CA1062255A

CA1062255A - Macrocyclic compounds and complexes thereof

Info

Publication number: CA1062255A
Application number: CA085,170A
Authority: CA
Inventors: Jean-Marie Lehn
Original assignee: Scherico Ltd
Current assignee: MSD International Holdings GmbH
Priority date: 1969-06-11
Filing date: 1970-06-10
Publication date: 1979-09-11
Also published as: DE2028556C2; DE2066192C1; FR2052947A1; KE2616A; CH550816A; DE2028556A1; CH544106A; FR2052947B1; SE383885B; HK31276A

Abstract

Abstract of Disclosure Described herein are novel macrocyclic compounds capable of complexing cations, and the complexes so obtained. The novel macrocyclic compounds are monocyclic or bicyclic compounds, and specified derivatives thereof, represented by the formula wherein each R1 is hydrogen, a hydrocarbon group or an alkoxycarbonyl group, or both R1 form together a grouping of the general formula (i.e. providing a third bridge between the two X-groupings in the molecule);
each A is a hydrocarbon group;
each X is nitrogen or phosphorus;
each D is oxygen, sulfur, ?N-R (R being hydrogen or a hydrocarbon group) or a hydrocarbon group, with the proviso that, at least two of the groups or atoms represented by D are selected from oxygen, sulfur and ?N-R, and that when each R1 is hydrogen, hydrocarbon or alkoxycarbonyl and X is nitrogen, then one of these two groups or atoms represented by D
is oxygen or sulfur and the other is oxygen or ?N-R; and m, n and p are integers from 0 to 5.
The preparation of the novel compounds by bridge form-ation between the X groups is described.
The compounds of the above formula are very strong complexing agents and are of value for use in much the same way and for the same purposes as chelating agents. The cation con-taining complexes of the compounds of this invention are equally useful in many fields such as, for example, as catalysts.

Description

10f~2Z55 This invention relates to novel macrocyclic compounds, to processes for their preparation, to complexes formed from the novel macrocyclic compounds and to processes for the preparation of such complexes.
The novel macrocyclic compounds of this invention may be illustrated by the general formula I

/ \ D- / L \ Al/ X (I~, wherein each Rl is hydrogen, a hydrocarbon group or an alkoxycarbonyl group, or both Rl form together a group-ing of the general formula II

A ~II).

(i.e. providing a third bridge between the two X-group-ings in the molecule);

. , , each A is a hydrocarbon group;
each X is nitrogen or phosphorus, each D is oxygen, sulfur, ~ N-R (R being hydrogen or a hydrocarbon group) or a hydrocarbon group, with the proviso that, at least ~ 06225S
two of the group~ or atoms represented by D are ~elected from oxygen, ~ulfur and > N-R, and that when each Rl is hydrogen, hydrocarbon or alkcxy-carbonyl and X i9 nitrogen, then one of these two groups or atoms represented by D is oxygen or 3ulfur and the other i~ oxygen or7 ~-R; and - m, n and p are integers from O to 5.
The invention includes N- and P-oxides of the compounds of formula I having a tertiary nitrogen or phosphorus atOm~
complexes formed from the compound~ of the general formula I
or from the N- and P-oxide~ thereof, and phosphonium and ammonium salts and acid addition salts of the compounds of the general formula I.
Thus included amongst the compounds of this invention .. are the phosphonium and/or ammonium salts of the nitrogen and/or phosphorus Qxides.
.^ In another aspect of the invention there is provided .~ a process for producing the macrocyclic compounds.
', , ~ .

~, pr 1~ ~ -- 2 ~

. . .
- :- ,.
.. - . , 1~;2255 The hydrocarbon groups represented by A and D
preferably have from 2 to 12 carbon atoms, Preferred are:
straight and branched chained alkylene and alkenylene groups having from 2 to 8 carbon atoms such as ethylene, propylene, butylene and hexylene and their unsaturated analogs; cycloalkylene and cycloalkenylene groups such a~ cyclopropylene, cyclobutylene, cyclohexylene an~
cycloheptylene and their unsaturated analogs, the corresponding cycloalkylene-di-alkyl groups such as cyclohexylene-dimethyl and aromatic groups such as phenylene and phenylene-di-alkyl, preferably phenylene-di-methyl. The groupings A which are adjacent to X
preferably have an aliphatic moiety attached to X.

~ ~ - 3 -10~2Z55 SK-cm The hydrocarbon groups represented by Rl preferably have from 1 to 12 carbon atoms. Preferred are straight and branched alkyl groups having from 1 to 8 carbon atoms and straight or branched alkenyl groups having from 2 to 8 carbon atoms. Other typical represent-atives are cycloalkyl, aralkyl and aryl groups. The preferred alkoxycarbonyl groups represented by Rl are those having up to ten carbon atoms.

The preferred compounds of this invention are those in which m, n and p are integers from O to 2 and in which both X are the same. Typical configurations are l~sted below:

. . : .: - - . . . . . .

SK-cm 106ZZ5~

1. ~A\ ,,A\ ~.A a) X-~

X~' ~0~ ~0~ ~X b) X=P
\A ~ `--A ~ --A /

2 .A ~ ~ A~ ~ ~A

X~ ~0 ~ ~ 0 ~ ~0~ ~X a) X=N
\A~ ~A~ \A ~ \A/ b) X=P

X~ ~S ~ \S~ ~X b) X=NP
A/ ~A ~ ~A/

4.A A` A
~A A ~A\ a) X-N

A~ ~A~ ~A

X~ ~S-~ ~S~ \~X b) X P
\A~ ~A~ --A/

6. A A A
/ ~O~ ~O ~ \ a) X--N :
/ A~ ~ A ~\ b) X=P
\A~ \A~ ~ A

. . , ~ , . .

-:10~i2ZSS SK-cm 7. A A A
~0~ ~ 0~ \ a) X=N ~, A -- A ~ A--~ X b) X=P
\A/`~A'' --A'~

8. R R
A ~ I A ' ¦ ~A a) X=N
//A ,,A\ ~A~ b) X=P

R
R
.

9. R R
A I A~ ¦ A a) X=N

X~' ~~ 0 ~ i o ~ ~X b) X=P
\`A ~ S~A~' ~ A /

10.A~ A` A
,/ `0~ `0~ \ a) X=N
X--Rl Rl--X
~A" ~A/ ~A/" b) X=P

'`~ o ~ ~' ''' \ a) X=N ~' 0 ~ ~ 0 ~ 0 ~ 1/ b) X=P

APRIL-2~i-1970 204X-FT - ,L
1062ZSS SK- cm 12. /A ` ~A ` A
X--Rl ~, S Rl~ a) X=N
A~ --A ' --A b) X=P

/~ ~ o ~ 0 ~A \ a) X=N
A ~ A-' b) X=P

A I A~ I A a) X=N
;~, S ~ ~ S ~ 1~ b) X=P

f 15. R R
A I ~ A~ ¦ A a) X_N
~ \A~ ~A/ b) X=P

16.A A A
/ ~ o ~ ~ O '' ~ a) X-N

\ A ~ ~ A ~ --A /

s: . -The typical representatives of the compounds of this invention may be illustrated by inserting various groups for A and Rl in the above formulae:
(i) C 2 CHR

(ii) 2 CHR-CH2- or -CHR-CH2-CH -(iii) A = ~ R

(iv) A = ~ R
_CH2 \ ~_ CH2_ (v) A = unsaturated analogs of the groupings (i) to (iv) (vi) A = ~ R

10(vii) A = ~ R -CH2 \--/ CH2 (viii) Rl = -CH3, -CH2 CH2R, -CH2 CH2R 3 and unsaturated analogs ~ R
( ix ) Rl~ CH2 ~
~-~ R
(x) Rl =

(xi) Rl = H
( xi i ) Rl = ~0 -C-OR
wherein R is as defined above.
The phosphonium and/or ammonium salts may be illustrated by the following general formulae: `

.. . .. . . . . . .
.. . ~
- ~

10~i2~55 Rl / ~D/~\Dk \ ~ R

\A~ \~;~/ J~ A/

B: ~ R- r R R .
A \\~LA~\(~/ \

\ A~ ~A

R R r R
Rl~ ~9/ \\~N3!~lA \\6~)I~A \ (~
R . X . _ _ X _R . (m+3)Z (~) \A~ \ A ;~ ~A /

... .

. - . :

lO~iZZSS

wherein A, D, R, Rl, X, m and p are as previously defined and Z is an inorganic or organic anion. It is obvious to one skilled in the art that several other configurations are possible.
The compounds of this invention may be prepared by using known chemical reactions. The principle of the processes is to introduce a further bridge into a starting compound having one or two bridges, whereby the desired mono or bicyclic compounds are obtained.
A suitable process for the preparation of the compounds of this invention is characterized in that a compound of the general formula III

~ ~ (III) is condensed with a compound of the general formula IV
~ 3P ~IV) whereby in the above formulae A, D, m and p are as pre~viously defined and either V is a good leaving group such as halogen, methane-sulphonate or p-toluenesulphonate and Y is selected from the groupings / \ / Rl R3 - -, , .
:: .
, - ,-:

X being nitrogen or phosphorus, Rl being as previously defined, R2 being an hydrogenolysable group and R3 being defined as Rl or as R2; or V is the grouping O and Y is the grouping Rl; that any -C-halogen H-N <
carbonyl group in a so-obtained compound is reduced to CH2; and that, if desired, a compound obtained by any of the previous steps is subjected to one or more of the following finishing steps:
a) hydrogenolysation of hydrogenolysable groups represented by R2 and/or R3;
b) transformation into a phosphonium and/or ammonium salt;
c) transformation into a nitrogen and/or phosphonium oxide.
The most preferred halogen atom in the above reaction is bromine and the preferred hydrogenolysable group~is the benzyl group. Other examples of hydrogenolysable groups are -C~2O~, -CH2-CH=CH2 and -CH2-CH2-CN.
Various embodiments of the above process may be illus-trated by the reaction schemes A to H below:

~062255 -- / D ~\ 3 ~ \
EI_N m N-- H +
\ A / ~ E--1--A/

~ A ,,~, [A }~ A \
\ D--E~ \ D~
> N ~ `D--E` \D1~A \
A~ ~~ ~A/

; ~
B ~ \D--~ \D¦ A--C~
H --N A~ `~A--~--A/ N--H + : .

Br \D~ \ D}~ ~Br ~ C A L~A\~A--C

> N ~D~ ~D}~

\` A~ --~A--~--A

/~ A E

\ A --{A--~ A -'/

.

10~;2255 C: A~ ¦_A } A

B /A ~D~LA~Dl~ A\Br _P

~A~ ~cA ~i~;A/ .2Br D: / D J- ~ D~ \
H +
\A/ ~LA./ ~A /

B / D ~ D ~p ~ C

C A . _A 1 C ~
~D~ \D~
A--D ~ ~A D~--A~ N

\ A D ~A~ ~ A /

CH2--A ~ D ~A ~ D~ A--CH2 ~ ~D~

\ A~ --~A~ ~\ A /

AE'~ L-27--1?70 106Z~:55 20llx- ~
SK-cm -- ~' \D ~ I \D~

Br/ D ~ ~ D~ `` Br ~, .

--D ~ ~ D¦~ \

A ~' `~ A ~ D~ A ~
.', '- , F: /A~ 1A~ ¦~A

~C ~ D ~_ ~ D ~ A C~O

' .
: A l-A ¦ A
==~ HN ~m NH
O~ ~A ~A-- C~

~---` HN NH

~ H2N~ \D ~ --D k~ \NH2 .

Br~ ~~ D ~fA \ 1~A \

/C--A \ ~ A ~A ~{) NH

R ~X ~ ~ X~R3 +
~ .

Br ~ ~ \Br ' ; ~ --E

A~ ~A~D~ / \ R3 .23r / ~ D ~ ~ Dk ~x

3 \ D ~ ~D~ /

., .
.
~ -- 15 --- -: .-, : ~

~062Z55 In order to prevent the formation of polymers, the condensation in the first step of the above described reactions is carried out using high dilution techniques.
Any inert solvent may be used, but benzene is preferred.
The acid formed during the reaction must be neutralized.
This may be accomplished by using two moles of the diamine to each mole of the halide, or by adding a further base, particularly a tertiary amine such as a trialkylamine or pyridine, preferably triethylamine.

.
The reduction of the carbonyl groups in the second step of the reactions B, D, F and G is preferably carried out by means of LiAlH4 or B2H6 in tetrahydro-` furane. Other possible reducing agents are mixed metal hydrides such as for example NaBH4, LiAlH3-OCH3, LiAlH4/AlC13 and NaBH4/BP3.

.. . .
~` For the preparation of cycric lactams according to the process indicated in reactions B and G preferably the disalt of the amide group, preferably the alkali metal, is used.

The transformation of a compound of formula I into a phosphonium and/or ammonium salt may be accomplished by using standard methods such as reaction with suitable quaternizing agents, for example alkyl-halides such as methyl iodid~.

' , ~ - 16 -.
-Similarly any hydrogenolysable groups may be removedby using standard techniques such as catalytical or electrolytical reduction. Examples of catalysts which may be used are platinum, palladium, rhodium, ruthenium and preferably, LiAlH4. Thus the immediate product of reaction scheme C (a phosphonium and/or ammonium salt) may, if desired, subsequently be transformed into the free macrocycle by reduction in presence of LiAlH4.

Also the transformation of a compound of formula I
into its phosphorus and~or nitrogen oxide may be accomplished by applying standard oxidation procedures such as treatment with excess dilute hydrogen peroxide :
in water or with perphthalic acid in ether.

Often the immediate product of the above reaction is not the free macrocyclic compound but rather a derivative thereof additionally containing part or all of the structural elements of other constituents of the reaction mixture, in such a case, the macrocyclic compound is subsequently liberated from such derivative, by standard procedures such as for example treatment with ,:
dilute acid whereby the acid addition salt of the macrocycle is formed, or with other hydrolyzing agents.
.: .

'.: , . :

Any such salt may be dissolved in water and treated with an anion exchange resin. The so-obtained aqueous solution of the free macrocycle may then be isolated by evaporation to dryness.

For the preparation of those compounds in which Rl is ` a hydrocarbon or alkoxycarbonyl group, it is also ;'r possible to use a starting compound of formula III
? in which Rl in the definition of Y is hydrogen, and to introduce the desired substituents at any stage of ; 10 the process. The introduction of these substituents may be accomplished by means of known methods.
; . .
Thus as an example the 4,13-dimethyl-1,7,10,16-tetraoxa-

4,13-diaza-cyclooctadecane may be obtained according to the following reaction schemes:

:, ., .
... .
f .

