KR970000949B1 - The preparation method of isoquinoline compounds containing formyl radical - Google Patents

Abstract

1-alkoxybenzyl-N-formyl-1,2,3,4,5,6,7,8-octahydroisoquinoline of the formula(I) is prepared by the reaction of 1-alkoxybenzyl-1,2,3,4,5,6,7,8-octahydroisoquinoline represented by formula(II) with methylformate under catalyst of organic carboxylic acids in shorter reaction time and improved productivity. Said organic carboxylic acids are aliphtic carboxylic acids containing 1-6 carboxyl group and 1-5 carbon or aromatic carboxylic acids containig 1-6 carboxyl group and 400 M.W or less(such as formic acid, acetic acid, benzoic acid etc.).

Description

Method for preparing isoquinoline compound having form group

The present invention relates to a method for preparing an isoquinoline compound having a form group, and more particularly, to a nitrogen atom of 1-alkoxybenzyl-1,2,3,4,5,6,7,8-octahydroisoquinoline. Method of shortening reaction time and improving yield by using organic carboxylic acid as a catalyst in the preparation of 1-alkoxybenzyl-N-1,2,3,4,5,6,7,8-octahydroisoquinoline by densification It is about. 1-alkoxybenzyl-N-formyl-1,2,3,4,5,6,7,8-octahydroisoquinoline is the main intermediate used in the preparation of textolomethorphan, a drug ingredient with antitussive expectorant effect As materials, methods for preparing these compounds are described in Examples in US Pat. Nos. 3,634,429, 3,914,232, and the like. The methods described in these specifications are the reaction of methyl formate or chloral to the corresponding octahydroisoquinoline, which is reacted with excess methyl formate in the absence of a catalyst or in a chloroform solvent. Methods have been introduced for reacting chloral to form or using strong bases such as sodium methoxide as catalysts. However, in the case of using sodium methoxide, which is a strong base, as the formation catalyst as described above, there are some problems as follows.

First, sodium methoxide used as a catalyst can function stably only when there is no moisture in the reaction mixture, and it can be used stably when it is completely blocked from moisture in the air. As investment increases, manufacturing cost increases, and secondly, even if the form reaction proceeds in the presence of sodium medoside catalyst, the reaction is not completed within a few hours and requires several hours of reaction time. Third, when chloral is used as a reactant, the reaction time can be shortened to several hours, but the price is higher than methyl formate, which has a problem of increasing the manufacturing cost in terms of economic efficiency.

Therefore, the present inventors have diligently studied to solve the above problems, and as a result, 1-alkoxybenzyl-1,2,3,4,5,6,7,8-octahydroisoquinoline contains a carboxyl group when reacted with methyl formate. The use of a weak acid catalyst to the surprisingly high purity and yield to the desired compound was found to complete the present invention.

Hereinafter, the present invention will be described in detail.

In the present invention, 1-alkoxybenzyl-1,2,3,4,5,6,7,8-octahydroisoquinoline represented by the following general formula (II) is reacted with methyl formate and the following general formula In preparing 1-alkoxybenzyl-N-formyl- 1,2,3,4,5,6,7,8-octahydroisoquinoline represented by (I), the reaction is carried out in the presence of an organic carboxylic acid catalyst. By providing a method for shortening the reaction time and increasing the yield.

In the formula, R represents an m- or P-alkoxy group.

1-alkoxybenzyl- 1,2,3,4,5,6,7,8-octahydroisoquinoline of the general formula (II), which is a raw material in the present invention, is a compound known in the literature, and corresponds to the preparation method thereof. A method of preparing a corresponding octahydro compound into an optically active material by synthesizing the corresponding octahydro compound by reducing the hexahydroisoquinoline compound to sodium borohydride is described in the specifications of US Pat. Nos. 3,634,429 and 3,914,232. , The method for producing by catalytic hydrogenation reaction is O. Schnider , Helv. 1445 (1950).

