CS231729B1 - Process for the preparation of ethyl 5-bromopentanoate - Google Patents

Abstract

Method for producing ethyl 5-bromopentanoate of formula I Br (CH2)4COOC2H5 (I) by reacting the potassium salt of ethylhexanedioate with bromine in an inert environment at elevated temperature

Description

BACKGROUND OF THE INVENTION The present invention relates to a process for the preparation of ethyl 5-thioanthanoate of formula

EtrCH ₂ (CH ₂ ) ₃ CO ₂ C ₂ H ₅ (I) an important intermediate in the synthesis of clinically used cytostatics. The known process, which is obtained from cyclopentanone, tetrehydrofuran, optionally from 1,4-butanediol or 1,4-butindiol, requires in the final stages the use of concentrated hydrobromic acid, which is highly corrosive to the production equipment. This drawback is overcome by the use of bromine in the preparation of ethyl 5-bromopentenoate from the ethylhexanedioate salt under Hunsdiecker reaction conditions.

According to Hunsdiecker (Hunsdiecker,, Hunsdiecker Cl., Chem. Ber. 75, 291 (1942)), it is generally possible to prepare bromine with a carboxylic acid salt, respectively. with the monoalkyl dicarboxylic acid salt of the corresponding alkyl bromide, respectively. The ω-bromoester of the acids which are o, the carbon atom is more intensive. Silver salts (Hunsdiecker, loc. Cit.) Are preferably used.

Various variants of the Hunsdiecker reaction have been developed using mercury salts (Cristol C., Firth W. C. Jr., J. Org. Chem. 26. 280 (1961); Davis J. A. et al., J. Org. Chem. 30

415 (1965); Baker F. W. et al., J. Org. Chem. 28, 514 (1963)), or thallium (McKillop A. et al., J. Org. Chem. J., 1, 72 (1969)).

It is known to prepare ethyl 5-pilentanoethane using a silver salt of ethyl hexanedioethate in a yield of 60% (Jílek J.O., Michajlyszyn V., Chem. Sheets 48, 12 (1954)). The use on a larger scale of the silver salt of ethyl hexanedioate is out of the question because of the high cost of the silver nitrate required for the preparation of said salt, the toxicity of mercury and thallium salts is impeded.

According to Hunsdiecker (loco cit.), Potassium salts can generally be used, but the yields are said not to exceed 40-50%. Hunsdiecker's potassium salts of carboxylic acids react slowly with bromine to form various by-products. The course of the Hunsdiecker reaction with various salts of ethylhexanedioate was followed by Asahara T. and Yanese F. (J. Soc. Org. Synth. Chem. Japan J, 223 (1953) Chem. Abstr. 48, 9, 328h (1954)). The best yields of ethyl 5-bromopentanoethane were achieved using silver, mercury and lead salts, and only low yields using potassium and copper salts.

Mostly, the Hundsdiecker reaction is carried out by dropping bromine into a suspension of the silver acid salt in an inert solvent, most commonly in carbon tetrachloride, with cooling or at room temperature. The reaction is then completed by boiling (see, e.g., Jilek, Michajlyszyn). The inventors investigated the reactivity of kelium ethylhexanedioate with bromine and found that this salt, suspended in carbon tetrachloride, only reacts with bromine while boiling the reaction mixture and therefore dropped thunder directly into the boiling reaction mixture. Although the time required for the reaction of large kBlium ethylhexanedioate (4 hours boiling) is considerably longer than the corresponding silver salt (1 hour at room temperature and 30 minutes boiling), the satisfactory ethyl 5-bromopentanoethate was obtained in 65% yield 99.9% % by gas chromatography (GLC) J, i.e. in yield corresponding to the preparation from silver salt (Jílek, Michajlyszyn, loc. cit.). Thus, in the process according to the invention, the use of potassium ethylhexanedioate does not involve side reactions to an extent greater than that of the silver salt.

A good course of the reaction is conditioned by the use of dry potassium ethylhexanedioate. Further details of the process for the preparation of dry potassium ethylhexanedioate and ethyl 5-bromopentenoate from the same salt by Hunsdiecker reaction will appear from the following examples.

23,729

Example,

Potassium ethylhexanedioate

A mixture of 34.8 g of ethyl hydrogen hexene dioate (0.2 mol) and a solution of 2 g of potassium hydroxide (0.2 mol) in 160 ml of ethanol is evaporated under reduced pressure to about half the original volume. 100 ml of anhydrous benzene (or toluene) is then added to the solution. After evaporation of the solvent in a water pump vacuum, the potassium ethylhexanedioate residue is dried at 110 psig for 6 hours. 39.5 g of salt is obtained, i.e. 93.2% of theory. The salt is a colorless, hygro scoping powder. Store in a closed container in a desiccator over potassium hydroxide.

Example 2

Ethyl 5-bromopentanoate

To a suspension of 42.4 g (0.2 mol) of dried potassium ethylhexanedioate in boiling dry carbon tetrachloride was added dropwise dry bromine (33.5 g; 0.21 mol) by adding each additional portion of bromine in each case. discolouration of the previous dose. Addition of bromine is complete when the last dose remains unstained for 15 minutes. The reaction mixture is then heated to boiling with stirring for an additional 15 min. The whole operation is completed in about 4 hours. After cooling the reaction mixture, the precipitated potassium bromide is filtered off with suction and washed with 100 ml of carbon tetrachloride. Shake the filtrate with the wash solution twice with 100 ml of a 0% sodium carbonate solution and 100 ml of water. After drying over anhydrous sodium sulfate, the organic phases are evaporated under reduced pressure (temperature of the lesion 50-55 ° C; 26 kPa). The residue (35.2 g) gave, after distillation under reduced pressure, 27.5 g (yield 65.5%) of ethyl 5-bromo-pentanoate having a content of 99.9% (by GLC); mp 1.1-1113 ° C at 2.6 kPa, n? ° = 1.4580.

Claims (1)

SUBJECT OF THE INVENTION A process for the preparation of ethyl 5-bromopentanoate of formula I BrCH ₂ (CH _{2) 3} CO ₂ C ₂ H ₅ (I), by reacting the potassium salt ethylhexendioátu II ko _{2-UP 2) 4 CO2 C2 H5} (II) with bromine in an organic solvent type of a halogenated alkane with 1 to 2 carbon atoms, preferably in carbon tetrachloride, characterized in that the reaction is carried out at the boiling point of the reaction mixture with an equimolar amount of bromine, added successively after the previous batch has been reacted.