FI66174C - FOERFARANDE FOER FRAMSTAELLNING AV PYRIDINKARBOXYLSYRA-PIPERAZIDER - Google Patents

Description

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w Patent aeddalat (51) K * j3 / tatCL3 C 07 D 213/78 FINLAND —FINLAND 782031 (22) Hrimnl ^ 1M — AtuBIwlngiin 26.06.78 (23) ΑΜηφβΜ — GIMfkatatfaf 26.06.78 (41) TMhftMkMnl —MvkaAiM 78 PMM-odh <*> 31.05.81, (32) (33) (31) «otoHnw — aagM prtorkK 30.06.77

Hungary-Hungary (HU) EE-2510 (71) E GY T Gyögyszervegyäszeti Gyär, 30, Kereszturi u., Budapest X, Hungary-Hungary (HU) (72) Zoltan Budai, Budapest, Tibor Mezei, Budapest,

Aranka Lay, Budapest, Hungary-Hungary (HU) (7 * 0 Oy Koister Ab (5A) Method for the preparation of pyridinecarboxylic acid piperazides -Förfarande för framstälIning av pyridininkarboxylsyra-piperazider

The invention relates to a new process for the preparation of pyridinecarboxylic acid piperazides and their acid addition salts. The compounds of this invention have the general formula I

ac- / n-R1 (I) o wherein R1 · is a methyl or benzyl group, and - together with their acid addition salts - have valuable cardiovascular and antidepressant properties.

2 66174

Compounds of general formula I are known in the art and have already been described in "Farmacia" (Bucharest) 10, 35, 81 (1962) and in Hungarian Patent No. 162,396.

The following three methods have been used to prepare the compounds of general formula I - in which R1 is as defined above:

a) the pyridinecarboxylic acid is reacted with a piperazine derivative of general formula V

Ht ^ _ ^ J-R1 (V) wherein R1 is as defined above, in a melt at a temperature between 140-250 ° C for 20-25 hours.

b) the pyridinecarboxylic acid is converted into the corresponding ester or amide derivative, which is then reacted with a piperazine derivative of general formula V - wherein R * is as defined above - in the same manner as described above in connection with method a).

c) the pyridinecarboxylic acid is converted into the corresponding acid chloride, which is then reacted with a compound of general formula V - which means the same as above - at a temperature between 0 ° C and 100 ° C.

Methods a) and b) can be carried out in a yield of about 40-60%, while in method c) a yield corresponding to 68% of the theoretical value is obtained. The product prepared by any of the above methods is purified by vacuum distillation.

To find a rational explanation for the relatively low yield when operating according to method a), the reaction was monitored thermogravimetrically. It has been found that when a pyridine-2-carboxylic acid melt is reacted with N-benzylpiperazine or when pyridine-2-carboxylic acid and N-benzylpiperazine are melted together, a significant weight loss can be observed already at 120 ° C due to the decarboxylating side reaction. In other words, the main reaction, when carried out in the optimum temperature range, involves a side reaction which results in a considerable 3 66174 loss in the final product.

The above method b) could theoretically be expected to have more favorable yields, but given that an additional reaction step is required for the preparation of the starting compounds, the overall yield is the same or even lower than in the case of method a).

On the other hand, methods b) and c) have additional disadvantages in that the preparation of the starting material in process b) and the considerable amount of ammonia generated during the reaction cause pollution problems and the hydrochloric acid formed in process c) is very difficult to bind and remove.

The present invention seeks to provide a process for the preparation of compounds of general formula I without the above disadvantages, i.e. low or reasonable yields, long reaction times, high temperatures and purification by fractional distillation in vacuo, and without the formation of environmentally polluting dvtu products.

It has now surprisingly been found that almost all of the disadvantages set out above can be eliminated and a very pure final product obtained by subjecting a pyridinecarboxylic acid of formula II

COOH (II)

an organic or mineral salt for reaction with a chloroformic acid ester of general formula III

Cl- CO2 - R (m)

wherein R is an alkyl group having 1 to 3 carbon atoms in an inert solvent and then reacting the resulting pyridinecarboxylic acid derivative of general formula IV

wherein R is -O-CO 2 R (IV) 'N 2 O 0 4 66174 wherein R is as defined above, preferably without separation, to react with a piperazine derivative of general formula V wherein R 1 is as defined above - and if desired , the compound of general formula I obtained is converted into its acid addition salt by reaction with a suitable organic or inorganic acid.

As the inert solvent, any solvent which does not participate in the chemical reaction under the given conditions and thus does not affect the course of the reaction can be used. For example, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, dioxane and ethyl acetate were found to be useful for this purpose.

The pyridine carboxylic acid salt used as a starting material can be prepared with a tertiary amine, e.g. triethylamine or N-methylmorpholine, or an inorganic base such as potassium hydroxide, but other alkali metal salts can also be used advantageously.

Starting from salts prepared with organic bases, the reaction takes place in a homogeneous medium and pre-preparation of the salt is not necessary, whereas in the case of a salt prepared with an inorganic base, the reaction takes place in a heterogeneous medium and the salt must be prepared in advance.

The reaction can be carried out over a wide range of temperatures without substantially varying the yield obtained. The temperature is generally between -20 ° C and + 40 ° C, preferably between -5 ° C and + 20 ° C.

