CA1105474A - 1-aziridine-carboxylic acid ester derivatives and the preparation thereof - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

A class of 1-aziridine-carboxylic acid ester derivatives is provided having an immune-stimulating thera-peutic effect; the derivatives can be prepared by reacting an appropriate aziridine derivative with a haloformic acid ester; elimination of a halogen molecule from an appropriate dihalo derivative with concomitant cyclization to form the aziridine nucleus; elimination of nitrogen from a triazoline a nitrene with an appropriately substituted ethylene compound certain of the derivatives have additional utility as inter-mediates in the preparation of 2-cyano-1-aziridine-carboxamide a known immune-stimulating therapeutic compound.

Description

The present invention is concerned with the preparation of l-aziridine-carboxylic acid ester derivatives, some of which are new; and with such new derivatives.
In Tetrahedron Letters, 1964, 2497, Lwowski et al.
have described ethyl 2-cyano-l-a2iridine-caxboxylate, as well as a process for the preparation thereof but without giving any indication of its pharmacological action. In the course of investigations concerning 2-cyano-1-aziridine-carboxa~ide, which is an immune-stimulating therapeutic compound in cases of bacterial and viral infections (see German Offenlegungsschrift No. 25 28 460.Q, U~ Bicker, filed 26.6.75, published 13.1.77), it has been found that ethyl 2-cyano-1-aziridine-carbo~ylate can be used as an intermediate for the preparation of this thera-peutic compound.
Furthermore, it has, surprisingly, also been found that ethyl 2-cyano-l-a7iridine-carboxylate displayæ an outstand-ing immune-stimulating action.
The invention thus provides a class of l-aziridine-carboxylic acid ester derivatives which have an immune-stimulating therapeutic action, and some of which canadditionally be employed as intermediates in the manufacture of 2-cyano-l-a2iridine carboxamide, a known therapeutic com~
po~lnd. The invention further provides processes for preparing the clas~ of useful derivatives, In one aspect the present invention is concerned with the preparation of compounds of the formula (I3:-~7X

C - OR (I) o in t~hich X is a nitrile, carbamoyl or alkoxycarbonyl radical, R is a straight or branched-chain, saturated or un.saturated 1~591~7~

aliphatic hydrocarbon radical, unsubstituted or substituted by one or more of halogen, alkoxy, amino, carbamoyloxy, cycloalkyl, hydroxyl or imido groups or by a heterocyclic radical, or R is a cycloalkyl, aryl, aralkyl, aryloxyalkyl or arylthioalkyl radical, the aryl radical being unsubstituted or substituted by halogen, alkyl, alkoxy, hydroxyl, amuno, nitro, cyano, acyl, carbalkoxy, thioalkyl, alkylsulphonyl, phenyl or trifluoro-methyl groups.
The present invention is also concerned with pharma-ceutical compositions with an immune-stimulating action which contain a compound of formula (I).
The aliphatic hydrocarbon and alkyl radicals are, in all cases, to be understood to be straight or branch-chained radicals containing up to 6 and preferably up to 5 carbon atoms, the more preferred radicals being the methyl, ethyl, isobutyl, sec.-butyl, tert.-butyl and n-pentyl radicals, The alkyl or aliphatic hydrocarbon chain can be substituted by halogen atoms, ` for example, one or more of fluorine, chlorine and bromine aioms, as well as by amino or hydroxyl groups. Additional or alternative substituents include carbamoyloxy radicals, suit-ably the 2-cyano-1-aziridine-carbonyloxy radical, imido groups, or example, the phthalimido radical, heterocyclic radicals, e~pecially the 2-tetrahydrofuryl or 2~tetrahydxothienyl radical, and aLkoxy and cycloalkyl radicals~
In the case of substituents X and R, the alkoxy radical is, in all cases, to be understood to be a radical containing 1 to 6 and preferably up to 5 carbon atoms, the - methoxy, ethoxy and isopropoxy radicals being especially preferred. The cycloalkyl radicals suitably contain 3 to 10 carbon atoms and may be bridged or non-bridged, the cyclopropyl, cyclopentyl, cyclohexyl radicals being preferred as non-brid~ed radicals, and the bornyl radical being especially preferred as a bridged radical.

~5gL~

Preferred unsaturated aliphatic hydrocaxbon radicals include the allyl and crotyl radicals, - The aryl radicals are suitably those containing 6 to 10 carbon atoms, especially the phenyl and naphthyl radicals.
The aralkyl radicals are preferably benzyl or phenethyl radicals, the aryloxyalkyl radical is preferably a

2-phenoxyethyl radical and the arylthioalkyl radical is pre-ferably a 2-phenylthioethyl radical, The thioalkyl radical is preferably the methylthio radical and the alkylsulphonyl radical is preferably the methyl-sulphonyl radical. The acyl radical is suitably an aliphatic acyl radical i~ which the aliphatic hydrocarbon portion has up to 5 carbon atoms or is a hydrogen atom: the aliphatic hydrocarbon portion may be straight or branch-chained, saturated or unsaturated, the preferred radicals are formyl !
and acetyl~ 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 specified substituents.
The present invention also includes within its scope all stereoisomeric forms of the compounds of formula (I~ which can be obtained due to the presence of an asymmetrical carbon atom.
In another aspect of the invention there is provided a new compound of the formula (I'):-~X

