CS223402B1 - /3a alpha,4 beta,5 alpha,hexahydro-5-hydroxy-4-alcoxycarbonyl-2h-cyclopenta/b/furan-2-on and method of making the same - Google Patents

Description

The invention relates to (3α ", 4 / 3,5", Baajhexahydro-5-hydroxy-4-alkoxycarbonyl-2H-cyclopenta [b] furan-2-ones, which are important intermediates in the synthesis of prostadienoic acid derivatives referred to as prostaglandins. The biological activity of this class of substances in both human and veterinary medicine has initiated their intensive research with the aim of preparing them completely synthetically.

Several synthetic processes are currently known which can be used to prepare not only all types of prostaglandins, but also many of their analogs. One of the most sophisticated synthetic processes is the norbornadien-based process, the so-called nor-hornadiene pathway [j. Amer. Chem. Soc. 95, 7522 (1973), J.C. Chem. Commun. 1974, 151; J. Org. Chem. 42, 786 (1977); U.S. Pat. No. 3,992,438, U.S. Pat. Most of these production methods lead to a key intermediate of the synthesis of prostaglandins-γ-lactone of formula A

wherein R ⁵⁴ is alkyl, benzyl or tetrahydropyranyl, has several challenging synthetic steps. In the individual stages of these syntheses, it is often necessary to isolate intermediates by chromatographic separation. This has a considerable economic disadvantage for the preparation of the χ-lactone of formula A.

The invention solves a novel variant of the norbornadiene pathway, which brings considerable simplification to the synthesis of prostaglandins. The subject of the invention is (33,4,4 / 2,5,4,630-hexahydro-23,440-r-5-hydroxy-4-alkoxycarbonyl-2H-cyclopenta [b] furan-2-ones of the general formula I)

(I) wherein R represents an alkyl group containing 1 to 5 carbon atoms.

The present invention provides a process for the preparation of (3α, 4β, 3,5α, 6aa) hexahydro-5-hydroxy-4-alkoxycarbonyl-2H-cyclopenta [b] furan-2-ones of formula I, which comprises: 5-halo-2-oxo-bicyclo- (2,2,1) -heptane-7-carboxylate-syn-isomer of alkyl II

wherein R is as defined above and X is chloro, bromo, and iodo, reacts with an organic or inorganic peroxy compound, in a basic environment at a temperature of 10 to 100 ° C and after removal of excess peroxy compound, the desired α-lactone of formula III

wherein R and X are as defined above, removing from the undesired isomer of Formula IV wherein R and X are as defined above, in an amount of 1 to 10% by crystallization from water or alcohols containing 1 to 3 carbon atoms. Then, the correct isomer of formula III in an environment of 15 to 100 moles of hydrogen peroxide and an organic solvent mixed with water is converted by the action of alkaline reagents to an alkyl ester of formula I. After removal of the peroxides, this is isolated by extraction into an organic solvent and purified by crystallization. It is preferred to use peracetic acid, m-chloroperbenzoic acid or hydrogen peroxide as the hydroxyl compound.

Sodium or potassium bicarbonate is preferably used to form a weakly basic medium. Tetrahydrofuran, dimethoxyethane or didioxane is preferably used as the water-miscible solvent. As alkali reacting agents, an alkali metal hydroxide, preferably lithium hydroxide, may be used. Excess hydrogen peroxide is effectively removed from the reaction mixture at 0-5 ° C after addition of methyl ethyl acetate by addition of sodium or potassium sulfite, and the product is purified by crystallization from an organic solvent, preferably methanol, benzene or toluene.

The advantage of the process according to the invention is, above all, the use of readily available and inexpensive reagents, easy feasibility of individual operations in simple apparatuses on a pilot scale. Further purification of the products in the individual stages of the synthesis is carried out by crystallization from water or alcohols.

These data show the economical advantage of the process according to the invention.

The invention and its effects are described in more detail in the following examples.

Example 1. Ε-Lactone (1α, 2β, 3α, 5α) (5-chloro-3-hydroxy-2-methoxycarbonylcyclopent-1-yl) acetic acid (compound of formula III where R = CH3, X = Cl) g of the compound of formula II (R = CH 3), together with 29 g of NaHCO _{3, were} suspended in 400 ml of dichloromethane, cooled to 0 ° C, and 42.5 g of m-chloroperbenzoic acid in 300 ml of dichloromethane were added dropwise over 2 hours. The reaction mixture was filtered, the filtrate was shaken with saturated NaHCO 3 solution and saturated sodium sulfite solution to remove peroxides, dried with magnesium sulfate, and after evaporation the residue was crystallized from water. 32 g (76%), mp 102-103.5 ° C.

