PL190548B1 - Method of obtaining 1,4,7,10-tetrazacyclodekane - Google Patents

Abstract

1. A process for the preparation of 1,4,7,10-tetraazacyclododexane of formula (I) from decahydro- -2a, 4a, 6a, 8a-tetraazacyclopent [fg] acenaphthylene of formula (II): characterized in that it comprises a direct hydrolysis step in in aqueous solution, in the pH range from 5.5 to 9, a primary diamine of formula (V) where x is in the range between 0 and 2 and Q is -CH2CH (OH) CH2-, or - (CH2) 2 NH (CH2) 2-, or - [(CH2) 2 NH] 2 (CH2) 2, when x is 1, or Q is -CH2-, when x is 2.

Description

The compound of formula (II) can be prepared by cyclizing intermediate (III), octahydro-3H, 6H-2a, 5,6,8a-tetraazaacenaphthylene, which in turn can be prepared from triethylenetetramine and glyoxal as disclosed in WO 97 / 49691 and in Italian patent application MI 96A 001257, or from two moles of ethylenediamine via an intermediate of formula (IV) according to the following scheme:

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Scheme 1

Η Λ © Η Λ ©

ΝΗ ₂ η Ν ^ ΝηΎ-νη ² Η (III)

and)

-►

(IV)

ΝΗ

ΝΗ

wherein step a) represents the step of condensing triethylenetetramine (or ethylenediamine) with glyoxal, in water or in water-soluble solvents or mixtures thereof, at a temperature ranging from 0 to 50 ° C, in the presence of stoichiometric amounts or slight excesses of calcium hydroxide to form a compound of formula (III) or (IV); and step b) represents, on the other hand, the condensation of a compound of formula (III) or (IV) with an alkylating agent X- (CH2) 2-X, wherein X is a halogen or a reactive derivative of sulfonic acid, in at least stoichiometric amounts, the presence of at least 2 moles of a base selected from alkali or alkaline earth metal carbonates per mole of compound (III) at a temperature of 25-150 ° C to give a compound of formula (II).

Intermediate (II) has considerable stability under hydrolytic conditions, unlike common diaminals, which are easily hydrolyzed:

• N h ₃ o ⁺

R /

-NH

RCHO 'N' NH

R

For example, the publications by Weisman (Tetrahedron Lett., 1980, 21, 335) and Koliński (Tetrahedron Lett., 1981, 22, 2217) on the synthesis of (II) starting from (I) and glyoxal confirm the exceptional stability (Π) against acidic or basic hydrolytic conditions as well as reducing agents.

The already cited Italian patent application MI 96A 001257 describes an oxidation process for cleavage of a two-carbon bridge characterizing (II) to obtain (I), which enables the conversion of (II) into oxidation products which can in turn be converted into (I) by alkaline hydrolysis. The entire process (II) to (I), described in MI 96A 001257, consists of two steps:

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1) oxidation (II)

2) hydrolysis of oxidation products (II)

(II)

«.Η,»

c) oxidation r- ^ ^N d) hydrolysis Λ ^H \ / '*

(AND)

As an alternative to oxidative cleavage, WO 96/28432 suggests direct hydrolysis of (II) with hydrobromic acid or hydroxylamine in ethanolic solution at reflux.

The hydrolysing effect of hydrobromic acid, not exemplified in WO 96/28432, apparently contradicts literature data which underline the surprising stability of the compound of formula (II) in acidic or basic aqueous solutions.

On the other hand, the reaction with hydroxylamine requires large excesses of the latter (10 molar equivalents) as the free base in ethanol at reflux.

These conditions, although acceptable on a laboratory scale, are however not very suitable for industrial processes as hydroxylamine is quite dangerous (especially hot) and requires careful handling, use and disposal.

It is therefore necessary to find conditions for the hydrolysis (II) which are as selective as possible and at the same time the simplest and most economical in order to improve the production method (I) by passing through (II).

It has now surprisingly been developed, and it is the subject of the present invention, a process for the preparation of (I) from (II) which comprises a hydrolysis step in an aqueous solution under slightly acidic, neutral or slightly basic pH conditions with a primary diamine of formula (V) as shown in the following diagram:

h ₂ n- (Q) _x -nh ₂ ^L ~~ 'N—

\ H / (V) (II)

(I) where x lies in the range between 0 and 2, a

Q is -CH ₂ CH (OH) CH2-, or - (CH ₂ ) ₂ NH (CH ₂ ) ₂ -, or - [(CH ₂ ) ₂ NH] 2 (CH ₂ ) 2 when x is 1 or

Q is -CH2- when x is 2.

In the general formula, x can be 0, 1 or 2. In the first case, diamine corresponds to hydrazine.