C - OR' (I') wherein X has the same meaning as above and R' has the same meaning as R in 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 formula (I) possess, surprising]y, 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 formula (I)j wherein X is a nitrile group, are reacted with ammonia to give 2-cyano-1-aziridine-carboxamide.
According to the invention compounds of formula (I), as defined above, are prepared by a process which comprises:-a) reaction of an aziridine derivative of the formula (II):-~7 ~II), wherein X has the same meaning as above, with a haloformic acid ester of the formula (III):-Hal-C-OR
0 (III), wherein R has the same meaning as above and Hal is a chlorine or bromine atom; or b) treatment of a compound of the formula (IV):-Hal-H2C-CH-X
I (IV) Hal-~-C-OR
lo wherein X, R and Hal have the same meanings as above, with a reagent effective to split off halogen; or c) conversion of a compound of the formula (V):-N = N ~ -\ N X or N~ X (V), C - OR C -OR
Il 1 O O

wherein X and R have the same meanings as above, by the catalytic or photochemical splitting of~ of nitrogen, to give a compound of formula (I), whereafter, if deslred, a compound obtained of general formula (I) is converted into another compound of formula (I).
The subsequent conversion of compounds of formula (I) into other compounds of formula (I) can be achieved by a variety of weli known.reactions and can, for example, take place by con-version of the substituent ~. Thus, for example, when X is an alkoxycarbonyl radical, it can be reacted with ammonia to give a compound in ~hich X is a carbamoyl radical which, in turn, can be treated with a dehydration agent to give a compound in which X is a nitrile group.
~ ompounds of formula (I) in which X is an alkoxy-carbonyl or carbamoyl group can, thereore, also be used as intermediates for the preparation of compounds of formula (I) in which X is a nitrile group, this applies particularly to 2-carbamoyl-l-aziridine-carboxylic acid esters of formula (I).
The conversion of an ester or amide group can best be carried out with gaseous ammonia in an organic solvent, pre-ferably in methanol or ethanol. It is preferable to use equimolar amounts of ammonia and to carry out the reaction at a temperature of 0 to 5C. The desired amide can then be iso-lated from the reaction mixture by, for example, column chroma-to~raphy.
For the conversion of a carbamoyl group into a nitrile group, there can be used dehydration agents which are known for this purpose from the literature, a mixture of tri-phenyl phosphine, carbon tetrachloride and triethylamine being especially preferred. As solvent, it is appropriate 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 substituents 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 a further aspect of the invention, the new com-pounds of formula (I') can be prepared by the reaction of nitrenes of the formula (VI):-R'-O-Il-~ (VI), O
wherein R' has the same meaning as above, with compounds of the formula (VII):-` CH2=cH-x (VII~, wherein X has the same meaning as above.
Nitrenes of general formula (VI~, which can be inter-mediately prepared by the photolysis o~ azidoformic acid esters or by ~-elimination with the help of a base, for example, triethylamine, from N-p-nitrobenzenesulphonyloxy-urethanes, readily react with the acrylic acid derivatives (VII) to give the deqired aziridines of formula (I') (see, for example, Tetrahedron Letters, 1964, 2497, J.A.C.S., 87, 3630/1965).
In the case of process a), the reaction components are suitably reacted in an inert solvent, for example, diethyl ether, methylene chloride, benzene or toluene, in the presence of a base. The base used is suitably a tertiary amine, for example, triethylamine or triethanolamine, however, other bases can also be employed. It is also possible to work in a two-phase system, for example water/diethyl ether, in which case an -in~rganic base, especially scdium carbonate, is preferably used~

It is preferred to employ chloroformic acid esters as the halo-formic acid ester (III). Some of these esters (III) have already been described in the literature but otherwise they can be prepared in known manner by the reaction of an appropriate alcohol or phenol with phosgene in the presence of a base, for example, p~ridine or N,N-dimethylaniline. As a rule, the chloroformic acid esters are purified by distillation but it is also possible to emplo~ the crude product in the reaction.
The dihalo compounds (IV) used in process b) are new and can be prepared by the reaction of corresponding compounds which are not halogenated on the nitrogen atom, with halo-genation agents, for example, sodium hypohalites or tert.-butyl hypochlorite, For splitting off the two halogen atoms to give the aziridine derivatives of formula (I), there can be used conventional dehalogenation agents, for example, zinc or sodium, The triazoline derivatives (V) used in process c) are also new and can be prepared by the reaction of a diazo-acetic acid derivative, for example, ethyl diazoacetate or diazoacetonitrile, with a methyleneurethane. The nitrogen can be split off either photochemically b~ illumination in a solvent, for example, diethyl ether or acetone, or catalytically.
~s catalysts, there can be used, for example, noble or semi-noble metals, preferably copper powder.
For the preparation of pharmaceutical compositions with immune-stimulating action, the compounds of ge~eral ormula (I) are mixed in ~nown 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, for example, olive oil, and filled into gelatine capsules. Since the active material is acid-labile, the com~
position 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 carbo~ymethylcellulose. 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 (for example, stearic acid), gelatine, agar-agar, calcium phosphate, magnesium steaxate, animal and vegetable Eats and solid high molecular weight polymers ~for example, polyethylene glycols). Com~
positions suitable for oral administration can, if desired, contain flavouxing and sweetening agents.
As injection medium, it is preferred to use water which contains the additi~es usual for injection solutions, for example, stabilisin~ agents, solubilising agents or weakly alkaline buffers. Additives of this type include, for example, phosphate and carbonate buffers, ethanol, complex formers (for example, ethylenediamine-tetraacetic acid and the non-toxic - salts thereof~ and high molecular weight polymers (for example, liquid polyethylene oxides) for viscosity regulation.
According to a particular embodiments of the invention there is provided a pharmaceutical composition comprising an immune-stimulating effective amount of ethyl 2-cyano-1 aziridine-carbo~ylate in association with a pharmaceutically acceptable Aolid or liquid carrier.
The aziridine derivatives of formula (I) are suit-ably administered in a dosage of about 1 to 50 mg/kg body weight, which can be administered either all at once or in several individual doses.
For treatment of humans the active material may be applied one or more tim~s with each dose containing about 25 to 3,000 and preferably about 50 to 500 mg of derivative 7~L

