HU187697B - Process for preparing chlorinated diphenyl-methane derivatives - Google Patents

Abstract

The present invention relates to a new process for the preparation of chlorinated diphenylmethane derivatives of formula I, wherein R is hydrogen or chloro-diphenylmethane by chlorination with chlorine gas, such that the reaction is carried out on the basis of 0.1-0 diphenylmethane; In the presence of 4 mol% α, α'-azo-bis-isobutyronitrile, at a temperature of between 70 ° C and 120 ° C, preferably between 70 ° and 80 ° C, optionally in the presence of a solvent, the unreacted diphenylmethane is optionally used. recirculated to the system in a known manner. -1-

Description

(57) EXTRAS

The present invention relates to a novel process for the preparation of chlorinated diphenylmethane derivatives of the formula I in which R is hydrogen or chlorine by chlorination of diphenylmethane with chlorine gas by reacting the reaction at a concentration of 0.1-0 per diphenylmethane. 4 mol% of α, α'-azo-bis-isobutyronitrile in the presence of a radicalizing agent, at a temperature of 70 ° C to 120 ° C, preferably 70 ° C to 80 ° C, optionally in the presence of a solvent and optionally unreacted diphenylmethane is recirculated to the system in a known manner.

187,697

The present invention relates to a novel process for the preparation of chlorinated diphenylmethane derivatives of formula (I)

wherein R is hydrogen or chlorine by chlorination in the presence of diphenylmethane in the presence of a radical.

The compounds of formula I are important intermediates in the pharmaceutical industry. Examples of benzhydryl chloride having R at the hydrogen are cinnarizine, an intermediate of 1-cinnamyl-4-benzhydrylpiperazine. Cinnarizine, first produced by Janssen (US 2,882,271), is used to improve blood supply, cure memory disorders, and dizziness in the elderly. Hydrolyzed dichlorodiphenylmethane containing R at the chlorine atom to benzophenone is also an important pharmaceutical intermediate.

The conventional preparation of benzhydryl chloride of formula I wherein R is hydrogen can be carried out in three steps. In the first step, benzophenone is prepared from benzoyl chloride by a FriedelCrafts reaction. In the second step, benzhydrol is prepared from benzophenone by catalytic hydrogenation. In the third step, benzhydrol is also converted to benzhydryl chloride with hydrochloric acid in a known manner.

The disadvantage of the known process is that it is very laborious to obtain the benzhydryl chloride product in 3 steps. The Friedel-Crafts reaction and the hydrogenation operation are labor-intensive, delicate and dangerous, and also highly polluting. The aluminum trichloride in the Friedel-Crafts reaction and the palladium catalyst used in the hydrogenation reactor are expensive, the operations being carried out with them being an explosion; ^., / decent, very expensive.

In order to overcome these drawbacks, it is an object of the present invention to provide a novel process that simplifies the preparation of the compounds of formula I with less equipment and labor. In the process of the present invention, the chlorinated diphenylmethane derivatives of formula I wherein R is hydrogen or chlorine are prepared by chlorinating diphenylmethane with chlorine gas in the presence of a radical scavenging α, α'-azobis-isobutyronitrile (AIBN), At a temperature of from 70 to 120 ° C, preferably from 70 to 80 ° C. Chlorination can preferably be carried out in the absence of a solvent, but optionally in the presence of a solvent.

There are two references to chlorination of diphenylmethane in the literature. Raffaello Fusco et al., Ann. Chim. (Rom. 46, 122-9 (1956)) diphenylmethane was chlorinated with chlorine gas at 80-100 ° C to produce benzhydryl chloride. However, the chlorination reaction with purely chlorine gas is partly very slow and on the other hand the reaction without chlorinating and UV light also causes chlorination of the ring, which heavily contaminates the target product, such as the purification of the target product or benzhydryl chloride. makes it virtually impossible to purify the product obtained by reacting its contents directly.

According to British Patent No. 940,969, diphenylmethane was chlorinated in the presence of UV light at 50-200 ° C to produce benzhydryl chloride. It is not considered possible to achieve the 87% yield in this patent. To prove this, experiments were performed, the results of which are shown in Figure 1. In the experiments, diphenylmethane was chlorinated without solvent at 85 ° C with a chlorine feed rate of 10 1 / mole per hour. The symbols used in the figure are as follows:

Chlorination without UV light in the presence of 0.0015 mol / mol AIBN (α, α'-azo-bis-isobutyronitrile) - Chlorination without UV light in the presence of 0.0001 mol / mol AIBN - · Chlorination in the presence of UV light,

Without AIBN - Chlorination without UV light and AIBN - · · Diphenylmethane consumption Π