When the reaction mixture is treated with water, the product dihydrate precipitates in crystalline form and subsequent purification by fractional distillation in vacuo can be omitted. The main advantages of the process according to the invention compared to the prior art processes are as follows: the reaction is completed in a short time; - no elevated temperature is required; - no special equipment is required; - the by-product is not harmful to the environment; and - the compounds of general formula I can be obtained almost quantitatively in excellent purity.

66174

Further details of the invention are illustrated by the following examples.

Example 1 Preparation of 1-benzyl-4- (2'-picolyl) piperazine 246.2 g (2.0 moles) of pyridine-2-carboxylic acid are reacted with 202.4 g (2.0 moles) of triethylamine in ethyl acetate. 217.1 g (2 moles) of ethyl chloroformate are then added at -5 to 0 ° C and the reaction mixture is stirred at this temperature for 30 minutes. The mixture is then treated with 352.5 g (2.0 mol) of N-benzylpiperazine in 400 ml of ethyl acetate for half an hour. After the addition of the above solution is complete, the reaction mixture is stirred for another 2 hours at 10 ° C. The ethyl acetate solution is evaporated in vacuo, then the residue is dissolved in methanol and precipitated with water.

Yield: 615 g. (97%).

Melting point of the corresponding dihydrate: 81 ° C to 82 ° C.

Analysis for C17H23N3O2H2O:

Calculated: C = 64.33%; H = 7.30%; N = 13.24%; Found: C = 64.25%; H = 7.42%; N = 13.15%;

Melting point of the corresponding hydrogen fumarate: 165 ° C to 166 ° C (literature m.p. 164 ° C).

Example 2 Preparation of 1-methyl-4- (3'-nicotinoyl) piperazine 16.1 g (0.1 mol) of the potassium salt of nicotinic acid are reacted with 10.8 g (0.1 mol) of ethyl chloroformate in a mixture of dimethylformamide and tetrahydrofuran - At 5 ° C to 0 ° C and 10.0 g (0.1 mol) of an ethyl acetate solution of methylpiperazine are added to the reaction mixture at the same temperature.

The mixture is stirred at + 10 ° C for a further 2 hours and evaporated in vacuo. The residue is dissolved in dichloroethane, the solution obtained is washed with water, evaporated and the residue is partitioned in vacuo.

Yield: 18.25 g (89.0%).

Boiling point: 146 ° C - 149 ° C / 0.1 mmHg.

Analysis for CH 2 Cl 2: N 3 O:

Calculated C = 64.46%; H = 7.3%; N * 20.47%; Found: C = 64.15%; H = 7.43%; N = 20.56%.

Melting point of the corresponding dichlorohydrate: 130 ° C.

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Example 3 Preparation of 1-methyl-4- (4'-isonicotinoyl) piperazine 12.3 g (0.1 mol) of isonicotinic acid are salified by reaction with 10.1 g (0.1 mol) of N-methylmorpholine in ethyl acetate solution. To the reaction mixture is added 9.40 g (0.1 mol) of methyl chloroformate at a temperature between -5 ° C and 0 ° C, followed by the addition of 10.0 g (0.1 mol) of N-methylpiperazine in ethyl acetate at the same temperature. The reaction mixture is stirred for 2 hours at + 10 [deg.] C. The N-methylmorpholine hydrochloride salt obtained is filtered off, the filtrate is evaporated and the residue is partitioned in vacuo.

Yield: 17.2 g (84%)

Boiling point: 147 ° C - 149 ° C / 0.2 mmHg.

Analysis for C - ^^ H ^^ NjO:

Calculated: c = 64/36%. H = 7.37 n = 20.47%; Found: C = 64.52%, H = 7.48%; N = 20.31%.

Melting point of the corresponding dichlorohydrate: 271 ° C.

Claims (5)

66174 A process for the preparation of pyridine carboxylic acid piperazides of the general formula I (P ^ cn ^ Yh1 wa in which R · * · is a methyl or benzyl group and Tiide acid addition salts, characterized in that a pyridinecarboxylic acid having is an organic or inorganic salt of formula II O-COOK (II), optionally without separation, to react with a chloroformic acid ester of general formula III C1-CO-R2 (lii) wherein R is alkyl having 1 to 3 carbon atoms, in a homogeneous or heterogeneous in the system, in the presence of an inert solvent, and further reacting the resulting pyridinecarboxylic acid derivative of general formula IV (R 2 -CO-CO 2 R S, <R 11 n 0 66174 wherein R is the same as above, preferably without separation, with a substituted piperazine, of the general formula V / 1, _I} -R (V) in which R 1 is the same as above, and if desired, the base of the general formula I obtained is converted into its acid addition salt in this way. Process according to Claim 1, characterized in that a tertiary amine, preferably triethylamine or N-methylmorpholine, is used as the organic base. Process according to Claim 1, characterized in that an alkali metal hydroxide, preferably potassium hydroxide, is used as the inorganic base. 9 66174 A process for the further preparation of pyridinecarboxylic acid piperazide according to the formula I | T ^ -Cl / n-B1 l v_y (I) for a methyl or benzyl group, and for the addition of a methyl or benzyl group, for which a mixture is used. organic or organic sites of pyridinecarboxylic acid in the form of formula II O-COGH (II) valfrite after separation, with chlorohydroxyester under the formula III C1-CO2-R (III) with R is an alkyl of 1-3 cholaters, which is homogeneous or the hetero-Gent system in which the inert solution and the mixture are derived from pyridine carboxylic acid derivatives having the formula IV Qr ~ * "0