... .

..

.i .
,~ ~

' ,: - ' ' ' ~ . ~ . , : . . , .

o o - N-CH3 O O CH3-N + ~ O Cl H H

r~O~O~ ~0~0/~
> CH3N o N-CH3 __~ CH3-N N-CH3 o~ ~o' ~/~1 ~1 ' ' :V

r~
~ / O O KOR O O
-.` H-N N-H ~ K-N N-K
~0~0~ ~ ~
S04(CH3)2 3 ~ CH3 - r~r~
~ 3 N o o N-CH3 ~''' \1 ~
.

.

:
,- . ~ . , - .
. -- - - . . , SK- cm ~1062ZSS

, .
~ H-N ~ N-H S04 (CH3 ) 2 . . .

CH3-/~ 9 9~ CH3 : L ~~`0 0 ~
H-N~AA~N-H ClC02CH3 ",~ .

:~:1, CH3-C02-N/~9 N-C02-CH3 ~ , j1 ~ CH3~ o/ \N~C}~ ~

,~ . .

... . ..

., .~ .

j .

.', .~ .
. -- 20 --.
, , APRIL-28-lg70 SK-cm ~0~2~:SS

In the above reactions the reagents mentioned may be replaced by any other suitable reagents. If the methylation agents or reagents are replaced by other alkylating agents, compounds in which Rl represents higher hydrocarbon groups are obtained.

The compounds in which Rl represents alkenyl groups may be obtained following the same procedures.
::`
The starting compounds of the general formulae III
~ and IV may be obtained according to known methods.
- 10 Some of the most convenient methods are illustrated by ~xamples.

The compounds of this invention are readily soluble in -~ most common organic solvents and in water.

The novel macrocyclic compounds have an unusual ability to form stable complexes with compatlble cations. In the monocyclic compounds, i.e. those compounds of formula ~; , I in which Rl is hydrogen, alkyl, alkenyl or alkoxy-carbonyl~ the cation presumably is held in the centre of . the macrocycle. In the bicyclic compounds, i.e. those - 20 compounds of formula I wherein both Rl together form a third bridge between the two nitrogen atomsJ the bridges ~; between the two nitrogen atoms probably form a "cage"
~- in which the cation is situated~ The ability to form , , - 21 -., ~ . .. . :: .

APRIL-2~ 70 ~K-cm complexes and the stability Or the complexcs formed - seem to depend on the arrangement of the hetero atoms or groups surrounding the cation and on the relative diameters Or the ring(s) and the cation. Comple~es `; 5 of the monocyclic compounds are much less stable than the complexes formed from the same cation with bicyclic compounds, and macrocyclic compounds forming stable complexes with cations of a certain diameter are not able to rorm complexes with cations having much larger diameters.
.-j .
.,., ~
:
Each macrocyclic molecule is able to form a complex with one cation. The magnitude of the charge on the cation has no influence. The cations may be inorganic ; or organic.
i The complexes formed are generally readily soluble in water, CHC13, CH2C12, and in acetone or other polar solvents, whereas they are slightly soluble or essen-tially insoluble in non polar organic solvents. They ;' - dissociate at a more or less acid pH. Protonation of the free diamine hinders complex formation and leads to the dissociation of the complex by displacement of .~, the equilibrlum.
The same dissociation is accomplished by treatment with any acid including Lewis acids. Release of the cation may also be accomplished by treating the complex with a quaternizing agent.

- .. . ~ - . .
~, ~

SK/cm The complexes are normally formed by dissolving the macrocyclic compound and the cation yielding compound in a common solvent, such as for example acetone3 methanol or water. The mixture normally is heated approximately to the boiling point of the solvent.
If the complex formed is insoluble in the solvent usedJ
the complex will crystallize and may be separated by ~;~ filtration. If the complex formed is soluble in the solvent used, it may be isolated by evaporating the solution to dryness. The complexes may be purified ~ ~
by recrystallization.

Complexes may also be formed when the cation yielding , , . -compound (e.g. the salt) is insoluble in the solvent used. It is sufficient to bring a solution of the 15 macrocyclic compound together with the crystalline `` salt and agitate the mixture with or without heating.
r. ' I . , The formation of complexes is possible even if the cation yielding compound and the complex are insoluble ~, r'~ in the medium used. In this case the macrocycle and the cation yielding compound are mixed in the presence ~- -of a medium which is then agitated 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, as the addition of the cation causes changes in the spectral patterns o~ the macrocycle - in solution.

,., :. , : .

MAY-11-1'~70 204X-FTE- l~
ED-cm The novel complexes make it possible to use certain chemical reagents in solvents where they are normally insoluble. For example potassium fluoride is insoluble in chloroform, whereas a complex of the salt with 4~7,1~J 16J 21,24-Hexaoxa-l, 10--diaza-bicyclo[8,8,8]hex-acosane is readily soluble.
' The cation complexing properties of the macrocyclic compounds of this invention make them of value for use in much the same way and for the same purposes as chelating agents. Thus, the cation complexing prop-erties of the compounds render them of value in : -. .
processes directed to the desalination of brines or to the separation of metals, for example to the sep-aration of metals such as the transition metals and the actinides from low grade sources of these metals and to subsequently obtaining such metals in high purity form. In this connection, the compounds are considered to be particularly useful in the separation of high cost metals such as those of the platinium group. In the separation of uranium from crude ores, the uranium `1 may be complexed with the macrocycle compound and the ; resulting complex subsequently separated by water. The compounds of the invention may also advantageously be used for cation transport and for the preparation of ion selective membranes and electrodes.

- ~ - . . . -. .

MAY~ 70 204X-FI_-ED-cm 1~62ZSS
. .

The compounds are also of use in chemical syntheses9 e.g. in polypeptide and protein syntheses, wherein the compounds advantageously selectively protect one of the ammonium cation groups in the amino acid. Additionally9 the compounds may be used as a catalyst for ionic react-ions in a polar organic media wherein the macrocyclic compounds activate the reaction via an "agent-separated ion pair" mechanism.

. .

:........ : -: ,, :, . . . ~, . ,, : - . ` :

- ' ~ .

ED/cm ~062Z55 Stability constants of macrocycle complexes in aqueous _olution ` General We have determined by measuring the pH, in water, the equilibrium constants for reactions of the following type, the type being illustrated by bicyclic amine macrocycles:-; (1) A + M+ = AM+
:~ K = [AM ]
~;~ s [A~ ~M+~ ; -' where Ks = law of mass action constant;
'~i A = bicyclic amine un~er consideration;
.. ' AM+ = macrocycle complex;
M+ = cation;
[ ] = activity of the ionic species.

E~uilibria present :`
1 Complexation : (1) A + M ~_ AM (Ks) s = [AM+]
~Aj [M~]

.

., .

~. I ~ -. - - . . - -- --- ------- -- .
: . . .

MAY-8-1~70 E~ cm Protonation of the diamine (2) AH2 ~--?AH+ + H+ (Kl) (3) AH+~--~ A + H+ (K2) Kl = [AH+] [H+] K2 = [A] [H+]
[AH2 ] [AH+] ;

`~ 5 Protonation of the macrocycle complex :~
(4) AMH23+~_ AMH2++H (Kl ) ~ .
~; AMH2+ ~ ~ AM+ +H+ (K2~) .
~ Kl' = [AMH++] [H ] K ' tAM+] [H+]

:1 [ AMH2~ ] AMHt~ , We have verified that the last two equilibria of protonation of the macrocycle complex, remain compar-itively negligible and have established a formula r.
relating Ks to the pH and all constants of the mixture:

Ks = bCA-aC , b bCM-(bCA-aC) C

where: C = CH+[OH ] [H+]
a = 1 + [H+] + [H+]
K2 Kl K2 b = LH ] + 2 [H+]2 K2 Kl K2 .

ED~Jl CH ~ Corlcentration of added acid (moles/litre) CA = Concentration of the amine~ if no reaction took place (moles/litre) CM = Concentration o~ the metal, if no reaction took place (moles/litre~
- Ks is expressed i.n moles 1. litre Kl and K2 are preliminary determined by titrating the diamine with dilute . hydrochloric acid~ in the presence of a supporting electrolyte (reference salt) of known concentration (N Me4 Br for the small cages, Li Cl for the large cages).

After addition of a known quantity of the salt to a solution of the amine of known concentration, in the presence of a non-complexed referenoe salt of the same concentration used for the determination o~ Kl and K2, the solution is titrated with dilute HCl taking pH
measurements of the solutions. Each point of addltion 20 provides a value f Ks (by applying the preceding formula). Calculation should provide a value of Ks which is approximately constant throughout the titration.

' ~, .
., ~,~ , ... ... . .. . . . .
."', . .~ ', ~ ' ' ' ED/jl Results obtained (at 25.0~ + 0.2C) (A) Alkali Metals ':

. ~ ~ N Reference salt = NMe4 Br (lNo ) -- ----: Cation Ks -PKS Protonation of the amine ~ -8 Li+ 1.5x102 4.18 Kl= 3.0xlO; -pKl=7.52 NK+ 5.5xlO 2.74 K2=1.2xlO , -pK2=9.92 L ~ (pKs ) ~ O .10 , ,, ,. .
,- .
:;::
.~ 10 2)- r O~-~O ~
, N ~ 0 ~ N Reference salt = NMe4 Br(lN0) .:, ,.,. ....
. Cation Ks -PKS Protonation o~ the amlne Q
.-- Li+ 2.7x102 2.43 K1=3.2xlO; -pKl=7.50 . Na+ l.9x105 5.28 K2=3.0xlO ; -pK2=10.52 . K+ 8,2x103 ~.91 Rb+ 3.5x102 2.54 ~(PKS)~ 0.10 Cs+ ~lol~5 - cl.5 :~

-'"

~' ~ -29-' ~ -. - - ~ -:106Z~55 hD/jl ~ ~o~
3~. N ~ 0 ~ 0 ~ ~ Reference salt = NMe4Br (lNo ) --/
- -Cation Ks ~pK~Protonation of the amine _ -8 Li+ 1.5 C1-5 ~10 ¦Na 5.6x103 3.75 K2=2.5xlO ; -pK2-9-60 .~. 5 K 1.5xlO 5.17 ~pK nJ 0.10 Rb~ 1.6xlO 4.20 s Cs+ lol.5-- 1.5 ~ ~ 0 ~ N Referen~e salt = LiCl (10) :,`. ~ ( Cation ~ P s Protonation of the amine Kl=4.7xlO; pKl=7.33 Na+ clOl-5 ~1.5 _9 . K+ 2 K2=3.2x109 pK2=8.50 : Rb+ 4xlO 2.60 ~(PKS)~ 0.10 Cs+ 1.5xlo2 2 1o ;

Reference salt = LiC1 (lNo ) -pKl = 7-31 PK2 = 8.16 . . .
for Li, Na, K, Rb : Ks C101 5 . Cs+ : Ks~ 60 -pKs~ 1.7 (+ 0.5) ~:
: -30-JUNE-2~-1971 106225S ED/Jl ~ ~ r_~
6)- N~0~,0 ~ O~,N Re~erence salt = LiCl(lNo) _J~_ ~ -pKl = 6.96 -PK2 = 7 7 .~ For the alkali metals Ks C101 5 :~` 5(B) Alkaline ~ Earth Metals ~ N~O~N Re~erence salt = NMe4 Br(lN0) ;~ For all the alkaline earths K c 102 ., .~ s .: . , :.
2). r~ 0~ Re~erenoe'salt = NMe4 Br(10) :.- . _ .. __ l~(pKS) = + 0.10 :;, Cation Ks -pKs Mg++ ~ 102 < 2 Ca++5.0x106 6.70 Sr++1~2x107 7.7 . Ba++ . _ . . . .
......

N ~ ~ N Re~erence salt = NMe4 Br(10) ~, ~(pKs) = ~ 0.10 -.~ 15 Cation K2 -PKS
.. . . _ Mg+t < 1042 <
~ Ca 1.74xlO 4.24 .. Sr++ 1.02x108 8.01 ~;i Ba 3.0xlO9 9.48 ~:
.. .:j .
.. . . .

:.:
-31- : :
,-~ . .
-:

10~;2255 204X
ED/ j l ~r~rl 4). 1 0 0 0 ~
N'\,O~\,O~\,N Reference salt = LlCl (lNo ) Cati on s -PKs __ _ _ .

Cg+~ 1~lo2 ~c.'2

5 Sr++ 2xlO ~ ~ . 30 Ba+ 5. 6x105 5 . 75 5 ~ . r,~ 0~ Reference salt = LiCl (lNo ) /\
~(PKs ) = + 0.20 - ~ .
Cati on Ks -PKS
10 j~ ~

. ~

6). 1=
N~ J~ Reference salt = LiCl (lNo) 15 For Mg, Ca, Sr: -PKS 2 `.',!For Ba++ : Ks = 5 . lx104 .
~ -PKs = 4 71 + 0 20 .~

` .

.
: . ' 1062255 JUNE-2~-1971 ED/Jl (C) Other cations studied 1). rO/-~O~-\
N Reference salt = NMe4+Br (lNo) ~, ' Cu++ : KS~ 101 -PKs = 10 + 1 N~O~I.

' ~'' ' ' .`!, 5 Catt on K pKs ~pKs Reference Salt Ag 4.1xlO 9.61+ 0.20 Without re~erence salt ~' Tl+2.1x1066.32+ 0.20 Without reference salt Pb++ 12.05~ O lo NMe4Br ( *) :~t ~ N ~ O ~ ~ N Re~erence salt = LiCl(lo) .l + 4 -.
~,, 10 T1 : Ks = 3.10 ; -PKs = 4.48+0.10 ~l Pb++ : Ks = 1.3xlO ; -pKs= 8.11+0.10 '1 , ,, -., ~ ':
;~ --.. , ,~.~, .
':'," ~ :

,. :

; ~

.. ...

