HU176872B - Process for producing n-alkyl-anilin derivatives - Google Patents

Abstract

Process for preparing compounds of the formula I <IMAGE> by reductive amino-alkylation. The process is carried out in the presence of a borohydride and of an acid, or of a reaction product of these two substances. The compounds can be used as intermediates in the preparation of pharmaceutical products.

Description

Sandoz AG., Basel, Switzerland

Process for the preparation of N-alkylaniline derivatives

The present invention relates to a process for the preparation of compounds of formula I wherein:

R 1 and R _{2 represent the} same or different C 1-3 alkyl groups, however, R 1 and R ₂ may contain up to 4 carbon atoms in total,

Rj and _R4 are independently hydrogen, fluoro, chloro, C1-4 straight chain alkyl or alkoxy or trifluoromethyl, with the proviso that R _4, 5 or 6-position is linked to the benzene ring and at most one of R ₃ R ₄ is trifluoromethyl, or

R ₃ and R _{4 taken} together may form a C 1 or C 2 alkylenedioxy group, and

X is a cyano group, a group of formula -COOR (where R is C 1-5 alkyl or hydrogen) or a group of formula (a) wherein Y and Y ₍ independently of one another hydrogen, fluoro, chloro, C 1-4) alkyl or alkoxy or trifluoromethyl, provided that at most one of Y and Y1 is trifluoromethyl.

The compounds of formula (I) according to the invention are prepared by reacting a compound of formula (II) wherein R ₃ , R ₄ and X are as defined above in a liquid medium with an acid and a borohydride or an acid ^and a borohydride. in the presence of a compound of formula III wherein R ₍ and R ₂₎ are as defined above.

The compounds of formula (I) and the alkylation processes for their preparation are known in U.S. Patent No. 1,805,501. German publication. One advantage of the claimed process over the known process is the significant reduction in the reaction time required for its preparation. This is clearly evidenced by the fact that, for example, 2- (N-isopropylamino) -4-methylbenzophenone requires 5 days according to Example 3 of the above-mentioned German Patent Application, as described in Examples 20, 26, 10 and 30 of the specification. hours at 10 minutes, 90 minutes, and 165 minutes. A further significant advantage of the claimed process is that, compared to the isopropyl halides used in the process described in the above-mentioned German Patent Application, only the substantially easier and cheaper acetone and sodium borohydride are used. Thus, the notified procedure provides significant and surprising technical progress.

In the process according to the invention, the usual boron hydrides used as reducing agents, especially alkali metal borohydrides containing exclusively an alkali metal as the metal component, can be used. Preferred reagents are alkali metal borohydrides such as lithium borohydride, potassium borohydride or, preferably, sodium borohydride. Other alkali metal borohydrides having a reducing effect which can be used in the process of the invention include sodium cyanoborohydride.

Boron hydrides are preferably used as fine-grained materials. Preferably, the borohydrides are on a 20, target 30, 60 screen (Tyler Standard

Screen) may be a cross-sectional material. Powdered borohydrides are particularly preferred.

A wide variety of acids can be used in the process of the invention. It will be appreciated that the preferred reaction conditions to be maintained in the process of the invention will be determined to some extent by the nature of the acid used and other factors such as the starting materials and the borohydride used. In the following, three generally proven methods for carrying out the process of the present invention are described.

One method (hereinafter "Method A") uses a strong acid as the acid. Strong acids can be used in the reaction which have a pH of 10% in aqueous solution up to 2, preferably 0.5 and

Values of about 1.5 are preferably about 1. Strong acids include mineral acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid and nitric acid, and organic derivatives of mineral acids such as methane, ethane or p-toluenesulfonic acid. Carboxylic acids, such as trifluoroacetic acid, which meet the above requirements may also be used in the reaction; however, the use of these compounds is less advantageous since their presence may result in the formation of unwanted by-products. Particularly unfavorable in this respect are carboxylic acids having multiple carboxyl groups, such as oxalic acid. Picric acid can also be used in the reaction, but the use of this compound is not preferred. According to Method A, sulfuric acid is preferably used as the acid.

According to Method A, the reaction is generally carried out at a temperature of 0 ° C to 35 ° C, preferably 10 ° C to 30 ° C, preferably 15 ° C to 28 ° C.

As stated above, the reaction is carried out in a liquid medium such as a solution phase. Preferably, at least a portion of the reaction medium is provided by excess of the compound of formula (III). Preferably, the compound of formula (III) is used in an excess of at least 20% relative to the compound of formula (II). Preferably the molar ratio of the compounds of the formulas III and II is at least 3: 1. preferably at least 4: 1, particularly preferably at least 8: 1. The upper limit of this molar ratio may be, for practical reasons, about 70: 1. The compound of formula (III) and (II) is preferably used in a molar ratio of from 15: 1 to 50: 1, preferably from 20: 1 to 45: 1.

The reaction mixture should preferably contain at least the small amount of water required to initiate the reaction: however, in the presence of too much water, the reaction may be slowed down or, in some cases, stopped. Preferably, the water is introduced into the system by adding the strong acid in the form of an aqueous solution. The concentration of the aqueous acid solution is preferably 10 to 90%, preferably 15 to 70, particularly preferably 25 to 60%. The percentages given are by weight.

The reaction mixture may optionally contain additional inert organic solvents, in particular polar solvents such as ethers (e.g. dioxane or tetrahydrofuran) or alcohols corresponding to the compounds of formula (III). for example, it may also contain isopropanol.

The molar ratio of acid to starting material of formula II is preferably up to 12: 1, preferably up to 5: 1, most preferably up to 4: 1. The acid (especially sulfuric acid) is preferably used in a molar ratio of 1: 1 to 3: 1, preferably from 1.15: 1 to 2: 1, relative to the starting material of formula (II). with them.

It should be noted that the composition of the reaction mixture, in particular the amount of the compound of formula III, water, acid and other organic solvents, may be varied according to the reaction conditions found to be advantageous. The reaction is preferably carried out under conditions such that the compound of formula (II) is substantially completely soluble in the other liquid components of the reaction mixture and the reaction is initiated at a suitable rate.

The acid is preferably used in at least a small molar excess relative to the borohydride compound. The acidic protons of the acid used are then reacted with 1 to 1 mol of a borohydride compound to form products which are also involved in the reduction process of the invention. The acid is preferably used in an excess such that the pH of the reaction mixture is less than 2, preferably between 0.5 and 1.5, preferably about 1.0. Accordingly, the acid is preferably used in an excess of 1.0 to 50%, preferably 1.5 to 25%, relative to borohydride. Values given are data relative to equivalent quantities.

