DE2048080C3 - Process for the preparation of N-substituted 33-disubstituted β-lactams - Google Patents

Description

R ³

R ₅ -C — O — CH — C — C — NH-R ¹ (H)

R ³ O

From the Belgian patent 7 33 442 the production of 3,3-disubstituted /? - lactams is by Dehydiohalogenation of 0-halocarboxamides known in the presence of basic compounds at elevated temperature.

The process has the disadvantage that when using ß-chlorocarboxamides as starting materials the achievable yields leave something to be desired. This disadvantage does not occur when one starts from the / J-bromoarboxamides. at To carry out a process on an industrial scale, however, the bromine, which in deir reaction as Hydrogen bromide is split off, be recovered for reasons of economy. A low-loss one The cycle process for the recovery of the bromine requires a considerable technical Expenditure.

It has now been found that N-substituted 3ß-disubstituted, fl-lactain of the general formula

in which R ^{1 is} an aryl radical optionally substituted by one or more alkyl groups with 1-4 carbon atoms, alkoxy groups with 1 to 4 carbon atoms, halogen atoms or nitro groups, R ² , R ³ , R ^{4 are} identical or different and each is an aliphatic, cycloaliphatic, araliphatic or aromatic radical, in addition R * can mean a hydrogen atom and R ² and R ³ together with the adjacent carbon atom can form a cycloaliphatic ring, optionally containing a hetero atom, characterized in that N-monosubstituted, «A-disubstituted β- Acyloxycarboxamides of the general formula

15th

R ²

R ³ - CC = O (I)

R ⁴ —C — N — R ¹

in which R ^{1 is} an aryl radical optionally substituted by one or more alkyl groups with 1 to 4 carbon atoms, alkoxy groups with 1 to 4 carbon atoms, halogen atoms or nitro groups, R ² , R ³ , R ^{4 are} identical or different and each is an aliphatic, cycloaliphatic, araliphatic or aromatic radical, in addition R ⁴ can denote a hydrogen atom and R ² and R ³ together with the adjacent carbon atom can form a cycloaliphatic ring, optionally containing a hetero atom, advantageously obtained when N-monosubstituierje, «A-disubstituted β- Acyloxycarboxamides of the general formula!

30th

in which R ¹ , R ² , R ³ and R ^{4 have} the meaning given and R ^{5 stands} for a hydrogen atom, an alkyl group with 1 to 3 carbon atoms or a phenyl radical, heated ^{to temperatures of 150 to 400 ° C. in the presence of basic compounds.}

2. The method according to claim I, characterized in that sodium carbonate and / or Sodium hydrogen carbonate is used as a basic condensing agent.

R ²

R ⁵ —C — O — CH — C — C — NH — R ¹

R ³ O

in which R ¹ , R ² , R ³ and R ^{4 have} the meaning given and R ^{5 represents} a hydrogen atom, an alkyl radical having 1 to 3 carbon atoms or a phenyl radical, heated ^{to temperatures of 150 to 400 ° C. in the presence of basic compounds}

The inventive method provides a great

Number 33-disubstituted ^ -lactams the easy way. Compared to the known method is in the Cyclocondensation the leaving group, d. H. the emerging bromine, by a cheaper acylate group replaced. The starting compounds that are monosubstituted on the nitrogen, disubstituted in the α-position and optionally additionally substituted 0-acyloxycarboxamides of the general formula II in the ^ position are much more easily accessible than the correspondingly substituted / J-bromocarboxamides.

O-acetoxycarboxylic acid derivatives of this type can easily and easily be obtained by conventional esterification reactions without «. Create difficulties.

