DD141023A5 - PROCESS FOR PREPARING A 2,3-DIHYDROBENZOFURANDERIVATE - Google Patents

Description

206342

Process for the preparation of a 2,3-dihydrobenzofuran derivative "

Field of application of the invention

The invention relates to a process for the preparation of a 2,3-dihydrobenzofuran derivative which can be used as a warm-blood lipogenesis inhibiting agent.

Characteristic of the known technical solutions

Various means of inhibiting lipogenesis in warm-blooded animals have been known, but they have been associated with various deficiencies.

Object of the invention

With the invention of these shortcomings should be remedied.

Explanation of the essence of the invention

The invention is intended to provide a process for preparing a compound of the formula I '

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in del R is attached to a carbon atom in the 5- or 6-position and a cycloalkyl group having 3 to 6 carbon atoms, an alkyl group having 4 to 8 carbon atoms, an alkoxy group mif 4 to 8 carbon atoms, a phenyl, phenoxy, benzyl or Benzoyl group, wherein each of the latter four groups optionally substituted by 1 or 2 substituents from the group of nitro groups, chlorine or bromine atoms or alkyl groups having 1 to 6 carbon atoms substituted

can be and R be put for a disposal,

and R is an allylamino group, for

In these compounds, each alkyl, alkyloxy, alkenyloxy and alkynyloxy group may be straight or branched chain. Preferably, each such alkenyloxy and alkynyloxy group contains from 2 to 4 carbon atoms.

The 2,3-Dihydrobenzofuranderivate the formula Σ may be present in the form of two optically active isomers due to their asymmetric configuration in the 2-position of the molecule. The invention therefore relates to agents which contain an optically active isomer and various combinations of the individual optically active isomers.

Because of their particularly high activity in the inhibition of lipogenesis, preferred are ^ -phenyl-benzofurancarboxylic acid, 2,3-dihydro-5-phenyl-2-benzofurancarboxylic acid and 2,3-dihydro-phenyl-N -allyl-benzofurancarboxamide ,

By way of illustration, the preparation of typical compounds of formula I is illustrated in the examples. Other typical compounds of the formula I are those in which R has the following meaning:

"3-206342 a 6-phenoxy b 5- (4-Ohlor-phenoxy) C 5-cyclohexyl d 5- (p-tolyl) e 5-Benzovl f 5-benzyl S-, 5- (2,4-dichloro-phenoxy) H 5- (2-meth ^ lpropyl) i 5- (l, 1,3,3-Tetramethvlbutyl) C-J. 5-Hexvloxy k 5_ (4_Hitrophenyl).

In particular, the invention relates to a process for the preparation of 2,3-dihydrobenzofuran derivatives of the formula I, wherein an alkyl-dihydro-2-benzofurancarboxylate of the formula II

in which R has the meaning given in formula I and R

is an alkyl group reacted with allylamine in the presence of a solvent. The alkyl group in the allyl ester. suitably contains 1 to 5 carbon atoms and is in particular a Ätlrylgruppe _e Ethanol is a suitable solvent. The reaction proceeds at room temperature, but higher temperatures may also be used to set the reaction time, eg, the mixture may be heated to reflux. Preferably, an approximately 4 to 6-fold excess of the amine is used. The desired product may be recovered by evaporation of the solvent and excess amine followed by use of conventional techniques such as selective extraction, recrystallization and / or dry column chromatography to isolate the desired product.

Many of the precursor phenols are known compounds. Others can be made by conventional methods. Thus, the phenols for the compounds a, i, 1, e and h are commercially available. The phenols for the compounds j, gb can be prepared by diazotization of the corresponding anilines; the phenols for compound f can be prepared by Wolff-Kischner reduction corresponding phenols, the phenols for the compounds d and k are indicated in the Beilstein. If necessary, for example, when R is a phenoxy group, the aniline can be prepared by reacting the sodium salt of R-phenyl with the corresponding chloronitrobenzene and reduction (hydrogen, palladium on carbon catalyst, ethanol or acetic acid as solvent) of the nitro group to the Amino group _e

The 2,3-diltidrobenzofuran derivatives of formula I can be used to control lipogenesis in warm-blooded animals, such as domestic animals, zoo animals, herd animals (cattle), fur animals, etc., such as Z ₀ B ₀ dogs, cats , Mink, sheep, goats, pigs, cattle, horses, mules, donkeys and poultry. The effect is achieved by administering an effective amount of one or a mixture of two or more of the compounds of formula I, orally or parenterally "The compounds can be administered as such or as an active ingredient in a common drug." The compositions of the invention are therefore suitable for inhibition lipogenesis in warm-blooded animals, when such animals are administered an effective amount of a compound of formula I or an agent containing such a compound.

