IE45287B1 - Improvements in or relating to a process for the preparation of n-(unsubstituted or substituted) alkyl-n-nitrosocarbamoylazides - Google Patents

Description

This invention relates to a process for the preparation of N-alkyl-N-nitrosocarbamoyl azides, in which the alkyl radical may be ; substituted or unsubstituted, and to certain such azides per se.

The azides can be used in the preparation of asymmetrically 1.3- disubstituted nitrosoureas.

It will be understood that the term ‘'asymmetrical as used herein refers to a lack of a plane of symmetry through the carbonyl group in the 2-position of the substituted urea. A molecule lacking such a plane of symmetry need not, of course, lack any plane of symmetry; a number of such compounds are Irish Patent Specification No. 45286 (compounds 1 to 5 of Table I) which have a plane or symmetry which is not through the 2-position carbonyl group of the substituted urea.

Specific l-(2-chloroethyl)-l-nitrosoureas, particularly 1.3- bis-(2-chloroethyl)-l-nitrosourea (BCNU), have been used successfully as chemotherapeutic agents for the treatment of a number of experimental and clinical tumours (see Adv. in Cancer Res. 16, 237 to 332, (1972)).

A number of studies have been made of the working mechanism and the chemotherapeutical activity of such compounds, leading to the conclusion that their toxicity is probably influenced mostly by the carbamoylating activity of the decomposition products (Wheeler et al., Cancer Res. 34, 194 to 2000, (1974)). However, the biological effects of the alkylating and carbamoylating agents, obtained by the breakdown of the nucleus in vivo and in vitro, are little known.

It appears to us to be very desirable to prepare analogues of the abovementioned nitrosoureas in order to influence their chemotherapeutical activity, particularly the toxicity or the anti-tumour activity itself, as well as to modify their solubility in water or in tissue fluids. &52h1 However when preparing an asymmetrical ’ .i-iisubstituteti N-nitrosoures the selective nitrosoation of a specified nitrogen atom of the urea is of outstanding importance. for example, the nitrogen atom may be that wnicfc carried the 2-ehloroethyl group, in the case of an asymmetrically substituted analogue of BCNU. it has been ' demonstrated that for nitrosaticr; in ..ndlijuc formic acid (Johnston et al., J. MaU. Chon £32 to 311 (1966)» tne formation of 1- (2-i,hloroetr:y’,-i'o-fiosoui'ea is favoured o?:ly in those cases where the geometry c.f tne substituent in the 3-position provides steric control and directs the nitro-group into the required position. The selective nitrosation fails wnen such steric control is not present.

According to ore aspect of the present invention, there is provided a process for the preparation of an N-unsubstituted alkyi-N-nitroiocarbamcvl azide an N-substituted alkyl-N-nitrosoca-rbamoyl azide, wheisin sc N-unsubstituted alkyl carbamoyl azide or an N-substituted alkyl carbamoyl azide is reacted with nitrogen tetroxide in the cold in a solvent which under the reaction conditions is inert to tha reactants, Preferably, the N-unsubstituted alkyl carbamoyl azide or the N-substituted alkyl carbamoyl azide is an N-(C7 to Cg)unsubstituted a'iKyj carbamoyl azide ur an K-substituted (Cg to Cg) alkyl carbamoyl azide- ii is further preferred that the N-substituted alkyl carbamoyi azide ->z an N-haloalkyl carbamoyl azitia, advantageously 2- ehloroethyl carbamoyl azide.

According to a second aspect of the present invention, there is provideci a process for the preparation of an N-unsubstituted alkyl-Nnitrcsocarbaisoyl azide or an H-substituted alkyl-N-nitrosocarbamoyl azide, which process comprises reacting an unsubstituted alkyl isocyanate «S38 ? or a substituted alkyl isocyanate with an azide to form an N-unsubstituted alkyl carbamoyl azide or an N-substituted alkyl carbamoyl azide and reacting the N-unsubstituted alkyl carbamoyl azide or the N-substituted alkyl carbamoyl azide with nitrogen tetroxide in the cold in a solvent which under the reaction conditions is inert to the reactants.

The unsubstituted alkyl isocyanate or the substituted alkyl isocyanate is preferably reacted with an alkali metal azide in the cold. Advantageously, the unsubstituted alley! isocyanate or the substituted alkyl isocyanate is reacted with activated sodium azide in an inert solvent with the addition of hydrochloric acid. (Activation of sodium azide is well known).

In an especially preferred embodiment of the present invention, the . N-unsubstituted alkyl carbamoyl azide or the N-substituted alley! carbamoyl azide is reacted with nitrogen tetroxide at about 0°C.

