DE2028556C2 - New macrocyclic compounds, their production and their use as complexing agents - Google Patents

Description

is condensed, wherein in the formulas A, D, m, η and ρ are as defined in claim 1; A "represents a group corresponding to group A in which a CH2 group adjacent to group V has been replaced by a CO group and V is halogen, and in which the CO groups in the compound thus obtained are subsequently reduced _{to CH 2 groups} will;

a compound of the general formula

D.
D.

D.
D.

with a compound of the general formula

Hal D

Shark

is condensed, wherein in the formulas A, D, m and ti are as defined in claim 1 and R3 represents a liydrogenolysable group, and that the $ 0 obtained quaternary salt of the general formula

R ₃

\ _β ν \

Va /

7 shark ⁹

is subjected to finer hydrolysis; and

6, use of the connections according to claims * Chen 1 to 4 as complexing agents for cations,

are represented in the

A each for a hydrocarbon residue,
D in each case represents an oxygen atom, a sulfur atom, a group of the formula I> N - R (where R is a hydrogen atom or a hydrocarbon radical) or a hydrocarbon radical, at least two of the groups or atoms for which D stands. Are oxygen atoms, sulfur atoms or a group of the formula I> N - R, and

m, η and ρ are integers from 0 to 5.

The compounds according to the invention include the ammonium salts and the nitrogen oxides.

The hydrocarbon radicals A and D represent preferably have 2 to 12 carbon atoms. Preferred be straight-chain and branched: alkylene and Alkenylene radicals with 2 to 8 carbon atoms such as ethylene, propylene, butylene and hexylene and their unsaturated ones Analogs, cycloalkylene and cycloalkenylene radicals such as cyclopropylene, cyclobutylene, cyclohexylene and cycloheptylene and their unsaturated analogues, the corresponding cycloalkylenedialkyl radicals such as cycloalkylenedimethyl and aromatic radicals such as phenylene and phenylenedialkyl, preferably phenylenedimethyl.

The groups A, which are adjacent to the bridge ends, preferably have one at N bound aliphatic part.

Preferred of the compounds according to the invention are those in which m, η and ρ are integers from 0 to 2. Typical configurations are listed below:

2, A A A A

0 0

AAAA

NOOON

\ 0 OO

AAAA

3. A A A

0 0

ι A A

N S-S N

0 0 /

AAA

8. AAA

IY / ν IV S

A A A \

NR NR N

4. A A A

/ 0 0

/ AAA

NSSN

S S

5. A A A

S S

AAA

NSSN

S S

AAA

R ^x ' R ^x '

AAA

9. ARARA

N N

AAA

\ / \ / \ NOON

S S

AAA

10. A AA

0

AAA

NOSN

S S

AAA

The typical representatives of the Verbiodungetl according to the Invention can be illustrated by ver-65 different groups can be used for A in the above formulas:

I. A = -CH ₂ -CHR

II. Λ = —GHj — CHR - CIf ₂ -

or

- CHR - CH ₂ --CH ₂ -

V. Λ = Unsaturated analogs; of groups (I) to (IV)

Vl. A =

III. A =

VIl. Λ

R.
CH ₂

IV, Λ

...OIL.

I t I

Here, R has the meaning given above. The ammonium salts can be given by the following

A: R - N D

N — R 2Ζ ^Θ

RR _r

B: R-N

X-R

Herein, A, D. R, m, π and ρ have produced the above through known chemical reactions

Meanings, while Z is an inorganic or. The principle of the procedure is to create a

organic anion is It is obvious for the 05 to introduce a further bridge in a starting compound.

Those skilled in the art will recognize several other configurations containing two bridges, creating the desired

possible smd. Bieyciischen connections are obtained.

The compounds according to the invention can be used in a suitable process for the preparation of the

Compounds according to the invention is characterized in that nian compounds of the general Formula III

d '

or V for the group
O

- CN Ilalogen

Y (Ht)

and Ϋ for the group

in

Ii-N

with a compound of the general formula IV

y ν

V V

stands that carbonyl groups in the compounds thus obtained are _{reduced to CH 2} and, if appropriate, the compounds obtained in the preceding steps are one or more of the final ones

condensed, where in the above form a Aj D, m, η and ρ have the meanings given above and V is an easily split off group, such as e.g. B. halogen, melhansulphonate or p-toluenesulphonate and Y for the groups

H H

I I

NON

30th

stands, where R _{2 is} a hydrogenolysable group,

a) Hydrogenolysis of hydrogenolysable groups, for which R2 stands,

b) conversion to ammonium salts,

c) Conversion into a nitrogen oxide.

The most preferred halogen atom in the above reaction is bromine, and the preferred one The hydrogenolysable group is the benzyl radical. Further examples of hydrogenolyzable groups are

-CH ₂ OH, -CH ₂ -CH = CH ₂
and -CH ₂ -CH ₂ -CN.

Various embodiments of the method described above can be implemented by the following Reaction schemes A to D are shown:

A: Η — Ν

D.
D.

Br D

Br

Il

Ii

C -

12th

B: H-N

Il

Λ —C

N-H +

A. \ b A. \ b / Br

O
CA

\ Λ

D D

O A-C

CH ₂ -A

D D

C:

CH ₂ -N

i / \ Λ

Br D

D Dl

N-CH ₂ - <f

2Br®

D: Η — N

-in the

ν - Η + c '

Br

A O

j In order to prevent the formation of polymers, Ae condensation is llirchgeführt in the first stage of the above ^1! 'wrote around reactions under high dilution. Any inert solvent is suitable, but benzene is preferred.The acid formed during the reaction must be neutralized, it can be done by using 2MoI diamine per Jloi halide or by adding a further base, especially a tertiary amine such as trialkylamine or pyridine, preferably triethylamine .

The reduction of the carbonyl groups in the second stage of reactions B and D is preferably carried out with Help from L1AIH4 or B ^ He in tetrahydrofuran Also suitable as reducing agents are mixed metal hydrides, e.g. B.

NaBH ₄ -LiAlHj-OCH ₃ , LiAIH ^ AlCl ₃ and
NaBH ^ BF ₃ .

For the preparation of cyclic lactams according to the procedure illustrated by Reaction B, use is made preferably the disalt of the amide group, preferably

> * a treatment of compounds of the formula (I) in ammonium salts can be carried out by customary methods, e.g. B. by reaction with suitable quaternizing agents, e.g. alkyl halides such as methyl iodide.
Any hydrogenolyzable groups can also be prepared by conventional methods, e.g. B. by catalytic or electrolytic reduction, can be removed. Av catalysts are, for example, platinum, palladium, rhodium, ruthenium and preferably LiAlH.). The immediate product of Reaction Scheme C (an ammonium salt) can thus optionally subsequently be converted into the free macrocycle by reduction in the presence of LiAlHi.

The conversion of a compound of the formula I into its nitrogen oxide can also be carried out according to known methods Oxidation processes, e.g. B. by treatment with excess dilute hydrogen peroxide in Water or with perphthalic acid in ether will.

Often the immediate product of the above reaction is not the free macrocydic compound, but a derivative of this compound, which also eliminates the struc- ture of other components of the reaction mixture partly or wholly contained in one

such case becomes the macrocyclic compound then of this derivative by the usual methods, e.g. by treatment with dilute Acid, whereby the acid addition salt of the macrocycle is formed, or with other hydrolyzing agents Funds freed

All of these salts can be dissolved in water and treated with an anion exchange resin. the The aqueous solution of the free macrocycle obtained in this way can then be isolated by evaporation to dryness will.

The starting compounds of the general formula IV can be prepared by known processes will. Some of the most convenient procedures are illustrated in the examples

The starting compounds of the formula III and their Manufacture are the subject of patent application No. 20 66 192.1.

The compounds according to the invention are in most common organic solvents and easily soluble in water.

The new.i macrocyclic compounds have a unusual ability to form stable complexes with compatible cats.

In these bicyclic compounds, the bridges between the two nitrogen atoms are likely to form a "cage" in which the cation is located. The ability to form complexes and the stability of the complexes formed seem to depend on the arrangement of the heteroatoms or groups that make up the Cation surrounded, and depend on the relative diameters of the ring or rings and the cation.

Macrocyclic compounds that form stable complexes with cations of a certain diameter, are unable to form complexes with cations which 3ϊ have much larger diameters.

Every macrocyclic molecule can form a complex with a cation. The size of the cargo an cation has no influence. The cations can be inorganic or organic. 4n

The complexes formed are generally in water. CHCli, CHjCl ₂ and easily soluble in acetone or other polar solvents, while they are sparingly soluble or essentially insoluble in non-polar organic solvents. They dissociate at a more or less acidic pH. Protonation of the free diamine hinders the complex formation and leads to the dissociation of the complex by shifting the equilibrium.

The same dissociation is caused by treatment with ίο any acid including Lewis acids. The cation can also be split off by treatment of the complex can be achieved with a quaternizing agent.

The complexes are usually formed as follows: the macrocyclic compound and the that Cation donating compound are in a common solvent /. B. acetone. Methanol or Water, dissolved. The mixture is normally heated to about the boiling point of the solvent. If the complex formed is insoluble in the solvent used, it crystallizes and can be filtered off If the complex formed is soluble in error, it can be removed by evaporation of the solvent used Solution to be isolated to dryness. The complexes can be purified by recrystallization. Complexes can also be formed if the compound supplying the cation (e.g. the salt) is in the The solvent used is insoluble Combine solution of the macrocyclic compound with the crystalline salt and the mixture to stir with or without heating.

The formation of complexes is also possible if the compound supplying the cation and the Complex are insoluble in the medium used. In this case the macrocycle and the cation delivering compound mixed in the presence of a medium which is then stirred and heated, whereby the crystalline macrocycle gradually changes into the crystalline complex

The presence of a complex in solution can be determined by spectroscopic analysis, since the addition of the cation causes changes in the spectra of the macrocycle in solution

The new complexes allow the use of certain chemical reagents in solvents, in which they are usually insoluble. For example, potassium fluoride is insoluble in chloroform while a Complex of the salt with 4,7.13.16,21,24-hexaoxa-l.lO-diaza-bicyclic [8,8,8] hexacosane is easily soluble

The ability of the macrocyclic compounds according to the invention to form complexes with cations make them valuable for use in much the same way and for the same purposes as Chelating agents. For example, this makes the compounds valuable in processes for the desalination of Brines or for separating metals, e.g. B. for the separation of metals such as transition metals and Actinides from low-value sources of these metals and for subsequent recovery of these metals in high purity form. In this context, the compounds are considered to be particularly valuable for the separation of high quality metals, e.g. B. those of the platinum group. When separating uranium from crude The uranium can be converted into a complex with the macrocyclic compound and the ores obtained complex are then separated with water. The compounds according to the invention can also be beneficial for cation transport and for the production of ion-selective membranes and electrons are used.

The compounds are also suitable for chemical syntheses, e.g. B. for polypeptide and protein synthesis, the compounds advantageously selectively protecting one of the ammonium cation groups in the amino acid. In addition, the compounds can be used as catalysts for ionic reactions in polar organic Media are used in which the macrocyclic compounds the reaction via an »agent-separated Activate ion pair «mechanism.