The compounds of formula I or agents containing these compounds can be administered orally in any suitable manner. Thus, they can be administered orally as a solution by intubation, in the diet and the

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Yeasts for the animal, in a food supplement or in a preparation intended specifically for the administration of the medicament. Suitable formulations include solutions, suspensions, dispersions, emulsions, tablets, tablets, powders, capsules, syrups and elixirs. For parenteral administration, the agents may be in the form of a solution, suspension, dispersion or emulsion. They may be applied in the form of an implant or other controlled release sustained release preparation. Inert pharmaceutically acceptable carriers such as water, food grade oils, gelatin, lactose, starch, magnesium stearate, talc and / or vegetable gums may be used.

The dose of compound of formula I required to. To inhibit lipogenesis depends on the particular compound used and the particular animal to be treated. In general, however, satisfactory results are achieved when the compounds are administered at a dose of from about 1 to about 500 mg per kg of body weight. They may be given as a single dose or in a series of doses on the same day or over several days. For each particular animal, a particular dosage should be determined according to the individual need, the particular compound used, and the experience of the person administering the agent or monitoring the administration.

Exemplary embodiments C ₁

The invention is further illustrated by the following examples. In the Preparation Examples, the identity of the product and the precursors were confirmed by appropriate chemical and spectroscopic analyzes.

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example 1

Ethyl S-phenylene-benzofurancarboxylate (Compound 1)

22 gp-phenylphenyl were dissolved in 95% ethanol. A solution of 40 g of sodium hydroxide in 80 ml of water was added quickly. The resulting solution was heated to 75 to 80 ⁰ C and 20 ml of chloroform added within 1 h and the mixture was heated slightly under reflux. The mixture was then stirred for 3 h, cooled and ethanol and excess chloroform evaporated under reduced pressure. The resulting residue was cooled and poured into cold water. The resulting mixture was replaced by ':. acidified slowly addition of hydrochloric acid and extracted with diethyl ether. The solvent was evaporated from the extract under reduced pressure, the residue poured into twice the volume of saturated sodium metabisulfite solution and the mixture shaken vigorously for 45 minutes.

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The resulting semi-solid bisulfite addition compound was allowed to stand for 1 hour, filtered in the dark and washed with small portions of ethanol and diethyl ether to remove the phenol. The bisulfite addition compound was decomposed with dilute sulfuric acid, the mixture was heated on the water bath for 30 minutes, the cooled mixture was extracted with diethyl ether and dried over Na ₂ SO ₄ , and the solvent was evaporated under reduced pressure. The residue was treated with charcoal and recrystallized from ethanol / water. 5-phenylsalicylaldehyde, compound 1A, was obtained as yellow crystals. Mp 98-99 ° C.

A mixture of 0.99 g of Compound 1A, 0.096 g of diethyl bromomalonate and 1.25 g of anhydrous potassium carbonate in 20 ml of 2-butanone was refluxed for 10 hours. The solvent was evaporated under reduced pressure, the residue was cooled, poured into 100 ml of water and extracted with diethyl ether. The extract was washed with cold 5% sodium hydroxide solution and with water and then evaporated under reduced pressure. The residue was recrystallized from ethanol. Compound 1 was obtained as v / eiße crystals, mp. 109-110 ⁰ C.

Example 2

p-phenyl-2-benzofurancarboxylic acid (compound 2)

A mixture of 1.3 g of Compound 1 and 50 ml of 10% alcoholic potassium hydroxide solution was refluxed for 4 hours. The solvent was evaporated under reduced pressure and the residue was washed with diethyl ether and dissolved in water. The basic solution was acidified with dilute hydrochloric acid and extracted with diethyl ether. The ether layer was extracted with dilute sodium bicarbonate solution. The aqueous solution was reconstituted with dilute hydrochloric acid.

