CS227225B1 - Method of preparing 7-acyloxymethyl-5-halogen-bicyclo(2,2,1)heptan-2-one - Google Patents

Description

R is C1-C3 alkyl X is chlorine, bromine or iodine.

The compounds of formula I are prominent intermediates in the synthesis of prostadienoic acid derivatives, the so-called prostaglandins including prostacyclins and analogues thereof. Prostaglandins are substances with broad biological activity, acting as modulators of cell functions and tissue hormones. They also influence the regulation of the endocrine, nervous, reproductive, digestive, respiratory, cardiovascular and renal systems. A set of these compounds is now used in both human and veterinary medicine as an active drug with a specific and broad spectrum of activity.

To date, a number of processes for the preparation of prostaglandins, their analogs and derivatives have been described. Synthesis in which the riorboi * nadien is used as the starting material, the so-called norbornadiene pathway, occupies an important place. Most of these processes are patent protected:

U.S. Pat. U.S. Pat. No. 3,943,151j; U.S. Pat. 3,992,438; Ger. Offen 2,704,029; GDR pat. 122 817; Ger.

Offen 2,327,813; U.S. Pat. U.S. Pat. 4,008,325; Cs. U.S. Pat. 211,526 and 211,527; A0 215 681 et seq

227 225 books: J.S.Bindra, R.Bindra: Prostaglandin Synthesis (1977); Mitra: Prostaglandins (1977); Roberts S.M., F. Scheinmann: Chemistry, Biochemistry, and Pharmacological Activity of Prostanoids (1978).

The compound of formula (I) is prepared according to the prior art by acylation of 7-hydroxymethyl-5-halobicyclo (2,2,1) heptan-2-one of formula (A).

CHOO '

HIM

ALKO

HIM

X

OH OH O O

F G H A where

Alk denotes an alkyl group having 1 to 6 carbon atoms and

Z is a protecting group such as benzyl, triarylmethyl, acyl and the like.

As shown in the above scheme, these are multistage syntheses. In the first case, the ketoacid of formula D is prepared by oxidation of C or a diol of formula P and in subsequent steps after protection of the keto group, the carboxyl is reduced to the primary hydroxyl group (see D- * E * A). specific reaction conditions protect the primary hydroxyl group in the diol of formula F in the form of an ether or ester to form a compound of formula G, in which the secondary hydroxyl group is oxidized to a ketone to form a compound of formula H. S provides the desired product of formula A. Although the processes for the preparation of compound A according to the first process are well elaborated, they are relatively inefficient in both technology and economics. The methods of the second method require the use of special, relatively expensive reagents, work under controlled conditions, or are not sufficiently optimized so that it has not yet been possible to utilize them technologically.

These known processes are followed in a positive manner by the process according to the invention, which overcomes the disadvantages of the processes known so far.

The essence of the process according to the invention consists in the readily available bisformiate of the formula II

HCOO

OOCH converts by transesterification with an alcohol of general formula r'oH where r 'denotes alkyl having 1 to 4 carbon atoms under the catalytic action of a strongly basic ion exchanger in the OH' to the diol of formula XII

The reaction is carried out by adding an ion exchanger in a weight ratio of 100: 2 to 10 to a solution of the bisformiate of formula II in anhydrous alcohol and stirring the reaction mixture at 10 to 40 ° C for 1 to 6 hours. After filtering off the catalyst and evaporating the alcohol, a highly pure diol of formula III is obtained, which is converted into the monoacyl derivative of formula IV by selective acylation in the next step,

RCOO (lil)

OH

RCOO

OH where

R is as defined above.

This acylation is carried out with acetylating agents of formula RCOY, wherein R is as defined above and Y is a chlorine, bromine or RCOO group in an organic solvent in the presence of a tertiary amine at a reaction temperature of 0 to 30 ° C. The molar ratio of diol: acylating agent: tertiary amine is 1: 1.0 to 1.1: 1: 1.22. Its organic solvent is preferably chlorinated alkanes, for example chloroform, dichloroethane and triethylamine or pyridine as the tertiary amine, and pyridine can be used as both a base and a solvent. After washing with sodium bicarbonate and subsequent evaporation of the solvents, a very pure product is obtained which can be used as such or purified before further processing by crystallization or distillation. In the next reaction step, the monoacyl derivative of the formula IV is oxidized with chromium trioxide in dilute sulfuric acid and an aliphatic ketone containing 3 to 6 carbon atoms, preferably acetone or methyl tertiary butyl ketone, to the ketoester of the formula V,

RCOO ^ X * ^(A)

About where

R is as defined above.

This oxidation is carried out at a temperature of -20 to +10 ° C with a small excess of oxidizing agent. Practically identical results are obtained with oxidation of a compound of formula IV with an alkali hypochlorite or hypobromite in a C1 -C4 alkanoic acid medium at 0 to +5 ° C or a chlorine-thioanisole complex in a haloalkane medium at a reaction temperature of -30 to 0 ° C and quench the reaction with tertiary amine.