Accordingly, the borohydride and the compound of formula II are preferably reacted in a molar ratio of at least 1.7: 1. The upper limit of this molar ratio is preferably 8: 1. The borohydride and the compound of the formula II are preferably used in a molar ratio of from 2: 1 to 6: 1, preferably from 2: 1 to 4: 1, particularly preferably from 2: 1 to 3: 1.

According to Method A, it is preferable to first form a solution by mixing the compounds of formula (II) and (III) in an appropriate ratio with an aqueous solution of the strong acid, and to this solution add borohydride according to the desired degree of reaction control. pace. A less advantageous method is that the acid and the borohydride are alternately added in small portions to the other components of the reaction mixture, but in this case, care must be taken to ensure that the reaction mixture always contains more acid than is necessary to neutralize the borohydride. Alternatively, the reagents may be added at a temperature below the reaction temperature. and starting the reaction by increasing the temperature. For example, the reaction time may range from 20 minutes to 10 hours, but is usually complete in about 0.5 to 4 hours.

The resulting product may contain a portion of the compound of formula (I) in the form of a chemically bound base (e.g., an acid addition salt). These compounds can be converted to the free bases in a known manner, for example by treatment with a strong base such as sodium hydroxide or anhydrous tertiary amine.

In another process (hereinafter referred to as "Method B"), the acid used is a saturated aliphatic carboxylic acid having from 2 to 4 carbon atoms containing at least one carboxyl group and except for the oxygen atoms of the carboxyl group. A 98% aqueous solution of these acids may have a pH of from 3.0 to 5.0, preferably from 3.5 to 5.0, preferably from 4.0 to 4.6. Exemplary carboxylic acids that may be used include monocarboxylic acids such as acetic acid and propionic acid. It is particularly preferred to use acetic acid in the reaction.

The reaction is generally carried out at temperatures between 10 ° C and 35 ° C, preferably 15 to 35 ^Q C, preferably 15-28 ° C.

According to Method B, the borohydride and the starting material of the formula II are preferably from 1.7: 1 to 4: 1, preferably from 2: 1 to 3.2: 1, particularly preferably from 2: 1 to 2.8 : 1 molar ratio. The acid is preferably used in an excess relative to the borohydride. However, in this case, the acid may also act as an auxiliary solvent, so that the acid can usually be used in relatively large amounts. The acid and the starting material (II) are generally at least 6: 1, preferably 6: 1 to 50: 1, preferably 8: 1 to 30: 1, especially 10: 1 to 20: 1. molar ratio.

The reaction is preferably carried out in a solution phase. In addition to the excess carboxylic acids used in the solution, an excess of the reagents of formula (III) may be used as auxiliary solvents. The compounds of formula (III) and (II) are generally reacted with each other in a molar ratio of at least 3: 1, preferably at least 4: 1, preferably at least 6: 1. For practical reasons, this molar ratio may be up to about 50: 1. The compounds of formula (III) and (II) are preferably used in a molar ratio of from 8: 1 to 30: 1, preferably from 10: 1 to 20: 1.

Other inert organic solvents, such as those listed in Method A, may be optionally added to the reaction mixture. The carboxylic acid used usually contains a small amount of water which is still permissible for the reaction. Preferably, the reaction mixture contains up to 8% by weight, preferably up to 5% by weight of water, of the carboxylic acid. The reaction is usually carried out in a solution containing from 0.1 to 2.5% by weight of water, based on the weight of the carboxylic acid.

Method B generally involves the addition of borohydride to a solution of the other reagents. The reaction is exothermic; accordingly, the addition of borohydride should be controlled to avoid overheating of the mixture. The borohydride is preferably added to the further components at a temperature of at least 10 ° C, preferably at least 15 ° C. The addition rate is preferably controlled so that the temperature of the resulting mixture is below 35 ° C, preferably below 30 ° C, preferably below 25 ° C, and after each addition the temperature of the reaction mixture is up to 10 ° C, preferably up to 5 ° C. ° C, preferably not more than 2 ° C. Each borohydride moiety is preferably added at intervals of at least 30 minutes, preferably at least 50 minutes. The individual portions to be added are selected in accordance with the desired temperature increase. For example, the total reaction time may range from 40 minutes to 10 hours, usually from 1 hour to 4 hours.

The third and most preferred process (hereinafter "Method C") uses the so-called "rigid, coplanar, divalent organic carbonic and / or sulfonic acids" as the acid. By this designation is meant bivalent organic acids which contain carboxyl and / or sulfo groups as acid groups and are located in the same geometric plane. These acids fall into three main groups:

1. An acyclic, unsaturated divalent acid containing a carbon-carbon double bond, wherein an unsaturated carbon atom is bonded to an acid group and the compounds are in the cis configuration (e.g., maleic acid);

2. ring-unsaturated cyclic divalent acids having a carbon-carbon double bond in which a ring of two unsaturated carbon atoms is attached to each other and the carbon atoms are

a) adjacent to each other (e.g., o-phthalic acid, 1,2-benzenesulfonic acid, 2-carboxybenzenesulfonic acid, o-dicarboxynaphthalenes (such as 2,3-dicarboxynaphthalene) or o-disulfonaphthalenes (such as 2,3-disulfonaphthalene) )], obsession

b) adjacent to a common carbon atom of the fused ring system (e.g., naphthalic acid);

3. Cyclic divalent acids in which two groups of saturated ring carbon atoms are attached to one acid group and are consequently rigidly attached to each other in exo or endo configuration with respect to the structure of the molecule (e.g. bicyclo [2.2.1] hept-5). ene-2,3-dicarboxylic acid).

Particularly preferred are those shown in Figures 1 and 2a. acids that can be classified in port cso15. Particularly preferred of these acids are the compounds of formula (IV): - where AC] and C ₂ each independently represent -COO or salt thereof group, and these groups are located relative to each other in the cis-configuration, and Z, and Z ₂ 0 are independently hydrogen, or an organic group (preferably a hydrocarbon group), or Z ₁ and Z ₂ may be linked together.

Particularly preferred are dibasic acids in which the two acid groups are identical. The two acid groups may be both carboxylic groups.

The aforementioned acids may be used in a similar manner to those described above, but it is more preferable to carry out Method C by reacting the compounds of Formulas II and III in a liquid medium (preferably in solution) to form a rigid coplanar divalent organic a preformed reaction product of carbonic and / or sulfonic acid and boron tetrahydride (preferably an alkali metal borohydride).

These reaction products are boron-containing salts which contain at least predominantly compounds of formula (V) - wherein X represents the anion of a rigid, coplanar, divalent organic carbonic and / or sulfonic acid, and M represents one equivalent of the metal cation present in boron tetrahydride. 0 For instance, when using a compound of formula acid (IV), the reaction product of a boron-containing salt are obtained, probably at least predominantly correspond to the general formula (Va) - wherein Z _f, Z _2, ACJ, AC _2, and M is 5 above.

