17 bicarbonate solution, dried over magnesium sulfate, and 18 concentrated ln vacuo to dryness to yield 207 g. (93~) of 19 2-methyl-5-methoxy-6,7-dichloro-1-indanone.
Step B: 2-Methyl-2-phenyl-5-methoxy-21 6,7-dichloro-1-indanone 22 2-Methyl-5-methoxy-6,7-dichloro-1-indanone 23 (245 g., 1.0 mole), 2.19 liters of t-butanol (sieve-dried) 24 and 1.74 liters of benzene (azeotropically dried) are mixed under a nitrogen atmosphere and heated to 50. A solution 26 of potassium t-butoxide (190 g., 1.7 moles) in 1.74 liters 27 of t-butanol (sieve-dried) is added all at once. The batch 28 is heated to reflux (78) and refluxed for 30 minutes. Cooled 29 to 30 and bromobenzene (372.5 g., 2.5 moles) added over 15 minutes (initial temperature rise). The mixture is 1038~96 1 heated to reflux (71), refluxed for 10 minutes and cooled 2 again to 30. Water (903 ml.) is added,gradually, at 30-40 3 and the batch is concentrated in vacuo to a volume of 887 ml.
4 The solids are collected by filtration. The filter cake is washed with 3 x 350 ml. of water and dried in vacuo at 45 6 giving a crude yield of 200 g. 60% of 2-methyl-2-phenyl-5-7 methoxy-6,7-dichloro-1-indanone.
8 The crude material is recrystallized from 1.37 9 liters of boiling ethanol, cooled to 0-5 and filtered.
The solids are washed with cold ethanol and dried ln vacuo 11 at 45 to yield 100 g. 50% of 2-methyl-2-phenyl-5-methoxy-12 6,7-dichloro-1-indanone.
13 Following the procedure above but using p-chloro-14 bromo benzene or 2-thienyl bromide in place of bromobenzene in Step B, there is prepared an equivalent amount of 2-methyl-16 2-p-chloro-5-methoxy-6,7-dichloro-1-indanone and 2-methyl-17 2-(2-thienyl)-5-methoxy-6,7-dichloro-1-indanone.
19 2-Methyl-2-phenyl-5-methoxy-6,7-dichloro-1-indanone 2,3-Dichloroanisole (177 g., 1.0 mole), anhydrous 21 aluminum chloride (280 g., 2.10 mole) and 545 ml. of carbon 22 disulfide are mixed under a nitrogen atmosphere. The 23 mixture is stirred at 25-30 while adding 261.5 gm. (1 mole) 24 of a-methyl-a-phenyl-~-bromo propionyl chloride over 1-1/2 hours. The reaction mixture is aged at 25-30 for one hour, 26 then at 43-45 for 4 hours. After finally stirring overnight 27 at 25 the batch is quenched, carefully, into a mixture of 28 2.73 liters of ice and water. The temperature increases to 29 28 during the quench and the batch is aged for 10 minutes.
1 The layers are separated and the aqueous phase is extracted 2 with 2 x 550 ml. of toluene. The combined organic phase is 3 washed with 275 ml. of 10% sodium bicarbonate solution, dried 4 over magnesium sulfate, and concentrated in vacuo to dryness to yield 207 g. (93%) of 2-methyl-2-phenyl-5-methoxy-6,7-6 dichloro-l-indanone.
7 Following the procedure above but using a-methyl-8 p-chlorophenyl or 2-thienyl-~-bromo propionyl chloride in 9 place of ~-methyl-~-phenyl-~-bromo propionyl chloride, there is produced an equivalent amount of 2-methyl-2-p-chloro-11 phenyl-5-methoxy-6,7-dichloro-1-indanone and 2-methyl-2-12 (2-thienyl)-5-methoxy-6,7-dichloro-1-indanone respectively.
14 2-Methyl-2-phenyl-5-methoxy-6,7-dichloro-1-indanone Step A: 2-Methyl-5-methoxy-6,7-dichloro-16 1-indanone 17 This compound is prepared by a procedure identical 18 to Example 1 except ~-chloro-2-methyl propionyl chloride is 19 substituted for the dibromo analog.
Step B: 2-Methyl-2-phenyl-5-methoxy-21 6,7-dichloro-1-indanone 22 This compound is prepared by a procedure identical 23 to Example 1.
2-Methyl-S-methoxy-6,7-dichloro-1-indanone _ 26 Step A: 2-Methyl-5-methoxy-6,7-dichloro-27 l-indanone 28 This compound is prepared by a procedure ldentical 29 to Example 1 except ~-chloro-2-methylpropionyl chloride is substituted for ~-bromo-2-methylpropionyl bromide.
~038396 1Step B: 2-Methyl-5-methoxy-6,7-dichloro-2l-indanone 3This compound is prepared by a procedure 4 identical to Example 1.
62-Methyl-2-phenyl-5-methoxy-6,7-dichloro-1-indanone 7Step A: 2-Methyl-5-methoxy-6,7-dichloro-8l-indanone 9This compound is prepared by a procedure identical to Example 1.
11 Step B: 2-Methyl-2-phenyl-5-methoxy-126,7-dichloro-1-indanone 13 This compound is prepared by a procedure identical 14 to Example 1 except that chlorobenzene is substituted for bromobenzene as alkylating agent.
172-Methyl-2-phenyl-5-methoxy-6,7-dichloro-1-indanone 18Step A: 2-Methyl-5-methoxy-6,7-dichloro-19l-indanone 20This compound is prepared by a procedure identical 21 to Example 1, Step A.
22 Step B: 2-Methyl-2-phenyl-5-methoxy 23 6,7-dichloro-1-indanone 24 This compound is prepared by a procedure identical to Example 1, Step B, except that 317 grams of diphenyl 26 iodonium chloride are substituted for 372.5 grams of 27 bromobenzene.
