CS201499B1 - Method of preparing 5-/4-chlorphenyl/-5-hydroxy-2,3-dihydro-5h-imidazo/2,1-a/isoindole - Google Patents

Description

The invention relates to a "process for the preparation of 5- (4-chlorophenyl) -S-hydroxy-2 H -dihydro-5 H -imidazo [2,1-a] isoindole of formula (I),

which is used in medicine as anorectics.

So far, this compound has been produced from 9b- (4-Chlorophenyl) -1,2,3,9b-tetrahydro-5H-imidases [2,1-a] isoindolobutane II

Reductions with lithium aluminum hydride and Oxidation of reaction products with air or oxygen in an ether or alcohol medium (WJ Houlihan, CSI Pat. 141217; Sv. Pat. 499529), optionally also with other oxidizing agents such as hydrogen peroxide, alkyl peroxides and acylperoxides (acylperoxides) GA Cooke, HA Deuvilie, WJ Houlihan, Ger Offen, 2103359).

Another known method for the preparation of a compound of formula I is the catalytic hydrogenation of a compound of formula IIb and 2- (beta-aminoethyl) -3- (4-chlorophenyl) phthalimidine, its reduction with bilinium lithium hydride at boiling point in aliphatic or cyclic higher boiling. ether of 5- (4-chlorophenyl) -2,3-dihydro-5H-hidazo [2,1-a] isoindole and oxidation of the latter with air or oxygen in methanol or ethanol (W.). Houlihan, Csl. Another method for preparing a compound of Formula 1 from a compound of formula Π is by hydrolyzing it with hydrochloric acid] to 2- (aminoethyl) -3- (4-chlorophenyl) -3-hydroxyphthalimidine hydrochloride, which is transformed with pyridine by p-toluenesulfochloride in pyridine. to 1- (p-toluenesulfonyl) -1H-imidazoZ2, 1α / isoindoilone-5 and this provides a compound of formula I (TS Sulkowski, US Pat. 3763178) with a sulfuric acid or phosphoric acid salt. Another known synthesis is based on 2- (4-chlorophenyl). ben201499 zoyl chloride which treatment with N- (2-amino-, ethyl) alkyl- or arylsulfonamide provides 2r (alkyl- or arylsulphonylaminoethyl) -3 (4-c-chlorophenyl) -3-hydroxyphthalimidine and this is treated with sulfuric or phosphoric acid to give the compound of formula I.

The process according to the invention is carried out by adding to a solution of 1.5 to 2.2 moles of sodium bis (2-methoxyethoxy) sodium hydride in anhydrous aromatic hydrocarbon, preferably in benzene or toluene or in a linear or cyclic ether, preferably in diethyl ether. , tetrahydrofuran or dioxane or a mixture of these solvents is added with stirring to 1 mole of the compound of formula II so as to maintain the temperature of the reaction mixture between 4 and 35 ° C, preferably below 10 ° C, under an inert gas atmosphere. The inert gas used is helium, argon, preferably nitrogen The addition of the compound of formula II can also be carried out in an ether solution, for example diethyl ether, tetrahydrofuran or dioxane, or a solution of benzene, toluene and other aromatic hydrocarbons. Upon completion of the reaction, unreacted sodium bis (methoxyethoxy) sodium hydride is decomposed, for example by the addition of ethyl acetate, water, aqueous alkaline hydroxide, or a mixture of water and water. The reaction mixture which has precipitated from the reaction mixture is most preferably separated by suction, washed with water until neutral and is preferably dried under reduced pressure. chu. The reduction product is a mixture of a number of compounds which, either directly or via another intermediate, give the compound of formula I by the process of the invention. This process is based on dissolving the reduction product by stirring it in an aliphatic alcohol having 1-5 carbon atoms. preferably in butanol, in the presence of a catalytic amount of a lower "aliphatic acid having from 1 to 3 carbons, preferably formic acid - in common and in the form of a carboxylic acid"; in an inert atmosphere or under vacuum, further evaporating this solution preferably under vacuum to a syrupy consistency, dissolving the syrupy residue in a lower aliphatic ketone having a carbon number of 3 to 6, preferably in acetone and exposed to air. solution. with intensive stirring for 1 to 3 days _; The reaction can also be carried out by adding a lower aliphatic ketone having a carbon number of 3 to 6, preferably acetone, instead of evaporating the alcohol from the alcoholic solution, and treating it with air or oxygen in analogy to the previous case. may be effected by bubbling air or oxygen through a solution of the syrup residue in the lower aliphatic ketone for 1 hour. up to 3- <hours, Prementproduct reduction -to- _? zl.účeninu. formula. It can also be carried out by treatment of air or oxygen with its solutions, an aliphatic alcohol having a carbon number of 1 to 5, preferably in butanol at a rate of from 1 to 5; in the presence of a catalytic amount of a lower aliphatic acid having a carbon number of 1 to 3, preferably formic acid, but at a lower yield and for a longer time than in the process of the invention. room temperature.

