SE526012C2 - Process for the preparation of 3-isochromanone - Google Patents

Abstract

The invention relates to a method for producing possibly substituted 3-isochromanone of the formula (I), according to which 2-halogen methyl phenyl acetonitriles of the formula (II) are reacted with a halogen acid. In said formulas R<SP>1</SP>, R<SP>2</SP>, R<SP>3</SP> and R<SP>4</SP> are identical or different and represent H, halogen, OH or OR<SP>5</SP>, R<SP>5</SP> representing a C<SB>1</SB>-C<SB>4</SB>-alkyl, or R<SP>1</SP> and R<SP>2</SP> or R<SP>2</SP> and R<SP>3</SP> or R<SP>3</SP> and R<SP>4</SP> together form a C<SB>3</SB>- or C<SB>4</SB>-alkyl rest or a C<SB>3</SB>- or C<SB>4</SB>-alkylene rest and X is chlorine or bromine.

Description

oiqcc 10 20 25 30 safety risks when the process is carried out on an industrial scale. Thus, it must be ensured that the reaction temperature is accurately observed and in addition that the addition of the hydrogen peroxide or peroxyacids is accurately observed to prevent a large excess of these compounds in the reaction system. In many cases, in addition, labile reaction intermediates are formed, such as, for example, diacetyl peroxide.

In addition, S-isochromanone can be prepared from Z-methoxycarbonylmethylbenzoic acid by reaction with a) ethyl chloroformate in ethylamine and b) with sodium borohydride (Chem.

Pharm. Bull. 16 (1968), 492, 496). B-isochromanone is also available by reacting isolcroman-S -ol with chromium dioxide (Tetrahedron Letters 1973, 2359).

Another process for the preparation of II isochromanone comprises two steps: first, o-tolylacetic acid is reacted with N-bromosuccinimide (NBS) to give 2-bromomethylphenylacetic acid, which is accompanied by cyclization of this 2-bromomethylphenylacetic acid in basic medium, which ger 3-isochromanone (Zh. Org. Khim. 9 (1973), 2145). However, the use of the expensive bromination reagent in the first step means that this process cannot be carried out economically on an industrial scale. According to WO 97/48692, however, the process can be improved by reacting o-tolyl acetic acid with sulfuryl chloride and azobisisobutyronitrile (AIBN) as free radical initiator in the first step. In the second step, the Z-chloromethylphenylacetic acid formed is then converted to 3-isochromanone using a base; The first step is carried out in an inert solvent at a temperature of 50-90 ° C. Bases which can be used in the second step are conventional compounds, such as alkali metal or alkaline earth metal hydroxides and alkali metal carbonates. However, the only low overall yields of 49-60% are disadvantageous in this process.

In view of the stated disadvantages of the hitherto known methods for the synthesis of 3-isochromanone, the object of the present invention was to adopt an improved process which enables the preparation of 3-isochromanone in a technically simpler and harmless manner from the point of view of safety with high yields. . This object is achieved by a process for the preparation of optionally substituted 3-isochromanone of formula I, wherein Z-halomethylphenylacetonitriles of formula II are reacted with a hydrohalic acid, R * R 'cN R * o R * O.

R3 Rs R * R * x I 11 where R1, Rz, Ra and R4 are the same or different and are H, halogen, OH or ORS, where Rs is C1- ci-oiicyi, cncf RI and 112 cncf R * and 113 clicf 113 and Rt - nccmmooo form co-cycloalkylene group or C8-Cphalkenyl group, and X is chlorine or bromine.

The hydrohalic acid used in the process of the invention is preferably hydrochloric acid or hydrobromic acid.

R 1, R 2, R a and R 4 are preferably the same or different and are H or halogen, in particular chlorine or bromine. In particular, all four groups R 1 to R 4 are hydrogen, or one of the four groups is chlorine or bromine, while the other three groups are hydrogen.

The reaction of the 2-halomethylphenylacetonitrile of formula II with the hydrohalic acid constitutes an acid hydrolysis and thus takes place at a pH of O-7, preferably 0.5-5, in particular 1.5-4.5. The reaction temperature is 70-150 ° C, preferably 80-120 ° C and at 20 ° C. z ae oc: :: '° ... oo o g o Q Q. I. .And. u. o ll. Û. In IQ acidity 90-110 ° C. The molar ratio of halohydric acid to 2-halomethylphenylacetoninil is (0.1-10): 1, preferably (0.5-5): 1 and especially (3-5): 1. No solvents are needed to carry out the reaction. If a solvent is used, the solvent used is preferably one, which is also used after the reaction for the extraction of 3-isochromanone from the aqueous phase. Organic solvents such as toluene, methylene chloride, chlorobenzene or chlorobenzene are commonly used.

