close

Вход

Забыли?

вход по аккаунту

?

Model Reactions for Synthesis of Pharmacologically Active Polymers by Way of Monomeric and Polymeric Reactive Esters.

код для вставкиСкачать
l-Methyl-4-phen~l-l,2.3-triazole( I a )
Pure dimethylnitrosamine (1.62 ml, 22 mmol) is added with
stirring to a solution of lithium diisopropylamide (23 mmol)
in anhydrous THF (70 ml) (from 3.22 ml of diisopropylamine and 14.2 ml of n-butyllithium; 1.6 M in n-hexane)
at -78°C and the mixture is treated 10 min later with
benzonitrile (1.03 ml, 10 mmol). After being kept for 10 h
at the temperature of Dry Ice, the mixture is treated with
a solution of glacial acetic acid (1.32 ml, 23 mmol) in THF
( 5 ml). Working up with methylene dichloride affords a
crystalline crude product that, recrystallized from CCI, or
ligroin, forms colorless needles, m. p. 122 "C (yield 1.I
5 g,
72%).
Received: September 21,1972 [Z 724b I€]
German version : Angew. Chem. 84, 1187 (1 972)
.____
[I] D. Seebach and D. Enders, Angew. Chem. 84, 350, 1186 (1972);
Angew. Chem. internat. Edit. 11, 301, 1101 (1972).
[2] r-Triazoles have previously been prepared from: a) 1,2-dicarbonyl
compounds and hydrazines or hydroxylamineihydrazines; b) a-diazo
carbonyl compounds and primary amines; c) nitriles and diazo compounds; and d) acetylenes and azides (the most important method):
F. R. Benson and W L. Sacell, Chem. Rev. 46,1 (1950).
[3] H. Hoberg, Liebigs Ann. Chem. 707, 147 (1967).
[4] C. W Rees r t al., Chem. Commun. 1971, 532, 1518. 1519.
[S] For example, acetonitrile gives no triazole on treatment with
lithiated dimethylnitrosamine.
drugs themselves or only after release of lower-molecular
species. The problem is to effect linkage[21 of the drug
with monomers and polymers under mild conditions to
ensure complete retention of the biological activity and
exclusion of side reactions.
We have examined reactive esters, of the type known in
peptide chemi~try'~],
for their suitability as precursors of
pharmacologically active polymers. By treating unsaturated acid chlorides or anhydrides, esters or isocyanates with
N-hydroxy compounds and chloro- or n i t r o - p h e n o l ~we
~~~
have prepared the reactive unsaturated esters ( I ) to ( 9 )
shown in Table 1.
The monomers ( I ) , (Z), (7), and (8) are resistant to
hydrolysis; they react at 0°C in neutral or weakly alkaline
water/dioxane solution with amines, giving amides in
yields of up to 80%. The monomers ( 4 ) and ( 5 ) react at
room temperature with alcohols as well as with amines and
are hydrolyzable. Compounds ( 3 ) , ( 6 ) , and ( 9 ) were
subjected to reaction only as polymers since the monomers
lose acetaldehyde relatively easily[51.
All the monomers were subjected to radical polymerization. The homopolymers of (1)-(4) and (6) are soluble
in dimethyl sulfoxide, and the other polymers dissolve also
in other polar solvents, e.g. tetrahydrofuran and methylene
dichloride. Copolymers that dissolve in water or organic
Table 2. Model reactions for synthesis of pharmacologically active
polymers [22 T , in methylene dichloride, polymer 0.4 mol,'l (monomer
units), cyclohexylamine 0.8 moljl].
Model Reactions for Synthesis of Pharmacologically
Active Polymers by Way of Monomeric and
Polymeric Reactive Esters[**]
By Hans-Georg Batz, Giselher Franztnann, and
Helmut Ringsdorf'"
Cpd.
Reagent
Reaction course
Time
[dl
Poly-/4)
Cyclohexylamine
Cyclohexylamine
Cyclohexylamine
Cyclohexylamine
Cyclohexylamine
