GB2361475A

GB2361475A - Method for producing 3-isochromanone

Info

Publication number: GB2361475A
Application number: GB0115218A
Authority: GB
Inventors: Dr Josef Kaesbauer; Alexander Dr Klausener; Wolfram Eichinger
Original assignee: Bayer AG
Current assignee: Bayer AG
Priority date: 1998-12-18
Filing date: 1999-12-07
Publication date: 2001-10-24
Anticipated expiration: 2019-12-07
Also published as: WO2000037454A1; DE19858738C2; GB0115218D0; DE19858738A1; AU3035800A; SE0101989L; DE19982749D2; SE0101989D0; SE526012C2; GB2361475B

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

Process for the PreDaration of 3-isochromanone The present invention

relates to a process for the preparation of optionally substituted 3-isochromanone starting from 2-halomethylmethylphenylacetonitrile.

3-Isochromanone is an important intermediate in the preparation of specific crop protection agents, in particular of fungicides of the strobilurin type disclosed in EP-A-0 278 595. Various processes for the preparation of 3-isochromanone are known from the literature.

On a laboratory scale, 3-isochromanone can be prepared, for example, by a Baeyer Villiger oxidation of 2-indanone. Synthesis 1973, 107, discloses that 2-indanone can be oxidized in the presence of hydrogen peroxide, sulfuric acid and acetic anhydride.

It is disadvantageous here that the 3-isochromanone is obtained in a yield of only 68%.

Synthesis 1981, 818, Synthesis 1987, 497, and J. Heterocyclic Chem. 32, (1995) 73, furthermore describe the performance of the oxidation of 2-indanone in the presence of 3-chloroperbenzoic acid. Yields of 86 and 90% respectively are obtained here, but an incomparably long reaction time of from 20 to 24 hours or even 10 days respectively is necessary for this. Synth. Commun. 1989, 829, discloses the use of a mixture of 3-chloroperbenzoic acid and trifluoroacetic acid for the oxidation.

Although this shortens the reaction time, the yield is, however, only 71%.

J. Chem. Soc. 1949, 1720, discloses the performance of the oxidation of 2-indanone using a mixture of potassium peroxomonosulfuric acid and sulfuric acid. Synthesis 1991, 739, furthermore describes the use of peroxotrifluoroacetic acid or sodium percarbonate and trifluoroacetic acid. Even at long reaction times of 15 hours, however, yields of only 78% are obtained.

A common feature of all the abovementioned variants of the Baeyer-Villiger reaction is that the use of hydrogen peroxide or peroxy compounds results in safety risks when the process is carried out on an industrial scale. Thus, it must be ensured that the reaction temperature is observed precisely and furthermore that the addition of the hydrogen peroxide or the peroxy acids is monitored precisely in order to prevent a large excess of these compounds in the reaction system. In many cases, the formation of labile reaction intermediates, such as, for example, diacetyl peroxide, furthermore occurs.

3-1sochromanone can furthermore be obtained from 2-methoxycarbonylmethylbenzoic acid by reaction with a) ethyl chloroformate in triethylamine and b) with sodium borohydride (Chem. Pharm. Bull. 16 (1968), 492, 496). 3-Isochromanone is 5 also accessible by reaction of isochroman-3-ol with chromium trioxide (Tetrahedron Letters 1973, 2359).

Another method for the preparation of 3-isochromanone comprises two steps: firstly, o-tolylacetic acid is reacted with N-bromosuccinimide (NBS) with formation of 2-bromomethylphenylacetic acid, which is followed by ring closure of this 2-brornomethylphenylacetic acid in basic medium to give the 3-isochromanone (Zh. Org. Khim. 9 (1973), 2145). However, the use of the expensive brominating 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-tolylacetic acid in the first step with sulfuryl chloride and azobisisobutyronitrile (AIBN) as free-radical initiator. In the second step, the 2-chloromethylphenylacetic acid formed is then converted into 3-isochromanone using a base. The first step is carried out in an inert solvent at temperatures of 50-90'C. Bases which can be employed 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 from 49 to 60% are disadvantageous in this process.

Against the background of the listed disadvantages of the processes known hitherto for the synthesis of 3-isochromanone, the object of the present invention was to provide an improved process which enables the preparation of 3-isochromanone in a technically simpler and non-dangerous manner from the safety point of view with high yields.

This object is achieved by a process for the preparation of optionally substituted 3-isochromanone of the formula I in which 2-halomethylphenylacetonitriles of the formula II are reacted with a hydrohalic acid, R R CN R 2 0 R 2 3 1 i' 3 R 4. R R R 4 X 1 11 where R', R', R' and R4 are identical or different and are H, halogen, OH or OR5, where R 5 is Ci-C4-alkyl, or R' and R 2 or R 2 and R 3 or R 3 and R4 together form a C3- or C45 alkylene radical or a C3- or C4-alkenyl radical, and X is chlorine or bromine.

The hydrohalic acid employed in the process according to the invention is preferably hydrochloric acid or hydrobro.mic acid.

R', R 2, R 3 and R 4 are preferably identical or different and are H or halogen, in particular chlorine or bromine.

In particular, all four radicals R' to R4 are hydrogen or one of the four radicals is chlorine or bromine while the three other radicals are hydrogen.

The reaction of the 2-halomethylphenylacetonitrile of the formula II with the hydro halic acid is an acidic hydrolysis and thus occurs at a pH of 0-7, preferably 0.5-5, in particular 1.5-4.5. The reaction temperature is 70 - 150'C, preferably 80 -120'C and in particular 90 - I 10'C. The molar ratio between hydrohalic acid and 2-halomethyl phenylacetonitrile is (0.1 - 10):I, preferably (0.5 - 5):1 and in particular (3 - 5):1.

