CS217347B1 - Method of production of derivatives / 3a ot, 4 β, 5 oc, 6a oi. hexahydro-5-hydroxy-4-hydroxymethyl-2H-cyclopen [b] furan-2-one - Google Patents

Abstract

The invention relates to a method for the production of derivatives of (3αΛ , 4/3,- 5εt , 6αεt (hexahydro5-hydroxa-4-hydroxymethyl-2H-cyclopentaQb) furan-2-one. The essence of the invention lies in the fact that (3α«t, ,46 , 5εt ,6α«t)hexa - hydro-5-hydroxy-4-hydroxymethyl-2H-cyclopentaQb]furan-2-one is treated with triphenylhalomethane in an organic solvent in the presence of a base or directly in a heteroaromatic amine. The resulting triphenylmethyl ether is converted by reaction with the corresponding halides or isocyanates into a compound which, in an acidic medium, provides the desired derivative. The starting material can preferably be treated with 1.1 to 1.5 equivalents of triphenylhalomethane in organic solvents in the presence of a base or directly in a heteroaromatic amine, preferably pyridine, at a temperature of -20 to -60 °C and the product is isolated by crystallization. Protection of the secondary hydroxyl group is carried out with an excess of reagent at a temperature of 10 to 60 °C in a basic environment. Selective cleavage of the triphenylmethyl group is carried out using ion exchangers in the cycle.

Description

BACKGROUND OF THE INVENTION The present invention relates to a process for the preparation of (3a, c, 4, 3,5, 3, 6 and 6) hexahydro-5-hydroxy-4-hydroxymethyl-2H-cyclopenta b furan-2-one derivatives of the general formula I

(I). ?

or a 4-R-CgH-NHCO- group, wherein R is hydrogen or opAphenyl, or a 4-R-CgH4-NHCO- group wherein R is as defined above or a (R) -Si group wherein R ⁴ is alkyl of 1 to 4 carbon atoms. These derivatives are important intermediates in the synthesis of biologically active substances of the prostaglandin and prostacyclin type.

Process according to the invention from the readily available (3α, 4, 3, 5, 6aco) -hexa-hydro-5-hydroxy-4-hydroxymethyl-2H-cyclopenta [b] -furan-2-one of formula la, which corresponds to the above of formula I wherein R = H. According to the invention, this compound is treated with triphenyl halomethane in an organic solvent in the presence of a base or directly in a heteroaromatic amine, for example pyridine and its alkyl derivatives. In this reaction, the bulky triphenylmethyl group only enters the primary hydroxyl group on the carbon atom δ, thus forming a well-isolable, crystalline (3a co, 4 / 3,5,5 ° C, 6a oC) hexahydro-5-hydroxy-4- in high yield. triphenyloxymethyl-2H-cyclopentafb] -furan-2-one of formula II

The compound of formula II is then converted by a known method, such as by reaction with the corresponding acyl halide or arylisocyanate, to a compound of formula III

wherein R is as defined above. In the next reaction step, the triphenylmethyl group is selectively cleaved from the compound of formula III under acidic conditions. In this reaction, in addition to inorganic and organic acids, ion exchangers can also be used in the cycle.

The following sequence of reactions can be prepared in a simple manner from a readily available (3a α, 4/3, 5 α, 6α) -hexahydro-5-hydroxy-4-hydroxymethyl-2H-cyclopenta [b] furan-2-one (formula la) compound of formula (I) wherein R is as defined above, which are most preferred for further synthesis of the prostaglandin or prostacyclin type derivatives in terms of both yield and steric reactions.

217 347

The compound of formula (Ia) and (ea) are prepared by simple alkaline hydrolysis of (3a, 4/3, 6, 6a-c) -hexahydro-5-) 1,1-biphenyl-4-carbonyl (oxy-4-) 1,1'-biphenylcarbonyl ) oxymethyl-2H-cyclopenta [b] furan-2-one, which is obtained as a by-product in the synthesis of prostaglandin intermediates according to the known procedure.

The invention and its effects are given by way of specific examples, which are illustrative only and do not limit the scope of the invention in any way.

