HU226423B1 - Process for producing a 1(2h)-naphtalene-1-ylidene derivative - Google Patents

Abstract

The invention relates to a process for the preparation of (+/-)-4-(S,R)- [(3,4-dichlorophenyl) -3,4-dihydro-1(2H) -naphthalene-1-ylidene] -methylamine of Formula (I) by reacting 4-(3,4-dichlorophenyl) -3,4-dihydro-1(2H) -naphthalene-1-one of Formula (II) with methyl amine which comprises carrying out the reaction in the absence of a dehydrating agent, in a lower alkanol. The compound of Formula (I) is a useful pharmaceutical intermediate.

Description

The scope of the description is 4 pages (including 1 page figure)

EN 226 423 Β1

The present invention relates to the preparation of a pharmaceutical intermediate.

More particularly, the present invention relates to a (±) -4- (S, R) - [(3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalen-1-ylidene of formula (I)] methylamine.

The compound of formula (I) is a valuable pharmaceutical intermediate, for example, the anti-depression agent sertraline, the cis (1S, 4S) -N-methyl- (3,4-dichlorophenyl) -1, of formula III, It can be used in the preparation of 2,3,4-tetrahydro-1-naphthalenamine.

Several methods are known from the literature for the preparation of Schiff bases related to the compound of formula (I). As a balance reaction, the balance offset must be ensured. This can be solved in many ways. One method involves removing the resulting water by azeotropic distillation [Morimoto, Sekiya Chem. Lett. 1371 (1985)]. According to other methods, the reaction is carried out in the presence of a dehydrating agent. Titanium tetrachloride [Chup, White J. Org. Chem. 32, 3246 (1967)], magnesium sulfate (Evans J. Am. Chem. Soc. 100, 8170 (1978)] or dehydrating molecular sieve [Bonnett, Emerson J. Chem. Soc. 4508 (1965)].

The compound of formula (I) can be prepared according to U.S. Patent No. 4,536,518 to 4- (3,4-dichlorophenyl) 3,4-dihydro-1 (2H) - (II). naphthalene-1-one is reacted with tetrahydrofuran in the presence of titanium tetrachloride with methylamine. Methylamine is used in excess of six times, and the resulting methylamine chlorohydrate and titanium dioxide are removed from the reaction mixture by filtration. The procedure has several disadvantages. Titanium tetrachloride is a difficult to handle, highly corrosive material that causes serious pollution problems. The titanium dioxide and methylamine chlorohydrate formed in the reaction are very difficult to filter and can be washed away, the separation of these by-products is difficult, and the yield is reduced. There is also a risk of contamination of the product with titanium.

According to U.S. Patent No. 4,855,550, the reaction of the compound of formula (II) with methylamine is carried out under pressure in the presence of a molecular sieve as a dewatering agent. The disadvantage of the process is the use of pressure and dehydrating agent.

It is an object of the present invention to provide a process for the preparation of a compound of formula (I) in the absence of known drawbacks of the known processes and without the use of a dewatering agent and pressure.

The above object is solved by the method according to the invention.

The present invention relates to a (±) 4- (S, R) - [(3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalen-1-ylidene] methyl of formula (I). amine by reaction of 4- (3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalen-1-one of formula (II) with methylamine such that the reaction is dehydrated. without the use of an agent in lower alkanol.

The invention is based on the surprising finding that the reaction of the compound of formula (II) and methylamine in a low alkanol medium without the use of a dewatering agent can be carried out with an excellent conversion of 97-98%, and can also be carried out in a simple manner in working sizes.

As lower alkanol, straight or branched chain alkanols having 1 to 3 carbon atoms, i.e., methanol, ethanol, n-propanol or isopropanol may be used. In a preferred embodiment of the process, methanol or ethanol may be used as lower alkanol.

The process of the invention can be carried out at 0-40 ° C, preferably at 10-30 ° C. According to a particularly preferred embodiment of the process, it is possible to work at room temperature.

The reaction time is from 10 to 48 hours, preferably from 10 to 30 hours; at room temperature the reaction is ca. It takes 24 hours.

In the process of the invention, it is preferred to proceed as follows:

The compound of formula (II) is suspended in the lower alkanol, preferably methanol or ethanol, and then a solution of the methylamine in the lower alkanol is added. In a preferred embodiment of the process, the same lower alkanol is used to dissolve the methylamine and suspend the compound of formula (II). The reaction is preferably carried out at room temperature under stirring.