The ketoester of formula (V) is isolated from the reaction mixture by extraction with an organic solvent and obtained pure enough for the next reaction step. In the next step, the ketoester of formula (V) is converted to the haloketoester of formula (I) by treatment with a hydrohalic acid in an inert organic solvent and a C 1 -C 4 alkanoic acid, the acid itself may serve as a solvent.

RCOO o

where

R is as defined above.

The reaction is carried out by introducing hydrogen halide gas into the reaction mixture at 40 to 150 ° C for 0.5 to 4 hours. The course of the reaction can be controlled by thin layer chromatography. After completion of the reaction, the product, after evaporating the alkanoic acid and the organic solvent from the distillation residue, is extracted again into an organic solvent, preferably a halogenated hydrocarbon such as diohalomethane, dichloroethane, chloroform. The solution obtained is freed of residual acid with sodium bicarbonate, the solvents are distilled off to give a high purity product which can be processed further without purification or recrystallized from a suitable solvent.

Said process for the production of intermediates according to the invention brings a number of advantages: ease of carrying out all reaction steps, simple isolation and high purity and product yields at the various stages of the synthesis, use of readily available, cheap and safety-friendly solvents and reagents it is possible to work with relatively large handles.

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 and scope of the invention.

Example 1

7-Hydroxymethyltrioylclo (2,2,1,0 ² '®) heptan-3-ol (III)

To a solution of 30 g of bisformate II in 250 ml of anhydrous methanol was added with stirring 2 g of an OH-C ^- ion exchange resin (Dowex 2, 100-200 mesh) at a reaction temperature of 20-25 ° C. After stirring at this temperature for 1 hour, the ion exchanger was filtered off (can be used in the next experiment) and the solvents were distilled off under reduced pressure. 20.8 g (97%) of the diol of formula III was obtained, which was 96% by gas chromatography. The product was compared to a standard preparation and characterized by mass spectrum: m / z (% rel. Ing): 140 (3.3) corresponds to molecular ion, 122 (23.2) corresponds to Mt-HgO, 104 (13.3) lithium-2 HgO, 109 (46) lithium-CHgOH, 79 (100).

Example 2

7-Acetyloxymetyltricyklo (2,2,1,0 ^2, 6) heptane-3-ol (Formula IV; R = CH)

20.8 g of the diol of formula III was dissolved in 200 ml of di-chloroethane, and at 0-5 ° C 17.0 g of anhydrous triethylamine and 16.5 g of acetic anhydride were added. After 24 hours, the reaction mixture was washed with 100 ml of brine, the organic phase was dried over magnesium sulfate, and after evaporation of the solvents, 22.5 g (83%) of the product was analyzed which contained 93% of the formula IV where R = CH3. . The mass spectrum is in accordance with the proposed structure m / z (% rel. Ing): 122 (62) lithium - CH 2 COOH, 104 (23) lithium - CH 3 COOH, H ₂ O, 93 (69), 78 (100) , 43 (76) CH ₃ CO ⁽⁺⁾ .

Example 3

7-Acetoxymethyltricyclo (2,2,1,0,2,6) heptan-3-one (Formula V; Η = CH 2, X = Cl)

18.9 g of the monoacetate of the general formula IV, where B = CH-j was dissolved in 200 ml of acetone and the reaction mixture was cooled to -5 ° C with vigorous stirring. Then 32.2 ml of Jones reagent (prepared from 60 grams of chromium trioxide dissolved in 60 ml of conc. Sulfuric acid and 200 ml of water) were added at -5 to 10 ° C over 30 minutes and finally stirred for 0.5 to 30 minutes. 1 hour. After addition of 3 ml of isopropyl alcohol (removal of excess oxidant), the solution was poured into 250 ml of ethyl acetate, washed with 200 ml of common salt solution, in which the equivalent of triethylamine was dissolved. 14.2 g (76%) of the ketoacetate of formula V, where R = CH3, which is 95% by gas chromatography analysis, was isolated from the organic layer after drying over magnesium sulfate and distilling off the solvents. In the mass spectrum, ionic species m / z (% rel. Int.): 180 (5), 120 (58), 92 (65), 43 (100) confirming the proposed structure.

Example 4

7-Acetoxymethyl-5-chlorobicyclo (2,2,1) heptan-2-one (Formula I; R = CH-j, X = Cl) g of the ketoacetate of formula V wherein R = CH 2 was dissolved in 100 ml of ice acetic acid, and then anhydrous hydrogen chloride was introduced into the reaction mixture at a bath temperature of 90-110 ° C. After completion of the reaction (monitored by thin layer chromatography), the solvents were evaporated in vacuo, the residue distilled in 50 ml of dichloroethane, washed with sodium bicarbonate solution, dried over magnesium sulfate and the solvents were again distilled off. The distillation residue 11.5 g (95%) solidified crystalline upon cooling and after recrystallization it had mp 69.5-71.5 ° C. The mass spectrum is in accordance with the proposed structure and contains characteristic ionic species m / z {% rel. Int.): 216 (0.5), 188 (9), 174 (22), 60 (27), 43 (100).

