SPECTINOMYCIN DERIVATIVES, THEIR SALTS WITH ACIDS AND PROCESSES FOR THEIR PREPARATION

DERIVES DE LA SPECTINOMYCINE, LEURS SELS ACIDES ET PROCEDE DE PREPARATION

English Abstract

ABSTRACT OF THE DISCLOSURE
The invention is compounds of formula
<IMG> I
wherein X is hydrogen or a protective group easily removable by treatment
with acid or base or by reduction, and Y is a compound removable by reduc-
tion, and acid addition salts of those compounds of formula I which contain
basic groups. The compounds are useful intermediates in the preparation of
spectinomycylamines, which display strong antrimicrobial activity.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing compounds of the general formula
<IMG> (I)
wherein X is a hydrogen atom or a protective organic group which is easily
removable by treatment with acid or base or by reduction and Y represents a
hydroxy, methoxy, benzyloxy or piperidino group or a group of formula
<IMG> ,
wherein Z represents an oxygen or sulfur atom and R1 represents a methyl
group (which is unsubstituted or is substituted by a cyano, morpholino, N-
methylanilino or N,N-methyl-benzylamino group), a phenyl group (which is
unsubstituted or is substituted by a hydroxy or amino group), a pyridyl
group, an amino or anilino group, an alkoxy group with 1 to 6 carbon atoms,
an aralkoxy group with 7 to 10 carbon atoms or a phenoxy group, or Y rep-
resents a group of general formula
-NH-SO2-R2,
wherein R2 represents a methyl or p-tolyl group, or Y is a group of general
formula
<IMG>
wherein R3 and R4 represent a methyl, phenyl or amino group, or Y represents
a pyridyl-(2)-amino, pyrimidyl-(2)-amino, benzoxazole-2-one-3-yl, 3,4-
17

dihydro-chinoline-2-one-1-yl or the tetrahydroisoquinoline-4,4-dimethyl-1,3-
dione-2-yl group (which is unsubstituted or is substituted in the aromatic
part by a methoxy group), a imidazolidine-2-one-1-yl group or imidazolidine-
2,4-dione-1-yl group (which is unsubstituted or is substituted in the 3-
position by a phenyl radical) an oxazolidine-2-one-3-yl group (which is un-
substituted or is substituted in the 5-position by a methyl, ethyl, benzyl
or p-chloro-benzyl group or by a phenyl group which is unsubstituted or is
substituted by 1 to 3 halogen atoms or by a methoxy group), and acid addition
salts of compounds of formula I which contain basic groups, which process
comprises reacting a compound of formula
<IMG> , (II)
wherein X is as defined above, or an acid addition salt thereof, with com-
pounds of formula
NH2-Y III
wherein Y is as defined above and, if the compound of formula I contains a
basic group and the acid addition salt is required, reacting the compound of
formula I with a suitable organic or inorganic acid.
2. A process according to claim 1 wherein the reaction is carried
out in water or an organic solvent at a temperature between 0° and 100°C.
3. A process according to claim 1 wherein X is a benzyloxy carbonyl
group, a 4-bromo-, 4-nitro- or 4-chloro-benzyloxy carbonyl group, a 4-
methoxy-, 3,4-dimethoxy-, 3,4-methylene-dihydroxy-, 3,4,5-trimethoxy-, 4-
decyloxy-, 4-acetoxy- or 4-ethoxy- carbonyloxy-benzyloxy carbonyl group, a
18

saturated or unsaturated alkoxy carbonyl group with 1 to 12 carbon atoms,
(which is unsubstituted or is substituted by a furyl-(2)-group, a p-tolyl-
sulfonyl group, one or more halogen atoms, an alkoxy or alkoxy-alkoxy group
with 1 to 3 carbon atoms in the alkyl part and 1 to 3 carbon atoms in the
alkylene part), a cycloalkyloxy carbonyl group with 5 to 12 carbon atoms
(which is unsubstituted or is substituted by a methyl, ethyl or tert.-butyl
group), an isobornyloxy carbonyl or adamantyl-(1)-oxycarbonyl group, a
phenyl- or biphenylalkoxy carbonyl group, (which is unsubstituted or is sub-
stituted in the phenyl radical by one to three methyl or methoxy groups and
whose alkylene group is straight or branched contains 2 to 4 carbon atoms)
a diphenyl-methoxy-carbonyl group, a phenyloxy carbonyl group, (which is
unsubstituted or is substituted by a nitro, methoxy or methyl group), a
dialkylaminooxy carbonyl group a piperidinooxy-carbonyl group, an alkylthio
carbonyl group with 1 to 4 carbon atoms in the alkyl part, a benzylthio
carbonyl group, a formyl group, an aliphatic acyl group with 1 to 10 carbon
atoms, (which is unsubstituted or is substituted by 1 to 3 halogen atoms,
hydroxy groups, acyl radicals or by a nitro group), a benzoyl, 2-nitro-
benzoyl, 4-toluene sulfonyl, benzylsulfonyl p-methoxybenzene sulfonyl benzyl
or trityl group.
4. A process according to claim 1 wherein X is a furyl-(2)-methoxy
carbonyl, alkyloxy carbonyl, 2-(p-tolylsulfonyl)-ethoxycarbonyl, 2-bromo-
ethoxy carbonyl, 2,2,2-trichloro-ethoxy carbonyl, 2-(2-methoxy-ethoxy)-ethoxy
carbonyl, 3-methyl-pentyl-(3)-oxycarbonyl or tert.-butyloxy carbonyl group.
5. A process according to claim 1 wherein X is an .alpha.,.alpha.-dimethyl-3,5-
dimethoxy-benzyloxy carbonyl, 2-[biphenylyl-(4)]propyl-(2)-oxycarbonyl
group, a cyclopentyloxy carbonyl, a cyclohexyloxy carbonyl (which are un-
substituted or are substituted by a methyl, ethyl or tert.-butyl group) or a
dimethylaminooxy carbonyl group.
19

