CS236117B1 - Method of 3-acyloxy-7-acyloxymethyltricyclo(2,2,-1,0 2,6)-heptanes making - Google Patents

Abstract

Method of Production 3-Acyloxy-7-acylQxymethyltricyclo / 2,2,1,02,6 / heptanes of formula I wherein R is hydrogen or methyl of norbornadiene, formaldehyde, alkane groups RCOOH, wherein R is as defined above, it is according to the invention that it is the catalyst uses organic sulfonic acid acid or Lewis acid or strong acid ion exchangers in the H '+' molar cycle the ratio of reactants norbornadiems formaldehyde with alkanoic acid t catalyst 1 with 1.05 to 1.1: 12 to 15: 0.001 up to 0.05, then, after the reaction is complete, the catalyst it neutralizes the poetic responding with an agent, the alkanoic acid evaporates, distillates the residue is dissolved in the organic the solvent from which it is removed the solvent residue is evaporated to obtain the product of formula I. The compounds of formula I are the starting compounds intermediates in prostanoid synthesis on the Norbornadien Road.

Description

The present invention relates to 3-acylox.v-7-acyloxymethyltricyklo / 2,2, l, 0 ² »6 / heptane of Formula I / wherein R is hydrogen or methyl compounds of formula I are intermediates in the synthesis of the input at prostanoids and called the Norbornadien Road (see JS Bindra, R. Bindra in Prostaglandin Synthesis, Academic Press, New York 1977, SM Roberts, R.Fo Newton in Prestaglandins and Thromboxanes, Butterworths, London 1982). Prostanoids - derivatives of prostanoic acid - exhibit a broad spectrum of biological activity. At present, many derivatives have been successfully used in both human and veterinary medicine. Other derivatives with specific effects, without undesirable side effects, are in the preclinical and clinical research stage (see, for example, R.Ao Johnson et al., Chem. Eng.News 1982, Augo 16, p. 30, S.Mo Roberts and F. Scheinmann in New Synthetic Routes to Prostaglandins and Thromboxanes, Academic Press,

London 1982 /.

In the processes used hitherto, the compounds of formula 1 wherein R is hydrogen were prepared by reacting norbornadiene with formaldehyde generated by paraformaldehyde, formic acid and sulfuric acid catalysts. The molar ratio of the reactants was 1: 0.93: 14.75: 0.2 (see above). The procedure is such that a solution of paraformaldehyde in a mixture K0.nc _of formic acid and sulfuric acid was added at 20 ° -25 ° 0 was added gradually norbornadiene. After completion of the reaction, the reaction mixture was poured at about equal volume of ice and water and extracted three times with half volume of ether. After removal of acidic organic reactants share / wash several times with water and sodium chloride / sodium was necessary target product distilled at reduced pressure ₀ In this embodiment, the above process from the technological hle236 117

- 2 discs a number of drawbacks: a) isolation of the product by high volume extraction using flammable solvents, b / a relatively large amount of sulfuric acid is used in the reaction to reduce pax yields of the desired product, c / removal of acid residues from the organic solution it is laborious, d / before further operations, the product must be purified by distillation under reduced pressure and if the acid residues have not been sufficiently removed, the product is destroyed.

These known processes are followed by a method according to the invention in a positive sense which removes the above disadvantages.

The process according to the invention is characterized in that the catalyst used is a C1 -C4 alkanesulphonic acid or arenesulphonic acid or a Lewis acid or a strongly acidic ion exchanger in the H @ 4 cycle, wherein the ratio of the reactants norbornadiene: paraformaldehyde: alkanoic acid catalyst is 1: 1. 05 to 1.1: 12 to 15.0: 0.001 to 0.05, preferably 0.005 to 0.01.

In this process, the mixture of paraformaldehyde, alkanoic acid and catalyst is heated to 30 to 60 ° C and, after obtaining a clear solution, cooled to 15 to 25 ° C and added with norbornadien gradually with stirring. arylsulfonic acid or boron trifluoride etherate / neutralizes with a base, preferably sodium or potassium bicarbonate or carbonate, excess alkanoic acid is distilled off under reduced pressure, the distillation residue is dissolved in an organic solvent preferably 1,2-dichloroethane, chloroform, dichloromethane, tetrachloromethane, The solution was washed with brine, dried and distilled off to obtain the target product of formula I in high purity and yield above 95%. The catalyst used is preferably benzenesulfonic acid, p-toluenesulfonic acid, p-bromo benzenesulfonic acid, naphthalenesulfonic acid, or an ion exchanger containing an SO5H group.

- 3 236 117

From the above description the advantages according to the method of the invention are evident: a / reduction of the catalyst amount and substantial reduction of the reaction mixture volume leads to reduced labor and energy savings b / removal of flammable solvents substantially reduces equipment hygiene and safety requirements c / regenerated alkanoic acid d) simplified product isolation and high yields make this process advantageous from an economic point of view.

The invention and its effects are illustrated in more detail in the following examples, which are illustrative only and in no way limit the scope of the invention.