N-unsubstituted alkyl-N-nitrosocarbamoyl azides or N-substituted alkyl-N-nitrosocarbamoyl azides may be reacted with a diamine, an amino alcohol not an amino-sugar, sn amino acid or an amino acid derivative to produce an asymmetrically (as hereinbefore defined) 1,3-disubstituted nitroso urea. We refer to our Patent Specification No. 45286 , from which this Application was divided, which describes and claims a process for the preparation of an asymmetrically (as hereinbefore defined) 1,3-disubstituted nitroso urea, wherein an N-unsubstituted alkyl-Nnitrosocarbamoyl azide or an N-substituted alkyl-N-nitrosocarbamoyl azide is reacted with a diamine, an amino alcohol not an amino sugar, an amino acid or an amino acid derivative, the reaction taking place in a solvent which under the reaction conditions is inert to the reactants.

The amino acid derivative can be an amide. The preferred N-haloalkyl-N-nitrosozarbamoy! azide is N-(2-chioroethyl)-hnitrosocarbamoyl azide.

We have found that synthesis cf selectively nitrosated ureas may 5 be achieved simply and completely if a«. ii-(—os dieted alkyl)-NriitiOsocsrb’f.::/! azije in ιΜζα the substituent is a halogen atom is used in the prepara^iori of ^substituted nitroso ureas. Particularly useful are N-(2-ha1oethylJ-ii-nit'Osocdrbasucyl azides, advantageously the N-(2-chloro-ethyl)-cwpcunds and N-(2-fluoroethyl) compounds. 1C The N-(substituted alkyll-N-nitrosocarbamoy’ azides may ba obtainea easily in one step, ana without the use of pyridine, from the corresponding carbamoyl azide, which in turn may be prepared by the reaction of the corresponding isocyanate with actuated sodium azide.

Such a reaction scheme is une.-.yected as the synthesis of fl-alkyl-N-nitrosocarbamoy’ azides described in Helv. Chim. Acta, vol. 52, Fasc. 8, (1969), No. /:, and vol. 57, fasc 8, (1974), No. 289 requires the preparation of first, tno chloride and then the azide, and also requires the presence of pyridine.

The N-nitrosation of easily available alkyl carbamoyl azides, for example 2-chloroeuiyl carbamoyl azide, has shown mat the nitroso group is attached to the desired position. Subsequent amination of the nitrosated carbamoyiatir.g agent yields alkyl-N-nitroso ureas, (for example the 2-ch‘oroethyl-N-nit.'oso urea), which are substantially free from isomers. The invention enablas the preparation of a large number of unsucstitutc-d or substituted alkyl-N-nitroso ureido compounds, which previously were not obtainable, or were only obtainable in low yields, by conventional method;; in which the urea structure was first obtained and then nitrosated. 887 The invention will now be described and illustrated by way of non-limiting Examples. The chemical compounds and the solvents used in the Examples were of synthesis grade or chemically pure. Nitrogen tetroxide was used in the form commercially available (from BASF, Ludwigshafen).

EXAMPLE 1 Preparation of 2-chloroethylcarbamoyl azide (I) A solution of 2-chloroethyl isocyanate (0.2 mole) in 100 ml of benzene was slowly added to a stirred solution of activated sodium azide (0.2 mole) in 100 ml of hydrochloric acid (132) maintained at 0°C. The two-phase reaction mixture was stirred for 4 hours at 0°C and the water phase was then removed. 2-chloroethylcarbamoyl azide was crystallized from benzene/petroleum ether in the form of white needles. Yield: 882. Mp: 49.6 to 50.2°C. NMR (CDCIg-TKS): δ = 3.4 to 3.9 ppm (unres., 4H, CHg-CHg-CT); 6.12 ppm (br, s, 1H, NH). MS(14v): m/e 148 (M+) m/e 106(mn3)+, m/e 105/M-HNj) + = base peak. Intensity ratio of m/e 148/m/e 150 is typical for a raonochlorinated compound.

EXAMPLE 2 Preparation of N-(2-chloroethyT)-N-nitrosocarbamoylazide (II) Nitrogen tetroxide (0.3 mole) was slowly added to a suspension of anhydrous sodium acetate (0.6 mole) in 300 ml of carbon tetrachloride at -10°C. After warming to 0°C 2-chloroethylcarbamoyl azide (0.2) was slowly added with a spatula to the stirred suspension.