Formation of diphenylchloromethane X

Formation of diphenyl dichloromethane O

Formation of ring chlorinated derivatives

As shown by the curves in Figure 1, in the presence of radical or UV light, the chlorination reaction of diphenylmethane proceeds in a similar manner, with only a difference in the rate of the reaction. In our experiments without the use of a solvent, the curve for the formation of benzhydryl chloride peaks at 74-76% benzhydryl chloride. However, by this time the reaction mixture already contained about 13% diphenyl dichloromethane. Thus, the 87% yield of benzhydryl chloride in the above patent is refuted by our experimental data. The curves in Figure 1 also show that chlorination in the presence of less AIBN already begins to produce ring-chlorinated derivatives; when chlorinated in the absence of UV light and AIBN, these ring-chlorinated derivatives will appear more rapidly in the reaction mixture.

comparing the chlorination reaction in the presence of UV light and the rooting agent, with the aim of industrial application, it is technologically much simpler to perform the chlorination reaction in the presence of the rooting agent. When applied as a rooting agent, the reaction can be carried out in an ordinary enamelled autoclave of any size. However, when using UV light, if the illumination is from the outside, a narrow quartz tube reactor is needed, which is known to be fragile. Inside, illuminating the reaction space is expensive and difficult to implement in industry. A further disadvantage of chlorination using UV light is that it is very difficult to enlarge the reactor, and because of the low penetration of UV light, the chlorination of the ring also occurs along with the chlorination of the side chain, which heavily contaminates the target product. In contrast, the use of an appropriate amount of a radical scavenger has shown that benzhydryl chloride can be safely produced on a large scale, free of ring chlorinated material. When a radical scavenger is used, control of the exothermic chlorination reaction, i.e., ensuring the optimum reaction temperature, can be achieved by appropriately lowering or, if necessary, adjusting the scavenger dosing rate and adjusting the chlorine stream without

There would be a risk of chlorination because the slow thermal decomposition of the rooting agent would provide an appropriate radical concentration in the total weight of the reaction mixture even when the rooting agent feed was temporarily stopped. By switching off the UV light source for similar purposes, the chlorination of the ring is virtually simultaneously initiated without being a radical replacement.

Detailed Description of the Invention

In the new process of the present invention, diphenylmethane is chlorinated with chlorine gas in the presence of a radical at a temperature of 70-120 ° C, preferably 70-80 ° C. Chlorination is preferably carried out in the absence of a solvent, but may optionally be chlorinated in the presence of a solvent. The rooting agent is α, α'-azo-bis-isobutyronitrile (AIBN). The amount of AIBN in the reaction is 0.1-0.4 mol%, based on diphenylmethane.

The use of AIBN seems particularly useful because it decomposes at 80 ° C and is very well suited to the chlorination temperature. Solvents include saturated lower aliphatic chlorinated hydrocarbons, preferably carbon tetrachloride.

The chlorination reaction is conducted to prevent the formation of the ring-chlorinated substance by introducing 15 to 50% of the required amount of rooting agent into the reaction 5 to 10 minutes before starting the chlorine introduction, thereby providing the necessary initial radical concentration that precludes chlorination of the aromatic seed. then proceeding with the introduction of the chlorine, and proceeding with the addition of the remaining rooting agent.

A double-walled tube is used to simultaneously introduce the rooting agent and chlorine. The chlorine introduced into the outer tube cools the rooter introduced into the inner tube, thereby preventing any possible thermal decomposition of the rooter in the tube.

In the process according to the invention, benzhydryl chloride or diphenyl dichloromethane can be prepared according to the purpose. If benzhydryl chloride is to be prepared, it is desirable to continue the chlorination to about 50% conversion, whereby the yield of benzhydryl chloride, which can be directly reacted from the reaction mixture to the pure product, is about 98% based on the converted diphenylmethane.

Figure 1 also shows. Unreacted diphenylmethane can be recovered and recycled to the chlorination process, with or without distillation. If it is necessary to remove a few% of the benzophenone from the diphenyl dichloromethane in the recovered diphenylmethane, it may be achieved by heating a small amount of chlorinated hydrocarbon, preferably carbon tetrachloride, in the presence of 10-20% of diphenylmethane and cooling. , the diphenylmethane crystallizes out and the benzophenone remains in solution, which can be separated by centrifugation. The progress of chlorination is monitored by gas chromatography analysis or by titrimetry.

The novel process of the present invention provides a single step preparation of benzhydryl chloride from a cheap starting material in a simple apparatus which, due to the very different nature of the two compounds (one containing a highly reactive chlorine atom) and the unreacted diphenyl methane a simple alkyl aromatic hydrocarbon) can be reacted to the desired reaction such that the entire amount of unreacted diphenylmethane can be recovered and reintroduced into the chlorination reaction. In this way, virtually all diphenylmethane can be utilized.