The reaction is very high, approx. 99% conversion is achieved. The reaction mixture can be processed very simply. The compound of formula (I) can be isolated by cooling the reaction mixture and then separating the resulting product by filtration or centrifugation. The resulting compound of formula (I) is of sufficient purity for further transformation and no recrystallization is required.

Alternatively, the compound of formula (I) may not be isolated from the reaction mixture, but the reaction mixture obtained as a suspension is directly converted to the compound of formula (IV) by reduction.

The present invention has the following advantages over the known methods:

- no use of polluting, difficult to handle, corrosive titanium tetrachloride is required;

- eliminating the use of other dehydrating agents;

- no titanium oxide polluting the environment is difficult to handle in the reaction;

avoiding the risk of contamination of the compound of formula (I) with titanium;

titanium dioxide and methylamine which are difficult to separate from the product and which are poorly separable from the product and which are degraded by washing are not produced in the reaction;

as a solvent, instead of the expensive tetrahydrofuran, a substantially more economical methanol or ethanol is used;

- there is no need for higher temperature and pressure in the process;

- the reaction mixture can be processed very simply;

the yield obtained is higher than that of the known processes.

EN 226 423 Β1

The following examples further illustrate the present invention without limiting the invention to the examples.

Example 1 G (6.86 mmol) 4- (3,4-dichlorophenyl) -3,4-dihydro (2H) -naphthalen-1-one was suspended in methanol (40 mL) and stirred at room temperature with 20 mL of 20%. methylamine in methanol was added. The reaction vessel is sealed with a liquid stopper to keep the methylamine in solution. The reaction mixture was stirred at room temperature for 24 hours.

The resulting suspension was cooled to 0 ° C and the crystals were filtered off. 1.94 g of (±) -4- (S, R) - [(3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalen-1-ylidene methylamine are obtained. Yield: 93.5%, mp 146-148 ° C.

Example 2 G (13.72 mmol) 4- (3,4-dichlorophenyl) -3,4-dihydro (2H) -naphthalen-1-one was suspended in 80 ml of ethanol and then stirred at room temperature with 25 ml of 33% strength. ethanol methylamine was added. The reaction vessel is sealed with a liquid stopper to keep the methylamine in solution. The reaction mixture was stirred at room temperature for 24 hours.

The reaction mixture was cooled to 0 ° C and the crystals were filtered off. 3.75 g of (±) -4- (S, R) - ((3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalen-1-ylidene) methylamine are obtained. Yield: 90.3%, mp 146-148 ° C.

Example 3

2.40 kg (3.00 liters) of methanol was charged to a clean dry apparatus, cooled to 0 to -5 ° C, and 0.70 kg of methylamine was consumed.

In another apparatus, 3.20 kg (4.00 liters) of methanol and 0.45 kg of 4- (3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalene-1 are charged. The methanolic methylamine solution prepared according to the preceding paragraph is slowly added to the suspension at room temperature with stirring. The suspension was stirred at room temperature for 24 hours. Methanol was then carefully distilled off. The slurry was then cooled to 0-5 ° C, filtered and washed with cold methanol and dried. 0.446 kg of (±) -4- (S, R) - [(3,4-dichlorophenyl) -3,4-dihydro (2H) -naphthalen-1-ylidene] methylamine are obtained. Yield: 94.5%, mp 146-148 'C.

Claims (8)

PATENT CLAIMS A process for the preparation of (±) -4- (S, R) - [(3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalen-1-ylidene] methylamine of formula (I) by reacting a 4- (3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalen-1-one of formula (II) with methylamine, characterized in that without lower alkanol. 2. A process according to claim 1 wherein the lower alkanol is methanol or ethanol. Process according to claim 1 or 2, characterized in that the reaction is carried out at 0-40 ° C. Process according to claim 3, characterized in that the reaction is carried out at 10-30 ° C, preferably at room temperature. 5. A process according to any one of claims 1 to 3, wherein the solution of methylamine in lower alcohol is added to a suspension of the compound of formula (II) in lower alkanol. 6. A process according to claim 5, wherein the same lower alkanol is used to process the methylamine and suspend the compound of formula II. 7. A process according to any one of claims 1 to 3, characterized in that the compound of formula (I) is isolated by cooling the reaction mixture and separating it by filtration or centrifugation. 8. Process according to any one of claims 1 to 3, characterized in that the suspension formed during the reaction is further processed without isolating the compound of formula (I).