CS252928B1

CS252928B1 - Method of 7-acetyloxymethyltricyclo (2,2,1,02,6)heptane-2-on's production

Info

Publication number: CS252928B1
Application number: CS862113A
Authority: CS
Inventors: Bohumil Zak; Vladimir Votava; Jan Stanek; Jiri Mostecky; Jaroslav Palecek
Original assignee: Bohumil Zak; Vladimir Votava; Jan Stanek; Jiri Mostecky; Jaroslav Palecek
Priority date: 1986-03-26
Filing date: 1986-03-26
Publication date: 1987-10-15
Also published as: CS211386A1

Abstract

Řešení se týká způsobu výroby „ z 7-acetyloxymethyltric^klo (2,2,1,0^’°) heptan-2-onu, důležitého meziproduktu tzv. norbornadienové syntézy prostaglandinů a jejich analogů. Podstata způsobu výroby spočívá v tom, že oxidace hydroxylové skupiny příslušného alkoholu se provádí chlorem za přítomnosti bezvodého octanu sodného nebo draselného v prostředí ledové kyseliny octové.The present invention relates to a process for the production of 7-acetyloxymethyltriclo (2.2.1.0); heptan-2-one, an important intermediate so-called norbornadien prostaglandin synthesis and their analogues. The nature of the method The production is based on hydroxyl oxidation the appropriate alcohol group chlorine in the presence of anhydrous sodium or potassium acetate in the medium glacial acetic acid.

Description

252 928

The present invention relates to a process for the preparation of 7-acetyloxymethyltricyclo

Said substance is an important intermediate in the so-called norbornadien synthesis of prostaglandins and their analogues (Kontakte / Merck / 1983, 2, 27, 1984 2, 50, Chem. Eng. News 1982, 30, Aug. 16 {Adv. Prost, Thromb. Leuk Res, 14, 73 (1985)). Currently, prostaglandins are used in both human and veterinary medicine as pharmaceuticals with irreplaceable and unique effects.

According to the prior art, a compound of formula I is prepared by oxidizing an alcohol of formula II

(II) 2,252,928

The process protected by SeO AO No. 227 225 is used in the oxidation of the alcohols of formula II with chromium trioxide in dilute sulfuric acid and acetone. On an industrial scale, this has not been proven particularly because of the partial hydrolysis of the ester in the acidic environment, thereby reducing the yields of the desired ketone of formula I. In addition, the chromium oxide used is a relatively expensive and chromium salt is toxic. Thus, it is an economically disadvantageous process which is associated with wastewater treatment problems.

The oxidation of the compound of formula II with chlorine in a chlorinated hydrocarbon environment using a tertiary amine protects the MS. AO No. 233 033. Although this process is simple, it utilizes domestic reagents, but working with tertiary amines such as pyridine and its homologs requires special precautions (toxic substances), while imposing increased demands on Sewage. The aforementioned disadvantages are eliminated by the process for the preparation of 7-acetyl-oxymethyltricyclo- (2,2,1,10 ') -heptan-2-one according to the invention, in that the oxidation of the hydroxyl group of the alcohol of formula II is carried out with chlorine in the presence of anhydrous acetate sodium or potassium in the glacial acetic acid medium. The procedure is that dry chlorine gas is introduced at a temperature of 10 to 40 ° C (preferably 25 to 35 ° C) of a solution of the alcohol of the formula II and of anhydrous sodium or potassium acetate, where the molar ratio of the components is alcohol. II: chlorine acetate 1: 1.0 to 4.0 µ 1.0 to 2.0 preferably 1 to 1.5 to 2.5: 1.02 to 1.4 · When chlorine is introduced in 1 to 10 3 It is not necessary to cool the reaction mixture to 252,928 hours. After completion of the introduction, the reaction mixture is stirred for 5 to 20 hours at room temperature, while the oxidation is monitored by thin layer chromatography. After the oxidation is complete, the excess chlorine is removed with an aqueous solution of sodium sulfite, the aqueous phase is basified at max. 50 ° C with ammonia at 2 to 7, and then the aqueous phase is extracted with a chlorinated hydrocarbon containing 1 to 2 carbon atoms and 2 to 5 carbon atoms. 4 chlorine atoms preferably dichloroethane or chloroform. The combined extracts are processed by techniques well known to those skilled in the art. After evaporation of the solvents, the oily residue crystallizes. The sub-gas chromatography analysis contains over 98% of the formula I product.

The process according to the invention yields the product of formula I in high yields and purity. Said process is carried out easily even in large volumes. In doing so, it uses relatively small amounts of solvents, which are cheap and especially safe for work safety. It is therefore very advantageous in economic terms.

The following examples illustrate the invention. EXAMPLE 1 To a solution of 547 g of alcohol of formula II and 600 g of anhydrous acetic acid in 1700 ml of glacial acetic acid was introduced gaseous 4 252 928 chlorine so that the temperature of the reaction mixture did not exceed 35 DEG C.

After the addition of 220 g of chlorine (about 4 hours), the reaction mixture was stirred at room temperature for about 15 hours. After removing the excess boiling by adding 200 g of sodium sulfite dissolved in 1000 ml of water, the pH of the reaction mixture was adjusted to about pH 3 with ammonia. The temperature during this neutralization did not exceed 50 ° C (water-cooled). The aqueous phase was extracted with chloroform (3 x 300 ml), the combined extracts washed with water (2.times.100 ml), the solvents evaporated under reduced pressure on a rotary evaporator, and the oily residue crystallized on cooling. 510 g of the product of formula I were obtained, which contained 98% by weight of gas chromatographic analysis. product. The spectral characteristics are the same as the standard. Example 2 To a solution of 1,367.5 g of alcohol of formula II and 1,650 g of potassium anhydrate in 4,250 ml of glacial acetic acid, chlorine was introduced as in Example 1, totaling 568 g for 3.5 hours with external cooling of the reaction mixture. . After analogous treatment of the reaction mixture as in Example 1, 1297 g of the product of formula I were obtained.

Claims

EXAMPLE 252 928 2 A

A process for the preparation of 7-acetyloxymethyltricyclo- (2,2,1,10) -heptan-2-one of formula I from an alcohol of formula II

oxidation with chlorine in the presence of basically reactive agents, characterized in that the oxidation of the compound of formula (II) with chlorine gas is carried out in acetic acid in the presence of anhydrous sodium or potassium acetate, wherein the molar ratio of the alcohol components of formula (II) to acetate: chlorine is 1: 1.0 to 4.0: 1 to 2 at a reaction mixture temperature of 10 to 40 ° C, preferably 25 to 35 ° C,

2. A process according to claim 1 wherein the alcoholic ratio of the components of formula (II): acetate: chlorine is from 1.5 to 2.5: 1.02 to 1.4.

3. The process according to claim 1, wherein chloroalkanes having from 1 to 2 carbon atoms and from 2 to 4 chloro atoms, such as dichloromethane, chloroform, and / or alkyl alkanoates containing from 3 to 6 carbon atoms, such as ethyl acetate, are used as the organic solvent.