If the diphenyl dichloromethane is to be produced, this reaction is practically complete in the first step, so that a simple and inexpensive, environmentally friendly process is available compared to the processes using aluminum trichloride.

The present invention is illustrated by the following non-limiting examples.

Example 1

Preparation of benzhydryl chloride in the presence of AIBN and solvent:

In a 250 ml double-necked flask with a stirrer, a reflux condenser, a plunger and a condenser and chlorine inlet, run to the bottom of the vessel, add 16.8 g (0.1 mol) of diphenylmethane and add 50 ml of carbon tetrachloride. heating the solution to a temperature between 70 and 80 ° C. When 70 'C is reached, about 20% of the solution of the fuming carbon tetrachloride is added, and after 5 to 10 minutes, the introduction of chlorine begins and the addition of the AIBN carbon tetrachloride solution is continued. The concentration of the AIBN solution is 0.34 g / 100 ml carbon tetrachloride and the rate of administration is 4 ml / hour. The chlorine flow rate found for optimization was 2 l / h.

Under these reaction conditions, the following product was obtained in about 90 minutes: Diphenylmethane 48-49.

Benzhydryl chloride, 48-49%

Diphenyl dichloromethane 2-4%

When the desired composition is obtained, the radical addition and the introduction of chlorine are discontinued, the dissolved chlorine is discarded to nitrogen, and the carbon tetrachloride solution is washed with water, followed by 2% sodium bicarbonate solution, again with water, dried or dissolved directly in anhydrous sodium sulfate. The recovered diphenylmethane can be chlorinated again.

The reaction was monitored by gas chromatography analysis of samples taken every 30 minutes.

Example 2

Preparation of benzh 'dril chloride in the presence of AIBN without solvent

In a 250 mL flask fitted as described in Example 1, 158 g (0.94 mole) of diphenylmethane was charged and heated to 70-80 ° C.

When reaching 70 ° C, 0.16-0.33 a (0.001-0.002 mol) of AIBN dissolved in 10-20 g (0.06-0.12 mol) of diphenylmethane are added and after 5-10 minutes the of chlorine at a rate of 5 l / h. Such

Under 187,697 conditions, the following product is obtained in about 3 hours:

Diphenylmethane 52-54%

Benzhydryl chloride 48-46% ₅

After the initial addition of about 15% of the rooting agent, it can be continuously added to the system, evenly distributed over the above reaction time. For continuous administration, the continued introduction of chlorine for a short time after administration of the radical generator to the input of AIBN diphenylmethane ^one can react.

Once the desired composition has been obtained, the introduction of chlorine is stopped, the dissolved chlorine and hydrochloric acid gas are quenched with nitrogen or air after cooling the reaction mixture to 25 ° C, and the product is fractionated or used directly for the desired reaction. The recovered diphenylmethane can be chlorinated again.

Example 3

Preparation of dichlorodiphenylmethane

To a 250 ml flask equipped as described above was added 138 g (0.82 mole) of diphenylmethane and 0.5 g (0.003 mole) of AIBN dissolved in 30 g (0.18 mole) of diphenylmethane in three portions. (at zero time, 3 and 6 hours) or continuously distributed over a period of about 9 hours. The chlorine flow rate in this case is preferably ³⁰ to 10 1 / h.

The resulting product composition:

Dichlorodiphenylmethane 93-95%

Benzhydryl chloride 7-5%

Patent claims

Claims (3)

A process for the preparation of chlorinated diphenylmethane derivatives of formula I wherein R is hydrogen or chlorine by chlorinating diphenylmethane with chlorine gas, wherein the reaction is in the range of 0.1 to 0.4 mol% based on diphenylmethane. α, α'-azo-bis-isobutyronitrile is carried out at a temperature of 70 ° C to 120 ° C, preferably 50 ° C to 80 ° C, optionally in the presence of a solvent, and to prepare a compound of formula I wherein R is hydrogen, conducting the chlorination reaction to a conversion of 45 to 55%, preferably 50%, or to a 90 to 95% conversion of the compound of formula I wherein K is chlorine and optionally deactivating unreacted diphenyl; methane is recycled to the system in a known manner. Process according to claim 1, characterized in that the solvent used is a saturated lower aliphatic chlorinated hydrocarbon, preferably carbon tetrachloride. The process according to claim 1, wherein from 5 to 10 minutes prior to initiating the chlorine introduction, 15 to 50% of the required amount of rooting agent is introduced into the reaction. 2 pieces of figure Published by the National Office of Inventions Responsible for publishing: Zoltán Himer, Head of Department - Taken by the Printing Photocopier Factory (877659/09) 87-2413 Dabasi Printing House, Budapest - Dabas Chief Executive Officer: Csaba Bálint Director -4187 697 ί NGO ₄ : C 07 C 21/24 o-