292-Methyl-2-p-chlorophenyl-5-methoxy-6,7-dichloro-1-indanone 30Step A: 2-Methyl-5-methoxy-6,7-dichloro-31l-indanone 32This compound is prepared by a procedure identical 33 to Example 1, Step A.
1 Step B: 2-Methyl-2-p-chlorophenyl-5-2 methoxy-6,7-dichloro-1-indanone 3 This compound is prepared by a procedure identical 4 to Example 1, Step B,except that 387 grams of di-p-chloro-phenyl iodonium chloride are used in place of 372.5 grams 6 of bromobenzene.
8 2-Methyl-2-phenyl-5-methoxy-6,7-dichloro-1-indanone 9 Step A: 2-Phenyl-5-methoxy-6,7-dichloro-l-indanone 11 This compound is prepared by a procedure identical 12 to Example 1 except that 266 g., 0.91 mole, of a-bromo-2-13 phenylpropionyl bromide is substituted for a-bromo-2-methyl-14 propionyl bromide. ~he crude yield is 285 g. (93%) of 2-phenyl-5-methoxy-6,7-dichloro-1-indanone. After 16 recrystallization from benzene-cyclohexane 2:1, the m.p.
17 is 193-195C.
18 Step B: 2-Methyl-2-phenyl-5-methoxy-6,7-19 dichloro-l-indanone 2-Phenyl-S-methoxy-6,7-dichloro-1-indanone 21 (50.84 g.~ was dissolved in dry dimethylformamide (700 ml.) 22 and dry benzene (700 ml.) in a 3 liter flask equipped with 23 a nitrogen inlet tube, air condenser, and hopper for sodium 24 methoxide. Iodomethane (103 ml.) was added to the solution under nitrogen while cooling in an ice-water bath, and 26 sodium methoxide (13.5 g.) was added portionwise from the 27 hopper through the Gooch tubing over 3/4 hour. During the 28 addition, the reaction mixture turned bright red, then the 29 color slowly disappeared and a solid precipitate formed.
After stirring for 1/2 hour in an ice-water bath, the reaction .
103~i 1 mixture was added to water (~4 liters) and extracted with 2 benzene. Upon drying the benzene solution over molecular 3 sieves and concentrating to dryness, a pale yellow solid 4 product formed; yield: 45.6 g., m.p. 161-165C. (86%).
A sample recrystallized from benzene-cyclohexane (1:2) 6 melts at 164-165C.
8 (1-Oxo-2-cyclopentyl-2-methyl-6,7-dichloro-5-indanyloxy)-9 acetic acid Step A: (l-Oxo-2-methyl-6,7-dichloro-5-11 indanyloxy)-acetic acid 12 This compound is prepared by a procedure identical 13 to Example 1 except that 2,3-dichlorophenoxyacetic acid is 14 substituted for 2,3-dichloroanisole.
Step B: (l-Oxo-2-phenyl-2-methyl-6,7-16 dichloro-5-indanyloxy)-acetic acid 17 This compound is prepared by a procedure identical 18 to Example 1 except that (1-oxo-2-methyl-6,7-dichloro-5-19 indanyloxy)-acetic acid is substituted for 2-methyl-5-methoxy-6,7-dichloro-1-indanone.
22 (1-Oxo-2-phenyl-2-methyl-6,7-dichloro-5-indanyloxy)-23 acetic acid 24 Step A: (l-Oxo-2-methyl-6,7-dichloro-5-indanyloxy)-acetic acid 26 This compound is prepared by a procedure identical 27 to Example 3 except that 2,3-dichlorophenoxyacetic acid is 28 substituted for 2,3-dichloroanisole.
29 Step B: (l-Oxo-2-phenyl-2-methyl-6,7-dichloro-5-indanyloxy)-acetic acid 31 This compound is prepared by a procedure identical 32 to Example 3 except that (1-oxo-2-methyl-6,7-dichloro-5-33 indanyloxy)-acetic acid is substituted for 2-methyl-5-34 methoxy-6,7-dichloro-1-indanone.
2 (1-Oxo-2-phenyl-2-methyl-6,7-dichloro-5-indanyloxy)-3 acetic acid 4 Step A~ Oxo-2-methyl-6,7-dichloro-5-indanyloxy)-acetic acid 6 This compound is prepared by a procedure identical 7 to Example 4 except that 2,3-dichlorophenoxyacetic acid is 8 substituted for 2,3-dichloroanisole.
9 Step B: (l-Oxo-2-phenyl-2-methyl-6,7-dichloro-5-indanyloxy)-acetic acid 11 This compound is prepared by a procedure identical 12 to Example 4 except that tl-oxo-2-methyl-6,7-dichloro-5-13 indanyloxy)-acetic acid is substituted for 2-methyl-5-14 methoxy-6,7-dichloro-1-indanone.
16 (1-Oxo-2-phenyl-2-methyl-6,7-dichloro-5-indanyloxy)-17 acetic acid 18 Step A: (l-Oxo-2-methyl-6,7-dichloro-5-19 indanyloxy)-acetic acid _ This compound is prepared by a procedure identical 21 to Example 5 except that 2,3-dichlorophenoxyacetic acid 22 is substituted for 2,3-dichloroanisole.
23 Step B: (l-Oxo-2-phenyl-2-methyl-6,7-24 . dichloro-5-indanyloxy)-acetic acid This compound is prepared by a procedure identical 26 to Example 5 except that (1-oxo-2-methyl-6,7-dichloro-27 5-indanyloxy)-acetic acid is substituted for 2-methyl-28 5-methoxy-6,7-dichloro-1-indanone.
