Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-09-25
2002-02-19
Rotman, Alan L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06348603
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to an advantageous process for the preparation of isochroman-3-ones.
Isochroman-3-one is of great interest as an intermediate in the synthesis of pharmaceuticals and plant protection agents.
The use of isochroman-3-one as an intermediate in the preparation of fungicides and pesticides follows, for example, from WO 97/12864.
As a rule, the quality of traditional chemical processes is defined by the space/time yield. In catalytic chemical processes, however, the catalytic turnover number (TON, i.e. the value which indicates how often a catalyst particle is used in the reaction) and the catalytic turnover frequence (TOF, i.e. the value which indicates how often a catalyst particle is used in the reaction in one hour) are generally used as quality criteria. In comparison with the space/time yield, the TON and TOF additionally give information about the quality of the catalyst employed in the reaction.
Various processes for the preparation of isochroman-3-one are known in the literature.
Thus in Tetrahedron Lett. 1997, Vol. 38, 3747 to 3750, Yamamoto describes a synthesis of isochroman-3-one by reaction of 1,2-bishydroxymethylbenzene and carbon monoxide in the presence of 1 mol % of a palladium catalyst and 10 mol % of hydrogen iodide. At 90° C. and a carbon monoxide pressure of 9 MPa in acetone/water as a solvent, isochroman-3-one is obtained in isolated form in 56% yield after a reaction time of 42 hours.
Disadvantages of this process which may be mentioned are the presence of the very corrosive hydrogen iodide and the fairly long reaction time.
In J. Am. Chem. Soc. 1980, Vol. 102, 4193 to 4198, Stille describes the synthesis of isochroman-3-one by reaction of ortho-bromomethylbenzyl alcohol, carbon monoxide and potassium carbonate in the presence of 1.6 mol % of a palladium catalyst and one drop of hydrazine in tetrahydrofuran as solvent. After 24 hours at 25° C. and a carbon monoxide pressure of 0.1 MPa, isochroman-3-one is obtained in isolated form in a yield of 71%.
It is a disadvantage that the ortho-bromomethylbenzyl alcohol needed as a starting substance is not easily accessible. Moreover, the use of potassium carbonate makes simple carrying-out of the process difficult (release of CO
2
). Furthermore, a comparatively long reaction time has to be accepted.
A two-stage process for the preparation of isochroman-3-one derivatives follows from WO 97/00850 A1, where initially a 1,2-bishalomethylbenzene derivative of the formula (A)
in which R is H, a halogen, a C
1
-C
6
-alkyl or C
1
-C
6
-alkoxy radical and X is a halogen, carbon monoxide and water are reacted in an organic solvent in the presence of a hydrogen halide absorbent and a catalyst and the salt of the ortho-hydroxymethylphenylacetic acid of the formula (B) occurring as an intermediate, in which M is an alkali metal or alkaline earth metal and n is 1 or 2,
is subsequently treated with an acid and converted into the corresponding isochroman-3-one. Suitable catalysts are palladium, cobalt and iron catalysts. The hydrogen halide absorbents used can be bases, in particular inorganic bases, for example calcium hydroxide. In the second reaction stage of this process, the acid used is, for example, hydrochloric acid in order to bring about the conversion of the salt of the ortho-hydroxymethylphenylacetic acid derivative of the formula (B) into the corresponding isochroman-3-one. The maximum TOF is 153×h
−1
; TON=153; yield 76.7% (cf. Working Example 4). The maximum TON is 170 (TOF=24×h
−1
); yield 84.7% (cf. Working Example 17).
According to this process, a yield of up to 87.4% of isochroman-3-one can indeed be achieved, but where a comparatively small amount of 8.75 g of &agr;,&agr;N-ortho-xylylene dichloride (1,2-bischloromethylbenzene) is reacted in not less than 100 g of tert-butanol. For further work-up, the reaction mixture is treated with water, insoluble solids are removed by filtration and the filtrate is extracted several times with ether. After acidifying with concentrated hydrochloric acid, it is extracted again with ether and isochroman-3-one is obtained from the collected ether fractions (TON=87; TOF=4.2×h
−1
; cf. also Working Example 5).
Owing to the use of bases in the first step of the process and to the acidification in the second step, not fewer than 3 equivalents of monovalent salt are formed per equivalent of isochroman-3-one. Disadvantages in this process are, on the one hand, the use of large amounts of solvents and the formation of large amounts of salt and, on the other hand, the two-stage nature of the process and the numerous purification and extraction steps as well as the repeated use of ether as an extractant.
SUMMARY OF THE INVENTION
In view of the disadvantages of the process outlined above, the present invention is based on the object of making available a novel process for the preparation of isochroman-3-ones which, on the one hand, can be carried out with comparatively low expenditure and, on the other hand, avoids the disadvantages of the processes of the prior art described beforehand and makes the desired product accessible in good yield and high purity.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
This object is achieved by a process for the preparation of an isochroman-3-one of the formula (I)
by reaction of a 1,2-bishalomethylbenzene of the formula (II)
in which X is chlorine, bromine or iodine, with carbon monoxide and a compound of the formula (III)
R
5
R
6
R
7
C—OH (III)
at a CO pressure of 0.1 to 50 MPa and a temperature of 20 to 200° C. in the presence or absence of an ionic halide, in the presence of a palladium catalyst and of a dipolar aprotic solvent, with addition of water or without addition of water, where in the formulae (I) and (II) the radicals R
1
, R
2
, R
3
and R
4
independently of one another are:
a hydrogen or fluorine atom;
an NC or F
3
C group;
an alkyl, alkoxy or acyloxy radical, in each case having 1 to 18 carbon atoms; or a C
6
-C
18
-aryloxy, aryl or heteroaryl radical, where 1 to 3 atoms from the group consisting of O, N and/or S are present as heteroatoms;
or in which at least two of the radicals R
1
, R
2
, R
3
and R
4
are linked to one another and form at least one aliphatic or aromatic ring having 5 to 18 carbon atoms, and in formula (III) the radicals R
5
, R
6
and R
7
are identical or different and are a C
1
-C
18
-alkyl, an HOC(═O)—, H
3
CC(═O)CH
2
— or (C
6
-C
18
-aryl)-CH
2
— radical or at least two of the radicals R
5
, R
6
and R
7
are linked to one another and form at least one aliphatic or aromatic ring having 5 to 18 carbon atoms.
The reaction of the 1,2-bishalomethylbenzene of the formula (II) can be described schematically—substantiated by means of a 1,2-bischloromethylbenzene as an example of a compound of the formula (II) and by means of tert-butanol as an example of a compound of the formula (III)—in simplified form by the following equation.
As follows from this equation which serves here as an illustrative example, the corresponding isochroman-3-one of the formula (I), tert-butyl chloride and water are formed.
The process according to the invention makes it possible to react the 1,2-bishalomethylbenzene of the formula (II) in concentrations which are significantly higher than in the process according to WO 97/00850 A1. Owing to this, the space/time yield is advantageously increased and an industrial procedure is favored to a corresponding extent.
A further advantage is that, in comparison to the process of WO 97/00850 A1, the salt of the formula (B) is not to be formed and also the salt is not obtained which is formed by the reaction of the hydrogen halide absorbent (base) with hydrogen halide. Thus, the process according to the invention proceeds in the absence of a hydrogen halide absorbent of this type and it is moreover advantageously possible to dispense with addition of acid in the second reaction step.
The radicals R
1
, R
2
, R
3
and R
4
are, in particular, independently
Geissler Holger
Pfirmann Ralf
Clariant GmbH
Covington Raymond
Hanf Scott E.
Rotman Alan L.
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