"
, ~,i. .. ~, .. ~, .. . . . . ..
' ' ' i~ ' ~ ! , . . , ~ , , '. '' ' ~ ~ , ' '. " ' ' ' ' ' . '., ' ' ' E~XAMPLE 1 Preparatîon of Triqlycolyl Chloride A. Preparation of Triqlycolic Acid 100 g. of nitric acid (density = 1.38) are heated to 45C. 20 g. of triethylene glycol are added in small : portions so as to keep the temperature at about 45C
to 50C. After this step the mixture is agitated for about 20 minutes at 45C and then for one hour at about 80C. The solution is evaporated under vacuum . lo at 70C for 2 to 3 hours. A viscous paste of a brownish colour is obtained. 100-120 ml of benzene are added and water is distilled off. Upon cooling, .
-:
the diacid crystallizes and is recrystallized from a mixture of acetone and benzene. The solid is dried 5 . ~ under a vacuum of 0.1 mm. Hg and the acid obtalned has '~ m.p. = 74C-75C.
~ r.
~;` PMR (in D2O): 3.80 ppm (singlet), 4.25 ppm (singlet) ~...

B. Preparation of Tri~lycolyl Chloride ' - 15 g. of the acid obtained above, 30 g. of oxalyl ~ 20 chloride, 100 ml. anhydrous benzene and three drops of ; pyridine are mixed and agitated for 24 hours. Petroleum ~ ` ether is added and the product is decanted. The mixture ..
; is flltered and the benzene and the excess of oxalyl , " chlorde is evaporated on a rotatory evaporator without ~ ;:
heating. The evaporation is repeated twice, each time with 100 ml. of benzene. The product obtained is a :
;~

, ,~: .

- 34 _ "
:
.: .

yellow oil. The oil is diluted with a mixture of ethyl ether and petroleum ether and after cooling to a temp-erature between room temperature and -70C, the product crystallizes out. The crystals are then washed with petroleum ether, care belng taken that the product does not come into contact with moisture in the air. After - recrystallizing twice and washing twice with ether, the product is dried under a vacuum of 0.1 mm. Hg. m.p. =
20C-30C (crude product).
PMR (CDC13): 3.85 ppm (singlet); 4.52 ppm (singlet).

. ~ ~

Preparation 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 ara slowly added to 100 g. of phosphorous . ~ , tribromide while agitating and cooling the mixture. ~
~, . " .
;-~ After stan~ing overnight at room temperature, the mixture `

; is poured on to icé and the organic phase is decanted, . ~ .
washed ~i'th water and dilute hydrochloric acid and dried over sodium sulphate~ After distillation under vacuum ~; (95C and 0.5 mm. Hg) the title compound is obtained. , Yield: 60-700~o ~ -PMR (CDC13): 3.4-4.0 ppm (multiplet), 3.70 ppm (singlet) ;^
, ..
.
. y . ~i . ...................................................................... .
:..
., ` i ~ - 35 -:~:
. ~ -B. Preparation of Triethylene Glycol_Diphtalimide 161 g. of phtalimide are mixed with 50 g. of potassium hydroxide in 500 ml. ethanol. The mixture is agitated for 24 hours and filtered and potassium phthalimide is obtained. 7.5 g. of the dibromide obtained in part A of this example is mixed with 30 ml. dimethylformamide and 9 g. of the potassium phthalimide obtained above, and the mixture is heated for one hour at 100C.
After cooling, 50 ml. water and 50 ml. chloroform are added. After decantation, the organic layer is washed with dilute potassium hydroxide, then with water and is dried over potassium sulphate and evaporated.-The title compound crystallizes out and is recrystallized from acetic acid. Yield 95%., m.p.: 175C.
PMR (CDC13): 3.5-3.85 ppm (multiplet); 3.60 ppm (singlet),

7.80 (multiplet).

C. Preparation of 1,8-Diamino-3,6-dioxaoctane 22.4 g. of the product obtained in step B are suspended - in 250 ml. ethanol and heated under reflux'. 19 ml. of ~2H4 and water (50/O) are added and the heating under reflux is c~ntinued for 2 hours. After this time, the reaction is practically finished. 25 ml. of lON hydro-chloric acid is added and the mixture is heated under reflux for an additional half hour. The majority of the alcohol is distilled off, and the residual solution is filtered and saturated with potassium hydroxide. The mixture is poured into a liquid-liquid extractor and extracted with benzene. The benzene solution is evaporated, and the diamine distilled under a vacuum of 0.5 mm. Hg at 88C. Yield = 70/O.
PMR (CDC13): CH2-N: 2.85 ppm (triplet); CH2-O:
3.50 ppm (triplet) and 3.60 ppm (singlet).

Pre~aration of 5,12--Dioxo-1,7,10,16-tet-raoxa-4,13-diaza-cyclooctadecane This reaction is carried out applying a high dilution technique. A solution of 14.8 g. of the diamine obtained in Example 2 (0.1 mole) in 500 ml. anhydrous benzene and a solution of 11.2 g. of the dichloride obtained in Example 1 in 500 ml. anhydrous benzene are added to 1,200 ml. anhydrous benzene over a period of 8 hours under vigorous agitation and under a nitrogen atmosphere.
: On termination, the benzene solution is filtered and - -evaporated to dryness. The crystalline residue is dissol-ved in anhydrous benzene and passed through a column of aluminium oxide., The polymers formed during the reaction are retained and a pure solution of the desired compound is obtained. After recrystallization from a mixture of benzene and heptane, the title product is produced. m.p. = 111C. Yield = 70/O.
PMR (CDC13): -CO-CH2-O: 4.00 ppm (singlet), -CH2-N and -CH2-O: 3.6 ppm (multiplet) ~ .

.

Preparation of l~7~lo~l6-Tetraoxa-4ll3-diaza octadecane .
A solution of 18.5 g. of the diamide obtained in Example 3 in 450 ml. anhydrous tetrahydrofurane is slowly added to a mixture of 150 ml. anhydrous tetrahydrofurane and 12 g.
LiAlH4 while stirring and heating at the reflux temp-erature. After theaddition is completed, the mixture is ~tirred under reflux and under a nitrogen atmosphere for 24 hours. 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 residue is dissolved in benzene and the solution is passed through a column of A1203 with benzene as eluant.
The solution is evaporated to dryness and after recrystallization from benzene/petrol ether 13.5 g. of the desired product is obtained. m.p. = 115C-116C.
Yield: 80%.
PMR (CDC13): -CH2-0: 3.58 ppm (singlet + triplet), -CH2-N: 2.78 ppm (triplet) Preparation of 2,9-Dioxo-4,7,13,16,21,24-hexaoxa-1,10--~ diazabicyclo[8,8,8~hexacosane The reaction is carried out applying the high dilution technique.

A solution of 5.24 g. of the cyclic diamine obtained in Example 4 and 4.4 g. of triethylamine in 500 ml.
anhydrous benzene and a solution of the dichloride (4.4 g. in 500 ml. anhydrous benzene) obtained in Example lB is added to 1000 ml. anhydrous benzene during 10 hours under nitrogen atmosphere and under agitation. The salt of triethylaminé and the hydrochloric acid precipitates and is filtered off. The filtrate is evaporated to dryness. The residue is dissolved in benzene and passed through a column of A1203 using ` benzene as an eluant. The product is crystallized from a hexane-benzene mixture. m.p. = 114nC. Yield 50/0.
PMR (CDC13): several peaks between 3.3 and 4.6 ppm Preparation of 4,7,13,16,21,24-hexaoxa-1,10-diaza-bicyclo[8,8,8]hexacosane ;, B2H6 iS prepared according to the process described in "Org. Reactions" 13, 31-32 (1963).

' , ,, :, .
;, - . - ' ' ' ' -: - .. - - ~

A solution of 1 g. of the bicyclic diamide obtained in Example 5 in 20 ml. tetrahydrofurane is slowly added to 15 ml. of the fre~h prepared B2H6 solution under nitrogen atmosphere and at a temperature of 0C. The mixture is agitated at this temperature for 30 minutes and thereafter 1 hour at reflux temperature. The excess reagent is destroyed by adding 5 ml. of water and the solution is evaporated on a rotatory evaporator under vacuum. 1 g. of the diborane of the title compound is obtained:

- 4~b/~ ~o/~d- -BH3-N o ~-BH3 \ A~ /, This compound is hydrolysed by adding 20 ml. 6~ hydro-chloric acid under heating and a solution is obtained. -The mixture is evaporated to dryness under vacuum on a rotatory evaporator. The residue is dissolved in 10 ml.
water and the solution is passed through a column of an anion exchange resin (Dowex 1). The column is washed with water until there is no basic reaction. The water is evaporated. The residue is recrystallized from hexane and dried in vacuum (0.1 mm. Hg). 890 mg. of the desired product is obtained. m.p.= 68C-69C. Yield 95%.
PMR (CDC13): -CH2-~: 2.6S ppm (triplet); -CH2-0:
3.65 ppm (singlet + triplet) , -Preparation of 4,13-DimethoxYcarbonyl-1,7,10,16-tetra-oxa-4,13-diazacyclooctadecane 3.6 g. of the diamine obtained in Example 4 are dissolved in 30 ml. methanol and 3 ml. water. A solution of 3.6 g.
ClCO2CH3 in 15 ml. methanol is added while cooling and agitating. The agitation is maintained for 24 hours.
The mixture is filtered and the filtrate evaporated to dryness. The residue is recrystallized from CHC13/
petroleum ether. m.p. = 104C. Yield ~0O/
PMR (CDC13): Signals at about 3.65 ppm.

EXAMPLE 8 ~ -Preparation of 4,13-DimethYl-1,7,10,16-tetraoxa-4,13-diazacyclooctadecane A: 3 g. of the compound of Example 7 dissolved in 20 ml.
- dry ether are slowly added to 3 g. LiAlH4 in 5 ml. dry ether. The mixture is agitated for 24 hours. Then 3 g. KOH in 6 ml. H2O is added followed by 10 ml. H2O.
The mixture is filtered and evaporated to dryness.
The residue is extracted with ether and benzene. The solution is evaporated to dryness and an oil which boils at 97C by a pressure of 0.05 mm. Hg is obtained.
PMR (CDC13): -CH2-N: 2.70 ppm (triplet); ~-CH3: 2.32 ppm (singlet), -CH2-O: 3.65 ppm (singlet + triplet) B: Alternatively this compound may be obtained by reacting N,N'-dimethyl-1,8-diamino-3,6-dioxaoctane with triglycolyl chloride following the procedure of Examples 3 and 4.

Preparation of the KSCN-Complex of 1,7,10,16-Tetraoxa-4,13-diaza-cyclooctadecane 524 mg. of the macrocyclic compound and 194 mg. of KSCN
are refluxed in 20 ml. of acetone for 5 minutes. The acetone is then removed under vacuum, and the residue is recrystallized from CHC13/Pétroleum ether. The crystalline complex melts at 167C-168C.

-` Preparation of the CuC12-Complex of 1_,7,10,16-Tetra-~ oxa-4,13-diaza-cyclooctadecane . .
A solution of 2.62 g. of the macrocyclic compound in 10 ml. CH30H is mixed with a solution of 1.70 g. of CuC12.2H20 in 10 ml. CH30H. The blue complex is immediately formed and precipitates. After filtration and recrystallization from CHC13~CH30H the pure complex is ootained.

~' Preparation of the RbSCN-Complex of 4,7,13,16,21,24-hexaoxa-l,10-diazabicYclo[8,8,8]hexacosane 130 mg. amine and 35 mg. RbSCN are mixed in a flask.
20 ml. acetone are added. The mixture is heated to the boiling point until all solid material has dissolved.
After evaporation to dryness the residue is extracted with chloroform, which dissolves the complex. The chloroform solution is also evaporated to dryness, yield-ing the crystalline complex. The complex may be recrystallized from acetone-heptane. It melts at 163C-164C.
PMR (CDC13): -CH2-N: 2.56 ppm (triplet) Preparation of the BaC12-Complex of 4,7,13,16,21,24-hexaoxa-l,10-diazabicyclo[8,8,8]hexacosane 37.6 mg. amine and 21 mg. BaC12,2H20 are dissolved in 10 ml. water. The solution is then evaporated to dryness.
The solid residue is extracted with methylene chloride.
After filtration-of the solution, ether is added until crystallization sets in. The crystalline complex does not melt but darkens at about 200~C.
PMR (CDC13): -CH2-N: 2.80 ppm (triplet) . .

Preparation of Tetraalvcolyl Chloride A: Preparation of Tetraqlycolic Acid 100 g. of nitric acid (density = 1.38) are heated to 45C 20 g. of tetraethylene glycol are added in small portions so as to keep the temperature at about 45C-50C. After this step the mixture is agitated for about 20 minutes at 45C and then for one hour about 80C. The solution is evaporated under vacuum at 70C
for 2 to 3 hours. A viscous paste of a brownish colour is obtained. 100 to 120 ml. of benzene are added and water is distilled off. The diacid is a viscous oil which does not crystallize.
PMR (D2O): 3.75 ppm (singlet), 4.22 ppm (singlet) B: Preparation of Tetra~lycolyl Chloride 28 g. of the acid obtained above, 50 g of oxalyl chloride, 200 ml. anhydrous benzene and six drops of pyridine are mixed and agitated for 6 hours. The mixture is filtered and the benæene and the excess of 20 oxalyl chloride is evaporated on a rotatory evaporator without heating. The evaporation is repeated twice, each time with 100 ml. of benzene. The product obtained is a yellow oil, which does not crystallize.
PMR (CDC13): 3.75 ppm (multiplet)j 4.52 ppm (~inglet) '`' , .

,, .

~062ZSS

Preparation of 1,11-Diamino-3,6,9-trioxundecane A: Pre~aration of Tetraethylene Glycol Dibromide 300 g. of tetraethylene glycol and 100 g. of anhydrous pyridine are slowly added to 727 g. of phosphorus tri-bromide, while agitating and cooling the mixture. After cooling to room temperature, the mixture is poured on to ice and the organic phase is decanted, washed with water and dilute hydrochloric acid and dried over sodium sulphate, After distilIation under vacuum (123C-125C and 0.4 mm. Hg) the title compound is obtained.
Yield: 60%~
PMR (ODC13): 3.70 ppm (multiplet) B: Preparation of Tetraethylene Glycol Diphthalimide 161 g. of diphtalimide are mixed with 50 g. of potassium hydrcxide in 500 ml. ethanol. The mixture is agitated for 24 hours and filtered and potassium phtalimi~le is obtained. 217 g. of the dibromide obtained in part A
of this example is mixed with 1000 ml. dimethylformamide and 260 g. of the potassium phtalimide obtained above, and the mixture is heated for eight hours at 100C.
After cooling, the mixture is poured into 3 liter cold water. The precipitate is filtered, washed with water and acetone and dried under vacuum. The title compound is recrystallized from ethanol. Yield 85%, m.p. 108C-PMR (CDC13): 3.60 ppm (singlet); 3.80 ppm (multiplet);
7.80 (multiplet) : . . . ;: : :- ~ . -.

