PROCESS FOR THE PREPARATION OF PROSTAGLANDIN E1

Abstract: New process for the preparation of prostaglandin E1 of formula (I) starting from the compound of formula (II).

Description: Process for the preparation of prostaglandin E l This invention relates to a new process for the preparation of ( 1 1 . 13 E. 1 5 S )- 1 1 5- dιhydroxy-9-oxopros 3-en- l -oιc-acιd (prostaglandin E l PGE ) ) of formula (I) starting from the compound of formula (II) Endogen PGEi plays a significant regulating role in the living organism and it can be used advantageously for the treatment and prevention of diseases of cardiovascular origin nthetιc PGE I is formed from dihomo-v-hnolenic acid (Prostaglandin 20. I S". 1980) Several total synthesis of PGEI has been performed (J Chem Soc Chem Comm 304. 1972, J Chem Soc Chem Comm 180, 1973, J .-Vm Chem Soc 94, 3643. 1972. J Am Chem Soc 95, 1676, 1973, J Org Chem 3". 292 1. 1972), the but their industπal realization is very cumbersome Another possible approach is the regioselective saturation of the cis double bonds of the prostanoid structure of the formula (III) containing cis and trans double bonds Hvdrogenation of 5(Z). l l α, 13E, 15(S)- 1 1. 1 5-dιhydroxy-9-oxoprosta-5.1 -dιene- l -oιc-acιd (PGE;. ) of formula (IV) in ethvl acetate yields only 6°/o of PGE, of formula (I ) (J Biol Chem 239. 4091 1964) By the application of homogen catalysis at room temperature in case of Wilson type catalvst PGEi of formula (I) is formed m 72% yield in a 2 3 mixture of benzene and acetone from PGE: of formula (IV) This reaction is accompanied formation in significant amounts of the compound of formula (VI) b\ the elimination of water and of dihydro-PGEi of formula (V) (J Labelled Compd Radiopharm 14, 5 15, 1978 and J Org Chem 38, 95 1 , 1973) By examining the hydrogenation of PGE: of formula (IV) in the presence of ethyl acetate, acetone, benzene, chloroform, methanol and dioxane. catalysts such as palladium on barium sulfate and carbon, platinum on carbon, and nickel and copper on calcium carbonate and Lindlar catalyst, the formed quantity of PGEi of formula (I) did not exceed 70° o and was accompanied by significant amounts of starting PGE 2 of formula (IV), dihvdro-PGE of formula (V) and other prostaglandin derivatives (J Labelled Compd Radiopharm 2 ^ . 1243, 1989 ) Similar difficulties are encountered if the derivative containing hydroxyl groups in positions 1 1 and 1 5 of PGE of formula (IV) is used as tne staπing material (J Labelled Compd Radiopharm 27, 1243, 1989) Hydrogenation of PGF 2u of formula (II) protected by tetrahydropirany groups (US-4,085, 13^. L " S-4, 122.282, J .Am Chem SOC 92, 2586 1970), and PGF: α derivatives containing other protective groups (J Am Chem Soc 93, 73 19, 1971 ) has been caned out in ethvl acetate at room temperature and in methanol in the presence of the palladium on carbon catalyst at -20 °C but beside the expected compound of formula (VTI) significant quantity of the dihydro deπvative of formula (VIII) has also been formed It is \ ery difficult to separate chromatographicalK (J Am Chem Soc 92, 2586 1970) the non- hydrogenated staπing material (e g compound of formula (II)) and the reduction products (e g compounds of formula (VII) and VIII)) Thus there remains a need in the art for a regιoselectι\ e. simple catalytic reduction process for the preparation of PGEI The present invention is directed to such a regioselective catalytic hydrogenation of the double bond in the 5,6 position selected from the two double bonds existing in the compound of formula (II), forming a diastomeπc mixture in the given case We intended to achieve such a selectivity beside a minimum of 97° 0 conversion that the puπrv of the formed compound of formula (VII) should allow its fuπher use without chromatographic purification We reached the above goal by an unexpected observation which is the base of our new process Compound of the formula (ID containing two double bonds can be saturated in positions 5 and 6 with good regioselectivity and appropriate reaction speed in the following way The compound of formula (II) is hydrogenated optionally as a diastereomeric mixture m halogenated hydrocarbon solvent and in the presence of a catalyst containing transitional metal and transform the compound of formula (VII) obtained as a diastereomeric mixture in this case to PGEi of formula (I) with the methods known per se The thus prepared PGF ! u derivative of formula (VII ) can be transformed to the product PGE i of formula (I) if necessary with known methods such as by the oxidation of the 9-hydroxy group with Jones reagent (J Am Chem Soc 92 397, 1970), and by the removal of tetrahydropiranyl protective groups bv acidic hvdrolvsis If necessary the sequence of hydrolysis and oxidation steps can be inverted Transitional metals mean those chemical elements which are defined in Romp s Chemical Lexikon (Mϋszaki Konyvkiadό Budapest, 198 1 ) on the following pages volume 1 pages 232-234 In this case preferablv heterogen phase catalysts containing palladium platinum, rhodium rhenium or ruthenium optionally linked to carriers or homogen catalysts containing compounds of the above listed metals can be used The metal content of heterogen catalysts are preferably from 1% to 50% by weight For halogenated hydrocarbons aromatic, aliphatic or alicyclic hydrocarbons containing one or more fluorine, chlorine, bromine or iodine atoms, can be applied It is especially preferable to use dichloromethane, 1 ,2-dιchloroethane or 1 ,2- dichlorobenzene as solvents According to our invention in manv cases it is advantageous to carry out the hvdrogenation in the presence of nitrogen containing basic compounds, for example tπalkylamines/preferably triethylamine or diisopropyl-ethvl-amin According to the invention the procedure can be done in a wide temperature range, preferablv between -20°C and +40°C The applied pressure can be atmospheric or higher than atmospheric but it is optimal to work in the pressure range up to 5 bar Compound of formula (II) and the applied catalyst ratio can be chosen in a wide range but the most advantageous weight ratios are those between 1000 1 and 2 1 Hydrogenation can be done in solutions of different concentrations It is advantageous to work in solutions havinu concentrations of 1 to 50 mixed % The preparation of starting compound of formula (II) can be carried out by well known methods (J Amer Chem. Soc 92 397 ( 1970), J Amer Chem Soc 9], 5675 ( 1969)) The following examples are intended to provide those of ordinary skill in the an with a complete disclosure and descπption of how to conduct the present synthetic process and are not intended to limit the scope of our claims EXAMPLES Example 1 210 g PGF 2α bis-tetrahydropiranyl ether of formula (II) was dissolved in 200 ml 1,2- dichloroethane and 10 g triethylamine and 50 g charcoal containing 10% palladium by weight were added to the reaction mixture The obtained mixture was stirred under hydrogen pressure of 0 6 bar at room temperature When no further absorption of hydrogen could be detected the catalyst was filtered cut and the filtrate was extracted with aqueous solution of sodium hydrogen sulfate then with water After drying the organic phase on water free sodium sulfate the solvents were evaporated This way we obtained 200 g PGF iα protected by tetrahydropiranyl groups of formula (VII) By introducing ammonia gas into its diisopropyl ether solution, we obtained the ammonium salt of the compound of formula (VII) Melting point 65-68°C Element analysis based on molecular formula C 30 FL? NO? Calculated C 66 45% H 9 7% N 2 5% Found C 66 3% H 9 6% N 2 4% Example 2 The process was carried our according to Example 1 but the hvdrogenation was done at a hydrogen pressure of 2 5 bar and 0°C and the working up was effected in accordance of Example 1 We obtained 205 g of compound of the formula (VII) which is identical with the product of Example 1 Example 3 The process was carried our according to Example 2 but diisopropyl ethyl amine was applied instead of methyl amine and we obtained 210 g of compound of the formula (VII) which is identical with the product of to Example 2