Example 1

Mixture 45 ml conc. formic acid, 2.65 g (0.0883 mol) paraformaldehyde, 0.1 g (5.8.8 mol) p-toluenesulfonic acid was heated to 40-45 ° C and after dissolution of the solid phase cooled to 20-25 ° G. While stirring, 7.5 g (0.0815 mol) of norbornadiene were added dropwise. After stirring for 2 hours, 0.4 g of solid sodium bicarbonate was added to the reaction mixture. Formic acid was evaporated on a rotary-vacuum evaporator / bath temperature of 50 ° C, pressure. 2 kPa / near dryness. The distillation residue was dissolved in 70 ml of chloroform, the solution was shaken with 2 x 20 ml of saturated sodium chloride solution, dried over MgSO4 and, after evaporation of the solvents, 12.4 g of product (95%) were obtained, whose IR spectrum shows characteristic bands of 1,738 cm. ¹ and 1195 cm ^-1 corresponding to the presence of formic acid ester. Characteristic ionic species with m / z values were present in the mass spectrum:

/ HCOO / ⁴ ·, 59 / CH ² COOH / ⁴ ·, 55, 69, 41, 39 hydrocarbon ions, molecular ion intensity m / z 196 depends on source temperature, at higher temperature is replaced by ion m / z 152 / 11-002 / ^4- .

Example 2

A mixture of 40 ml of formic acid, 2.65 g (88.3 mmol) of paraformaldehyde and 0.1 ml (0.8 mmol) of N, N-etherate was heated to 50 ° C and after dissolution of the solid phase the reaction mixture was cooled to 20-25 [deg.] C. and 7.5 g are added gradually with stirring

- 4 23B 117 / 81.5 millimole / norbornadiene. After stirring for 2 hours, the reaction mixture was worked up as in Example 1. It was obtained

12.2 g (94%) of a product whose Rp value is 0.85 (silica gel Merck thin layer - eluent of 5% methanol in benzene) is identical to the standard material.

Example 3

To a solution of 90 ml of glacial acetic acid, 2 ml of acetic anhydride, 5.3 g of paraformaldehyde and 0.15 g of benzenesulfonic acid was added portionwise a total of 15.0 g of norbornadiene in 15 minutes with stirring at 25-30 ° C. After stirring for 2 hours, the reaction mixture was worked up as in Example 1. 28.5 g (78.1%) of the product of formula I was obtained, wherein Rp = 0.87 on a thin layer of Merck silica gel, eluting with 5% methanol in benzene. In infrared spectrum, characteristic bands corresponding to the presence of acetate at 1735 cm ^"1 · · and 1240 cm ^'1. Characteristic ionic species with m / z values were present in the mass spectrum:

224 (M / ⁺⁾ , 43 (CH5GO) ⁺ , 59 (CH5COO) ⁺ and 73.

Example 4

A mixture of 40 ml of formic acid, 2.65 g of paraformaldehyde and 0.2 g of zinc chloride was cooled to room temperature after heating to 40-45 ° C and dissolving the solids. After adding

7.5 g of norbornadiene treated as in Example 1. It was obtained

10.9 g (84%) of the product of formula (I) wherein R = H, whose spectral characteristics are identical to the standard compound.

Example 5

A mixture of 45 ml of formic acid, 2.65 g of paraformaldehyde, 0.5 g of ion exchange resin (Dowex 50 X-8) in an H 2 C cycle and 7.5 g of norbornadiene gave 12.4 g (96%) after analogous treatment to Example 1. the product of formula (I) wherein R = H having the same physical-chemical parameters as the standard substance,

Claims (9)

SUBJECT OF THE INVENTION 236 117 A process for the preparation of 3-acyloxy-7-acyloxymethyltricyclo [2.2.1.0 '] heptanes of the general formula I, wherein R is hydrogen or methyl from norbornadiene, formaldehyde, alkanoic acid RGOOH, wherein phi is as defined above, characterized by: by using organic sulfonic acid or Lewis acid or a strong ion exchanger in the H / ⁺ / cycle in the molar ratio of the reactants norbornadiene: formaldehyde: alkanoic acid: catalysator 1 as catalyst; 1.05 to 1.1; 12 to 15: 0.001 to 0.05, after which the catalyst is neutralized with a base reagent, alkanoic acid is evaporated, the desxilation residue is dissolved in an organic solvent from which the solvents are evaporated after removal of the catalyst residue to give the product of formula 1. 2. The process of claim 1 wherein the alkanesulfonic acid is methanesulfonic acid. . Process according to claim 1, characterized in that benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid is preferably used in the molar ratio of 0.005 to 0.01 per mole of norbornadiene as arensulfonic acid. 4. The process of claim 1 wherein the Lewis acid is boron trifluoride etherate, zinc chloride or ferric chloride. 5. The method of claim 1 wherein the strong acidic ion exchanger is Dowex 50 X-8. 6. The process of Claim 1 wherein the base reacting agent is sodium or potassium carbonate or bicarbonate. 7. The process of claim 1 wherein the organic solvent is 1,2-dichloroethane, dichloromethane, chloroform, carbon tetrachloride. 236 117 - 6 8. A process according to claim 1, wherein the catalyst residues are removed from the organic phase with an aqueous solution of sodium bicarbonate, common salt or water. 9. The process of claim 1 wherein the regenerated acid to alkane is used in the repeated preparation of the product.