DD240010A1 - PROCESS FOR PREPARING SUBSTITUTED 2-IMINO-1H-PYRIDINE-1-AMINES - Google Patents

Abstract

The invention relates to a process for the preparation of substituted 2-imino-1H-pyridin-1-amines. Such compounds are important for the preparation of cardiovascular drugs. The aim of the invention is to make available substituted 2-imino-1H-pyridin-1-amines, starting from readily accessible and easily handled starting materials which do not yet contain a pyridine ring. According to the invention, this object is achieved by reacting 4-amino-1-cyano-butadiene- (1,3) with hydrazines advantageously in an organic solvent to give the substituted 2-imino-1H-pyridin-1-amines of general formula I. , The invention can be used in the chemical and pharmaceutical industries. Formula I

Description

in the R 'and R ^{2 are} identical or different hydrogen, alkyl or aryl or R' R ² together a tetra-, penta-, 3-oxapenta or 3-azapentamethylene bridge, R ^{3 is} hydrogen or an aryl radical, R ⁴ and R ^{5 is} hydrogen , an alkyl, aryl or heteroaryl radical or R ⁴ R ⁶ together form a tri-, tetra- or pentamethylene bridge or a benzo-fused alkenylene bridge, for example 0-C ₆ H ₄ -CH ₂ -OdBrO-C ₆ H ₄ -CH ₂ - CH ₂ -, and R ^{e represents} an aryl radical, a cyano, carbonyl or nitro group, are prepared by reacting a 4-amino-1-cyano-butadiene (1.3) of the general formula II [P. Köckritz, J. Liebscher: DD 219 022]

R ³ R ⁴ R ⁵ R ⁶

7 8 i 1 IIR ⁷ R ⁰ NC = CC = C-CN

II

with R ^3, R ^4, R ^5, R ⁴ R ⁵ and R ^e stated meaning and R ⁷ and R ⁸ the same or different is an alkyl and / or aryl group or R ⁷ R ⁸ together form a tetra-, penta- , 3-oxapenta or 3-azapentamethylene bridge, with a hydrazine of the general formula III

R ¹ R ² N-NH ₂

III

with the meaning explained for R ¹ and R ² or R ¹ R ² or a salt of a hydrazine of the general formula III, advantageously in an organic solvent.

The inventive method makes it possible to make the substituted 2-lmino-1 H-pyridin-1-amines of the general formula I accessible in a simple manner, starting from easily accessible and easy to handle, durable compounds that do not yet contain a pyridine. The required reaction times are short and the yields achieved are high. The resulting products are new, allowing them to access new cardiovascular drugs. Surprisingly, in the process according to the invention by hydrazine no cleavage of the C ¹ , C ² double bond in the 4-amino-1-cyan-butadienen- (1,3) of the general formula II used, although under comparable conditions as in the known reaction of 4-chloro-1-cyano-butadiene- (1,3) was worked with hydrazine. The expected afterwards acroleinazines do not arise.

embodiments

The substituted 2-imino-1H-pyridine-1-amines of the general formula I prepared by the different variants are compiled in Table 1.

option A

To a suspension of 5 mmol of 4-amino-1-cyanobutadiene (1.3) of the general formula II (R ⁷ = CH ₃ ; R ⁸ = C ₆ H ₅ ) in isopropanol (see Table 1) while stirring at room temperature, 1.79 g of 70% hydrazine hydrate dropwise. After stirring for 30 minutes, the end product of the general formula I is filtered off with suction and dried in air. The product is obtained in high purity and can optionally be recrystallized.

Table 1 (Anfang) Prepared substituted 2-lmino-1H-pyridin-1-amines of the general formula I (R ³ = H; R ⁶ = CN) R ¹ > R ² R ⁴

CH ₃

CH ₃

- (CHj) ₃ -

R ⁵ F./°C Ausb./ Vari - F ml of Lö colour % d. Th. ante sung (Recryst.) medium CH ₃ 160-167 (Zers.) 56 A A 10 light yellow 37 B D 10 (Iso-propanol) 53 F F 15 C ₆ H ₅ 143-145 81 A 10 light yellow 48 C 15 (Iso-Pr, Opanol) 54 F 20 Fur-2-yl 186-187 (Zers.) 86 A 25 ' yellow 61 e 20 (Ethanol / water) 90 F 20 Thien-2-yl 172-175 (Zers.) 79 A 40 yellow (Water) H 161-165 (Zers.) 28 F 5 yellow (N-butanol) C ₆ H ₅ 173-175 77 2.5 light yellow (Iso-propanol) 161-166 (Zers.) 83 10 helloliv 55 10 (Iso-propanol) 61 '15

Ausb./ Vari ml Lo % d. Th. ante tration medium

Table 1 (in conclusion) Prepared substituted 2-imino-1H-pyridin-1-amines of the general formula I (R ³ = H; R ⁶ = CN)

R'R ² R ⁴ R ⁵ F./°C

Color (Umkrist.)

