DE1169458B - Process for the preparation of 2-chloro-3, 5-dialkoxyphenols - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY DEUTSCHES WJT Im PATENTAMT Internat. Class: C 07 c

EDITORIAL

German: 12 q- 14/04

Number: 1169 458

File number: F 33377 IV b / 12 q

Registration date: .9. March 1961

Opening day: May 6, 1964

For syntheses that lead to the antifungal antibiotic griseofulvin or "griseofulvin-like" Leading compounds is 2-chloro-3,5-dimethoxyphenol an important raw material. For the preparation of this phenol are in the literature several routes indicated (see Journal of the Chemical Society [London], 1952, pp. 3967 to 3977). Special Interest claims for the sake of simplicity among these routes the direct chlorination of 3,5-dimethoxyphenol with sulfuryl chloride (see Journal of the Chemical Society, 1952, p. 3974). Included but not only 2-chloro-3,5-dimethoxyphenol is produced, but also that which cannot be used any further 4-chloro-3,5-dimethoxyphenol. According to the information in the cited literature, for example 57% of theory | obtained on monochlorination product, of which 39% 2-chloro-3,5-dimethoxyphenol and 18% 4-chloro-3,5-dimethoxyphenol. The separation of these two phenols is difficult. Well can separate the 2-chloro-3,5-dimethoxyphenol from the 4-isomers due to its steam volatility, However, this type of separation, as can also be seen from the cited literature, incomplete and disadvantageous because of the necessary distillation of large amounts of liquid. the fractional distillation, which are also used to separate the 2- and 4-chloro compounds can, runs fuzzy and requires a lossy recrystallization of the individual fractions. The mentioned Difficulties arise especially in the production of large amounts of 2-chloro-3,5-dimethoxyphenol on. In addition, 3,5-dimethoxyphenol is in itself an expensive starting material.

It has now been found that 2-chloro-3,5-dialkoxyphenols are obtained in good yields by chlorinating 3,5-dialkoxyphenols if the chlorination is carried out with N-chlorosuccinimide in the presence of an inert organic solvent, preferably carbon tetrachloride a temperature of 35 to 75 ⁰ C carries out.

Such 3,5-dialkoxyphenols are preferably used as starting materials for the process of the invention Consider the low molecular weight alkoxy radicals, especially methoxy, ethoxy or propoxy radicals, as substituents contain.

The isomeric 4-chloro compounds are only present in such small amounts in the process of the invention indicates that a separation is already necessary in the course of the distillation necessary for the purification of the crude product he follows.

It was not to be expected that the chlorination of 3,5-dialkoxyphenols with N-chlorosuccinimide prior process for the production of 2-chloro-3,5-dialkoxyphenols

Applicant:

Farbwerke Hoechst Aktiengesellschaft

formerly Master Lucius & Brüning, Frankfurt / M.

Named as inventor:

Dr. Gerhard Korger, Frankfurt / M.- Höchst,

Johann König, Niederhofheim (Taunus)

preferably in the o-position to the phenolic hydroxyl group would run. The N-chlorosuccinimide takes, as corresponding experiments have shown, as Chlorinating agents of phenols occupy a special position. So could z. B. 3,5-dimethoxyphenol with others N-chloramides, e.g. B. N-chlorophthalimide or N-chlorotoluenesulfonamide, under comparable conditions can only be chlorinated with poor yield.

The chlorination products obtained in this way are not uniform and contain the starting phenol as well as the starting phenol the 2- and 4-chloro isomers in little different proportions.

It is known from Journal of Organic Chemistry, Vol. 23, 1958, pp. 16 and 17 that pyrogallol-1,3-dimethyl ether with N-chlorosuccinimide in o- or p-position to the two methoxy groups, ie in 4 - (or 6-) position of the benzene nucleus, can be chlorinated. However, this formal correspondence of the reactions is only apparent, since in pyrogallol-1,3-dimethyl ether the 4- and 6-positions because of the double activation by the o- and p-methoxy groups compared to the only single activated 5-position is preferred for electrophilic substitutions, while the 3,5-dialkoxyphenols of the invention do not have a preferred site of attack for electrophilic substitutions.
The examples illustrate the process of the invention.