Starting material: according to the definition of general formula II and, accordingly, end products of general formula I are those in whose formulas R ¹ , R ² , R ³ and R ^{4 are} identical or different and R ² , R ³ and R ^{4 are} each an alkyl radical with I to 10, preferably 1 to 6 carbon atoms, such as a methyl, ethyl, propyl, butyl, isobutyl or isooctyl radical, a cycloalkyl radical with 5 to 10 carbon atoms, such as a cyclopentyl, cyclohexyl, CyeloheptyU or cyclooctyl radical. an aralkyl radical with 7 to 10 carbon atoms, such as a benzyl or phenylethyl radical, R ¹ , R ² , R ', R ⁴ an aryl radical with 6 to 12 carbon atoms, such as a phenyl, naphthyl or

b5 is a diphenyl radical and, in addition, R ^{4 is} also a hydrogen atom.

R ² and R ^J can also be used together with the adjacent carbon atom with which both radicals

are connected, preferably a 5- or ole-membered form cycloaliphatic or heterocyclic ring, so that under the conditions of the process spiro compounds, for example 2-aryl- [1-oxo-2-a3a-spiro (3 ^) - nonanl can be produced.

Ri represents an aryl radical, such as a phenyl or Naphthyl radical or one by one or more substituents, such as alkyl groups with 1 to 4 carbon atoms, Alkoxyl groups with 1 to 4 carbon atoms, halogen atoms or nitro groups Phenyl radical, of which aromatic radicals, such as the Phenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-chlorophenyl, 2,4-dichlorophenyl or ^ -naphthyl radical are particularly suitable.

If R ² and R ^{3 have} the same meaning, they are preferably straight-chain alkyl radicals having 1 to 4 carbon atoms, in particular methyl, ethyl or n-propyl radicals, or phenyl radicals. If R ² and R ³ together with the adjacent carbon atom form a cycloaliphatic ring, then R ² and R ³ together preferably denote a tetramethylene or pentamethylene radical

If R ² and R ^{3 are} not identical, one radical advantageously represents an alkyl radical with 1 to 4 carbon atoms and the other an aryl radical.

R ⁴ is preferably hydrogen or methyl.

In the particularly preferred cases in which R ⁴ denotes a hydrogen atom, the starting compound of the general formula II is an O-hydroxypropionic acid derivative that is doubly substituted in the α-position. R ^{4 is} a methyl group, the starting compound is a derivative of an appropriately substituted / I-hydroxybutyric acid . The re ^ te R ² iv.d R ³ in this case in particular each denote a methyl group or together a pentamethylene-α

Accordingly, examples of N-substituted, α-disubstituted / I-acyloxycarboxamides are «Α-dimethyl-,« A-diethyl-, awx-di-n-propyl-, «, at-di-nbutyl-, "-Methyl-a-propyl-, α-ethyl-a-n-butyI-," -Me thyl-Ä-phenyl-p-acetoxypropionsäureamide, the corresponding substituted 0-aceioxybutyric acid amides or 1 - (acetoxymethylJ-hexahydrobenzoic acid amides, which are formed on the amide nitrogen by phenyl, 4-chlorophenyl, 4-methoxyphenyl-, 4-ethoxyphenyl, 3-nitrophenyl, 2,4-dichlorophenyl or 0-naphthyl, or by Methyl, ethyl are substituted.

R ^{5 represents} a hydrogen atom, an alkyl group having 1 to 3 carbon atoms or a phenyl radical. The methyl group is of particular technical importance, since the acetoxy group is a very good and equally economical leaving group. The starting compounds are therefore expediently α-acetoxycarboxamides substituted in accordance with the general formula II.

The basic compounds used as condensing agents are at least stoichiometric Amount used. They are advantageously used in a 1 to 5 molar excess in relation to the starting material used.

The basic compounds are compounds w) from the metals of the first, second, and third main group, first, second, third, fourth, seventh or eighth subgroup of the periodic system of the Elements in consideration. Preferred basic compounds are the carbonates, hydrogen carbonates and oxides h5 of the aforementioned metals. Carbonates or hydrogen carbonates of the metals are particularly suitable Lithium, sodium, potassium and lead, especially sodium carbonate and sodium hydrogen carbonate or Mixtures of this saUe,

However, tertiary amines with a base constant greater than or equal to JO- ⁶ can also be used as basic compounds as condensing agents.