C: Pre~aration of 1,11-Diamino-3,6,9-trioxaundecane 254 g. of the product obtained in step B are suspended in 1000 ml ethanol and heated under reflux. 90 g. of N2H4 in 90 g. water is added and the heating under reflux is continued for 3 hours. After this time, the reaction is practically finished. lON hydrochloric acid is added until pH 1 is obtained and the mixture is heated under reflux for an additional half hour.
The residual mixture is filtered, the solution is evaporated to dryness. 250 ml. water are added and the solution is saturated with potassium hydroxide.
The mixture is again filtered to remove precipitated KC1 and is poured into a liquid-liquid extractor and extracted with benzene. The benzene solution is evap~
orated, and the diamine distilled under a vacuum of 0.2 mm Hg at 114C-116C. Yield - 72%.
PM~ (CDC13), -~H2: 1.30 ppm (singlet), CH2-N: 2.85 ppm (triplet), -CH2-0: 3.48 ppm (triplet) and 3.60 ppm (singlet).
~AMPLE 15 Preparation of 5,15-Dioxo-1,7,10,13,19,22-hexaoxa-4,16=
diaza-cYclotetracosane This reaction is carried out applying a high dilution technique. A solution of 15.4 g. of the diamine obtained in Example 14 in 500 ml. anhydrous benzene and a solution of 10.4 g. of the dichloride obtained in Example 13 in 500 ml. anhydrous benzene are added to 1,200 ml. anhydrous benzene over a period of 10 hours under vigorous agitation and under a nitrogen atmosphere.
; On termination, the benzene solution is filtered and evaporated to dryness. The oily residue is dissolved in anhydrous benzene and passed through a column of aluminium oxide. The polymers formed during the reaction are retained and a pure solution of the desired compound is obtained. After evaporation of the benzene, the title product is produced as a viscous oil.
Yield - 68% .
PMR (CD~13): -CH2-O and -CH2-~: 3.60 ppm (three peaks) -CO-CH2-O: 3 . 8 5 ppm (singlet) .

Preparation of 1,7,10,13,19,22 He~aoxa-4,16-diazacYclo-tetracosane -A solution of 30 g. of the diamide obtained in Example 15 in 200 ml. anhydrous tetrahydrofurane is slowly added to a mixture of 50 ml. anhydrous tetrahydrofurane and 18 g. LiAlH4 while stirring and heating at the reflux temperature. After the addition is completed, the mixture is stirred under reflux and under a nitrogen atmosphere for 24 hours. After cooling to room temperature the reducing agent is destroyed by adding a mixture of - water and THF (1:2). The mixture is filtered and the filtrate is evaporated to dryness. The residue is ., '....................................................................... : ' .~;

. . .

1 ~ ~ APRIL-30-1970 ~62255 204X-FTE
SK-cm dissolved in benzene and the solution is passed through a column of A1203 with benzene as eluant. The solution is evaporated to dryness and the desired product is obtained as a colourless oil which crystallizes at low temperatures. mOp. = 15C Yield 95%.
PMR (CDC13). NH. 2.10 ppm (singlet); CH2-N 2.80 ppm (triplet); CH2-0- 3.60 ppm (singlet and triplet).

Preparation Or 291?-dioxo-4~7,10,16,19,22,?7?~0,~3-nonaoxa-1,13-diazabicyclo[ll?ll,ll~pentatriacontane The reaction is carried out applying the high dilution technique. A solution of 7.0 g~ of the cyclic diamine obtained in Example 16 and 4.4 g. of triethylamine in 500 ml. anhydrous benzene and a solution of the dichloride ;~
(5.2 g. in 500 ml. anhydrous benzene) obtained in Example 13B is added to 1200 ml anhydrous benzene during ten hours under nitrogen atmosphere and under agitation. The salt of triethylamine and the hydro~
chloric acid precipitates and is filtered off. The filtrate is evaporated to dryness. The residue is dissolved in benzene and passed through a column of A1203 using benzene as an eluant. The product is a colourless oil which crystallizes on standing. m.p. 72 - 74C
Yield _ 65~
PMR (CDC13): 3.4-3.8 ppm (broad peaks); -C0-CH2-N
4.33 ppm (broad peak).

_ 48 -` - \

lO~ZZSS

Preparation of 4,7,10,16,19,22,27,30,33-nonaoxa-1,13-diaza-bicyclo~ll,ll,ll]pentatriacontane B2H6 is prepared according to the process described in 'Org. Reactions' 13, 31-32 (1963).

A solution of 1.3 g. of the bicyclic diamide obtained in Example 17 in 20 ml. tetrahydrofurane is slowly added to 15 ml. of the fresh prepared B2H6 solution (1.6 mole) under nitrogen atmosphere and at a temperature of 0C.
The mixture is agitated at this temperature for 30 minutes and thereafter 2 hours at 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 rotatory evaporator under vacuum. The bis-amine-- borane of the title compound is obtained by extraction of the residue with chloroform.

,, This compound is hydrolysed by adding 25 ml. 6~ hydro-chloric acid under heating to reflux for 3 hours and a solution is obtained. The mixture is evaporated under vacuum on a rotatory evaporator. The residue is dissolved in 10 ml. water and the solution is passed : ~ .
through a column of an anion exchange resin (Dowex 1).
The column is washed with water until there is no basic reac-ion. The water is evaporated. The residue lS
' .

., ,', , ,~

,~

~ ~ . - .' --` .J UN~ G~
2~4~~TE-,l SK-cm the desired product, obtained as a colourless oil.
Yleld 95~;.
PMR (ODCl3) -CH2-N: 2.85 ppm (triplet); -CH2-0:
3.65 ppm (singlet and triplet) Preparation of 5,12-Dioxo-1,7,10,16,19-pentaoxa-~
.
diaza-cvcloeneicosane : . . . v This reaction is carried out applying a high dilution technique. A solution of ~1.8 g. of ~the diamine obtained in Example 14 in 1000 ml. anhydrous benzene and a ` solution of 17.8 g. of the dichloride obtained in Example - l in 1000 ml. anhydrous benzene are added to 1,200 ml.
anhydrous benzene over a period of 14 hours unde~
- vigorous agitation and under a nitrogen atmosphere.
On termination, the benzene solution is filtered and . .
evaporated to dryness. The crystalline residue (25 g,3 is dissolved in anhydrous benzene and passed through a , - column of aluminium oxide. The polymers formed during `~ the reaction are retained and a pure solution of the desired compound is obtained. After recrystallization ! from a mixture of benzene and heptane, the title ~, product is produced. m.p. = 90C-9l C. Yield 75~.

PMR (CDC13): -CH2-0- and -CH2-N~ ~.5 to ~.9 ppm ~complex multiplet); -CO-CTI2-Oo 4.05 ppm (singlet).

~- .

~ - , , . ~

Preparation of 1,7,10,16,19-Pentaoxa-4,13-diazacyclo-eneicosane A solution of 6.7 g. of the diamide obtained in Example 19 in 100 ml. anhydrous tetrahydrofurane is slowly added to a mixture of 50 ml. anhydrous tetrahydrofurane and 3.8 g. LiAlH4 while stirring. After the addition is complete, the mixture is stirred under reflux and under a nitrogen atmosphere for 11 hours. After cooling to room temperature, the reagent is destroyed by adding 10 ml. water in 25 ml. THF, followed by 10 ml.
NaOH (15% in water) and then 30 ml. water. 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 A12O3 with benzene as eluant. The solution is evaporated to dryness and the desired product is obtained as a colourless oil which crystallizes at low temperature. m.p. about 0C
Yield 70/O, PMR (CDC13): ~H: 2.50 ppm (singlet); -CH2-N: 2.80 ppm (triplet) -CH2-O: 3.5-3.7 ppm (two singlets + triplet). ;

- 51 , 10~;2Z55 Preparation of 14,21,Dioxo-4,7,10,16/19,24 ~7-heptaoxa-1,13-diazabicyclor8,8,11~nonacosane The reaction i9 carried out applying the high dilution technique. A solution of 2.45 g. of the cyclic -~ diamine obtained in Example 20 and 2 g. of triethyl-amine in 200 ml. anhydrous benzene and a solution of the dichloride (1.8 g. in 200 ml. anhydrous benzene) obtained in Example lB is added to 1200 ml. benzene during 5 hours under nitrogen atmosphere and under agitation.
The salt of triethylamine and hydrochloric acid precipitates and is filtered off. The filtrate is evaporated to dryness. The residue is dissolved in benzene and passed through a column of A1203 using benzene as an eluant. After evaporation of the solvent, the residue crystallizes on standing. The product obtained is the desired compound. m.p. 97C-98C. Yield 65%.
PMR (CDC13): CH2-N and CH2-0: 3.5-3.9 ppm (broad peaks);
` C0-CH2-0: 4.0-4.3 ppm (very broad peaks).
~ 20 EKAMPLE 22 ; PreParation of 4,7,10,16,19,24,27-heptaoxa-1,13-diaza-:.
bicvclor8,8,11lnonacosane - B2H6 is prepared according to the process descri~ed in "O~g. Re~tions", 13, 3l-32 (I963).

'--_ 52 -. .
. - . ~. .: .: - .
.

-lO~Z255 A solution of 1.5 g. of the bicyclic diamide obtained in Example 21 in 15 ml. anhydrous tetrahydrofurane is slowly added to 15 ml. of the fresh prepared B2H6 solution (1.2 M) under nitrogen atmosphere and at a temperature of 0C. The mixture is agitated at this temperature for 30 minutes and thereafter 2 hours at reflux temperature. The excess reagent is destroyed by adding 5 ml. of water and the solution is evaporated on a rotatory evaporator under vacuum. The bis-amine-borane of the title compound is obtained.
This compound is hydrolysed by adding 30 ml. 6N hydro-chloric acid under heating at reflux for 2 hours and a solution is obtained. The mixture is evaporated under vacuum on a rotatory evaporator. The residue is dissolved in 10 ml. water and the solution is passed through a column of an anion exchange resin (Dowex 1). -The column is washed with water until there is no basic reaction. The water is evaporated. The residue is `
dried in vacuum (0.1 mm. Hg). 1 g. of the desired product is obtained as a colourless liquid. Yield 75%. -PMR (CDC13): -CH2N: 2.75 ppm (triplet), -CH2-0:
3.70 ppm (singlet); 3.65 ppm (triplet).

... ..
. -:, - : ,: .

E~CAMPLE 23 Preparation of_2,12-Dioxo-4,7,10,16119,22,27,30-octaoxa-1,13-diazabicyclor8,11,111dotr acontane The reaction is carried out applying the high dilution technique.
A solution of 1.67 g. of the cyclic diamine obtained in Example 20 and 1.2 g. of the triethylamine in 100 ml.
anhydrous benzene and a solution of the dichloride (1.30 g. in 100 ml. anhydrous benzene) obtained in Example 13B is added to 1000 ml. benzene during 2 hours under nitrogen atmosphere and under agitation. The salt of triethylamine and the hydrochloric acid precipitates and is filtered off. The filtrate is evaporated to dryness. The residue is dissolved in benzene and passed through a column of A1203 using benzene as an eluant.
^ The desired product is obtained as a colourless viscous oil. Yield 50/0.
PMR (CDC13): 3.4-3.8 ppm (Broad peaks); -C0-CH2-0, 4.35 ppm (broad peak) Pre~aration of_4,7,10,16,19~2,27l 30-octaoxa-1,13-diaza-bicyclor8,11,11 ldotriacontane B2H6 is prepared according to the process described in "Org. Reactions" 13, 31-32 (1963).

:' . :-10~2Z55 A solution of 1.2 g of the bicyclic diamide obtained in Example 23 in 20 ml. tetrahydrofurane is slowly added to 10 ml. of the fresh prepared B2H6 solution (1.6 M) under nitrogen atmosphere and at a temperature of 0C. The mixture is agitated at this temperature for 30 minutes and thereafter 2 hours at reflux temperature. The excess reagent is destroyed by adding 3 ml. of water and the solution is evaporated on a rotatory evaporator under vacuum. 1.13 g. of the bis-amide-borane of the title compound i5 obtained by extractingthe residue with chloroform.
This compound is hydrolysed by adding 40 ml. 6N hydro- - -chloric acid under heating for 2 hours and a solution is obtained. The mixture is evaporated under vacuum ^ on a rotatory evaporator. The residue is dissolved in - 10 ml~ water and the solution is passed through a column of an anion exchange resin (Dowex 1). The column is washed with water until there is no basic reaction. The water is evaporated. The residue is the desired product, obtained as a colourless liquid.
Yield 95%.
PMR (CDC13): -CH2-N: 2.80 ppm (triplet), -CH2-0-:
3.4-3.8 ppm (singlet and triplet~

,;

Preparation of the CsSCN complex of 4,7,10,16,19,22,27,-30,33-nonaoxa-1,13-diazabicyclo[ll,ll,lllpentatriac ntana 100 mg. of the macrocyclic compound obtained in Example 18 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 evaporated to dryness.
The complex is crystallized f~om acetone/ethyl acetate.
m.p. = 155C - 156C.
PMR (CDC13): -CH2-N: 2.60 ppm (triplet); -CH2-0:
3.55 ppm (triplet) and 3.62 ppm (singlet) Preparation of Ethylene-bisthioqlycolic acid dichloride A. Preparation of EthyIene-bisthioqlycolic acid Thioglycolic acid (20 g.), water (20 ml.), ethanol (20 ml.), and a solution of sodium hydroxide (17.6 g.) in water (30 ml.) are mixed in a flask and heated at reflux temperature. 1,2-Dibromoethane (18.5 g.) is added with strong agitation over a period of three hours. The mixture is refluxed for another two hours.-After filtration, the filtrate is evaporated to dryness and taken up in a mixture of water (100 ml.) and 12 ~

1062~SS

hydrochloric acid (60 ml.). The mixture is extracted with ether (50 ml. three times). The organic layer is separated, dried over sodium sulfate and evaporated to dryness to give the crystalline title compound which is then recrystallized from toluene.
m.p. = 107C (Yield 80%) PMR (D2O): S-CH2-CH2-S. 3.0 ppm (singlet; 4H) S-CH2-CO: 3.55 ppm (singlet 4H).

