DE1000381C2 - Process for the preparation of 2-thio-3, 3-dialkyl- or 2-thio-3, 3-dialkenyl-4-oxo-1, 2, 3, 4-tetrahydropyridines - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

PATENT LETTER 1 000 REGISTRATION DAY:

B EANNTMACHONG THE REGISTRATION AND ISSUE OF EDITORIAL:

ISSUE OF PATENT LETTERING:

kl 12 p 1/01

INTERNAT. KL. C 07 β

NOVEMBER 2, 1953

JANUARY 10, 1957 JUNE 19, 1957

agrees with the exposition

1 000 381 (H 18193 IV b / 12 p)

It has been found that the compounds of the general formula

ίο

wherein R ₁ and R _{2 represent} lower alkyl or alkenyl radicals with ι to 4 carbon atoms, are characterized by deep, short-lasting sleep effect.

According to the invention, the hitherto unknown 2-thio-3, 3-dialkyl- or 2-thio-3, 3-dialkenyl-4-oxo, 2, 3, 4-tetrahydropyridines are prepared by adding an α, α-Dialkyl- or α, α-dialkenyl-acetacetonitrile, in which the α-substituents have the meanings given above for R ₁ and R ₂ , with a formic acid ester in the presence of an alkaline condensation agent, such as sodium, potassium or sodium alcoholate , into the alkali compound of the corresponding γ-oxymethylene compound and converts this with ammonia into the γ-aminomethylene compound, cyclizes this with an alkaline condensing agent such as alkali alcoholate and the resulting substituted 2-imino-4-oxotetrahydropyridine compound with hydrogen sulfide or a hydrogen sulfide-releasing agent treated.

The α, α-dialkyl or a , α-dialkenyl-acetacetonitriles are obtained by alkylation of the by E. Mohr (Journal for practical chemistry [2], vol. 75 [1907], p. 551, and [2], vol . 90 [1914], p. 189 ff.) Obtained a-alkyl-acetacetoni'.ri! E. The alkylation can be carried out with alkenyl or alkyl ricilogenides using the methods customary for α-alkyl acetic acid esters. The α, α-dialkyl or α, a-dialkenyl-y-oxymethylene-acetacetonitriles are advantageous by reacting the corresponding nitriles with a formic acid ester in an inert organic solvent, such as. B. benzene, toluene or carbonic acid diethyl ester, in the presence of an alkaline condensing agent such as sodium, potassium or sodium alcoholate, shown.

The α, α-dialkyl- or α, α-dialkenyl-acetacetonitriles , which are sparingly soluble in water, do not form any salts with aqueous alkaline solutions and are slightly different from α, α-dialkyl- or α, α-dialkenyly-oxymethylene, which are readily soluble in aqueous alkaline solutions -acetoacetonitrile to separate. This alkali metal salt solutions can be converted with ammonia and ammonium chloride in the poorly soluble in aqueous solution, a, α-dialkyl or a, a-dialkenyl-y-aminomethylene. The yield in the condensation and the conversion to the aminomethylene compounds is about 85%.

Process for the preparation of 2-thio-3, 3-dialkyl- or 2-thio-3, 3-dialkenyl-4-oxo-l, 2, 3, 4-tetrahydropyridines

Patented for:

F. Hoffinann-La Roche & Co. Aktiengesellschaft, Basel (Switzerland)

Claimed priority: Switzerland of December 4, 1952

Dr. August-Hans Lutz, Basel (Switzerland), has been named as the inventor

With alkaline condensation agents, such as alkali alcoholate, advantageously in an organic solvent, such as B. methanol, the α, α-dialkyl or α, a-dialkenyl-y-aminomethylene-acetacetonitrile in about Cyclize 9O% yield. By reacting the condensation product with hydrogen sulfide or with hydrogen sulfide donating agents, such as. B. Phosphorus pentasulfide together with water arise the 2-TM0-3, 3-dialkyl- or 2-TIU0-3, 3-dialkenyl-4-oxoi, 2, 3, 4-tetrahydropyridines in 90% yield.