When added to pharmaceutical preparations, the compounds according to the invention "bind" trace metals and in this way prevent the occurrence of catalytic oxidation as a result of the presence of trace metals. B. Mammals, an effect on biological cation mechanisms, 7. B. Nerve conduction. Sodium-potassium pump and the calcium metabolism of muscles and bones, these compounds are therefore valuable for deep tirilef conditions under which the regulation of the cation exchange in the recipient is necessary «

It was also found that the bicyclic macrocyclic compounds according to the invention, z. B. ^, la.ie ^ l ^ Hexäoxa'l.lO'diäzäbicyclofS.S.Sjhe * xacosan, the catecholamine-induced mobilization

230 217/22

Inhibit the generation of free fatty acids when tested in vitro on isolated adipose tissue. These Compounds are therefore of value in the treatment of diabetes and hyperlipemia.

Stability constants

of macrocyclic complexes

in aqueous solution

General

By measuring the pH value in water, the applicant determined the equilibrium constants for Reactions of the following type are determined, the type being determined by macrocycles of the bicyclic amines illustrated is:

C = C ₁₁ H- [OH] - [H ⁺ ]
[H ⁺ ]. [H ⁺ ] ³

1 + ·

[H ⁺ ]
K ₂

K ₁ K ₃

2 [H ⁴

K ₁ K ₂

is

(1) A.

K.

VI * ^ AM ⁺

20th

K ₁ = constant of the law of mass action A = respective bicyclic amine AM ⁺ = macrocyclic complex M ⁺ = cation [] = activity of the ion species

Existing equilibria complex formation

(1) A + M ⁺ ^ AM ⁺ (K ^

30th

_ [AM ⁺ ]
' [AT THE']
Protonization of the diamine

(2) AH ₂ ⁺ * ^ AH * +

(3) AH ⁺ ^ ^Λ + H '

Ch = concentration of acid added (mol / liter),

Ca = concentration of the amine if no reaction took place (mol / liter),

Cm = concentration of the metal when no reaction took place (mol / liter).

Ks is expressed in moles - 'liters

K \ and K2 are previously by titration ^«1 is diamine with dilute hydrochloric acid in the presence of a reference salt of known concentration determined (N ⁺ Me ₄ Br for the small cages, LiCl for the large cages).

After adding a known amount of the salt to a solution of the amine of known concentration in the presence of a non-complexed reference salt of the same concentration as that used for the determination of K1 and K2 , the solution is titrated with dilute HCl, whereby pH- Measurements of the solutions are made. Each additional point gives a value of K- (using the formula above). The calculation must result in a value of K _s which is approximately constant during the entire titration.

Results obtained (at 25.0 ± 0.2 ⁰ C)
(A) alkali metals

(K ₂ )

K, =

_ [AH *] [H *]
[AH ₂ "]

[AH*]

Protonization of the macrocyclic complex (4) AMHj * ^ AMH ²⁺ + H * (KO AMH ² * ^ AM * + H ⁺ (ZiT ₂ ')

", ₌ [AMH **] [H ⁺ ]

¹ [AMHj ⁺ ]

_K , ₌ [AM-J [H-]

² AMH **

It has been found that the last two equations · ω

Weight def protonization of the macrocyclic coni 'proloriization of the amine plexes remain comparatively negligible, and it
a formula was drawn up, the K _s with the pH value -g

and all constants of the mixture in relation Af = 30 · 10 · pK = 7 52

brings: 65 '* _ _I0 ' ²

bC _A -AC b ^ = 1.2 x 10; pKj - 9.92

/ £ 111 Ii u: ϊ_ι · _ ^ "

- loc

1 »N- ^N \ O O
O \
/ \ \
\
N -pK, O
V ⁰ Reference salt = NMe ₄ 4.18 cation K, * (-)
\ 10 / 2.74 Li " 1.5 · N / A* 5.5 · 10 ⁴ <1.S K ' 10 ² <1 Rb * 0 " Cs ¹

2) N

Reference salt = NMe ₄ Br (-)

cation

-pK,

Li *

Well ^r
K ⁺
Rb *
Cs *

2.7 · 10 ^:

1.9 · iü ^;

8.2 ■ 10 '3.5 · 10- ¹ <10 ¹⁵

Protonization of the anvns
-8th

K _x = 3.2
K _: = 3.0 • 10;
-11
• 10; PK;
PK; Il Il 7.50
IC 5? N ^ KpK ₁ ) - 0.10 - \ \ /
O - \ O O
/ O

Reference salt = NMe ₄ Br

cation

Li * <10 " N / A* 5.6 ■ 10 ' K * 1.5 10 ' Rb * 1.6 IO ⁴ Cs * <10 ^{! 5} Protonization of the amine

-8th
K ₁ = 5.2 x 10; pK, = 7.28

-10
K ₂ = 2.5 x 10; ρΚ ₂ = 9.60

20th

4) N

Reference salt = LiCl (- λ

cation

Li ⁺ Na ⁺ K ⁺ Rb ⁺ Cs ⁺

4-

15 ■

2.60 2.18

Protonation of the amine

-8th

K _x = 4.7 · 10; pK, = 7.33

-

K ₂ = 3.2 x 10; pK, = 8.50 Λ (ρΚ,) ~ 0.10

/ 5) N

O

Reference salt = LiCl (-

PK, - 7.31 pKj = 8.16

For Li, Na, K, Rb = Ä ", <10 ¹⁵ Cs ⁺ : ä:, - 60 pK, ~ 1.7 (± 0.5)

6) Ν \ 0 \ 0 \ 0 \ ν

ßezugssaiz = LiCI (-ρ ρΚ, = 6.96 PfC ₂ = 7-70 For the alkali metals K ₁ < ΙΟ ¹ - ⁵

21

(B) alkaline earth metals

1) N

Reference salt = NMe ₄ Br f— λ For all alkaline earth salts κ <XQr

2) N

Reference salt = NMe ₄ Br (- 4 (pK _s ) = ± 0.10

cation

A ',

Mg ⁺⁺ Ca ⁺ * Sr ⁺⁺ Ba ^{t +}

3) N

<10 ² 5.0 · 10 "1.2 ■

(N \ - J

A (pK,) = ± 0.10 22

, 4) N \ O

O O

¹⁰ reference salt = LiCI (- λ

V IO J

A (pK,) = ± 0.10

cation

Mg ⁺

Sr ^{+ +}

<10 ²

2 ■ 10 '5.6 · ΙΟ ⁵

0 0 0

0 O 0 0

³¹ reference salt = LiCl (-)

C,) = ± 0.20

jo 5) N

cation

K-,

Mg ^++
45 Ca ⁺⁺

6) N

<10 ²

3 · 10 ^y

cation K, ■ ΙΟ ⁴ -pK, Q Mg ⁺⁺ <io ² • 10 ^s <2 Ca ^{f +} 1.74 10 " 4.24 Sr ** 1.02 8.01 I. Ba " 1.0 · 9.48

Reference salt = LiCI (- = J

For Mg, Ca, Sr: pK, <2 For Ba ⁺⁺ : λ, = 5.1 · 10 ⁴

pK, = 4.71 ± 0.20

<2

3.30 5.75

-pK _s

<2

3.48

(C) Other cations studied Γ

1) N

Reference salt = NMe ₄ + Br " ( ¹ TT) Οι ⁺⁺ : Λ ' ₅ ^ 10' ° pK, = 10 ± 1

cation

3) N

2) NVOVO \ N

Reference salt

Ag ⁺ 4.1 10 ' 9.6Ϊ ± 0.20 without reference salt Tl ⁺ 2.1 · 10 ⁶ 6.32 ± 0.20 without reference point Pb ⁺⁺ 1.13 • 10 ¹² 05/12 ± 0.10 NMe ₄ Br (f)

Reference salt = LiGl f—

Tl ⁺ : K ₁ = 3.1O ⁴ PK ₁ = 4.48 + 0.10 Pb ⁺ ": K ₅ = 13 - 10 ^s pK, = 8.11 ± 0.10

Preparation of starting compounds I.

60

Manufacture of triglycolyl chloride A. Manufacture of triglycolic acid

100 g of nitric acid (density = 138) are heated to 45 "C. 20 g of triethylene glycol are in small Portions added so that the temperature is maintained at about 45 to 50 ° C. After this action will be the mixture is stirred for about 20 minutes at 45 ° C. and then for 1 hour at about 80 ° C. The solution is divided evaporated under reduced pressure for 2 to 3 hours at 70 ° C. A brownish viscous paste wire obtain. After adding 100 to 120 ml of Benzol wire the water is distilled off. Crystallizes after cooling! the dicarboxylic acid and is recrystallized from a mixture of acetone and benzene. The solid wire dried under a vacuum of 0.1 mm Hg. The acid obtained has a melting point of 74 bi: 75 ° C

NMR (fm D ₂ O): 3.80 ppm (singlet); 4.25 ppm (Sin glett).

B. Preparation of triglycolyl chloride

15 g of the acid obtained in the manner described above, 30 g of oxalyl chloride, 100 ml of anhydrous benzene and 3 drops of pyrodine are mixed and stirred for 24 hours. After adding petroleum ether, the product is decanted. The mixture is filtered and the benzene and the excess oxalyl chloride are evaporated on a rotary evaporator without heating. The evaporation is repeated twice, each time with 100 ml of benzene. The product obtained is a yellow oil. The oil is diluted with a mixture of ethyl ether and petroleum ether. After cooling to a temperature between room temperature and -70 ⁰ C, the product crystallizes out. The crystals are then washed with petroleum ether, taking care that the product does not come into contact with atmospheric moisture. After recrystallizing twice and washing twice with ether, the product is dried under a vacuum of 0.1 mm Hg. Melting point 20 to 30 ⁰ C (crude product).

NMR (CDCIi): 3.85 ppm (singlet: 4.52 ppm (singlet).

II.

Production of 1,8-diamino-3,6-dioxaoctane
A. Preparation of triethylene glycol dibromide

66 g of triethylene glycol and 13.3 g of anhydrous pyridine Add slowly to 100 g of phosphorus tribromide while the mixture is stirred and cooled. That The mixture is left to stand at room temperature overnight and then poured onto ice. the organic phase is decanted, washed with water and dilute hydrochloric acid and over sodium sulfate dried. The desired compound is obtained after vacuum distillation (95 ° C. and 0.5 mm Hg). Yield 60 to 70%.

NMR (CDCl ₃ ): 3.4 to 4.0 ppm (multiplet); 3.70 ppm (singlet).

B. Manufacture of
Triethylene glycol diphthalimide

161 g of phthalimide are mixed with 50 g of potassium hydroxide in 500 ml of ethanol. The mixture will last 24 hours stirred and filtered to obtain potassium phthalimide. 7.5 g of that obtained in Part A of this example Dibromides are obtained with 30 ml of dimethylformamide and 9 g of in the manner described above Potassium phthalimide mixed The mixture is heated to 100 ° C for 1 hour. After cooling down 50 ml of water and 50 ml of chloroform were added The organic layer is washed with dilute potassium hydroxide, then with water and decanting dried over potassium sulfate and evaporated. The desired compound crystallizes out and becomes out Acetic acid recrystallized. Yield 95%. Melting point 175 ° C

NMR (CDQ ₃ ) 3.5 to 3.85 ppm (multiplet); 3.60 ppm (singlet); 7.80 (multiplet).