Example 5

7-Propionyloxymethyltricyclo (2,2.1,0,4,6) heptan-3-ol (Formula IV; R = θ2 ^Η 5)

1.5 g of the diol of formula III was dissolved in 15 ml of dichloroethane, and after cooling the mixture to 0 ° C, 1.1 g of triethylamine and 1 g of propionic acid chloride were added. The reaction mixture was then allowed to stir at this temperature for 24 hours with occasional stirring, washed with brine (10 ml), the organic phase was dried over magnesium sulfate, and the solvents were evaporated in vacuo to give 1.97 g (94%). is in line with the proposed structure; characteristic ionic species m / z (% rel. int.): 139 (7), 122 (17), 78 (100), 57 (40).

Example 6

7-Acetoxymethyl-5-bromobicyclo (2,2,1) heptan-2-one (Formula I; R = CH 2, X = Br)

To a solution of 1 g of the ketoester of formula V, where R = CH 3 in 1.0 ml of acetic acid, hydrogen bromide gas was introduced for 1 hour while the reaction mixture was boiling (reaction progress was monitored by thin layer chromatography). Then the solvents were evaporated on a vacuum rotary evaporator and the residue 1.2 solidified crystalline upon cooling. The mass spectrum has the following characteristic ionic species m / z (% rel. Int.): 260 (0.3), 232 (5), 217 (20), 180 (15), 43 (100), which confirm the structure of the product .

Example 7

7-Acetoxymethyltricyclo (2,2,1,0 ') heptan-3-one (Formula V; R - CH3)

0.41 g of an aqueous solution of 0.9 M sodium hypochlorite was added to a solution of 1 g of the monoacetate of the formula IV in which R = GH3 dissolved in 15 or acetic acid was added at 0-5 ° C. After stirring at this temperature for 18 hours, the solvents were distilled off and the residue was extracted with dichloromethane, the combined organic phases were washed with aqueous sodium bicarbonate solution, dried over magnesium sulfate and evaporated to give 0.72 g of the ketoester of formula V, where R = CH 2, whose mass spectrum is in accordance with the proposed structure; characteristic ionic species m / z (% rel. int.): 180 (5), 120 (57), 92 (66), 43 (100).

Claims (8)

t PREVENTION OF THE INVENTION A process for the preparation of 7-acyloxymethyl-5-halobenzoylclo (2,2,1) heptan-2-one of formula I, RCOO ^ S χ. A (I) where R is C1-C3 alkyl and X is chlorine, bromine or iodine starting from the readily available bisformate of formula II, HCOO OOCH, characterized in that the compound of formula II is converted by transesterification with an alcohol of the formula R @ ¹ OH, wherein r @ 1 is C1 -C4 alkyl, by catalytic treatment of a strongly basic ion exchange resin in the OH @ ^- cycle at 10 to 40 DEG C. diol III, HO (III) OH which, by treatment with an acylating agent of the formula RCOY, wherein R is as defined above and Y represents a chlorine, bromine or iodine atom or an RCOO group, in the presence of a tertiary amine in an inert organic solvent at 0 to 30 ° C : 1 to 1.1: 1 to 1.2 gives the monoacyl derivative of formula IV wherein R is as defined above, RCOO OH from which the ketoester of formula V is oxidized at -30 to +10 ° C, RCOO (IV) (V) where R is as defined above which, by treatment with a hydrohalic acid in an organic solvent medium and a C 1 -C 4 alkanoic acid at a temperature of 40 to 150 ° C, provides the product of formula (I). 2. A process according to claim 1, wherein the strongly basic ion exchangers are polymeric supports containing trialkylammonium methyl groups. 3. The process of claim 1 wherein the tertiary amine is triethylamine, diisopropylethylamine or pyridine. 4. A process according to claim 1, wherein the chlorinated alkanes are chloroform, dichloromethane, dichloroethane. 5. The process of claim 1 wherein the oxidation is carried out with chromium trioxide in a sulfuric acid medium and an aliphatic ketone such as acetone, methyl tertiary butyl ketone. 6. The process of claim 1, wherein the oxidation is carried out with an alkali hypochlorite or a hypobromite in a C1 -C4 alkanoic acid medium. 7. The process of claim 1 wherein the oxidation is carried out with a chloro-thioanisole complex in a haloalkane medium and the reaction mixtures are treated with a tertiary amine, e.g. triethylamine. 8. The process of claim 1 wherein the hydrogen halide is hydrogen chloride, hydrogen bromide or hydrogen iodide.