CS196865B1 - Method of preparing /rs/-7-/2,3-dihydroxylpropyl/theophylline and 3-0-substituted derivatives of the same - Google Patents

Description

The present invention provides a process for the preparation of (RS) -7- (2,3-dihydroxypropyl) theophylline and its 3-O-substituted derivatives of the general formula I

CH ₅ wherein R is hydrogen, C 1 -C ₆ alkyl or benzyl.

(RS) -7- (2,3-dihydroxypropyl) theophylline is used under the names "Diprophyllin", "Neophyllin", "Glyphyllin", "Neutrophyllin", "Theal" in human medicine as a medicine and prophylactic with bromcholytic and vasodilatory effect . Its pharmacological properties are close to theophylline, but it is less toxic and has no diuretic effect (RA Artšuler, Med. Thought USSR 16, No. 7, 57 (1962); Sachsse B .: Dtsch. Med. Wiss. 78, 1563 (1953) Katz S., McCormick GF: Int. Rec. Med. 167, 271 (1851R) Another use of this compound is in combination with griseofulvin, which enhances resorption of substances in the gastrointestinal tract (DOS No. 1, 911, 279).

Previous methods for the preparation of this compound consisted either in hydroxylation of 7-allyltheophyllin Gorezyca M .: Dissert. Pharm. 14, 171 (1962), reaction of alkali salts of theophylline with 1-chloropropane-2,3-diol (Auslander FF: Sci. Pharm. Proc. 1985, 75 (1966); USSR Patent No. 190, 902), hydrolysis of 7- (3-chloro-2-hydroxypropyl) -, respectively. 7- (2,3-epoxypropyl) theophylline (Polish Patent 59,071) and finally in the reaction of 1,3-dimethyl-5,6-diaminouracil with epichlorohydrin and subsequent condensation of the resulting formic acid intermediate (French Patent No. 2,000,854 ).

2,3-Cyclic carbonates and 3-O-carbamates (Japanese Patent No. 7,116,752), 3-O-acetyl and 3-O- were prepared from 7- (RS) - (2,3-dihydroxypropyl) theophylline derivatives so far. benzoyl derivative (DeMartiis F., Avico U., Toffoli F., Rend. Inst. Super. Sanita 26, 1031 (1963); and phosphoric acid ester (Seita, T., Yamauchi, K., Kinoshita, M., Imoto, M., Bull. Chem., Soc., Japan 46, 1563 (1973).

The present invention provides a simple preparation of 7- (RS) - (2,3-dihydroxypropyl) theophylline and its 3-O-alkylsubstituted aralkylderivatives, characterized in that theophylline is heated with 1,2-cyclic glycerol carbonate or 3-O- substituted derivatives of general formula II

II o

wherein R is hydrogen, alkyl of one to six carbon atoms or benzyl, in dimethylformamide or dioxane as solvent, at temperatures of 100 to 140 ° C and in the presence of sodium or potassium hydroxide or carbonate.

The starting materials of formula II are readily available by reacting glycerol or its 1-O-substituted derivatives with aliphatic carbonic esters (Cunningham J., Glgg, R., J. Chem. Soc. 1965, 1553; U.S. Patent No. 2,915,529) ). The reaction is simple and the reaction products can be obtained directly without isolation of the intermediates. Advantageously, the reaction is carried out in dioxane, which dissolves theophylline to a limited extent, so that the unreacted substance can be easily recovered and separated from the product of formula I. Isolation of the compounds of formula I is possible after solvent removal either by direct crystallization from water or organic solvents especially in the case of diprophyllin (I, R = H) also by acetylation of the crude mixture with acetic anhydride in the presence of pyridine or 4-dimethylaminopyridine and isolation of the well-crystallized 2,3-dl-O-acetylderivative, which affords the pure product of formula I by methanolysis or ammonolysis.

The 3-O-substituted derivatives of formula (I) may be used to prepare other theophylline derivatives with potential pharmacological activity.

In the following, the invention is illustrated by way of non-limiting examples.

Example 1. 7- (RS) - (2,3-Dihydroxypropyl) theophylline of formula I wherein R = H.

A mixture of 1.8 g (10 mmol) of theophylline, 2.1 g (17.8 mmol) of glycerol-1,2-cyclic carbonate, 0.4 g of potassium carbonate and 15 ml of dimethylformamide is heated to reflux at 1.5. h, cooled, filtered through a frit, washed with 10 ml of dimethylformamide, and the filtrate was evaporated in vacuo, and the residue was crystallized by recrystallization from ethanol (4X20 ml) and recrystallized from ethanol.