When o-phthalic acid is used as the acid, the reaction product is believed to be at least predominantly salt (Vaa) - wherein M is as defined above.

D If naphthalic acid is used as the acid, the reaction product is a boron-containing salt, which is believed to contain predominantly a compound of formula (Vab), where M is as defined above.

As is evident from the foregoing, in these compounds 5 M is preferably an alkali metal cation, preferably a lithium, potassium or sodium ion, particularly preferably a sodium ion.

Reaction products of rigid coplanar divalent organic carbonic and / or sulfonic acids with tetraborohydrides may be used as reducing agents.

These compounds can generally be prepared by reacting the acid in a liquid medium at a temperature of -40 ° C to + 85 ° C with an appropriate tetraborohydride in a molar ratio of 0.7: 1 to at least 5: 1.

Preferred methods for preparing these reaction products are described below, together with their use in the preparation of compounds of formula (I).

According to Method C, the reaction is preferably carried out at a temperature of 0 ° C to 100 ° C, preferably 20 ° C to 85 ° C, particularly preferably 30 ° C to 65 ° C. As stated above, the reaction is carried out in a liquid medium, preferably in a solution phase. Preferably, at least a portion of the reaction medium is an excess of the compound of formula (III). The compounds of formula (III) and (II) are preferably used in the ratios given in Method A. As in Method A, the reaction mixture may again contain other inert organic solvents; these solvents may conveniently be the liquids mentioned in Method A. Given that the reaction uses commercially available starting materials which may contain a certain amount of water. the reaction mixture may optionally contain a small amount of water. Preferably, the water content of the reaction mixture should not exceed 8% by weight, based on the total amount of solvent; the water content of the mixture is preferably up to 2% by weight based on the total amount of solvent, most preferably up to 0.5% by weight. In this context, the term "solvent" also refers to compounds of formula (III) minus the amount that reacts with compounds of formula (II). The reaction mixture generally contains from about 0.05 to about 0.4% by weight of water based on the total amount of solvent.

The reaction product (i.e., the boron-containing salt) of the rigid coplanar divalent organic carbonic and / or sulfonic acid and the tetraborohydride may be formed either in the reaction mixture itself (i.e. in the presence of at least one additional reagent) or in a preliminary step. The borohydride or boron-containing salt and the compound of the formula II are generally in the range of 0.7: 1 to 2.5: 1, preferably 0.7: 1 to 1.65: 1, preferably 1: 1 to 1.5 In a molar ratio of from about 1: 1, particularly preferably from 1: 1 to 1.3: 1, most preferably from 1: 1 to 1.15: 1. It will be appreciated that when the boron-containing salt is formed in the reaction mixture itself, the borohydride used as a reagent is included in the calculation of the above molar ratios, while the boron-containing salt is prepared in a preliminary step to the boron-containing salt.

As stated above, the boron-containing salt can be prepared in the reaction mixture itself or in the preliminary step, but it is more preferred to form the boron-containing salt in the reaction mixture itself. In this case, the appropriate reaction medium is preferably the appropriate compound of formula (III) and the reaction is carried out in the presence of other components of the reaction mixture to form the compound of formula (I), including the starting materials of formula (II). Generally, borohydride is added to a mixture of other reagents. The addition is usually carried out at a temperature below the main reaction temperature, for example at 0 to 30 ° C, preferably at 10 to 25 ° C. After the initial reaction between the borohydride and the acid is completed, the temperature of the reaction mixture is increased to the desired value, for example 30-85 ° C, preferably 40-65 ° C, thereby completing the salt formation and providing the necessary reaction favorable conditions.

When boron-containing salts are prepared in the reaction mixture itself, the rigid acid and the borohydride are usually in the range of 0.7: 1 to 10: 1, preferably 1: 1 to 2: 1, preferably 1.1: 1 to 1.8: 1 in a molar ratio of from about 1.1: 1 to about 1.6: 1. The reaction mixture should preferably contain a free acid to stabilize the boron-containing salt. The role of the free acid may also be fulfilled by the excess of rigid acid used as reagent; however, it is also possible to add another acid, preferably a carboxylic acid, as the free acid to the reaction mixture.

As stated above, the boron-containing salts may also be formed in a preliminary step. In this case, the reaction is preferably carried out in an inert solvent such as tetrahydrofuran. The reaction temperature may be from -40 ° C to +85 ° C, preferably from 0 ° C to 35 ° C, preferably from 10 ° C to 30 ° C. In the latter case, the stiff acid may be used in smaller amounts than the borohydride. The molar ratio of rigid acid to borohydride is, for example, 0.7: 1 to 5: 1, preferably 1: 1 to 2: 1, preferably 1.1: 1 to 1.8: 1, especially 1.1: 1. and preferably from 1.1: 1 to 1.3: 1. The reaction is preferably carried out by adding the borohydride in portions to a solution of the rigid acid; adjusting the feed rate to the desired temperature. The resulting boron-containing salt may be used directly in the preparation of the compound of formula (I) to form the compound, but may be isolated and purified in a known manner if desired.

As stated above, the boron-containing salt is preferably formed in a solution phase; however, it will be appreciated that depending on the amount and quality of the reagents used, the reaction mixture may optionally be a mixture of a multiphase system which may contain, for example, a portion of one or more components in suspension.

The compounds of formula I obtained by the process of the present invention can be isolated and purified by methods known per se. If desired, the free bases of the formula I can be converted into their acid addition salts or the bases can be liberated from the salts of the compounds of the formula I.

The compounds of formula (I) are known intermediates for the preparation of therapeutic agents. These compounds are particularly useful in the synthesis of known compounds of formula (VII) having anti-inflammatory activity - wherein R ₁ , R ₂ , R ₃ , R ₄ , Y and Y ₍ as defined above).

The compounds of the present invention are useful in the preparation of compounds of formula (VII) by reacting compounds of formula (I) wherein X and Yj are as defined above, with the N-C-O bond. by cyclization. This is accomplished by reacting a compound of formula (II) with a compound of formula (III), optionally containing X, where X is -CN or -COOR, wherein R is as described above. The compounds of formula (I) wherein X is a group of formula (a) wherein Y and Y are Y; and are cyclized in the presence of reagents containing an N-C-O bond.

The cyclization can be carried out in a manner known per se. Reagents containing N-C-O bonds for cyclization, including urea and alkyl carbamates, are well known to those skilled in the art. The group of formula (a) may also be introduced into the compounds of formula (I) by methods known per se. For example, compounds of formula I wherein X is -CN or -COOH may be reacted with the appropriate aryl-Grignard reagent or aryl-lithium compound and the product hydrolyzed. The compounds of formula (I) wherein X is an alkoxycarbonyl group are first hydrolyzed, for example, to form the corresponding carboxylic acids and then proceeded as described above.