C manufacture of
ii

this time the reaction is practically over. After adding 25 ml of IO η hydrochloric acid, the mixture is refluxed for a further half hour. The greater part of the alcohol is distilled off and the remaining solution is filtered and saturated with potassium hydroxide. The mixture is poured into a liquid-liquid extractor and extracted with benzene. The benzene solution svird evaporated and the diamine under reduced pressure abdestilliefl of 0.5 mm Hg at 88 ⁰ C. Yield 70%.

NMR (GDCl ₃ ): CH ₂ -N: 2.85 ppm (triplet); CH ₂ -O: 3.50 ppm (triplet) and 3.60 ppm (singlet).

III.

Manufacture of tetraglycolyl chloride
A: Production of tetragiycolic acid

iöOg nitric acid (uicnte i, 3B) weraen sut 45 ¹ C heated. 20 g of tetraethylene glycol are added in small portions so that the temperature is kept at about 45 to 50.degree. According to this measure, the mixture is stirred for about 20 minutes at 45 ⁰ C and then for 1 hour at about 8O ⁰ C. The solution is evaporated ^{at 70 °} C. under reduced pressure for 2 to 3 hours. A brownish viscous paste is obtained here. After adding 100 to 120 ml of benzene, water is distilled off. The dicarboxylic acid is a viscous oil that does not crystallize.

JO NMR (D ₂ O): 3.75 ppm (singlet); 4.22 ppm (singlet).

B: Production of tetraglycolyl chloride

28 g of the acid obtained in the manner described above. 50 g oxalyl chloride, 200 ml anhydrous benzene and 6 drops of pyridine are mixed and stirred for 6 hours. The mixture is filtered, followed by the benzene and evaporate the excess oxalyl chloride on a rotary evaporator without heating. The evaporation is repeated twice, namely

■ to each time with 100 ml of benzene. The product obtained hl a yellow oil which does not crystallize.

NMR (CDCl ₃ ): 3.75 ppm (multiplet); 4.52 ppm (singlet).

IV.

Production of
1,1-diamino-3,6,9-trioxaundecane

A: Manufacture of
Tetraethylene glycol dibromide

22.4 g of the product obtained in step B are suspended in 250 ml of ethanol and heated under reflux. 19 ml of N ₂ H * and water (50%) are added, whereupon the mixture is refluxed for a further 2 hours. After 300 g of tetraethylene glycol and 100 g of anhydrous pyridine are slowly added to 727 g of phosphorus tribromide while the mixture is stirred and cooled. After cooling to room temperature, the mixture is poured onto ice and the organic phase is decanted, washed with water and dilute hydrochloric acid and dried over sodium sulfate. The desired compound is obtained after vacuum distillation (123 to 125 ° C./0.4 mm Hg). Yield 60%.

NMR (CDQ ₃ ): 3.70 ppm (multiplet).

B: Manufacture of
Teiraethylene glycol diphihalimide

161 g of diphthalimide are mixed with 50 g of potassium hydroxide in 500 ml of ethanol

Stirred for hours and filtered to obtain potassium phthalimide. 217 g of the dibromide obtained according to Part A are mixed with 1000 ml of dimethylformamide and 260 g of the potassium phthalimide obtained in the manner described above. The mixture is ^{kept at 100 11} C for 8 hours. After cooling, the mixture is poured into 3 l of cold water. The precipitate is filtered off, washed with water and acetone and dried under vacuum. The desired compound is urchfislällisiefl from ethanol. Dent 85%. Melting point 108 to 109 ° C.

NMR (CDCl ₃ ): 3.60 ppm (singlet); 3.80 ppm (multiplet); 7.80 (multiples).

C: Manufacture of
1.1 l-diamino-3,6,9-trioxaundecane

254 g of the product obtained in step B will be

m 5000 in Äinäfiöi Suspendier ί ufii! Applies reflux crhitZi. After adding 90 g of N2H4 in 90 g of water, the mixture is refluxed for a further 11 hours. After this time, the reaction is practically over. The pH is adjusted to 1 by adding 10 η hydrochloric acid and the mixture is refluxed for another half hour. The remaining mixture is filtered and the solution is evaporated to dryness. After adding 250 ml of water, the solution is saturated with potassium hydroxide. The mixture is filtered again to remove precipitated KCI and poured into a liquid-liquid extraction apparatus and extracted with benzene. The benzene solution is evaporated and distilled the diamine under reduced pressure of 0.2 mm Hg at 114 to 116 ⁰ C. Yield 72%.

NMR (CDCl ₃ ): -NH ₂ : 1.30 ppm (singlet); CH ₂ -N: 2.85 ppm (triplet); -CH ₂ -O: 3.48 ppm (triplet) and 3.60 ppm (singlet).

V.

Production of
Ethylene bisthioglycolic acid dichloride

A. Manufacture of
Ethylene bisthioglycolic acid

One kilob contains 20 g of thioglycolic acid, 20 ml of water, 20 ml of ethanol and a solution of 17.6 g Sodium hydroxide is mixed in 30 ml of water and heated under reflux. 18.5 g are obtained over the course of 3 hours 1,2-dibromoethane was added with vigorous stirring. The mixture is refluxed for an additional 2 hours heated. After filtration, the filtrate becomes dry evaporated and taken up in a mixture of 100 ml of water and 60 ml of 12 η-hydrochloric acid. The mixture is extracted three times with 50 ml of ether each time. The organic layer is separated over sodium sulfate dried and evaporated to dryness to give the desired crystalline compound, the is then recrystallized from toluene. Melting point 107 ° C, yield 80%.

PMR (D ₂ O): S-CH ₂ -CH ₂ -S: 3.0 ppm (singlet; 4H): S-CH ₂ -CO: 3.55 ppm (singlet; 4H).

B. Manufacture of the
DicbJorids of the above acid

To a mixture of 100 ml of anhydrous benzene and 100 ml of anhydrous ether add 15 g of the

given above dicarboxylic acid. Then 30 g of oxalyl chloride is added while protecting the flask with a calcium chloride tube. The mixture is stirred for 36 hours, the dicarboxylic acid gradually dissolving as it is converted to the corresponding dichloride. The solution is evaporated to dryness (without heating) to give a brownish solid residue remains, which is recrystallized from a mixture of anhydrous ether and petroleum ether by cooling to -70 ⁰ G in a mixture of dry ice and acetone.

The solid yellowish dichloride is obtained in an almost quantitative yield. Melting point about 30 ° C (raw Product).

PMR (CDCI ₃ ): S-CH ₂ -CH ₂ -S: 2 92 ppm (singlet; 4H): S-CH ₂ -CO: 3.55 ppm (singlet: 4H).

VI.
Production of 3,6-dithia-le-diamino-octane

8.5 g of potassium metal are dissolved in 100 ml of anhydrous tert-butanol (the Process accelerated). After the metal has completely dissolved, 15.4 g of cysteamine are added all at once. The mixture is stirred for 1 hour until all of the solid has dissolved. Then 18.8 g of 1,2-dibromoethane are added added slowly (within about 30 minutes). The reaction is exothermic. The mixture is stirred overnight at room temperature and then filtered through a sintered glass funnel. The firm one The residue is washed with benzene. The combined organic layers are brought to dryness.

steams. A viscous brownish oil is obtained. This oil is taken up in 100 ml of benzene and passed through a short column of aluminum oxide (approx. 20 g) filtered. The column is washed with a further 250 ml of benzene. The benzene solutions become dry

4ö evaporated. The yellowish residue crystallizes. Melting point about 35 to 40 ° C. Yield 85%

PMR (CDCl ₃ ): -NH ₂ : 1.32 ppm (singlet: 4H): S-CH ₂ -CH ₂ -S: 2.72 ppm (singlet: 4H): N-CH ₂ -CH ₂ -S: 2.75 ppm (multiplet: 8H).

VII.
Manufacture of 1,5-diamino-3-oxapentane

1,5-dichloro-3-oxapentane is treated with potassium phthalimide treated. This is followed by hydrazinolysis of the obtained Diphthalimido derivative and then acidification, the bis-hydrochloride of the desired compound is obtained.

The bis-hydrochloride is treated with a highly concentrated (about 10 normal) solution of potassium hydroxide in water and continuously extracted with benzene in a liquid-liquid extraction apparatus for a few (3 to 5) days. The solvent is evaporated and the liquid residue is distilled under reduced pressure to give the desired compound. Boiling point 48 to 50 ⁰ C / 1 mm Hg. Yield 3G% (from the used JS-dichloro-S-oxa-pentane).

PMR (CDQ ₃ ): -NH ₂ : 130 ppm (singlet: 4H); -CH ₂ -N: 230 ppm (triplet: 4H); -CH ₂ -O: 3.50 ppm (triplet: 4H).

20 28 556 30th 29 χ. viii.

Production of diglycolic acid dichloride

To 13.4 g of diglycolic acid, which is covered with chloroform (130 ml), 45 g of Phosphofpeiitachlofid are added in one msl. The mixture is left to stand for 10 Kiintiten at room temperature and then slowly heated to the reflux temperature within 1 hour and refluxed for 1.5 hours. The solvent is evaporated off at room temperature under reduced pressure (water jet pump). Then the phosphofoxy chloride formed during the resection is removed at room temperature under a pressure of •, 5 mm Hg (oil pump). The remaining Cl is distilled (oil bath at 8O ⁰ C) to give 14.8 g of the desired dichloride is obtained.

Boiling point 56 to 57 ° C / 0.5 mm Hg. Yield 86%.

PMR (CDCI ₃ ): O-CH ₂ -CO: 4.65 ppm (singleu).

The dichloride is unstable to heat and must be at low temperature below sufficiently low Pressure to be distilled.

IX.
A: Production of 5,12-dioxo-l, 7,10,16-

tetraoxa-4,13-diazacyclooctadecane ^2j

This reaction is carried out with high dilution. A solution of 14.8 g of the under II C Contained diamine (0.1 mol) ir 500 ml anhydrous feenzol and a solution of 11.2g according to IB The dichloride contained in 50 ml of anhydrous benzene is used within 8 hours under vigorous Stir and add to 1200 ml of anhydrous feenzene under nitrogen. After the addition, the filtered fairy teal solution and evaporated to dryness. The crystalline residue is dissolved in anhydrous benzene dissolved and passed through an aluminum oxide column. The polymers formed during the reaction Are withheld and a pure solution of the desired compound is obtained. According to »Crystallization with a mixture of benzene and heptane the desired compound is formed. Melting point 111 ° C. Yield 70%.

NMR (CDCI ₃ ): -CO-CH ₂ -O: 4.00 ppm (singlet); -CH ₂ -N and -CH ₂ -0: 3.6 ppm (multiples).