.
The imlnuno-stimulant activity of the novel derivatives ~I) is demonstrated as follows:
Each time 10 female adult Sprague-Dawley rats were kept fasting overnight and the following morning blood was taken from the retroorbital venous plexus. After decomposition of the erythrocytes with saponin, the leucocytes were counted by means of a Coulter counter. Subsequently thereto, the test com~
pounds were orally administered to the rats by means of a throat tube at a dosage of 200 mg. per kilo in 5% Tylose (a trademar~ for a water soluble cellulose ether).

Four days after the application, again after keeping the rats fasting overnight, blood was taken from the retroorbital venus plexus by means of a heparinized puncture capillary and the leucocytes were again counted. The averages with standard deviations were calculated for 10 animals each time. As control, 10 adult Sprague-Dawley rats (Messrs. Wiga, Gassner, Sulzfeld) were treated in similar manner except that, instead of the preparation, only 5% Tylose (10 ml per kilo) were applied.
Table I below contains the results of the leuco-cytosis. The first column indicates the test derivative administered, the second column contains the leucocyte values prior to the administration of the derivatives. The fourth and fiftll columns indicate the control values, i.e., the fourth column the value for the control on day zero and the fifth column the value for the control day ~4. The increases in leucocytes resulting from administration of the novel derivatives are physiologically significant. Increases in leucocytes of less than 25% as shown by the controls are not significant.

'~`'~ i Leucocytes Upon Adm~nistration 200 mg/kg to Rats per os TABLE
Leucocytes in thousands Active Control Compound Initially Initially of ExamDle Dav 0 _ _ _ Dav 4 Da~ n~y 4 1 7.5 15.5 7.6 9.4 - 1.1 6.0 15.8 6.8 7.9 1.2 7,2 13.7 7.6 9.4 1.3 7.4 11.8 6.3 7.0 1.4 6.0 11.2 6.3 7~0 1.8 5.6 10.7 6.8 7.9 4.1 6.8 18 0 7.3 9.5 11.10 6.2 10.6 6.2 8.2 11.15 6.7 12.5 6.5 7.7 11.16 6.3 11.3 6.5 7 7 11.19 7.2 12,5 6.4 8.2 11.21 6.6 12.2 6.4 8.2 11.23 5.8 11.2 6.5 7~7 11.25 6.0 12.3 7.0 9.2 11.26 7.1 13~4 6.4 8.2 11.33 6.3 12~5 6.2 8.2 Comparison 8.9 9,5 8.7 9.4 l-Carboxamido-2-cyanoaziridine ~ 10 _ Preferred compounds according to the present invention include not only those specifically mentioned in the following Examples but also the following compounds:
l-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-1-aziridine-carboxylate 2-chlorophenyl 2-cyano-1-aziridine-carboxylate

3-chlorophenyl 2-cyano-1-aziridine-carboxylate 2,~,6-tribromophenyl 2-cyano-1-aziridine-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-tri~luoromethylphenyl 2-cyano-1 aziridine-carboxylate 3-trifluoromethylphenyl 2-cyano-1-aziridine-carboxylate 4-nitrobenzyl 2-cyano-1-aziridine-carboxylate 2-hydroxyethyl 2-cyano-1-aziridine-carboxylate cyclopropyl 2-cyano-1-aziridine-carboxylate 2,2,2-trifluoroethyl 2-cyano-1-aziridine-carboxylate 2-propoxyethyl 2-cyano-1-aziridine-carboxylate benzyl 2-carbamoyl-1-aziridine-carboxylate cyclohexyl 2-carbamoyl-1-aziridine-carboxylate 4-chlorophenyl 2-carbamoyl-1-aziridine-carboxylate i~opropyl l-ethoxycarbonyl-2-aziridine-carboxylate phenyl 2-ethoxycarbonyl-1-aziridine-carbo~ylate 2,2,2-trichloroethyl 2-isopropoxycarbon~l-1-azîridine-carboxylate allyl 2-ethoxycarbonyl-1-aziridine~carboxylate.

