GB1559916A

GB1559916A - 1-aziridine-carboxylic acid ester derivatives

Info

Publication number: GB1559916A
Application number: GB50910/77A
Authority: GB
Original assignee: Boehringer Mannheim GmbH
Current assignee: Roche Diagnostics GmbH
Priority date: 1976-12-11
Filing date: 1977-12-07
Publication date: 1980-01-30
Also published as: NL7713460A; SU751322A3; FI773711A; ES464855A1; FR2373528A1; ATA882877A; CS198277B2; IT1089634B; JPS5373555A; DD132659A5; IL53549A; PL202798A1; CH637116A5; NZ185901A; NO774225L; DK550377A; IL53549A0; FR2373528B1; PT67378A; SE7713876L

Abstract

An aziridine derivative of the formula II is reacted with a haloformic ester of the formula III, in which Hal denotes chlorine or bromine, e.g. in an inert solvent. 1-Aziridinecarboxylic ester derivatives of the formula I are obtained, in which X and R have the meaning listed in Claim 1. The compounds of the formula I possess, for example, a pronounced immunostimulatory effect. <IMAGE>

Description

(54) 1-AZIRIDINE-CARBOXYLIC ACID ESTER DERIVATIVES (71) We, BOEHRINGER MANNHEIM GMBH., of Mannheim-Waldhof, Federal Republic of Germany, a Body Corporate organised under the laws of the Federal Republic of Germany, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: The present invention is concerned with the preparation of 1 - aziridine - carboxylic acid ester derivatives, some of which are new.

In Tetrahedron Letters, 1964, 2497, Lwowski et al. have described ethyl 2 - cyano 1 - aziridine - carboxylate, as well as a process for the preparation thereof but without giving any indication of its pharmacological action.

In the course of investigations concerning 2cyano - 1 - aziridine - carboxamide, which is an inununestimulating therapeutic compound in cases of bacterial and viral infections (see German Patent Application No. 25 28 460.0), we found that ethyl 2 - cyano - 1 - aziridinecarboxylate can be used as an intermediate for the preparation of this therapeutic compound.

Furthermore, we surprisingly also found that ethyl 2 - cyano - 1 - aziridine - carboxylate displays an outstanding immune-stimulating action. Therefore, we have further investigated this type of compound, as well as processes for the preparation of the known and new compounds.

Thus, the present invention is concerned with the preparation of compounds of the general formula: -

in which X is a nitrile, carbamoyl or alkoxy carbonyl radical, R is a straight or branched chain, saturated or unsaturated aliphatic hydrocarbon radical, which can be substituted by halogen, alkoxy, amino, unsubstituted or substituted carbamoyloxy, cycloalllyl, hydroxyl or phthalimide groups or by a heterocyclic radical, or R is a cycloalkyl, aryl, aralkyl, aryloxyalkyl or arylthioalkyl radical, the aryl radical being optionally substituted by halo gen, alkyl, alkoxy, hydroxyl, amino, nitro, cyano, acyl, carbalkoxy, alkylthio, alkylsulph onyl, phenyl or trifluoromethyl groups.

The present invention is also concerned with pharmaceutical compositions with an immune-stimulating action which contain these compounds.

The aliphatic hydrocarbon and alkyl radicals are, in all cases, to be understood to be straight or branched-chained radicals contain ing up to 5 carbon atoms, the preferred radicals being the methyl, ethyl, isobutyl, sec. butyl, tert.-butyl and n-pentyl radicals. The aliphatic hydrocarbon chain can be substi tuted by halogen atoms, such as fluorine, chlorine and/or bromine atoms, as well as by amino or hydroxyl groups. Further substituents which can be present therein include unsub stituted or substituted carbamoyloxy radicals, preferably the 2 - cyano - 1 - aziridine - carb onyloxy radicals, phthalimido radicals, hetero cyclic radicals, especially 2 - tetrahydrofuryl or 2 - tetrahydrothienyl radicals, and alkoxy and cycloalkyl radicals. In the case of sub stituents X and R, the alkoxy radical is, in all cases, to be understood to be a radical containing up to 5 carbon atoms, the methoxy, ethoxy and isopropoxy radicals being pre ferred. The cycloalkyl radicals contain 3 to 10 carbon atoms, the cyclopropyl, cyclopentyl and cyclohexyl radicals being preferred, as well as bridged cycloalkyl radicals, for example bomyl radicals. Preferred unsaturated aliphatic hydrocarbon radicals include the allyl and crotyl radicals.

The aryl radicals are preferably those containing 6 to 10 carbon atoms, especially the phenyl and naphthyl radicals.

The aralkyl radicals are preferably the benzyl or phenethyl radicals, the aryloxyalkyl radical is preferably a 2-phenoxyethyl radical and the arylthioall:yl radical is preferably a 2-phenylthioethyl radical.

The alkylthio radical is preferably the methylthio radical and the allylsulphonyl radical is preferably the methylsulphonyl radical. The acyl radical is preferably a formyl or acetyl radicaL The halogen atom is to be understood to be a fluorine, chlorine or bromine atom. In all cases, the aryl radical can be substituted one or more times by the above-mentioned substituents.