Particularly preferred compounds of formula I or VII are those wherein R ₍ and R ₂ are methyl, R ₄ is hydrogen and R _{3 is} at the same time methyl, or R ₃ and R _{4 taken} together are methylenedioxy. and in the group of formula (a) Y represents hydrogen and / or Y represents hydrogen or fluorine.

The following examples illustrate the invention without limiting it. 35

Examples 1-19

2- (N-Isopropylamino) -4-methylbenzophenone ("Method A")

2- (N-Isopropylamino) -4-methylbenzophenone was prepared under the experimental conditions listed in Table 1 below. In each case, starting from 21.1 g (0.1 mol) of 4-methyl-2-aminobenzophenone, the amount of the other 10 components of the reaction mixture was varied. Acetone is used as reagent (III), sodium borohydride as borohydride and sulfuric acid as acid; the reaction mixture also contains water in addition to these components. The reaction is always carried out at 20-25 ° C and the rate of borohydride addition is controlled accordingly. In most cases, the addition of borohydride takes 60 minutes. The reaction mixture was stirred for an additional 60 minutes, then filtered and the filtrate was concentrated. The residue was dissolved in about 88 ml of H 2 O 2 and the resulting solution was extracted with 20 ml of 4N aqueous ammonium hydroxide solution and 3 x 10 ml of 2N aqueous sulfuric acid. Finally, the solution was washed with 10 ml of 0.5 N aqueous sulfuric acid and the heptane was distilled off. 2- (N-isopropylamino) -4-methylbenzophenone is obtained as a solid. mp: 180-185 ° C / 5 mmHg.

Table 1 shows that in some cases the desired product is obtained in relatively low yields. However, it should be emphasized that the experiments summarized in Table 1 were conducted to determine the optimal reaction conditions; accordingly, not all experiments illustrate the most advantageous solution. By appropriately modifying the reaction conditions, experiments with relatively low yields can be used to significantly increase yields.

Table 1

Example number Amount of acetone Acetone: <RTIgt; (I1) </RTI> molar ratio of compound Weight of sulfuric acid Weight of water Weight of NaBH ₄ Acid: molar equivalent of borohydride Yield% of compound of formula (I) weight M First 55 0.95 9.50 1 14 464 10.4 1,050 1 6.5 Second 55 0.95 9.50 1 14 172 10.4 1,050 1 59 Third 55 0.95 9.50 1 14 86 10.4 1,050 1 96 4th 55 0.95 9.50 1 14 43 10.4 1,050 1 79 5th 75 1.3 13.00 1 14 43 10.4 1,050 1 80 6th 55 0.95 9.50 1 14 24 10.4 1,050 1 88 7th 75 1.3 13.00 1 14 24 10.4 1,050 1 90 8th 125 2.16 21.60 1 14 24 8.0 1,360 1 94 9th 200 3.45 34.50 1 14 24 10.4 1,050 1 99 10th 25 0.43 4.30 1 14 15 10.6 1,025 1 75 11th 50 0.86 8.60 1 14 15 10.6 1,025 1 86 12th 56 0.97 9.70 1 14 15 10.6 1,025 1 88 13th 100 1.72 17,20 1 14 15 10.6 1,025 1 90 14th 190 3.28 32.80 1 14 15 10.6 1,025 1 98 15th 17 0.295 2.95 1 14 0.3 10.6 1,025 1 4 16th 55 0.96 9.60 1 14 0.3 10.6 1,025 1 51 17th 200 3.45 34.50 1 14 0.3 10.6 1,025 1 90 18th 125 2.16 21.60 1 28 24.3 8.0 2,730 1 99 19th 125 2.16 21.60 1 56 24.6 8.0 5.460 1 28

Example 20

2- (N-Isopropylamino) -4-methylbenzophenone (Method A)

To a solution of 2-amino-4-methylbenzophenone (63.3 g) in acetone (722 ml) was added 49% aqueous sulfuric acid (87 g). The reaction mixture was cooled to 20 ° C and 31.2 g of sodium borohydride was added portionwise over 70 minutes while stirring. After the addition, the mixture was stirred for an additional 5 hours at 25 ° C. The suspended solid was filtered off and washed with acetone (300 mL). The acetone solutions were combined, concentrated, and 200 ml of heptane and 60 ml of 4N aqueous ammonium hydroxide were added to the concentrate. The liquid phases were separated and the heptane phase was washed with water (20 mL), extracted with 2N aqueous sulfuric acid (2 x 20 mL), and washed with water to neutral. The heptane phase was dried over magnesium sulfate, filtered and dried in vacuo to constant weight. 74.5 g (98%) of crude 2- (N-isopropylamino) -4-methylbenzophenone are obtained. Analytical data give a pure product with an actual yield of 95%.

Example 21

2- (N-Isopropylamino) -4-methylbenzophenone (Method A)

In the same manner as in Example 20, 114 g of 28% aqueous hydrochloric acid are used instead of sulfuric acid, and the reaction mixture is stirred only for 1 hour after the addition of borohydride. The crude product is obtained in 100% yield, which corresponds to an actual yield of 96%.

Example 22

2- (N-Isopropylamino) -4-methylbenzophenone (Method A)

Example 20 was repeated except that an equivalent amount of 30% aqueous sulfuric acid was used. The product is obtained in good yield.

Example 23

2- (N-Isopropylamino) -4-methylbenzophenone (Method A)

Into a 12 liter flask placed in an ice-water bath equipped with a stirrer and thermometer, 3.9 liters of acetone, 528.3 g of 2-amino-4-methylbenzophenone, 462 ml of water and 263 g of 98% sulfuric acid were successively stirred. in. Meanwhile, the temperature of the mixture was maintained at 20 ° C. Thereafter, 200 g of sodium borohydride are added to the reaction mixture under stirring at 72 g / h, keeping the temperature between 20 ° C and 25 ° C. After addition of borohydride, the reaction mixture was stirred at 20-25 ° C for 4 hours, then the precipitated solid was filtered and washed with acetone (1.5 L). The filtrate and the acetone wash were combined and the acetone was evaporated in vacuo. To the dark orange-red liquid residue was added 2 liters of heptane and 350 ml of 4N aqueous ammonium hydroxide solution and stirred vigorously until the initially precipitated solid dissolved. The aqueous layer was separated and the organic layer was washed with 2 x aqueous sulfuric acid (3 x 125 mL) followed by aqueous 0.5N ammonium hydroxide (120 mL). The organic phase is distilled under vacuum at 80 ° C until a residue of constant weight is formed. 594 g of 2- (N-isopropylamino) -4-methylbenzophenone are obtained. mp: 180-185 ° C / 5 mmHg; Yield: 94%.

