DD241411A1 - PROCESS FOR THE PREPARATION OF N-ACYL-IMINOKOLE-ACID ACID-ALKYKESTER-DIAKYLAMIDES - Google Patents

Abstract

The invention relates to a novel process for the preparation of hitherto predominantly unknown N-acyl-iminokohlensäure-alkyl ester dialkylamides. The invention has for its object to apply a novel phase transfer process for the optimal preparation of N-acyl-iminokohlensäure-alkyl ester dialkylamides (N, N, N-trisubstituted O-alkyl-isoureas) having a broad substituent spectrum. According to the invention, they are solid / liquid prepared from N, N-disubstituted O-alkyl-isoureas and aliphatic or aromatic carboxylic acid halides in the presence of inorganic bases and PT catalysts in the two-phase system. The invention can be used for the rational and extensive production of the substances, which in turn can be used for the direct and indirect production of chemical products, in particular bioactive substances, in the chemical industry.

Description

Field of application of the invention

The invention relates to a novel process for the preparation of previously largely unknown N-acyl-iminokohlensäurealkylester dialkylamides of the general formula

O _y OR ³

Il /

RCN = C _x

NR- ¹ R

where R ¹ = R ² or RVR ^{2 is} a saturated, optionally substituted aliphatic, cycloaliphatic, heterocyclic and aromatic radical which may be substituted by monovalent functional groups and R ^{3 is} a branched or unbranched, optionally interrupted by the heteroatoms N, O or S. Alkyl, cycloalkyl or aralkyl radical and allylic radical and R is an aliphatic or aromatic radical.

The compounds of general formula I, in addition to their use in the intermediates chemistry in particular for the direct or indirect production of bioactive substances in the chemical industry use.

Characteristic of the known technical solutions

The substances synthesized by the process according to the invention 2 to 8 (Table) have not been known. The possibility of direct acylation with carboxylic acid chloride / triethylamine in an inert solvent, which is known for the iminocarbonic acid aryl ester dialkylamides, has hitherto only been described in one case with an activated carboxylic acid chloride (monochloroacetic acid chloride) for the O-alkyl esters (US Pat. No. 3,984,410 [1976] Erf ADGUTMAN). As a common method, it is not considered due to unsatisfactory results. The acylative cleavage of N-trimethylsilyl-iminocarbonic acid aryl ester dialkylamides is not known for the O-alkyl esters (D.MARTIN, K. WITKE, P. REICH, K. NADOLSKI, Chem. Ber., 101, 3185 [1968]).

Isolated representatives of N-acyl-iminocarbonic acid alkyl ester-dialkyl amides prepared by specific processes are known (eg 1), which in their last reaction step involve the reaction of a wide variety of starting materials, which often compared to the starting materials used in the process according to the invention to produce and handle with a significant amount of experimental overhead. It requires substances that are either expensive, toxic or accessible only by multi-stage reactions, the yields are often lower than achieved by the method according to the invention are. The following alternative syntheses can be mentioned:

a) The electrophilic substitution reaction of N-halocarboxamides with dialkylformamide dialkyl acetals, whereby 1 was synthesized (H. BREDERECK, G. SIMCHEN, H. POCKERT, Chem., 103, 245 [1970]).

b) The basically possible exchange reactions of acyl iso-cyanide dichlorides with N- and O-nucleophiles via the N-acylcarbamimidoyl halides and N-acyl-chloroformimidic acid esters have long been practiced, although for the specific substituent pattern of the N-acyl imino-carbonic acid alkyl ester dialkylamides according to the general formula I hitherto no examples are known (R. NEIDLEIN, W. HAUSMANN, Angew. Chem. 77, 733 [1965]).

c) The N-acylcarbamimidoyl halides ("haloformamidines"), which are also accessible via the route of the reaction of aprotic cyanamides with aliphatic and aromatic carboxylic acid chlorides activated by electron-withdrawing substituents, only allow the substitution with alcohol nucleophiles in exceptional cases the reaction with alcohols, phenols or their salts to give N-acyl-iminocarbonic acid alkyl or aryl ester dialkylamides, only bis-carbamimidoyl chlorides give the bis-carbamimic acid alkyl or aryl esters (W. RIED, B. KÜMBEL, M L.-TAUER, Liebigs Ann. Chem. 1984, 564; W. RIED, B. KÜMBEL, Chemiker Ztg. 108, 184 [1984]).

