HU184766B - Process for preparing 5-chloro-2-oxo-bicyclo/2,2,1/heptane-7-carboxylic acid alkyl esters - Google Patents

Abstract

The invention relates to the synthesis of 5-chloro-2-keto-bicyclo- / 2,2,1-heptane-7-carboxylic acid alkyl esters (formula I). The synthesis of these substances is based on norbornadiene (formula II), which is converted by formic acid and paraformaldehyde into 2-formyloxy-7-formyloxymethyl-tricyclo- / 2,2,1,0-3,5-heptane (formula III) , By oxidation of the acetone solution of III with chromium (VI) oxide in sulfuric acid, the 2-keto-tricyclo- / 2,2,1,0-high 3,5 / -heptane-7-carboxylic acid (formula IV) formed by Influence of hydrogen chloride in the corresponding alcohol in the required alkyl ester (I) is converted.

Description

The present invention relates to a process for the preparation of 5-chloro-2-oxobicyclo [2.2.1] heptane-7-carboxylic acid alkyl esters which are valuable starting materials, in particular for the preparation of prostadienoic acid derivatives. Prostagenoic acid and its derivatives, called prostaglandins, have recently become the focus of interest in both human and veterinary medicine due to their high biological activity. As a result, intensive chemical research has begun in the field of these types of compounds, primarily with a view to their complete synthesis.

Various starting compounds have already been proposed for the synthesis of prostaglandins. One of the known syntheses is based on norbomadiene; an important intermediate in this synthesis is the methyl 5-bromo-2-oxobicyclo [2.2.1] heptane-7-carboxylic acid, which is prepared according to the following reaction scheme: norbomadiént of formula (II) is reacted with paraformaldehyde and formic acid to give the corresponding (ΙΠ) 2-formyloxy-7-formyl-oxymethyl formula tricyclo [2,2, l, 0 ^{3 '5]} heptane is oxidized to sulfuric acid (IV) and was concentrated Hydrogen bromide is cleaved to form 5-bromo-2-keto-bicyclo (2,2,1-l) heptane-7-carboxylic acid (Va). The latter acid is then esterified with diazomethane to give the corresponding methyl ester of formula (Vb) as illustrated in Scheme (A).

The ester (Vb) thus obtained has the configuration necessary for the synthesis of prostaglandins and their derivatives.

However, this process has several disadvantages. In the first step of the synthesis, the conversion of the norbomadiene (Π) to the compound (III) requires the use of a large excess of formic acid and the reaction mixture is diluted with a large amount of water. Thus, large amounts of ether are also required as the extraction agent and the production rate of this reaction is low. Another important disadvantage is that diazomethane is used for the esterification of the acid of formula (Va), which is both explosive and carcinogenic and renders practically impossible the industrial application of the process.

It has also been proposed to modify this pathway from norbomadiene by not mentioning the 5-bromo-2-oxo-bicyldolo (2,2,1-heptane-7-carboxylic acid methyl ester Vb) as an intermediate. but 5-chloro-2-oxobicyclo (2.2.1) heptane-7-carboxylic acid, which is then further processed into prostaglandins, not through the alkyl ester.

The present invention is directed to a novel variant of said pathway of norbomadiene synthesis, which overcomes the said drawbacks of prior art procedures and enables the synthesis of prostaglandins by simple, easy-to-carry operations.

The present invention relates to a process for the preparation of 5-chloro-2-keto-dicyclo (2,2,1-heptane) -7-carboxylic acid alkyl esters of formula (I) according to the attached drawing, wherein R * represents a C 1-6 alkyl group. These compounds are prepared by reacting norbomadiene in a molar ratio of 1:10 to 1:18 with formic acid and additionally with paraformaldehyde in the presence of a strong acid, and after completion of the reaction, 40-80% of formic acid is distilled off to give an oily residue in ice-water. and the organic layer is extracted with an organic solvent, preferably ether, the organic phases are combined, washed with a saturated sodium chloride solution, dried with an inorganic salt and distilled off. The distillate is dissolved in acetone, then oxidized with a mixture of chromium trioxide and a strong inorganic acid, the resulting oxidation product recrystallized and the solid product is treated at elevated temperature with a lower alcohol and gaseous hydrogen chloride, and the alcohol is distilled off to give the alkyl ester is recrystallized from water or a mixture of water and a lower alcohol. In this way, highly pure 5-chloro-2-bicyclo [2.2.1] heptane-7-carboxylic acid alkyl esters can be obtained in almost quantitative yield.

Practical implementation of the process according to the invention does not require costly plant equipment, we use cheap and readily available materials, and the process can be carried out without difficulty on a large scale.

A further advantage of the process according to the invention is that the use of water as a solvent significantly improves safety at work and is also beneficial from a health point of view.

Practical embodiments of the process of the invention are illustrated by the following examples, however, it should be noted that the invention is in no way limited to these particular embodiments.