6. A process according to claim 1 wherein X is a trifluoroacetyl,
acetoacetyl, 2-nitro-phenoxyacetyl, monochloroacetyl, 3-chloro-butyroyl or
3-hydroxy-isocaproyl group.
7. A process according to claim 1 wherein X is hydrogen.
8. A process according to claim 1 wherein X is a phenoxy carbonyl,
p-tosyl, p-methoxybenzene sulfonyl, trichloroacetyl, benzoyl, isobornyloxy-
carbonyl, chloroacetyl or acetyl group.
9. A process according to claim 1 wherein Y is a hydroxyl,
benzyloxy, methoxy, phenoxy, benzoylamino, p-tosylamino, N-phenylthioureido,
phenoxycarbonylamino, ethoxycarbonylamino, p-methoxy benzyloxycarbonylamino,
p-aminophenylcarbonylamino, morpholino-acetylamino, p-hydroxyphenylcarbonyl-
amino, N-phenyl-N-methyl-aminoacetylamino, pyridyl-(2)-amino, 2-amino-6-
methyl-pyrimidyl-(4)-amino, pyrimidyl-(2)-amino, 2,6-dimethyl-pyrimidyl-(4)-
amino, 2-methyl-6-amino-pyrimidyl-(4)-amino, 2-methyl-6-phenyl-pyrimidyl-
(4)-amino, imidazolidin-one-(2)-yl-(1), imidazolidine-dione-(2,4)-yl-(1),
3-phenyl-imidazolidine-dione-(2,4)-yl-(1), 5-phenyl-oxazolidinone-(2)-yl-(3),
5-methyl-oxazolidinone-(2)-yl-(3), oxazolidinone-(2)-yl-(3), 5-benzyl-
oxazobilinone-(2)-yl-(3), 5-ethyl-oxazolidinone-(2)-yl-(3), 5-p-chlorobenzyl-
oxazolilinone-(2)-yl-(3), 5-(3,4-dichloro)phenyl-oxazolidinone-(2)-yl-(3),
5-p-chlorophenyl-oxazolidinone-(2)-yl-(3), 5-p-methoxyphenyl-oxazolidinone-
(2)-yl-(3), 5-p-bromophenyl-oxazolidinone-(2)-yl-(3), 4,4-dimethyl-7-
methoxy-1,2,3,4-tetrahydro-isoquinoline-(1,3)-dione-yl-(2), 4,4-dimethyl-
1,2,3,4-tetrahydro-isoquinoline-(1,3)-dione-yl-(2), piperidine-yl-(1), 2,3-
dihydro-benzoxazole-(2)-one-yl-(3), 1,2,3,4-tetrahydro-quinoline-(2)-one-yl-
(1) benzylamino or acetylamino group.
10. A process according to claim 1 wherein X is a benzyloxy carbonyl,

2,2,2-trichloro ethoxy carbonyl, isobornyloxy carbonyl, p-methoxybenzene-
sulfonyl or benzoyl group.
11. A compound of Formula I as defined in claim 1 when made by a pro-
cess according to claim 1 or an obvious chemical equivalent thereof.
12. A process according to claim 1 wherein the starting material of
Formula II is reacted as the dihydrochloride pentahydrate.
13. A process for preparing spectinomycin-benzyloxime which comprises
reacting spectinomycin-dihydrochloride-pentahydrate with O-benzylhydroxylamine.
14. The compound spectinomycin-benzyloxime whenever prepared by the
process of claim 13 or an obvious chemical equivalent thereof.
15. A process for preparing 6,8-bis-2,2,2-trichloro-ethoxy-carbonyl
spectinomycin-benzyloxime which comprises reacting 6,8-bis-2,2,2-trichloro-ethoxy
carbonyl spectinomycin with O-benzylhydroxylamine-hydrochloride.
16. The compound 6,8-bis-2,2,2-trichloro-ethoxy-carbonyl spectino-
mycin-benzyloxime whenever prepared by the process of claim 15 or an obvious
chemical equivalent thereof.
17. A process for preparing 6,8-bis-benzyloxy carbonyl-spectinomycin-
-oxime which comprises reacting 6,8-bis-benzyloxy carbonyl spectinomycin with
hydroxylamine.
18. The compound 6,8-bis-benzyloxy carbonyl-spectinomycin-oxime when-
ever prepared by a process according to claim 17 or an obvious chemical equiva-
lent thereof.
21