The present invention also includes within its scope all stereoisomeric forms of the compounds of general formula (1) which can be obtained due to the presence of asymmetrical carbon atoms.

The present invention also provides new compounds of the general formula:

wherein X has the same meaning as above and R' has the same meaning as R in general formula (I) but with the proviso that when X is a nitrile group, R' is other than an ethyl radical.

As already mentioned above, the compounds of general formula (I) possess, surprisinglv, an outstanding immune-stimulating action. Furthermore, when X is a nitrile group, they are valuable intermediates for the preparation of 2 - cyano - 1 - aziridine - carboxamide. For this purpose, compounds of general formula (I), wherein X is a nitrile group, are reacted with ammonia to give 2 - cyano - 1aziridine - carboxamide.

The compounds of general formula (I) can be prepared by one of the following processes: a) reaction of an aziridine derivative of the general formula: -

wherein X has the same meaning as above, with a haloformic acid ester of the general formula:

wherein R has the same meaning as above and Hal is a chlorine or bromine atom; or b) treatment of a compound of the general formula : -

wherein X, R and Hal have the same meanings as above, with a reagent splitting off halogen; or c) conversion of a compound of the general formula: -

wherein X and R have the same meanings as above, by the catalytic or photochemical splitting off of nitrogen, to give a compound of general formula (I); whereafter, if desired a compound obtained in which X is a carbamoyl group is converted into the corresponding nitrile by means of a dehydrating agent and a compound obtained in which X is an allroxycarbonyl radical is converted into the corresponding carbamoyl compound by reaction with ammonia.

Compounds of general formula (I) in which X is an alkoxycarbonyl or carbamoyl group can, therefore, also be used as intermediates for the preparation of compounds of general formula (I) in which X is a nitrile group, this applying particularly to 2 - carbamoyl - 1aziridine - carboxylic acid esters of general formula (1).

The conversion of an ester or amide group can best be carried out with gaseous ammonia in an organic solvent, preferably in methanol or ethanol. It is preferable to use an equimolar amount of ammonia and to carry out the reaction at a temperature of 0 to 5"C.

The desired amide can then be isolated from the reaction mixture by, for example, column chromatography.

For the conversion of a carbamoyl group into a nitrile group, there can be used de hydration agents which are known for this purpose from the literature, a mixture of triphenyl phosphine, carbon tetrachloride and triethylamine being especially preferred. As solvent, it is usual to employ a halogenated hydrocarbon, for example, methylene chloride or chloroform. The desired nitrile is, as a rule, isolated from the reaction mixture by distillation.

On the other hand, for example, the sub stituents R and R' can be converted from one to another by generally known methods of esterification: in general, a small addition of a basic substance, for example of an alkali metal or aLkaline earth metal hydroxide or of an alkali metal alcoholate, is necessary.

In addition, the new compounds of general formula (I') can be prepared by the reaction of nitrenes of the general formula: -

wherein R' has the same meaning as above, with compounds of the general formula: CH2=CH-X (VII) wherein X has the same meaning as above, with the proviso that when X is a nitrile group, R' is other than an ethyl radical.

Nitrenes of general formula (VI), which can be intermediately prepared by the photolysis of azidoformic acid esters or by eelimina- tion with the help of bases, such as triethylamine, from N - p - nitrobenzenesulphonyloxyurethanes, readily react with the acrylic acid derivatives (VII) to give the desired aziridines of general formula (I') (see, for example, Tetrahedron Letters, 1964, 2497; J.A.CS., 87, 3630/1965).

In the case of process a), the reaction components can be reacted in an inert solvent, for example, diethyl ether, methylene chloride, benzene or toluene, in the presence of a base.

The base used is preferably, for example, a tertiary amine, such as triethylamine or triethanolamine. However, it is also possible to work in a two-phase system, such as water/ diethyl ether, in which case inorganic bases, especially sodium carbonate, are preferably used. As a rule, the haloformic acid esters used are chloroformic acid esters. Some of these have already been described in the literature but otherwise they can be prepared in known manner by the reaction of appropriate alcohols or phenols with phosgene in the presence of a base, such as pyridine or N,N - dimethylaniline. As a rule, the chloroformic acid esters are purified by distillation but can possibly also be further reacted as crude products.

The dihalo compounds used in process b) are new and can be prepared by the reaction of appropriate compounds which are not halogenated on the nitrogen atom with halogenation agents, such as sodium hvpohalites or tert.-butyl hypochlorite. For splitting off the two halogen atoms to give the aziridine derivatives of general formula (I), there can be used conventional dehalogenation agents, preferably zinc or sodium.

The triazoline derivatives used in process c) are also new and can be prepared by the reaction of diazo-acetic acid derivatives, such as ethyl diazoacetate or diazoacetonitrile, with methyleneurethanes of the general formula H2C=N-COOR1 wherein R has the same meaning as above.

The nitrogen can be split off either by illumination in a solvent, such as diethyl ether or acetone, or catalytically. As catalysts, there can be used, for example, noble or semi-noble metals, preferably copper powder.

