JPS604817B2 - Production method of aminopyridine - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing 4-aminopyridine, in which the amino group at position 41 may be present in free or substituted form.

The reaction products serve in particular as acylation catalysts or are suitable as intermediates for the production of pharmaceutical active substances. Amin [L.M. LiWinenko
) Others, Chemical Apstruck (C.A.), vol. 68, 68325 (1968)] and alcohol [W.SPglich and Höffle (G.
．． Written by Angewante Hemy
．． Chemie), volume 81, page 1001 (196g King)
, Tetrahedron Letters
LeMrs, p. 4727 (1970) and Synthesis, 1972, p. 619] in the selective and accelerated acylation of 4-dialkylaminopyridines, especially 4-dimethylaminopyridine and 4-dimethylaminopyridine.
-Pyrrolidinopyridine as an acylation catalyst (West German Patent Publication No. 1958954, German Patent Publication No. 213785)
No. 6) Used.

The conventionally known processes for preparing substituted 4-aminopyridines are, however, difficult to carry out. Furthermore, the necessary starting materials can only be produced through a number of expensive steps. That is, for example, 4-chloropyridine is aminated with dimethylamine at 150°C under pressure [benchmarking (L
．． Pentimalli), Gazz. Chim. l
tal. , No. 94, p. 902 (1964)] or the silylated 4-pyridone is reacted with an amine such as pyrrolidine under acidic catalysis [Fuorbrütsgen (Japan.
4-pyridyl phenyl ether [D.
l) Ike, Chemische Berichte (Chem.Be
r), Vol. 91, p. 1266 (1958 Wang)] is converted with a secondary amine into the corresponding 4-dialkylaminopyridine. By the way, the 4-aminopyridine can be easily obtained in an industrially usable manner with a suitable acid amide which is likewise easily obtainable from 4-pyridyl-pyridinium chloride or a salt thereof, preferably a hydrochloride. It has been found that it can be produced immediately by reacting.

Therefore, the present invention relates to the general formula [1}: [wherein R and R2 may be the same or different and, together with hydrogen or a lower alkyl group or a nitrogen atom, additionally one or more 4-pyridyl-pyridinium-chloride or a salt thereof is prepared by using the general formula '2): [In the formula, R and R2 are as described above, and Z is a group -CO mountain R3 (in the formula, R3 is hydrogen, lower alkyl, or a group in which R4 and R5 are a hydrogen atom or a lower alkyl group), or The present invention relates to a process for the preparation of aminopyridines, characterized in that they are reacted at elevated temperatures with acid amides of the group (R4 and R5 are as defined above).

Lower alkyl groups for R,, R2, R3, R4 and R5 are straight-chain and branched saturated hydrocarbon groups having 1 to 6 C atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, Sec-butyl, bentyl,
Mention may be made of hexyl, tert-butyl, especially those having 1 to 4 C atoms. R, and R2 together with the nitrogen atom may additionally contain one or more heteroatoms, preferably other heteroatoms, such as N, 0 or S. When a member polycyclic ring is represented, it is a hydrogenated heterocycle such as pyrrolidone, piveridine, lower alkyl group, and the above-mentioned R. N4-alkylpiveridines, morpholines, thiomorpholines and azepines having an alkyl group of the meaning ˜R5. Preference is given to 5- or 6-membered rings.
Acid amides of the general formula '21 are especially amides of intermediate strong and weak acids, preferably of formic, acetic, carbonic and phosphoric acids.

Examples of acid amides include: dimethylformamide, dimethylacetamide, tetramethylurea, hexamethylphosphoric triamide, N-formylpyrrolidine, N-formylpiveridine, N-formylmorpholine, N-methylformamide, N- Methylacetamide, formamide, urea, acetamide, etc.

When carrying out the process of the invention, the acid amide of the general formula (2) used is generally a solvent which does not prevent the optional addition of an inert organic solvent as a diluent or as a dissolving agent to the reaction mixture. useful at the same time.

However, if the acid amide is present in solid form, the reaction is carried out in the melt or optionally in the presence of an inert organic solvent. The reactants are reacted in molar amounts. However, it is advantageous to use an excess of acid amide, preferably 1 to 5 equivalents. The reaction is carried out at an elevated temperature, for example at the boiling point of the acid amide or solvent used, preferably from 120 DEG to 220 DEG C.
In order to achieve the best yield of the desired reaction product, it is advantageous to remove the pyridine formed during the reaction continuously from the reaction mixture, for example via a short distillation column. The reaction ends when about 1 mole of pyridine formed is distilled off. The reaction products can be isolated in a conventional manner, for example by adding an aqueous alkali to the reaction mixture in excess, preferably 2 to 3 molar, and separating the reaction products by steam distillation or exhaustive extraction with, for example, methylene chloride. Next, the present invention will be explained in detail with reference to embodiments.

Example 1 Crude 4-pyridyl-pyridinium chloride hydrochloride (0r
g. Synthesis Coil. (Refer to Vol. V, page 977) 299 mmol (1 mol) was mixed with 146 mmol of dimethylformamide.
Dissolve at about 140-150°C in 2 mols (2 moles) and heat under a rope at a normal temperature of 18 pico Celsius for 2 hours.