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Acid acidified and extracted with diethyl ether. The ether extract was dried over Na 2 SO 4, and evaporated under reduced pressure. The residue was recrystallized from ethanol. The connection ^ C. were obtained as a white solid, mp. 220-221 ⁰

Example 3 '

2,3-Dihydro-5-phenyl-2-benzofurancarboxylic acid (compound 3)

5.0 g of Compound 2 was mixed with 90 ml of 10 -6% sodium hydroxide solution. Then, sodium amalgam (prepared from 1.5 g of sodium and 50 g of mercury) was added to the mixture with stirring within 1 hour. The mixture was then stirred for 24 h and allowed to stand at room temperature for a further 24 h. The mercury was separated, the solution was neutralized with dilute hydrochloric acid and extracted with diethyl ether. The extract was washed with dilute sodium bicarbonate solution, the aqueous layer separated, acidified again with dilute hydrochloric acid and extracted with diethyl ether. The extract was dried over Na ₂ SO- and evaporated under reduced pressure. The residue was recrystallized from ethanol. Compound 3 was obtained as white crystals, m.p. 186-187 ° C

Example 4

2,3-dihydro-1-phenyl-benzofuran-2-carboxylate (Compound 4)

A mixture of 2.5 g of Compound 3, 60 ml of ethanol, 20 ml of dry benzene and 2 ml of concentrated sulfuric acid was refluxed for 7 hours to remove the resulting water. The resulting mixture was concentrated and the residue was dissolved in diethyl ether. The solution was washed with saturated sodium bicarbonate solution and with water.

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The aqueous portion was extracted with diethyl ether. The combined organic layers were over Na _? SO, dried and the solvent removed under reduced pressure. The residue was distilled. The compound is k obtained as a colorless liquid, b.p. 180-181 ⁰ C, 47 Pa.

Example 5 .

2,5-Dihydro-p-phenyl-N-2-propenyl-2-benzofurancarboxamide (Compound 5)

An ethanolic solution of k and an excess of allylamine were refluxed for 2.5 days. The excess amine and the solvent were evaporated under reduced pressure and the resulting gummy product recrystallized from methylene chloride / hexane. 5 was obtained as a white solid, mp 112 ^° C.

Examples 6 to 10 Attempts to Detect the Lipogenesis Inhibitors;

The potency of Compounds 1 to 5 for inhibiting lipogenesis in tissue from warm-blooded animals was determined by immersing samples of pork fat tissue in a liquid medium containing radioactive glucose and the compound to be tested for a while and then separating the lipid from the treated tissue and the uptake of radioactive carbon by scintillation counting. The experiments were carried out on pig adipose tissue, since in pigs the main site of lipogenesis appears to be adipose tissue. In particular, the experiments were carried out according to the following general procedures:

150 mg sections of pork fat were shaken for 2 h in 3 ml of Krebs-Ringer bicarbonate solution ,. containing half of the normal calcium concentration, 60 / μM glucose, 0.5 / UCi glucose-U C and 300, uE insulin and 5 % dimethyl sulfoxide (DMSO) incubated. The compounds to be investigated were added as a solution or suspension in DMSO and were present in a concentration of 100 μg / ml with the incubation mixture. ,

The incubation was stopped by adding 0.25 ml of 1 η sulfuric acid. The resulting mixture was extracted with a total of 25 ml of chloroform: methanol (2: 1, volume). The extracts were washed according to Folch et al. (J. Biol. Chem., 226, 497-509, (1957)), dried in air and in a liquid scintillation counter with 15 ml counting fluid (2 parts toluene containing 0.4 % w / v, New England Nuclear Omnifluor and 1 part Triton X-100). The experiments were carried out in triplicate and accompanied by comparative experiments, in which all components. Amounts and conditions were the same except that no test compound was added. From the data obtained, the percentage inhibition of lipid synthesis by the test compound was calculated. The values obtained in the experiments are given in Table I as percentage inhibition of lipogenesis compared with the results obtained in the comparative experiments in which only the test compound was omitted.

Table I

Example No. Compound No. Percent Inhibition

.6. .1 12

7 2 49

8 3 50

9 .'4 21 10 5 · 59

Claims (1)

ZU6 3 4.2 invention claim Process for the preparation of a 2,3-dihydro-2-benzofuran derivative of the formula (I) C - R ^J (D in which R is attached to a carbon atom in the 5- or 6-position in the molecule and a cycloalkyl group having 3 to 6 carbon atoms, an alkyl group having 4 to 8 carbon atoms, an alkoxy group having 4 to 8 carbon atoms, a phenyl, phenoxy, Benzyl or benzoyl group, wherein each of the latter four groups may optionally be substituted by one or two nitro groups, chlorine or bromine atoms or alkyl groups having 1 to 6 carbon atoms, and R is an allylamino group, characterized in that an alkyl dihydro 2-benzofurancarboxylate of the formula (II): C - (ID wherein R has the meaning given for the formula (I) and R represents an alkyl group, reacted with an allylamine in the presence of a solvent Process according to item 1, characterized in that R in formula (II) has 1 to 5 carbon atoms » Process according to item 2, characterized in that R 'is formula (II) an ethyl group.