d) In addition, some syntheses of N-sulfonyl-iminocarbonic acid alkyl ester dialkylamides are known, but their application to the type of compound according to the invention is not reported (R. NEIDLEIN, W. HAUSMANN, Tetrahedron Letters, 1966, 2217, R. MOLL , Zeitschrift fur Chemie, 19, 250 [1979], M. REGITZ, G. HIMBERT, Liebigs Ann. Chem. 734, 70 [1970]; RF MEYER, J. Org. Chem. 28, 2902 [1963].).

For the reasons mentioned above, these processes prove to be inferior in comparison with the process according to the invention, whereby the limitations of the substituent diversity must also be mentioned in some synthesis possibilities.

Object of the invention

The aim of the invention is to avoid the mentioned deficiency in the previous production process for N-acyl-iminokohlensäurealkylester-dialkylamides and to ensure by a new process, the optimal synthesis of these compounds under mild conditions, for the direct or indirect production in particular of Biowirkstoffen in find use in the chemical industry.

Explanation of the essence of the invention

The invention has for its object to develop a phase transfer method that allows the acylation of o.g. Iminokohlensäure-alkyl ester dialkylamides under mild technically easy to control conditions in the most economical manner possible with relatively easily accessible, non-toxic starting materials in a large variety of substituents with high yield at a non-hydrolysis-favored separation. For these reasons, the process should make it possible to use cheap and easy-to-use alkali metal hydroxides, with the greatest possible elimination of side reactions, and to permit easy and as complete as possible recovery of the organic solvent.

In accordance with the invention, iminocarbonic acid alkyl ester dialkylamides II are dissolved with carboxylic acid halides III in an aprotic polar or nonpolar solvent (CH ₂ Cl ₂ , ether, THF, dioxane, toluene) in the presence of compounds which possess phase transfer transfer properties, such as, for example, US Pat. B. tetraalkylammonium salts, tertiary amines and crown ethers in catalytic amounts of 1 to 10 mol% in the two-phase solid / liquid in the presence of an excess of inorganic base (metal hydroxides) as solid phase at temperatures below 30 ° C for a maximum of 2 hours as intensively stirred. This results in compounds of general formula I.

HN = CCρ + R- < ^Bas9 ' ^PT - J! Il> RC f

II III I

The reaction is generally carried out so that the dissolved acylating agent is slowly added dropwise with vigorous stirring to the presented suspension of iminoxycarbonyl-dialkylamide, base, catalyst and indifferent solvent at the temperature favorable for the reaction and after completion of the reaction, the work-up from the solvent ,

It was surprising in the reaction that the hydroxide ions formed during the reaction neither cause a priority hydrolysis of the acylating reagent nor cause other side reactions in measurable extent. The iminocarbonic acid alkyl ester dialkylamides are advantageously obtained from the PT-catalyzed addition of alkanols to aprotic cyanamides. The latter are accessible via the transamidation of urea to 1,1-disubstituted ureas and their PTC dehydration (W. SCHROTH, H. KLUGE, R. FRACH, W. HODEK, H.-D. SCHÄDLER, J. prakt. Chem. 325, 787 [1983]) and by reactions of amines with cyanogen bromide (W.LGARBRECHT, RMHERBST, J. Org. Chem. 18, 1003 [1953]). The thermal constants of the N-acyl-iminocarbonic acid alkyl ester dialkylamides prepared by the process according to the invention are summarized in the following table:

Table N-Acyl-iminocarbonic acid alkyl ester dialkylamides (I)

R-CO-N = C.

OR " ³ NR ¹ R ²

Verb.

