CZ297577B6 - Process for preparing 1,4,7,10-tetraazacyclododecane and N-acyl derivatives thereof - Google Patents

Abstract

In the present invention, there is disclosed a process for preparing 1,4,7,10-tetraazacyclododeane alias cyclene and N-acyl derivatives thereof of the general formula I, in which Y represents a hydrogen atom, tert-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, 9-fluorenyl methoxycarbonyl wherein the preparation process is characterized by electrophilic catalyzed rearrangement (cyclotetrameration) of N-acyl aziridines of the general formula II, in which Y represents tert-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl or 9-fluorenyl methoxycarbonyl.

Description

A process for the preparation of 1,4,7,10-tetraazacyclododecane and its N-acyl derivatives

Technical field

The present invention relates to a process for the preparation of 1,4,7,10-tetraazacyclododecane and its N-acyl derivatives of the general formula I, in which Y is hydrogen, tert-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, electrophile catalyzed rearrangement.

(D

BACKGROUND OF THE INVENTION

Cyclene (1,4,7,10-tetraazacyclododecane; formula 1, where Y = H), is a starting material for the preparation of a wide group of highly sophisticated chemical species with real applications primarily in human medicine (cancerostatics, radioimmunotherapeutics, virostatics, diagnostics).

The methods used to prepare cyclene and its derivatives hitherto used are based on the formation of condensation products of glyoxal derivatives with triethylenetetramine (the so-called bisimidazoline pathway: CZ 295713; WO 2005/000823; WO 00/32581; US 6653470; US 6156890; US 5886174; ibid., Richman and Atkins method (tosylamide pathway: J. Amer. Chem. Soc. 96, 2268 (1974)), difficult to implement by the method of Weisman and Reed (J. Org. Chem. 61,5186 (1996)) , and finally the method of targeted tetramerization of N-benzylaziridine (the so-called aziridine pathway: CZ 290128). The common denominator of these methods for the preparation of cyclene is the necessity to perform in many reaction stages, resulting in low total yield of cyclene (between 3 to 35%), high loss of molar mass on used substrates (typical for tosylamide pathway) or high demands on strict empirical conditions. Embodiments (typical for bis-imidazoline routes).

From the point of view of theoretical organic synthesis, of course, the best method is targeted cyclotetrameration of aziridine, which optimally combines factors from the group of so called Chemistry Economy (ie usability of substrate molecules to the product skeleton) and so-called Green Chemistry (ecological aspects) ). Unfortunately, aziridine fails to catalytically target and selectively tetramerize because the secondary amino group also appears to be active in the electrophilic rearrangement process. Such oligomerization results in the formation of tertiary polyamines with varying degrees of cross-linking. The solution is the use of N-protected aziridines. In practice, targeted cyclotetramerization of N-benzylaziridine (CZ 290128 and literature cited therein) and N-tosylaziridine has been realized and subsequently described. In the first case, cyclene yields from N-benzylethanolamine do not exceed 37% (CZ 290128 reports up to 58%). critical point in the process of degrading N-tosyl protecting groups.

- 1 GB 297577 B6

SUMMARY OF THE INVENTION

The present invention provides the preparation of 1,4,7,10-tetraazacyclododecane and its N-acyl derivatives of formula I wherein Y is hydrogen, tert-butoxycarbonyl I (BOC), methoxycarbonyl (MOC), ethoxycarbonyl (EOC), benzyloxycarbonyl (Z) ), 9-fluorenylmethoxycarbonyl (FMOC), by electrophilic catalyzed rearrangement of aziridine N-acyl derivatives of the general formula II

Y

N

A (1D) wherein Y is tert-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl.

N-acylated (i.e., deactivated) aziridines are disadvantaged to electrophilically catalyzed rearrangement at the stage of attack of the reactive intermediate (electrophilic particles) to another substrate molecule (N-acylated aziridine). However, the nitrogen acidity of the N-acylamino group greatly facilitates the formation of a reactive intermediate by the action of an electrophilic rearrangement (electrophilic particle) catalyst on N-acylated aziridine to such an extent that a significantly less effective catalyst can be used in other cases. It is an object of the present invention to utilize electrophilic catalysis of a lithium cation, which is both the initiator of the cyclotetramerization process and the control element of the cyclooligomerization process where it initiates the so-called template effect. The use of a lithium cation further makes it possible to carry out cyclotetramerization with N-acyls particularly sensitive to the presence of a hydrogen cation (tert-butoxycarbonyl) or an acidic protic medium in general (methoxycarbonyl). Lithium cation is a hard acid with a high surface charge density and its catalytic efficiency is therefore strongly dependent on the reaction medium. It is an object of the present invention to use protic or aprotic environments in which the catalyst acquires varying degrees of activity.

The cyclotetramerization is carried out according to the invention by heating the N-acyl derivative of the aziridine of the formula II at temperatures in the range of 45 to 280 ° C in the absence or presence of a solvent and in the presence of a catalyst. The catalyst according to the invention is chosen in the range of 0.2 to 300 mol% in the reaction mixture. If the end product of the synthesis is cyclene (Y = H in formula I), the in situ degradation of the corresponding N-acyl is carried out using conventional procedures.

The cyclotetramerization according to the invention is completed in the range of 10 minutes to 48 hours depending on the chemistry of the embodiment, the concentration of the reactant, the type of catalyst, the temperature and the macroscopic arrangement of the reaction mixture.

Optimized cyclotetramerization yields range from 29 to 84% depending on the composition of the reaction mixture and condensation conditions.