Example 1 (3α-o, 4/3, 5α, 6a-c) haxahydro-5-hydroxy-4-triphenyloxymethyl-2H-cyclopenta [b] furan-2-one (compound of formula II)

To a solution of 1.00 g (5.8 mmol) of the starting material of formula Ia, in 15 ml of pyridine, was added 1.78 g (6.39 mmol, i.e. 1.1 eq) of triphenylchloromethane and the reaction mixture was left at room temperature. 24 h. After this time, starting material disappeared from the reaction mixture according to thin-layer silica gel chromatography (chloroformethanol 100: 2 system). A few drops of water were added to the reaction mixture and after standing for 2 hours 150 ml of chloroform. The chloroform solution was shaken successively with cold 10% sulfuric acid (until the acidic reaction of the aqueous layer), water, 1% sodium bicarbonate solution and again with water. After drying over magnesium sulfate and evaporation of the solvent, a crystalline residue was obtained, which was recrystallized from ethanol-petroleum ether to give 1.99 g (4.81 mol, i.e., 83%) of the compound of formula II, m.p. 135 ° C. H, 6.32; H, 6.32%.

77.99% C, 6.41% H, in the iC spectrum (chloroform) a band was present at 3.677 µm (secondary OH group), in the mass spectrum a low intensity molecular ion at m / e 414, then ions at m / e 337 / M ⁺ -77), at 243 (M ⁺ -77-77-17) etc.

Example 2 (3a, 0, 4, 3, 5, 6a) hexahydro-5- (1,1'-biphenyl-4-carboxyl) -oxy-4-triphenyloxy-ethyl-2H-cyclopenta [b] furan-2- he (a compound of formula III wherein R = 4-C 8 H 4 -CO-).

To a solution of 500 mg (1.21 mmol) of the triphenyl derivative of formula II in 5 mL of anhydrous pyridine was added 338 mg (1.56 mol) of prenylbenzoic acid chloride and the reaction mixture was left at room temperature for 24 hours. It was then quenched with a few drops of water and diluted for 1 hour with 50 ml of chloroform. The chloroform solution was successively shaken with cold 10% sulfuric acid, water, 1% sodium bicarbonate solution and again with water, dried over magnesium sulfate and evaporated to dryness. The crystalline residue was freed of p-phenylbenzoic acid (resulting from excess chloride) by filtering its chloroform solution through a 5 g column of alumina. Evaporation of chloroform gave 600 mg (1.01 mol), 83% of the derivative of formula III, where R 5a-C 8 H 3 -C 8 -H 2 -CO-, which was crystallized from dichloromethane-petroleum ether for analysis, had a melting point of 193 to 195 ° C. For C 5 j ^ ,Oj (594.7) calculated: 80.78% C, 5.76% H, found: 80.56% C, 6.01% Η; in ΐδ spectrum of this substance was not present OH group, intense absorption bands at 1770 cm ^ Z-OO of five-membered lactone /, at 1 720 cm ^-1 (MC = 0 group group 4-CgH.-CgH_-CO-) and at 1610 and 1490 cm (aromatic core).

[b] furan-2-one / a compound of formula III wherein R = HOCH 8 '217 347

Example 3 / 3a α, 4 / 3,5β, 6αAhexahydro-5- / 2,3,4,5,6-penta-O-acetyl-D-gluconoyloxy / -4-triphenyloxymethyl-2H-cyclopenta-CH- ? H-CH-CH-CO- /