Example 24

2- (N-Isopropylamino) -4-methylbenzophenone (Method A)

The procedure described in Example 22 was followed except that an equivalent amount of methanesulfonic acid, nitric acid, hydrobromic acid, trifluoroacetic acid and picric acid was used as the acid. The title product is obtained in a yield of at least 70%. During the reaction in the presence of trifluoroacetic acid, a trace amount of 2-trifluoroethylamino-4-methylbenzophenone is also formed as a by-product; the amount of this by-product increases with increasing acid concentration.

Example 25 (Method A)

1 to 24. The following compounds were prepared by essentially the same amount of starting materials as described in Example 1b.

a) 2- (N-isopropylamino) -5-chlorobenzophenone; IR (CH ₂ Cl ₂ in) -NH-band 3300 cm ^_1, .delta.

b) 2- (N-isopropylamino) -4,5-methylenedioxybenzophenone; mp 77-78 ° C.

c) 2- (N-isopropylamino) -4'-fluorobenzophenone; mp: 184-187 ° C / 2.5 mmHg.

Example 26

2- (N-Isopropylamino) -4-methylbenzophenone (Method B)

To a solution of 21.1 g of 2-amino-4-methylbenzophenone in 100 ml of acetone was added 100 ml of glacial acetic acid and the solution was cooled to 20 ° C. Sodium borohydride (10 g) was added portionwise over 70 minutes with stirring. After addition, the solution was stirred for an additional 20 minutes at 20 ° C and extracted with 100 ml of chloroform and 50 ml of water. The aqueous phase was extracted with chloroform (2 x 50 mL). The chloroform phases were combined, treated with 150 ml of 20% aqueous ammonium hydroxide solution, dried over magnesium sulfate, filtered and distilled to a residue of constant weight. There was thus obtained crude 2- (N-isopropylamino) -4-methylbenzophenone (25 g, 99%); this value corresponds to an actual yield below 90% of pure product.

Example 27

2- (N-Isopropylamino) -4-methylbenzophenone (Method B)

The same procedure as in Example 26 was used, but instead of acetic acid, a molar equivalent of propionic acid was used. The desired product is obtained in 85% yield.

Example 28

2- (N-Isopropylamino) -4-methylbenzophenone (Method B)

The procedure described in Example 26 was followed, however, using a water acetic acid solution of 90% by weight, 60% by weight and 36% by weight. The product was obtained in 59%, 27% and 9% yield respectively.

Example 29 (Method B)

26-28. The compounds of Example 25 were prepared using essentially equivalent amounts of the starting materials described therein.

Example 30

2- (N-1-Isopropylamino) -4-methyl-benzophenone (Method C)

422.6 g (2 mol) of 2-amino-4-methylbenzophenone are dissolved in 2.34 L (40.29 mol) of acetone and 540 g (3.25 mol) of phthalic acid are added with stirring. To the resulting suspension was added portions of sodium borohydride (80 g, 2.14 mol) over 45 minutes at such a rate that the reaction temperature was between 20 ° C and 25 ° C. After the addition, the reaction mixture was allowed to warm to 30-35 ° C and held at this temperature for 30 minutes. The cooling bath was then removed and the mixture was carefully heated to 50 ° C and kept at 50-55 ° C for 90 minutes. The mixture was then cooled to 15 ^h, 808 g of 8% aqueous solution of NaOH (= 1.625 mol NaOH) was added and the layers separated. The acetone solution obtained as the upper phase was concentrated. The aqueous phase is extracted with 1 L of heptane and the residue obtained after concentration of the acetone solution is added to the heptane extract. The resulting solution was washed with water (250 mL) and then distilled. 496 g (99%) of 2- (N-isopropylamino) -4-methylbenzophenone are obtained; mp: 180-185 ° C / 5 mmHg.

Example 31 (Method C)

In a similar manner to that described in Example 30, the compounds listed in Example 25 were prepared using substantially equivalent amounts of starting materials.

Example 32

Sodium dihydrogen phthalate borate ("Pea")

To a solution of 10.8 g of phthalic acid in 100 ml of tetrahydrofuran is added 1.6 g of powdered sodium borohydride in portions over 5 minutes with stirring. The temperature of the mixture is maintained at 25 ° C to 30 ° C by ice-cooling. The resulting mixture was stirred for 16 hours at 25 ° C, then filtered and the filtrate was evaporated. The resulting solid (15.2 g) was triturated with chloroform, filtered and dried under vacuum at 60 ° C under nitrogen. The crude sodium dihydrophthaloborate (1 -) is obtained as a white solid. The product melts at 15-60 ° C and decomposes at 150 ° C to form a white foam.

Example 33

Sodium dihydrogen phthalate borate ("Pea")

The procedure described in Example 32 was followed, but using 1.15 g of phthalic acid instead of 10.8 g. Sodium dihydro-25-phthalate borate (1 -) is obtained as a white solid, m.p.> 320 ° C. The product is very slightly yellowish at 180 ° C.

Example 34

2- (N-Isopropylamino) -4-methylbenzophenone (Method C)

The compound prepared as in Examples 32 and 33 was added at 30-35 ° C to a mixture of the corresponding 2-aminobenzophenone and acetone. The reaction gave 2-N-isopropylamino) -4-methylbenzophenone.

Example 35

2-Isopropylamino-4-methyl-benzonitrile

264 g of 2-amino-4-methylbenzonitrile, 504 g of phthalic acid and

To a mixture of 2.32 liters of "reagent" grade acetone, add 80 g of sodium borohydride in portions at 18-30 ° C. Addition takes 40 minutes. The resulting solution was stirred for 30 minutes. During this time, the temperature of the mixture 50 rises from 29-30 ° C to 35 ° C and then decreases to ° C. The resulting solution was heated at 34 ° C to 53 ° C for 30 minutes and then heated at 55 ° C for 1 hour. After cooling to 37 ° C, water (500 ml) was added followed by 417 g of 50% aqueous sodium hydroxide solution, and the mixture was allowed to warm to ° C to maintain the solution phase. An additional 92 ml of water was added and the acetone phase was separated from the aqueous brine at 45-50 ° C. The acetone layer was concentrated in vacuo and 800 ml of an aqueous saline solution diluted with 60 heptane were added to the resulting brown oil. The aqueous and heptane phases are separated. The heptane phase was dried, filtered and cooled to 10 ° C. The bulk of the desired 2-isopropylamino-4-methylbenzonitrile precipitates out of solution. The product melts at 55-57 ° C. Further amounts of product can be isolated from the mother liquor.