For the preparation of pharmaceutical com positions with immune-stimulating action, the compounds of general formula (I) are mixed in known manner with an appropriate solid or liquid pharmaceutical carrier or diluent and formed, for example, into tablets or dragees or, with the addition of appropriate adjuvants, suspended or dissolved in water or in an oil, such as olive oil, and placed into gelatine capsules. Since the active material is acid-labile, the composition is provided with a coating which only dissolves in the alkaline medium of the small intestines or is admixed with an appropriate carrier material, for example a high molecular weight fatty acid or carboxymethylcellulose. Solid carrier materials which can be used include, for example, starch, lactose, mannitol, methyl cellulose, talc, highly dispersed silicic acids, high molecular weight fatty acids (such as stearic acid), gelatine, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats and solid high molecular weight polymers (such as polyethylene glycols). Compositions suitable for oral administration can, if desired, contain flavouring and sweetening agents.

As injection medium, it is preferred to use water which contains the additives usual for injection solutions, such as stabilising agents, solubilising agents or weakly alkaline buffers.

Additives of this type include, for example, phosphate and carbonate buffers, ethanol, complex formers (such as ethylenediamine - tetraacetic acid and the non-toxic salts thereof) and high molecular weight polymers (such as liquid polyethylene oxides) for viscosity regulation.

Preferred compounds according to the present invention include not only those specifically mentioned in the following Examples but also the following compounds: 1 - chloroethyl 2 - cyano - 1 - aziridine- carboxylate 1,2 - dichloroethyl 2 - cyano - 1 - aziridine carboxylate 1,2,2,2 - tetrachloroethyl 2 - cyano - 1 aziridine - carboxylate 2 - methylphenyl 2 - cyano - 1 - aziridine carboxylate 2 - methoxyphenyl 2 - cyano - I - aziridine carboxylate 2 - chlorophenyl 2 - cyano - 1 - aziridine carboxylate 3 - chlorophenyl 2 - cyano - 1 - aziridine carboxylate 2,4,6 - tribromophenyl 2 - cyano - 1 - aziri dine- carboxylate 2 - nitrophenyl 2 - cyano - 1 - aziridine- carboxylate 2 - aminophenyl 2 - cyano - 1 - aziridine carboxylate 3 - aminophenyl 2 - cyano - 1 - aziridine carboxylate 4 - aminophenyl 2 - cyano - 1 - aziridine carboxylate 2 - hydroxyphenyl 2 - cyano - 1 - aziridine carboxylate 4 - hydroxyphenyl 2 - cyano - 1 - aziridine carboxylate 2 - trifluoromethylphenyl 2 - cyano - 1 aziridine - carboxylate 3 - trffluoromethylphenyl 2 - cyano - 1 aziridine - carboxylate 4 - nitrobenzyl 2 - cyano - 1 - aziridine carboylate 2 - hydroxyethyl 2 - cyano - 1 - azin.din carboxylate cyclopropyl 2 - cyano - 1 - aziridine - carb oxylate 2,2,2 - trifluoroethyl 2 - cyano -1- aziridine carboxylate 2 - propoxyethyl 2 - cyano - 1 - aziridine carboxylate benzyl 2 - carbamoyl - 1 - aziridine - carb oxylate cyclohexyl 2 - carbamoyl - 1 - aziridine carboxylate 4 - chlorophenyl 2 - carbamoyl -1- aziridine carboxylate isopropyl 1 - ethoxycarbonyl - 2 - aziridine carboxylate phenyl 2 - ethoxycarbonyl - 1 - aziridine carboxylate 2,2,2 - trichloroethyl 2 - isopropoxycarbonyl 1 - aziridine - carboxylate allyl 2 - ethoxycarbonyl - 1 - aziridine carboxylate.

The following Examples are given for the purpose of illustrating the present invention: Example 1 Phenyl 2 - cyano - 1 - aziridine - carboxylate A solution of 12.6 g. phenyl chloroformate in 40 ml. diethyl ether and 40 ml. 2N aqueous sodium carbonate solution are added simultaneously, at ambient temperature, to 6.8 g.

2 - cyanoaziridine in 70 ml. water. The reaction mixture is stirred for 2 hours at ambient temperature, the phases are then separated and the ethereal layer is extracted twice with water, dried and the organic phase evaporated. The evaporation residue is recrystallised from diisopropyl ether. There are obtained 10.3 g. (about 67% of theory) phenyl 2 cyano - 1 - aziridine - carboxylate; m.p. 60 62"C.

The following compounds are obtained in an analogous manner by reacting 2-cyanoaziridine with 1. methyl chloroformate: methyl 2 - cyano - 1 - aziridine - carb oxylate; b.p. 7e72"C./0.02 mm.Hg.

2. 2,2,2 - trichloroethyl chloroformate: 2,2,2 - trichloroethyl 2 - cyano - 1 aziridine - carboxylate; b.p. 138-139 C./0.1 mm.Hg; m.p. 86 88 C. (recrystallised from diisopropyl ether).

3. allyl chloroformate: allyl 2 - cyano - 1 - aziridine - carboxy late; b.p. 102-105 C./0.2 mm.Hg.

4. tert. - butyl chloroformate (used in the forra of an ethereal solution): tert. - butyl 2 - cyano - 1 - aziridine- carboxylate; b.p. 57-59 C./0.01 mmHg.