OH OH OH

To a solution of 500 mg (1.21 mmol) of the trityl derivative of formula (II) in 20 mL of anhydrous 1,2-dichloroethane was added 620 mg (1.46 mmol), i.e., 1.2 eq / acid chloride 2,3,4,5 6-pentaacetyl-D-gluconic acid and then dropwise freshly distilled trimetbylamine until the reaction is permanently alkaline; Already during the addition of trimethylamine crystalline trimethylamine hydrochloride began to precipitate. After 24 h, the reaction mixture was shaken with 2 x 15 mL of water and, after drying with magnesium sulfate, the dichloromethane solution was evaporated to a syrup which was purified by silica gel column chromatography (eluent: benzene-ethanol 100: 2). The title compound was obtained as a colorless syrup (680 mg). In its NMR spectrum, 15 protons of the CH-1 CO-group were present in the region of about 2.05 and 15 protons on the aromatic nucleus in the region of 7.2 to 8.1 cT (cT in ppm, internal standard tetranethylsilane). EXAMPLE 4 / 3a oC, 4/3, 5a, 6a oC (hexahydro-5-phenylcarbamoyloxy-4-triphenyloxymethyl-2H-tilententa[.b3furan-2-one) a compound of formula III wherein R = C8H4NHCO-.

To a solution of 500 mg (1.21 mmol) of the substance in 15 mL of anhydrous tetrahydrofuran was added 173 mg (1.45 mmol), i.e., 1.2 equivalents of phenyl isocyanate and a few drops of triethylamine; The reaction mixture was allowed to stand overnight, then evaporated to dryness, the residue dissolved in chloroform and the chloroform solution shaken with water. Drying over magnesium sulphate and evaporation of chloroform gave the product of formula III, where R 5 C 8 H 4 NHCO- in the form of a syrup which solidified on standing at room temperature.

Example 5 / 3a ob, 4 / 3,5o, 1,6ao (hexahydro-5- (1-biphenyl-4-carbonyl) oxy-4-hydroxymethyl)

-2H-cyclopenta [b] furan-2-one], a compound of formula (I) wherein RM-C18-C ^H H-CO-)

To a solution of 400 mg / 0.672 mmol / materials of formula III wherein R = 4-CgH5CgH _i j CO / in 10 ml of acetone was added 1 ml of 1 N hydrochloric acid and the reaction mixture allowed to stand overnight at room temperature; the next day it was heated at 40 ° C for 4 h at which point all starting material had disappeared by thin layer chromatography on silica gel (chloroform-ethanol 100: 1 system). The reaction mixture was then neutralized with solid sodium bicarbonate, evaporated to dryness and the residue filtered in a benzene solution through a 10 g silica gel column. The silica gel column was washed with a further 50 ml of benzene to which triphenylmethanol had passed, and the product retained on the column was washed with 100: 5 benzene-ethanol. 217 mg (0.616 mmol, 92%) of the ester of formula (I) were obtained, wherein the R @ 1 --C @ 8 H @ C @ 8 H @ CO-- whose melting point, IR and mass spectra were identical to those of the authentic material.

EXAMPLE 6 (3a) b, 4 (3, 5 et, 6a) (hexahydro-5-phenylcarbamoyloxy-4-hydroxymethyl-2H-cyclopenta [b] furan-2-one) a compound of formula I wherein R = C8 H4 NHCO--]

217 347

A solution of 300 mg (0.56 mmol) of the carbamoyl derivative of formula III wherein R = C 8 H 4 NHCO in 15 mL of acetone and 1 mL of water was stirred at 30 ° C and 1 mL of Dowex 50 WX / H ^{+ for} 4 hours. The ion exchanger was then filtered off, washed with acetone and the combined filtrates evaporated to dryness. The residue was treated as described in Example 5, i.e. by filtration through a silica gel column. The amorphous product of the formula I where R = ₅ NHCO- CGH obtained in 83% yield, ES coincided / _Rf value, IR, NMR, mass spectra / with an authentic specimen.

Example 7/3 and N, 4 / 3,5w, 6a oo / Hexahydro-5- [1,1'-biphenylcarbamoyl] oxy-4-triphenyloxymethyl-2H-cyclopenta [b} furan-2-one] Compound of Formula III, where R = C 8 H 9 C 8 H 4 NHCO 3

To a solution of 1000 mg (2.42 mmol) of the compound of formula II in 35 mL of anhydrous tetrahydrofuran was added with stirring 587 mg (3 mmol) of p-phenylphenyl isocyanate and 0.1 g of 1-azabicyclo [2.2.2] octane. After stirring at 25 + 5 ° C for 12 hours, the reaction mixture was allowed to stand overnight and treated as in Example 4. 1,432 mg of the product of formula III was obtained, where R 8 C 8 H 8 C 8 H 4 NHCO-, m.p. 76-78 ° C. C. Mass spectra are consistent with the proposed structure.