Description

The invention relates to novel spectinomycin derivatives. Specto-
mycin is the compound of formula
H OH
CH3 - N ~~
HO ~ O ~ 4
H ~' \CH
The present invention relates to compounds of general formula I
X OH
3 - ~ 1O ~ 1 ~ (I)
HO ~ 5 ~ I ~
N \ OH N - Y
X CH3
their acid addition salts with inorganic or organic acids, if basic radicals
~ are contained in the compounds of general formula I, and processes for their
; preparation. The compounds of general formula I are valuable intermediates
for the preparation of spectinomycylamines which display strong antimicrobial
activity.
In the above general formula I,X represents a hydrogen atom or a
protective organic group, which is easily removable by treatment with acids
and bases or by reduction. For example the following groups, which are used
as protective groups in peptide chemistry, are suitable: a benzyloxy car-
bonyl group, a 4-bromo-, 4-nitro- or 4-chloro-benzyloxy carbonyl group, a 4-
methoxy-, 3,4-dimethoxy-, 3,4-methylene-dihydroxy-, 3,4,5-trimethoxy-, 4-
decyloxy-, 4-acetoxy- or 4-ethoxy- carbonyloxy-benzyloxy carbonyl group, a
saturated or unsaturated alkoxy carbonyl group with 1 to 12 carbon atoms,
(which is unsubstituted or is substituted by a furyl-(2)-group, a p-tolyl
sulfonyl group, one or more halogen atoms, an alkoxy or alkoxy-alkOXY group
- 1 -
.~'

with 1 to 3 carbon atoms in the alkyl part and 1 to 3 carbon atoms in the
alkylene part), for example a furyl-(2)-methoxycarbonyl, allyloxy-carbonyl,
2-(p-tolylsulfonyl)-ethoxy-carbonyl, 2-bromo-ethoxy-carbonyl, 2,2,2-tri-
chloro-ethoxy-carbonyl, 2-(2-methoxy-ethoxy)-ethoxy carbonyl, 3-methyl-
pentyl-(3)-oxycarbonyl group, but particularly the tert.-butyloxy carbonyl
group, a cycloalkyloxy carbonyl group with 5 to 12 carbon atoms, for example
a cyclopentyloxy carbonyl or cyclohexyloxy carbonyl group, which both are
unsubstituted or are substituted by a methyl, ethyl or tert.-butyl group), an
isobornyloxy-carbonyl or an adamantyl-(l)-oxy-carbonyl group, a phenyl or
biphenylalkoxy-carbonyl group, which is unsubstituted or is substituted in
the phenyl radical by one to three methyl or methoxy groups and whose alkylene
group, which may be straight or branched, contains 2 to 4 carbon atoms),
such as for example a ~ ~-dimethyl-3,5-dimethoxy-benzyloxy carbonyl or 2/ [bi-
phenylyl-(4 ~propyl-(2)-oxy carbonyl group, a diphenylmethoxy carbonyl
group, a phenyloxy carbonyl group, (which is unsubstituted or is substituted
~: by a nitro, methoxy or methyl group), a dialkylaminoxy carbonyl group such
as a dimethylaminoxy carbonyl group or a piperidinooxy carbonyl group,)
an alkylthio carbonyl group with l to 4 carbon atoms in the alkyl radical,
a benzylthio carbonyl group, a formyl group, an aliphatic acyl group with l
to 10 carbon atoms,(which is unsubstituted or is substituted by 1 to 3 halogen
atoms, hydroxy groups, acyl radicals or by a nitro group), such as a tri-
fluoro acetyl, aceto acetyl, 2-nitro-phenoxy acetyl, monochloro acetyl, 3-
chloro butyroyl, 3-hydroxyisocaproyl group. The easily removable group
: represented by X may also be a benzoyl, 2-nitrobenzoyl, 4-toluene sulfonyl,
benzylsulfonyl, p-methoxybenzolsulfonyl, benzyl or trityl group, Y represents
a hydroxy, methoxy,benzyloxy or piperidino group or a group of formula
z
-NH-C-Rl,
-- 2 --