B. Prep_ration_of the dichloride of the precedinq acid 15 g. of the above diacid are added to a mixture of 100 ml. anhydrous benzene and 100 ml. anhydrous ether.
Then 30 g. oxalyl chloride are added the flask being ~' protected by a calcium chloride tube. The mixture is 1~ stirred for 36 hours and the diacid progressively - ~
; dissolves as Lt is being transformed into the corres-ponding dichloride. The solution is then evaporated to dryness (without heating) leaving a brownish solid residue which is recrystallized from a mixture of anhyd-rous ether and petroleum ether by cooling at -70C in a dry ice-acetone mixture.
The solid yellowish dichloride is obtained in a nearly quantitative yield. m.p. = approx. 300e (crude product) PMR (CDC13): S-CH2-CH2-S: 2.92 ppm (singlet; 4H):
S-CH2-CO: 3.55 ppm (singlet: 4H) ~ - :
; ~ `. . . - ' -.
Preparation of 3,6-dithia-1,8-diamino-octane

8.5 g. potassium metal are dissolved in 100 ml. anhydrous tertio-butanol (heating at ~0C accelerates the process).
When the metal is entirely dissolved 15.4 g. cysteamine are added at once. The mixture is stirred for one hour until all the solid has dissolved. 18.8 g.
1,2-dibromoethane are then added slowly (over approx.
thirty minutes), the reaction is exothermic. The mixture is stirred overnight at room temperature, then filtered through a sintered glass funnel, the solid residue is washed with benzene. The combined organic layers are evaporated to dryness. A viscous brownish oil is obtained. This oil is taken up into benzene (100 ml.) and filtered through a short column of alumina (approx. 20 g.) The column is washed with an addit-ional 250 ml. of benzene. The benzene solutions are evaporated to dryness. The yellowish residue crystal-lizes.
m.p. = approx. 35C - 40C ~Yield: 8S%) PMR (CDC13): -NH2: 1.32 ppm (singlet: 4H):
S-CH2-CH2-S: 2.72 ppm (singlet: 4H): N-CH2-CH2-S:
2.75 ppm (multiplet: 8H) Preparation of 3,14-Dioxo-1,16-dioxa-7,10-dithia-4,13-diaza-cy~looctadecane This reaction is carried out applying a high dilution technique. A solution of 10.2 g. of the diamine obtained in Example 27 in 500 ml, anhydrous benzene and a solution of 6.1 g. of the dichloride obtained in Example lB in 500 ml. anhydrous benzene are added to 1,200 ml. anhydrous benzene over a period of ten hours under vigorous agitation and under a nitrogen atmos-phere. On termination, the benzene solution is fil-tered, the residue is washed with benzene and the combined benzene solutions are evaporated to dryness.
The residue is dissolved in anhydrous benzene and passed through a short column of alumina (30 g.) The polymers formed during the reaction are retained and a pure solution of the desired compound is obtained.
After recrystallization from a mixture of benzene and heptane, the title product is produced.
m.p. = 145C Yield = 60%
PMR (CDC13): S-CH2-CH2-S: 2.80 ppm (singlet: 4H):
S-CH2-: 2.80 ppm (multiplet: 4H); ~-CH2: 3.45 ppm (multiplet: 4H), -O-CH2-CH2-0: 3.72 ppm (singlet: 4H), O-CH2-CO: 4.0 ppm (singlet: 4H) .

1~62255 Preparation of 1,16-dioxa-7,10-dithia-4,13-diaza cyclooctadecane A solution of 7 g. of the cyclic diamide obtained in Example 28 in 100 ml. anhydrous tetrahydrofurane is added slowly to S0 ml. of a freshly prepared solution (1.5 M) of diborane in anhydrous tetrahydrofuran under nitrogen atmosphere and at a temperature of 0C.
The mixture is then heated to reflux for two hours.
The excess reagent is destroyed by adding 10 ml. of water and the solution is evaporated to dryness on a ~; rotatory evaporator under vacuum. 100 ml. 6N hydro-chloric acid are added to the residue and the mixture is refluxed for two hours; a clear solution is obtained.
~his solution is then evaporated to dryness under vacuum. The residue is dissolved in 30 ml. water and the solution is pressed through a column of an anion exchange resin (Dowex 1, Trade Mark). The column is washed with water until there is no basic reaction. The combined water solutions obtained are evaported to dryness under vacuum on a water bath (80C - 100C). The residue is recrystallized.
Yield = 70~O m.p. = 45C -PMR (CDC13): CH2-N+CH2-S: 2.77 ppm (complex band:
16H): CH2-O: 3.59 ppm (singlet: 4H; triplet: 4H) ~0622S5 Preparation of 2,9-Dioxo-4,7,13,16-tetraoxa-21,24-dithia-l,10-diazabicYclo[8,8,8~]hexacosane The reaction is carried out applying the high dilution technique. A solution of 3.5 g. of the cyclic diamine obtained in Example 29 and 1.3 g. of triethylamine in 400 ml. anhydrous benzene and a solution of the dichloride (2.7 g. in 400 ml. anhydrous benzene) obtained in Example lB are added to 1000 ml. benzene ~ -during eight hours under nitrogen atmosphere and under agitation. The triethylamine hydrochloride precipitates and is filtered off. The filtrate is evaporated to dryness. The residue is dissolved in benzene and passed through a column of A12O3 (20 g.) using benzene as an eluant. The solutions are evaporated to dryness. The product is a viscous oil.
Yield 50O/o -PMR -cH2_s_cH2_cH2_s_cH2 2-8 ppm (complex broad band: 8H~ CH2-O+C0-N-CH2: 3.6 ppm (broad signals --20H) CO-CH2-O-: 4.0 ppm (broad signals: 4H).

-106Z~S

Preparation of 4,7,13-16-tetraoxa-21,24-dithia-1,10-diazabicYclo[8,8,8]hexacosane A solution of 1.6 g. of the bicyclic diamide obtained in Example 30 in 30 ml. anhydrous tetrahydrofuran is slowly added to 20 ml. of the fresh prepared diborane solution (1.5 N) under nitrogen atmosphere and a temperature of 0C. The mixture is stirred two hours at reflux temperature. The excess reagent is destroyed by adding 5 ml. of water and the solution is evaporated on a rotatory evaporator under vacuum.
This residue is treated with 50 ml. 6 N hydrochloric acid under heating at reflux for two hours and a solution is obtained. The mixture is evaporated under vacuum on a rotatory evaporator (water bath 80 - 100C).
The residue is dissolved in 50 ml. water and the solution is passed-through a column of an anion exchange resin (Dowex 1, Trade Mark). The column is washed with water until there is no basic reaction.
- 20 The water is evaporated. The residue is dried in vacuum (0.1 mm. Hg) and recrystallized from a benzene and heptane mixture, yielding the desired compound.
m.p. = 78C - 80C (Yield: 95%) PMR (CDC13): N-CH2-CH2-S+N-CH2: 2.65 ppm (multiplet:
16H); S-CH2-CH2-S: 2.90 ppm (singlet: 4H); 0-CH2-:
3.60 ppm (triplet: 8H), 3.65 ppm (singlet: 8H) ,.. .

-Preparation of 5,12-dioxo-1,7,10,16-tetrathia-4,13-diaza-cyclooctadecane This reaction is carried out applying a high dilution technique. A solution of 18 g. of the diamine obtained in Example 27 (0.1 mole) in 500 ml. anhydrous benzene and a solution of 12.4 g. of the dichloride obtained in Example 26 in 500 ml. anhydrous benzene are added to 1,200 ml. anhydrous benzene over a period of eight hours under vigorous agitation and under a nitrogen atmosphere. Most of the desired amide precipitates during the course of the reaction. On termination, the benzene solution is filtered and evaporated to dryness. A small amount (2 g.) of solid residue is obtained. The solid precipitates-formed during the high dilution reaction are extracted three times with 250 ml. boiling chloroform. The ~. . .
residue obtalned from the benzene layer is added to the combined chloroform extracts. This solution is then filtered through a short column of alumina (30 g.), the column being washed with an additional 1,000 ml.
of chloroform. The,solution obtained is concentrated and the desired diamide crystallizes out.
m.p. = 148C - 149C (Yield = 85%) PMR (CDC13): -CH2-S-: 2.65-2.90 ppm (complex band: 12H), -CO-CH2-S: 3.25 ppm (singlet: 4H), -~-CH2-: 3.52 ppm (multiplet: 4H) .. .. . .

Preparation of 1,7,10,16-tetrathia-4,13-diazacyclo-octadecane A solution of diborane (20 ml., 1.5 N) in anhydrous tetrahydrofuran is added dropwise to a suspension of 2 g. of thè diamide obtained in Example 32 in 50 ml. anhydrous tetrahydrofurane under nitrogen at room temperature. The solid dissolves giving a clear solution. After the addition is completed the mixture is refluxed during four hours and a solid precipitate is formed. After cooling to room temperature, the excess reagent is destroyed by add-ing carefully 10 ml. of water. The solvents are evaporated to dryness and 6 N hydrochloric acid (50 ml.) is added to the solid residue. The mixture is refluxed for three hours: the solid does not dissolve, the mixture remaining heterogeneous. The mixture is evaporated to dryness and a solution of 10% sodium ; hydroxide in water (50 ml.) is added to the resldue.

.
The heterogeneous mixture is extracted three times with chloroform (50 mI.) The combined chloroform layers are dried over sodium sulfate and filtered through a short alumina (20 g.) column. The solvent is removed and the solid product is recrystallized from ethanol.
m.p. = 125C Yield 50~/O
PMR (CDC13): one complex band from 2.75 to 2.83 ppm.

Preparation of 2,9-dioxo-4,7-dioxa-13,16,21,24-tetrathia-l,10-diazabicyclo[8,8,8Jhexacosane The reaction is carried out applying the high dilution technique. A solution of 1.0 g. of the cyclic diamine obtained in Example 33 and 0.3 g. of triethylamine in 100 ml. anhydrous benzene and a solution of the dichloride (0.8 g. in 100 ml. anhydrous benzene) obtained in Example lB are added to 1,000 ml.
anhydrous benzene during two hours under nitrogen atmosphere and under vigorous agitation. The salt ~- of triethylamine and the hydrochloric acid precip-itates and is filtered off. The filtrate is evapor-ated to dryness. The residue is dissolved in benzene and filtered through a column of A12O3 (20 g.) followed by 500 ml. of chloroform.

.. - .
,, The solvents are evaporated, leaving the title compound as a viscous oil which may crystallize on standing.
Yield: 40/O
PMR (CDC13): CH2-S: 2.75 ppm (broad band: 16H);
CH2-N and CH2-0: 3.65 ppm (broad bands: singlet +
j triplet: 12H); C0-CH2-O; around 4 ppm (several broad peaks: 4H) .. . . . .
.

Preparation of 4,7-dioxa-13,16,21,24-tetrathia-1,10-diazabicyclo[8,8,8~hexacosane A solution of 0.6 g. of the bicyclic diamide obtained in Example 34 in 10 ml. tetrahydrofuran is slowly added to 10 ml. of the freshly prepared B2H6 solution (1.5 M) under nitrogen atmosphere and at a temperature of 0C. The mixture is refluxed for two hours. The excess reagent is destroyed by adding 5 ml. of water and the solution is evaporated on a rotatory evapor-ator under vacuum. The solid residue is treated with 50 ml. 6 N hydrochloric acid under reflux for two hours. The mixture is evaporated to dryness under -vacuum on a rotatory evaporator. The residue is 2 treated with a solution of tetraethylammonium hydroxide until a basic reaction is obtained. The mixture containing a precipitate, is extracted several times with chloroform. The solutions are filtered through alumina and evaporated to dryness leaving the title compound as a crystalline residue.

The solid residue is recrystallized from a benzene-hexane mixture and dried in vacuum (0.1 mm Hg.) m.p. = 86C - 87¢ (Yield = 95%) PMR (CDC13): ~-CH2-CH2-S+~-CH2: 2.70 ppm (multiplet: 20H) S-CH2-CH2-S: 2.90 ppm (broad bànd: 8H), CH2-0: 3.60 ppm (triplet: 4H): 3.68 ppm (singlet: 4H).

Preparation of 2,9-dioxo-4,7,13,16,21,24-hexathia-1,10-diazabicyclo[8,8,8]hexacosane The reaction is carried out applying the high dilution technique. A solution of 4.5 g. of the cyclic diamine obtained in Example 33 and 1.5 g. of triethyl-amine in 500 ml. hot anhydrous benzene (maintained at approx. 60C during the addition) or in 400 ml. anhyd-rous chloroform and a solution of the dichloride (3.5 g. in 400 ml. anhydrous benzene) obtained in Example 26B is added to 1000 ml. anhydrous benzene during six hours under nitrogen atmosphere and under vigorous agitation. The salt of triethylamine and the hydrochloric acid and the product precipitate and are filtered off. The benzene layer contains only a very small amount of product. The solid is extracted ~1 three times with hot chloroform. The combined chloro- ~
form solutions are filtered through an alumina ~} column. The bicyclic amide is eluted with methanol.
20 After evaporation to dryness the title product is obtained as a viscous oil.
Yield 20%
PMR ~CDC13): CH2-S: several broad peaks between 2. 5 and 3.1 ppm ( 20H); COCH2-S+CH2-~: several broad peaks between 3. 2 and 3.8 ppm ( 12H).

1~)62Z55 Preparation of 4,7,13,16,21,24-hexathia-1,10-diaza-bicyclo~8, 8, 8]hexacosane 20 ml. of the fresh prepared B2H6 solution is added to a suspension of 1 g. of the bicyclic diamide obtained in Example 36 in 20 ml. tetrahydrofuran under nitrogen atmosphere and at a temperature of 0C. The mixture is agitated at this temperature for thirty minutes and thereafter four hours at reflux temperature. The excess reagent is destroyed by adding 5 ml. of water and the solution is evaporated on a rotatory evaporator under vacuum. 50 ml. 6 N
hydrochloric acid are added and the mixture is heated under reflux for four hours. The mixture is evap-orated to dryness under vacuum on a rotatory evaporator.
The mixture is made alkaline with NaOH N~10 and~is extracted three times with chloroform. The chloro-form solutions are filtered through alumina and evap orated to dryness. The residue is recrystallized from a chloroform/hexane mixture leading~to the title compound.
m.p. = 172C Yield = 80%
PMR (CDC13): N-CH2-CH2-S: 2.68 ppm (singlet: 24H):
S-CH2-CH2-S: 2.90 ppm (singlet: 12H) EX~MPLE 38 Preparation of l!_-diamino-3-oxapentane 1,5-Dichlorc-3-oxapentane is treated with potassium phthalimide, followed by hydrazinolysis of the result-ing diphthalimido-derivative and consecutive acid-ification whereby the bis-hydrochloride of the title compound is obtained.