According to the present invention, in the reaction of 1-alkoxybenzyl- 1,2,3,4,5,6,7,8-octahydroisoquinoline of the general formula (II) with methyl formate, When organic carboxylic acid was used as a catalyst, the reaction rate was about several times to several tens of times faster than those of the conventional methods, and the reaction was completed in a short time, and the yield was very high. In addition, the contact time between the reactants and the air is shortened, which reduces the decomposition rate of methyl formate and increases the recovery rate of methyl formate by distillation. It is unnecessary to use nitrogen gas to avoid atmospheric contact during the reaction, and extremely mild reaction conditions. The reaction proceeds smoothly even under a short time, so that the desired compound is 1-alkoxybenzyl-N-1,2,3,4,5,6,7,8-octahydro of the general formula (I). Isoquinoline can be prepared. In addition, the methanol produced in the reaction of the present invention can be separated from the excess methyl formate by fractional distillation, and the organic carboxylic acids used as catalysts can be separated from the target by classical methods, for example, by boiling distillation. Alternatively, the reactant dissolved in the organic solvent can be separated from the catalyst used by the method of removing by washing with water. In general, the catalyst used in the preparation of the furanol ring, which is the next reaction step, can be transferred to the furanol ring production reaction without any influence even in the presence of a small amount of the organic acid catalyst used in the case of the strong acid catalyst.

As the organic carboxylic acid catalyst used in the present invention, an aliphatic carboxylic acid having 1 to 6 carboxyl groups and having 1 to 15 carbon atoms or an aromatic carboxylic acid having an aromatic ring having about 1 to 6 carboxyl groups having a molecular weight of 400 or less can be used. Can be.

Specific examples of such organic carboxylic acid catalysts include formic acid, acetic acid, propionic acid, butanoic acid, pantanic acid, hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, decanoic acid, undecanoic acid, dodecanoic acid, butene acid, pentenoic acid, hexenoic acid, Heptenoic acid, octenic acid, nonenoic acid, dekenic acid, malonic acid, benzoic acid, naphthalic acid, phthalic acid, naphthalene-2,3-dicarboxylic acid or anthracenic acid.

In particular, when the catalyst is to be removed from the product, aliphatic carboxylic acids having 1 to 6 carbon atoms, which are relatively easy to separate from the product, such as formic acid, acetic acid, propionic acid, butanoic acid, pentanoic acid or aromatic carboxylic acids having relatively low molecular weight, benzoic acid, Naphthalic acid, phthalic acid, naphthalenedicarboxylic acid, etc. can be used preferably.

The most suitable catalyst is acetic acid, which is relatively inexpensive and is advantageous because it is easily separated from the product by distillation or washing with water.

The amount of the catalysts used generally corresponds to 1-alkoxybenzyl-1,2,3,4,5,6,7,8, -octahydroisoquinoline of the general formula (II) used as starting material. 0.1 to 50 equivalent% is used. Preferably it is used to about 1 to 40 equivalent%, more preferably about 2 to 20 equivalent%.

In the reaction of the present invention, it is most preferable to use an excess of methyl formate without using a solvent so that the excess can be directly acted as a reaction medium. However, in some cases, nonpolar organic compounds such as hexane, heptane, benzene, toluene, and xylene Solvents, aliphatic alcohols such as methanol and isopropane that do not inhibit the reaction, and propane can be used, and low-chain or cyclic aliphatic ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane Lower aliphatic ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone, or lower chain or cycloaliphatic organic compounds such as ethyl acetate, acetonitrile and dimethylformamide can be used. If desired, lower aliphatic halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride or substituted aromatic oils and fats such as chlorobenzene and nitrobenzene may be used.

Each of the solvents listed above may be used alone, or two or more solvents may be mixed and used in an appropriate mixing ratio. In the case of combinations which are not mixed with each other, for example, when aromatic hydrocarbons or aliphatic halogenated hydrocarbons are used together with alcohols, the two-layer system is used. In this case, small amounts of phase transfer catalysts such as quaternary ammonium salts, sulfone salts, and phosphonium salts are added. Desirable results are obtained.

The reaction of the present invention is immediately initiated by patching 1-alkoxybenzyl-1,2,3,4,5,6,7,8-octahydroisoquinoline and methyl formate of formula (II), In some cases, an exothermic reaction may occur. The product of the formula 1-alkoxy-benzyl -N- _formyl-1, 2,3,4,5,6,7,8 of (Ⅰ) - octahydro-isoquinoline is in the state of an organic base an oily liquid having a high boiling point It is preferable that the reaction temperature is maintained at 100 ° C. or lower, and more preferably, the reaction is performed at room temperature to 40 ° C. because it is present and has a property of insufficient stability with respect to heat. When methyl formate is used as the solvent, it will be most preferable to react at its heated reflux temperature.

In some cases, cooling the outside of the reaction vessel properly may be a method of controlling the reaction rate.

The reaction pressure is generally at atmospheric pressure to proceed with the reaction, or if necessary, the reaction may be carried out under pressure, at which time the pressure does not exceed 500 psi.

In addition, although the reaction of the present invention proceeds extremely smoothly under the above conditions and is usually completed within a few hours, it may be terminated in several minutes to several tens of minutes in some cases.