~
wherein Z represents an oxygen or sulfur atom and R1 represents a methyl
group (which is unsubstituted or is substituted by a cyano, morpholino, N-
methylanilino or N,N-methyl-benzylamino group), a phenyl group (which is un-
substituted or is substituted by a hydroxy or amino group), a pyridyl group,
an amino or anilino group, an alkoxy group with 1 to 6 carbon atoms, an
aralkoxy group with 7 to 10 carbon atoms o:r a phenoxy group, or Y represents
a group of general formula
-NH-S02-R2,
wherein R2 represents a methyl or p-tolyl group, or a group of general for-
mula
N R3
_ NH ~ / N
R4
wherein R3 and R4 represent a methyl, phenyl or amino group, or Y represents
a pyridyl-(2)-amino, pyrimidyl-(2)-amino, benzoxazole-2-one-3-yl, 3,4-di-
hydro-chinoline-2-one-1-yl or the tetrahydroisoquinoline-4,4-dimethyl-1,3-
dione-2-yl group, (which is unsubstituted or is substituted in the aromatic
part by a methoxy group), an imidazolidine-2-one-1-yl group or imidazolidine-
2,4-dione-1-yl group (which is unsubstituted or is substituted in the 3-
position by a phenyl radical) an oxazolidine-2-one-3-yl group(which is un-
substituted or is substituted in the 5-position by a methyl, ethyl, benzyl
or p-chloro-benzyl group or by a phenyl group which is unsubstituted or is
substituted by 1 to 3 halogen atoms or by a methoxy group).
The compounds of general formula I may be prepared according to
the following way: By reaction of spectinomycine derivatives of general for-
mula

N \ OH O
X CH3
wherein X is as defined above, with compounds of general formula
NH2 ~ Y , (III)
wherein Y is as defined above.
The reaction is suitably carried out in water or in an organic
solvent, for example in an alcohol such as ethanol, or isopropanol, in a
carboxylic acid such as glacial acetic acid, in an ester or an ether such as
dioxane or in a mixture of such solvents, preferably at temperatures between
O and 100 C, most preferably at temperatures between 0 and 50 C.
It is known from the literature (see P. F. Wiley, A. D. Argoudelis
and H. Hoeksema, J. Am. chem. Soc. 85, 2652 to 2659 ~196~ ) that the ketonic
carbonyl group in a spectinomycin (in the literature still called actino-
spectacin) of general formula II possesses only a slight reactivity and that
it does not react with most of the carbonyl reagents; only with thiosemi-
carbazide a thiosemicarbozone is formed, the latter, however, at its forma-
....
tion sets free a molecule of water, whereby in the molecule an olefinic bond
is formed. The more surprising however, is the fact that already at tem-
peratures until 50C hydrazones of general formula I can be obtained in very
good yields when using a compound of general formula II, and for example a
hydrazine of general formula III.
Those compounds of general formula I which contain a basic radical,
may be converted, if desired, to their acid addition salts with organic or
inorganic acids. Suitable acids are, for example, hydrochloric acid, sul-
-- 4 --

furic acid, phosphoric acid, fumaric acid, malic acid.
The starting compounds of general formula II are known from the liter-
ature ~see the literature reference cited above) or they may be prepared in accor-
dance to known methods.
The spectinomycin derivatives of general formula I are starting com-
pounds for the preparation of pharmacologically valuable 4-spectinomycylamines
which display very good effects against grampositive and gramnegative bacteria.
The preparation of 4-spectinomycylamines from compounds of general formula I is
the subject of our Canadian Patent Application Serial No. 318,316, filed December
20, 1978.
By reduction of compounds of general formula I, e.g. by means of hydro-
gen in the presence of metal catalysts such as platinum, palladium or platinum
dioxide, spectinomycin derivatives of general formula
CH3 pH
X - N - ~ ~ `r--CH
HO ~ ~ 3 (IV),
X~N~cH OH NH2
are obtained. Those compounds in which X is other than hydrogen, can subsequently
be converted to 4-spectinomycylamine of formula IV, in which X represents hydro-
gen, for example by hydrogenolytic, acidolytic or basic removal of the radical X.
The 4-spectinomycylamine resp. the decahydro-4a,7,9-trihydroxy-4-amino-
2-methyl-6,8-bis-(methylamino)-pyrano-~2,3-b] ~1,4]benzodioxine consisting of a
4 R-form with an axial amino group and/or consisting of a 4 S-form with an equa-
torial amino group and the pharmacologically compatible salts with inorganic or
organic acids thereof display, particularly the 4-R-isomer, very distinct anti-
microbial effect and are significantly superior to the actinospectacin known up
-
.