29 EXAMæLE 13 (1-Oxo-2-phenyl-2-methyl-6,7-dichloro-5-indanyloxy)-acetic acid -31 This compound is prepared by a procedure identical 32 to Example 2 except that 2,3-dichlorophenoxyacetic acid is 33 substituted for 2,3-dichloroanisole.
1 Following the above procedure but using a-methyl 2 a-p-chlorophenyl or 2-thienyl-~-bromo propionyl chloride in 3 place of a-methyl-a-phenyl-~-bromo propionyl chloride there 4 is produced an equivalent amount of [1-oxo-2-methyl-2 (p-chlorophenyl or 2-thienyl)-2-methyl-6,7-dichloro-5-6 indanyloxy]acetic acid.
8 2-Methyl-5-methoxy-6,7-dichloro-1-indano_e 9 Step A: 2-Methyl-5-methoxy-6,7-dichloro-l-indanone 11 This compound is prepared by a procedure identical 12 to Example 1 except methacrylic acid acid chloride is 13 substituted for a-bromo-2-methylpropionyl bromide.
Preparation of (l-Oxo-2-phenyl-2-methyl-6,7-dichloro-16 5-indanvloxy)-acetic acid 17Step A: 2-Phenyl-2-methyl-5-hydroxy-6,7-18dichloro-l-indanone -192-Phenyl-2-methyl-5-methoxy-6,7-dichloro-1-20indanone (3.5 g., 0.0109 mole) is added to dry hexane 21(180 ml.) and aluminum chloride (4.36 g., 0.0327 mole) 22 is added. The mixture is refluxed for one hour and the 23 hexane is decanted from the gummy residue which then is 24 added to ice water (200 ml.) containing 12N hydrochloric acid (15 ml.). The solid that separates is crystallized 26 from benzene to obtain 2.84 g. of 2-phenyl-2-methyl-5-27 hydroxy-6,7-dichloro l-indanone.
28Step B: (l-Oxo-2-phenyl-2-methyl-6,7-29dichloro-5-indanyloxy)-acetic acid 302-Phenyl-2-methyl-5-hydroxy-6,7-dichloro-1-31indanone (2.84 g., 0.00926 mole) is added to dimethyl-32 formamide (DMF) (40 ml.). Potassium carbonate (3.21 g., 10383g6 , 1 0.0232 mole) and ethyl bromoacetate (3.34 g., 0.0232 mole) 2 are added. The mixture is stirred at 55-60C. for 2-1/2 3 hours, then 40 ml. of 10% sodium hydroxide are added and 4 the mixture is stirred at 80-85C. for 1-1/2 hours. The mixture is then added to 500 ml. of 2% hydrochloric acid.
6 The solid that separates is taken up in ether. The ether 7 extract is washed with water, dried over magnesium sulfate 8 and evaporated, leaving a gummy solid that is crystallized 9 from acetic acid to obtain 183 mg. of (1-oxo-2-phenyl-2-methyl-6,7-dichloro-5-indanyloxy)-acetic acid.
11 Following the procedure above but using 2-p-12 chlorophenyl or 2-(2-thienyl)-2-methyl-5-methoxy-6,7-13 dichloro-l-indanone in place of 2-phenyl-2-methyl-5-methoxy-14 6,7-dichloro-1-indanone, there is produced an equivalent amount of[l-oxo-2-(p-chlorophenyl or 2-thienyl)-2-methyl-16 6,7-dichloro-5-indanyloxy]acetic acid, respectively.
18 [1-Oxo-2-(p-chlorophenyl or 2-thienyl)-2-methyl-6,7-19 dichloro-5-indan loxv]-acetic acid y Step A: (l-Oxo-2-methyl-6,7-dichloro-5-21 indanyloxy)-acetic acid 22 This material is prepared in a manner identical 23 to Example 1, Step A, except that 2,3-dichlorophenoxyacetic 24 acid is substituted for 2,3-dichloroanisole.
Step B: [l-Oxo-2-(p-chlorophenyl or 2-thienyl)-26 2-methyl-6,7-dichloro-5-indanyloxy]-27 acetic acid 28 This product is prepared by a procedure identical 29 to Example 1, Step B, except that (l-oxo-2-methyl-6,7-dichloro-5-indanyloxy)-acetic acid is substituted for 31 2-methyl-5-methoxy-6,7-dichloro-1-indanone.
32 Any departurefrom the above description which cOnforms 33 to the present invention is intended to be included within 34 the scope of the claims.
12 Thus, it is an object of the present invention 13 to provide a specific, highly efficient unified process 14 for the preparation of [1-oxo-(2-phenyl, halophenyl or thienyl~2-methyl-6,7-dichloro-5-indanyloxy]-acetic acid 16 and its non-toxic pharmaceutically acceptable salt, ester 17 and amide derivatives. It is also an object of the present 18 invention to provide useful intermediates (II, above) which 19 are involved in the process of this invention. One advan-tage of the instant process is that it allows one to use 21 relatively cheaper starting materials than previous processes.
22 The process of this invention can be shown 23 chemically by the following reaction sequence~
Cl ` 1~83~
Cl_ ~ + CH2=C-COX
RO_ ~ (a) or I R Step A
CH3-CXCOX Lewis (b) Acid or ,R
z (c) II
Cl ~ R Step E
RO_ Z if Z is hydrogen III \
\ - if Z is methyl ~<CH3 Ether Cleavage >~30 ~\CRH3 V VI
StepOD
~XCH2COR"
Cl O Cl CH3 Cl - ~ ~ CH3hydrolysis Cl_ ~ R' C-CH2 - ~ R' ~if R" is not H O
VIII VII
; 1038396 1 In the above reaction sequence 2 R = lower alkyl having up to 5 carbon atoms, 3 preferably methyl; H or CH2CO2R", wherein 4 R" is lower alkyl or hydrogen;
X = Cl, Br or I;
6 R = phenyl, methyl, halophenyl, preferably p-7 chloro or p-fluorophenyl and thienyl, 8 preferably z-thienyl;
9 R' = phenyl, halophenyl, preferably p-chloro or p-fluorophenyl and thienyl, preferably 2- thienyl;
11 R" = lower alkyl or H;
12 Z = H or methyl but is not methyl when R is 13 methyl, i.e. Z and R cannot be methyl at 14 the same time;
Y = phenyl, halophenyl, thienyl, diphenyliodo, 16 dihalophenyliodo, dithienyliodo.