The main advantage of the process according to the invention is the use of less dangerous bis (sodium methoxyethoxy) sodium hydride over the first-used lithium aluminum hydride. 'Other advantages of using sodium bis (methoxyethoxy) sodium hydride' are its availability in Czechoslovakia and also the possibility of using its concentrated solution in an aromatic hydrocarbon, resulting in its lighter and more accurate dosage over alumina hydride, preferably the above-described two-step conversion of the reduction product to the compound of formula I over the previously described action of air or oxygen in pure alcohol the environment is in a short reaction time and thus the production capacity of the device is increased;

Hereinafter, the invention is described in the examples without being limited thereto. .

Example 1

To a solution of 11.6 g (0.04 mol) of synhydride [70% solution of sodium aluminum bis (2-methoxyethoxy) hydride in toluene] in 20 ml abs. benzene was added dropwise a solution of 5.68 g (0.02 mol) of 9b _: (p-chlorophenyl) 1,2,3,9b-tetrahydro-5H-imidazole [2,1-a] isoindpl-5-one (compound II in 5 ml abs. of dioxane at a temperature of max. After standing for several hours, an almost quantitative reduction product crystallized to give 4.5 g of a white crystalline solid, mp 126-129 ° C.

To a stirred solution of 11.6 g (0.04 mol) of synhydride in 25 ml abs. of dioxane is added dropwise a solution of 5.68 g (0.02 mol of compound II in 25 ml of abs dioxane over 5 minutes at a maximum of 35 [deg.] C. The reaction mixture is stirred for 20 minutes at room temperature. After stirring for 10 minutes with 4 ml of water, the organic layer was decanted and the product crystallized and an equal volume of n-pentane was added to the mother liquor after sucking off the product, crystallizing another portion of the reduction product (4.0g, mp 127-129 ° C).

Example 3 · «

To a stirred suspension of 11.6g (0.04mol) synhydride in 40ml abs. of dioxane, 5.68 g (0.02 mol) of compound U are gradually added under cooling (15 to 18 ° C). The reaction mixture is then stirred for a further 2.5 hours. at room temperature. In the insulation reduced ^; The lactam was proceeded as in Example 2. Yield of reduction product 4.5g with mp 126-131 ° C.

Example 4

To a vigorously stirred solution of 11.6g (0.04mol) of synhydride in 40ml abs. 5.68 g (0.02 mol of compound II at 15-18 [deg.] C.) are gradually added to the tetrahydrofuran while introducing nitrogen, and the reaction mixture is then stirred at room temperature for 2 hours, and the unreacted synhydride is decomposed first with 4 ml of ethyl acetate. After 4 ml of water are added dropwise, the organic layer is separated and crystallized by the reduction product, after concentration of the mother liquor to pov4 of the flood volume, a further reduction is obtained (total 5.0 g with mp 126-128 ° C).

Example 5

The solution. 487g (1.7mol) of synhydride v

3.5 g of anhydrous benzene, which is below the atmosphere of nitrogen, are gradually added at temperatures of 15-18 ° C to 222 g (0.8 mol) of the compound. Thereafter, the reaction mixture is stirred at room temperature for 1 hour, at the end of which the reaction mixture is turned red until the unreacted synliidium is decomposed (max. 18 ml with 40 ml of ethyl acetate, 35 ml of water is added dropwise and finally The reaction mixture was thoroughly mixed with a solution of 64 g of sodium hydroxide * in 700 ml of water, the alkaline aqueous layer was melted and the organic product was filtered off with suction, dried at a maximum of 40 DEG C. Product yield 198g, mp 134-137 DEG Example 6

To a stirred and cold solution of 63.6g of (0.22mol) synhydride in 400ml of anhydrous toluene under nitrogen atmosphere is added successively 28.4g (0.1mol of compound II) at a temperature range of 8-13 ° C. The unreacted synhydride is decomposed unax at 10 ° C by the careful addition of a mixture of 6 ml of water and 20 ml of tetrahydrofuran and the reaction mixture is stirred thoroughly with 150 ml of 12% sodium hydroxide solution. The organic product is washed with 100 ml of 6% sodium hydroxide solution and 200 ml of water, and the product is filtered off with suction, washed with 70 ml of diethyl ether and finally with 100 ml of water, dried at maximum 40 DEG C. 26.7 g of the reduction product are obtained. 132-134 ° C.

- Example 7

0.3 ml of 85% formic acid is added dropwise to a vigorously stirred suspension of 10 g of finely divided reduction product prepared according to Examples 1 to 6 in 200 ml of n-propanol. After two hours of vigorous stirring, during which all the lactams are dissolved, the mechanical impurities are aspirated and the vigorous stirring is continued in the open vessel 42h. During this time, 5- (4-chlorophenyl) -2,3-dihydro-5-hydroxy-5H-imidazo [2,1-a] isoindole (compound I) crystallizes out in the form of fine needle needles of m.p. t. 189.5 to 19.1 ° C.