5. n-pentyl chloroformate (b.p. 98-100 C./ 100 mm.Hg.): n - pentyl 2 - cyano - 1 - aziridine - carb oxylate; b.p. 93 C./0.01 mmHg.

6. cyclohexyl chloroformate (b.p. 47 C/ 4 mm.Hg.): cyclohexyl 2 - cyano - 1 - aziridine - carb oxylate; b.p. 97 C./0.01 mm.Hg.

7. benzyl chloroformate: benzyl 2 - cyano - 1 - aziridine - carb oxylate; b.p. 145-1500C./0.01 mm.Hg.

8. phenethyl chloroformate (b.p. 1200C./ 18 mm.Hg.): phenethyl 2 - cyano - 1 - aziridine carboxylate; b.p. 1300C./0.01 mm.Hg.

Example 2 Diethyl 1,2 - aziridine - dicarboxylate A solution of 1.9 g. ethyl chloroformate in 10 ml. benzene is added dropwise at 0 C. to 2 g. ethyl 2 - aziridine - carboxylate and 1.7 g. triethylamine in 20 ml. benzene and the reaction mixture is then stirred for 2 hours at ambient temperature, thereafter extracted three times with water and the benzene phase dried and evaporated. The residue obtained is subsequently distilled. There are obtained 2.0 g. (about 62% of theory) diethyl 1,2aziridine - dicarboxylate; b.p. 94 C./0.2 mm.

Hg.

Example 3 Phenyl 2 - carbamoyl - 1 - aziridine - carb oxylate A solution of 4.7 g. phenyl chloroforate in 20 ml. diethyl ether and 30 ml. aqueous 2N sodium carbonate solution are added dropwise and simultaneously to 2.6 g. 2 - aziridinecarboxamide in 20 ml. water. The reaction mixture is further stirred for 10 minutes, while cooling with ice. The precipitate obtained is filtered off with suction and well washed with diethyl ether. There are obtained 4A g. (about 71% of theory) phenyl 2-carb amoyl - 1 - aziridine - carboxylate; m.p.

140142 C., after recrystallisation from toluene.

Example 4 Allyl 2 - cyano - 1 - aziridine - carboxylate 32 g. Allyl chloroformate in 20 ml. benzene is added dropwise at 0 C. to 2 g. 2 - cyanoaziridine in 20 ml. benzene and 3 g. triethylamine. The reaction mixture is further stirred for 2 hours at ambient temperature and the benzene solution is extracted twice with water, dried and the organic phase evaporated. The residue obtained is then distilled. There are obtained 2.9 g. (about 64.5% of theory) allyl 2 - cyano - 1 - aziridine - carboxylate; b.p.

102--105"C./0.2 mm.Hg.

In an analogous manner, by reacting 2cyano - aziridine with ethyl chloroformate, there is obtained ethyl 2 - cyano - 1 - aziridine - carboxylate; b.p. 7e75"C./0.01 mm.

Hg.

Example 5 Ethyl 2 - carbamoyl - 1 - aziridine - carb oxylate A solution of 3.25 g. ethyl chloroformate in 20 ml. diethyl ether and 15 ml. aqueous 2N sodium carbonate solution are added dropwise and simultaneously to 2.6 g. 2 - aziridinecarboxamide in 20 ml. water. The reaction mixture is further stirred for 1 hour, while cooling, the phases are then separated, the aqueous phase is evaporated and the residue is boiled with ethanol. The ethanolic solution obtained is filtered and the filtrate evaporated to give a residue which is recrystallised from toluene. There are obtained 2.6 g. (about 56% of theory) ethyl 2 - carbamoyl -1- aziridine - carboxylate; m.p. 125--128"C.

In an analogous manner, by reacting 2aziridine - carboxamide with methyl chloroformate, there is obtained methyl 2 - carbamoyl - 1 - aziridine - carboxylate which, after recrystallisation from toluene, melts at 117--120"C.

Example 6 Preparation of 2 - cyano - 1 - aziridine - carb oxamide from phenyl 2 - cyano - 1 aziridine - carboxylate 19 g. Phenyl 2 - cyano - 1 - aziridinecarboxylate are dissolved in 30 ml. diethyl ether and the resulting solution is added dropwise to 20 ml. liquid ammonia. The reaction mixture is stirred for 2 hours at the boiling temperature of ammonia and then allowed to come to ambient temperature overnight.

The precipitated 2 - cyano - 1 - aziridinecarboxamide is then filtered off with suction, the yield being 0.85 g. (about 77% of theory); m.p. 74--76"C.

Example 7 Methyl 2 - cyano - I - aziridine - carboxylate 14.4 g. Methyl 2 - carbamoyl - 1 - aziridinecarboxylate are added to a solution of 27.5 g. triphenyl phosphine, 10.1 g. triethylamine and 15A g. carbon tetrachloride in 300 mL methylene chloride and the reaction mixture then boiled under reflux for 4 hours. The reaction mixture is subsequently filtered, the filtrate is extracted twice with water and the organic phase is dried and evapotated. The residue obtained is distilled to give 3.4 g. (about 27% of theory) methyl 2 - cyano - 1 - aziridinecarboxylate; b.p. 7e-72"C./0.02 mm.Hg.