In other cases, the nature of the diamine depends on the nature of Q as shown schematically as follows:

x Q

- 1 -CH ₂ CH (OH) CH ₂ 1 -CCH)) ₂ NH (CH ₂ ) ₂ 1 [CCHzhNHihCCHih

-CH ₂ Dimma

Hydaazine / -DDamr ^ in ^ - ^ - r ^ ropanol Diethylene orrimima Triethyleneternmama Ethyenediamine

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The reaction is extremely selective, not only making it possible to produce (I) of high quality in good yield but also recycling the reaction by-products in some cases as they can be converted back into (II).

The reaction takes place in water in the pH range from 5.5 to 9, preferably from 6 to 8, at a temperature from 60 to 150 ° C, preferably 60 to 100 ° C, in the presence of 2-20 moles of diamine per mole of (II), under normal pressure under inert gas or in air for 12-48 h, or under pressure for 3-10 h.

Upon completion of the reaction, the solution is basified with a base such as sodium hydroxide, concentrated to a small volume or to a residue, then (I) extracted with a suitable solvent such as toluene, chloroform, butanol, amyl alcohol. The organic phase is concentrated to a residue to give the crude macrocyclic compound (I) which is finally recrystallized from toluene or ethyl acetate.

When the extraction solvent is toluene, it is sufficient to concentrate the toluene solution to a convenient volume and then crystallize the macrocyclic compound (I).

Depending on the diamine used, more elaborate methods for recycling reaction by-products can be identified.

For example, in the case of triethylenetetramine, the reaction gives (I) and (III) as shown in the scheme below:

Η.ΛΛ.Η -N NNH,

HjN

The toluene mother liquor from crystallization of (I), containing essentially (III) and an excess of triethylenetetramine, can be concentrated to a residue which is in turn redissolved in water and reacted with glyoxal under the conditions described in MI 96A 001257 to produce (III) which can be optionally purified and then converted to (II) according to the procedure reported in MI 96A 001257 and finally recycled to the process.

In the case of ethylenediamine, the hydrolysis reaction (II) also produces recyclable by-products:

(II) (I) UV)

Compound (IV) can also be recovered from the toluene mother liquor and converted back to (II) as already described in MI 96A 001257.

(IV)

ΛΓΑ

(II)

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Certain production examples according to the process of the invention are given in the following experimental section.

Example 1

Preparation of (I) by hydrolysis of (II) with diethylenetriamine.

g (II) (0.257 mol) is dissolved in 350 ml of water. 132.5 g of diethylenetriamine (1.285 mol) are added and the pH is adjusted to 8 using concentrated HCl (265 g). The resulting solution is refluxed for 24 h, then cooled, made basic with pellets NaOH, concentrated under reduced pressure to a residual weight of 350 g and extracted with toluene (I). The combined organic extracts are concentrated to a volume of about 90 mL and allowed to crystallize. 31.5 g of 1,4,7,10-tetraazacyclododecane of high purity (GC titer: 99.5%) are obtained. Yield 71%.

Example 2

Hydrolysis of (II) with triethylenetetramine and recovery of reaction by-products.

g (II) (0.257 mol) is dissolved in 350 ml of water. 105 g (0.640 mol) of triethylenetetramine monohydrate are added and the pH is adjusted to 7.5 with concentrated HCl. The resulting solution is refluxed for 18 h, then cooled, made basic with pellets of NaOH, concentrated under reduced pressure to a residual weight of 330 g and extracted several times with toluene. The combined organic extracts are concentrated under reduced pressure to about 120 mL and allowed to crystallize. 29.4 g of 1,4,7,10-tetraazacyclododecane are obtained in good purity (GC titer:> 98.5%). Yield 66%.

The toluene mother liquor is concentrated to a residue which is redissolved in water. The content of triethylenetetramine and (III) is determined by GC analysis. Glyoxal and calcium hydroxide are added in such amounts as to convert triethylenetetramine to (III) according to the conditions described in MI96A001257. After the reaction is complete, the inorganic salts are filtered off, the filtrate is concentrated to a residue and hexane is added, the insolubles are filtered off, and the solution is concentrated to dryness. 67.2 g (0.40 mol) of (III) are obtained, which can be used to prepare (II) according to the procedure described in MI 96A 001257.

Example 3

Hydrolysis of (II) with ethylenediamine and recovery of reaction by-products.

g (II) (0.257 mol) is dissolved in 300 mL of water. 157.5 g of ethylenediamine (2.57 mol) are added and the pH is adjusted to 8 using concentrated HCl (310 g). The resulting solution is refluxed for 18 h, then cooled, made alkaline with pellets of NaOH, concentrated under reduced pressure to 400 g and extracted several times with toluene. The combined organic extracts are concentrated to a volume of 100 mL and allowed to crystallize. 24.8 g of high-quality 1,4,7,10-tetraazacyclododecane (GC titer:> 99%) are obtained. Yield 56%.