(IV)

NMR:

5.18 (m, 1H, H-3);

4.36 (dd, J = 3.5 Hz and J = 7.5 Hz, 1H, H-5),

3.74 (s, 3H, OCH 3),

3.12 (na, 3H, CH - COOR),

2.40-3.00 (m, 3H, 2 * H-4, H-1).

Example 2 (1α, 2R, 5α, 5α) (5-chloro-2-hydroxy-2-methoxycarbonylcyclopent-1-yl) acetic acid d-lactone (compound of formula III wherein R = CH 3, X = Cl )

Working as in Example 1, only the peracid was added as a solution in 100 ml of chloroform. The product was isolated in 69% yield.

Example 3 α-lactone (1α, 2 / 3,3α, 5α) (5-chloro-3-hydroxy-2-n-propyloxycarbonylcyclopent-1-yl) acetic acid (compound of formula III wherein R = n-propyl , X = Cl)

Starting from the compound of formula II (R = n-C3H7), the product of m.p. 94 DEG-96 DEG C. was obtained in a yield of 61% as described in Example 1.

Example 4

5-lactone (1α, 2 / 3,3α, 5α) (5-chloro-3-hydroxy-2-methoxycarbonylcyclopent-1-yl) acetic acid (compound of formula III wherein R = CH 3, X = Cl)

2.9 g of a compound of formula II wherein R = CH3, X - Cl are dissolved in a mixture of 25 ml of acetic acid and 2.5 g of sodium acetate. 8 ml of 40% peracetic acid are added in one portion at room temperature with stirring, and the mixture is stirred in the dark for 20 hours. Excess peracid was removed with saturated sodium sulfite solution and acetic acid was neutralized with solid NaHCO 3. The resulting mixture is extracted with chloroform, the organic phase is washed with a sulphite solution, dried over magnesium sulphate and evaporated to give 2.1 g (67%) of the product.

Example 5 (5-chloro-3-hydroxy-2-methoxycarbonylcyclopent-1-yl) acetic acid δ-lactone (1a, 2 / 3,3ia, 5a) (compound of formula III wherein R = CH 3, X = Cl)

Working according to Example 4 except that a mixture (30 ml) of hydrogen peroxide (30%) and acetic anhydride was used in place of peracetic acid, which was stirred at 20 ° C for 1 hour. The ratio of both components was 1: 2 and the temperature was maintained by cooling while stirring. The product was isolated in 42% yield.

Example 6 (1α, 2 / 3,3α, 5α) (5-chloro-3-hydroxy-2-methoxycarbonylcyclopent-1-yl) acetic acid α-lactone (compound of formula III wherein R = CH 3, X = C1 g of the compound of formula II wherein R = CH3, X = Cl in 20 ml of dichloromethane was stirred with 2 g of crude permaleic acid (1 g containing 0.0042 equivalents of " O-O "). After 4 hours, another portion of permaleic acid (2 g) was added After 4 hours, the mixture was diluted with two volumes of dichloromethane, filtered, the filtrate was treated with NaHCO 3 and sodium sulfite until alkaline and loss of reaction to peroxides, dried with magnesium sulfate. 0.82 g of crude product was obtained, which was recrystallized from water to give the pure product in 63% yield.

Example 7 (1, 2 / 3,3α, 5α) (5-Chloro-3-hydroxy-2-methoxycarbonylcyclopent-1-yl) acetic acid α-lactone

The procedure was carried out according to Example 6, only 1 equivalent of NaHCO 3 was added together with the peracid. After 44 hours of reaction, the product was isolated in 49% yield.

Example 8

(1, 2 / 3,3', 5-a) (5-Bromo-3-hydroxy-2-methoxy-carbonyl-cyclopent-1-yl) -acetic acid 5-lactone (a compound of formula III wherein R = CH 3, X = Br)

The procedure of Example 1 was followed, but starting from the compound of formula II wherein R = CH 3, X = Br. The product was isolated in 75% yield.