B: Preparation of 1,7,10,16-tetraoxa-4,13-diazacyclooctadecane

A solution of 18.5 g of the compound obtained according to A in 450 ml of anhydrous tetrahydrofuran is slowly added to a mixture of 150 ml of anhydrous tetrahydrofuran and 12 g of LiAlH ₄ with stirring and heating under reflux. After the addition, the mixture is refluxed for 24 hours with stirring under a nitrogen atmosphere. After cooling to room temperature, the excess reagent is destroyed by adding a mixture of water and THF (1: 2). The mixture is filtered and the filtrate is evaporated to dryness The eo residue is dissolved in benzene and the solution passed through an Al ₂ O ₃ column, benzene being used as the eluent. The solution is evaporated to dryness and, after recrystallization from benzene / petroleum ether, 13.5 g of the desired product are obtained. Melting point 115-116 ° C. Yield 80%.

NMR (CDCl 3): -CH ₂ -O: 338 ppm (singlet + triplet): - CH ₂ -N: 2.78 ppm (triplet).

Preparation of 4,13-dimethyl-1,7,10,16-tetraoxa * 4,13-diaz3cyclooctadecane

A: Manufacture of

4,13 ^ Whore thoxycarbony 1-1,7,10,16-f ef raoxa-4,13-diazacyclooctadecane

3.6 g of the diamine obtained according to IX B are dissolved in 30 ml of methanol and 3 ml of water. A solution of 3.6 g of ClCO ₂ GH ₃ in 15 ml of methanol is added while cooling and stirring. The mixture is then stirred for 24 hours. The mixture is filtered and the filtrate is evaporated to dryness. The residue is recrystallized from CHCV petroleum ether. Melting point 104 ° C. Yield 80%.

NMR (CDCl 3): signals at about 3.65 ppm.

B: A solution of 3 g of the compound obtained according to A in 20 ml of dry ether is slowly added to 3 g of LiAlH ₄ in 5 ml of dry ether. The mixture is stirred for 24 hours. Then 3 g of KOH in 6 ml of H ₂ O and then 10 ml of H ₂ O are added. The mixture is filtered and evaporated to dryness. The residue is extracted with ether and benzene. The solution is evaporated to dryness to give an oil which boils at 97 ° C / 0.05 mm Hg.

NMR (CDCl 3): -CH ₂ -N: 2.70 ppm (triplet); N-CH ₃ : 2.32 ppm (singlet); -CH ₂ -O: 3.65 ppm (singlet + triplet).

B. This compound can also be prepared by using N, N'-dimethyl-1,8-diamino-3,6-dioxaoctane with Triglycolyl chloride is reacted in the manner described in Examples 3 and 4.

XI.

A: Manufacture of

5,15-010X0-1,7,10,13,19,22-116X30X3-4,16-diaza-cyclotetracosane

The reaction is carried out by the method of strong dilution. A solution of 15.4 g of des diamine obtained according to IV C in 500 ml of anhydrous benzene and a solution of 10.4 g of the according to III B obtained dichloride in 500 ml of anhydrous benzene become 1200 ml anhydrous within 10 hours with vigorous stirring and under nitrogen Given benzene. After the addition is complete, the benzene solution is filtered and evaporated to dryness The oily residue is dissolved in anhydrous benzene and passed through an aluminum oxide column. the Polymers formed during the reaction are retained and it becomes a pure solution of the desired connection. After evaporation of the benzene, the desired compound is as viscous oil obtained. Yield 68%.

NMR (CDCl ₃ ): -CH ₂ -O and -CH ₂ -N: 3.60 ppm (3 peaks) -CO-CH ₂ -0: 3.85 ppm (singlet).

B: Manufacture of

tetracosan

A solution of 30 g of the diamine obtained in step A in 200 ml of anhydrous tetrahydrofuran is slowly with stirring and heating to reflux temperature to a mixture of 50 ml of anhydrous Tetrahydrofuran and 18 g LiAI H4 added. To After the addition, the mixture is under for 24 hours

Stir and reflux under nitrogen. To Cooling to room temperature is the reducing agent by adding a mixture of water and Tetrahydrofuran (1: 2) destroyed. The mixture is filtered and the filtrate is evaporated to dryness. Of the The residue is dissolved in benzene and the solution passed through a column of AIiOi, benzene as Elution center! is used. The solution is evaporated to dryness and the desired product as colorless oil is obtained which crystallizes at low temperatures, melting point 15 ° C. Yield 95%.

NMR (CDCl ₃ ): NH: 2.10 ppm (singlet); CH ₂ -N: 2.80 ppm (triplet); CH ₂ -O-: 3.60 ppm (singlet and triplet).

Ii

XII.

A: Manufacture of
5,12-Dioxo-1.7.10.16.19-pent joxa-4.13-

dia / a-cycloeneicosane

This reaction is carried out according to the strong dilution method. A solution of 31.8 g of the obtained according to IV C diamine in 1000 ml of anhydrous benzene and a solution of 17.8 g of the according to I B ^ Diehlonds obtained in 1000 ml of anhydrous benzene are under vigorous within 14 hours Stir and add to 1200 ml of anhydrous benzene under nitrogen. After the addition, the Benzoilos' ng filtered and evaporated to dryness, jo The crystalline residue (25 g) is dissolved in anhydrous benzene and passed through an alumina column guide! The polymers formed during the reaction are retained. A pure solution to the desired compound is obtained. After revision> crystallization from a mixture of benzene and heptane gives the desired compound. Melting point 90 to 91 C yield 75%.

NMR (CDCI,) - CH ₂ -O- and -CH, -N: 3.5 to 3.9 ppm (complex multiple »): —CO —CH .-- O: jo 4.05 ppm (singlet)

B: Manufacture of

1.7.10.16.19 Pentaoxa-4.13-diazacyclo
eneicosan

t-ine solution of b.7 g of the diamide obtained in step A in 100 ml of anhydrous tetrahydrofuran is slowly added with stirring / ti to a mixture of 50 ml -, n anhydrous tetrahydrofuran and 3.8 g Ι.ιΑΙΗ *. After the addition, the mixture 11 hours under stirring and under nitrogen at reflux for e ^r hit / t .ml After cooling room temperature, the reagent by the addition of 10 ml water 25 ml η v. Tetrahydrofuran destroyed, whereupon in ml of NaOH (I 5 "om water) and then io ml of water are added. The mixture is filtered and the Hltrat evaporated to dryness. The residue is dissolved in benzene and the solution passed through an AIjO ι column, where mi Bcruul is used as Llutiunsmittel. the solution is evaporated to dryness and z.ur obtain the desired product as a colorless oil which crystallized at low temperature. m.p. about 0 ⁰ C. yield 70%. EE

NMR (CDCI,): NH: 2.50 ppm (singlet): -CH; -N: 2.80 ppm (triplet); - (Hj-O: 3.5 to 3.7 ppm (two Singlets + triplet).

XIII.

A: Manufacture of

3,14-dioxo-1,16-dioxa 7,10-dithia-4,13-diaza-cyclooctadecane

This reaction is carried out according to the method of strong dilution. A solution of 10.2 g of diamine obtained according to VI in 500 ml of anhydrous benzene and a solution of 6.1 g of the dichloride obtained according to IB in 500 ml of anhydrous benzene are vigorously within 10 hours Stir and under nitrogen to 1200 m! given anhydrous benzene. After the addition has taken place, the benzene solution is filtered and the residue is washed with benzene. The combined benzene solutions are evaporated to dryness. The residue is dissolved in anhydrous benzene and passed through a short aluminum oxide column (30 g). The polymers formed during the reaction are retained. A pure solution of the desired compound is obtained. After recrystallization from a mixture of benzene and heptane, the desired compound is obtained. Melting point 145 ^C C. Yield 60%.

PMR (CDCI,): S-CH.-CH.-S: 2.80 ppm (singlet: 4H): S-CH ₂ -: 2.80 ppm (multiple »: 4H); N-CH ₂ : 3.45 ppm (multiples: 4H); O-CH ₂ -CH ₂ -O: 3.72 ppm il

B: Manufacture of

1.16-Dioxa-7.10-dithia-4.13-diazacyclooctadecane

A solution of 7 g of the obtained according to stage A cyclic diamide in 100 ml of anhydrous tetrahydrofuran is slowly added under nitrogen at a temperature of 0 ⁰ C to a freshly prepared solution (0.1 mol) of diborane in anhydrous tetrahydrofuran. The mixture is then refluxed for 2 hours. The excess reagent is destroyed by adding 10 ml of water. The solution is evaporated to dryness on a rotary evaporator under reduced pressure. After adding 100 ml of 6N hydrochloric acid to the residue, the mixture is refluxed for 2 hours. A clear solution is obtained here. This solution is evaporated to dryness in vacuo. The residue is dissolved in 50 ml of water and the solution is passed through a column of an anion exchange resin (Dowex 1). The column is washed with water until a basic reaction no longer takes place C) / evaporated to dryness. The residue is timknllistert Yield 70% melting point 4i (

PMR (CD (T): (H.-N * CH.-S, 2.77 ppm (Koni piexbande: IbH) (H-O: 3.59 ppm (singlet: 411 Triplet 4M)

XIV

Λ manufacture vui

Vl 2 Dk.xo- I /.10.Ib tctrnthw 4 I i

diaza-cyclooctadecane

This reaction is carried out according to the method of greater dilution. A solution of 18 g de; diamine obtained according to VI (0.1 mol) in 500 m of anhydrous benzene and a solution of 12.4 g of de; according to V B obtained dichloride in 500 ml of anhydrous em benzene are divided within 8 hours

230 217/2:

vigorous stirring and under nitrogen to t200ml given anhydrous benzene. Most of the desired amide becomes during the reaction failed. After the addition, the benzene solution is filtered and evaporated to dryness. One a small amount (2 g) of a solid residue is obtained. The during the with strong dilution The solid precipitate obtained is extracted three times with 250 ml of boiling chloroform each time. The residue obtained from the benzoin layer is added to iu given to the combined chloroform extracts. This solution is then replaced by a short aluminum oxide acid (30 g) filtered. The column is washed with a further 1000 ml of chloroform. The solution obtained is concentrated, the desired diamide crystallizing out

Melting point 148 to 149 ° C. Yield 85%.

PMR (CDCI3): -CH ₂ -S-: 2.65 to 2.90 ppm (complex band: 12H): -CO-CH ₂ -S: 3.25 ppm (singlet: 4H); - N-CH ₂ -: 3 , 52ppmMu] tiplet: 4H).

B: Manufacture of

1,7,10,16-tetrathia-4, l 3-diazacyclo-

octadecane

A solution of diborane (20 ml; 1.5 mol) in anhydrous tetrahydrofuran is added dropwise Nitrogen at room temperature to a suspension of

2 g of the diamide obtained in step A are added to 50 ml of anhydrous tetrahydrofuran. The solid dissolves to form a clear solution. After 3η Once the addition has taken place, the mixture is refluxed for 4 hours, a solid precipitate being formed. After cooling to room temperature, the excess reagent is removed by careful addition of 10 ml of water destroyed. The solvents are evaporated to dryness. To the solid residue 50 ml of 6N hydrochloric acid are added. The mixture will

Heated under reflux for 3 hours. The solid does not dissolve, rather the mixture remains heterogeneous. The mixture is evaporated to dryness. To the rear w was given a 10% sodium hydroxide in water (50 ml).