Crude Product Yield 4.5g The content of the product is only trace impurities (monitored

TLCj. After two crystallizations from ethanol or n-butanol, it melts at 198-200 ° C. Example 8

1 ml of 85% formic acid was added to a vigorously stirred suspension of 32 g of the reduction product in 600 ml of methanol. Within 5min. the reduced lactam dissolves. The reaction mixture was stirred in an open vessel for 48h. Subsequently, compound I is aspirated and the mother liquor is stirred with 3 ml of triethylamine for a further 24 hours. An additional portion of Compound I is obtained, together 12.4g with t. t. Mp 194-195.5 ° C. . ·

Example 9

Mixture. 10 g of finely divided reduction product, 200 ml of n-butanol and 0.3 ml of formic acid are stirred vigorously for 2 hours. The insoluble residue is aspirated and the filtrate is vigorously stirred in an open vessel 46h. While stirring, compound I crystallizes _; which contains trace impurities (TLC). Yield 4.83g, mp 193-194 ° C.

Example 10 10 g of the reduction product are dissolved in 100 ml of n-butanol with the addition of 0.3 ml of formic acid, the mechanical impurities are sucked off and 100 ml of acetone are added to the filtrate. The solution thus obtained is stirred for 24 hours. in an open container, or with ^! and 6h. Air is bubbled through the solution and allowed to crystallize in another cool place.

After aspirating the first crop of compound I, the mother liquor is evaporated to dryness under reduced pressure, and the residue is crystallized from acetone. Together 5.5g of compound I with t. t. Mp 194-196 ° C. Example 11 ','

20 g of the reduction product is dissolved in 400 ml of n-butanol in the presence of 0.5 ml of 85% formic acid, the insoluble residue is filtered off with suction and the filtrate is stirred vigorously in an open vessel for 42h. The crystallized first crop of Compound I is aspirated (Dg) and the mother liquor is concentrated to a syrupy mass under reduced pressure. This was dissolved in 150 ml of acetone, through the solution for 2h. air is bubbled through and allowed to crystallize overnight. A further proportion of Compound (I) is obtained in total 11.8g, m.p. t. Mp 196-198 ° C.

EXAMPLE 12 10 g of the reduction product are dissolved in 150 ml of n-butanol (n-propanol or isopropanol) with the addition of 0.3 ml of 85% formic acid under vacuum (2.4 kPa). The mechanical impurities are sucked off and the filtrate is concentrated to a syrupy mass. Dissolve in 150 ml of acetone, starting to crystallize Compound I. Air is bubbled through the reaction mixture for 3 hours and allowed to crystallize overnight to give 5.5g of Compound I, mp 196.5-198.5 ° C. The mixture is allowed to stand in a filled vessel for 6 to 7 months and then mixed in 500 ml of acetone with addition of 2 ml of formic acid for 3 hours, air is bubbled through the suspension for 1 hour and allowed to stand overnight. C.

Claims (1)

P RED MET Preparation method, 5- (4-chlorophenyl) -5-hydroxy-2,3-dihydiro-5H-imidazo [2,1-a] isoindole of formula I by reducting 9b- (4-chlorophenyl) -1,2,3,9b-tetrahydro-5H-imidazo [2,1-a] isoindolone-5 of formula II OUT ........................ ........; And by subsequent oxidation of the reaction product, characterized in that it is used for the reduction of the 1-molar compound of formula (II) either alone or in solution in a linear or cyclic ether, e.g. in diethyl ether, dioxane, preferably in tetrahydrofuran, respectively. a solution thereof in an aromatic hydrocarbon of a benzene series, preferably in benzene or toluene, using a solution of 1.5 to 2.2 moles of sodium bis (2-methoxyethoxy) sodium hydride in anhydrous hydrocarbon anhydrous , e.g. in benzene or toluene, respectively. in an aliphatic or cyclic ether, e.g. in diethyl ether, dioxane, preferably in tetrahydrofuran, or in a mixture of these solvents in a temperature range of 4 to 35 ° C, preferably in the range of 4 to 10 ° C, in an inert gas atmosphere, e.g. of helium, argon, with nitrogen, whereupon the isolated reductive product is first subjected to catalytic action of any of the aliphatic acids having from 1 to 3, preferably formic acid, in an aliphatic alcohol having carbon numbers of 1 to 5, preferably butanol and the formation of substances is effected by air or oxygen addition of an aliphatic ketone with a carbon number of 3 to 6, preferably acetone. Jihočeské, tisk-árny, o .. p. ', Operation 6 Elsewhere. HradecPrice: 2,40 Kčs REPAIR OF THE DESCRIPTION OF THE INVENTION FOR THE AUTHORIZATION NO. 201 <99 (51) Int. Cl3 -, C 07 O 487/04 - In the description of the invention to the author's Certificate No. 201499, the author of the invention is missing in the heading: SZEMES FRIDRICH RNDr., Bratislava, / i OFFICE FOR DISCOVERY AND DISCOVERY