The bis-hydrochloride is treated with a very concen-trated (approx. 10~) solution of potassium hydroxide in water and continuouslyextracted with benzene in a liquid-liquid extractor for several (three to five) days.
The solvent is evaporated and the liquid residue is distilled under reduced ~ressure giving the desired compound.
b.p.: 48 - 50/lmm Hg: Yield 30~/O (from the initial 1,5-dichloro-3-oxapentane).
PMR (CDC13)- -~H2: 1.30 ppm (singlet: 4H); -CH2-N:
2.90 ppm (triplet: 4H); -CH2-0: 3.50 ppm (triplet:
4H).

.. ~ . . . . .
- - .:

-Preparation of diqlycolic acid dichloride To 13.4 g. of diglycolic acid covered with chloroform (150 ml.), 45 g. phosphorus pentachloride are added at once.

After standing for ten minutes at room temperature the mixture is heated slowly to reflux temperature over a period of one hour and is then left under reflux for 1.5 hours. The solvent is then evaporated at room temperature under reduced pressure (water pump). Then, the phosphorus oxychloride formed during the reaction is taken off at room temperature under 0.5 mm Hg pressure (oil pump). The remaining oil is distilled (oil bath below 80C) giving 14.8 g.
of the desired dichloride.
b.p. = 56 - 57~0.5 mm Hg. Yield = 86%
PMR (CDC13): 0-CH2-C0: 4.65 ppm (singlet).
The dichloride is unstable to heat and must be distilled at low temperature at sufficiently low pressure~

..
, .- ' :;

106225~

Preparation of 5,9-dioxo-1,7,13-trioxa-4,10-diaza-cyclopentadecane This reaction is carried out applying a high dilution technique. A solution of 29.6 g. of the diamine - -obtained in Example 2 (0.2 mole) in 1000 ml. anhydrous benzene and a solution of 17.2 g.(0.1 mole) of the dichloride obtained in Example 39 in 1000 ml. anhydrous benzene are added to 1,200 ml. anhydrous benzene over a period of eighteen hours under vigorous agitation and under a nitrogen atmosphere. On termination, the benzene solution is filtered and evaporated to dryness.
The crude solid residue is almost pure (m.p. 147 -148C). It is recrystallized from a hot mixture of tetrahydrofuran and heptane giving the title product.
m.p. = 149 - 150C Yield = 75%
PMR (CDC13): ~-CH2-CH2-0: 3-60 ppm (mu t p )~
0-CH2-CH2-O: 3.67 ppm (singlet: 4H); -C0-CH2-0:
4.08 ppm (singlet: 4H); ~H: 7.15 ppm (broad band:
2H).

Preparation of 1,7 ! 13-Trioxa-4,10-diazacycloPentadecane A solution of 15.7 g. of the diamide obtained in Example 40 in 300 ml. hot anhydrous tetrahydrofuran is slowly added to a mixture of 50 ml. anhydrous .

iOf~Z255 tetrahydrofuran and 15 g. LiAlH4 while stirring over a period of 1.5 hours. After the addition is completed, the mixture is stirred under reflux and under a nitrogen atmosphere for twenty hours. After cooling to room temperature the excesq reagent is destroyed by adding a mixture (45 ml.) of water and THF (1:2), followed by lS ml. NaOH 15% and 45 ml. water. 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 A1203 with benzene as eluant. The solution is evaporated to dryness and a semicrystalline product is obtained (mixture of crystals and an oil) which proves to be the desired product, ^ Yield = 8~%
- PMR (CDC13): CH2-N: 2.75 ppm (triplet: 8H);
CH2-0: 3.60 ppm (triplet + singlet: 12H) Preparation of 2,9-dioxo-4,7,13,16,21-pentaoxa-1,10-diazabicyclor8,8,5ltricosane The reaction is carried out applying the high dilution technique. A solution of 8.72 g. of the cyclic diamine obtained in Example~41 and 8.8 g. of triethyl-amine in 500 ml. anhydrous benzene and a solution of the dichloride (8.6 g. in 500 ml. anhydrous benzene) obtained in Example lB is added to 1000 ml. anhydrous _ 72 -'- '' ' -1062~55 benzene during ten hours under nitrogen atmosphere and under agitation. The salt of triethylamine and the hydrochloric acid precipitates and is fil-tered off. The filtrate is evaporated to dryness, The residue is dissolved in benzene and passed through a column of Al2o3 (100 g.) using benzene as an eluant. The title compound is obtained as an oil which crystallizes on standing. The product is recrystallized ~rom a hexane-benzene mixture.
m.p. = 105C Yield 45%
PMR (CDC13): several peaks between 3.3 and 4.6 ppm.

Preparation of 4,7,13,16,21-Pentaoxa-l,10-diazabi_yclo-r8~8~5ltricosane A solution of 5 g. of the bicyclic diamide obtained in Example 42 in 50 ml. anhydrous tetrahydrofuran ; is slowly added to 50 ml. of the fresh prepared B2H6 solution (l.OM) under nitrogen atmosphere and at a temperature of 0C. The mixture is agitated at this temperature for thirty minutes and thereafter 1.5 hours at reflux temperature. `The excess reagent is destroyed by adding 10 ml. of water and the solution is evaporated on a rotatory evaporator under vacuum.
3.5 g. of the diborane of the title compound is obtained (m.p. = 205-209C).

,~3 1 \o~o \,3 H3B -N ~ o ~ N -BH3 ~ /'~/

This compound is hydrolysed by adding 50 ml. 6N hydro-` chloric acid under heating and a solution is obtained.
The mixture is evaporated to dryness under vacuum on -a rotatory evaporator. The residue is dissolved in 30 ml. water and the solution is passed through a column of an anion exchange resin (Dowex 1~ Trade Mark). The column is washed with water until there is no basic reaction. The water is evaporated.
The title compound is obtained as a colourless oil -(3 g-) Yield = 95%
PMR (CDC13): -CH2-N: 2.65 ppm (triplet: 12H) -CH2-0: 3.60 ppm (triplet: 12H), 3.70 ppm (singlet: 8H).

~ ~ .

Pre~aration of 5,9-dioxo-1,7-dioxa-4,10-diaza-cyclo-dodecane -This reaction is carried out applying the high dilution technique. A solution of 10.4 g. of the diamine obtained in Example 38 (0.1 mole) in 100 ml. anhydrous benzene and a solution of 8.6 g. (0.05 mole) of the dichloride obtained in Example 39 in 100 ml. anhydrous benzene are added to 1000 ml, anhydrous benzene over a period of 50 minutes under vigorous agitation.
The reaction mixture is filtered and the residue is washed with hot chloroform (3 x 500 ml.) The combined solutions are evaporated to dryness leaving a crystal-line residue (m.p. = 180-181C) which is recrystallized from a hot mixture of chloroform and heptane giving the desired product.
m.p. = 182 - 183C Yield = 65%
PMR (CDC13): ~-CH2-CH2-o: 3.60 ppm (broad multiplet:
8H), CO-CH2-O: 4.15 ppm (singlet: 4H), NH: 7.65 ppm (broad band: 2H) Preparation of 1,7-dioxa-4,10-diazacyclodecane ` A suspension of 5.0 g. of the diamide obtained in Example 44 in 100 ml. hot anhydrous tetrahydrofuran and 4.8 g. LiAlH4 while stirring over a period of one hour. After the addition is completed, the mixture is stirred under reflux and under a nitrogen atmos-phere for eighteen hours. After cooling to room temperature the excess reagent iq destroyed by adding a mixture (15 ml.) of water and THF (1:2) followed by 5 ml. NaOH 15% and 15 ml. water. The mixture is filtered and the filtrate is evaporated to dryness. The - . ,.. . ~:

10~2Z55 residue is dissolved in benzene and the solution is passed through a column of A1203 with benzene as eluant.
The solution is evaporated to dryness and after recrystallization from hot benzene/heptane the desired product is obtained.
m.p. = 83 - 84C Yield = 70YO
PMR (CDC13): NH: 2.40 ppm (singlet: 2H); -CH2-N:
2.80 ppm (triplet: 8H), -CH2-0: 3.66 ppm ~triplet: 8H).

- : . .. . . .. .

Stronqly_basic solutions When solid potassium hydroxide is added to a solution of 4,7,13,16,21,24-hexaoxa-1,10-diaza-bicyclo[8,8,8]-hexacosane (obtained in Example 6) in anhydrous tetrahydrofuran, a very strongly basic solution is obtained as KOH dissolves in the solvent under complex formation with the bicyclic diamine.
The strong basicity may be shown by adding some fluorene: an intense red colour, due to the formation of the fluorenyl anion, develops immediately. By ~- treating this strongly basic solution with air the fluorenone is obtained. When no bicyclic amine is present the anion is not formed and the solution remains colourless.
The same observations may be made when KOH is replaced by another base such as sodamide.

Purification of Tetraqlvcolic acid A. Preparation of tetraqlycolic acid dianilid Tetraglycolic acid dichloride is prepared as described in Example 13~ 22 g. of this dichloride in 50 ml.

anhydrous benzene are treated at 0C (ice bath) with 35 g.
aniline in 50 ml. anhydrous benzene. The mixture is heated to 60C for ten minutes and is poured into a separation funnel, 200 ml. water and 200 ml.
chloroform are then added. The organic layer is separated and washed with 200 ml. 5% hydrochloric acid and then with 200 ml. water.

~' .
The solution is dried over sodium sulfate and the solvents are evaporated. The dianilide thus obtained is an oil which is recrystallized~
1) first from acetone-water (dissolved in hot acetone, water added until the -~ mixture becomes cloudy);
2) then from acetone-hexane (dissolved in hot acetone; hexane added until cloudy) using a crystal from (1) to initiate crystallization (m.p. 56C) 3) finally again from acetone-water; a white crystalline product (19 g.) containing one mole of water, is thus ob~ained, m.p. 58C Yield = 60%
PMR (CDC13): 0-CH2-CH2-0: 3.75 ppm (singlet: 8H);
O-CH2-C0: 4.06 ppm (singlet: 4H); aromatic protons:
7.0-7.6 ppm (multiplet: lOH).
All signals are sharp; no impurities present.

. ~

B. Hydrolysis of the dianilid 19 g. of the dianilid obtained previously are suspended in 200 ml. 15% sodium hydroxide in water. The mixture is refluxed for approx. twenty hours. After cooling to room temperature, the liquid mixture (the aniline formed forms an upper layer) is washed three times with 150 ml. benzene. The water layer is then brought to pH 1 using 10% hydrochloric acid and evap-orated first at the water pump and then at the oil pump while heating on the steam bath. The residue (NaCl + tetraglycolic acid) is washed with acetone, filtered and the solid on the funnel is washed two times with acetone. The acetone solution is evaporated to dryness. The oily residue obtained is pure tetraglycolic acid, PMR spectrum as described in Example 13A;
small peaks due to contaminating compounds have completely disappeared (purity approx. 99/O) Yield = 90YO

PreParation of 17,24-dioxo-4,7,13,16-tetraoxa-1,10-diazabicyclo[8,8,8]hexacosane The reaction is carried out applying the high dilution technique. A solution of 10.48 g. of the cyclic .

diamine obtained in Example 4 and 8.8 g. of triethyl-amine in 300 ml. anhydrous benzene and a solution of the dichloride of octane-1,8-dicarboxylic acid (8.44 g.
in 500 ml. anhydrous benzene) is added to 1200 ml.
anhydrous benzene during ten hours under nitrogen atmosphere and under agitation. The salt of triethyl-amine and the hydrochloric acid precipitates and is filtered off. The filtrate is evaporated to dryness.

The product is an oil which crystallizes on standing.
m.p. = 96 - 98C. Yield = 45%

PMR (CDC13): -(CH2)6-: 1.4-2.0 ppm (broad peaks: 12H);
CH2-N and CH2-0: several peaks between 3.3 and 4.6 ppm.

Preparation f 4,7 ! 13,16-tetraoxa-1,10-diazabicYclo-[8,8,8]hexacosane A solution of 7 g. of the bicyclic diamide obtained in Example 48 in 80 ml. anhydrous tetrahydrofuran is slowly added to 70 ml. of the fresh prepared B2H6 solution (l.OM) under nitrogen atmosphere and at a temperature of 0C. The mixture is agitated at this temperature for thirty minutes and thereafter 1.5 hour at reflux temperature. The excess reagent is destroyed by adding 20 ml. of water and the solution is evapor-ated on a rotatory evaporator under vacuum. 6 g.
of the diborane of the title compound i9 obtained (m.p. = 139C) r~O~O~
H3B -N ~ ~-- ~ N - BH
~/0 /o\_,/

This compound is hydrolysed by adding 100 ml. 6N
hydrochloric acid under heating and a solution is obtained. The mixture is evaporated to dryness under vacuum on a rotatory evaporator. The residue is dissolved in 20 ml. water and the solution is passed through a column of an anion exchange resin (Dowex 1, Trade Mark). The column is washed with water until there is no basic reaction. The water is evaporated.
The title compound is obtained as a white crystalline solid.
m.p. = 90 -91C Yield = 85%
PMR (CDC13): -(CH2)6-: 1.4 ppm (broad peak: 12H);
-CH2-N: 2.40 ppm (broad peak: 4H) 2.65 ppm (triplet: 8H); -CH2-0: 3.53 ppm (triplet: 8H);
3.70 ppm (singlet: 8H).

-Preparation of the KSCN-com~lex of 4,7,13,16,21-pent~=~10-diazabicyclor8,8,5]tricosane 100 mg. Of the macrocyclic compound are dissolved in chloroform and an excess solid KSCN is added. After standing overnight at room temperature the mixture is filtered and the solution is evaporated to dryness.
The residue is crystallized from an ether-acetone mixture. The crystalline compex melts at 131 - 132C.

Preparation of the Ba(SCN)2-complex of 4,7,10,16,19,24,27-:
heptaoxa-1,13-diazabicYclo r 8,8,11lnonacosane 70 mg. Of the macrocyclic compound and 70 mg. solid - -Ba(SCN)2, H20 are refluxed in 20 ml. acetone for five minutes. The acetone is then removed under vacuum and the residue is treated with 25 ml. chloroform.
After filtration, the chloroform is evaporated and the residue i9 crystallized from a chloroform-benzene-ether mixture. A crystalline complex is obtained.
m.p. = above 260C.