1.6 g (63%), mp 140-141 ° C. UV spectrum (pH 2, pH 7, pH 11): λ max ^{274 nm} , ε max ¹⁰⁰⁰⁰ , λ min ²⁴⁶¹ ™.

Example 2. 7- (RS) - (2,3-Dihydroxypropyl) theophylline of formula I, wherein R = H.

A mixture of 6 g (33 mmol) of theophylline, 9 g (76 mmol) of glycerol-1,2-cyclic carbonate,

1.5 g of sodium hydroxide and 80 ml of dioxane were heated at reflux for 3 hours and filtered while hot and washed with 50 ml of dioxane. The precipitate contains theophylline and theophylline sodium. The filtrate was evaporated in vacuo, 100 ml acetic anhydride and 0.5 g were added

4-dimethylaminopyridine and stir until dissolved (about 1 hour). It is allowed to stand at room temperature for 15 hours and the acetic anhydride is evaporated to dryness in vacuo. The residue is dissolved in 200 ml of chloroform, washed with 50 ml of water, the chloroform solution is dried over sodium sulfate, filtered and evaporated to dryness in vacuo. The residual oil was stirred with 200 ml of petroleum ether until recrystallized, filtered off with suction and recrystallized from ethanol (adding ether to turbidity) to give 6.8 g (60%) of chromatographically pure 2,3-di-O-acetylderivative of formula I where R = H, mp 142-143 ° C.

This product was dissolved in 100 mL of 30% methanolic ammonia and allowed to stand overnight at room temperature. The mixture was evaporated in vacuo and the residue crystallized from ethanol. 90-95% of a substance having the same properties as in Example 1 is obtained.

Example 3. 7- (RS) - (3-Methoxy-2-hydroxypropyl) theophylline of formula I, wherein R = CH ₃

A mixture of 1.8 g (10 mmol) of theophylline, 2.0 g of 10-methyl-sn-glycerol-2,3-cyclic carbonate of formula II wherein R = CH ₃ , 0.5 g of sodium carbonate and 15 ml of dimethylformamide is heated It is filtered and washed with 10 ml of dimethylformamide for 2 hours under reflux and the filtrate is evaporated in vacuo and the residue is chromatographed on two plates (40X12X0.3 cm) of silica gel (30-60 mesh) with a fluorescent indicator in chloroformethanol (9: 1j. The product bands (R _P = 0.13) were eluted with methanol (500 mL), the eluate was evaporated and the residue crystallized from ethanol (adding ether to turbidity) in the refrigerator overnight to give 1 g (37.5%). mp 188-189 ° C, UV spectra identical to the compound of formula I, wherein R = H. Example 4. 7- (RS) - (3-Benzyloxy-2-hydroxypropyl) theophylline of formula I, wherein R = CH ₂ C ₆ H ₃ .

A mixture of 1.8 g (10 mmol) of theophylline, 2.1 g (10 mmol) of 10-benzyl-sn-glycerol-2,3-cyclic carbonate of formula II wherein R = benzyl, 0.4 g of sodium hydroxide and 15 ml dimethylformamide was heated under reflux for 1 h and filtered while hot and washed with 10 ml of dimethylformamide. The filtrate was evaporated in vacuo and the residue chromatographed on two plates of silica gel (see Example 3) in chloroform-ethanol (95: 5). Product bands _(Rf = 0.45) were eluted with methanol (500 ml), the eluate was evaporated in vacuo and crystallized from ether (100 mL) in the fridge. 1.6 g (46.5%) of the product are obtained, mp 92 ° C. UV spectrum (pH 2, pH 7, pH 11):

: λ max ^274mn , ε max ^10,000 , λ min ²⁴⁶ ™ ¹ .

Claims (1)

Process for the preparation of (RS) -7- (2,3-dihydroxypropyl) theophylline and its 3-O-substituted derivatives of the formula I and II CH ₄ —C — GHgGft AND CH 2 wherein R is hydrogen, C ₁ -C ₆ alkyl or benzyl, characterized in that theophylline is heated with glycerol 1,2-cyclic carbonate or a 3-O-substituted derivative thereof wherein R is hydrogen, alkyl of one to six carbon atoms or benzyl, in dimethylformamide or dioxane as solvent, at temperatures of 100 to 140 ° C and in the presence of sodium or potassium hydroxide or carbonate.