Example 8 / 3a oc. (4/3, 5a, 6a) (Hexahydro-5-1,1'-biphenylcarbamoyl) oxy-4-hydroxymethyl-2H-cyclopenta [b] furan-2-one) Compound of formula (1), wherein R ^gH ^ CgH4 NHCO- (to 1200 mg of the compound of formula III, wherein Rg3H4CgH4 NHCO) in 60 ml acetone, 5 ml water and 5 ml Dowex 50 WX (H ⁺ ) was stirred for 4 hours at 30 + 5 Deň: 32 ° C. After filtering out the ion exchanger, the reaction mixture was worked up as in Example 6. An oily product of the formula I was obtained, wherein R ^gH ^CgHHNHCO, which crystallized solidly. The spectral data is in accordance with the proposed structure.

Example 9 / 3a, 4 / 3,5 (hexahydro-5-hydroxy-4-hydroxymethyl-2H-cyclopentane) furan

-2-one (compound of formula Ia)

Mixture 2 g / 3a Λ, 4/3, 5 <*,, 6a <*. (hexahydro-5-1,1'-biphenylcarbamoyl) oxy-4- (1,1'-biphenylcarbamoyl) oxymethyl-2H-cyclopentan [byfuran-2-one, 10 ml 1,2 dichloroethane, 100 ml methanol and 2 g carbonate The mixture was stirred at room temperature for 8 hours. The progress of the reaction was followed by thin layer chromatography. After completion of the reaction, the reaction mixture was neutralized with dilute hydrochloric acid (1: 1). The precipitated inorganic salts were aspirated and washed with chloroform. The combined fractions were evaporated to dryness and filtered on a silica gel column, eluting first with methyl p-phenylbenzoate and then with chloroform-ethanol (10: 1). Pure product (Ia) in 92-95% yield. The mass and NMR spectra are consistent with the proposed structure.

Claims (4)

SUBJECT OF THE INVENTION A process for the preparation of derivatives of 3a Λ. 4 (3 35Λ, 6aC) hexahydro-5-hydroxy-4-hydroxymethyl-2H-cyclopenta [b] furan-2-one of the general formula I 0- (1) * Ro * in CH ₂ 0H wherein R is a group R CO wherein R is alkyl of 1 to 16 carbon atoms, optionally further substi2 2 tuovaných 1 to 6 hydroxyl groups, 4-R-NHCO- -CgH group wherein R is as give or R (1) is a group in which R (1) is (C 1 -C 4) -alkyl as intermediates for the production of prostaglandin, characterized in that it is replaced by (3a), (4, 3, 5? - 6a) / hexahydro-5? -hydroxy-4-hydroxymethyl-2H-cyclopenta [b] furan-2-one of formula Ia, which corresponds to the above general formula I, wherein R = H, is treated with triphenyl halomethane in an organic solvent in the presence of a base or directly in a heteroaromatic amine; The resulting triphenylmethyl ether of formula II is converted by reaction with organic halides or isocyanates containing radicals of the abovementioned Substituent R into a compound of formula III (III) wherein: R is as defined above, from which it is selectively cleaved in the acidic medium by the triphenylmethyl group to give the above product of formula (I). 2. The process of claim 1 wherein the starting material of formula (Ia) is treated with 1.1 to 1.5 equivalents of triphenyl halomethane in organic solvents in the presence of a base or directly in a heteroaromatic amine, preferably pyridine, at a temperature of -20 to 60 °. C. 3. A process according to claim 1, wherein the protection of the secondary hydroxyl group in the compound of formula II is carried out by excess of the appropriate reagent at a temperature of 10 to 60 [deg.] C. in a basic environment. 4. The process according to claim 1, wherein the selective cleavage of the triphenylmethyl group from the compound of formula III is carried out by means of ion exchangers in an H @ + cycle.