Ammonia [a]
Homogeneous
after co. 1 min
Heterogeneous
Id
Heterogeneous
3d
Heterogeneous
3d
Homogeneous
1
100
5
70
5
60
5
60-70
5
15
1
90
Poly-(I)
Pharmacologically active polymers have aroused increasing interest in recent years[". These polymers may act as
Poly-(2)
Poly-/3)
c1
0
Poly-(8)
Poly-(I)
Heterogeneous
10 h
Conversioii
[a] Solvent: H,O. Polymer 0.1 mol/l (monomer units); NH, 1.3 mol I.
Table 1. Reactive esters ( l ) - ( / 9 J .
Cpd
R
C H ,=CH -C 0
CH,=C(CH,)-CO
CH ,=CH -N H-C 0
C H *=C H-C 0
CH ,=C(CH 3)-C0
C H >=C H -N H -C 0
C H 2=CH -CO
CH,=C(CH ,)-CO
C 13 ,=CH -N H -C 0
68
103
111
122
40
140
65
60
130
65
76
85
30
30
80
70
65
40
1735,1775
1730-1 770
1730-1 770
1705
1785
1725
1750
1740
I725
[*] Dr. H -G. Batz, Dip].-Chem. G. Franzmann, and
Prof. Dr H. Ringsdorf
Institut fur organische Chemie der Universitlt
65 Mainz. Johann-Joachim-Becher-Weg 18 (Germany)
[**] Part 3 of Pharmacologically active polymers.--Part 2 : H . R ; n p
dorf, A . G . Herder, F . H . Miiller, E. H . Grou1.and W Rutlirr, Biol.Aspects
Rad. Protect. /Y7/. 138.
Anyew. Chem. internat. Edit. i Vol. I 1 (1972) 1 No. 12
6.1 3
5.95
4.39
6.15
6.0
4.51
6.05
5.82
4.45
6.70
6.45
1.68
6.78
6.57
5.08
6.73
6.47
4.65
6.50
6.57
7.38
6.50
6.32
-
6 65
solvents were prepared by copolymerization of the monomers ( I } -(9) with I-vinylpyrrolidone, methacrylamide,
acrylamide, or styrene.
Like the monomers, the polymers of active esters react
readily with nucleophilic reagents. This makes possible
to effect reaction of pharmacologically active compounds
1103
with polymers without racemization or side reactions.
Table 2 shows the model reactions effected with cyclohexylamine and ammonia. Methyl polyacrylate and polymethacrylate d o not react under the stated conditions.
The polymers prepared from (4)-(6)
and containing
benzotriazole are hydrolyzed in aqueous sodium carbonate
solution even at room temperature. If polymeric (4)-(6)
undergoes partial reaction with the model compounds
and is then hydrolyzed, polymers are obtained containing
carboxyl groups [from poly-(4) and poly-(5)] or amino
groups [from poly-(6)]. Neutral polymers are obtained
by treatment of the residual active ester groups with an
excess of amine or ammonia.
The Primary Step in the Halogenation of Cyclooctatetraene
By RolfHuisgen and Johann Gasteiged.1
The dichloride IS) of cyclooctatetraene, isolated by Reppe,
Schlichting, Klager, and Toepel"l, and the corresponding
dibromide are the result of a multi-stage reaction sequence that is analogous for chlorination and bromination. We have obtained thedichlorides ( 3 )to ( 5 ) in crystalline form and have elucidated their thermodynamic and
kinetic interrelationships"! Halogenation of ( I ) is unusually rapid and affords the cis-dichloride (4) exclusively.
c1
N-Hydroxysuccinimide methacrylate (2) 16'
Triethylamine (0.5 mol) and methacryloyl chloride (0.5
mol), each in 150 ml of CH,Cl,, are added dropwise with
stirring and ice cooling to N-hydroxysuccinimide (0.5 mol)
in anhydrous methylene dichloride (200 ml). After 6 hours'
stirring at room temperature the precipitated triethylammonium chloride is removed and the filtrate is shaken
with, successively, water, a little saturated sodium hydrogen
carbonate solution, and again water, dried and evaporated.
The residue is recrystallized from ethyl acetate/light petroIeum ; yield 70 g (77%).
Polymerization
The ester (2) (0.1 mol) is kept in anhydrous tetrahydrofuran