17 More specifically, Step A of this invention 18 involves a reaction of 2,3-dichloroanisol or a related lower 19 alkyl ether or 2,3-dichlorophenoxyacetic acid or a related lower alkyl ester and a suitable substituted or unsubstituted 21 acyl halide of the formulae shown in the reaction sequence.
22 These compounds are reacted under Friedel-Crafts reaction 23 conditions with an appropriate catalyst to produce an 24 intermediate 2-substituted indanone shown as Formula III.
If an a,a-disubstituted acyl halide is used in Formula II(c) 26 such as for example a-methyl-a-phenyl-~-bromopropionyl 27 chloride and R is CH2CO2H, then the desired indanone V is 28 formed directly. This reaction proceeds through a dehydro-29 halogenation introducing a side chain followed by a ring 1 closure to give intermediate Formula III. Typical substi-2 tuted or unsaturated acyl halides are acrylyl chloride-, 3 a-halo isobutyryl chloride, or ~-halo isobutyryl chloride.
4 The Friedel-Crafts reaction conditions under which Step A
of the reaction is carried out are the use of a catalyst 6 such as Lewis acid particularly aluminum chloride or tin 7 chloride and use of a solvent particularly an inert organic 8 solvent which does not react appreciably with the reactants.
9 Typical of such inert solvents are methylene chloride, tetrachloroethane, hexane, carbon disulfide or nitrobenzene.
11 Step A of the reaction is carried out at a temperature from 12 about 0 to the reflux temperature of the solvent, but 13 20-50 is preferred for a length of time sufficient to 14 substantially complete the reaction but generally from about 4 to 6 hours at about 40C.
16 The a,c-disubstituted-~-halo propionyl halide of 17 Formula II(c) can be prepared by the general method of 18 Nicolaus, Mariani and Testa, "A New General Synthesis for 19 ~-Substituted Propionic Acid and its Derivatives", Bruno J.R.
Nicolaus, Luigi r~ariani and Emilio Testa (Lepetit Spa, Milan) 21 Chem. Abst. 55 27271d (1961).
22 Step B of the process involves alkyla~ing the 23 intermediate 2-methyl indanone, Formula III, if the ini'-ial 24 reactant Formula II was not an a,a-disubstituted propionyl halide using an alkylating agent, YX wherein Y and X are 26 as defined above, particularly with diaryliodium halide or 27 methyl halide to yield an intermediate indanone, Formula V.
28 The alkylation reaction is carried out in the presence of 29 a suitable basic catalyst such as sodium tertiary butoxide, 1 sodium hydride, sodamide, sodium methoxide or the like 2 in a suitable solvent such as any inert non-aqueous 3 organic solvent, particularly benzene or toluene. The 4 alkylation reaction is carried out for a time sufficient to complete the reaction and preferably at a temperature 6 from about room temperature to a reflux temperature of the 7 particular solvent used. If in the compound Formula V
8 which is formed R' is phenyl, halophenyl or thienyl and 9 R is CH2CO2H, then the desired indanone is already formed.
It can be isolated from the reaction mixture by methods 11 known in the art such as by extracting the desired compound 12 from its reaction mixture with a solvent, boiling off said 13 solvent and then recrystallizing the desired indanone from 14 acetone or other suitable solvent.
If in the compound of Formula V R is lower alkyl, 16 this compound must further undergo an ether cleavage which 17 comprises treating the compound of Formula V with an ether 18 cleavage reagent and then treating the 5-hydroxy product 19 formed, Formula VI, with a haloacetic or ~seudohaloacetic acid or ester thereof of the formula XCH2C-OR" wherein X is 21 Cl, Br, I, mesyl or tosyl and R" is hydrogen or lower alkyl.
22 Finally, if R" in the halo acetic acid ester is 23 lower alkyl, the product formed, Formula VII, must further 24 undergo a hydrolysis to form the desired indanone. If a halo acetic acid is used as the reactant, then Formula VII
26 is the desired indanone.
27 Step C of the reaction scheme, namely, the ether 28 cleavage, is carried out with ether cleaving reagents, such 29 as aluminum chloride, pyridine hydrochloride, hydrogen bromide, 1 sodium in liquid ammonia and the like. When aluminum 2 chloride is employed, the solvent may be heptane, carbon 3 disulfide, methylene chloride and the like and when pyridine 4 hydrochloride is employed, it is not necessary to employ a solvent.
6 Generally, this ether cleavage is carried out 7 at temperatures from room temperature to reflux temperature 8 of any solvent used for any time sufficient to complete 9 substantial formation of the intermediate of Formula VI.
The reaction wherein the product of Formula VI
11 is reacted with a halo acetic acid or ester, the reaction 12 is generally conducted in the presence of a base, such as 13 alkali metal carbonate, hydroxide or alkoxide such as 14 potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, sodium ethoxide and the like. Any solvent 16 which is inert or substantially inert to the reactants and 17 in which the reagents are reasonably soluble may be employed.
18 Ethanol, dimethylformamide, benzene and toluene, for example, 19 have proved to be particularly advantageous solvents. The reaction may be conducted at a temperature in the range of 21 from about 25C. to the reflux temperature of the particular 22 solvent employed. The reaction with the haloacetic acid or 23 ester is generally complete in about 10 to 60 minutes. If 24 the haloacetic acid ester is employed, the ester obtained may be hydrolyzed to the free acid by methods well known 26 to those skilled in the art.