~ s~

The following Examples are given for th~3 purpose of illustrating the present invention, it will be recognized that different compounds of formula (I) may be readily obtained using the procedures described hereinbefore and those illustrated in the following examples, with different starting materials whereby any of the compounds of the invention including those mentioned above may be readily obtained.
Example 1.
Phenvl 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 mi~ture 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 iq recrystallised from diisopropyl ether, There are obtained 10.3 g. (about 6~/o of theory) phenyl 2-cyano-1-aziridine-carboxylate; m~p, 60 ~ 62C.
The following compounds are obtained in an analogous manner by reacting 2-cyanoaziridine with 1. methyl chloroformate:
methyl 2-cyano-1-aziridine-carboxylate, b.p. 70 - 72C./0.02 mm,Hg 2. 2,2,2-trichloroethyl chloro~ormate-2,2,2-trichloroethyl 2-cyano-1-aziridine-carboxylate;
b~p. 138 - 139C~/0.1 mm.Hg; m.p, 86 - 88C, (recrystallised from diisopropyl ether) 3. allyl chloroformate:
allyl 2-cyano-1-aziridine-carboxylate, b.p. 102 - 105C./0.2 mm.Hg, ~1~5~74 4. tert~-butyl chloroformate (used in the form of an ethereal solution):
text.-butyl 2~cyano-1-aziridine-carboxylate~
b.p. 57 - 59C./0.01 mm.Hg.

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

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

7. benzyl chloroformate acid:
benzyl 2-cyano-1-aziridine-carboxylate, b.p. 145-150C./0.01 mm.Hg.

8. phenethyl chloroformate (b.p. 120C./18 mm.Hg):
phenethyl 2-cyano-1-aziridine-carboxylate b.p. 130C./0.01 mm.Hg~
Exam~le 2.
Diethyl 1,2-aziridine-dicarboxylate.
A solution of 1.9 g~ ethyl chloroformate in 10 ml.
benzene is added dropwise at 0C. 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 1,2-aziridine-dicarboxylate, b~p.
94C./0.2 mm.Hg.
Example 3.
Phenyl 2-carbamoyl-1-aziridine-carboxvlate.
A solution of 4.7 g. phenylchloroformate in 20 ml~di-ethyl ether and 30 ml. aqueous 2N sodium carbonate solution are added dropwise and simultaneously to 2.6 g, 2-aziridine-~S~ 74 - c æ~oxamide in 20 ml, water, The reaction mixture is further stirred for 10 minutes, while cooling with ice. ~he precipitate obtained is filtered off with suction and well washed with diethyl ether. There are obtained 4.4 g. (about 71% of theory) phenyl 2-carbamoyl-1-aziridine-carboxylate, m.p. 140 -142C., after recrystallisation from toluene.
Example 4.
Allyl 2-cyano-1-aziridine-carboxylate 3,2 g. Allyl chloroformate in 20 ml, benzene is added dropwise at 0C. 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 ~.9 g. (about 64.5% of theory) allyl 2-cyano-1-aziridine-carboxylate; b.p. 102 - 105C,/0.2 mm.Hg.
In an analogous manner, by reacting 2-cyano-aziridine with ethyl chloroformate, there is obtained ethyl 2-cyano-1 a2iridine-carboxylate, b.p. 70 - 75C./0.01 mm.Hg.
Example 5, Ethvl 2-carbamovl-1-aziridine-carbo~vlate.

. _ . . . . .
A solution of 3.25 g. ethyl chloroformate in 20 ml.
diethyl ether and 15 ml. aqueous 2~ sodium carbonate solution are added dropwise and simultaneously to 2,6 g, 2 aziridine carboxamide 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% o theory) ethyl 2-carbamoyl-1-aziridine-carboxylate, m.p, 125 - 128C.

7~

In an analogous manner, by reacting 2-aziridine-carboxamide with methyl chloroformate, there is obtained methyl 2-carbamoyl-1-aziridine-carboxylate which, after recrystallisation rom toluene, melts at 117 - 120C.
Example 6 .