The previously separated aqueous saline solution was diluted to 4.5 liters with water, filtered and the filtrate was acidified with sulfuric acid. The bulk of the phthalic acid used is then regenerated. Prior to processing, the aqueous saline solution is combined with other aqueous alkaline solutions obtained in the previous steps.

Example 36

N-Isopropyl-anthranilic

To a mixture of 2.7 g of anthranilic acid, 5.4 g of phthalic acid and 23 ml of acetone, 0.7 g of powdered sodium borohydride is added portionwise at 20-30 ° C over 30 minutes. The resulting suspension was stirred for 4 hours at 35-40 ° C, then diluted with 25 ml of chloroform and filtered. The filtrate was concentrated in vacuo. The residue was dissolved in chloroform (20 ml), hexane (30 ml) was added, the mixture was filtered and the filtrate was concentrated in vacuo. The crude product obtained is recrystallized five times from cyclohexane. After the fifth recrystallization, a second generation of N-isopropyl anthranilic acid, m.p. 109-109.5 ° C, is obtained.

Example 37

The procedure described in Example 36 was followed, but using an equimolar amount of anthranilic acid ethyl ester instead of anthranilic acid. The product was obtained as N-isopropylethyl ester.

Claims (61)

A process for the preparation of compounds of the formula I and their acid addition salts, wherein R 1 and R _{2 represent the} same or different C 1-3 alkyl groups, however R ₁ and R ₂ may contain up to 4 carbon atoms in total, Rj and _R4 are independently hydrogen, fluoro, chloro, C1-4 straight chain alkyl or alkoxy or trifluoromethyl, with the proviso that R _4, 5 or 6-position is linked to the benzene ring and at most one of R ₃ and R ₄ is trifluoromethyl, or R ₃ and R _{4 taken} together may be C 1 or C 2 alkylenedioxy, and X represents cyano, a group -COOR (where R is hydrogen or C1-5 alkyl group) of the formula or a group (a) wherein Y and Y are _{independently} selected from hydrogen, fluoro, chloro, 1- C 4 straight alkyl or alkoxy or trifluoromethyl, provided that at most one of ¥ and Yj is trifluoromethyl, wherein a compound of formula II wherein R ₃ , R ₄ and X in the above liquid medium, in the presence of a reaction of a strong acid, a C 2 -C 4 saturated aliphatic carboxylic acid or a rigid coplanar divalent organic carboxylic acid and / or sulfonic acid (hereinafter referred to as an acid) and a With a compound of formula III wherein R 1 and R ₂ are as defined above and optionally converting the bases of formula (I) to their acid addition salts; optionally releasing the base from salts of the compounds of formula (I). (Priority: January 27, 1977) 2. The process according to claim 1, wherein the borohydride is boron tetrahydride. (Priority: January 27, 1977 3. The process of claim 2 wherein the borohydride is an alkali metal borohydride. (Priority: January 27, 1977) 4. A process according to claim 3 wherein the borohydride is sodium borohydride. (Priority: January 27, 1977) 5. A process according to any one of claims 1 to 3, characterized in that the borohydride is used in the fine-grained state. (Priority: January 27, 1977) 6. A process according to any one of claims 1 to 6, wherein the acid is a strong acid having a pH of 2 or less in a 10% aqueous solution. (Priority: January 27, 1977) 7. Process according to any one of claims 1 to 3, characterized in that the acid used is a strong acid having a pH of not more than 2 in a 10% aqueous solution, the reaction being carried out at 0-35 ° C with respect to water and the compound of formula II. in a reaction medium containing at least 20% molar excess of compound (III), using borohydride and compound (II) in a molar ratio of at least 1.7: 1, and using an excess of molar equivalent of acid to borohydride up. (Priority: January 27, 1977) 8. A process according to claim 7, wherein the reaction is carried out at a temperature of from 10 to 30 ° C and the compounds of formula (III) and (II) are used in a molar ratio of at least 3: 1. (Priority: January 27, 1977) Process according to claim 7 or 8, characterized in that the borohydride and the compound of the formula II are in a molar ratio of 2: 1 to 6: 1, while the compounds of the formulas III and II are The compound is used in a molar ratio of at least 8: 1 and the reaction is carried out in the presence of 10 to 90% by weight of aqueous acid solution in the presence of systemic water. (Priority: January 27, 1977) 10. Process for carrying out the process according to any one of claims 1 to 4, characterized in that the reaction is carried out at a temperature of 15 to 28 ° C, the borohydride and the compound of the formula II being 2: 1 to 4: 1, the and the compound of formula (I) is used in a molar ratio of 15: 1 to 50: 1 and the acid is used in an excess of 1.0-50% equimolar to the borohydride. (Priority: January 27, 1977) 11. Figures 7-10. A process according to any one of claims 1 to 4, wherein the strong acid is sulfuric acid. (Priority: January 27, 1977) 12. The process of claim 11 wherein the acid is present in an excess of 1.5 to 50% equimolar to the borohydride, generally (III) and (II). The compound of formula I is used in a molar ratio of 20: 1 to 45: 1 and the reaction is carried out with 25-60% by weight aqueous acid solution in the presence of systemic water. (Priority: January 27, 1977) 13. A process according to any one of claims 1 to 4, wherein the strong acid is hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, methanesulfonic acid, ethanesulfonic acid or p-toluenesulfonic acid. (Priority: January 27, 1977) 14. A 6-13. A process according to any one of claims 1 to 3, wherein the product of the reaction of the compounds of the formulas II and III is treated with a strong base. (Priority: January 1977 27.) 15. A process according to any one of claims 1 to 6, wherein the acid is a saturated carboxylic acid having from 2 to 4 carbon atoms having a pH of from 3 to 5 in a 98% by weight aqueous solution. (Priority: January 27, 1977) 16. Process according to any one of claims 1 to 3, characterized in that the acid is used in a 98% by weight aqueous solution of C 2 to C 4 saturated carboxylic acids having a pH of 3 to 5, and the reaction is carried out at 10 to 35 ° C borohydride and compound (II) in a molar ratio of 1.7: 1 to 4: 1, carboxylic acid and compound (II) in a molar ratio of at least 6: 1, and (III) and (II) ) in a molar ratio of at least 3: 1. (Priority: January 27, 1977) 17. A process according to claim 16, wherein the reaction is carried out at 15-30 ° C. (Priority: January 27, 1977) 18. A16. A process according to claim 1 or 17, wherein the borohydride and the compound of the formula II are in a molar ratio of 2: 1 to 3.2: 1, the carboxylic acid and the compound of the formula II in a ratio of 8: 1 and 30. 