27 The invention herein can be illustrated by the 28 following examples:
. .
2 2-Methyl-2-phenyl-5-methoxy-6,7-dichloro-1-indanone 3 Step A: 2-Methyl-5-methoxy-6,7-dichloro-l-indanone 4 2,3-Dichloroanisole (177 g., 1.0 mole), anhydrous aluminum chloride (280 g., 2.10 mole) and 545 ml. of carbon 6 disulfide are mixed under a nitrogen atmosphere. The 7 mixture is stirred at 25-30 while adding 110 ml. of ~-bromo-8 2-methylpropionyl bromide (209 g., 0.91 mole) over 1-1/2 9 hours. The reaction mixture is aged at 25-30 for one hour, then at 43-45 for 4 hours. After finally stirring 11 overnight at 25 the batch is quenched, carefully, into a 12 mixture of 2.72 liters of ice and water. The temperature 13 increases to 28 during the quench and the batch is aged 14 for 10 minutes. The layers are separated and the aqueous phase is extracted with 2 x 550 ml. of toluene. The combined 16 organic phase is washed with 275 ml. of 10% sodium 17 bicarbonate solution, dried over magnesium sulfate, and 18 concentrated ln vacuo to dryness to yield 207 g. (93~) of 19 2-methyl-5-methoxy-6,7-dichloro-1-indanone.
Step B: 2-Methyl-2-phenyl-5-methoxy-21 6,7-dichloro-1-indanone 22 2-Methyl-5-methoxy-6,7-dichloro-1-indanone 23 (245 g., 1.0 mole), 2.19 liters of t-butanol (sieve-dried) 24 and 1.74 liters of benzene (azeotropically dried) are mixed under a nitrogen atmosphere and heated to 50. A solution 26 of potassium t-butoxide (190 g., 1.7 moles) in 1.74 liters 27 of t-butanol (sieve-dried) is added all at once. The batch 28 is heated to reflux (78) and refluxed for 30 minutes. Cooled 29 to 30 and bromobenzene (372.5 g., 2.5 moles) added over 15 minutes (initial temperature rise). The mixture is 1038~96 1 heated to reflux (71), refluxed for 10 minutes and cooled 2 again to 30. Water (903 ml.) is added,gradually, at 30-40 3 and the batch is concentrated in vacuo to a volume of 887 ml.
4 The solids are collected by filtration. The filter cake is washed with 3 x 350 ml. of water and dried in vacuo at 45 6 giving a crude yield of 200 g. 60% of 2-methyl-2-phenyl-5-7 methoxy-6,7-dichloro-1-indanone.
8 The crude material is recrystallized from 1.37 9 liters of boiling ethanol, cooled to 0-5 and filtered.
The solids are washed with cold ethanol and dried ln vacuo 11 at 45 to yield 100 g. 50% of 2-methyl-2-phenyl-5-methoxy-12 6,7-dichloro-1-indanone.
13 Following the procedure above but using p-chloro-14 bromo benzene or 2-thienyl bromide in place of bromobenzene in Step B, there is prepared an equivalent amount of 2-methyl-16 2-p-chloro-5-methoxy-6,7-dichloro-1-indanone and 2-methyl-17 2-(2-thienyl)-5-methoxy-6,7-dichloro-1-indanone.
19 2-Methyl-2-phenyl-5-methoxy-6,7-dichloro-1-indanone 2,3-Dichloroanisole (177 g., 1.0 mole), anhydrous 21 aluminum chloride (280 g., 2.10 mole) and 545 ml. of carbon 22 disulfide are mixed under a nitrogen atmosphere. The 23 mixture is stirred at 25-30 while adding 261.5 gm. (1 mole) 24 of a-methyl-a-phenyl-~-bromo propionyl chloride over 1-1/2 hours. The reaction mixture is aged at 25-30 for one hour, 26 then at 43-45 for 4 hours. After finally stirring overnight 27 at 25 the batch is quenched, carefully, into a mixture of 28 2.73 liters of ice and water. The temperature increases to 29 28 during the quench and the batch is aged for 10 minutes.
1 The layers are separated and the aqueous phase is extracted 2 with 2 x 550 ml. of toluene. The combined organic phase is 3 washed with 275 ml. of 10% sodium bicarbonate solution, dried 4 over magnesium sulfate, and concentrated in vacuo to dryness to yield 207 g. (93%) of 2-methyl-2-phenyl-5-methoxy-6,7-6 dichloro-l-indanone.
7 Following the procedure above but using a-methyl-8 p-chlorophenyl or 2-thienyl-~-bromo propionyl chloride in 9 place of ~-methyl-~-phenyl-~-bromo propionyl chloride, there is produced an equivalent amount of 2-methyl-2-p-chloro-11 phenyl-5-methoxy-6,7-dichloro-1-indanone and 2-methyl-2-12 (2-thienyl)-5-methoxy-6,7-dichloro-1-indanone respectively.
14 2-Methyl-2-phenyl-5-methoxy-6,7-dichloro-1-indanone Step A: 2-Methyl-5-methoxy-6,7-dichloro-16 1-indanone 17 This compound is prepared by a procedure identical 18 to Example 1 except ~-chloro-2-methyl propionyl chloride is 19 substituted for the dibromo analog.
Step B: 2-Methyl-2-phenyl-5-methoxy-21 6,7-dichloro-1-indanone 22 This compound is prepared by a procedure identical 23 to Example 1.
2-Methyl-S-methoxy-6,7-dichloro-1-indanone _ 26 Step A: 2-Methyl-5-methoxy-6,7-dichloro-27 l-indanone 28 This compound is prepared by a procedure ldentical 29 to Example 1 except ~-chloro-2-methylpropionyl chloride is substituted for ~-bromo-2-methylpropionyl bromide.