Preparation of 2-cyano-1-aziridine-carboxamude from phenyl 2-cyano-l-aziridine-carboxylate.
1.9 g. Phenyl 2-cyano~l-aziridine-carboxylate 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 over-night. The precipitated 2-cyano-1-aziridine-carboxamide is - then filtered off with suction, the yield being 0.85 g. (about 77/O of theory); m.p. 74 - 76C.
Example 7.
Methyl 2-cyano-1-aziridine-carboxylate.
14.4 g. Methyl 2-carbamoyl-1-aziridine-carboxylate are added to a solution of 27.5 g. triphenyl phosphine, 10.1 g.
triethylamine and 1504 g. carbon tetrachloride in 300 ml.
methylene chloride and the reaction mixture then boiled under xeflux ~or 4 hours. The reaction mixture is subseqeuntly iltered, the filtrate is extracted twice with water and the organic phase is dried and evaporated. The residue obtained i~ distilled to give 3.4 g. (about 27% of theory3 methyl 2-cyano-l-aziridine-carboxylate, b.p. 70 - 72C./0.02 mm.Hg.
Example 8.
Ethyl 2-carbamoyl-1-aziridine-carboxylate.
To 4.67 g. (0.025 mole3 diethyl 1,2~aziridine-dicarboxylate in 30 ml. ethanol there is added th~ equimolar amount of gaseous ammonia dissolved in ethanol and the reaction mixture is then left to stand overnight in a refrigeratorO The :
reaction mixture is subsequently evaporated and the desired ethyl 2-carbamoyl-1-aæiridine-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 - 128C.
Example 9.
Preparation of 2-cyano-1-aziridine-carboxamlde from ethyl 2-cyano-l-aziridine-carboxylate.
4 g. Ethyl 2-cyano-1-aziridine-carboxylate are added to a ~olution of 0.7 g. gaseous ammonia in 80 ml. water, The xeaction 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 addition of diethyl ether, There is obtained 1.05 g. (about 2~/o of theoryl 2-cyano-1-aziridine-carboxamide, m.p. 74 - 76C~
Example 10~
Ethyl 2-cyano-1-aziridine-carboxylate 0.33 g. of activated zinc dust and some zinc chloride were added to 2.11 g of 2-(~-carbethoxy-N-chloroamino)-3-chloropropionitrile in 25 m of ethanol and were stirxed for 12 hours at room temperature, filtered under suction, where-after the filtrate was evaporated and the residue distilled.
The yield was 0.11 g (about ~/O of theory); boiling point 73 - 80C./0.01 mm,Hg, - The starting material 2-(N-carbethoxy-~-chloxoamino)-2-chloro propionitrile was prepared as follows:
5,0 g. of 2-amino-3-chloropropionitrile hydro-chloride ~m.p, 153 - 155C,) was dissolved in 20 ml of water and then was mixed at room temperature simultaneou ly with 3,7 g. of ethylchloroformate in 30 ml of diethylether and 36 ml of a ~ sodium carbonate solution. After 30 minutes the phases were separated, the ether phase was washed twice with water, dried, and the solvent evaporated. There was thus obtained 4.7 g. (about 76% of theory) of 2-(N-carbethoxy-amino)-3-chloropropionitrile as a yellow oil. To 4.6 g, of this oil in 20 ml of benzene was added 3~2 g of tert.-butyl hypochlorite, and the resulting solution was allowed to stand in the dark, at room temper~ture, for 120 hours. After evaporation there was recovered 5.5 g. (about 100% of theory) of the 2-(N-carbethoxy-N-chloroamino)-3-chloropropionitrile as an oily substance. The mass spectrum confirmed the chemical structure of the compound.
Example 11.
In the manner described in Example 1, there are obtained, by the reaction of 2-cyanoaziridine with \

1. isobutyl chloroformate:
isobutyl 2-cyano-l-aziridine-carboxylatet b.p. 108 - 110C./0.1 mm.Hg.
2. Cyclopropylmethyl chloroformate (b.p. 45-46C~/12 mm.Hg):
cyclopropylmethyl 2-cyano-1-aziridine-carboxylate b.p. 107 - 109C./0.1 mm.Hg.
3. but-2-enyl chloroformate (b.p. 25-28C./0.1 rlun.Hg):
but-2-enyl 2-cyano-1-aziridine-carboxylate, oily product.
4. cyclopentyl chloroformate (b.p. 60-61C./16 mm.Hg):
cyclopentyl 2-cyano-1-aziridine-carboxylate, oily product~
5. bornyl chloroformate (b.p. 108 - 110C./12 mm.Hg):
bornyl 2-cyano-l~aziridine-carboxylate b.p. 153C./0.1 mm.Hg.
6. 2-fluoroethyl chloroformate (b.p. 110-113C.):
2-fluoroethyl 2-cyano-1-aæiridine-carboxylate b.p. 120C./0.1 mm.Hg.
7. 2-chloroethyl chloroformate (b~p. 83-86C~/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-aziridine-carboxylate b.p. 119 - 120C./0.1 mm.Hg.

10. tetrahydrofurfuryl chloroformate (b.p. 68C./0.2 mm.Elg):
tetrahydrofurfuryl 2-cyano-1-aziridine-carboxylate oily product.

11. ethylene glycol 1,2-bis-chloro~ormate (b.p. 110C,/
34 mm~Hg):
1,2-~bis-(2-cyanoaziridine-1-carbonyloxy)]-ethane, oily product,

12. 2-phenoxyethyl chloroformate (b.p. 97 - 99C,/0~1 mm.Hg):
2-phenoxyethyl 2-cyano-1-aziridine-carboxylate, oily product.

13. 2-phenylthioethyl chloroformate:
2-phenylthioethyl 2-cyano-1-aziridine-carboxylate, oily product~

14. l-naphthyl chloroformate (b.p, 86-90C,/0,1 mm,Hg):
l-naphthyl 2-cyano-1-aziridine-carboxylate, oily product.

15. 4-methylphenyl chloroformate (b,p~ 105-106C./30 mm.Hg):
4-methylphenyl 2-cyano-1-aziridine-carboxylate;
m.p. 88 - 90C. (recrystallised from isopropanol).