(200 ml) containing 0.5 mo1-X of azodiisobutyronitrile for
8 h at 60°C. The precipitated polymer is filtered off, digested
with tetrahydrofuran, filtered off again, and dried ; yield
15 g, 81 %.
Reaction with amines: poly-N-acryloylcyclohexylarnine
Poly-I-acryloyloxybenzotriazole[poly-(4)] (1.89 g, 0.01
mol) is mixed with cyclohexylamine (2.26 ml, 0.02 mol) in
methylene dichloride (25 ml). The solution becomes homogeneous after ca. 1 min. After 1day the product is precipitated by ether and reprecipitated from methanol/water. The
poly-I-acryloyloxycyclohexylamine was characterized by
elemental analyis and its IR and NMR spectra. The
conversion amounted to 100%.
Received : June 23,1972
Supplemented: October 16, 1972 [Z 725 I€]
German version: Angew. Chem. 84,1189 (1972)
(5)
c1
The endo-8-chlorohomotropylium chloride (2) presumed
to be the primary product provided the key to the understanding of the fast rate of chlorination and of the anomalous course leading to the cis-compound. The fluorosulfonate (2) (FSO; in place of C1-) combines with a
chloride ion to give the cis-dichloride ( 4 ) , whereas the
exo-8-chlorohomotropylium salt (6) and C1- afford the
trans-dichloride (3)13]. Our attempts to demonstrate the
primary endo-chlorination ( I ) (2) were not at first entirely successful. Chlorination of ( I ) at -90°C in the presence of antimony pentachloride afforded mixtures of
endo- and exo-8-chlorohomotropylium hexachloroantim ~ n a t e ' ~the
] ; disturbing formation of (6) was ascribed
to the subsequent reaction (4) SbCI,--f (61, which occurred quantitatively in a separate experimentr4].
--f
+
c1
[I]H . Lee, Polymer Reprints 12, No. 2, p. 73 (1971); S. J . Korenko and
Yu. J . Lisunkin, Farm. Zh. (Kiev) 26, 17 (1971); H . RingsdorJ Strahlentherapie 32, 627 (1967); K . P. Khomyakov, A . Virnik, and Z . Rogoun,
Russ. Chem. Rev. 33,462 (1969).
[2] R . Axen and S. Ernback, Eur. J. Biochem. 18, 351 (1971); E. M .
Crook, K . Brocklehurst, and C . H . Warton in S. P. Colowick and N . 0
Kaplan: Methods in Enzymology. Academic Press, New York 1971,
Vol. 19, pp. 963 ff.; L. Goldstein, ibid. pp. 935 8 ;H.P. Orrh and W Briimmer, Angew. Chem. 84,319 (1972); Angew. Chem. internat. Edit. 11,249
(1972).
[ 3 ] G . CC.: Anderson, J . E. Zimmermann, and F. M. Callahan, J. Amer.
Chem. SOC.86, 1839 (1964); F . Weygand, D. Hofjmann, and E. Wiinsch,
2. Naturforsch. 21 b, 426 (1966); W KGnig and R . Geiger, Chem. Ber.
103, 788 (1970).
[4] H . Morawetz, J. Amer. Chem. SOC.83,1738 (1961).
[S] G. Welzel, Dissertation, Universitat Freiburg 1960; C. J . Ouerberger, G. Montando, and S. lshida, J. Polymer Sci. A 1, 7, 35 (1969).
[6] H.-G. Batr, Dissertation, Technische Universitat Miinchen 1970.
1104
c1
In our search for a chlorinating agent that would stop the
reaction of ( I ) reliably at the homotropylium stage (2), we
have found that antimony pentachloride itself plays a
unique double role as C1+ donor and strong Lewis acid.
When 2 equivalents of SbCI, react with ( I ) in methylene
chloride at - 60°C the crystalline endo-salt (8) separates
[*] Prof. R. Huisgen and Dr. J. Gasteiger
Institut fur Organische Chemie der Universitat
8 Miinchen 2, Karlstrasse 23 (Germany)
Angew. Chem. internat. Edit.
Vol. I 1 (1972) 1 N o . I 2
Документ
Категория
Без категории
Просмотров
2
Размер файла
218 Кб
Теги
polymer, synthesis, mode, reaction, monomeric, activ, esters, way, polymeric, reactive, pharmacological
1/--страниц
Пожаловаться на содержимое документа