~038396 1Step B: 2-Methyl-5-methoxy-6,7-dichloro-2l-indanone 3This compound is prepared by a procedure 4 identical to Example 1.
62-Methyl-2-phenyl-5-methoxy-6,7-dichloro-1-indanone 7Step A: 2-Methyl-5-methoxy-6,7-dichloro-8l-indanone 9This compound is prepared by a procedure identical to Example 1.
11 Step B: 2-Methyl-2-phenyl-5-methoxy-126,7-dichloro-1-indanone 13 This compound is prepared by a procedure identical 14 to Example 1 except that chlorobenzene is substituted for bromobenzene as alkylating agent.
172-Methyl-2-phenyl-5-methoxy-6,7-dichloro-1-indanone 18Step A: 2-Methyl-5-methoxy-6,7-dichloro-19l-indanone 20This compound is prepared by a procedure identical 21 to Example 1, Step A.
22 Step B: 2-Methyl-2-phenyl-5-methoxy 23 6,7-dichloro-1-indanone 24 This compound is prepared by a procedure identical to Example 1, Step B, except that 317 grams of diphenyl 26 iodonium chloride are substituted for 372.5 grams of 27 bromobenzene.
292-Methyl-2-p-chlorophenyl-5-methoxy-6,7-dichloro-1-indanone 30Step A: 2-Methyl-5-methoxy-6,7-dichloro-31l-indanone 32This compound is prepared by a procedure identical 33 to Example 1, Step A.
1 Step B: 2-Methyl-2-p-chlorophenyl-5-2 methoxy-6,7-dichloro-1-indanone 3 This compound is prepared by a procedure identical 4 to Example 1, Step B,except that 387 grams of di-p-chloro-phenyl iodonium chloride are used in place of 372.5 grams 6 of bromobenzene.
8 2-Methyl-2-phenyl-5-methoxy-6,7-dichloro-1-indanone 9 Step A: 2-Phenyl-5-methoxy-6,7-dichloro-l-indanone 11 This compound is prepared by a procedure identical 12 to Example 1 except that 266 g., 0.91 mole, of a-bromo-2-13 phenylpropionyl bromide is substituted for a-bromo-2-methyl-14 propionyl bromide. ~he crude yield is 285 g. (93%) of 2-phenyl-5-methoxy-6,7-dichloro-1-indanone. After 16 recrystallization from benzene-cyclohexane 2:1, the m.p.
17 is 193-195C.
18 Step B: 2-Methyl-2-phenyl-5-methoxy-6,7-19 dichloro-l-indanone 2-Phenyl-S-methoxy-6,7-dichloro-1-indanone 21 (50.84 g.~ was dissolved in dry dimethylformamide (700 ml.) 22 and dry benzene (700 ml.) in a 3 liter flask equipped with 23 a nitrogen inlet tube, air condenser, and hopper for sodium 24 methoxide. Iodomethane (103 ml.) was added to the solution under nitrogen while cooling in an ice-water bath, and 26 sodium methoxide (13.5 g.) was added portionwise from the 27 hopper through the Gooch tubing over 3/4 hour. During the 28 addition, the reaction mixture turned bright red, then the 29 color slowly disappeared and a solid precipitate formed.
After stirring for 1/2 hour in an ice-water bath, the reaction .
103~i 1 mixture was added to water (~4 liters) and extracted with 2 benzene. Upon drying the benzene solution over molecular 3 sieves and concentrating to dryness, a pale yellow solid 4 product formed; yield: 45.6 g., m.p. 161-165C. (86%).
A sample recrystallized from benzene-cyclohexane (1:2) 6 melts at 164-165C.
8 (1-Oxo-2-cyclopentyl-2-methyl-6,7-dichloro-5-indanyloxy)-9 acetic acid Step A: (l-Oxo-2-methyl-6,7-dichloro-5-11 indanyloxy)-acetic acid 12 This compound is prepared by a procedure identical 13 to Example 1 except that 2,3-dichlorophenoxyacetic acid is 14 substituted for 2,3-dichloroanisole.
Step B: (l-Oxo-2-phenyl-2-methyl-6,7-16 dichloro-5-indanyloxy)-acetic acid 17 This compound is prepared by a procedure identical 18 to Example 1 except that (1-oxo-2-methyl-6,7-dichloro-5-19 indanyloxy)-acetic acid is substituted for 2-methyl-5-methoxy-6,7-dichloro-1-indanone.
22 (1-Oxo-2-phenyl-2-methyl-6,7-dichloro-5-indanyloxy)-23 acetic acid 24 Step A: (l-Oxo-2-methyl-6,7-dichloro-5-indanyloxy)-acetic acid 26 This compound is prepared by a procedure identical 27 to Example 3 except that 2,3-dichlorophenoxyacetic acid is 28 substituted for 2,3-dichloroanisole.
29 Step B: (l-Oxo-2-phenyl-2-methyl-6,7-dichloro-5-indanyloxy)-acetic acid 31 This compound is prepared by a procedure identical 32 to Example 3 except that (1-oxo-2-methyl-6,7-dichloro-5-33 indanyloxy)-acetic acid is substituted for 2-methyl-5-34 methoxy-6,7-dichloro-1-indanone.
2 (1-Oxo-2-phenyl-2-methyl-6,7-dichloro-5-indanyloxy)-3 acetic acid 4 Step A~ Oxo-2-methyl-6,7-dichloro-5-indanyloxy)-acetic acid 6 This compound is prepared by a procedure identical 7 to Example 4 except that 2,3-dichlorophenoxyacetic acid is 8 substituted for 2,3-dichloroanisole.