For example

2-chloro-3,5-dimethoxyphenol

100 g of 3,5-dimethoxyphenol are in 600 ecm

Dissolved dry carbon tetrachloride and 94 g of N-chlorosuccinimide into the solution within 1 hour (93% active chlorine) entered with mechanical stirring at a temperature of 35 to 40 ° C. the

409 588/439

Solution first turns yellow and later orange. After completion of entering the reaction mixture is stirred first for 45 minutes at 50 ⁰ C and then 15 minutes at 7O ⁰ C. After cooling, the succinimide formed is suctioned off and washed with carbon tetrachloride. The filtrates are combined, shaken twice with water and dried over sodium sulfate.

The carbon tetrachloride is distilled off and the residue is fractionated under reduced pressure; Kp iobisi3 = 152-157 ⁰ C. The yield is 89 g corresponding to 73% of theory. In contrast to the products obtained with sulfuryl chloride, the distillate crystallizes completely without inoculation. Distilling off the carbon tetrachloride gives 40 g, corresponding to 93% of theory, of an oil which crystallizes completely. This product is purified by distillation at a bath temperature of 155 to 16O ⁰ C and a pressure of 0.05 Torr. 35 g, corresponding to 82% of theory, of 2-chloro-3,5-diethoxyphenol, which is sufficiently pure for further reactions, are obtained. F. = 66 to 71 ⁰ C. After recrystallization from ether and ίο a mixture of petroleum ether (mixing ratio 1: 4) the melting point rises to 72 to 74 ° C.

To ₀ in a manner analogous to give 2-chloro-3,5-di-n-butoxy-phenol in a yield of 66% of theory as an oil, bp., ₀₀₅ = 147-151 ⁰ C. The output

by. The 2-chloro-3,5-dimethoxyphenol obtained is used for the well-known 3,5-di-n-butoxyphenol (cf. i ifi i iiid ii

is still slightly contaminated with succinimide. For further purification, the distillate is dispersed in warm water, cooled with stirring, and the resulting product is filtered off with suction, washed with water and dried. The yield is 85 g, ao about 70% of theory; F. = 57 to 59 ° C. The product obtained is identical in the infrared spectrum, melting point and mixed melting point with the 2-chloro-3,5-dimethoxyphenol prepared according to Journal of the Chemical Society, 1952, p. 3974. z $

Example 2 2-chloro-3,5-diethoxyphenol

36 g of 3,5-diethoxyphenol are dissolved in 270 ecm of dry carbon tetrachloride. 33 g of N-chlorosuccinimide (85% active chlorine) are introduced into the solution at a temperature of 35 to 40 ° C. over the course of 15 minutes while stirring. The reaction mixture is then ^{heated to 65 °} C. for 5 minutes and cooled to room temperature. The precipitated succinimide is filtered off with suction and washed with carbon tetrachloride. The combined filtrates are washed twice with 100 ecm of water from Journal of the Chemical Society, Vol. 78, 1956, p. 5643).

Claims (1)

Claim: Process for the preparation of 2-chloro-3,5-dialkoxyphenols by chlorinating 3,5-dialkoxyphenols, characterized in that the chlorination with N-chlorosuccinimide in the presence of an inert organic solvent, preferably carbon tetrachloride, carried out at temperatures of 35 to 75 ° C. Considered publications: Journal of the American Chemical Society, Vol. 48, 1926, pp. 2719-2721; MONTHS FOR CHEMISTRY, Vol. 49, 1928, pp. 173 to 186; Journal of the Chemical Society (London), 1952, p. 3974; Journal of Organic Chemistry, Vol. 23, 1958, pp. 16-17; W. Teilheimer "Synthetic Methods of Organic Chemistry", Vol. 11, 1957, pp. 263 to 264, No. 609; L. F. Fieser and M. Fieser, »Textbook of shaken and dried with sodium sulfate. According to 4 ° organic chemistry, 1960, pp. 665 to 672. 409 588/439 4.64 © Bundesdruckerei Berlin