to now (see J. Am. chem. Soc. 85, 2652 - 2659 ~1963]). In this connection we
refer to our Canadian Patent Application Serial No. 318,320, filed December 20,
1978.
The following examples serve to illustrate the present invention:
Example 1
Spectinomycin-benzyloxime
6 g (0.012 mol) of spectinomycin-dihydrochloride-pentahydrate and
3 g of O-benzylhydroxylamine were dissolved in 25 ml of water and 25 ml of
methanol. The solution was s~irred over night, evaporated, the residue was dis-
solved in little abs. ethanol and ether was added until turbitidy began. 5.0 g(83% of theory) of colourless powder were obtained (decomposition at 175C) Rf-
value 0.8 (silica gel, chloroform/methanol/conc.ammonia = 20:20:3). NMR-spectrum
(solvent CD30D)
ppm: 1.3 (doublet 3H ~- 2-CH3)
2.8 (doublet 6H - -N-CH3)
4.45 (singlet lH A lOaHO)
5.2 (singlet 2H A benzyl-CH2)
7.4 (singlet 5H - C6H5)
The free compound was obtained by reacting the aqueous-methanolic solu-
tion of the dihydrochloride with an ion exchanger (Dowex* 2 x 8 (OH-form)) until
the pH-value of 10.4 remained. Yield: Colourless crystals of melting range 86 -
` 106C.
The following compounds may be obtained in the same way:
(a) 6,8-Bis-benzyloxy carbonyl-spectinomycin-oxime from 6,8-bis-benzy-
loxy carbonyl spectinomycin and hydroxylamine.
Rf: 0.38 (silica gel, chloroform/methanol = 9:1)
C30H37N3011 Weight of mol: 615.6
Calc.: C 58.52 H 6.06 N 6.82
* trade mark
~,.

c~
Found: 58.00 6.21 6.65
The starting material 6,8-bis-benzyloxy carbonyl spectinomycin is
known from the literature (J. A. C. S. 85, S. 2657 (1963)).
b) 6,8-Bis-benzyloxy carbonyl-spectinomycinbenzyloxime from 6,8-
bis-benzyloxy carbonyl spectinom~ycin and 0-benzylhydroxyl amine
Rf: 0.42 (silica gel, chlorofrom/methanol = 9:1)
c) 6,8-Bis-benzyloxy carbonyl spectinomycin-methyloxime from 6,8-
bis-benzyloxy carbonyl spectinomycin and 0-methylhydroxyl amine
Rf: 0.40 (silica gel, chlorofrom/methanol = 9:1)
d) 6,8-Bis-p-tosyl spectinomycin-oxime from 6,8-bis-p-tosyl
spectinomycin and hydroxyl amine
Rf: 0.3 (silica gel, chloroform/methanol = ll:l)
The starting material 6,8-bis-p-tosyl-spectinomycin was obtained from
spectinomycin and p-toluene sulfochloride according to the method described
in J. Antibiotics XXVIII, p. 140 (1975) for the 6,8-bis-benzyloxy carbonyl-4-
dihydrospectinomycin.
Rf: 0.29 (silica gel, chloroform/methanol 9:1)
e) 6,8-Bis-p-methoxybenzene sulfonyl spectinomycin-oxime from
6,8-bis-p-methoxybenzene sulfonyl spectinomycin and hydroxyl amine
Rf: 0.32 (silica gel, chloroform/methanol = 11~1).
The starting material 6,8-bis-p-methoxybenzene sulfonyl spectinomycin was
prepared from spectinomycin and p-methoxybenzene sulfochloride, as described
before.
Rf: 0.40 (silica gel, chloroform/methanol = 9:1).
f) 6,8-Bis-2,2,2-trichloro ethoxy carbonyl-spectinomycin-
benzyloxime from 6,8-bis-2,2,2-trichloro ethoxy carbonyl spectinomycin and
0-benzylhydroxyl amine.
Rf: 0.30 (silica gel, chloroform/methanol = 9:1)
- 7 -

$
The starting material 6,8-bis-2,2,2-trichloro ethoxy carbonyl spectinomycin
was prepared from spectinomycin and 2,2,2-trichloroethoxy carbonyl chloride,
as described before.
Rf: o.c6 ~silica gel, chloroforrn/methanol = 11:1).
g) 6,8-Bis-phenoxy carbonyl spectinomycin-oxime from 6,8-bis-
phenoxy carbon;yl spectinomycin and hydroxyl amine.
Rf: 0.35 (silica gel, chloroform/methanol = 9:1)
The starting material 6,8-bis-phenoxy carbonyl spectinomycin was obtained
from spectinomycin and phenoxy carbonyl chloride as described above.
Rf: 0.54 (silica gel, chlorofrom/methanol = 5:1).
h) 6,8-Bis-benzoylspectinomycin-oxime from 6,8-bis-benzoyl-
spectinomycin and hydroxyl amine.
Rf: 0.24 (silica gel, chloroform/methanol = 9:1).
The starting material 6,8-bis-benzoylspectinomycin was obtained from
spectinomycin and benzoyl chloride as described before.
Rf: 0.20 (silica gel, chloroform/methanol = 9:1).
i) 6,8-Bis-isobornyloxycarbonyl-spectinomycin-benzyloxime from
6,8-bis-isobornyloxy carbonyl-spectinomycin and 0-benzylhydroxyl amine.
Rf: 0.55 (silica gel, chloroform/methanol = 10:1).
The starting product 6,8-bis-isobornyloxy carbonyl-spectinomycin was prepared
from spectinomycin and isobornyloxy carbonyl chloride, as described before.
Rf: 0.42 (silica gel, chloroform/methanol = 10:1).
;) 6,8-Bis-chloroacetyl spectinomycin-benzyloxime from 6,8-bis-
chloroacetyl spectinomycin and 0-benzylhydroxyl amine.
Rf: 0.3 (silica gel, chloroform/methanol = 10:1).
The starting product 6,8-bis-chloroacetyl-spectinomycin was prepared from
spectinomycin and chloroacetyl chloride as described above.
Rf: 0.17 (silica gel, chloroform/methanol = 10:1).
-- 8 --
.
:

k) 6,8-Bis-acetyl-spectinomycin-benzyloxime from 6,8-bis-acetyl-
spectinomycin and 0-benzylhydroxyl arnine
Rf: 0.25 (silica gel, chlorofrom/methanol = 10:1)
The starting product 6,8-bis-acetyl-spectinomycin was prepared from spectino-
mycin and acetyl chloride as described bef`ore.
Rf: 0.1 (silica gel, chloroform/methanol = 10:1).
1) Spectinomycin-benzhydrazone dihydrochloride from spectinomycin
dihydrochloride pentahydrate and benzoylhydrazine.
Point of decomposition 180C,
Rf: 0.35 (cellulose, butanol/methanol/water = 90:25:20).
m) Spectinomycin-p-tosylhydrazone-dihydrochloride from spectino-
mycin-dihydrochloride-pentahydrate and p-tosylhydrazine.
Range of decomposition 130 - 143 C,
Rf: 0.32 (cellulose, butanol/methanol/water = 90:25:20).
n) Spectinomycin-acetylhydrazone dihydrochloride from spectino-
mycin-dihydrochloride-pentahydrate and acetylhydrazine.
Range of decomposition 160 - 180 C,
- Rf: 0.29 (cellulose, butanol/methanol/water = 90:40:20),
o) Spectinomycin-methylsulfonyl hydrazone-dihydrochloride from
spectinomycin-dihydrochloride-pentahydrate and methylsulfonyl hydrazine.
Rf: 0.22 (cellulose, butanol/methanol/water = 90:25:20).
p) Spectinomycin-4-pyridoylhydrazone-dihydrochloride from
spectinomycin-dihydro chloride pentahydrate and pyridine-4-carbonic acid
hydrazide.
Rf: 0.31 (cellulose, butanol/methanol/water = 90:25:20).
q) Spectinomycin-phenylthiosemicarbazone-dihydrochloride from
spectinomycin-dihydrochloride pentahydrate and 4-phenylthiosemicarbazide
M.p.: 180 - 185C (ethanol/ether).
: _ g _

L~
r) Spectinomycin-semicarbazone-dihydrochloride from spectinomycin
dihydro chloride-pentahydrate and semicarbazide.
M.p.: 205 - 210C.
s) Spectinomycin-phenoxy carbonylhydrazone-dihydrochloride from
spectinomycin-dihydrochloride-pentahydrate and hydrazine carbonic acid phenyl
ester.
Rf: 0.45 (cellulose, butanol/methanol/water = 90:25:20).
t) Spectinomycin-ethoxy carbonylhydrazone-dihydrochloride from
spectinomycin-dihydrochloride-pentahydrate and hydrazine-carbonic acid ethyl
ester.
Rf: 0.26 (cellulose, butanol/methanol/water = 90:25:25).
u) Spectinomycin-cyanoacetylhydrazone-dihydrochloride from
spectinomycin-dihydrochloride-pentahydrate and cyanoacetylhydrazide.
Rf: 0.29 (cellulose, butanol/methanol/water = 90:25:25).
~; v) Spectinomycin-p-methoxybenzyloxy carbonyl-hydrazone-dihydro-
chloride from spectinomycin-dihydrochloride-pentahydrate and hydrazine car-
bonic acid-p-methoxybenzyl ester.
Rf: 0.45 (cellulose, butanol/methanol/water = 90:25:25).
w) Spectinomycin-p-aminobenzoylhydrazone-dihydrochloride from
spectinomycin-dihydrochloride-pentahydrate and p-aminobenzoic acid hydrazide-
dihydrochloride.
M.p.: 200 - 205 C.
x) Spectinomycin-morpholino acetylhydrazone-dihydro chloride from
spectinomycin-dihydrochloride-pentahydrate and morpholino-acetylhydrazide.
M.p.: 165 - 170 C.
y) Spectinomycin-p-hydroxybenzoyl hydrazone-dihydro chloride from
spectinomycin-dihydro chloride-pentahydrate and p-hydroxy-benzoic acid
hydrazide.
-- 10 --