Example 1

2-Formyloxy-7-formyloxymethyl-tricyclo [2.2.2] (Pf-heptane-III)

To a mixture of 2400 ml of concentrated formic acid, 120 g of paraformaldehyde and 45 ml of sulfuric acid was added 396 g of norbomadiene at 20 ° C under vigorous stirring and moderate cooling, under a nitrogen atmosphere. The reaction mixture was then stirred for an additional 3 hours. After completion of the reaction, 1560 ml (65%) of formic acid was distilled off in vacuo. the distillation residue is diluted with an equal volume of ice water, the organic solvent phase is separated off, and the aqueous phase is extracted three times with 300 ml of ether. The organic solvent layers were combined, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated. Thus 771.5 g of 2-formyloxy-7-formiloximetil-tricyclo [2,2, l, 0 ³ · ^5] heptane (91.5% of theory) having a 1 mm Hg 124-126 ''Con boiling.

Example 2

5-Chloro-2-oxo-bicyclo [2.2.1] heptane-7-carboxylic acid methyl ester, R '= methyl

220 g of 2-oxo-tricyclo [2,2, l ^3-5] heptane-7-carboxylic acid in refluxing anhydrous hydrogen chloride dissolved in the solution using viszszafolyató refrigerant introduced for 6 hours in 5000 ml of absolute methanol. After completion of the reaction, the mixture of hydrogen chloride and methanol was distilled off in vacuo and the distillation residue solidified in crystalline form. This crude product is recrystallized from water; This gives 250 g of analytical grade 5-chloro-2-oxobicyclo [2.2.1] heptane-7-carboxylic acid methyl ester (84% of theory), 75-75.5 ° C. are good.

The starting material for the above process, 2-oxo-tricyclo [2.2.1.0 < ³ > ^S ] heptane-7-carboxylic acid of formula IV, is known in the art, 2-formyloxy-7-formyloxymethyl-tricyclo [2.2.1] , 0 ^{3 5} ] by the oxidation of heptane in acetone solution with chromium trioxide sulfuric acid (Ionic Reagent).

184,766

Example 3

Ethyl 5-chloro-2'-oxo-bidklo (2,2,1 L) heptane-7-carboxylic acid in a solution of 2-oxo-tricyclo [2.2.1.0 < 3 > ^S ] heptane-7-carboxylic acid in 1000 mg absolute ethanol while refluxing, anhydrous hydrogen chloride gas was introduced for 7 hours. The reaction mixture was worked up in a similar manner to that described in Example 1; 69.6 g of ethyl 5-chloro-2-oxobicyclo (2.2.1) heptane-7-carboxylate (89.1% of theory) are obtained, which is recrystallized from a mixture of water and ethanol. m.p. 61-63 ° C.

Example 4

5-Chloro-2-oxo-bicyclo (2,2,1-l) heptane-7-carboxylic acid propyl ester 15

110 g of 2-oxo-tricyclo [2,2, l, 0 ^{3 '5]} heptane-7-carboxylic acid are dissolved in 2350 ml of absolute propyl alcohol and this was passed dry hydrogen chloride gas under gentle reflux using the return solution cooling to 4 hours length. At the end of the reaction, excess propyl alcohol was distilled off in vacuo and the residue was recrystallized from a mixture of water and propyl alcohol. This way

121.5 g of propyl ester of 5-chloro-2-oxobicyclo (2.2.1) heptane-7-carboxylic acid (73% of theory) are obtained, m.p. 74-75 ° C. 25

Claims (4)

A process for the preparation of the novel 5-chloro-2-oxo-bicyclo (2,2,1-heptane-7-carboxylic acid) alkyl esters of formula I wherein R ^{1 is C} 1 -C 5 alkyl, characterized in that: reaction of norbomadiene with formic acid and paraformaldehyde in a molar ratio of 1:10 to 1:18 in the presence of a strong acid, and after 2-3 hours, 40-80% of the formic acid is distilled off from the reaction mixture and the resulting oily residue is poured into water and ice, separating the organic solvent layer, extracting the aqueous phase with an organic solvent, washing the combined organic solvent layers with a saturated sodium chloride solution, drying with an inorganic salt, distilling off the residue in a lower ketone, triturating with sulfuric acid, the resulting oxidation product is anhydrous hydrogen in a C 1 -C 5 alcohol hydrochloric acid at 50-120 ° C for 2-10 hours, the excess alcohol was distilled off and the product recrystallized from water or a mixture of water and a lower alcohol. 2. The process of claim 1, wherein the process is a lower alcohol C 1 -C 5 primary or secondary alcohol is used. 3. A process according to claim 1 or 2 wherein the lower alcohol is methyl alcohol. 4. A process according to claim 1, wherein the strong acid is preferably sulfuric acid.