16. 2,4-dimethylphenyl chloroformate (b,p. 100 - 101C,/
12 mm.Hg):
2,4-dimethylphenyl 2-cyano-1-aziridine-carboxylate m.p. 90 - 91C, (recrystallised from ethanol),

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

18. 4-biphenyl chloroformate:
4-biphenyl 2-cyano-1-aziridine-carboxylate, m.p. 107 - 109Co

19. 4-methoxyphenyl chloroformate (b,p. 115 - 117C,/
12 mm,Hg):
~0 4-m~athoxyphenyl 2-cyano-1-aziridine~carboxylate, m,p. S4 - 57C~ (recrystallised from diisopropyl ether), ~5~

20. 4-chloro-2-methoxyphenyl chloroformate (b,p. 138 -140C./20 mm,Hg):
4-chloro-2-methoxyphenyl 2-cyano-1-aziridine-carboxylate~
m.p. 114 - 115C, (recrystallised from isoproPanol).

21. 2-fluorophenyl chloroformate (b,p. 68 - 70C~/12 rnrn.Hg):
2-fluorophenyl 2-cyano-1-aziridine-carboxylate, m.p. 55 - 56C. (recrystallised from isopropanol/water).

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

23~ 4-chlorophenyl chloroformate (b.p. 97-99C,/12 mm.Hg):
4-chlorophenyl 2-cyano-1-aziridine-carboxylate;
m,p, 79 - 82C, (recrystallised from diisopropyl ether).

24. 2,4-dichlorophenyl chloroformate (b.p, 112-117C./ 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 60C,):
2,4,S-trichlorophenyl 2-cyano~l-aziridine-carboxylate;
m,p, 100-103C, (recrystallised from diîsopropyl ether),

26, 4-bromophenyl chloroformate (b,p" 111-113C,/12 mm.Hg):
4-bromophenyl 2-cyano-1-aziridine-carbo~cylate;
m.p, 96-100C, (recrystallised from diisopropyl ether).
27a 3-nitrophenyl chloroformate (b,p, 120-122C./0,5 mm.Hg):
3-nitrophenyl 2-cyano-1-aziridine-carboxylate, m,p, 98-lOO~C, (recrystallised from isopropanol), 28, 4-nitrophenyl chloroformate:
4-nitrophenyl 2-cyano-1-aziridine-carbo~ylate;
m.p. 107-111C~ (recry~3tallised from diisopropyl ether)~
302g. 4-methylthiophenyl chloroformate (b,p, 108C./0~2 mm,Hg):
4-methylthiophenyl 2-cyano-1-aziridine-carboxylate;
m,p, 73-75~C. ~recrystallised from isopropanol)O

~5~7~

30. 2-methylsulphonylphenyl chloroforma-te (m,p~ 100-103C.):
2-methylsulphonylphenyl 2-cyano-1-aziridine-carbo~ylate;
m.p. 145-150C. (recrystallised from isopropanol).
31. 3-formylphenyl chloroformate (b.p. 125C./0.4 mm.Hg):
3-formylphenyl 2-cyano-1-aziridine-carboxylate, oily product.
32. 4-acetylphenyl chloroformate (b.p. 121-123C./5 mm.Hg):
4-acetylphenyl 2-cyano-1-aziridine-carboxylate, m.p. 104 - 107C.
33. 4-carbomethoxyphenyl chloroformate (m.p. 47-50C):
4-carbomethoxyphenyl 2-cyano-1-aziridine-carboxylate, m.p. 86-87C. (recrystallised from isopropanol).
! 34. 4-cyanophenyl chloroformate (b,p. 92-94C,/0~1 mm~Hg):
4-cyanophenyl 2-cyano-1-aziridine-carboxylate, m.p. 95-99C. (recrystallised from ethyl acetate/
ligroin).
35. 2-phthalimidoethyl chloroformate (m.p. 75-77C,):
2-phthalimidoethyl 2-cyano-1-aziridine-carboxylate m.p. 160-163C. (recrystallised from ethanol).
Compounds which are obtained as oily products were characterised by NMR and mass spectroscopy.
Process c) employing triazoline derivatives (V) can be carried out in accordance with the teachings of "Ethylenimine and other aziridines", 0. C. Dermer and G~ E, Ham, Acad. Press, ~ew York and London, 1969, page 68 et seq,