A white precipitate was forms-d (AcO.-l). After 15 minutes the reaction mixture was pcured into ice water. The separated organic phase was extracted twice -.-/7tr. όΰ ml of a «old solution of feHCO, (1 molar) and was then washed neutral with 2 z 5G ml of ice cold water saturated with had. it was then arisd over annydrou: sclium sulpnate. No attempt was mass tc : ·, ‘w·-. ?-(cr.loroechyl;-.2-/-: trosocarbamoyl aziee as it is potent'’ally r4-ve. Tna h'S spoctrocopic examination of the CC1(- solution (internal scanaard TKSj shewed the complete absence of ar. Nh- sigral and showed a pattern which is typical for the A^B^ system of the nitrosation S-ciiloroethylamino group. = 3.50 ppm (t, 2n, -CH„-t-iffi,: 4.15 ρρω (*. 2H, Cl-C’U). The solution should be stored as cold as possible, for example deep-freezed, as it turns out that on stancing at rot® temperature the Upfield pseudotriplet gradually diszocor. s and at tne same time a new pseudotriplet appears, i a/i.w the centre at 5 =4.87 ppm. This specfal change was in one case complete after 48 hours. If the solution is maintained at -30°C, no such phenomenon fakes place.

The reaction described in Examples 1 and 2, can also be carried out with the ct-rrespci-.eir,g 2-fluoro, 2-bromo- or 2-iodo-compound.

Examples 3, 4, 5 and 6 of our Patent Specification No. show tne use of 3-(2-cnloroethylJ-N-nitrosocarbaaoyi azide for the preparation of various disubstituted 2-nitroso ureas.

The sequence of tne chemical reaction steps can be schematically shows as fol.ows: (1) CI-C.!z-CH2-NCO + KN, ·* Cl-C.^-CHg-NKCOi^ (li) Cl-CHgCrlg-NHCON, + N,04- Cl-Cri,-CK2-N(N0)C0N3

Claims (13)

1. A process for the preparation of an N-unsubstituted alkyl-Nnitrosocarbamoyl azide or an N-substituted alkyl-N-nitrosocarbamoyl azide, wherein an N-unsubstituted alkyl carbamoyl azide or an 5 N-substituted alkyl carbamoyl azide is reacted with nitrogen tetroxide in the cold in a solvent which under the reaction conditions is inert to the reactants.

2. A process according to Claim 1, 'wherein the N-unsubstituted alkyl carbamoyl azide or the N-substituted alkyl carbamoyl azide is 10 an N-(Cg to C g ) unsubstituted alkyl carbamoyl azide or an N-substituted (Cg to C g ) alkyl carbamoyl azide.

3. A process according to Claim 1 or 2, wherein the N-substituted alkyl carbamoyl azide is an N-haloalky! carbamoyl azide.

4. A process according to Claim 3, wherein the N-haloalkyl 15 carbamoyl azide is ’2-chloroethylcarbamoyl azide.

5. A process for the preparation of an N-unsubstituted alkyl N-nitrosocarbamoyl azide or an N-substituted alkyl-N-nitroso -carbamoyl azide, which process comprises reacting an unsubstituted alkyl isocyanate or a substituted alkyl isocyanate with an azide to form an 20 N-unsubstituted alkyl carbamoyl azide or an N-substituted alkyl carbamoyl azide and reacting the N-unsubstituted alkyl carbamoyl azide or the N-substituted alkyl carbamoyl azide with nitrogen tetroxide in the cold in a solvent which under the reaction conditions is inert to the reactants. .4-238 7 1C

6. A process according to Claim 5, wnsrein tne ’wsubstituted alkyl isocyanate or the substituted alkyl isocyanate is reacted with an alkali metal aziae in tne cold.

7. A process according to Claim 5 or 6, wherein the unsubstituted alkyl isocyanate or the sabs-itutec akyl isocyanate is reacted with c.,.1 vated ^odicr; t ;.lcie in an inert Sol.'.*./; =ia toe addition of hydrochloric a'io. ύ. 5 process dccaroinj to any one of Claims 1 to 7, wherein the N-unsucstituted alkyl carbamoyl azide or the N-substituted alkyl carbamoyl azide is reacted with nitrogen tetrexide at a:>c>ut 0°C. ?. Ar Y-hal•'alkyl-N-nit'Osocar.w.icyl azide.

8. 10. An N-ha'to{C, to ; ‘ 6 )a’kyi -fi-iiitrosocar-amoyl azide.

9. 11. An .i-h-Joethyl-N-ritresocarbsiiioyl aziae.

10. 12. N-(2-chloroetl’yl)-fi-i:itrosocarbamoyl azide.

11. 13. N-(2-r1uoroethyl /-.i-nitresocaroatacyl azide.

12. 14. A process ft ,.-ie preparation of ii-(2-chloroethyl/-N-nitrosocarbamoyl azide substantially as described in foregoing Example 2.

13. 15. An ti-halcdkyi N-iiitresoe»rbamoyl azide whenever prepared by a process according to any one of Claims 1 tc 3 and 14,