a~
M.p.: 185 - 190C.
z) Spectinomycin-(N-methylanilino)-acetyl hydrazone-dihydro-
chloride from spectinomycin-dihydrochloride-pentahydrate and (N-methyl-
anilino)-acetylhydrazide.
M.p.: 175 - 180 C.
aa) Spectinomycin-(N-methyl-N-benzyl)amino-acetyl-hydrazone-
dihydrochloride from spectinomycin-dihydrochloride-pentahydrate and (N-
methyl-N-benzyl)amino-acetylhydrazide.
M.p.: 175 - 180 C.
ab) Spectinomycin-pyridyl-2-hydrazone-dihydrochloride from
spectinomycin-dihydrochloride-pentahydrate and 2-hydrazino-pyridine.
M.p.: 80 C.
ac) Spectinomycin-(2-amino-6-methylpyrimidyl-4)-hydrazone from
- spectinomycin-dihydrochloride-pentahydrate and 2-amino-4-hydrazino-6-methyl-
pyrimidine.
' M p.: 150C.
ad) Spectinomycin-pyrimidyl-(2)-hydrazone-dihydrochloride from
spectinomycin-dihydrochloride-pentahydrate and 2-hydrazino-pyrimidine.
M.p.: 160 - 165 C (decomp.).
ae) SpectinomycinL~,6-dimethyl-pyrimidyl-(4 ~hydrazone-dihydro-
chloride from spectinomycin-dihydrochloride-pentahydrate and 2,6-dimethyl-4-
hydrazino-pyrimidine.
M.p.: 170 - 175 C.
af) Spectinomycin ~ -amino-2-methyl-pyrimidyl-(4 ~hydrazone-
dihydrochloride from spectonomycin-dihydrochloride-pentahydrate and 6-amino-
2-methyl-4-hydrazino-pyrimidine.
M.p.: 165 - 170 C.
ag) Spectinomycin ~ -methyl-6-phenyl-pyrimidyl-(4 ~hydrazone-
-- 11 --
. .

dihydrochloride from spectinomycin-dinydrochloride-pentahydrate and 2-methyl-
6-phenyl-4-hydrazino-pyrimidine.
M.p.: 170 - 175 C.
ah) SpectinomycinL~midazolidine-one-(2)-yl-l~imine-dihydro
chloride from spectinomycin-dihydrochloride-pentahydrate and 1-amino-
imidazolidinone-(2).
M.p.: 180 C (decomp.).
ai) Spectinomycin~midazolidine-dione-(2,4)-yl-(117imine-
dihydrochloride from spectinomycin-dihydrochloride-pentahydrate and 1-amino-
10 imidazolidine-dione-(2,4).
M.p.: 190 - 195 C (decomp.).
aj) Spectinomycin~¦3-phenyl-imidazolidine-dione-(2,4)-yl~ 7-
imine-dihydrochloride from spectinomycin-dihydrochloride-pentahydrate and
l-amino-3-phenyl-imidazolidine-dione-(2,4).
M.p.: 185 - 190C.
ak) Spectinomycinr5-phenyl-oxazolidinone-(2)-yl-(3I7-imine-
dihydrochloride from spectinomycin-dihydrochloride-pentahydrate and 3-
amino-5-phenyl-oxazolidinone-(2).
M.p.: 175 - 180 C.
al) SpectinomycinL~-methyl-oxazolidinone-(2)-yl-(3~7-imine-
dihydrochloride from spectinomycin-dihydrochloride-pentahydrate and 3-
` amino-5-methyl-oxazolidinone-(2).
M.p.: 180 - 185 C.
am) SpectonomycinLIoxazolidinone-(2)-yl-(3 ~-imine-dihydro-
chloride from spectinomycin-dihydrochloride-pentahydrate and 3-amino-
oxazolidinone-(2).
m.p.: 180 C (decomp.).
'

an) spectinomycinL3-benzyl-oxazolidinone-(2)-yl-(3 ~imine-
dihydrochloride from spectinomycin-dihydrochloride-pentahydrate and 3-
amino-5-benzyl-oxazolidinone-(2).
M.p.: 170 - 175 C.
ao) Spectinomycin G -ethyl-oxazolidinone-(2)-yl-(3 ~imine-
dihydrochloride from spectinomycin-dihydrochloride-pentahydrate and 3-
amino-5-ethyl-oxazolidinone-(2).
M.p.: 170 - 175 C.
ap) spectinomycinL~-p-chloro-benzyl-oxazolidinone-(2)-yl-
(3~7imine-dihydrochloride from spectinomycin-dihydrochloride-pentahydrate
and 3-amino-5-p-chloro-benzyl-oxazolidinone-(2).
M.p.: 175 - 180 C.
aq) SpectinomycinL~-(3,4-dichloro)-phenyl-oxazolidinone-(2)-
yl-(3 D imine-dihydrochloride from spectinomycin-dihydrochloride-pentahydrate
and 3-amino-5-(3,4-dichloro)-phenyl-oxazolidinone-(2).
M.p.: 170 - 175 C.
ar) SpectinomycinL~-p-chloro-phenyl-oxazolidinone-(2)-yl-(3~7-
imine-dihydrochloride from spectinomycin-dihydrochloride-pentahydrate and
3-amino-5-p-chloro-phenyl-oxazolidine-one-(2).
M.p.: 185 - 190 C (decomp.).
as) SpectinomycinL--p-methoxyphenyl-oxazolidinone-(2)-yl-
(3 ~-imine-dihydrochloride from spectinomycin-dihydrochloride-pentahydrate
and 5-p-methoxy-phenyl-3-amino-oxazolidinone-(2).
M.p.: 175 - lôO C.
at) SpectinomycinL~-p-bromo-phenyl-oxazolidinone-(2)-yl-
(3D imine-dihydrochloride from spectinomycin-dihydrochloride-pentahydrate
and 3-amino-5-p-bromophenyl-oxazolidinone-(2).
M.p.: 185 - 190 C.
- 13 -
,.