The heterogeneous mixture is extracted three times with 50 ml of chloroform each time. The combined chloroform layers are dried over sodium sulfate and 4> through a short column of aluminum oxide (20 g) filtered. The solvent is removed and the solid product is recrystallized from ethanol. Melting point 125 ° C. Yield 50%.

PMR (CDCI,): A complex band from 2.75 to -, n 2.83 ppm.

XV.

A: Manufacture of

5.9-Dioxo-1.7.1 S-trioxaAIO-dia / acyclo- "

pentadecane

This reaction becomes stronger after the melhode Dilution carried out. A solution of 29.6 g of the diamine obtained according to II B (0.2 mol) in 1000 ml w> anhydrous benzene and a solution of 17.2 g (0.1 Mol) of the dichloride obtained according to VIII in 1000 ml of anhydrous benzene are within 18 hours with vigorous stirring and under nitrogen to 1200 ml given anhydrous benzene. After addition, $ 6 The benzene solution is filtered and evaporated to dryness. The raw solid residue is almost pure (Melting point 147 to 148 ° C). It is recrystallized from a hot mixture of tetrahydrofuran and heptane, whereby the desired product is recovered.

Melting point 149 to 150 ° C. Yield 75%.

PMR (CDCI ₃ ): N-CH ₂ -CH ₃ -O: 3.60 ppm (multiples: 8H); 0-CH ₂ -CH ₂ -O: 3.67 ppm (singlet: 4H); -CO-CH, -O: 4.08 ppm (singlet: 4H); NH: 7.15 ppm (broad band: 2H).

B: Manufacture of
1,7,1 S-Trioxa ^ .lO-diazacyclopentadecane

A solution of 15.7 g of the diamide obtained in step A in 300 ml of hot anhydrous tetrahydrofuran is slowly added over 1.5 hours with stirring to a mixture of 50 ml of anhydrous tetrahydrofuran and 15 g of L1AIH4. When the addition is complete, the mixture is refluxed for 20 hours with stirring and under nitrogen. After cooling to room temperature, the excess reagent is destroyed by adding a mixture (45 ml) of water and tetrahydrofuran (1: 2), whereupon 15 ml of 15% NaOH and 45 ml of water are added. The mixture is filtered and the filtrate is evaporated to dryness. The residue is dissolved in benzene and the solution is passed through a column of Al ₂ O.

Benzene is used as the eluant. The solution is evaporated to dryness, whereby a semi-crystalline product (mixture of crystals with an oil) is obtained, which turns out to be the desired one Product proves. Yield 89%.

PMR (CDCl 3): CH ₂ -N: 2,75 ppm (triplet: 8H): CH ₂ -0: 3.b0 ppm (triplet + singlet: 12H).

XVI.

A: Manufacture of

5.9-Dioxo-1.7-dioxa-4, 10-diaza-cyclo-

dodecane

This reaction is carried out according to the strong dilution method. A solution of 10.4 g of the according to VII obtained diamine (0.1 mol) in 100 ml of anhydrous benzene and a solution of 8.6 g (0.05 Mol) of the dichloride obtained according to VIII in 100 ml of anhydrous benzene are within 50 minutes added to 1000 ml of anhydrous benzene with vigorous stirring. The reaction mixture is filtered and the residue with hot chloroform (3 χ 500 ml) washed. The combined solutions are evaporated to dryness, leaving a crystalline residue (Melting point 180 to 181 C) is raised from a hot mixture of chloroform and heptane urr. is crystallized, with the desired product is obtained.

Melting point 182 to 183 "C. Yield 65%.

PMR: (CDCIj): N-CH ₂ -CH, -O: 3.60 ppm (broad multiple: 8H); CO-CH ₂ -O-. 4.15 ppm (singlet: 4H): NH 7.65 ppm (broad U.mdc 2H |

Production of
1.7-dioxa-4. 10-dia / acyciodecane

A suspension of 5.0 g of the diamide according to stage A in 100 ml of hot anhydrous Tetrahydrofuran is slowly stirred within 1 hour to a mixture of 4.8 g of LiAlHi and 100 ml of anhydrous tetrahydrofuran are added. After the addition has been made, the mixture is stirred and stirred refluxed under nitrogen for 18 hours. After cooling to room temperature, the excess is

Reagent destroyed by adding a mixture (25 ml) of water and tetrahydrofuran (1: 2), whereupon 5 ml of 15% NaOH and 15 ml of water are added. The mixture is filtered and the filtrate is evaporated to dryness. The residue is dissolved in benzene and the solution is passed through an Al ₂ O ₃ column. Benzene is used as the eluant. The solution is evaporated to dryness.After recrystallization from hot benzene / heptane, the desired product is obtained obtain. Melting point 83 to 84 ° C. Yield 70%.

PMR (CDCI ₃ ): NH: 2.40 ppm (singlet: 2H); -CH ₂ -N: 2.80 ppm (triplet: 8H); -CH ₂ -O: 3.66 ppm (triplet: 8H).

XVII.

Production of
1,2-Di- (chlorocarbonyl-mettioxy) -benzene

A. 1.2-Di (carb! "> Ny! Methoxy) -benzene, 200 g of sodium hydroxide (5 mol) Ir. 200 ml of water and 50% of pyrocatechol (1 mol) are mixed in a 1 -1 flask. 189 g of monochloroacetic acid are then mixed (2 mole) slowly over 3 hours added The mixture is heated over a period of 2 hours at 100 ⁰ C. After cooling, 100 ml of hydrochloric acid are added. The acid precipitates and is recrystallized from water

Melting point 177''C, yield 50%.

PMR (basic NaOH) D ₂ O
-O-CH ₂ -: 4.40ppm (singlet; 4H)
aromatic protons:
6.9 ppm (multiple ". A H).

B. Acid dichloride

30 g of the above acid are added to a mixture of IW ml of anhydrous benzene. Then 35 g of oxalyl chloride are added while protecting the flask with a calcium chloride tube. The mixture is stirred for 4 days, the dicarboxylic acid gradually dissolving as it is converted into the corresponding dichloride. The solution is then evaporated to dryness (without heating) leaving a brownish solid residue which is recrystallized from a mixture of chloroform and benzene to give white crystals.

Melting point 50 ° C. - \ usbut80%.

PMR (CDCl,): - 0-CH ₂ -COCI-:

5 ppm (single »4H)
.. aromatic protons:
7 ppm (singlet: 4H).

Preparation of the compounds according to the invention
and their complexes

Example I.

A manufacture of

2.9-D10X0-4.7.13.16.21.24-hexaoxa-1.10-diazabicyclo [8,8,8] hexacosane

The reaction is carried out according to the strong dilution method.

'A solution of 5.24 g of the obtained according to IX cyclic diamine and 4.4 g of Triäthylärnifi in 500 ml Anhydrous benzene and a solution of the dichloride obtained according to 1 B (4.4 g in 500 ml of anhydrous

Benzene) are added to 1000 ml of anhydrous benzene within 10 hours under nitrogen. The salt of triethylamine and hydrochloric acid separates and is filtered off. The filtrate is evaporated to dryness. The residue is dissolved in senzene and passed through an Al ₂ O ₃ column, benzene being used as the eluent. The product is crystallized from a hexane-benzene mixture, melting point 114 ° C. Au. Yield 50%.

NMR (CDCl3): several peaks between 3.3 and 4.6 ppm.

B. Manufacture of

[8.8.8] hexacosane

B ₂ Hb is produced according to the process described in »Org. Reactions «13: 31-32 (1963).

A solution of 1 g of the bicyclic diamide prepared according to stage A in 20 ml of tetrahydrofuran is slowly added under nitrogen at a temperature of 0 ° C. to 15 ml of the freshly prepared B ₂ H ₆ solution. The mixture is stirred at this temperature for 30 minutes and then for 1 hour at the reflux temperature. The excess reagent is destroyed by adding 5 ml of water and the solution is evaporated on a rotary evaporator under reduced pressure. This gives 1 g of the diborane of the desired compound.

This compound is hydrolyzed by adding 20 ml of 6N hydrochloric acid with heating, with a Solution is obtained. The mixture is evaporated to dryness in vacuo on a rotary evaporator. The residue is dissolved in 10 ml of water and the solution through a column of an anion exchange resin (Dowex 1). The column is washed with water until the basic reaction no longer takes place The water is evaporated. The residue is recrystallized from hexane and reduced under reduced pressure Print (0.1 mm Hg) dried. This gives 890 mg of the desired product. Melting point 68 up to 69 ° C. Yield 95%.

NMR (CDCI,): -CH ₂ -N: 2.65 ppm (triplet): -CH ₂ -0: 3.65 ppm (singlet + triplet).

Example 2

A. Production of 2.12- dioxo-4.7.10.16.19.?2.27.30J3-nonaoxa-l.l3·
diazabicyclofj U 1.1 l] pentatriacontane

The reaction is carried out according to the strong dilution method. A solution of 7.0 g of the according to XI B obtained cyclic diamine and 4.4 g

η triethylamine in 500 ml of anhydrous benzene and a solution of the dichloride obtained according to III B (5.2 g in 5DOTiI wavse Ben-free oil) are added within ¹ O hours under nitrogen with stirring to 1200 ml of anhydrous Ben7ol. The salt of triethylamine and hydrochloric acid separate out and film off. The filtrate is evaporated to dryness. The residue is dissolved in benzene and passed through a column of Al ₂ O ₃ using benzene as the eluent. The product is a colorless oil which crystallizes when left to stand, melting point 72 to 74 "C. Yield 65%,

NMR (CDCl3): 3.4 to 3.8 ppm (broad maxima); -CO-CH, -N: 4.33 ppm (broad maximum).

B. Manufacture of
4,7,10,16,19,22,27,30,33-Nonaoxa-1,1
bicyclo [11,11,1 ljpentatriacontan

BjHb is manufactured using the process described in “Org. Reactions ”3, 31 to 32 (1963).

A solution of 13 g of the obtained according to stage A acyclic diamide in 20 ml of tetrahydrofuran is slowly added under nitrogen at a temperature of 0 ⁰ C to 15 ml of freshly prepared aer BjHb solution (1.6 MoI). The mixture is stirred for 30 minutes at this temperature and then for 2 hours at the reflux temperature. After cooling to room temperature, the excess reagent is destroyed by adding 10 ml of water and the solution is evaporated on a rotary evaporator under vacuum. The bis-amine borane of the desired compound is obtained by extracting the residue with chloroform.

This compound is hydrolyzed by adding 25 ml 6N hydrochloric acid are added and the mixture is refluxed for 3 hours. Here is a solution obtain. The mixture is evaporated under reduced pressure on a rotary evaporator. Of the The residue is dissolved in 10 ml of water and the solution passed through a column of an anion exchange resin (Dowex 1). The column is filled with water washed until no more basic reaction takes place. The water is evaporated. The residue is the desired product, which is obtained as a colorless oil.

Yield 95%.

NMR (CDCI.): -CHj-N: 2.85 ppm (triplet): -CHj-O: 3.65 ppm (singlet and triplet).