Claims (43)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:-

1. A process for the preparation of a l-aziridine-carboxylic acid ester derivative of the formula (I):- (I) in which X is a nitrile, carbamoyl or alkoxycarbonyl group and R is a straight or branched-chain, saturated or unsaturated aliphatic hydrocarbon radical, which is unsubstituted or substituted by one or more of halogen, alkoxy, amino, carbamoyl-oxy, cycloalkyl, hydroxyl, imido and heterocyclic radical, or R is a cycloalkyl, aryl, aralkyl, aryloxyalkyl or arylthio-alkyl radical, the aryl radical being unsubstituted or sub-stituted by one or more of halogen, alkyl, alkoxy, hydroxyl, amino, nitro, cyano, acyl, carbalkoxy, thioalkyl, alkyl-sulphonyl, phenyl or trifluoromethyl and stereoisomeric forms thereof in the case where said ester derivative contains an asymmetrical carbon atom, comprising a) reacting an aziridine derivative of the formula (II):- (II) in which X is as defined above, with a haloformic acid ester of the formula (III):- (III) in which R is as defined above and Hal is a chlorine or bromine atom; or b) splitting off halogen from a compound of the formula (IV):- (IV) in which X, R and Hal are as defined above, with a reagent splitting off halogen; or c) subjecting a compound of the formula (V):- or (V) in which X and R are as defined above, to the catalytic or photochemical splitting off of nitrogen; or d) reacting a nitrene of formula (VI):
(VI) with a compound of formula (VII):-CH2=CH-X (VII) in which X is as defined above and R' has the same meaning as R, with the proviso that when X is a nitrile group, R' is other than ethyl, whereafter, if desired, the compound (I) obtained is converted into a different l-aziridine-carboxylic acid ester (I).

2. A process according to claim 1, comprising reacting said aziridine derivative (II) with a chloroformic acid ester of said formula (III).

3, A process according to claim 1, wherein said reacting is carried out in an inert solvent in the presence of a base,

4. A process for the preparation of novel l-aziridine-carboxylic acid ester derivatives of the formula (I'):- (I') in which X is a nitrile, carbamoyl or alkoxycarbonyl group and R' is a straight or branched-chain, saturated or unsatu-rated aliphatic hydrocarbon radical, which is unsubstituted or substituted by one or more of halogen, alkoxy, amino, carbamoyloxy, cycloalkyl, hydroxyl or imido groups or by a heterocyclic radical, or R' is a cycloalkyl, aryl, aralkyl, aryloxyalkyl or arylthioalkyl radical, the aryl radical being unsubstituted or substituted by one or more of halogen, alkyl, alkoxy, hydroxyl, amino, nitro, cyano, acyl, carbalkoxy, thioalkyl, alkylsulphonyl, phenyl or trifluoromethyl with the provisio that when X is nitrile, R' is other than ethyl, and stereoisomeric forms thereof in the case where said ester derivative contains an asymmetrical carbon atom; comprising a) reacting an aziridine derivative of the formula (II):- (II) in which X is as defined above, with a haloformic acid ester of the formula (III):- (III) in which R'is as defined above and Hal is a chlorine or bromine atom; or b) splitting off halogen from a compound of the formula (IV):- (IV) in which X, R' and Hal are as defined above, with a reagent splitting off halogen, or c) subjecting a compound of the formula (V):- or (V) in which X and R' are as defined above, to the catalytic or photochemical splitting off of nitrogen; or d) reacting a nitrene of formula (VI):- (VI) in which R' is as defined above, with a compound of formula(VII) CH2=CH-X (VII) in which X is as defined above, whereafter, if desired, the compound (I) obtained is converted into a different l-aziridine-carboxylic acid ester (I').

5. A process according to claim 4, for the preparation of novel l-aziridine-carboxylic acid derivatives of the formula (I'):- (I') in which X and R' are as defined in claim 4, which comprises reacting a nitrene of the formula (VI):- (VI) in which R' is as defined above, with a compound of the formula (VII):-CH2=CH-X (VII) in which X is as defined above.

6. A process according to claim 1, 4 or 5, in which aliphatic hydrocarbon and alkyl radicals in the definitions of the substituents are straight or branch-chained, saturated or unsaturated radicals containing up to 5 carbon atoms' said cycloalkyl radical is a bridged or non-bridged radical of 3 to 10 carbon atoms, said aryl radical contains 6 to 10 carbon atoms, said acyl radical contains up to 5 aliphatic hydro-carbon atoms; and said halogen is fluorine, chlorine or bromine.

7. A process according to claim 2, for preparing phenyl 2-cyano-1-aziridine-carboxylate comprising reacting 2-cyanoaziridine with phenyl chloroformate.

8. A process according to claim 2, for preparing methyl 2-cyano-1-aziridine-carboxylate comprising reacting 2-cyanoaziridine with methyl chloroformate.

9. A process according to claim 2, for preparing 2,2,2-trichloroethyl 2-cyano-1-aziridine-carboxylate comprising reacting 2-cyanoaziridine with 2,2,2-trichloroethyl chloro-formate.

10. A process according to claim 2, for preparing allyl 2-cyano-1-aziridine-carboxylate comprising reacting 2-cyanoaziridine with allyl chloroformate.

11. A process according to claim 2, for preparing tert.-butyl 2-cyano-l-aziridine-carboxylate comprising reacting 2-cyanoaziridine with tert.-butyl chloroformate.

12. A process according to claim 2, for preparing phenethyl 2-cyano-1-aziridine-carboxylate comprising reacting 2-cyanoaziridine with phenethyl chloroformate.

13. A process according to claim 2, for preparing ethyl 2-cyano-1-aziridine-carboxylate comprising reacting 2-cyano aziridine with ethyl chloroformate.