Favorable yields, cyclotetramerization in one reaction stage at high concentrations of reactants in the reaction mixture, and short reaction times minimize the ecological burden of production and significantly improve the economic balance of performance over existing methods.

- 2 GB 297577 B6

DETAILED DESCRIPTION OF THE INVENTION

Example 1: Cyclene

9.3 liters of dry dioxane and 0.555 kg of well-dried N-tert-butoxycarbonylaziridine (N-BOC-azidine; content of at least 98.6% by weight; HPLC) are charged to a 151 liter reaction boiler. 0.35 L of dry tert-butanol (water content max. 0.02% by weight) is added to the mixture, and after heating to 40 ° C, while maintaining this temperature, a total of 0.505 kg of lithium bromide dissolved in 1.8 is added over one hour. 1 dry tert-butanol (water content max. 0.02 wt.%). The mixture was heated to 80 ° C for 26 hours. After heating, the reaction mixture was evaporated to dryness (<70 ° C) in vacuo and the residue was extracted with dichloromethane (6 x 500 mL). The dichloromethane solutions were evaporated in vacuo and the residue was dissolved in a mixture of 5.5 L of methanol and 1830 mL of concentrated hydrochloric acid (HCl content min. 35 wt%). The solution was stirred at 35 ° C for 14 hours and then made strongly alkaline by addition of sodium hydroxide. The mixture was cooled to -5 ° C and after standing for 6 hours it was quickly filtered on frit S3. The filtrate was concentrated in a vacuum evaporator (<40 ° C) and the concentrate eluted with a Dowex-50W cation exchange column (400 mesh, H ⁺ cycle; 240 x 930 mm). After washing the column with water, the crude cyclene is eluted with aqueous methanolic ammonia (12 wt%; acidimetry). Evaporation gave 0.358 kg (69.3%) of crude cyclene with 99.4% base material (HPLC; 99.6% acidimetric). The lithium salts are recovered by recrystallization.

Example 2: N, N ', N, N'-Tetra-tert -butoxycarbonyl-1,4,7,10-tetraazacyclododecane

28.6 g of well-dried N-tert-butoxycarbonylaziridine (N-BOC-aziridine; min.

98.6% by weight; HPLC) was dissolved in 230 ml of dry dimethylformamide (max. Water content 0.05 wt.%) And a total of 3.6 g lithium p-toluenesulfonate dissolved in 50 ml of dry dimethylformamide (max. Water content 0.05 wt.%) Was added to the solution. .). The mixture was heated to 125 ° C under a nitrogen atmosphere and maintained at this temperature for 9 hours. After completion of the heating, the reaction mixture was evaporated to dryness under vacuum (<55 ° C) and the distillation residue was dissolved in 200 L of water and extracted with 8x100 ml of dichloromethane. The dichloromethane extracts are combined, shaken with 150 ml of an aqueous saturated solution of ammonium sulfate, with 200 ml of water, and, after drying, evaporated in vacuo. Recrystallization from ethyl acetate-ethanol (3: 1) gave 14.6 g (51%) of pure N, N ', N' ', N'-tetra-tert-butoxycarbonyl-1,4,7,10-tetraazacyclododecane. For C28H52N4O8 (572.7) calculated: C 58.72%; H, 9.15%; Found: C, 58.60%; H, 9.33%;

Example 3: N, N ', N, N'-Tetrabenzyloxycarbonyl-1,4,7,10-tetraazacyclododecane

Prepared in analogy to Example 2 except that starting from N-benzyloxycarbonylaziridine, pyridine was used as solvent and lithium chloride (25 mol%) was used as catalyst. N, N ', N, N'-tetrabenzyloxycarbonyl-1,4,7,10-tetraazacyclododecane is obtained in a yield of 81%. Calcd for C 40 H 44 N 4 O 8 (708.3): C 76.78%; H, 6.26%; Found: C 67.70%; H, 6.38%.

Example 4: Cyclene

Prepared in analogy to Example 1 except that starting from N-benzyloxycarbonylaziridine and using the Dowex-50W in a Li ⁺ cycle (i.e., lithium salt of a sulfonated styrendivinylbenzene copolymer; 200 mesh; 300 mol% Li ⁺ ) as the catalyst. The deprotection is carried out by the action of hydrazine hydrate and palladium on activated carbon (5 wt%) in isopropanol. Cyclene was obtained in a yield of 31%.

Claims (5)

PATENT CLAIMS A process for the preparation of 1,4,7,1O-tetraazacyclododecane, cyclene and its N-acyl derivatives of the general formula I (D wherein Y is hydrogen, tert-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, characterized in that is carried out by electrophilically catalyzed rearrangement of the aziridine N-acyl derivatives of the general formula II Y N ZA (Π) / wherein Y is tert-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, by the action of a lithium cation in an amount ranging from 0.2 to 300 mol% relative to the aziridine reactant of formula II at temperatures ranging from 45 to 280 Deň: 32 ° C. Method according to claim 1, characterized in that the electrophilically catalyzed rearrangement is carried out by the action of soluble lithium salts or polymer-bound lithium cation, preferably by the action of a lithium salt cation exchanger, in the lithium cycle. The process according to claim 1, characterized in that the electrophilically catalyzed rearrangement is carried out in the presence of protic or aprotic solvents or mixtures thereof. The process according to claim 1, characterized in that the electrophilically catalyzed rearrangement is carried out with compounds of the formula II with N-acyls particularly sensitive to the presence of a hydrogen cation, such as tert-butoxycarbonyl. A process according to claim 1, characterized in that the cyclotetramerization of the compound of formula II is carried out for a period of from 10 minutes to 48 hours.