EXAMPLE 9 (1, 2 / 3,3a, 5 ', (5-Iodo-3-hydroxy-2-methoxycarbonyl-cyclopent-1-yl) -acetic acid 6-lactone (compound of formula III wherein R = CH 3, X = AND)

The procedure of Example 1 was carried out using a compound of formula II (R = CH 3, X = I) as starting material. The product was isolated by crystallization in a yield of 57%, mp 136 ^° C.

Example 10 (3a-a, 4 / 3,5a, 6aa) hexyhydro-5-hydroxy-4-methoxycarbonyl-2H-cyclopenta [b] furan-2-one (compound of formula I wherein R = CH3)

2.19 g of a compound of formula III (R = CH3, X = Cl) are dissolved in 50 ml of tetrahydrofuran and 35 ml of 30% hydrogen peroxide are added in one portion. The mixture was stirred and 1 equivalent of aqueous LiOH was added. After 1 hour the mixture was diluted with 300 mL ethyl acetate, shaken with excess solid sodium sulfite and ice until all peroxides were removed. The organic layer was dried with magnesium sulfate and the residue was crystallized from toluene after evaporation. 1.35 g (67%) of crystalline product are obtained, m.p. 67-69.5 ° C.

NMR:

5.08 (m, 1H, H-5);

4.51 (m, 1H, H-6a);

3.76 (s, 3H, OCH 3),

3.20 (m, 1H, H-3a);

2.80 (m, 3H, 2H-3 and H-4);

2.30 (m, 2H, 2 * H-5).

Example 11 (3aa, 4 (3,5a, 6aa) hexahydro-5-hydroxy-4-methoxycarbonyl-2H-cyclopenta [b]).

402 furan-2-one (compounds of formula I wherein R = CH 3)

The reaction was carried out according to the conditions of Example 8 except that the compound of formula III (R = CH 3, X = Br) was used as starting material. The product, mp 67-69.5 ° C, was isolated in 62% yield and its spectral characteristics were in accordance with the proposed structure.

Example 12 (3aa, 4 / 3,5a, 6aa) hexahydro-5-hydroxy-4- (propoxycarbonyl) -2H-cyclopenta [b] furan-2-one (compound of formula I wherein R = n-C3H7- )

The reaction was carried out according to the procedure of Example 10, but starting from the compound of formula III, wherein R = n-C3H7 and X = Cl. The product, m.p. 32-36 ° C, was isolated in 57% yield and its UI-NMR and mass spectrum were in accordance with the proposed structure.

Claims (7)

(3aa, 4, 3,5a, 6aa) hexahydro-5-hydroxy-4-alkoxycarbonyl-2H-cyclopenta [b] furan-2-ones of the general formula I wherein R represents an alkyl group having 1 to 5 carbon atoms. 2. A process for the preparation of (3aa, 4 (3,5a, 6aa) hexahydro-5-hydroxy-4-alkoxycarbonyl-2H-cyclopenta [b] furan-2-ones of the formula I) according to claim 1, characterized in that The isomer of 5-halo-2-oxo-bicyclo (2,2,1) heptane-7-carboxylate of alkyl of formula II of the invention wherein R is as defined above and X is chloro, bromo and iodo, is an organic or inorganic peroxy compound; at 10-100 ° C and after removal of excess peroxo compound, the desired α-lactone of formula III wherein R and X are as defined above is removed from the undesired isomer of formula IV wherein R and X are as hereinbefore defined in the mixture in an amount of 1 to 10% by crystallization from water or alcohols containing 1 to 3 carbon atoms, whereupon the correct isomer of formula III in an environment of 15 to 100 moles of hydrogen peroxide and an organic solvent mixed with water is converted to an alkyl ester of formula I. 3. The process according to claim 2, wherein peracetic acid, m-chloroperbenzoic acid or hydrogen peroxide is used as the peroxy compound. 4. A process according to claim 2, wherein sodium or potassium bicarbonate is used to form a basic environment. 5. A process according to claim 2 wherein the water-miscible solvent is tetrahydrofuran, dimethoxyethane or dioxane. 6. Process according to claim 2, characterized in that alkali metal hydroxides, preferably lithium hydroxide, are used as the alkali reacting substances. 7. A method according to claim 2, characterized in that. The method according to claim 1, wherein the excess hydrogen peroxide is removed from the reaction mixture at 0-5 ° C after addition of methyl acetate or ethyl acetate by addition of sodium or potassium sulfite.