Example 3

A. Manufacture of

14.21-Dioxo-4.7.10.16,19,24.27-Heptaoxa-1.13-dia / abicyclo [8.8.1 Ijnonacosan

The reaction becomes stronger after the method Dilution carried out. A solution of 2.45 g of the cyclic diamine obtained according to XIIB and 2 g Triethylamine in 200 ml of anhydrous benzene and a solution of the dichloride obtained according to I B (1.8g in 200 ml of anhydrous benzene) become 1200 ml within 5 hours under nitrogen and with stirring Ben / ol given. The salt of triethylamine and hydrochloric acid separates and is filtered off The filtrate is evaporated to dryness. The residue is dissolved in ben / ol and passed through a column of AbO, passed, with ben / ol being used as the eluent. After evaporation of the solvent the residue crystallizes when left to stand; The product obtained is the one you want Link. Melting point 47 to 98 "C. Extensions 65%

PVIR (CDCIt): CH-- M and CHj-O: 3.5 to 3.9 ppm (broad peaks); CO CHj-O 4.0 to 4.3 ppm (very broad peaks).

IV Manufacture of

4.7, IO _< 16.19.24.27 · Heptaoxa-1,13-diazabicyclo [8.8.1 L] nonacosane

B2H6 is manufactured using the process outlined in “Org. Reactions «. 13.31-32 (1963).

A solution of 1.5 g of the obtained according to stage A. Acyclic DiamiJi in 15 ml of anhydrous tetrahydro

furan is slowly added to 15 ml of the freshly prepared under nitrogen at a temperature of 0 ° C BjHb solution (1.2 mol) given. The mixture becomes 30 Stirred minutes at this temperature and then for 2 hours at the reflux temperature. The excess The reagent is destroyed by adding 5 ml of water. The solution is un'er on a rotary evaporator evaporated under reduced pressure. The bisamine borane of the desired compound is obtained.

ίο This compound is hydrolyzed by adding 30 ml 6N hydrochloric acid is added and the mixture is refluxed for 2 hours, a solution being obtained. The mixture is evaporated in vacuo on a rotary evaporator. The residue is dissolved in 10 ml

Γι dissolved water and the solution through a column of a Anion exchange resin (Dowex I) passed The column is washed with water until no basic Reaction takes place more. The water is evaporated and the residue under reduced pressure (0.1 m * n Hg) dried. Here is 1 g of the desired Product received as a colorless liquid. yield 75%.

PMR (CDCI ₁ ): -CHj-N: 2.75 ppm (triplet);

- CH j - 0: 3.70 ppm (singlet): 3.65 ppm (trinette).
2>

Example 4

A. Manufacture of

2.12Dioxo-4.7.10.16.19.22.27.30-OCIaOXajfi 1.13-dia / abicyclo [8.11.11] dotriacontane

The reaction is carried out according to the strong dilution method.

A solution of 1.67 g of that obtained according to XII B

r> cyclic diamine and 1.2 g of triethylamine in 100 ml anhydrous benzene and a solution of the dichloride obtained according to III B (UOg in 100 ml of anhydrous Benzene) become 1000 m! Within 2 hours under nitrogen and with stirring! Given benzene.

4 (i The salt of triethylamine and hydrochloric acid separates and is filtered off. The precipitate is evaporated to dryness. The residue is dissolved in benzene and passed through an aluminum column, benzene being used as the eluent.

4-, duct occurs as a colorless, viscous oil. Yield 50%.

PMR (CDCI)): 3.4 to 3.8 ppm (broad peaks):

- CO - CH ₂ - 0: 4.35 ppm (broad peak).

B. Manufacture of

4.7.10.16.19.22.27.30-OcIaOXa-1.13-diazabicyclo [8.11.11] dotriacontane

BjHh is moved to Hern in »Org. Reactions «13. 31-32 (■ <S & 3) described method.

A solution of 1.2 g of the acyclic piamide obtained in step A in 20 ml of tetrahydrofuran is slowly to 10 ml of the freshly herges, hurried BjHh-Lösting (1.6 molar) 'inter nitrogen at a temperature of OC given. The mixture is stirred for 30 minutes at this temperature and then for 2 hours at the reflux temperature The excess reagent is destroyed by adding 3 ml of water. The Lösrag is on evaporated on a rotary evaporator under reduced pressure. By extracting the residue with 1.13 g of the bisamine borane of the desired compound are obtained in chloroform.

This compound is hydrolyzed by adding 40 ml of 6N hydrochloric acid over 2 hours

is heated. In doing so, a solution is obtained. That Mixture is evaporated under reduced pressure on a rotary evaporator. The residue will Dissolved in 10 ml of water and the solution through a column an anion exchange resin (Dowex 1). The column is washed with water until it is not basic Reaction takes place more. The water is evaporated. The residue is the desired product that is obtained as a colorless liquid. Yield 95%.

PMR (CDCl ₃ ): -CH ₂ -N: 2.80 ppm (triplet): - CH ₂ - O -: 3.4 to 3.8 ppm (single and triplet).

Example 5

A. Manufacture of

2,9-dioxo-4,7.13,16-tetraoxa-2l,24-dithia-1,10-diazabicyclo [8,8,8] hexacosane

The reaction becomes stronger after the method

rr: ι ü - "- r> tz _» -i

t-IHC f-iU3Ulfg TUIf * I, U g UC3

cyclic diamine obtained according to XIII B and 1.3 g of triethylamine in 400 ml of anhydrous benzene and a solution of the dichloride obtained according to IB (2.7 g in 400 ml of anhydrous benzene) are added to 1000 ml of benzene within 8 hours under nitrogen and with stirring given. The triethylamine hydrochloride precipitates and is filtered off. The filtrate is evaporated to dryness. The residue is dissolved in benzene and the solution passed through an AI ₂ Or column (20 g), benzene being used as the eluent. The solutions are evaporated to dryness. The product is a viscous oil. Yield 50%. PMR:

-CH ₂ -S-CH ₂ -CH ₂ -S-CH ₂ : 2.8 ppm (complex broad band: 8H); CH ₂ -O + CO-N-CH ₂ : 3.6 ppm (broad signals: 20H); CO - CH ₂ - O -: 4.0 ppm (broad signals: 4H).

B. Manufacture of

4,7,13.16-Tetraoxa-24.24-dithia-1.10-

diazabicyclo [8.8,8] hexacosane

A solution of 1.6 g of the obtained according to stage A bicyclic diamide in 30 ml of anhydrous tetrahydrofuran is slowly added under nitrogen at a temperature of 0 ⁰ C to 20 ml of diborane (1.5 mol) of freshly prepared given. The mixture is stirred for 2 hours at reflux temperature. The excess reagent is destroyed by adding 5 ml of water. The solution is evaporated on a rotary evaporator under vacuum. The residue is treated with 50 ml of 6N hydrochloric acid for 2 hours under reflux, whereby a solution The mixture is evaporated under reduced pressure on a rotary evaporator (water bath from 80 to 100 ° C). The residue is dissolved in 50 ml of water and the solution is passed through a column of an anion exchange resin (Dowex 1). The column is washed with water until no more basic reaction takes place. The water is evaporated. The residue is dried under reduced pressure (0.1 mm Hg) and recrystallized from a mixture of benzene and heptane, the desired compound being obtained. Melting point 78 b; s 80 ^; C (yield <> 5% 5.

PMR (CDC :): S'-CH; -CH.- -SN -CH ;: 265 pc -! <Mi, 'i, peü 6Hv S-CH; -CH ₂ -S 2.90 ppm (.γπί - ::. -'!) O - CH. -: 3.c0 ppm ίΤπμίεπ. SH) 40
Example 6

A. Manufacture of
2,9-dioxo-4,7-dioxa-13,16,21,24-telralhia-

1, 10-diazabicyclot8,8,8] hexacosane

The reaction is carried out according to the strong dilution method. A solution of 1.0 g des according to XIVb obtained cyclic diamine and 0.3 g of triethylamine in 100 ml of anhydrous benzene and one

ίο Solution of the dichloride obtained according to Example IB (0.8 g in 100 ml of anhydrous benzene) are added to 1000 ml of anhydrous benzene under nitrogen and with vigorous stirring within 2 hours. The salt of triethylamine with hydrochloric acid is precipitated and filtered off. The filtrate is evaporated to dryness. The residue is dissolved in benzene and _{filtered through a column of Al 2} O ₁ (20 g), whereupon 500 ml of chloroform are passed through.
The solvents are evaporated, the

Hr desired Vcfuii'nJui'ig as viscous vyi iüfückuieiui.

that can crystallize if left standing. Yield 40%.

PMR (CDCIi): CH ₂ -S: 2.75 ppm (broad band: 16H); CH ₂ -N and CH ₂ -O: 3.65 ppm (broad bands: singletl + triplet: 12H); CO-CH ₂ -O: about 4 ppm (several broad peaks: 4H).

B. Manufacture of

4 7-Dioxa-13.16.21.24-tetrathia-1.I0-diazabicyclo [8,8,8] hexacosane

A solution of 0.6 g of the bicyclic diamide obtained in step A in 10 ml of tetrahydrofuran is slowly added under nitrogen at a temperature of O ³ C to 10 ml of the freshly prepared B ₂ H ₆ solution (1.5 mol). The mixture is refluxed for 2 hours. The excess reagent is destroyed by adding 5 ml of water. The solution is evaporated on a rotary evaporator under vacuum. The solid residue is treated with 50 ml of 6N hydrochloric acid under reflux for 2 hours. The mixture is evaporated to dryness under reduced pressure on a rotary evaporator. The residue is treated with a solution of tetraethylammonium hydroxide until it reacts basic. The mixture, which contains a precipitate, is extracted several times with chloroform. The solutions are filtered through alumina and evaporated to dryness to give the desired compound as a crystalline residue.

The solid residue is made from a benzene-hexane mixture umkristaüisiert and dried under reduced pressure (0.1 mm Hg) melting point 86 ois 87 ° C. Yield 95%.

PMR (CDCI ₃ ): N-CH ₂ -CH; - S + N-CH ₃ :

2.70 ppm (multiple: 20H); S -CH ₂ -CH ₂ -S: 230 ppm (broad band: 8H): CH ₂ -O: 3.60 ppm (triplet: 4H): 3.68 ppm (singlet: 4H).

Example 7

A. Manufacture of

23-Dioxo-4JA3A62 \ 24-hexath \ a-U0- diazabicyclo [8.8.8] hexacosane

The reaction is carried out according to the strong dilution method. A solution of 4j g des according to XFV B obtained cyclic diamine and 1_5 g Träthyiamine in 500 ml of anhydrous Bennos (as is kept at 60 ° C during the addition)

or in 400 ml of anhydrous chloroform and a solution of the dichloride obtained according to VB (3.5 g in 400 ml of anhydrous benzene) are added to 1000 ml of anhydrous benzene within 6 hours under vigorous stirring. The salt of s triethylamine and hydrochloric acid and the product are precipitated and filtered off. The benzene layer contains only ^p: ne small amount of product. The solid is extracted three times with hot chloroform. The combined chloroform solutions are filtered through an alumina column. The bicyclic amine is eluted with methanol. After evaporation to dryness, the desired compound is obtained as a viscous oil. Yield 20%.

PMR (CDCIj): CH ₂ -S: several broad peaks n between 2.5 and 3.1 ppm (20H); COCH ₂ -S + CH ₂ -N: several broad peaks between 3.2 and 3.8 ppm (12H).