1: 1 and III is used in a molar ratio of 8: 1 to 30: 1. (Priority: January 27, 1977) 19, pp. 16-18. A process according to any one of claims 1 to 3, wherein the borohydride and the compound of the formula II are in a molar ratio of 2: 1 to 2.8: 1, the carboxylic acid and the compound of the formula II in a molar ratio of 10: 1 to 20: 1. and the compounds of formula (III) and (II) in a molar ratio of from 10: 1 to 20: 1. (Priority: January 27, 1977) 20. A process according to any one of claims 1 to 3, wherein the acid is acetic acid or propionic acid. (Priority: January 27, 1977) 21. A process according to claim 20 wherein the acid is acetic acid. (Priority: January 27, 1977) 22, pp. 15-21. A process according to any one of claims 1 to 4, wherein the reaction is carried out in a mixture containing up to 8% water by weight of the carboxylic acid. (Priority: January 27, 1977) 23. The process according to claim 22, wherein the reaction is carried out in a mixture containing up to 5% water by weight of the carboxylic acid. (Priority: January 27, 1977 24. The process of claim 1 wherein the compound of Formulas II and III is in a liquid medium, one of boron tetrahydride and one of rigid coplanar divalent organic carbonic and / or sulfonic acids or one of boron tetrahydride. reacting with each other in the presence of a product formed by the reaction of a rigid coplanar divalent organic carbonic and / or sulfonic acid. (Priority: January 27, 1977) 25. The process according to claim 24, wherein the compound of formula (II) and (III) is reacted in a liquid medium in the presence of a boron tetrahydride and a rigid coplanar divalent organic carbonic and / or sulfonic acid product. with each other. (Priority: January 27, 1977) 26. The process according to claim 25, wherein the compound of formula (II) and (III) and the reaction product of boron tetrahydride and acid are reacted at 0-100 ° C. The compound (II) is used in an excess of at least 20% relative to the compound (II) and the compound (II) is used in a molar ratio of 0.7: 1 to 2.5: 1 relative to the reaction product. (Priority: January 1977 27.) 27. A process according to claim 26, wherein the reaction is carried out at a temperature of from 20 to 85 ° C, wherein the compounds of formula (III) and (11) are used in a molar ratio of at least 3: 1, and the compound of formula II is used in a molar ratio of 0.7: 1 to 1.65: 1 relative to the reaction product of the acid and boron tetrahydride. (Priority: January 27, 1977) 28. The process of claim 27, wherein the reaction is carried out at 30 to 65 ° C, wherein the compounds of formula (III) and (II) are used in a molar ratio of at least 8: 1, and the compound of formula (II) is used in a molar ratio of 1: 1 to 1.5: 1 relative to the reaction product of the acid and boron tetrahydride. (Priority: January 27, 1977) 29. A 26-28. Process according to any one of claims 1 to 3, characterized in that the compound of formula (III) and the compound of formula (II) is between 15: 1 and 50: 1 and the compound of formula (II) in a ratio of 1: 1 to 1.3: 1 molar ratio. (Priority: January 27, 1977) 30. A 26-29. Process according to any one of claims 1 to 3, characterized in that the compound of formula (III) and the compound of formula (II) is between 20: 1 and 45: 1, and the compound of formula (II) is 1: 1 and 1.15: 1 molar ratio. (Priority: January 27, 1977) 31. The process of claim 30, wherein the reaction is carried out in a mixture containing up to 8% by weight of water, based on the total amount of solvent. (Priority: January 27, 1977) 32. The process of claim 31, wherein the reaction is carried out in a mixture containing up to 2% by weight of water, based on the total amount of solvent. (Priority: January 27, 1977) 33. At pages 25-32. Process according to any one of claims 1 to 3, characterized in that the reaction product is a product obtained by reacting boron tetrahydride with an acid at a temperature of from -40 ° C to + 85 ° C with a molar ratio of borohydride to acid of at least 0.7: 1. (Priority: January 27, 1977) 34. In paragraphs 25-33. Process according to any one of claims 1 to 3, characterized in that the reaction product is formed in the reaction mixture itself by adding boron tetrahydride at 0 to 30 ° C to a mixture of further reagents and an acid: borohydride molar ratio of 0.7: 1 to 10: 1. (Priority: January 27, 1977) 35. The process of claim 34, wherein the boron tetrahydride is added at a temperature of 10 to 25 ° C, and the acid: borohydride molar ratio is maintained between 1: 1 and 2: 1. (Priority: January 27, 1977) 36. The process of claim 34 or 35 wherein the molar ratio of acid to borohydride is between 1.1: 1 and 1.8: 1. (Priority: January 27, 1977) 37. A 34-36. A process according to any one of claims 1 to 4, wherein the acid: borohydride molar ratio is maintained between 1.1: 1 and 1.6: 1. (Priority: January 27, 1977) 38. A 34-37. A process according to any one of claims 1 to 4, wherein after the addition of borohydride, the temperature of the mixture is raised to 30-85 ° C. (Priority: January 27, 1977) 39. The process of claim 38, wherein the temperature of the mixture is increased to 40-65 ° C. (Priority: January 27, 1977) 40. A 25-33. A process according to any one of claims 1 to 3, wherein the reaction product is prepared in a separate step such that the acid and boron tetrahydride are in an inert solvent at a temperature of -40 ° C to 85 ° C, between 0.7: 1 and 5: 1 acid: boron tetrahydride molar ratio. (Priority: January 27, 1977) 41. A process according to claim 40 wherein the inert solvent is tetrahydrofuran and the reaction is carried out at an acid to boron tetrahydride molar ratio of from 1: 1 to 2: 1 at 0-35 ° C. (Priority: January 27, 1977) 42. A process according to claim 40 or 41, wherein the acid and boron tetrahydride are used in a molar ratio of 1.1: 1 to 1.8: 1. (Priority: January 27, 1977) 43. The process of claim 42, wherein the acid and boron tetrahydride are used in a molar ratio of 1.1: 1 to 1.5: 1. (Priority: January 27, 1977) 44. The process of claim 43, wherein the acid and boron tetrahydride are used in a molar ratio of 1.1: 1 to 1.3: 1. (Priority: January 27, 1977) 45. In paragraphs 24-44. A process according to any one of claims 1 to 4, wherein the boron tetrahydride is an alkali metal borohydride. (Priority: January 27, 1977) 46. The process of claim 45, wherein the alkali metal borohydride is sodium borohydride. (Priority: January 27, 1977) 47. A 24-46. A process according to any one of claims 1 to 3, characterized in that it is an acid 1. acyclic, unsaturated divalent acids containing a carbon-carbon double bond in which a carboxylic or sulfonic acid group is attached to the unsaturated carbon atoms and the compounds are in the cis configuration; 2. unsaturated