Example 8 Ethyl 2 - carbamoyl - 1 - aziridine - carboxy late To 4.67 g. (0.025 mole) diethyl 1,2 - aziridine - dicarboxylate in 30 ml. ethanol there is added the equimolar amount of gaseous ammonia dissolved in ethanol and the reaction mixture then left to stand overnight in a refrigerator. The reaction mixture is subsequently evaporated and the desired ethyl 2 - carbamoyl - 1 - aziridine - carboxylate isolated by column chromatography (200 g. silica gel: elution agent acetone/toluene 1:1 v/v). There is obtained 1.4 g. (about 32% of theory) of the ester; m.p. 125 128"C.

Example 9 Preparation of 2 - cyano - 1 - aziridine carboxamide from ethyl 2 - cyano - 1 aziridine - carboxylate 4 g. Ethyl 2 - cyano - 1 - aziridine - carboxylate are added to a solution of 0.7 g. gaseous ammonia in 80 ml. water. The reaction mixture is stirred for 4 hours at ambient temperature, then extracted three times with diethyl ether and the aqueous phase thereafter freeze dried. The residue obtained is recrystallised from ethanol, with the addidon of diethyl ether. There is obtained 1.05 g. (about 29% of theory) 2 - cyano - 1 - aziridine - carboxamide; m.p. 74--76"C.

Example 10 Ethyl 2 - cyano - 1 - aziridine - carboxylate 0.33 g. Activated zinc dust and some zinc chloride are added to 2.11 g. 2 - (N - carb ethoxy - N - chloroamino) - 3 - chloropropio nitrile (oily substance; prepared by reacting 2 - amino - 3 - chloropropionitrile hydro chloride tvm.p. 153-155 0C.) with ethyl chloroformate in the presence of sodium car bonate and subsequent reaction with tert. butyl hypochlorite) in 25 mL ethanol. The reaction mixture is stirred for 12 hours at ambient temperature, filtered with suction and the filtrate evaporated and the residue distilled. There are obtained 0.11 g. (about 8% of theory) ethyl 2 - cyano - 1 - aziridinecarboxylate; b.p. 78-800C./0.01 mm.Hg.

Example 11 In the manner described in Example 1, there are obtained, by the reaction of 2cyanoaziridine with 1. isobutyl chloroformate: isobutyl 2 - cyano - 1 - aziridine - carb oxylate; b.p. 108-1100C./0.1 mm.Hg.

2. Cyclopropylmethyl chloroformate (b.p.

45-46 C./12 mm.Hg.): cyclopropylmethyl 2 - cyano - 1 - aziri dine - carboxylate; b.p. 107-109 C./0.1 mm.Hg.

3. but - 2 - enyl chloroformate (b.p. 25 28 C./0.1 mm.Hg.): but - 2 - enyl 2 - cyano - 1 aziridine carboxylate; oily product.

4. cyclopentyl chioroformate (b.p. 60- 61 C./16 mm.Hg.): cyclopentyl 2 - cyano - 1 - aziridine carboxylate; oily product.

5. bornyl chloroformate (b.p. 108-110 C./ 12 mm.Hg.): bornyl 2 - cyano - 1 - aziridine - carb oxylate; b.p. 153 C./0.1 mm.Hg.

6. 2 - fluoroethyl chloroformate (b.p. 110 113 C.): 2 - fluoroethyl 2 - cyano - 1 - aziridine carboxylate; b.p. 1200C./0.1 mm.Hg.

7. 2 - chloroethyl chloroformate (b.p. 83 86 C./40 mm.Hg.): 2 - chloroethyl 2 - cyano - 1 - aziridine carboxylate; oily product.

8. 2 - bromoethyl chloroformate: 2 - bromoethyl 2 - cyano - 1 - aziridine carboxylate; oily product.

9. 2 - methoxyethyl chloroformate: 2 - methoxyethyl 2 - cyano - 1 - aziri dine - carboxylate; b.p. 119-120 C./0.1 mm.Hg.

10. tetrahydrofurfuryl chloroformate (b.p.

68 C./0.2 mm.Hg.): tetrahydrofurfuryl 2 - cyano - 1 - aziri dine - carboxylate; oily product.

11. ethylene glycol 1,2 - bis - chloroformate (b.p. 110 C./34 mm.Hg.): 1,2 - [bis - (2- cyanoaziridine - 1 - carb onyloxy)l - ethane; oily product.

12. 2 - phenoxyethyl chloroformate (b.p.

97-99 C./0.1 mm.Hg.): 2 - phenoxyethyl 2 - cyano - 1 - aziri dine - carboxylate; oily product.

13. 2 - phenylthioethyl chloroformate: 2 - phenylthioethyl 2 - cyano - 1 - aziri dine- carboxylate; oily product.

14. 1 - naphthyl chloroformate (b.p. 86 90 C./0.1 mm.Hg.): 1 - naphthyl 2 - cyano - 1 - aziridine carb oxylate; oily product.

15. 4 - methyl chlroformate (b.p. 105 106 C./30 mm.Hg.): 4 - methylphenyl 2 - cyano - 1 - aziri dine - carboxylate; m.p. 88-90 C. (recrystallised from iso propanol).

16. 2,4 - dimethylphenyl chloroformate (b.p.