The 1-alkoxybenzyl-N-formyl-1, 1,2,3,4,5,6,7,8-octahydroisoquinoline of the general formula (I) as a product lacks stability against strong acids and bases. On prolonged contact with air-it is rather disadvantageous to prolong the reaction time unnecessarily or to use an excess of organic carboxylic acid because of the possibility of discoloration and oxidation.

The completion of the reaction can be easily confirmed by instrumental analysis means such as gas chromatography (GC) or high performance liquid chromatography (HPLC).

When the reaction is completed, the excess methyl formate and by-product methanol are removed by distillation. If the catalyst is a low boiling organic acid, it is removed by distillation under reduced pressure. In the case of a high boiling organic acid, the residue is dissolved in a solvent which does not mix with water and then low concentration. It can be removed by washing with a basic aqueous solution of. If the catalyst used does not inhibit the next reaction, it may be used as it is without removing the catalyst.

Hereinafter will be described in more detail based on the embodiment of the present invention.

Example 1

(-)-1- (p-methoxybenzyl) -1,2,3,4,5,6,7,8-octahydroisoquinoline 9.6 g (37.3 mmol) is dissolved in 20 ml of methyl formate and then glacial acetic acid 50 mg (0.8 mmol) was added as a catalyst and the mixture was stirred well and heated to reflux for 6 hours to complete the reaction. After the reaction was cooled to room temperature, excess methyl formate and methanol generated during the reaction were removed by distillation under reduced pressure, and the remaining reaction product was dissolved in 50 ml of toluene, washed with 30 ml of 10% ammonia water, and separated. (-)-1- (p-methoxybenzyl) -N-formyl-1,2,3,4,5,6,7,8-octahydroiso is removed by distillation under reduced pressure of the upper toluene layer to remove toluene. Quinoline 9.7 g (yield: about 92%) was obtained.

Examples 2-12

As shown in the following Table 1, the amount of (-)-1- (p-methoxybenzyl) -1,2,3,4,5,6,7,8-octahydroisoquinoline, and the amount of methyl formate , The reaction was carried out according to the method of Example 1 while varying the type and amount of the organic carboxylic acid catalyst, the reaction temperature and the reaction time (-)-1- (p-methoxybenzyl-N-formyl-1, 2,3,4,5,6,7,8-octahydroisoquinoline was prepared The yield is shown in Table 1 below.

Claims (10)

1-alkoxybenzyl- 1,2,3,4,5,6,7,8-octahydroisoquinoline represented by the following general formula (II) is reacted with methyl formate to the following general formula (I) A process for producing 1-alkoxybenzyl-N-formyl-1,2,3,4,5,6,7,8-octahydroisoquinoline as indicated, in the presence of an organic carboxylic acid catalyst. In the above formula, R represents an m- or p-alkoxy group. The method according to claim 1, wherein as the organic carboxylic acid catalyst, an aliphatic carboxylic acid having 1 to 6 carboxyl groups and 1 to 15 carbon atoms or an aromatic carboxylic acid having 1 to 6 carboxyl groups and a molecular weight of 400 or less. The method of claim 2, wherein the organic carboxylic acid catalyst is formic acid, acetic acid, propionic acid, butanoic acid, pentanoic acid, hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, decanoic acid, undecanoic acid, dodecanoic acid, butenoic acid, penic acid, Hexenoic acid, heptenoic acid, octenic acid, nonenoic acid, dekenic acid, malonic acid, benzoic acid, naphthalic acid, phthalic acid, naphthalene-2,3-dicarboxylic acid or anthracenic acid. The method of claim 3, wherein the organic carboxylic acid catalyst is formic acid, acetic acid, propionic acid, butanoic acid, pentanic acid, benzoic acid, naphthalic acid, or naphthalene-2,3-dicarboxylic acid. The catalyst according to claim 1, wherein the organic carboxylic acid catalyst has a carboxy group number of 0.1 to 1-alkoxybenzyl-1,2,3,4,5,6,7,8-octahydroisoquinoline of formula (II). To 50% by weight. The method according to claim 5, wherein the number of carboxyl groups of the catalyst is 1-40 equivalent%. The method according to claim 6, wherein the number of carboxyl groups of the catalyst is 2 to 20 equivalent%. The process according to claim 1, wherein the compound of general formula (I) is prepared at 0 to 100 ° C. The method of claim 8, wherein the compound of general formula (I) is prepared at room temperature to 40 ° C. 10. The method of claim 1, wherein the compound of formula (I) is prepared at normal pressure to 500 psi.