The new compounds are yellowish, heavy in water and in common organic solvents easily soluble. In alkaline solutions they dissolve with deepening of the color and, when acids are added, they become lighter in color unchanged. They should be used as a sleep aid.

example 1

125 parts by weight of a-ethyl-a-methyl-acetacetonitril are added with 90 parts by weight formic acid methylester in a suspension of 24 parts by weight of sodium in 800 parts by volume of toluene and stirred for 16 hours at 20 ^0th The resulting α-ethyl-α-methyl-γ-oxymethylene acetacetonitrile is dissolved as the sodium salt with water, separated off and converted directly into the aminomethylene compound with ammonium chloride and ammonia. The α-ethyl-α-methyl-γ-aöiinomethylene-acetacetonitrile, which is sparingly soluble in dilute ammonia solution, is extracted with benzene, the solution is dried and concentrated in vacuo. The remaining oil can be rectified in a high vacuum (bp ₁₀₁₀₈ = IOO ⁰ ).

152 parts by weight of a-ethyl-a-methyl-γ-aminomethylene-acetoacetonitrile become one out of 30 parts by weight

709 553/220

Sodium reacted in 500 parts by volume of alcohol prepared sodium alcoholate solution and left to stand for 12 hours. 80 parts by weight of hydrogen sulfide are then passed in, during which the solution warms up. After the decay of the reaction is mixed with 125 parts by volume of 37 ° / o% ^er hydrochloric acid dropwise, with hydrogen sulphide leaks. The dark-colored reaction material is filtered through animal charcoal and 500 parts by volume of water are added dropwise, the 2-thio-3-ethyl-3-methyl-4-oxo-i, 2, 3, 4-tetrahydropyridine precipitating in yellow crystals. After redissolving from methanol, the crystals melt at 113 to 114 ⁰ .

Example 2

139 parts by weight of propyl-a-methyl-acetacetonitrile are mixed with 90 parts by weight of ethyl formate and added dropwise to a suspension of 24 parts by weight of sodium in 600 parts by volume of benzene at room temperature. After stirring I2stündigem water is extracted with 500 parts and the separated aqueous layer with 60 parts by weight of ammonium chloride and 30 parts by volume of displaced 25 ° / ₀ aqueous ammonia and stirred at 6o ° 2 hours. The precipitated α-η-propyl-α-methyl- γ- aminomethylene-acetacetonitrile is extracted twice with 200 parts by volume of benzene and the solution is concentrated to dryness in vacuo.

In a manner analogous to Example 1, the 2-thio-3-n-propyl-3-methyl-4-oxo-i, 2, 3, 4-tetrahydropyridine produced. The melting point of the redissolved from methanol Substance is at 117 to 118 °.

The corresponding 2 ^ 1110-3 - ^^ 1-3-0160 ^ 1-4-0x0-i, 2, 3, 4-tetrahydropyridine was isolated as an oil by the same working method.

Example 3

α, a-diethyl-acetacetonitril can be in the same manner as described in Example 1, in the boiling 137-140 ⁰ under 0.1 mm pressure α, α-diethyl-y-aminomethylene-acetacetonitril transfer.

160 parts by weight of a, a-diethyl-γ-aminomethylene acetacetonitrile are heated with a solution of 24 parts by weight of sodium in 500 parts by volume of absolute alcohol and the reaction mixture is reacted with 50 parts by weight of hydrogen sulfide. After working up as in Example 1, the 2-thio-3, 3-diethyl-4-0x0-1, 2, 3, 4-tetrahydropyridine is obtained in yellow crystals with a melting point of 141 ° to 142 °.

Claims (1)

PATENT CLAIM: Process for the preparation of 2-thio-3, 3-dialkyl- or _2-Thio-3, 3-dialkenyl-4-oxo-i, 2, 3, 4-tetrahydro-, pyridines of the general formula wherein R ₁ and R ₂ denote alkyl or alkenyl radicals with 1 to 4 carbon atoms, characterized in that an α, o-dialkyl or a, a-dialkenylacetoacetonitrile, in which the ct-substituents have the meaning of R ₁ and R ₂ have, with a formic acid ester in the presence of an alkaline condensation agent such as sodium, potassium or sodium alcoholate, in die.Alkaliverbverbindungen of the corresponding y-oxymethylene compound and converts this with ammonia into the y-aminomethylene compound, this cyclized with an alkaline condensing agent such as alkali metal alcoholate and the resulting substituted 2-imino-4-0x0-tetrahydropyridine compound treated with hydrogen sulfide or a hydrogen sulfide-releasing agent. Considered publications:
German patent specification No. 634 284. 0 609 740/403 12.55 (709 553/220 6. 57)