B. Manufacture of

4,?, I3,} 5,2 ', 24-HcÄaii "i! A-i, iö-diazä ·

bicyclo [8.8.8] hexacosane

20 ml of freshly prepared ₂ B He-solution under nitrogen at a temperature of 0 ⁰ C to a suspension of 1 g of the obtained according to stage A bicyclic diamide in 20 ml of tetrahydrofuran. The mixture is stirred for 30 minutes at this temperature and then for 4 hours at the reflux temperature. The excess reagent is destroyed by adding 5 ml of water and the solution is evaporated on a rotary evaporator under reduced pressure. After adding 50 ml of 6N hydrochloric acid, the mixture is refluxed for 4 hours. The mixture is evaporated to dryness under reduced pressure on a rotary evaporator, made alkaline with O, In NaOH and extracted three times with chloroform. The chloroform solutions are filtered through aluminum oxide and diluted Evaporated dry. The residue is recrystallized from a chloroform-hexane mixture to give the desired compound. Melting point 172 ° C. Yield 80%.

PMR (CDCl ₃ ): N-CH ₂ -CH ₂ -S: 2.68 (singlet: 24H); S - CH ₂ - CH ₂ - S: 250 ppm (singlet: 12H).

Example 8

A. Manufacture of

23- Dioxo-4,7,13.1 62 1 -pentaoxa-1,10-

diazabicyclo [8,8.5] tricosan

B. Manufacture of

4,7,13.16,21-PCnIaOXa-1,10-diazabicyclo- [8.8.5] lricosane

A solution of 5 g of the acyclic diamide obtained in step A in 50 m! of anhydrous tetrahydrofuran is slowly added under nitrogen at a temperature of 0 C to ^a 50 mt of a freshly prepared solution BjH6 (I, 0'molar) was added. The mixture is stirred for 30 minutes at this temperature and then for 1.5 hours at the reflux temperature. The excess reagent is destroyed by adding 10 ml of water and the solution is evaporated on a rotary evaporator under vacuum. This gives 3.5 g of the diborane of the desired compound (melting point 205 to 209 ^° C.).

The reaction is carried out according to the method of strong dilution. A solution of 8.72 g of the cyclic diamine obtained according to XV B and 8.8 g of triethylamine in 500 ml of anhydrous benzene and a solution of the dichloride obtained according to Example IB (8.6 g in 500 ml ml of anhydrous benzene) is added to 1000 ml of anhydrous benzene under nitrogen and with stirring over a period of 10 hours. The salt of triethylamine and hydrochloric acid is precipitated and filtered off. The ritrate is evaporated to dryness and the residue is dissolved in benzene and passed through a column of Al ₂ O ₃ (100 g). Benzene is used as the eluent. The desired compound is obtained as an oil, the crystallizes when left standing. The product is recrystallized from a hexane-benzene mixture, melting point 105 ^° C., yield 45%.

PMR (CDCl ₃ ): several peaks between 33 and 4.6 ppm.

θ θ
N bra,

This compound is hydrolyzed by adding 50 ml of 6N hydrochloric acid with heating, with a Solution is obtained. The mixture is taken under reduced pressure on a rotary evaporator evaporated to dryness. The residue is dissolved in 30 ml of water and the solution is passed through a column Anion exchange resin (Dowex 1) passed The column is washed with water until no basic The more reaction takes place. The water is evaporated, leaving the desired compound as a colorless oil (3 g) is obtained. Yield 95%.

PMR (DCDl _3): -CH ₂ -N: 2,65 ppm (triplet: 12H); -CH ₂ -0: 3.60 ppm (triplet: 12H); 3.70 ppm (singlet: 8H).

Example 9
A. Manufacture of

diazabicycloßJ & Sjhexacosan

The reaction is carried out by the strong dilution method. A solution of 10.48 g of des according to IX B obtained cyclic diamine and 8.8 g of triethylamine in 300 ml of anhydrous benzene and one Solution of the dichloro of octane-1,8-dicarboxylic acid (8.44 g in 500 ml of anhydrous benzene) are within of 10 hours under nitrogen and with stirring to 1200 ml of anhydrous benzene. The salt of Triethylamine and hydrochloric acid are precipitated and filtered off. The filtrate is evaporated to dryness

The product is an oil that crystallizes on standing. Melting point 96 to 98 ° C, yield 45%.

PMR (CDCij): - {CHz / s-: 1.4 to 2.0 ppm free peaks: 12H); CH ₂ -N and CH ₂ -O: several peaks between 33 and 4.6 ppm.

B. Manufacture of

4,7.13,16-tetratixa-1,1O-diazabicyclo- [8,8,8] hexacosane

A solution of 7 g of the bicyclic diamide obtained in step A in 80 ml of anhydrous tetrahydrofuran is slowly added under nitrogen at a temperature of 0 ° C. to 70% of a freshly prepared B 2 H _{6 solution (1,} 5 mol). The mixture is stirred for 30 minutes at this temperature and then for 1.5 hours at the reflux temperature. The excess reagent is destroyed by adding 20 ml of water. The solution is evaporated on a rotary evaporator under reduced pressure. This gives 6 g of the diborane of the desired compound (melting point 139 ^° C.).

H ₃ DN

Melting point 151 to 152 ° C. Yield 45%.

PMR (CDCIj) ₁ : two very complex multiplets between 2.6 and 3.2 ppm (4H) and 3.4 and 4.8 ppm (20H).

B. yeast production of

4,7,13,18-tetraoxa-1,10-diazabicyclo- [5,5,8] eicosan

22 ml of a freshly prepared B ₂ H6 solution ίο (0.8 mol) are added with a syringe under nitrogen at a temperature of 0 ° C to a suspension of 2.9 g of the bicyclic diamide obtained in step A in 20 ml of anhydrous tetrahydrofuran given. The mixture is stirred for 30 minutes at this temperature and then for 3 hours at the reflux temperature. The excess reagent is destroyed by adding 5 ml of water and the solution is evaporated on a rotary evaporator under vacuum. The residue is extracted several times with chloroform and the resulting solution is evaporated to dryness. This gives 1.9 g of the diborane of the desired compound.
Melting point 171 to 112 ° C. Yield 98%.

This compound is hydrolyzed by adding 100 ml of 6N hydrochloric acid with heating, with a Solution is obtained. The mixture is taken under reduced pressure on a rotary evaporator evaporated to dryness. The residue is dissolved in 20 ml of water and the solution is passed through a column Anion exchange resin (Dowex 1) passed. The column is washed with water until it is not basic Reaction takes place more. The water is evaporated. The desired connection will appear as whiter crystalline solid obtained.

Melting point 90 to 91 ^° C. Yield 85%.

PMR (CDClj): - (CHj) ₆ -: 1.4 ppm (broad peak: 12H); -CH ₂ -N: 2.40 ppm (broad peak: 4H); 2.65 ppm (triplet: 8H); -CH ₂ -O: 3.53 ppm (triplet: 8H); 3.70 ppm (singlet: 8H).

Example 10

A: Manufacture of
2,9-dioxo-4,7,13,18-t etraoxyl, 10-diazabicyclo [5,5,8] eisocan

The reaction is carried out by the method of high dilution. A solution of 8.7 g of des according to XVI B obtained cyclic diamine and 11 g Triethylamine in 200 ml of anhydrous chloroform and 300 ml of anhydrous benzene and a solution according to I B obtained dichloride (f 0.8 g in 500 ml of anhydrous Benzene) become 1000 ml anhydrous within 8 hours under nitrogen and with stirring Benzoi given. The solution is filtered, and the solid Residues are washed several times with benzene. The combined organic layers become Evaporated dry, leaving an oily residue, which is then washed three times with hot benzene (3 χ 200 ml) is extracted by evaporating the benzene layers, a solid residue is obtained, which filtered through an alumina column in benzene solution The solid obtained after evaporation of the solvent is on a benzoi-heptane mixture "Recrystallized The desired product will be obtain.

θ Θ

N-BH ₃

This compound (1.7 g) is hydrolyzed by adding 20 ml of 6N hydrochloric acid with heating (2.5 hours), whereby a solution is obtained. The mixture is made under vacuum on a rotary evaporator Evaporated dry. The residue is dissolved in 10 ml of water and the solution is passed through a column Anion exchange resin (Dowex 1) passed The column is washed with water until no basic More reaction takes place The water is evaporated The desired compound turns out to be colorless Obtain oil. Overall yield 95%.

PMR (CDCI ₃ ): -CH ₂ -N: 2.75 ppm (triplet: 12H); -CH ₂ -O: 3.4 to 3.9 ppm (multiple «: 12H); 3.70 ppm (singlet: 4H).

Example 11

A. Manufacture of

2i-Dioxo-4,13,16-trioxa-7 ^ 1,24-trithia-1,10-diazabicyclo [8,8,8] hexacosane

This reaction is carried out by the method of strong dilution. A solution .on 4p g *, diamine obtained according to XIII B and 2 g of triethylamine in 200 ml of anhydrous benzene and a solution of 3.8 g of monothiotriglycolic acid dichloride in 200 ml of anhydrous benzene are within Z5 Hours with vigorous stirring and under nitrogen to 120OmI anhydrous benzene. After the addition, the benzene solution is filtered and evaporated to dryness. The oily residue is again dissolved in benzene (ΐ-ΟΟιπί) and filtered through an ammonium oxide acid (50 g). The product is treated with a mixture of chloroform and benzene (30% / 70%) elutes the solution

10

Evaporated wildly to dryness, leaving a viscous oil left that is the desired compound (yield about 50%).

PMR (CDCl ₃ ): very complex spectrum from 2.5 to 4.0 ppm; S-CH ₂ + NCH ₃ : from 2.5 to 2.9 ppm; D-CH ₂ : from 3.5 to 4.0 ppm.

B. Manufacture of

4,13,16-trioxa-7,21,24-trithia-1,10-

diazabicyclo [8,8,8] hexacosane

20 ml of a solution (1.2MoI) of diborane in anhydrous tetrahydrofuran are under nitrogen at 0 ° C. to a solution of 1.5 g of the acyclic diamide obtained in step A in 20 ml of anhydrous Given tetrahydrofuran. The mixture becomes> -5 for 2 hours "Heated to reflux. The excess reagent is destroyed by adding 5 ml of water. The solution will be evaporated in vacuo on a rotary evaporator. The residue is 2 with 40 ml of 6N hydrochloric acid Heated to reflux for hours. The mixture is lined 2h Evaporated under reduced pressure on a rotary evaporator Eur Trct V, ene. The residue is with treated with a solution of tetraethylammonium hydroxide until the reaction is basic. The mixture will extracted with benzene (3 × 50 ml). The organic layers are dried and passed through an alumina column filtered. The solution is evaporated to dryness leaving a viscous oil (1.4 g), that is the connection you want. Yield 95%.