For example, the following tertiary amines are suitable as condensing agents: trimethylamine, triethylamine, Tripropylamine, tributylammine, methyldiisopropylamine, Dimethylbenzylamine, DimethylcycIohexylaTiin, N-methylmorpholine, Ν, Ν'-dimethylpiperazine or diazabicyclo- [2A2] octane.

The cyclocondensation reaction is carried out at a temperature between 150 and 400 ⁰ C, in particular 170-370 ° C,

The reaction can depending on the selected starting materials of general formula II and the used Condensing agents in heterogeneous or homogeneous, solid or liquid phase, under normal pressure, at be carried out under reduced or increased pressure.

As a rule, the reaction when using metal carbonates, hydrogen carbonates and / or oxides carried out without the addition of solvents in a heterogeneous phase. If necessary, high-boiling, inert heat exchangers, e.g. B. paraffin oil, silicone oil or phthalic acid diester applied, in general in an amount of 100 to 1000% by weight, based on the raw material.

When using the preferred condensing agents sodium carbonate and sodium hydrogen carbonate two variations of the process have proven particularly effective.

In one embodiment of the process, the mixture of starting compound and condensing agent heated under normal pressure or under reduced pressure The reaction conditions, in particular Pressure and temperature are coordinated in such a way that the resulting / J-lactam, which is in the generally has a lower boiling point than the starting compound, during the reaction from the Reaction vessel can be distilled off. The reaction time here is generally 0.5 to 4 hours. The reaction product is usually obtained from the distillate by recrystallization or fractional distillation severed

According to another procedure, the condensation agent is in an inert heat exchanger, preferably a phthalic acid diester, the alcoholic component of which contains 4 to 8 carbon atoms, heated. The starting compound is metered in continuously at the same rate as the resulting j? -lactam is distilled off. Starting compounds with a melting point of up to 100 ° C are advantageously added dropwise or pumped in as a melt, while starting compounds in solid form by means of to the devices customary for this purpose, for example via a metering screw.

If tertiary amines are used as condensing agents, the implementation in is recommended Presence of solvents in a homogeneous liquid phase. It is carried out under pressure, provided that the Boiling points of the amines and / or the solvents are below the reaction temperature.

As solvents, the amines themselves, but also others, can be inert under the conditions of the reaction Solvents such as dioxane, tetrahydrofuran, chloroform, methylene chloride and preferred dimethylformamide as well as N-methylpyrrolidone.

The achievable with the method according to the invention Yields of ^ -lactams are generally somewhat lower than by the process mentioned Belgian patent specification, Due to the great advantages of easy accessibility of the starting products and the simple feasibility of the process, however, this disadvantage is far outweighed. All the more so more than one can rely on to recover the leaving group

R ⁵ -C-O- '°

especially when the inexpensive acetoxy group is used can do without. The reaction mixture is also significantly less corrosive than when it is present of halide ions.

The compounds which can be produced by the process are valuable for the production of textile auxiliaries and Pesticides and, inter alia, ^ -aminocarboxylic acids and pharmaceuticals.

Unless otherwise stated, the parts given in the examples are parts by weight.

example 1

25th

100 parts of 2 £ dimethyl-3-acetoxypropionylaniIid (MG 235; mp. 72-73 ° C) are mixed intimately with anhydrous sodium carbonate and 120 parts heated at 100 Torr rapidly to 220 ⁰ C. At a pressure between 100 to 200 Torr, the mixture is gradually ^{heated to a temperature of 350 °} C. over the course of 90 minutes.

The upper Continuous 170-250 ⁰ C distillate is by fractional distillation in 9 parts of starting material and 36.2 parts of i-phenyl-33-dimethylazetidinon- (2) aufgetrennL This corresponds, based on unreacted starting material, 51.8% of theory. The compound has a boiling point at 3 torr from 122 to 123 ⁰ CIR-CO 1733 cm- '.