Claims: CLAIMS 1 A process for the preparation of PGEi of formula (I) characterized in that the hydrogenation the compound of formula (II) optionally as a diastereomeric mixture is carried out in halogenated hydrocarbon solvent and in the presence of a catalyst containing one or more transitional metal(s) and the compound of formula (VII) thus obtained optionally as a diastomeπc mixture is transformed to PGE ! of formula (I) using processes known per se 2 A process according to claim I characterized in that the applied aliphatic, aromatic or alicyclic hydrocarbon solvents contain one or more chlorine atoms 3 A process according to claim 1 characterized in that the catalyst is applied in the heterogen phase 4 A process according to claim 1 characterized in that ofthe catalyst is applied in the homogen phase 5 A process according to claim 1 characterized in that the process is carried out in the presence of a basic compound containing nitrogen 6 A process according to claim 1 characterized in that palladium, platinum. rhodium, rhenium or ruthenium are applied as transitional metal catalysts in the metallic state optionally attached to a carrier and/or in the form of their compounds 7 A process according to claim 5 characterized in that trialkyl amines preferablv ethyl amine or dnsopropoyl-ethyl-amine are applied as nitrogen containing basic compounds 8 A process according to claim 2 characteπzed in that dichloromethane, 1,2- dichloroethane or 1.2-dιchlorobenzene are applied as a solvent containing one or more chloπne atoms 9 A process according to claim 1 characterized in that a palladium on carbon catalyst is applied 10 Process according to claim 1 characterized in that the hvdrogen pressure is from atmospheric pressure to 5 bar 11 A process according to claim 1 characterized in that the temperature is from -20°C to +40°C 12 A process according to claim 1 characterized in that the mass ratio of compound of formula (II) to the catalyst is from 10001 to 21 13 A process according to claim 1 characterized in that the hvdrogenanon is earned out in a solution with concentration of 1 to 50 mix %

Inventors: DALMADI GYULA, HAJDU FELIX, HERMECZ ISTVAN, MOZSOLITS KAROLY, SZABO TIBOR, SZEVERENYI ZOLTAN, VAJDA ERVIN, DALMADI, GYULA, HAJDU, FELIX, HERMECZ, ISTVAN, MOZSOLITS, KAROLY, SZABO, TIBOR, SZEVERENYI, ZOLTAN, VAJDA, ERVIN
Applicants: CHINOIN GYOGYSZER ES VEGYESZET, DALMADI GYULA, HAJDU FELIX, HERMECZ ISTVAN, MOZSOLITS KAROLY, SZABO TIBOR, SZEVERENYI ZOLTAN, VAJDA ERVIN, CHINOIN GYOGYSZER ES VEGYESZETI TERMEKEK GYARA RT, DALMADI, GYULA, HAJDU, FELIX, HERMECZ, ISTVAN, MOZSOLITS, KAROLY, SZABO, TIBOR, SZEVERENYI, ZOLTAN, VAJDA, ERVIN
Application year: 1996
Main classification: C07C405
IPC codes: B01J23, C07B61, C07C405