Further comPlexes of 4,7,13L16,21,24-hexaoxa-1,10-diazabicyclor8,8,8lhexacosane The following complexes have been obtained by the method already described in Example 11, or else their formation has been observed by spectroscopic methods:
TlHC00 complex (m.p. = 50 - 52C) Ca(SCN)2 complex (m.p. = above 260C) Zn(BF4)2 Pb(SCN)2 7 Complexes of 4,7,13,16,21-pentaoxa-1,10 diazabicyclo-r8~8~5ltricosane This compound, obtained in Example 43 gives stable complexes with various metal salts in particular it readily forms complexes with transition metal salts. ~-~
The complexes of the following salts have been prepared by mixing methanol solutions of the salt and of the complexing agent and letting the complex crystallize out, or else their formation has been observed by spectroscopic methods:
KSCN BaC12 Co(SCN)2 Ni(BF4)2 ( 4)2 - : , Preparation of 2~9-dioxo-4,7/13(18-tetraoxa-1,10-diazabicyclor5,5,81eicosane The reaction i~ carried out applying the high dilution technique. A solution of 8.7 g. of the cyclic diamine obtained in Example 45 and 11 g. of triethyl-amine in 200 ml. anhydrous chloroform and 300 ml.
anhydrous benzene and a solution of the dichloride (10.8 g. in 500 ml. anhydrous benzene) obtained in Example lB is added to 1000 ml. anhydrous benzene during eight hours under nitrogen atmosphere and under agitation. The solution is filtered and the solid re~idues are washed several times with benzene.
The combined organic layers are evaporated to dryness leaving an oily residue which i then extracted three times with hot benzene (3 x 200 ml.) Evaporation of the benzene layers give a solid residue which is filtered in benzene solution through a column of alumina.
5, The solid obtained after evaporation of the solvent, ~ -is recrystallized from a benzene-heptane mixture.
The desired product is obtained.
m.p. = 151 - 152C Yield - 45%
PMR (CDC13): two very complex multiplets between , ! 2.6 - 3.2 ppm (4H) and 3.4 - 4.8 ppm (20H).

Preparation of 4,7,13,18-tetraoxa-1,10-di~ y~
r5~5-~8leicosane 22 ml. of a freshly prepared B2H6 solution (0.8 m) are added with a syringe to a suspension of 2.9 g.
of the bicyclic diamide obtained in Example 54 in 20 ml. anhydrous tetrahydrofurane under nitrogen atmosphere and at a temperature of 0C. The mixture ' is agitated at this temperature for thirty minutes and thereafter three hours at reflux temperature. The excess reagent is destroyed by adding 5 ml. of water and the solution lS evaporated on a rotatory evaporator under vacuum. The residue is extracted several times with chloroform and the solution obtained is evaporated to dryness. 1.9 g. Of the diborane of the title compound is obtained.
m.p. = 121 - 122C Yield = 98~/o /~0/~0~
t gH3_N ~ ~ / N BH3 o -This compound (1.7 g.) is hydrolysed by adding 20 ml.

20 6N hydrochloric acid under heating (2.5 hours) and ~06Z255 a solution is obtained. The mixture is evaporated to dryness under vacuum on a rotatory evaporator.
The residue is dissolved in 10 ml. water and the sol-ution is passed through a column of an anion exchange resin (Dowex 1, Trade Mark). The column i9 washed with water until there is no basic reaction. The water is evaporated. The title compound is obtained as a colourless oil.
Overall yield = 95%
PMR (CDC13): -CH2-N: 2.75 ppm (triplet: 12H) -CH2-O: 3.4-3.8 ppm (multiplet: 12H), 3.70 ppm (singlet: 4H).

Com~lexes of 4,7,13,18-tetraoxa-1,10-dlazabicYclo-r5!5,81eicosane Complex formation with the title compound (obtained in Example 55) has been observed spectrometrically (~MR) for the following salts:
Li Cl Li SCN
Na Cl K Br K SC~ Ba C12 Co(SC~)2 Some of these complexes are unstable in water.

Strongly basic solutions have also been obtained by following the procedure of Example 46. Also here the formation of the fluorenyl anion has been observed when adding fluorene to an anhydrous tetrahydrofurane solution of the complex formed with KOH.

A. Preparation of 2-chloroethyl-chloromethyl ether 322 g. Of ClCH2CH2OH, cooled in ice-water, was saturated with gaseous HCl, and 120 g. of trioxymethylene was added, after which the solution was again saturated with HCl. The lower layer was separated, dried over CaC12, and dry CO2 passed through the solution to remove excess HCl. Upon fractionation at reduced pressure the major portion b23 765-73. A small amount of trioxy-methylene appears in the forerun. The yield is approx. 380 g.
B. Preparation of 2-chloroethoxv acetonitrile Mixing of 315 g. of the product obtained in Example A
and 250 g~ copper cyanide Cu2(CN)2, followed by gentle heating, gives risè to a reaction which is controlled by cooling the flask with water. The : ?
. .
. .

reaction is finally completed by heating on a water bath for two hours. The reaction product is distilled at reduced pressure without removal of the Cu2(CN)2, yield-ing 250 g. of the title compound.
b.p. = 55 - 58/0.8 mm. Yield = 85%

C. Preparat_on of 2-chloroethoxy acetic acid This compound was prepared by treating 120 g. of the product obtained in Example 57B with 250 ml. of concentrated HCl. Reaction sets in after a short time, and it is necessary to cool the flask to control the reaction, which is finall,y, completed by heating on a steam bath for two hours. The mixture is diluted with an equal volume of water, and extracted four times with 50 cc portions of ether. The ether is evaporated and the product is distilled in vacuum, b3 5130.

D. Preparation of monothio-triglycolic acid

9.2 g. (0.1 Mole) of thioglycolic acid are dissolved in a solution o~ 12 g. NaOH in 100 ml. water. 13.8 g.
Of the product obtained in Example 57 C are added slowly (over approx. fifteen minutes) and the mixture is l~Z255 heated to 80C for two hours. After cooling the solution is acidified with concentrated HCl and extracted three times with ether (3 x 50 ml.).
The ether layers are combined, dried over sodium sulfate and evaporated to dryness. The title product (14.5 g.) is obtained as a very viscous oil.
Yield = 85%
PMR (D20): -S-CH2-: 2.85 ppm (triplet, 2H), -S-CH2-CO: 3.4 ppm (singlet: 2H), -0-CH2-: 3.85 ppm (triplet: 2H); -0-CH2-C0: 4.2 ppm (singlet: 2H~.
E. Preparation of monothio-triqlycolic~ acid dichloride ; The dichloride of the diacid obtained in Example 57D
is prepared using oxalyl chloride in the same way as described in Example 26B. The product is a viscous oil.
Yield = ~uantitative~
PMR (CDC13): -S-CH2-: 2.85 ppm (triplet: 2H):
-S-CH2-C0-: 3.8 ppm (singlet: 2H); -0-CH2-: 3.8 ppm (triplet: 2H) -0-CH2-OH: 4.45 ppm (singlet: 2H) ., ~ - . ~ , ~, .
., - -~,, . :

Preparation of 2,9-dioxo-4, 13,16-trioxa-7,21,24-trithia-1,10-diazabicyclor8,8,8~hexacosane This reaction is carried out applying the high dilution - technique. A solution of 4.5 g. of the diamine obtained in Example 29 and 2 g. triethylamine in 200 ml.
anhydrous benzene and a solution of 3.8 g. of the dichloride obtained in Example 57E in 200 ml. anhydrous benzene are added to 1,200 ml. anhydrous benzene over a period of 2.5 hours under vigorous agitation and under a nitrogen atmosphere. On termination, the benzene solution is filtered and evaporated to drynesq.
The oily residue is redissolved in benzene (100 ml.) -and is filtered through a column of aluminium oxide (50 g.) The product is eluted with a mixture of chloroform and benzene ( 3C%/7G%) . The solution is evaporated to dryness leaving a viscous oil, which is the desired compound (yield approx. 50/O) PMR (CDC13): very complex spectrum from 2.5 to 4.0 ppm S-CH2+~CH2- from 2.5 to 2.9 ppm: O-CH2: from 3.5 to 4,0 ppm.

~: . . , ,: '' Preparation of 4,13,16-trioxa-7,21,24-trithia-1,10-diazabic~clor8,8,8lhexacosane 20 ml. of a solution (1.2 M) of diborane in anhydrou~
tetrahydrofuran are added to a solution of 1.5 g. of the bicyclic diamide obtained in Example 58 in 20 ml.
anhydrous tetrahydrofuran, under nitrogen atmosphere and at 0C. The mixture is refluxed for two hours.
The excess reagent is destroyed by adding 5 ml. of water and the solution is evaporated on a rotatory evaporator under vacuum. The residue is treated with 40 ml. 6N hydrochloric acid under reflux for two hours.
The mixture is evaporated to dryness under vacuum on a rotatory evaporator. The residue is treated with a solution of tetraethylammonium hydroxide until a ; basic reaction is obtained. The mixture is extracted with benzene (3 x 50 ml.) and the organic layers are dried and filtered over a column of aluminium oxide.
The solution is evaporated to dryness, leaving a viscous oil (1.4 g.), which is the desired compound.
Yield = 95%
PMR (CDC13): (-S-CH2-) + (-N-CH2_) 2.4-2.9 ppm (complex band: 24H: the -S-CH2-CH2-S group gives a singlet at 2.9 ppm); -0-CH2-: 3.4-3.7 ppm (complex band: 12H) - , ,. - -21,24-Dimethyl-4,7,13,16-tetraoxa-1,10,21!24-tetraaza-bic~c1 ~ 8,8,8lhexacosane A. Following the procedure of Example 3, 3,6-dimethyl-3,6-diaza-1,8-octane-diamine is reacted with the dichloride obtained in Example lB, to give 10,13-dimethyl-6,17-dioxo-1,4-dioxa-7,10,13,16-tetraaza-cyclooctadecane.
B, The product of step A is reduced at the oxo-groups, following the procedure of Example 4 to give 10,13-dimethyl-1~4-dioxa-7~10~13~16-tetraaza-cyclooctadecane~
C. Following the procedure of Example S the product of step B is condensed with the dichloride of Example lB to give 2l~24-dimethyl-2~9-dioxo-4~7~l3~l6-tetraoxa 1,10,21,24-tetraaza-bicyclo[8,8,8]hexacosane.
D. Reduction of the oxo-groups following the procedure of Example 6 gives the title compound.

Preparation of 4,7,13,16 ! 21,24-hexaoxa-1,10-dis~hos-E~bicyclor8,8,81hexaco~ane A. A mixture of 27.6 g. of triethylene glycol dibromide obtained according to Example 2A and 60.8 g.
of tribenzylphosphine i~ heated on a steam bath for .

three to four hours under nitrogen atmosphere. The diphosphonium dibromide of the formula ~ C ~ C~2-,13 P~ C~2 O -l3 ~3r [3,6-dioxa-1,8-bis(tribenzylphosphonium)-octane dibromide] is obtained.
B, Two equivalents of lithium aluminium hydride are added to a suspension of the phosphonium salt obtained according to step A in dry tetrahydrofuran.
The mixture is refluxed for several hours and the excess LiAlH4 is destroyed by adding wet ether followed by aqueous NaOH. The ether layer is separated off and the solvent is evaporated. The diphosphine of the formula ~ ~ CH2--~ P ~ O~----\p ¦--CH2 ~ ]2 [3,,6-dioxa-1,8-bis(dibenzylphosphine)-octane] is obtained.

- 93 _ .
- :, . ,: , ~ , . .:

106ZZS~

C. A mixture of the diphosphine obtained according to step B and one equivalent of triethylene glycol dibromide obtained according to Example 2A in dimethyl formamide are slowly added drop~wise over a period of several hours to hot dimethyl formamide (high dilution) under vigorous stirring and under nitrogen, After : the evaporation of the solvent and purification of the residue the monocyclic diphosphonium salt of the formula ~ ~ ~ ]2 ~2Br [1,7,10,16-tetraoxa-4,4,13,13-tetrabenzyl-4,13-diphos-phonium-cyclooctadecane dibromide] is obtained.
D. The diphosphonium salt obtained according to step C is transformed into the diphosphine of the formula ~ 2 ~ ~ ~ -CH2 - ~ >

[4,13-dibenzyl-1,7,10,16-tetraoxa-4,13-diphospha-cyclooctadecane] by treating the salt with LiAlH4 in tetrahydrofuran according to the process of step B
above.

- 94 _ SK/jl E. The product of step D is further reacted with triethylene glycol dibromide according to the process of step C and the bicyclic diphosphonium salt of the formula ~ H2 ~,1 \,~ \~,P---CH2 ~ . 2Br ~ . , [4J 7,13,16,21,24-hexaoxa-1,10-dibenzyl-1,10-diphosphonium-bicyclo[8J8,8~hexacosane dibromide]
` is obtained.
~ .
F. The benzyl groups are removed following the process o~ step B and the title compound of the formula 0/ \
P~pi\,,o~.p \~,\ 0 [4,7,13916g21g24-hexaoxa-l,10-diphosphabicyclo[8,8g8]-hexacosane] is obtained.

: -l-MAY-1970 SK/jl EXAMPLE 6?

- Preparation of 1,2-di-(chlorocarbonyl-methoxy)-benzene.