CH ₃ H - (CHa) ₃ - 132.5-135 (dec.) 45 H 5

green

(Iso-propanol)

- (CH ₂ J ₅ - - (CH ₂ J ₃ - 152,5-154 53 J 5

golden yellow (iso-propanol)

HH - (CH ₂ J ₄ - 137-153 (dec.) 57 A 5

light yellow 56 F 5

(Iso-propanol)

HH -CH ₉ -C = CH-CHi = CH-CH = C-198-202 (dec.) 99 A 50

^ J J 'light green 45 G 20

(Dimethylformamide)

H H 187-194 (Zers.) 59 A 15

- (CH ₂ X ₂ -C = CH-CH = CH-CHi = C-light yellow

j [(iso-propanol)

Variant B

Analog variant A using 5 mmol of 4-amino-1-cyanobutadiene (1.3) of the general formula II (R ⁷ = R ⁸ = C ₂ C ₅ ).

Variant C

Analogous variant A using 5 mmol of 4-amino-1-cyano-butadiene- (1,3) of the general formula II (R ⁷ R ⁸ = (CH ₂ ) ₂ O (CH ₂ ) ₂ ).

Variant D

Analog variant A using 5 mmol 4-amino-1-cyanobutadiene {1.3) of the general formula II (R ⁷ R ⁸ = (CH ₂ ) ₅ ).

Variant E

Analog variant A, but instead of hydrazine hydrate 25 mmol hydrazine sulfate and 5 ml of triethylamine are used.

Variant F

A solution of 5 mmol of 4-amino-1-cyano-butadiene- (1,3) of the general formula II (R ⁷ = CH ₃ , R ⁸ = C ₆ H ₅ ) and 20 mmol of 42% hydrazine hydrate in ethanol (see Table 1) is heated to boiling for 2 minutes. After cooling the reaction mixture is the

The final product of general formula I is filtered off with suction and dried.

Variant G

Analogous variant F, but dioxane (see Table 1) is used as the solvent instead of the ethanol.

Variant H

Analog variant C, but 10 mmol of methylhydrazine are used instead of the hydrazine hydrate.

Variant J

Analog variant C, but instead of the hydrazine hydrate 10 mmol of piperidin-1-amine are used.

Claims (1)

Claim: Process for the preparation of substituted 2-imino-1H-pyridin-1-amines of general formula I, R ⁵ - NH; I 1 Z NRR. in the R 'and R ^{2 are} identical or different hydrogen, alkyl or aryl or R ¹ R ² together a tetra, penta, 3-oxapenta or 3-azapentamethylene bridge, R ^{3 is} hydrogen or an aryl radical, R ⁴ and R ^{5 is} hydrogen , an alkyl, aryl or heteroaryl radical or R ⁴ R ⁵ together form a tri-, tetra- or pentamethylene bridge or a benzo-fused alkylene bridge, for example 0-C ₆ H ₄ -CH ₂ - or 0-C ₆ H ₄ -CH ₂ -CH ₂ -, and R ^{6 represent} an aryl radical, a cyano, carbonyl or nitro group, characterized in that a 4-amino-1-cyano-butadiene (1.3) of the general formula II R ³ R ⁴ R ⁵ R ⁶
R ⁷ R ⁸ NC = CC = C-CN II with stated for R ^3, R ^4, R ^5, R ⁴ R ⁵ and R ⁶ meaning and R ⁷ and R ⁸ the same or different is an alkyl and / or aryl group or R ⁷ R ⁸ together form a tetra-, penta- , 3-oxapenta or 3-azapentamethylene bridge, with a hydrazine of the general formula III R ¹ R ² N-NH ₂ III with the meaning explained for R ¹ and R ² or for R ¹ R ² or with a salt of a hydrazine of the general formula III is advantageously reacted in an organic solvent. Field of application of the invention The invention relates to a process for the preparation of substituted 2-imino-1H-pyridine-1-amines. Such compounds are important for the synthesis of cardiovascular drugs. Characteristic of the known technical solutions It is known that unsubstituted 2-imino-1H-pyridine-1-amine can be prepared by electrophilic amination of 2-aminopyridine with O-mesitylenesulfonylhydroxylamine [Y. Tamura, J. Minamikawa, M. Ikeda: Synthesis 1977, 1]. This process has the disadvantage that it is limited to the preparation of unsubstituted 2-lmino-1 H-pyridin-1-amine and in the form of O-Mesitylensulfonylhydroxylamins requires a very sensitive and difficult to prepare starting material. In addition, it is necessary to start from an already preformed pyridine system. Furthermore, it is known that 4-chloro-1-cyano-butadiene- (1,3) react with hydrazine under C-C bond cleavage to substituted acroleinazines [J. Liebscher, H. Hartmann: J. Prakt. Chem. 318, 705 (1976)]. Object of the invention The aim of the invention is to make accessible for the production of cardiovascular pharmaceuticals significant substituted 2-lmino-1 H-pyridin-1-amines, starting from easily accessible and easy to handle starting materials, which do not yet contain pyridine. Explanation of the essence of the invention The invention has for its object to develop a process that makes it possible to make available substituted 2-lmino-1 H-pyridine-1-amines in a simple manner, starting from easily accessible and easy to handle starting materials that are still no Pyridine scaffold included.
According to the invention this object is achieved in that substituted 2-lmino-1 H-pyridin-1-amines of the general formula I, R ³ -k N ^ Jsfc NK ¹ 1 2 NR R