At that time, crude pyridine (boiling point 111-11〆0) 90'
is annihilated. The colored residue is left in a homogenized solution with NaOHIOO, concentrated and separated from the black undissolved residue, and the residue and solution are thoroughly extracted with methylene chloride. After drying of methylene chloride extract (Na2S04) and treatment with a little carbon, crude 4-dimethylaminopyridine 68.3
An aqueous solution (56%) is obtained which dissolves at 112-1130 C after recrystallization from diisopropyl ether. Example 2 Same as Example 1, but instead of 146.2 moles of dimethylformamide (2 moles), 174 moles of dimethylacetamide (2 moles) was used.
2 mol) is used.

After similar heating and work-up, 74.2 g (61%) of 4-dimethylaminopyridine are obtained. Example 3 Example 1 is carried out, but 2 to 3 mol of tetramethylurea are used instead of dimethylformamide.

4-dimethylaminopyridine with a melting point of 112-11 C is obtained in a yield of 56%. Example 4 4 in 179 molar (1 mol) of hexamethylphosphoric acid triamide
-Pyridyl-pyridinium chloride hydrochloride 229mg (
1 mol) of pyridine and pyridine (40')
Heat to 220°C for an hour.

After cooling, the remaining liquid was collected in a container with a temperature of 0500 ml, and 1. Heat the insects in a steam bath for an hour. A weakly acidic solution (pH approximately 5) was placed on a soft folded monkey paper, and the non-stable brown component was washed twice with CIIOO for one day each time. 40% KO of purified monkey fluid
Make alkaline at about 200 H and thoroughly extract with methylene chloride. After drying (Na2S04) and evaporation, the remaining viscous oil (107.59%) is boiled with 1.5% diisopropyl ether and treated with a little carbon. pure 4-
65.79 g (53.8%) of dimethylaminopyridine crystallizes out. Example 5 Crude 4-pyridyl-pyridinium chloride hydrochloride 22.9 in N-formyl-pyrrolidine 30 (0.3 mol)
3. Yu (0.1 mol). Heat to 180℃ under a light bulb for a while.

At that time, pyridine is distilled off. One night of the color coin book -Na
Leave to stand with 250' of OH and thoroughly extract with methylene chloride. After drying (Na2S04), carbonation and evaporation, the extract yields a brown oil of 11.5 mm, which is boiled several times with methylene chloride/hexane.

Recrystallization of the extract from hexane gives a melting point of 55-570
4-pyrrolidium/-pyridine 8.95% (60.5%)
is obtained. Example 6 22.99 (0.1 mol) of crude 4-pyridyl-pyridinium chloride hydrochloride was prepared as described in Example 3 to 33.9 (0.1 mol) of N-formylupiveridine.
3 mol) and work-up.

4.352 (58%) of 4-piveridinopyridine is obtained after recrystallization from ligroin with a melting point of 81.degree. Example 7 The reaction of 4-pyridyl-pyridinium chloride hydrochloride and N-formyl-morpholine, carried out in exactly the same manner as in Examples 5 and 6, produced 4-morpholinopyridine with a melting point of 93-95°C (from chestnut groin) in a yield of 59%. bring about.

Example 8 Crude 4-pyridyl-pyridinium chloride hydrochloride 344
241 moles of N-methylformamide (1.5 mol)
4.2 mol) and heated to 190 oo for 2.5 hours under water.

At this time, pyridine 120 secretion is distilled off. After cooling, the black retentate is left in S-NaOHIOO for 1 hour and thoroughly extracted with methylene chloride. Drying (Na2S04)
After treatment with a little carbon and evaporation, crude yellow crystalline 4-methyl-aminopyridine 85% (52.5%)
is obtained, which after recrystallization from toluol is 121-1
Melt at 24oo. Example 9 The procedure is as in Example 8, but N-methylacetamide is used instead of N-methylformamide.

Yield: 4-methylaminopyridine 53%, melting point 121~
12400. Example 10 4-Pyridyl-pyridinium chloride hydrochloride 115 mol (0.5 mol) is heated to 150 qo in 100 mol of formamide (2.5 mol) under concentrated conditions.

At that time, everything becomes a solution and slowly and carefully heat it to 180°C.
Heat to remove the pyridine (the solution will be very foamy). After 1 hour at 18,000 degrees Celsius, it is cooled and heated at steam temperature for 3 hours with a solution of 20,500 degrees NaOH and 120 degrees Celsius, and the mixture is poured through glass cotton.

The residual liquid is washed with methylene chloride, and the slightly alkaline liquid is thoroughly (continuously) extracted with methylene chloride. At that time, 24.9 4-aminopyridine with a melting point of 156 to 158 °C
Evening (53%) is obtained. Example 11 The procedure is as in Example 7, but acetamide is used instead of formamide.

Yield: 58% of 4-aminopyridine. Example 12 4-pyridylupyridinium chloride hydrochloride is reacted as described in Example 10 with 3 to 5 equivalents of urea.

Claims (1)

[Claims] 1 General formula (1): ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R_1 and R_2 may be the same or different, and may be hydrogen, a lower alkyl group, or an 4-pyridyl-pyridinium-
Chloride or its salt with general formula (2): ▲ mathematical formula, chemical formula,
There are tables, etc. Acid amide and enhanced group ▲ has a mathematical formula, chemical formula, table, etc. ▼ ) or a group ▲ has a mathematical formula, chemical formula, table, etc. ▼ (wherein R_4 and R_5 are as above) A method for producing aminopyridine characterized by reaction at temperature.