Process for production of 3-hydroxy-3-methylphthalide or the nuclearly substituted derivatives thereof

A process for producing 3-hydroxy-3-methylphthalide or its nuclearly substituted derivative of the following general formula ##STR1## wherein R represents a lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group or a carboxyl group, and n is 0 or an integer of 1 to 3, which comprises reacting phthalic anhydride or its nuclearly substituted derivative of the following general formula ##STR2## wherein R and n are as defined, with malonic acid at an elevated temperature in at least one solvent selected from the group consisting of dialkylformamides, dialkylsulfoxides and aliphatic lower carboxylic acids in the presence of, as a catalyst, a salt of an inorganic or organic acid with a metal selected from the group consisting of metals of Groups IA, IIA, IIIB and VIII of the periodic table, manganese, copper and zinc.

This invention relates to a process for producing 
3-hydroxy-3-methylphthalide or its nuclearly substituted derivative of the 
general formula 
##STR3## 
wherein R represents a lower alkyl group, a lower alkoxy group, a lower 
alkoxycarbonyl group or a carboxyl group, and n is O or an integer of 1 to 
3, 
which comprises reacting phthalic anhydride or its nuclearly substituted 
derivative of the general formula 
##STR4## 
wherein R and n are as defined above, with malonic acid in an organic 
solvent at an elevated temperature. 
In the present specification and claims, the lower alkyl or lower alkoxy 
groups mean those having 1 to 4 carbon atoms. 
The 3-hydroxy-3-methylphthalide or its nuclearly substituted derivatives of 
general formula (II) are useful as intermediates for synthesis of 
medicines, agricultural chemicals and other organic compounds. For 
example, 5,7-dimethyl-6-ethoxycarbonyl-3-hydroxy-3-methyl phthalide is 
used as an intermediate for synthesizing 
6,8-dimethyl-7-ethoxycarbonyl-4-hydroxymethyl-1-phthalazone which is 
effective for prevention of arteriosclerotic diseases and thrombotic 
diseases (see Japanese Laid-Open Patent Publications Nos. 70377/75 and 
70378/75). 
It is known that as shown by the following formula, 
3-hydroxy-3-methylphthalide of general formula (II) is in a tautomeric 
relationship with a compound of general formula (II) having a 
2-acetylbenzoic acid structure, and depending upon conditions, either one 
of these structures is assumed (see, for example, J. Org. Chem., Vol. 32, 
page 3229). 
##STR5## 
In the following description, however, compounds of general formula (II) 
are consistently termed 3-hydroxy-3methylphthalide or its substituted 
derivatives for the sake of convenience. 
Synthesis of 3-hydroxy-3-methylphthalide by reacting phthalic anhydride 
with malonic acid in pyridine at an elevated temperature is well known as 
the Knoevenagel-Doebner method (see, for example, J. Am. Chem. Soc., Vol. 
69, page 1547). This method is also applicable to the synthesis of 
5,7-dimethyl-6-ethoxycarbonyl-3-hydroxy-3-methylphthalide, i.e. its 
nuclearly substituted derivative (see Japanese Laid-Open Patent 
Publication No. 84563/75). 
When this method is practiced on an industrial scale, decomposition of the 
starting malonic acid in the pyridine solvent is vigorous, and therefore, 
malonic acid must be used in a considerably large excess. In particular, 
in the synthesis of a compound having substituents at asymmetric 
positions, for example 
5,7-dimethyl-6-ethoxycarbonyl-3-hydroxy-3-methylphthalide as mentioned 
above, large amounts of compounds of a similar structure such as 
4,6-dimethyl-5-ethoxycarbonyl-3-hydroxy-3-methylphthalide inevitably occur 
as by-products. Accordingly, in addition to the aforesaid difficulty, this 
method also poses a problem in the selectivity of the final desired 
product, its separation and purification, etc. and has not proved to be 
entirely satisfactory. 
The present invention made extensive investigations about a process for 
synthesizing 3-hydroxy-3-methylphthalide or its nuclearly substituted 
derivatives with industrial advantage by reacting phthalic acid or its 
nuclearly substituted derivative with malonic acid. These investigations 
have led to the discovery that such a process can be performed with 
industrial advantage by performing the reaction in the presence of a 
specified catalyst in a specified organic solvent. 