~3~4~
au) Spectinomycin ~ ,4-dimethyl~-7-methoxy-1,2,3,4-tetrahydro-
isoquinoline-(1,3)-dione-yl-(2¦7imine-dihydrochloride from spectinomycin-
dihydrochloride-pentahydrate and 2-amino-4,ll-dimethyl-7-methoxy-1,2,3,4-
tetrahydro-isoquinoline-(1,3)-dione.
M.p.: lO9 - 111 C (decomp.).
av) SpectinomycinL~,4-dimethyl-1,2,3,4-tetrahydro-isoquinoline-
(1,3)-dione-yl-(2~T-imine-dihydrochloride from spectinomycin-dihydrochlo-
ride-pentahydrate and 2-amino-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinoline-
(1,3)-dione.
M.p.: 117 - 119 C (decomp.).
aw) Spectinomycin rpiperidine-yl-(1~ imine-dihydrochloride from
spectinomycin-dihydrochloride-pentahydrate and l-amino-piperidine.
M.p.: 123 - 125 C (decomp.).
ax) spectinomycinL~,3-dihydro-benzoxazole-(2)-one-yl-(3 ~imine-
dihydrochloride from spectinomycin-dihydrochloride-pentahydrate and 3-amino-
2,3-dihydro-benzoxazole-(2)-one.
M.p.: 220 - 222 C (decomp.).
ay) Spectinomycin C1,2,3,4-tetrahydro-quinoline-(2)-one-yl(1~7-
- imine-dihydrochloride from spectinomycin-dihydrochloride-pentahydrate and
1-amino-1,2,3,4-tetrahydro-quinoline-(2)-one.
M.p.: 129 - 131C (decomp.).
Example 2
6,8-Bis-2,2,2-trichloro-ethoxy-carbonyl spectinomycin-benzyloxime
6 g (o.oo8 mol) of 6,8-bis-2,2,2-trichloro-ethoxy carbonyl
spectinomycin and 1.5 g (0.01 mol) of o-benzylhydroxylamine-hydrochloride
were dissolved in 40 ml of dioxane and 40 ml of water. By addition of 4n-
sodium hydroxide solution the solution was adjusted to a pH-value of 3 to 4.
After stirring for 18 hours at room temperature the solution was added to
- 14 -
.A

; r~j
150 ml of water whilst stirring and extracted with ethyl acetate. The
organic phase was dried and evaporated. 6 g of a colourless product (93
of theory) were obtained.
Rf: 0.30 (silica gel, chloroform/methanol = 9:1)
NMR (solvent: deuterochloroform)
ppm: 1.35 doublet 2H (2-CH3)
3.15 doublet 6~ N-CH3)
1~.7 singlet lH (lOaH)
- 4.8 broad singlet (-CH - Cl )
5.2 singlet 2H (benzyl-CH2)
7.4 singlet 5H (phenyl)
The starting material 6,8-bis-~ -trichloro-ethoxy carbonyl
spectinomycin may be prepared from spectinomycin and chloroformic acid-
2,2,2-trichloro-ethyl ester according to the method described in J.
Antibiotics XXVIII, p. 140 (1975) for the 6,8-bis-benzyloxy carbonyl ~-
dihydro spectinomycin. Rf: 0.26 (silica gel, chloroform/methanol 11:1).
The following compounds are prepared in a similar manner.
The starting material 6,8-bis-p-methoxy benzene sulfonyl spectino-
mycin was obtained from p-methoxybenzene sulfochloride and spectinomycin as
mentioned above. Rf: 0.40 (silica gel, chloroform/methanol = 9:1).
a) 6,8-Bis-2,2,2-trichloro-ethoxy carbonyl spectinomycin-
methyloxime from 6,8-bis-2,2,2-trichloro-ethoxy carbonyl spectinomycin and
O-methylhydroxyl amine
Rf: 0.27 (silica gel, chloroform/methanol = 11:1).
b) 6,8-~is-2,2,2-trichloro-ethoxy carbonyl spectinomycin-
benzhydrazone from 6,8-bis-2,2,2-trichloroethoxy carbonyl spectinomycin and
benzhydrazide
Rf: 0.26 (silica gel, chloroform/methanol = 11:1).
- 15 -

~ ~L~ 5
c) 6,8-Bis-2,2,2-trichloroethoxy carbonyl spectinomycin-
acethydrazone from 6,8-bis-2,2,2-trichloroethoxy carbonylspectinomycin and
acethydrazide
Rf: 0.24 (silica gel, chloroform/methanol = 11.1).