14. A process according to claim 2, for preparing tetra-hydrofurfuryl 2-cyano-1-aziridine-carboxylate comprising react-ing 2-cyanoaziridine with tetrahydrofurfuryl chloroformate.

15. A process according to claim 2, for preparing 4-methylphenyl 2-cyano-1-aziridine-carboxylate comprising react-ing 2-cyanoaziridine with 4-methylphenyl chloroformate.

16. A process according to claim 2, for preparing 2,4-dimethylphenyl 2-cyano-1-aziridine-carboxylate comprising reacting 2-cyanoaziridine with 2,4-dimethylphenyl chlorofor-mate.

17. A process according to claim 2, for preparing 4-methoxyphenyl 2-cyano-1-aziridine-carboxylate comprising react-ing 2-cyanoaziridine with 4-methoxyphenyl chloroformate.

18. A process according to claim 2, for preparing 2-fluorophenyl 2-cyano-1-aziridine-carboxylate comprising react-ing 2-cyanoaziridine with 2-fluorophenyl chloroformate.

19. A process according to claim 2, for preparing 4-chlorophenyl 2-cyano-1-aziridine-carboxylate comprising react-ing 2-cyanoaziridine with 4-chlorophenyl chloroformate.

20. A process according to claim 2, for preparing 2,4,5-trichlorophenyl 2-cyano-1-aziridine-carboxylate comprising re-acting 2-cyanoaziridine with 2,4,5-trichlorophenyl chloro-formate.

21. A process according to claim 2, for preparing 4-bromophenyl 2-cyano-1-aziridine-carboxylate comprising reacting 2-cyanoaziridine with 4-bromophenyl chloroformate.

22. A process according to claim 2, for preparing 4-carbomethoxyphenyl 2-cyano-1-aziridine-carboxylate comprising reacting 2-cyanoaziridine with 4-carbomethoxyphenyl chloro-formate.

23. A process according to claim 1, wherein a first product obtained of said formula (I) is converted to a different product of formula (I).

24. A process according to claim 23, in which X in said different product is a nitrile group, wherein a corresponding compound (I) in which X is an alkoxycarbonyl radical is reacted with ammonia to give the corresponding carbamoyl compound, followed by treatment with a dehydration agent.

25. A process according to claim 23, in which X in said different product is a nitrile group, wherein a corresponding compound (I) in which X is a carbamoyl group is reacted with a dehydration agent.

26. A process for the preparation of 2-cyano-1-aziridine carboxamide comprising the step of reacting a derivative of formula (I) produced according to the process of claim 1, in which X is a nitrile group with ammonia.

27. A l-aziridine-carboxylic acid derivative of formula (I'), as defined in claim 4, whenever prepared by the process of claim 4, or an obvious chemical equivalent.

28. A l-aziridine-carboxylic acid derivative of formula (I'), as defined in claim 5, whenever prepared by the process of claim 5, or an obvious chemical equivalent.

29. Phenyl 2-cyano-1-aziridine-carboxylate whenever pre-pared by the process of claim 7, or by an obvious chemical equivalent.

30. Methyl 2-cyano-1-aziridine-carboxylate whenever pre-pared by the process of claim 8, or by an obvious chemical equivalent.

31. 2,2,2-Trichloroethyl 2-cyano-1-aziridine-carboxylate whenever prepared by the process of claim 9, or by an obvious chemical equivalent.

32. Allyl 2-cyano-1-aziridine-carboxylate whenever pre-pared by the process of claim 10, or by an obvious chemical equivalent.

33. Tert.-butyl 2-cyano-l-aziridine-carboxylate whenever prepared by the process of claim 11, or by an obvious chemical equivalent.

34. Phenethyl 2-cyano-1-aziridine-carboxylate whenever prepared by the process of claim 12, or by an obvious chemical equivalent.

35. Tetrahydrofurfuryl 2-cyano-1-aziridine carboxylate whenever prepared by the process of claim 14, or by an obvious chemical equivalent.

36. 4-Methylphenyl 2-cyano-1-aziridine-carboxylate when-ever prepared by the process of claim 15, or by an obvious chemical equivalent.

37. 2,4-Dimethylphenyl 2-cyano-1-aziridine-carboxylate whenever prepared by the process of claim 16, or by an obvious chemical equivalent.

38. 4-Methoxyphenyl 2-cyano-1-aziridine-carboxylate when-ever prepared by the process of claim 17, or by an obvious chemical equivalent.

39. 2-Fluorophenyl 2-cyano-1-aziridine-carboxylate when-ever prepared by the process of claim 18, or by an obvious chemical equivalent.

40. 4-Chlorophenyl 2-cyano l-aziridine-carboxylate when-ever prepared by the process of claim 19, or by an obvious chemical equivalent.

41. 2,4,5-Trichlorophenyl 2-cyano-1-aziridine-carboxylate whenever prepared by the process of claim 20, or by an obvious chemical equivalent.

42. 4-Bromophenyl 2-cyano-1-aziridine-carboxylate when-ever prepared by the process of claim 21, or by an obvious chemical equivalent.

43. 4-Carbomethoxyphenyl 2-cyano-1-aziridine-carboxylate whenever prepared by the process of claim 22, or by an obvious chemical equivalent.