DE2812400C2 - Process for the preparation of N- (2-mercaptoethyl) alkanamides and 2-mercaptoethylamine hydrochlorides - Google Patents

Description

ίο R ₂ -CN ^

CR
R ₃ -CO ^

15 R ₄

in which R denotes a hydrogen atom or an alkyl radical having 1 to 18 carbon atoms and Ri bis R »are hydrogen atoms, lower alkyl radicals, hydroxy-substituted lower alkyl radicals or phenyl radicals, under essentially anhydrous conditions, optionally in the presence of an inert organo-20 see solvent, reacts with hydrogen sulfide, and

b) then optionally the N- (2-mercaptoethyl) alkanamide obtained in a manner known per se hydrolyzed with aqueous hydrochloric acid to give the corresponding 2-mercaptoethylamine hydrochloride.

The invention relates to the subject matter specified in the claims.

The chemistry of oxazolines is detailed in the following three review articles: (1) Wiley et al.

Chemical Reviews 44: 447 (1949); (2) Seeliger et al, Angew. Chem, International Edition. 5, No. 10. p. 875 (1966)

30 and (3) Frump, Chemical Reviews 71 (1971), p. 5483. From these reviews it can be seen that a Variety of ring opening reactions for oxazolines is known. Surprisingly, however, so far only few reactions of hydrogen sulfide with oxazolines have been considered.

In US-PS 36 70 046 it is described that certain bisoxazolines with bismercaptans or hydrogen sulfide react to polymers. In US-PS 36 30 996, 37 23 451 and 37 46 691 it is described that Schwej5 hydrogen sulphide with certain 2-alkenyl-2-oxazolines to give the corresponding bis (2-oxazolinylethyl) sulphides reacted. However, none of these patents mention the preparation of N- (2-mcrcaptoethyl) alkanamides mentioned.

Finally, in J. Chem. Soc. 1948, 1919 f. Describes a process in which the addition of hydrogen sulfide on 2-phenyl-2-oxazoline N- (2-hydroxyethyl) thiobenzamides are obtained. The reaction takes place under 40 Addition of ammonia and thus the formation of ammonium sulfide. However, the reaction conditions Addition of the sulfur compound is directed in the 2-position.

It has now been found that N- (2-mercaptoethyl) alkanamides or 2-mercaptoethylamine hydrochlorides in excellent yield can be produced by the fact that

45 a) a 2H-2-oxzoline or a 2-alkyl-2-oxazoline of the general formula

C-R

R ₂ -C -N

Rj-C-O /
R «

in which R denotes a hydrogen atom or an alkyl radical having 1 to 18 carbon atoms and Ri to R4 Hydrogen atoms, lower alkyl groups, hydroxy-substituted lower alkyl groups or phenyl groups are, among essentially anhydrous conditions, optionally in the presence of an inert organic solvent, Reacts with hydrogen sulfide and

60 b) then optionally with the N- (2-mercaptoethyl) alkanamide obtained in a manner known per se aqueous hydrochloric acid hydrolyzed to the corresponding 2-mercapto-ethylamine hydrochloride.

The amides obtained have the general formula
65 HS-CR ₃ R ₄ -CRiR ₂ -NH-CO-R

and form a well-known class of compounds with their own exploitability, all with aqueous HCl too 2-mercaptoethylamine hydrochlorides can be hydrolyzed, which after neutralization as epoxy hardeners,

Acid scavengers or pharmaceutical intermediates can be used.

The reactants used in the process of the invention are known. The 2-H-2-Oxazolines and 2-AkIyI-2-Oxazolines have the formula

R ₂ -CN ^

CR
K ₃ - γ-CK

R.

in which R denotes hydrogen or an alkyl radical having 1 to 18 carbon atoms, preferably the methyl or ethyl group. Ri to R ₄ each represent hydrogen atoms, lower alkyl radicals (having 1 to 6 carbon atoms), hydroxy-substituted lower alkyl radicals or phenyl groups. Ri and R ₂ are preferably hydrogen atoms. Methyl, ethyl or hydroxymethyl groups, while Rj and R _{4 are} hydrogen atoms. In particularly preferred compounds, R 1 to R _{4 are} hydrogen atoms.
In special 2-alkyl-2-oxazoIines of the formula I, R and Ri to R _{4 have} the meaning given in Table I:

20 Table I.

R Ri R ₂ Rj R ₄

H H H H H

CH ₃ HHHH

C ₂ H ₅ HHHH

C ₇ H ₁₅ HHHH

C _n H ₂₃ HHHH

Ci ₇ H ₃₅ HHHH

CH ₃ Q ₁ H ₅ HHH

C ₅ H ₁ , C ₆ H ₅ HHC ₆ H ₅

C ₂ H ₅ G) ₃ HHH

CH ₃ CH ^ CHj HH

C ₈ H ₁₇ CH ₂ OH CH 2 OH HH

C ₂ H ₅ C ₄ Hq HHC ₆ H ₅

CH ₃ HH CHj CH ₃

C ₂ H ₅ HHH C ₂ H ₅

The 2-oxazolines are normally made by mixing an alkanoic acid with an ethanolamine converts to the corresponding acid-amine salt or amide and then this in the presence of an aluminum oxide catalyst heated to form the corresponding 2-alkyl-2-oxazoline. The reaction can in the invention Process without solvents or in an organic solvent! be performed, that behaves inert. Suitable solvents are e.g. B. lower alkanols, especially methanol, and mixtures from lower alkanols with common hydrocarbons, e.g. B. benzene or toluene. Preferably leads the process is carried out in the absence of a solvent or in methanol. Furthermore, the reaction takes place at essentially anhydrous conditions. The 2-oxazolines are namely hydrolyzable in water, so that for optimal Product yield anhydrous conditions are required.