No solvent is necessary for carrying out the reaction. If a solvent is used, the solvent employed is preferably the one also used after the reaction for the extraction of the 3-isochromanone from the water phase. Organic solvents, such as toluene, methylene chloride, chlorobenzene or fluorobenzene, are usually used.

In the acidic hydrolysis of the process according to the invention, firstly the 2-halo methylphenylacetic acid and, in equilibrium therewith, 2-hydroxymethylphenylacetic acid are formed from the 2-halomethylphenylacetonitrile, the two products cyclizing to give the 3-isochromanone. It is therefore important that the pH of 0-7 during the reaction is maintained. It has even proved particularly favorable to increase the pH during the reaction within the prespecified range, i.e. to a pH of a maximum of 7, preferably a maximum of 5 and in particular a maximum of 4.5, in order to obtain the 3-isochromanone quantitatively. This is achieved by partial dilution of the system with water or partial neutralization using an alkali metal base, preferably NaOH or KOH.

It is furthermore appropriate to stir the reaction mixture vigorously, which enables the shortest possible reaction time of usually 2-24 hours to be achieved. The reaction can be additionally accelerated by addition of catalytic amounts of an alkali metal iodide, in particular potassium iodide, or hydroiodic acid.

The process according to the invention is distinguished by the fact that it enables the preparation of 3-isochromanone in yields of at least 90%. Owing to this high yield, undesired by-products are only formed in a small amount, in particular the formation of dibenzy] ether, which is biodegradable with difficulty, is avoided.

2-Halomethylphenylacetonitrfles of the formula I can in principle be prepared by photohalogenation of the corresponding 2-methylphenylacetonitriles in organic aqueous systems at a pH of from -1 to +7. This process is the subject matter of a German patent application submitted on the same day. The photochlorination of 2-methylphenylacetonitffle is carried out at a temperature of from -10 to +30C, while the corresponding photobromination is carried out at from +10 to +60'C.

2-Bromomethylphenylacetonitrile can alternatively be prepared by brontination of 2-methylphenylacetonitrile using N-bromosuccinimide (NBS) as brominating reagent and dibenzoyl peroxide (DBP) as free-radical initiator Q. Heterocycl. Chem. 16 (1979),1443).

Examples Example 1 120 g of 2-bromomethylphenylacetonitrile are added to 111.6 g of 37 % hydrochloric acid, and the mixture is warmed to 100'C with stir-ring and stirred for a further 4 hours. Over the course of 12 hours, 696 g of water are added at 100'C with stirring, and the mixture is subsequently stirred for a further 8 hours. 60 g of methylene chloride are then added to the hot mixture, and the latter simultaneously cools to room temperature. The water phase obtained is then extracted twice with 60 g of methylene chloride each time. The inethylene chloride extract obtained is subsequently introduced into 490 g of toluene at 80'C, during which the methylene chloride distills off and is recovered. The toluene solution is filtered while hot and cooled for crystallization. After filtration and drying, 59 g: of 3-isochromanone having 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 having a content of 99.1% are obtained. 5.9 g of product having a content of 70% then remain in the mother liquor.

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

Example 2

In the same way, 39 g of 3-isochromanone having a content of 98.5%, corresponding to a chemical yield of 90%, are obtained from 50 g of 2-chloromethylphenylaceto- nitrile.

Claims

Patent Claims:

I Process for the preparation of optionally substituted 3-isochromanone of the formula I, characterized in that 2-halomethylphenylacetonitriles of the 5 formula III are reacted with a hydrohalic acid, R R' CN R 2 0 R2 3 R 3 4, R# R R 4 where R', R 2, R 3 and R' are identical or different and are H, halogen, OH or OR5, where R 5 is CI-C4-alkyl, or R' and R 2 or R 2 and R 3 or R 3 and R 4 together form a C3- or C4-alkylene radical or a C3- or C4-alkenyl radical, and X is 15 chlorine or bromine.
2. Process according to Claim 1, characterized in that the hydrohalic acid employed is hydrochloric acid or hydrobromic acid.
3. Process according to Claim I or 2, characterized in that all radicals R', R 2, R 3 and R 4 are hydrogen or one of the four radicals is chlorine or bromine while the three other radicals are hydrogen.
4. Process according to one or more of Claims I to 3, characterized in that the pH is 0-7, preferably 0.5-5, in particular 1.5-4.5.
5. Process according to one or more of Claims I to 4, characterized in that the reaction temperature is 70-150'C, preferably 80-120'C and in particular 901100C.
6. Process according to one or more of Claims I to 5, characterized in that the molar ratio between hydrohalic acid and 2-halomethylphenylacetonitrile is (0.1 - 10): 1, preferably (0.5 - 5):1 and in particular (3 - 5): 1.
7. Process according to one or more of Claims I to 6, characterized in that an organic solvent, preferably toluene, methylene chloride, chlorobenzene or fluorobenzene, is added to the reaction mixture after the reaction in order to separate off the 3-isochromanone.
8. Process according to Claim 4, characterized in that the pH during the reaction is increased to a value of a maximum of 7, preferably a maximum of 5 and in particular a maximum of 4.5, by addition of water or an alkali metal base, preferably sodium hydroxide solution.
9. Process according to one or more of Claims I to 8, characterized in that an alkali me tal iodide, preferably potassium iodide, or hydroiodic acid is added as catalyst during the reaction.