Thus, according to this invention, there is provided a process for 
producing 3-hydroxy-3-methylphthalide or its nuclearly substituted 
derivative of the general formula 
##STR6## 
wherein R and n are as defined hereinabove, which comprises reacting 
phthalic anhydride or its nuclearly substituted derivative of the general 
formula 
##STR7## 
wherein R and n are as defined, with malonic acid at an elevated 
temperature in at least one solvent selected from the group consisting of 
dialkylformamides, dialkylsulfoxides and aliphatic lower carboxylic acids 
in the presence of, as a catalyst, a salt of a metal selected from the 
group consisting of metals of Groups IA, IIA, IIIB and VIII of the 
periodic table, manganese, copper and zinc. 
Examples of the starting material of formula (I) used in the process of 
this invention include phthalic anhydride, 3-methyl-phthalic anhydride, 
3,4-dimethylphthalic anhydride, 3,4,5-trimethyl-phthalic anhydride, 
3-methyl-4-ethyl-phthalic anhydride, 3,5-dimethyl-4-ethyl-phthalic 
anhydride, 4-carboxyphthalic anhydride, 4-ethoxycarbonylphthalic 
anhydride, 4-t-butoxycarbonylphthalic anhydride, 
3-methyl-4-propoxycarbonyl-phthalic anhydride, 
3,5-dimethyl-4-methoxycarbonyl-phthalic anhydride, 
3,5-dimethyl-4-ethoxycarbonyl-phthalic anhydride, 
3-methyl-4,5-diethoxycarbonyl-phthalic anhydride, 3-methoxyphthalic 
anhydride, 3,4-dimethoxy-phthalic anhydride, 4,5-dimethoxy-phthalic 
anhydride, and 4-t-butoxy-phthalic anhydride. From these compounds, the 
corresponding compounds of general formula (II) can be synthesized. 
Organic solvents used for smooth proceeding of a reaction are required to 
be stable under the reaction conditions with no tendency to react with, or 
decompose, starting materials and the desired product, and to be capable 
of completely dissolving the starting materials and a catalyst. In the 
process of this invention, dialkylformamides, dialkylsulfoxides and 
aliphatic lower carboxylic acids have been found to be especially 
effective. Some typical examples of such organic solvents are 
N,N-dimethylformamide (DMF), N,N-diethylformamide, dimethylsulfoxide 
(DMSO), acetic acid (AcOH) and propionic acid. 
The salts of the aforesaid metals used as a catalyst are usually salts of 
the metals with inorganic acids such as hydrohalic acids, sulfuric acid, 
nitric acid, phosphoric acid and carbonic acid, and salts of the metals 
with organic acids such as acetic acid, propionic acid, naphthenic acid, 
oxalic acid and benzoic acid. Examples of especially effective metal salts 
are lithium acetate, sodium formate, sodium acetate, sodium benzoate, 
sodium phosphate, sodium carbonate, potassium acetate, cesium carbonate, 
magnesium chloride, magnesium sulfate, magnesium acetate, calcium acetate, 
strontium chloride, barium diorthophosphate, yttrium chloride, manganese 
chloride, ferric chloride, cobalt acetate, nickel acetate, palladium 
acetate, cuprous chloride and zinc acetate. Unstable salts which are 
decomposed under the reaction conditions or are hydrolyzed or degenerated 
by traces of unavoidable moisture, etc. included in the reaction system, 
and insoluble salts which do not at all dissolve in the reaction system 
cannot be used because they do not exhibit the desired catalytic effect. 
The mole ratio between the starting materials may be stoichiometric (i.e., 
the mole ratio is 1). Since, however, malonic acid is partly decomposed 
under the reaction conditions, it is preferred to use malonic acid in a 
slight excess. Usually, 1 to 10 moles, preferably 1.2 to 3.0 moles, of 
malonic acid is used per mole of phthalic anhydride or its nuclearly 
substituted derivative. The catalyst is generally more effective when used 
in a larger amount, but beyond a certain limit, no further increase in 
effect can be obtained. It is generally desirable to use the catalyst in 
an amount of 0.01 to 1.0 mole per mole of the phthalic anhydride or its 
nuclearly substituted derivative. The reaction temperature is usually 
60.degree. to 130.degree. C., preferably 90.degree. to 120.degree. C. If 
the reaction temperature is at least 140.degree. C., decomposition of the 
starting malonic acid is vigorous, and the yield of the product decreases 
extremely. On the other hand, at too low temperatures, the reaction time 
is prolonged, and no practical benefit is obtained. The reaction time 
varies depending upon various conditions such as the mole ratio between 
the starting materials, the concentration of the catalyst, and the 
reaction temperature. Under ordinary conditions, a reaction time of 5 to 
20 hours leads to satisfactory yields of the final product.