100-101 C./12 mm.Hg.): 2,4 - dimethylphenyl 2 - cyano - 1 aziridine - carboxylate: m.p. 9O-910C. (recrystallised from ethanol).

17. 4 - sec. - butylphenyl chloroformate (b.p. 122-123 C./12 mm.Hg.): 4 - sec. - butylphenyl 2 - cyano - 1 aziridine - carboxylate: m.p. 74-75 C. (recrystallised from ligroin).

18. 4 - biphenylyl chloroformate: 4 - biphenylyl 2 - cyano - 1 - aziridine- carboxylate; m.p. 107-109 C.

19. 4 - methoxyphenyl chloroformate (b.p.

115-117 C./12 mm.Hg.): 4 - methoxyphenyl 2 - cyano - 1 - aziri dine - carboxylate; m.p. 54-57 C. (recrystallised from di isopropyl ether).

20. 4 - chloro - 2 - methoxyphenyl chloro formate (b.p. 138-140 C./20 mm.Hg.): 4 - chloro - 2 - methoxyphenyl 2 - cyano 1 - aziridine - carboxylate; m.p. 114-1150C. (recrystallised from isopropanol).

21. 2 - fluorophenyl chloroformate (b.p. 68 70 C./12 mm.Hg.): 2 - fluorophenyl 2 - cyano - 1 - aziri dine - carboxylate; m.p. 55-56 C. (recrystallised from iso propanol/water).

22. 4 - trifluoromethylphenyl chloroformate (b.p. 82-84 C./12 mm.Hg.): 4 - trifluoromethylphenyl 2 - cyano - 1 aziridine - carboxylate; m.p. 75-77 C. (recrystallised from di isopropyl ether).

23. 4 - chlorophenyl chloroformate (b.p.

97-99 C./12 mm.Hg.): 4 - chlorophenyl 2 - cyano - 1 - aziri dine - carboxylate; m.p. 79-82 C. (recrystallised from di isopropyl ether).

24. 2,4 - dichlorophenyl chloroformate (b.p.

112-117 C./8 mm.Hg.): 2,4 - dichlorophenyl 2 - cyano - 1 aziridine - carboxylate; m.p. 82-84 C.

25. 2,4,5 trichlorophenyl chloroformate (m.p. 58-600C.): 2,4,5 - trichlorophenyl 2 - cyano - 1 aziridine - carboxylate; m.p. 100-103 C. (recrystallised from di isopropyl ether).

26. 4 - bromophenyl chloroformate (b.p.

111-1130C./12 mm.Hg.): 4 - bromophenyl 2 - cyano - 1 - aziri- dine- carboxylate; m.p. 96-1000 C. (recrystallised from di isopropyl ether).

27. 3 - nitrophenyl chloroformate (b.p. 120 122 C./0.5 mm.Hg.): 3 - nitrophenyl 2 - cyano - 1 - aziridine carboxylate; m.p. 98-1000 C. (recrystallised from iso propanol).

28. 4 - nitrophenyl chloroformate: 4 - nitrophenyl 2 - cyano - 1 - aziridine carboxylate; m.p. 1071110 C. (recrystallised from diisopropyl ether).

29. 4 - methylthiophenyl chloroformate (b.p.

108 C./0.1 mm.Hg.): 4 - methylthiophenyl 2 - cyano - 1 aziridine - carboxylate; m.p. 73-75C. /recrystallised from iso propanol).

30. 2 - methylsulphonylphenyl chloroform ate (m.p. 100-103 C.): 2 - methylsuphonylphenyl 2 - cyano 1 - aziridine - carboxylate; m.p. 145-150 C. (recrystallised from isopropanol).

31 3 - formyl phenyl chloroformate (b.p.

125 C/OA mm.Hg.): 3 - formylphenyl 2 - cyano - 1 - aziri- dine - carboxylate; oily product.

32. 4 - acetyl phenyl chloroformate (b.p.

121-123 C./5 mm.Hg.): 3 - acetylphenyl 2 - cyano - 1 - aziridine carboxylate; m.p. 104-107 C.

33. 4 - carbomethoxyphenyl chloroformate (m.p. 47-50!C.): 4 - carbomethoxyphenyl 2 - cyano - 1 aziridine - carboxylate; m.p. 86--87"C. (recrystallised from iso propanol).

34. 4 - cyanophenyl chloroformate (b.p

Claims

WHAT WE CLAIM IS:

1. Process for the preparation of l-aziridinecarboxylic acid ester derivatives of the general formula:

in which X is a nitrile, carbamoyl or alkoxycarbonyl group and R is a straight or branchedchain, saturated or unsaturated aliphatic hydrocarbon radical, which is optionally substituted by halogen, alkoxy, amino, unsubstituted or substituted carbamoyloxy, cydoallyl, hydroxy or phthalimide groups or by a heterocyclic radical, or R is a cycloalkyl, aryl, aralkyl, aryloxyalkyl or arylthioalkyl radical, the aryl radical optionally being substituted by halogen, alkyl, alkoxy, hydroxyl, amino, nitro, cyano, acyl, carbalkoxy, alkylthio, alkylsulphonyl, phenyl or trifluoromethyl; wherein either a) an aziridine derivative of the general formula:

in which X has the same meaning as above, is reacted with a haloformic acid ester of the general formula:

in which R has the same meaning as above and Hal is a chlorine or bromine atom; or b) a compound of the general formula: -

in which X, R and Hal have the same meanings as above, is treated with a reagent splitting off halogen; or c) a compound of the general formula

in which X and R have the same meanings as above, is subjected to. the catalytic or photochemical splitting off of nitrogen; whereafter, if desired, a compound obtained in which X is a carbamoyl group is converted into the corresponding nitride by means of a dehydrating agent and a compound obtained in which X is an alkoxycarbamoyl radical is converted into the corresponding carbamoyl compound by reaction with ammonia.