ring divalent acids having a ring-carbon-carbon double bond in which a carboxylic or sulfonic acid group is attached to the two unsaturated carbon atoms in the ring, and these carbon atoms (a) adjacent to each other, or (b) adjacent to a common carbon atom in the fused ring system, or 3. Cyclic divalent acids in which two carboxylic or sulfonic acid groups are attached to two saturated ring carbon atoms and which are consequently rigidly attached to each other in exo or endo configuration by the structure of the molecule. (Priority: January 27, 1977) 48th embodiment The method according to claim 47, characterized in that a compound of formula acid (IV) - wherein ACJ and AC ₂ are each independently -COO- or -SO ₃ groups and with respect to each other such groups in the cis configuration are located wherein Z ₁ and Z ₂ independently represent hydrogen or an organic group or Z ₁ and Z ₂ may optionally be bonded to one another. (Priority: January 27, 1977) 49. The process of claim 48, wherein the acids of formula IV are those wherein Z ₁ and Z ₂ are independently hydrogen or hydrocarbon. (Priority: January 27, 1977) 50. The method of claim 48 or 49 embodiment, characterized in that used as (IV) acid of formula in which both AC and ACJ ₂ represents a -COO group. (Priority: January 27, 1977) 51. A 48-50. A process according to any one of claims 1 to 3, wherein the acid is o-phthalic acid. (Priority: January 27, 1977) 52. A 48-50. A process according to any one of claims 1 to 4, wherein the acid is naphthalic acid. (Priority: January 27, 1977) 53. A 24-52. Process according to any one of claims 1 to 4, characterized in that the reaction product of the acid and boron tetrahydride is a compound of formula (V) - wherein X represents the anion of a rigid, coplanar, divalent organic carbonic and / or sulfonic acid, represents one equivalent of my metal. (Priority: January 27, 1977) 54. The process of claim 53, wherein the reaction product of the acid and boron tetrahydride is a compound of formula (Va) - wherein Z ₁ , Z ₂ , AC ₁ and AC ₂ are as defined in claims 48 to 50. and M is as defined in claim 53. (Priority: January 27, 1977) 55. The process of claim 54, wherein the reaction product of the acid and boron tetrahydride is a compound of formula (Vaa): wherein M is as defined in claim 53. (Priority: January 27, 1977) 56. The process of claim 54, wherein the reaction product of the acid and boron tetrahydride is a compound of formula (Vab): wherein M is as defined in claim 53. (Priority: January 27, 1977) 57. Process according to any one of claims 1 to 3, characterized in that the reaction products of the formula V, Va, Vaa or Vab, in which M represents an alkali metal atom, are obtained from the reaction of the acid and boron tetrahydride. (Priority: January 27, 1977) 58. The process according to claim 57, wherein the reaction product of formula V, Va, Vaa or Vab is obtained from the reaction of the acid and boron tetrahydride, wherein M is a sodium atom. (Priority: January 27, 1977) 59. A process for the preparation of compounds of the formula I and their acid addition salts - wherein _R} and _R2 are each independently C1-3 alkyl, but R, and R ₂ group may contain a total of up to 4 carbon atoms, R ₃ and R ₄ are independently hydrogen, fluoro, chloro, C 1-4 straight chain alkyl or alkoxy, or trifluoromethyl, with the proviso that R ₄ is attached at the 5 or 6 position on the benzene and at most one of R ₃ and R ₄ may be trifluoromethyl, or R ₃ and R _{4 taken} together may be C 1 or C 2 alkylenedioxy, and X is a group wherein Y and Yj are independently hydrogen, fluoro, chloro, C 1-4 alkyl or alkoxy, or trifluoromethyl, provided that at most one of Y and Yj is trifluoromethyl Characterized in that a compound of formula II - wherein R ₃ , R ₄ and X are as defined above - in a liquid medium in a C 2 -C 4 aqueous solution of 98% w / w is a pH of 3 to 5 and reacting a borohydride or a reaction product of such an acid with a borohydride with a compound of formula III wherein R 1 and R ₂ are as defined above and optionally converting the bases of formula I to their acid addition salts. optionally releasing the base from salts of the compounds of formula (I). (Priority: January 29, 1976) (653,361) 60. A process for the preparation of compounds of the formula I and their acid addition salts - wherein R ₁ and R _{2 are the} same or different C 1-3 alkyl groups, but R ₁ and R ₂ may contain up to 4 carbon atoms in total, R 1 and R ₄ are independently hydrogen, fluoro, chloro, C 1-4 straight chain alkyl or alkoxy, or trifluoromethyl, with the proviso that R ₄ is attached at the 5 or 6 position on the benzene ring and R _(R are one of up to ₄ represent a trifluoromethyl group, or R ₈ and R _{4 taken} together may form a C 1 or C 2 alkylenedioxy group, and X is a group wherein Y and Yj are independently hydrogen, fluoro, chloro, C 1-4 alkyl or alkoxy, or trifluoromethyl, provided that at most one of Y and Yj is trifluoromethyl Characterized in that a compound of formula II, wherein R ₃ , R ₄ and X are as defined above, is a strong acid with a pH of not more than 2 in a 10% aqueous solution and a borohydride or one such acid and, in the presence of a reaction product of a borohydride, with a compound of formula (III) wherein R 1 and R ₂ are as defined above, and optionally converting the bases of formula (I) to their acid addition salts, respectively. optionally releasing the base from salts of the compounds of formula (I). (Priority: January 29, 1976) (653,362) 61. A process for the preparation of compounds of the formula I and their acid addition salts - wherein R 1 and R _{2 represent the} same or different C 1-3 alkyl groups, however, R 1 and R ₂ may contain up to 4 carbon atoms together, R ₃ and R ₄ are independently hydrogen, fluoro, chloro, C 1-4 straight chain alkyl or alkoxy, or trifluoromethyl, with the proviso that R ₄ is attached at the 5 or 6 position on the benzene and at most one of R ₃ and R ₄ may be trifluoromethyl, or R ₃ and R _{4 taken} together may be C 1 or C 2 alkylenedioxy, and X is a group wherein Y and Yj are independently hydrogen, fluoro, chloro, C 1-4 alkyl or alkoxy, or trifluoromethyl, provided that at most one of Y and Yj is trifluoromethyl Characterized in that a compound of formula II, wherein R ₃ , R ₄ and X are as defined above, in a liquid medium, is a rigid coplanar divalent organic carbonic and / or sulfonic acid and an alkali metal tetraborohydride or an acid thereof; in the presence of a reaction product of an alkali metal tetraborohydride with a compound of formula (III) wherein R 1 and R ₂ are as defined above and optionally converting the bases of formula (I) to the acid addition salts or liberating the salts of the compounds of formula (I) base. (Priority: November 26, 1976)