Kp ° C / Pa F ⁰ C

_CH3 C2H5

- (CH ₂ I ₄ - - (CH ₂ J ₅ - - (CH ₂ J ₂ O (CH ₂ I ₂ - - (CH ₂ J ₂ O (CH ₂ J ₂ - - (CH ₂ J ₂ O (CH ₂ J ₂ - - (CH ₂ J ₂ O (CH ₂ I ₂ -

C ₂ H ₅ CH ₃ 53-54 / 6.66 C ₂ H ₅ CH ₃ 62-63 / 26.66 CH ₃ CH ₃ ^: 72-73 / 13,33 C ₂ H ₅ CH ₃ 79-80 / 13.33 CH ₃ CH ₃ 82-84 / 13.33 CH ₃ C ₆ H ₅ 190 / 6.66 CH ₃ P-NO ₂ -C ₆ H ₄ 120-122 CC ₆ H ₁₁ C ₆ H ₅ 70-72

embodiments

The invention will be explained below with reference to two embodiments:

Example 1:

Preparation of N-acetyl-iminocarbonic acid methyl ester pyrrolidide 3

A well-stirred suspension of 2.56 g (20 mmol) iminocarbonic acid methyl ester pyrrolidide, 1 mol% TBAH (67.8 mg, 0.2 mol) and powdered sodium hydroxide (2 g, 50 mmol) in 50 ml of purified methylene chloride is added dropwise to 2 , 35 g (30 mM) of acetyl chloride in 20 ml of methylene chloride within 30-40 minutes. Excessive heating (over 30 ° C) is cooled in a water bath. The mixture is then stirred for 1 hour, filtered and washed with methylene chloride. The filtrate is i.Vak. concentrated and the oily residue in 50ml ether, shaken with 5ml 1 η acetic acid and washed with 25% ammonia solution and water, the organic phase dried over Na ₂ SO ₄ , the ether i. Vak. evaporated and the

Rest fractionated.

Yield: 69% of theory Bp: 72-73 ° C / 13.33 Pa ng ⁵ : 1.4984:

Example 2:

Preparation of Np-nitrobenzoyl-iminocarbonic acid methyl ester morpholide 7 A solution of 7.2 g (40 m moles) of freshly distilled p-nitrobenzoyl chloride in 50 ml benzene is added with vigorous stirring below 30 ° C to a suspension of 4.33 g (30mMoI) iminocarbonic acid methyl ester morpholide, 3 g (73 mmol) of powdered sodium hydroxide and 1 mole% TBAH (101 mg, 0.3 mmol) in 50 ml benzene. After 2 hours, it is filtered and washed with benzene. The solvent is i. Vak. concentrated until a solid crystallizes out (possibly in a refrigerator).

The solid is filtered off, washed with ether and recrystallized from isopropanol / η-hexane.

Yield: 79% of theory. F: 120-122 ⁰ C

Claims (2)

claims: 1. A process for the preparation of N-acyl-iminocarbonic acid alkyl ester dialkylamides of the general formula I wherein R ¹ = R ² or PVR ^{2 is} a saturated, optionally substituted aliphatic, cycloaliphatic, heterocyclic and aromatic radical which may be substituted by monovalent functional groups can and R ^{3 is} a branched or unbranched optionally interrupted by the heteroatoms N, O or S alkyl, cyclalkyl or aralkyl radical and R eionen aliphatic or aromatic radical which may be substituted by monovalent groups, characterized in that iminocarbonic acid alkyl ester dialkylamides of the general formula II, in which R ¹ , R ² and R ^{3 have} the meaning given above, with a Carboxylic acid halide of the general formula III having the meaning given above for R and X is chloride or bromide, in the presence of metal hydroxides as condensing agent in the solid phase, in a solid / liquid two-phase system whose liquid phase is an aprotic polar or non-polar solvent, in the presence of compounds having phase transfer properties, such as tetraalkylammonium salts, tertiary amines and crown ethers in a catalytic amount (1-10 mol%). 2. The method according to claim!, Characterized in that one works with an excess of acid component and metal hydroxide in comparison with the iminocarbonic acid alkyl ester dialkylamide.