2. Process according to claim 1 for the preparation of 1 - aziridine - carboxylic add esters of the general formula given in claim 1, substantially as hereinbefore described and exemplified.

3. 1 - Aziridine - carboxylic acid esters of the general formula given in claim 1, whenever prepared by the process according to claim 1 or 2.

4. 1 - Aziridine - carboxylic acid derivatives of the general formula:

wherein X has the same meanings as in claim 1 and R' has the same meaning as R in claim 1, with the proviso that when X is a nitrile group, R' is other than an ethyl radical.

5. 1 - Chloroethyl 2 - cyano - 1 - aziridinecarboxylate.

6. 1,2 - dichloroethyl 2 - cyano - 1 - aziridine - carboxylate.

7. 1,2,2,2 - Tetrachloroethyl - 1 - cyan - 1aziridine - carboxylate.

8. 2 - Methylphenyl 2 - cyano - 1 - aziridine - carboxylate.

9. 2 - Methoxyphenyl 2 - cyano - 1aziridine - carboxylate.

10. 2 - Chlorophenyl 2 - cyano - 1 - aziridine - carboxylate.

11. 3 - Chlorophenyl 2 - cyano - 1 - aziri- line - carboxylate.

12. 2,4,6 - Tribromophenyl 2 - cyano - 1aziridine - carboxylate.

13. 2 - Nitrophenyl 2 - cyano - 1 - aziridine - carboxylate.

14. 2 - Aminophenyl 2 - cyano - 1 - aziridine - carboxylate.

15. 3 - Aminophenyl 2 - cyano - 1 - aziridine - carboxylate.

16. 4 - Aminophenyl 2 - cyano - 1 - aziridine - carboxylate.

17. 2 - Hydroxyphenyl 2 - cyano - 1aziridine - carboxylate.

18. 4 - Hydroxyphenyl 2 - cyano - 1 aziridine - carboxylate.

19. 2 - Trifluoromethylphenyl 2 cyano 1 - aziridine - carboxylate.

20. 3 - Trifluoromethylphenyl 2 - cyano 1- aziridine - carboxylate.

21. 4 - Nitrobenzyl 2 - cyano - 1 - aziridine - carboxylate.

22. 2 - Hydroxyethyl 2 - cyano - 1 - aziri dine - carboxylate.

23. Cyclopropyl 2 - cyano - 1 - aziridine carboxvlate.

24. 2,2,2 - Trifluoroethyl 2 - cyano - 1aziridine - carboxylate.

25. 2 - Propoxyethyl 2 - cyano - 1 - aziri- dine- carboxylate.

26. Benzyl 2 - carbamoyl - 1 - aziridinecarboxylate.

27. Cyclohexyl 2 - carbamoyl - 1 - aziridine - carboxylate.

28. 4 - Chlorophenyl 2 - carbamoyl - 1aziridine - carboxylate.

29. Isopropyl 1 - ethoxycarbonyl - 2aziridine - carboxylate.

30. Phenyl 2 - ethoxycarbonyl - 1 - aziridine - carboxylate.

31. 2,2,2 - Trichloroethyl 2 - isopropoxy carbonyl - 1 - aziridine - carboxylate.

32. Allyl 2 - ethoxycarbonyl - 1 - aziridine - carboxylate.

33. Phenyl 2 - cyano - 1 - aziridine - carboxylate.

34. Methyl 2 - cyano - 1 - aziridine - carb- oxylate.

35. 2,2,2 - Trichloroethyl 2 - cyano - 1- aziridine - carboxylate.

36. Allyl 2 - cyano - 1 - aziridine - carboxylate.

37. tert. - Butyl 2 - cyano - 1 - aziridinecarboxylate.

38. n - Pentyl 2 - cyano - 1 - aziridinecarboxylate.

39. Cyclohexyl 2 - cyano - 1 - aziridinecarboxylate.

40. Benzyl 2 - cyano - 1 - aziridine - carboxylate.

41. Phenethyl 2 - cyano - 1 - aziridinecarboxylate.

42. Diethyl 1,2 - aziridine - dicarboxylate.

43. Phenyl 2 - carbamoyl - 1 - aziridinecarboxylate.

44. Ethyl 2 - carbamoyl - 1 - aziridinecarboxylate.

45. Methyl 2 - carbamoyl - 1 - aziridinecarboxylate.

46. Isobutyl 2 - cyano - 1 - aziridinecarboxylate.

47. Cyclopropylmethyl 2 - cyano - 1aziridine - carboxylate.

48. But - 2 - enyl 2 - cyano - 1 - aziridinecarboxvlate.

49. Cyclopentyl 2 - cyano - 1 - aziridinecarboxylate.

50. Bornyl 2 - cyano - 1 - aziridinecarboxylate.

51. 2 - Fluoroethyl 2 - cyano - 1 - aziridine - carboxylate.