The toluene mother liquor is concentrated under reduced pressure. The residue is chromatographed on silica (eluent: chloroform: methanol: 25% ammonia = 6: 3: 1). 21 g (0.148 mol) of (IV) are obtained, which can be converted back into (II) under the conditions described in MI 96A 001257.

Example 4

Hydrolysis of (II) with various diamines at various pH and at various temperatures.

19.4 g (0.1 mol) of (II) was hydrolyzed by a procedure similar to Example 1, using diamines and the conditions reported in the following table:

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Table

Diamine mol / mol (II) PH T (° C) t (h) Performance % Hydrazine twenty 7 100 24 60% Hydrazine 10 6.5 100 48 55% Ethylenediamine 10 6.5 100 18 52% Ethylenediamine 8 7 80 24 45% Ethylenediamine 10 5.5 100 18 42% Diethylenetriamine 4 7.5 80 24 58% Diethylenetriamine 6 6.5 100 12 62% Diethylenetriamine 6 8 60 48 65% Triethylenetetramine 4 6 80 24 55% Triethylenetetramine 2 8 100 48 62% Triethylenetetramine 2 9 100 48 57% 1,3-Diamino-2-propanol 6 7 100 24 51% 1,3-Diamino-2-propanol 5 8 100 18 48%

Publishing Department of the Polish Patent Office. Mintage 50 copies. Price PLN 2.00.

Claims (9)

Patent claims 1. Preparation of 1,4,7,10-tetraazacyclododexane of formula (I) from decahydro-2a, 4a, 6a, 8a-tetraazacyclopent [g] acenaphthylene of formula (II): (II) h ₂ n- (q) _x -nh ₂ (V) N '(I) characterized in that it comprises a direct hydrolysis step in an aqueous solution, in the range of pH 5.5 to 9, with a primary amine of formula (V) in which x is in the range between 0 and 2, and Q is -CH ₂ CH (OH) CH ₂ -, or - (CH ₂ ) ₂ NH (CH ₂ ) ₂ -, or - [(CH ₂ ) ₂ NH] ₂ (CH ₂ ) ₂ when x is 1, or Q is -CH ₂ - when x is 2. 2. The method according to p. The process of claim 1, wherein the diamine is selected from the group consisting of diethylenetriamine, triethylenetetramine and ethylenediamine. 3. The method according to p. The process of claim 1 or 2, characterized in that the hydrolysis reaction is carried out in water at a pH of 5.5 to 9, at a temperature ranging from 60 to 150 ° C, in the presence of 2-20 mol of diamine per mole (Π), under normal pressure under an inert gas atmosphere or in air for 12-48 h, or under pressure for 3-10 h. 4. The method according to p. The process of claim 3, wherein the pH of the reaction ranges from 6 to 8. 5. The method according to p. A process according to any of the preceding claims, characterized in that the diamine is triethylenetetramine, shown in the following scheme: (II) (I) (III) where a compound of formula (ΠΙ), octahydro-3H, 6H-2a, 5,6,8a-tetraazacenaphthylene is simultaneously formed, which is an intermediate useful in the preparation of a compound of formula (Π). decahydro-2a, 4a, 6a, 8a-tetraazacyclopent [g] acenaphthylene according to known methods. 190 548 6. The method according to p. The process of claim 5, characterized in that the mother liquor from the crystallization of the compound of formula (I), essentially containing the compound of formula (HI) and an excess of triethylenetetramine, is concentrated to a residue which is in turn redissolved in water and can be used as an intermediate for producing a compound of formula (Π) according to known methods. 7. The method according to p. A process as claimed in any one of the preceding claims, wherein the diamine is diethylenetriamine. 8. The method according to p. A method according to any of the preceding claims, wherein the diamine is ethylenediamine according to the following scheme: (II) (I) NH th NH 'H (IV) where the compound of formula (IV) is simultaneously formed, decahydropyrazine [2,3-b] pyrazine, which is an intermediate useful for the preparation of the compound of formula (II), decahydro-2a, 4a, 6a, 8a-tetra-cyclopent [g] acenaphthylene according to known methods. 9. The method according to p. The process of claim 8, wherein the mother liquor of the crystallization of the compound of formula (I), essentially containing the compound of formula (IV), is concentrated to a residue which, in turn, is redissolved in water and can be used as an intermediate for the preparation of the compound of formula (IV). formula (II) according to known methods. The subject of the present invention is a process for the preparation of 1,4,7,10-tetraazacyclododecane (I) from decahydro-2a, 4a, 6a, -8a-tetraazacyclopent [fg] acenaphthylene (II):