The stoichiometry of the reaction requires 1 mole of hydrogen sulfide per M (A 2-alkyl-2-oxazoline, but amounts greater or less than the stoichiometric amount of any reactant can be used. It is preferred to use excess hydrogen sulfide to effect complete reaction and to increase the product yield at the expense of by-products, e.g., bis (alkanamidoethyl) sulfides.

The order of addition and the manner in which the reactants are mixed are not critical. Preferably directs However, the hydrogen sulfide in increasing amounts in the reaction vessel that was previously with the Oxazoün has been sent. This primarily enables the reaction temperature to be effectively controlled.

The reaction temperature is normally in the range from about 20 to 200 ^° C., preferably about 50 to 150 ° C. At these temperatures, the reaction can be carried out under autogenous or elevated pressure in conventional pressure equipment Reaction no additional heating necessary. The reaction is preferably carried out in a device in which the temperature can be regulated by cooling.

It has been found that lower reaction rates and product yields are achieved if a reaction temperature in the lower range is used, e.g. B. about 20 to 70 ° C. In these cases, the product yield can be increased by heating the reaction mixture to the preferred temperature range, e.g. B. 100 to 150 ⁰ C. This post-heating presumably causes at least one of the by-products, e.g. B. a hydroxyethylthiocarboxamide, thermally converted back into the starting materials and / or rearranged into the desired product.

example 1
(Manufacture of N- (mercaptoethyl) acetamide)

A Parr bomb with a capacity of 1 liter is b-sent with 192.2 g of anhydrous methanol and 73.0 g of hydrogen sulfide (2.14 mol; 7% excess) and heated ^{to 100 ° C. while stirring the solution.} 1693 g (1.99 mol) of 2-methyl-2-oxazoline are then pumped through a shut-off valve into the sealed bomb at a rate of about 2.5 g / min. During the addition, the temperature of the stirred solution rises to 1H ⁰ C and the bomb pressure drops from 22.4 to 4.59 kg / cm ² . This pressure drop shows the conversion of H ₂ S into the

asked for Älkanamid. To complete the reaction, the reactor is heated for a further 4 hours this temperature. During this reheating, the bomb pressure remains constant, which means that it is complete the reaction. The reaction mixture is cooled and the volatiles are taken deducted under reduced pressure. Analysis of the material obtained by standard iodide / iodate titration (Mercaptan analysis) gives 2013 g of the desired amide and a yield of 85.1%), based on the

used oxazoline. A 92.6% yield is obtained by distillation under reduced pressure water-clear, viscous liquid, b.p. 125 ° C / 1.2 mbar. Bis (acetamidoethyl) sulfide is a by-product in Amounts substantially equal to the remaining reactants. N- (2-mercaptoethyl) propionamide is formed under the same process conditions in similarly good yields:

Example 2

(Preparation of N- (2-fourcapiOcihyl; -propioriarriiu;

A 1 1 capacity Parr bomb made of stainless steel, which is equipped with a stirrer, a heating device and an inlet pipe for introducing H ₂ S below the surface of the liquid oxazoline. comes with * 96.4 g

(5.01 moles) of 2-ethyl-2-oxazoline. The oxazoline is then heated to 70 ° C and passed over the

Inlet tube 189.5 g (5.56 mol) of hydrogen sulfide at a rate of 3.7 g / min. The temperature

is maintained _{at 70 to 75 ° C. during the supply of H 2} S and for a further 4.3 hours after the addition has ended.

The reaction mixture is then heated to 150 ° C. for 5 hours. After this post-heating stage, the reaction mixture is cooled to 85 ° C., excess H ₂ S is blown off into a lye washer and passed into

the remaining liquid reaction mixture nitrogen in order to remove _{residual H 2 S.} Analysis of the

obtained clear brown liquid (653.7 g) shows that the desired N- (2-mercaptoethyl) propionamide in

a yield of 86.8%, based on the oxazoline used. The connection you want

is obtained from the crude product with the help of a falling film still as a water-clear liquid that has a low

Contains amount (less than 5%) of 2-ethyl-2-thiazoline. The presence of this thiazoline is not a disadvantage as it is

also hydrolyzed to mercaptoethylamine hydrochloride under the following conditions.

Example 3
(Manufacture of mercaptoethylamine hydrochloride)

An aliquot (119.2 g; 1.0 mol) of N- (2-mercaptoethyl) aceijrnide from Example 1 and 19.5% aqueous HCl (205.6 g; 1.10MoI) are brought together in a reaction vessel equipped with a magnetic stirrer and reflux condenser is equipped. The reaction mixture is refluxed (about 107 ° C.) under nitrogen for 4 hours. The volatile constituents of the reaction mixture are then removed under reduced pressure, with a viscous light yellow liquid remains which crystallizes to a white solid on cooling. That crystalline material (114.0 g) is identified by NMR and IR spectra from mercaptoethylamine hydrochloride. This salt is a commercial product with various uses, in particular as a drug intermediate.

Claims (1)

Claim: Process for the preparation of N- (2-mercaptoethyl) alkanamides or 2-mercaptoethylamine hydrochlorides, characterized in that
5 a) a 2H-2-oxazoline or a 2-alkyl-2-oxazoline of the general formula Ri