52. 2 - Chloroethyl 2 - cyano - 1 - aziri- dine - carboxylate.

53. 2 - Bromomethyl 2 - cyano - 1 - aziridine- carboxylate.

54. 2 - Methoxyethyl 2 - cyano - 1 - aziri- dine - carboxylate.

55. Tetrahydrofurfuryl 2 - cyano - 1 - aziriline- carboxylate.

56. 1,2 - [Bis - (2 - cyanoaziridine - 1carbonyloxy)] - ethane.

57. 2 - Phenoxyethyl 2 - cyano - 1 - aziridine - carboxylate.

58. 2 - Phenylthioethyl 2 - cyano - 1 - aziridine - carboxylate.

59. 1 - Naphthyl 2 - cyano - 1 - aziridinecarboxylate.

60. 4 - Methylphenyl 2 - cyano - 1 - aziridine - carboxylate.

61. 2,4 - Dimethylphenyl 2 - cyano - 1aziridine - carboxylate.

62. 4 - sec. - Butylphenyl 2 - cyano - 1aziridine - carboxylate.

63. 4 - Biphenylyl - 2 - cyano - 1 - aziri- dine - carboxylate.

64. 4 - Methoxyphenyl 2 - cyano - 1 - aziridine - carboxylate.

65. 4 - - Chioro - 2 - methoxyphenyl 2 cyano - 1 - aziridine- carboxylate.

66. 2 - Fluorophenyl 2 - cyano - 1 - aziridine - carboxylate.

67. 4 - Trifluoromethylphenyl 2 - cyano 1 - aziridine - carboxylate.

68. 4 - Chlorophenyl 2 - cyano - 1 - aziri- dine- carboxylate.

69. 2,4 - Dichlorophenyl 2 - cyano - 1aziridine - carboxylate.

70. 2,4,5 - Trichlorophenyl 2 - cyano - 1aziridine - carboxylate.

71. 4 - Bromophenyl 2 - cyano - 1 - aziri dine-carboxylate.

72. 3 - Nitrophenyl 2 - cyano - 1 - aziridine - carboxylate.

73. b - Niurophenyl 2 - cyano - 1 - aziridine - carboxylate.

74. 4 - Methylthiophenyl 2 - cyano - 1aziridine - carboxylate.

75. 2 - Methylsulphonylphenyl 2 - cyano 1 - aziridine - carboxylate.

76. 3 - Formylphenyl 2 - cyano - 1 - aziridine- carboxylate.

77. 4 - Acetylphenyl 2 - cyano - 1 - aziridine - carboxylate.

78. 4 - Carbomethoxyphenyl 2 - cyano - 1aziridine - carboxylate.

79. 4 - Cyanophenyl 2 - cyano - 1 - aziridine - carboxylate.

80. 2 - Phthalimidoethyl 2 - cyano - 1 aziridirie - carboxylate.

81. Process for the preparation of 1 - aziriline - carboxylic acid derivatives according to claim 4, wherein a nitrene of the general formula : -

in which R' has the same meaning as in claim 4, is reacted with a compound of the general formula CH2=CH-X in which X has the same meaning as in claim 1, with the proviso that when X is a nitrile group, R' is other than an ethyl radical.

82. Process according to claim 81 for the preparation of 1 - aziridine - carboxylic acid derivatives according to claim 4, substantially as hereinbefore described and exemplified.

83. 1 - Aziridine - carboxylic acid deriva tives according to claim 4, whenever prepared by the process according to claim 81 or 82.

84. Pharmaceutical compositions, compris ing at least one compound according to any of claims 3 to 80 and 83, in admixture with a solid or liquid pharmaceutical diluent or carrier.

85. Process for the preparation of 2 - cyano 1 - aziridine - carboxamide, wherein a com pound according to any of claims 3, 4 or 83, in which X is a nitrile group, is reacted with ammonia.

86. Process according to claim 85 for the preparation of 2 - cyano - 1 - aziridine - carb oxamide, substantially as hereinbefore des cribed and exemplified.

87. 2 - Cyano - 1 - aziridine - carboxamide, whenever prepared by the process according to claim 85 or 86.

88. Process for the preparation of 1 - aziri dine - carboxylic acid derivatives of the general formula given in claim 1 or 4, in which X is a nitrile group, wherein a corresponding compound in which X is an alkoxycarbonyl radical is reacted with ammonia to give the corresponding carbamoyl compound, followed by treatment with a dehydration agent.

89. Process for the preparation of 1 - aziridine - carboxylic acid derivatives of the general formula given in claim 1 or 4, in which X is a nitrile group, wherein a corresponding compound in which X is a carbamoyl group is reacted with a dehydration agent.

90. 1 - Aziridine - carboxylic acid derivatives of the general formula given in claim 1 or 4, in which X is a nitrile group, whenever prepared by the process according to claim 88 or 89.