9 Step B: (l-Oxo-2-phenyl-2-methyl-6,7-dichloro-5-indanyloxy)-acetic acid 11 This compound is prepared by a procedure identical 12 to Example 4 except that tl-oxo-2-methyl-6,7-dichloro-5-13 indanyloxy)-acetic acid is substituted for 2-methyl-5-14 methoxy-6,7-dichloro-1-indanone.
16 (1-Oxo-2-phenyl-2-methyl-6,7-dichloro-5-indanyloxy)-17 acetic acid 18 Step A: (l-Oxo-2-methyl-6,7-dichloro-5-19 indanyloxy)-acetic acid _ This compound is prepared by a procedure identical 21 to Example 5 except that 2,3-dichlorophenoxyacetic acid 22 is substituted for 2,3-dichloroanisole.
23 Step B: (l-Oxo-2-phenyl-2-methyl-6,7-24 . dichloro-5-indanyloxy)-acetic acid This compound is prepared by a procedure identical 26 to Example 5 except that (1-oxo-2-methyl-6,7-dichloro-27 5-indanyloxy)-acetic acid is substituted for 2-methyl-28 5-methoxy-6,7-dichloro-1-indanone.
29 EXAMæLE 13 (1-Oxo-2-phenyl-2-methyl-6,7-dichloro-5-indanyloxy)-acetic acid -31 This compound is prepared by a procedure identical 32 to Example 2 except that 2,3-dichlorophenoxyacetic acid is 33 substituted for 2,3-dichloroanisole.
1 Following the above procedure but using a-methyl 2 a-p-chlorophenyl or 2-thienyl-~-bromo propionyl chloride in 3 place of a-methyl-a-phenyl-~-bromo propionyl chloride there 4 is produced an equivalent amount of [1-oxo-2-methyl-2 (p-chlorophenyl or 2-thienyl)-2-methyl-6,7-dichloro-5-6 indanyloxy]acetic acid.
8 2-Methyl-5-methoxy-6,7-dichloro-1-indano_e 9 Step A: 2-Methyl-5-methoxy-6,7-dichloro-l-indanone 11 This compound is prepared by a procedure identical 12 to Example 1 except methacrylic acid acid chloride is 13 substituted for a-bromo-2-methylpropionyl bromide.
Preparation of (l-Oxo-2-phenyl-2-methyl-6,7-dichloro-16 5-indanvloxy)-acetic acid 17Step A: 2-Phenyl-2-methyl-5-hydroxy-6,7-18dichloro-l-indanone -192-Phenyl-2-methyl-5-methoxy-6,7-dichloro-1-20indanone (3.5 g., 0.0109 mole) is added to dry hexane 21(180 ml.) and aluminum chloride (4.36 g., 0.0327 mole) 22 is added. The mixture is refluxed for one hour and the 23 hexane is decanted from the gummy residue which then is 24 added to ice water (200 ml.) containing 12N hydrochloric acid (15 ml.). The solid that separates is crystallized 26 from benzene to obtain 2.84 g. of 2-phenyl-2-methyl-5-27 hydroxy-6,7-dichloro l-indanone.
28Step B: (l-Oxo-2-phenyl-2-methyl-6,7-29dichloro-5-indanyloxy)-acetic acid 302-Phenyl-2-methyl-5-hydroxy-6,7-dichloro-1-31indanone (2.84 g., 0.00926 mole) is added to dimethyl-32 formamide (DMF) (40 ml.). Potassium carbonate (3.21 g., 10383g6 , 1 0.0232 mole) and ethyl bromoacetate (3.34 g., 0.0232 mole) 2 are added. The mixture is stirred at 55-60C. for 2-1/2 3 hours, then 40 ml. of 10% sodium hydroxide are added and 4 the mixture is stirred at 80-85C. for 1-1/2 hours. The mixture is then added to 500 ml. of 2% hydrochloric acid.
6 The solid that separates is taken up in ether. The ether 7 extract is washed with water, dried over magnesium sulfate 8 and evaporated, leaving a gummy solid that is crystallized 9 from acetic acid to obtain 183 mg. of (1-oxo-2-phenyl-2-methyl-6,7-dichloro-5-indanyloxy)-acetic acid.
11 Following the procedure above but using 2-p-12 chlorophenyl or 2-(2-thienyl)-2-methyl-5-methoxy-6,7-13 dichloro-l-indanone in place of 2-phenyl-2-methyl-5-methoxy-14 6,7-dichloro-1-indanone, there is produced an equivalent amount of[l-oxo-2-(p-chlorophenyl or 2-thienyl)-2-methyl-16 6,7-dichloro-5-indanyloxy]acetic acid, respectively.
18 [1-Oxo-2-(p-chlorophenyl or 2-thienyl)-2-methyl-6,7-19 dichloro-5-indan loxv]-acetic acid y Step A: (l-Oxo-2-methyl-6,7-dichloro-5-21 indanyloxy)-acetic acid 22 This material is prepared in a manner identical 23 to Example 1, Step A, except that 2,3-dichlorophenoxyacetic 24 acid is substituted for 2,3-dichloroanisole.
Step B: [l-Oxo-2-(p-chlorophenyl or 2-thienyl)-26 2-methyl-6,7-dichloro-5-indanyloxy]-27 acetic acid 28 This product is prepared by a procedure identical 29 to Example 1, Step B, except that (l-oxo-2-methyl-6,7-dichloro-5-indanyloxy)-acetic acid is substituted for 31 2-methyl-5-methoxy-6,7-dichloro-1-indanone.
32 Any departurefrom the above description which cOnforms 33 to the present invention is intended to be included within 34 the scope of the claims.