In the acid hydrolysis of the process according to the invention, the 2-halomethylphenylacetic acid is first formed and, in equilibrium, Z-hydroxymethylphenylacetic acid from the 2-halomethylphenylacetonitrile, the two compounds cyclizing to form the 3-isochromanone. It is therefore important that a pH of 0-7 is maintained during the reaction. It has also been found to be particularly clumsy to raise the pH during the reaction within a pre-specified range, namely to a pH of a maximum of 7, preferably a maximum of 5 and in particular a maximum of 4.5, which quantitatively gives the B-isochromanone. This is achieved by partial dilution of the system with water or partial neutralization using an alkali metal base, preferably NaOH or KOH.

In addition, it is convenient to stir the reaction mixture vigorously, which allows the shortest possible reaction time to be achieved, usually of 2-24 hours. In addition, the reaction can be accelerated by the addition of catalytic amounts of an alkali metal iodide, in particular potassium iodide, or hydroiodic acid.

The process according to the invention is characterized in that it enables the production of 3-isochromanone in yields of at least 90%. Due to this high yield, undesirable by-products are formed only in small amounts, and in particular the formation of dibenzyl ether, which is only biodegradable with difficulty, is avoided.

Z-halomethylphenylacetonitriles of formula I can in principle be prepared by photohalogenation of the corresponding Z-methylphenylacetonitriles in organic-water-containing systems at a pH from -1 to +7. This procedure is the subject of a German patent application filed on the same day. Photochlorination of Z-methylphenylacetonitrile is carried out at a | u | I I '' ° '°' '' o o o 00 'u v u o - ~ I',, ° '. , n. u temperature from -10 to + 30 ° C, while the corresponding photobromination is carried out at + 10-60 ° C.

Z-bromomethylphenylacetonitrile can alternatively be prepared by bromination of 2-methylphenylacetonitrile using N-bromosuccinimide (NBS) as brominating reagent and dibenzoyl peroxide (DBP) as initiator of fi ia radicals (J. Heterocycl.

Chem. 16 (1979), 1443).

Example Example 1 120 g of Z-bromomethylphenylacetoriitrile are added to III, 6 g of 37% hydrochloric acid, and the mixture is heated to 100 ° C with stirring and stirred for a further 4 hours. For 12 hours, 696 g of water are added at 100 ° C with stirring, and the mixture is then stirred for a further 8 hours. 60 g of methylene chloride are then added to the hot mixture, and the latter is allowed to cool to room temperature at the same time. The resulting aqueous phase is then extracted twice with 60 g of methylene chloride each time. The resulting methylene chloride extract is then added to 490 g of toluene at 80 ° C, whereby the methylene chloride is distilled off and recovered. The toluene solution is hot filtered and cooled for crystallization. After filtration and drying, 59 g of 3-isochromanone with a content of 99.3% are obtained. 300 g of toluene are distilled off from the mother liquor, and a further 11.7 g of product with a content of 99.1% are obtained. 5.9 g of product with a content of 70% are then left in the mother liquor.

The chemical yield of 3-isochromanone is thus 90%.

Example 2 In the same manner, 39 g of 3-isolromanone with a content of 98.5 ° / °, corresponding to a chemical yield of 90%, are obtained from 50 g of Z-chloromethylphenylacetonitrile.

Claims (1)

1. Process for the preparation of optionally substituted 3-isochromanone of formula I, characterized in that Z-halomethylphenylacetonitriles of formula II are reacted with a halo hydrochloric acid, in R '1 cN R2 o Rz o Ra Ra R * R 4 X 1 - H where R 1, R 2, R a and R 4 are the same or different and are H, halogen, OH or ORS, where R 5 is C 1 -C 4 alkyl, or R 1 and R 2 or R 2 and R 3 or R 3 and R 4 together forms a C 3 -C 4 alkylene group or C 3 -C 4 alkenyl group, and X is chlorine or bromine, the pH being raised to a maximum value of 7 on the reaction. . Process according to Claim 1, characterized in that the hydrohalic acid used is in hydrochloric acid or hydrobromic acid. Process according to Claim 1 or 2, characterized in that all groups R 1, R 2, R 3 and R 4 are hydrogen or one of the four groups is chlorine or bromine, while the other three groups are hydrogen. 00000 I 10 20. Process according to one of Claims 1 to 3, characterized in that the pH value is 0 to 7, preferably 0.5 to 5, in particular 1.5 to 4.5. . Process according to one of Claims 1 to 4, characterized in that the reaction temperature is 70-150 ° C, preferably 80-120 ° C and in particular 90-110 ° C. . Process according to one of Claims 1 to 5, characterized in that the molar ratio of halohydric acid to Z-halomethylphenylaetonitrile is (0.1-10): 1, preferably (0.5-5): 1 and in particular (3-5): 1 . i. Process according to one of Claims 1 to 6, characterized in that an organic solvent, preferably toluene, methylene chloride, chlorobenzene or fluorobenzene, is added to the reaction mixture or the reaction to separate the S-isochromanone. . Process according to Claim 4, characterized in that the pH value during the reaction is raised to a value of at most 7, preferably at most 5 and in particular at most 4.5, by adding water or an alkali metal base, preferably sodium hydroxide solution. . Process according to one of Claims 1 to 8, characterized in that an alkali metal iodide, preferably potassium iodide, or hydroiodic acid is added as catalyst during the reaction.