PMR (CDCI ₃ ): (- S-CH _? -) + (-N-CH ₂ -): 2.4 to 2.9 ppm (complex band: 24H; _{gives the -S-CH 2} -CHj-S group a Singletl at 2.9 ppm); -0-CH ₂ -: 3.4 to 3.7 ppm (complex band: 12H).

given. The triethylamine hydrochloride precipitates and is filtered off. The filtrate is evaporated to dryness. The residue is dissolved in benzene and the solution is passed through a column of Al2O3 (20 g). as Benzene is used as the eluent. The solutions were evaporated to dryness. The product is a viscous oil. Yield 50%.

PMR (CDCl ₃ ); CH ₂ -N and CH ₂ O: 2.5 to 4.5 ppm (complex multiplet: 24H): 0-CH ₂ -CO: 5.0 ppm (AB system) aromatic protons: 7.0 ppm (single u. 4H).

B. Manufacture of
4.ll, 17,20.25,28-hexaoxa-1.14-diazatricycIo [12,8,8,0 ⁵¹⁰ ] -triacont-5,7,9-triene

35 ml of a freshly prepared solution (1.2 molar) of dibran are slowly under nitrogen at a temperature of 0 ⁰ C to a solution of 3 g of the amide obtained in step A in anhydrous tetrahydrofuran gpgRhpn The OpTiisoh is then 2 hours on

30th

35

Example 12

21,24-dimethyl-4,7,13,16-tetraoxa-1.10-21,24-tet raazabicyclo [8,8,8] hexacosane

A. On the

IX A

described manner, octanediamine is reacted with the chloride obtained according to I B, 10,13-dimethyl-6,17-dioxole, 4-dioxa-7, l 0.13.16-tetraaza-cyclooctadecane is obtained.

B. The product of stage A is reduced on the oxo groups in the manner described in IX B, wherein lO.lS-Dimethyl-l ^ -dioxa ^ .lO.lS.lö-tetraaza-cyclooctadecane is obtained.

C. In the manner described in Example I A, the product of stage B with the dichloride of Example I B becomes so condensed to give 21,24-dimethyl-2,9-dioxo-4.7.13,16-tetraoxa-1,10,21.24-tetraaza-bicyclo [8,8,8] hexacosane is obtained.

D. Reduction of the oxo groups to the level described in Example IB gives the desired compound.

Example 13

A. Production of 2,13-Dioxo-

4,11,17,20.25J28-hexoxa-l, t4-diaza-

tricyclo [1 Z8.8.O ⁵¹⁰ ] -triacont-5,75-triene

60

This reaction is carried out by the method of high dilution. A solution of 5.2 g of des according to IX B obtained diamine and 5 g of triethylamine in 30O ml of anhydrous benzene and a solution of 5.4 g de = DichJorids obtained according to XVII B in 300 mi ν. τ "» -free Benzo! will be delivered within 6 hours unTf- · c «" toff und urn »· stir to 1000 ml benzene gg

Heated to reflux. The excess reagent is destroyed by slowly adding 5 ml of water. the Solution is evaporated to dryness on a rotary evaporator in vacuo.

60 ml of 6N hydrochloric acid are added to the residue. The mixture is refluxed for 2 hours. the Solution is then evaporated to dryness in vacuo. The residue is dissolved in 30 ml of water dissolved and the solution passed through a column of an anion exchange resin (Dowex 1). the The column is washed with water until the basic reaction no longer takes place. The united received aqueous solutions are evaporated to dryness under reduced pressure on a water bath. Of the The residue is a viscous oil. Yield 80%.

PMR (CDCI ₃ ): -CH ₂ -N: 2.72 ppm (triplet: 8H), 2.90 ppm (triplet: 4H): -CH ₂ -O: 3.55 ppm (singlet: 8H and triplet 8H) : -CH ₂ -O (phenolic): 4.10 ppm (Tripffitt: 4H): aromatic protons: 6.85 ppm (singlet: 4H).

Example 14

Manufacture of the

RbSCN complex of 4.7,13,16 ^ U ^<i A-hexaoxa-l.lO-diazabicyclofS.S.ejhexacosan

130 mg of amine and 35 mg of RbSCN are mixed in a flask, after which 20 ml of acetone are added will. The mixture is heated to the boil until all of the solid has dissolved. After evaporation to When dry, the residue is extracted with chloroform, which dissolves the complex. The chloroform solution becomes also evaporated to dryness to give the crystalline complex. The complex can be recrystallized from acetone-heptane. He's melting at 163 to 164 ° C.

NMR (CDCl ₃ ): - CH ₂ - N: 2.56 ppm (triplet).

Example 15

Manufacture of the

BaCI ₂ complex of 4.7.13 1 62 ί, 24-

hexaoxa-l.lO-diazabicycIofe.S.Sjhexacosan

37.6 mg Amm and 21 mg BaCl? ■ 2 H ₂ O are dissolved in 10 ml of water. The solution is evaporated to dryness. The solid residue is extracted with methylene chloride. After the solution has been filtered, ether is added and the knstaüisittor is used

crystalline complex melt; not, but will with about 200 C dark

NMR (CDCI ₁ ): -CH-N: 2.80 ppm (triplet).

Example Ib

Preparation of the CsSCN complex of 4.7.10.16.19,22.27 i0.33-iionao \ a-l.1 3 diazabic \ clo [l 1.! Il Ijpeniairiaconi.in

100 mg of the macrocyclic obtained according to Example 2R The compound and 45 mg of CsSCN are refluxed in 20 ml of acetone for 5 minutes. After filtration the solvent is evaporated. The residue is extracted with chloroform, filtered again and used for Evaporated dry. The complex is crystallized from acetone / ethyl acetate. Melting point 155 to 156 "C.

PMR (CDCl ₁ ): -CH; -N: 2.60 ppm (triplet); - CH; 0: 3.55 ppm (triplet) and 3.62 ppm (singlet).

Example 17

Manufacture of the

KSC N complex of 4.7.1 3.1b_21 Pentaoxa-1.10 diazabicyclo [8.8.5] tricosan

100 mg of the macrocyclic compound are dissolved in chloroform. Solid KSCN is im Cover given. The mixture is at overnight Let stand room temperature and filter. The solution is evaporated to dryness. The residue is crystallized from an ether acetone mixture The crystalline complex schmil / i at 1 31 to 132 C.

Example 18

Manufacture of the

Ba (SC N): - complex of 4.7.10.16.19.24.27-heptaoxa-1.13-diazabicyclo [8.8.1 Ijnonacosan

70 mg of the macroeconomic compound and 70 mg of solid Ba (SCN) .. ■ H ₂ O are refluxed in 20 ml of acetone for 5 minutes. The acetone is then removed in vacuo and the residue treated with 25 ml of chloroform. After filtration, the chloroform is evaporated and the residue is crystallized from a chloroform-benzene-ether mixture. A crystalline complex is obtained. Melting point over 260 C.

Example 19

Further complexes of 4.7.13.16.21.24-hexaoxa-1.10-diazabicyclo [8.8.8] hexacosane

The following complexes were prepared according to the procedure described in Example 14, or their formation was observed by spectroscopic methods:

TIBCOO complex

(Melting point 50 to 52 ° C) CafSCNJrComplex

(Melting point over 260 ^r C)

Zn (BF ₄ J ₅
Pb (SCN) ₂

Example 20

Complexes of

4.7,13.16.21-Pentaoxd 1.10-diazabicyclo- [8.8.5] tncosane

This compound prepared according to Example SB gives stable complexes with various metal salts. In particular, it easily forms complexes with transition metal salts. The complex ·: the following Salts were made by mixing metanol solutions of the salt and the complexing agent and crystallizing of the complex prepared, or their formation was observed by spectroscopic methods:

KSCN
Co (SCN);

BaCI:

Cu (BF ₄ ):

Example 21 Strongly Basic Solutions

: ii When solid potassium hydroxide is added to a solution of 4.7.1 3.16.2 U4-Hexaoxa 1.10diaza-bic \ clo [8.8,8] -hexacosane (produced according to Example 1B in anhydrous Tetrahydrofuran becomes very strong during the dissolution of the KOH in solvent

;. basic solution obtained with complex formation with the acyclic diamine.

The basicity mark can be changed by adding something Detecting fluorene: Intense red color, which is due to the Formation of the fluorine anion is due. occurs

in an instant. By treating this strongly basic solution with air, the fluorenone is obtained. When no acyclic amine is present. will that * \ nion not formed and the solution remains colorless. The same observations can be made

ii the. if KOH by another base like sodamide is replaced.

Example 22

Complexes of

4.7.1 3.18-Tetraoxa LiO-diazabicyclo- [5.5,8] eicosane

Complcxbildung with the abovementioned compound (prepared according to Example 10B) was determined by spectrometry (NMR) for the following salts:

Co (SCN);

Some of these complexes are unstable in water.

Strongly basic solutions were also obtained in the manner described in Example 21. Furthermore, was Here the formation of the fluorenyl anion is observed when fluorene is formed in a solution of the KOH Complex was given in anhydrous tetrahydrofuran.

Listed below are some representative compounds that make up complexes with the macrocyclic Compounds according to the invention were formed:

LiCI LiSCN NaCl KBr KSCN BaCI

Theatrical Version

KCI

KUr

NaCI Na 1 NaSCN CaBr,
CaCI.

SrBr.

TICI

AgNOi

Mg (OAc) ₂

230 217/2

50

continuation

K! Na-SO ₄ SrCI, KOII Na- (COOIj BaCI: KMnO ₄ RbCI BaBr, KBI !, NII ₁ SCN BaSO ₁ KSCN RbSCN CuCIj Kj (COO) ₃ CsSCN Nile, I.

LiSCN

THICOO

Zn (BF ₄ );

Th (SCN),

Cu (SCN).

TINO,

Claims (4)

Patent claims: 1. Macrocyclic compounds of the general formula I 5. Process for the preparation of compounds of the general form! I as in claim 1 are defined, characterized in that in a manner known per se a) a compound of the general formula '\ Λ
D. \ Λ N / 15th 20th in which each radical A represents a hydrocarbon radical, D in each pail represents an oxygen atom, sulfur atom, a group> N — R (where R is a hydrogen atom or a hydrocarbon radical) or a hydrocarbon radical, with at least two of the groups or atoms, for which D stands. Are oxygen, sulfur or> NR and m, π and ρ are integers from 0 to 5; N-oxides of compounds of the formula I ₁ which contain tertiary nitrogen; as well as ammonium salts of the compounds of the formula (I). 2. A compound according to claim 1 having the formula A ' \ Λ
D. Y \ Λ
D. A ' with a compound of the general formula V D is condensed, where in the formulas A, D, m, π and ρ are as defined in claim 1, A 'represents a group corresponding to the group A in which a CH2 group adjacent to the nitrogen atom has been replaced by a CO group and V represents halogen, mesyloxy or tosyloxy, and that the CO groups present in the compound thus obtained are reduced to CH2;
b) a compound of the general formula 45 D.
D. D.
D. 3. A compound according to claim 1 having the formula with a compound of the general formula 4. A compound according to claim 1 having the formula 60 65 V D is condensed, wherein in the formulas A, D, m, η and ρ are as defined in claim 1 and V c) a compound of the general formula D.
D. with a compound of the general formula A " The invention relates to new macroecyclic compounds Process for their preparation and use of the compounds as complexing agents, The new macrocyclic compounds according to Invention can be represented by the general formula (I)