Claims (11)
1. A process for preparing compounds of the formula:
wherein R is lower alkyl or CH2CO2R", and R' is phenyl, halo-phenyl or thienyl, and R" is hydrogen or lower alkyl which comprises (a) reacting a compound of the formula:
with a compound selected from the group consisting of ; or wherein X is halo under Friedel-Crafts reaction conditions to form a compound of the formula:
wherein R is as above;
(b) reacting said latter compound with YX where Y is phenyl, halophenyl, thienyl, diphenyliodo, dihalophenyliodo, or dithienyliodo, and X is as above defined to form a compound of the formula:
wherein R and R' are as defined above.
wherein R is lower alkyl or CH2CO2R", and R' is phenyl, halo-phenyl or thienyl, and R" is hydrogen or lower alkyl which comprises (a) reacting a compound of the formula:
with a compound selected from the group consisting of ; or wherein X is halo under Friedel-Crafts reaction conditions to form a compound of the formula:
wherein R is as above;
(b) reacting said latter compound with YX where Y is phenyl, halophenyl, thienyl, diphenyliodo, dihalophenyliodo, or dithienyliodo, and X is as above defined to form a compound of the formula:
wherein R and R' are as defined above.
2. A process for preparing compounds of the formula wherein R is lower alkyl or CH2CO2R", R' is phenyl, halophenyl or thienyl, and R" is hydrogen or lower alkyl which comprises reacting a compound of the formula with a compound of the formula wherein X is halo and R and R' are as above defined under Friedel-Crafts reaction conditions to form the desired product.
3. A process according to Claim 1 for preparing compounds of the formula:
wherein R is lower alkyl or CH2CO2R" and R' is phenyl, halo-phenyl or thienyl, and R" is hydrogen or lower alkyl which comprises reacting a compound of the formula:
wherein R is as above with a compound of the formula YX wherein Y is phenyl, halophenyl, thienyl, diphenyliodo, dihalophenyl-iodo, or dithienyliodo, and X is halo.
wherein R is lower alkyl or CH2CO2R" and R' is phenyl, halo-phenyl or thienyl, and R" is hydrogen or lower alkyl which comprises reacting a compound of the formula:
wherein R is as above with a compound of the formula YX wherein Y is phenyl, halophenyl, thienyl, diphenyliodo, dihalophenyl-iodo, or dithienyliodo, and X is halo.
4. A process according to Claim 1, wherein the Friedel-Crafts reaction conditions are the use of an inert organic solvent and the use of a Lewis acid catalyst.
5. A process according to Claim 2, wherein the Friedel-Crafts reaction conditions are the use of an inert organic solvent and the use of a Lewis acid catalyst.
6. A process according to Claim 3, wherein the reaction is carried out in the presence of a basic catalyst, in an inert non-aqueous solvent.
7. A process according to Claim 1, wherein R is CH2CO2H.
8. A process according to Claim 2 wherein R
is CH2CO2H.
is CH2CO2H.
9. A process according to Claim 1 wherein the acyl halide used is .beta.-bromopropionylbromide.
10. A process according to Claim 2 wherein the acyl halide used is .alpha.-methyl-.alpha.-phenyl-.beta.-bromopropionyl chloride.
11. A process according to Claim 3 wherein R is -CH2CO2H and the reactant is YX wherein Y is phenyl and X is Cl or Br.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US49265374A | 1974-07-30 | 1974-07-30 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1038396A true CA1038396A (en) | 1978-09-12 |
Family
ID=23957086
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA210,646A Expired CA1038396A (en) | 1974-07-30 | 1974-10-03 | Process for the preparation of (1-oxo-2-phenyl, halophenyl or thienyl-2-methyl-6,7-dichloro-5-indanyloxy)acetic acid |
Country Status (11)
| Country | Link |
|---|---|
| JP (1) | JPS51125058A (en) |
| AT (1) | AT335444B (en) |
| CA (1) | CA1038396A (en) |
| CH (1) | CH613930A5 (en) |
| CS (1) | CS190440B2 (en) |
| DD (1) | DD114060A5 (en) |
| ES (1) | ES430903A1 (en) |
| HU (1) | HU170035B (en) |
| NL (1) | NL7412828A (en) |
| PL (1) | PL98291B1 (en) |
| YU (1) | YU272574A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0618182B1 (en) * | 1993-03-31 | 1996-12-18 | Kagome Kabushiki Kaisha | Indene derivatives and antimicrobial agents containing them |
-
1974
- 1974-09-27 NL NL7412828A patent/NL7412828A/en not_active Application Discontinuation
- 1974-10-02 DD DD18146374A patent/DD114060A5/xx unknown
- 1974-10-03 CA CA210,646A patent/CA1038396A/en not_active Expired
- 1974-10-08 AT AT808074A patent/AT335444B/en not_active IP Right Cessation
- 1974-10-09 HU HUME001783 patent/HU170035B/hu unknown
- 1974-10-10 YU YU272574A patent/YU272574A/en unknown
- 1974-10-10 PL PL17473674A patent/PL98291B1/en unknown
- 1974-10-10 ES ES430903A patent/ES430903A1/en not_active Expired
- 1974-10-10 CS CS693374A patent/CS190440B2/en unknown
- 1974-10-10 CH CH1366174A patent/CH613930A5/en not_active IP Right Cessation
- 1974-10-11 JP JP11698974A patent/JPS51125058A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| AT335444B (en) | 1977-03-10 |
| CS190440B2 (en) | 1979-05-31 |
| HU170035B (en) | 1977-03-28 |
| DD114060A5 (en) | 1975-07-12 |
| NL7412828A (en) | 1976-02-03 |
| ATA808074A (en) | 1976-07-15 |
| CH613930A5 (en) | 1979-10-31 |
| ES430903A1 (en) | 1977-01-16 |
| JPS51125058A (en) | 1976-11-01 |
| YU272574A (en) | 1982-06-30 |
| PL98291B1 (en) | 1978-04-29 |
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