A) lg2-di(carbonylmethoxy)-benzene.
200 g Sodium h~droxide (5 mol) in 200 ml Water and 110 g pyrocatechol (1 mole) are mixed in a 1 l.flask. 189 g of monochloracetic acid (2 mol) are added slowly over a period of ~ hours. The mixture is heated to 100 over a period of 2 hours. After coolingg hydrochloric acid (100 ml) are added, the acid precipitates and is recrystallized in water.
M.p.: 177C
Yield: 50%
PMR (basic(NaOH)D20) -0-CH2- : 4.40 ppm (singlet; 4H) aromatic protons: 6.9 ppm (multiplet; 4H) B) Acid dichloride.
~0 g of the above acid are added to a mixture of 200 ml anhydrous benzene. Then ~5 g oxalylchloride are added, t'he flask being protected by a calcium chloride tube.
The mixture is stirred for four days and the diacid progressively dissolves as it is being transformed into the corresponding dichloride. The solution is then evaporated to dryness (without heating) leaving a lO~;ZZSS
brownish solid residue which is recrystallized from a mixture of chloroform-benzene giving white crystals.
m.p. = 50C
Yield = 80%
P~ (CDC13): -QCH2-COCl-: 5 ppm (singlet 4H) aromatic protons: 7 ppm (singlet: 4H) Prel~aration of 2,13-d_oxo-4,11,17,20, 25, 28-hexaoxa-1,14_diaza_trlcyclorl2~,8, 05'1l-triacont-5,7,9-tr_ne This reaction is carried out applying the high dilution technique. A solution of 5.2 g. of the diamine obtained in Example 4, and 5 g. of triethylamine in - 300 ml. anhydrous benzene, and a solution of 5.4 g.
of the dichloride obtained in Example 57 in 300 ml.
anhydrous benzene, are added to 1000 ml. benzene during six hours under nitrogen atmosphere and under agitation, The triethylamine hydrochloride precipitates and is filtered off. The filtrate is evaporated to dryness. The residue is dissolved in benzene and passed through a column of A1203(20 g.) using benzene as an eluant. The solutions are evaporated to dryness. The product is a viscous oil.
Yield = 50/O
PMR (CDC13): CH2-N and CH20: 2.5 to 4.5 ppm (complex multiplet: 24H): 0-CH2-C0: g.0 ppm (AB system) aromatic protons: 7.0 ppm (singlet: 4H) -- 97 _ Preparation of 4,11,17,20,25,28-hexaoxa-1,14-diaza-- tricvclorl2,8,8,05'1~-triacont-5,7,9-triene 35 ml. of a freshly prepared solution (1.2 M) of diborane are added slowly to a solution of 3 g. of the amide obtained in Example 58 in 20 ml. anhydrous tetrahydrofuran under nitrogen atmosphere and at a temperature of 0C. The mixture is then heated to reflux for two hours. The excess reagent is destroyed by slowly adding 5 ml. of water. The solution is evaporated to dryness on a rotatory evaporator under vacuum.

60 ml. 6N Hydrochloric acid are added to the residue and the mixture i~ refluxed for two hours. The solution is then evaporated to dryness under vacuum. The residue dissolved in 30 ml. water and the solution is passed through a column of an anion exchange resin (Dowex 1, Trade Mark). The column is washed with water until there is no basic reaction. The combined water solutions obtained are evaporated to dryness under vacuum on a water bath. The residue is a viscous oil.
Yield = 8~/o PMR (CDC13): -CH2-N: 2.72 ppm (triplet: 8H), 2.90 ppm (triplet: 4H): -CH2-0: 3.55 ppm (singlet: 8H and triplet 8H): -CH2-0 (phenolic): 4.10 ppm (triplet: 4H): aromatic protons: 6.85 ppm (singlet: 4H) Listed below are some representatives of compounds from which complexes have been formed with the macrocyclic compounds of this invention:
KF Næl CaBr2 TlCl KCl NaI CaC12 AgN03 KBr NaSCN SrBr2 Mg ( OAC ) 2 K I 2 o4 SrC12 LiSCN
KOH Na2 ( COO ) 2 B aC 12 TlHCOO
KMn04 RbC l B aB r 2 Zn ( BF4 ) 2 KBH4 NH4SCN BaS04 Pb( SCN)2 KSCN RbSCN CuC12 Co( SCN)2 K2 (C)2 CsSCN TlN03 I~H4I

~.

, _ 99 _ ,, . . , - , ~ , ~

Claims

1. Macrocyclic compounds of the general formula I

(I), wherein each of R1 is hydrogen, a hydrocarbon group or an alkoxycarbonyl group, or both R1 form together a grouping of the general formula II

(II), (i.e. providing a third bridge between the two X-groupings in the molecule); each A is a hydrocarbon group;
each X is nitrogen or phosphorus; each D is oxygen, sulfur, > N-R (R being hydrogen or a hydrocarbon group) or a hydrocarbon group, with the proviso that at least two of the groups or atoms represented by D are selected from oxygen, sulfur and >N-R, and that when each R1 is hydro-gen, hydrocarbon or alkoxycarbonyl and X is nitrogen, then one of these two groups or atoms represented by D is oxygen or sulfur and the other is oxygen or >N-R; and m, n and p are integers from 0 to 5, the N- and P-oxides of the compounds of the general formula I having a tertiary nitrogen or phosphorus atom, complexes formed from the compounds of the general formula I or from the N- and P-oxides thereof, and phosphonium and ammon-ium salts and acid addition salts of the compounds of the general formula I.

2. Compounds according to claim 1, wherein each R1 is hydrogen, a hydrocarbon group or an alkoxycarbonyl group.

3. Compounds according to claim 2, wherein any hydrocarbon or alkoxycarbonyl group represented by R1 has from 1 to 12 carbon atoms.

4. Compounds according to claim 3, wherein any hydrocarbon or alkoxycarbonyl group represented by R1 has from 1 to 8 carbon atoms.

5. Compounds according to any one of claims 2 to 4,wherein m and n are integers from 0 to 3.

6. Compounds according to claim 1, wherein both R1 together form the grouping providing a third bridge between the two X-groupings of the molecule.

7. Compounds according to claim 6 wherein m, n and p are integers from 0 to 3.

8. Compounds according to claim 1, wherein the hydro-carbon groups represented by A and any hydrocarbon groups represented by D have from 2 to 12 carbon atoms.

9. Compounds according to claim 5, wherein the hydro-carbon groups represented by A and any hydrocarbon groups represented by D have from 2 to 8 carbon atoms.

10. Compounds according to claim 7, wherein the hydro-carbon groups represented by A and any hydrocarbon groups represented by D have from 2 to 8 carbon atoms.

11. Compounds according to any one of claims 8 to 10, wherein the hydrocarbon groups represented by A and any hydrocarbon groups represented by D are alkylene, alkenylene, cycloalkylene, cycloalkenylene, cycloalkylenen-di-alkyl, phenylene or phenylene-di alkyl.

12. Compounds according to any one of claims 1, 9 and 10, wherein both X are nitrogen.

13. Compounds according to any one of claims 1, 9 and 10, wherein both X are nitrogen and the compounds are in the form of a cation-containing-complex.

14. Compounds according to any one of claims 1, 9 and 10, wherein both X are phosphorus.

15. Compounds according to any one of claims 1, 9 and 10, wherein both X are phosphorus and the compounds are in the form of a cation-containing-complex.

16. A compound according to Claim 1 having the formula:

17. A compound according to Claim 1 having the formula:

18. A compound according to Claim 1 having the formula:

19. . A compound according to Claim 1 having the formula:

20. A compound according to Claim 1 having the formula:

21. A compound according to Claim 1 having the formula:

22. A compound according to Claim 1 having the formula:

23. A compound according to Claim 1 having the formula:

24. A compound according to Claim 1 having the formula:

25. . A compound according to Claim 1 having the formula:

26. A compound according to Claim 1 having the formula:

27. A compound according to Claim 1 having the formula:

28. A compound according to Claim 1 having the formula:

29. A compound according to Claim 1 having the formula:

30. A compound according to Claim 1 having the formula:

31. A compound according to Claim 1 having the formula:

32, A compound according to Claim 1 having the formula:

33. A compound according to Claim 1 having the formula:

34. A compound according to Claim 1 having the formula:

35. A compound according to Claim 1 having the formula:

36. A compound according to Claim 1 having the formula:

37. A compound according to Claim 1 having the formula:

38. A compound according to Claim 1 having the formula:

39. A compound according to Claim 1 having the formula:

40. A compound according to Claim 1 having the formula:

41. A compound according to any one of claims 16 to 18 and in the form of a cation-containing-complex.

42. A compound according to any one of claims 19 to 21 and in the form of a cation-containing-complex.

43. A compound according to any one of claims 22 to 24 and in the form of a cation-containing-complex.

44. A compound according to any one of claims 25 to 27 and in the form of a cation-containing-complex.

45. A compound according to any one of claims 28 to 30 and in the form of a cation-containing-complex.

46. A compound according to any one of claims 31 to 33 and in the form of a cation-containing-complex.

47. A compound according to any one of claims 34 to 36 and in the form of a cation-containing-complex.

48. A compound according to any one of claims 37 to 39 and in the form of a cation-containing-complex.

49. A compound according to claim 40 and in the form of a cation-containing-complex.

50. Process for the preparation of compounds of the general formula I

(I), wherein each of R1 is hydrogen, a hydrocarbon group or an alkoxycarbonyl group, or both R1 form together a grouping of the general formula II

(II), (i.e. providing a third bridge between the two X- groupings in the molecule); each A is a hydrocarbon group; each X
is nitrogen or phosphorus; each D is oxygen, sulfur, >N-R
(R being hydrogen or a hydrocarbon group) or a hydrocarbon group, with the proviso that at least two of the groups or atoms represented by D are selected from oxygen, sulfur and >N-R and that when each R1 is hydrogen, hydrocarbon or alkoxycarbonyl and X is nitrogen, then one of these two groups or atoms represented by D is oxygen or sulfur and the other is oxygen or > N-R; and m, n and p are integers from 0 to 5;
the N- and P-oxides of the compounds of the general formula I having a tertiary, nitrogen or phosphorus atom, complexes formed from the compounds of the general formula I or from the N- and P-oxides thereof, and phosphonium and ammonium salts and acid addition salts of the compounds of the gen-eral formula I, characterised in that a compound of the general formula III

(III), is condensed with a compound of the general formula IV

(IV), wherein A, D, m and n are as above defined and either V is a leaving group selected from halogen, methane-sulphon-ate and p-toluenesulphonate and Y is selected from the group-ings , , , R1 and X being as above defined, R2 being a hydrogenolysable group and R3 being the same as R1 or as R2: or V is the grouping and Y the grouping R1 being as above defined and Hal representing a halogen atom; that any carbonyl group in a so-obtained compound is reduced to CH2 and that, when desired, a compound obtained by any of the previous steps is subjected to one or more of the following finishing steps:

a) hydrogenolysation or any hydrogenolysable groups in the so-obtained compound;

b) conversion of a so-obtained compound of the for-mula I into a phosphonium salt, an ammonium salt or an acid addition salt thereof;

c) conversion of a so-obtained phosphonium salt, an ammonium salt or an acid addition salt of a com-pound of the formula I into the free compound of the formula I;

d) conversion of a so-obtained compound of the formula I into an N- or P-oxide;

e) conversion of a so-obtained compound of the formula I or an N- or P-oxide thereof, into a cation-containing-complex thereof;

f) conversion of a cation-containing-complex of a compound of the formula I into the free compound of the formula I.

51. Process according to claim 50, characterised in that V in the general formula IV is halogen or the grouping where Hal represents halogen, and when V is halogen then Y in the general formula III is selected from the groupings , , and when V is the grouping then Y is the grouping , the groups R1, R2, R3 and X

being as defined in claim 50.

52. Process according to claim 50, characterised in that a compound of the general formula is condensed with a compound of the general formula A, D, R2, R3, X, m and n being as defined in claim 50, followed, if desired, by hydrogenolysation of the hydro genolysable groups in the so-obtained quaternary salt of the general formula

53. Process according to claim 50 for the preparation of compounds in which both X are nitrogen, characterised in that a compound of the general formula is condensed with a compound of the general formula A, D, R1, m, n and Hal being as defined in claim 50.

54. Process according to claim 50 or claim 51, charac-terised in that condensation is performed using high dilution techniques.

55. Process according to claim 52 or claim 53, charac-terised in that condensation is performed using high dilution techniques.

56. Process according to claim 50 or claim 51 charac-terised in that conversion of a cation-containing-complex of the formula I into the free compound of the formula I
is effected by treatment with acid.

57. Process according to claim 52 or claim 53 charac-terised in that conversion of a cation-containing-complex of the formula I into the free compound of the formula I
is effected by treatment with acid.

58. Process according to claim 50 or claim 51 charac-terised in that conversion of a so-obtained compound of the formula I into a cation-containing-complex is effected by admixing the compound of the formula I with a cation-source-compound.

59. Process according to claim 52 or claim 53 charac-terised in that conversion of a so-obtained compound of the formula I into a cation-containing-complex is effected by admixing the compound of the formula I with a cation-source-compound.

60. A compound represented by the following formula in which each of R1, R2 and R3 independently is a chain of 4-12 methylene groups interrupted by 2-3 heteroatoms selected from oxygen and sulphur, with the proviso that no heteroatom is placed at the end of any chain between a nitrogen atom and a carbon atom, and that any two heteroatoms in any chain must be separated by at least one methylene group.

61. A compound according to claim 60, in which said heteroatoms are oxygen atoms.

62. A process for the preparation of 1,10-diaza-4,7,13,-16,21,24-hexaoxabicyclo[8.8.8]-hexacosane which consists of contacting1,10-diaza-4,7,13,16,21,24-hexacxa-2,9-dioxobicycllo-[8.8.8]-hexacosane with borane or diborane in tetrahydrofuran at no more than about 0°C., gradually warming to room temperature, and heating, decomposing excess reducing agent, and recovering the hexaoxabicyclo[8.8.8]-hexacosane.

63. A process for the preparation of 1,10-diaza-4,7,13,16,21,24-hexaoxabicyclo[8.8.8]-hexacosane which comprises contacting 1,10-diaza-4,7,13,16,21,24-hexaoxa-2,9-dioxobi-cyclo[8.8.8]-hexacosane with a reducing agent selected from borane and diborane in tetrahydrofuran at no more than about 0°C., heating the mixture thus obtained, decomposing excess reducing agent, and recovering said hexaoxabicyclo[8.8.8]-hexacosane.

64. A process according to claim 62 or 63, in which the reducing agent is diborane.

65. A process according to claim 62 or 63, in which said recovering comprises hydrolysing the obtained diborane derivative with an acid and neutralizing the resulting acid addition salt of said hexaoxabicyclo[8.8.8]-hexacosane to obtain said hexacxabicyclo[8.8.8]-hexacosane.

66. The cation-containing complex of a compound represented by the following formula:

in which each of R1, R2 and R3 independently is a chain of 4-12 methylene groups interrupted by 2 to 3 heteroatoms selected from oxygen and sulphur, with the proviso that no heteroatom is placed at the end of any chain between a nitrogen atom and a carbon atom, and that any two heteroatoms in any chain must be separated by at least one methylene group.

67. The complex according to claim 66, wherein said heteroatoms are oxygen atoms.

68. A dioxane-solution of the complex of potassium per-manganate with 1,10-diaza-4,7,13,16,21,24-hexaoxabicyclo-[8.8.8]-hexacosane.

69. A solution in an organic solvent of the complex of potassium permanganate with 1,10-diaza-4,7,13,16,21,24-hexa-oxabicyclo[8.8.8]-hexacosane.

70. The complex of potassium permanganate with 1,10-diaza-4,7,13,16,21,24-hexaoxabicyclo-[8.8.8]-hexaccosane.