Example 2

40

132.6 parts of 2,2-dimethyl-3-acetoxypropionyl-4'-methoxyanilide (MW 265.2; mp. 65-66 ⁰ C) are mixed intimately with anhydrous sodium carbonate and 150 parts heated at 40Torr quickly 24b ° C. At a pressure between 40 and 70 Torr, heating is gradually continued up to 350 ° C. over a period of 90 minutes

The distillate passing over between 180 and 260 ° C is divided into 5 parts by fractional distillation Starting material and 53 parts of N- (4'-methoxyphenyl) -33-dimethylacetidinone- (2) were separated. Corresponding, based on converted starting material, 53.6% of theory. The connection has one Boiling point at 1 Torr from 132 to 134 ° C, melting point 68 to 69 ° C (from benzene / petroleum ether).

Example 3 "

140 parts of 2,2-dimethyl-3-acetoxypropionyl- (3'-nitroanilide) (MW 280, mp. 118-119 ⁰ C) are mixed intimately with anhydrous sodium carbonate and 150 parts heated at 5 to 10 Torr rapidly to 220 ⁰ C. At a pressure between 20 and 60 Torr, the mixture is gradually heated up to 350 ° C. over a period of 90 minutes

The transitioning 200-260 ⁰ C distillate from benzene / petroleum ether (mixing ratio 3: 1) to give to give 46.6 parts of N- {3'-nitrophenyl) -33-dimethylacetidinon- (2). Based on the converted starting material, this corresponds to 42.1% of theory. The compound has a melting point of 105 to 106 ⁰ C.

Example 4

In a stirred vessel, a slurry of 150 parts of anhydrous sodium carbonate in 200 parts by volume of dioctyl phthalate to 270 ⁰ C is heated with vigorous stirring, is allowed in the course of one hour 135 parts of 2 £ -DimethyI-3-acetoxypropionyl- (4'-chlorani-Hd) ( MW 269.5) are poured in and the resulting reaction product is simultaneously distilled at 50 to 80 Torr into a receiver cooled with water. Fractional distillation of the crude discharge gives 7 parts of starting material and 48.8 parts of N- (4'-chlorophenyI) -33-dimethylacetidione- (2). Based on the converted starting material, this corresponds to 49% of theory. The compound has a boiling point at 2 Torr from 135 to 13 i> ° C melting point 59 to 6O ⁰ C (from benzene / petroleum ether).

Example 5

90 parts 1--Acetoxymethyl hexahydrobenzoylanilid (MW 275, mp. 59 to 6O ⁰ C) are mixed with 270 parts of sodium hydrogen carbonate intimately and rapidly heated at 5 to 10 Torr to 200 ⁰ C at a pressure of 5 Torr is gradually within 40 minutes heated to 250 ° C

The distillate passing between 150 and 200 ° C is separated by fractional distillation into 11 parts of starting material and 31.7 g of 2-phenyl- {l-oxo-2-aza-spiro (3 ^) - nonane]. This corresponds to the converted starting material , 51.7% of theory. The compound has a boiling point of 158-160 ⁰ C at 1 torr, and a melting point of 69 ° C (from petroleum ether).

Example 6

110 parts of 2-methyl-2-phenyl-3-acetoxy-propionylani-Hd (MW 297) are intimately mixed with 250 parts of sodium carbonate and heated ^{rapidly to 200 ° C. at a pressure of 1 to 2 Torr} after 30 minutes the temperature gradually increased to 270 ° C

The distillate passing over between 170 and 220 ° C is by fractional distillation into 8 parts of luigangsstoff and 46.5 parts of 13-diphenyl-3-methyl azetidinone- (2) separated This corresponds to 57% of theory, based on the converted starting material. the Compound has a boiling point of 175 ° C at 1 torr.

Claims (1)

Claims; 1. Process for the preparation of N-substituted 3,3-disubstituted ^ -lactams of the general Formula I. R ³ -CC = O
R * - C - N - R ¹
H (D