B-6 DESOXYTETRACYCLINES

PREPARATION OF .alpha.-6-DEOXYTETRACYCLINES

Abrégé anglais

A B S T R A C T
Hydrogenation of a mixture prepared from a 6-deoxy-6-demethyl-6-
methylenetetracycline compound, and a catalytic amount of a dicarboxy-
lato(triphenylphosphine)rhodium(II)or dicarboxylato(substituted
tiphenylphosphine)-rhodium(II) compound, in a reaction-inert solvent,
produces the corresponding 6-deoxytetracycline compound. The
hydrogenation takes place with a stereo-selectivity which favors the
6.alpha.-isomer over the 6.beta.-isomer. The products are known antibacterial
agents.

Revendications

The embodiments of the invention in which an exclusive
property or privilege is claimed are defined as follows:
1. A process for producing .alpha.-6-deoxy-5-hydroxy
tetracycline which comprises introducing a catalytic amount
of a compound of the formula Rh(OCOR)2(P[C6H5]3) and a tetra-
cycline compound selected from the group consisting of
<IMG>
and the acid-addition salts thereof into a reaction-inert
solvent, and maintaining hydrogen in contact with the reaction
mixture thus formed, at a temperature of from about 20 to about
100°C., and at a pressure from about 1 to about 100 atmospheres
until reaction of from about 1 to about 2 moles of hydrogen
per mole of tetracycline compound occurs:
wherein R is selected from the group consisting of
hydrogen, alkyl having from 1 to 6 carbon atoms, chloromethyl,
dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl,
trifluoromethyl, phenyl, chlorophenyl, tolyl or anisyl;
X is selected from the group consisting of hydrogen
and chloro;
and Y is selected from the group consisting of
hydrogen, hydroxy and alkanoyl having from 2 to 7 carbon atoms.
2. The process according to claim 1, wherein the said
13

tetracycline compound is selected from the group consisting of
<IMG>
and the acid-addition salts thereof, wherein X is hydrogen and
Y is hydroxy.
3. The process according to claim 2, wherein R is the
said alkyl.
4. The process according to claim 3, wherein R is methyl.
5. The process according to claim 3, wherein said tempera
ture is from about 40 to about 70°C.
6. The process of claim 3, wherein said catalytic amount
is about 0.1 to about 100 mol-per cent, based on said tetracycline
compound.
7. The process of claim 3, wherein said catalytic amount
is about 1 to about 10 mol-per cent, based on said tetracycline
compound.
8. The process of claim 3, wherein said reaction inert
solvent medium is selected from the group consisting of diethyl
ether, tetrahydrofuran, dioxan, 1,2-dimethoxy ethane, acetone,
methyl ethyl ketone, ethyl acetate, butyl acetate, methanol,
ethanol, isopropanol, ethylene glycol, propylene glycol,
diethylene glycol, 2-methoxyethanol, 2-(2-ethoxyethoxy)-ethanol,
acetic aaid, propionic acid, N,N-dimethylformamiae, N,N-di-
methylacetamide, N-methylpyrrolidone, and mixtures thereof.
9. The process of claim 3, wherein said pressure is
about 10 to about 1000 psig.
10. The process according to claim 1, wherein said
14

tetracycline compound is selected from the group consisting of
<IMG>
and the acid-addition salts thereof, wherein X is hydrogen and
Y is hydroxy.
11. The process according to claim 10, wherein R is the
said alkyl.
12. The process according to claim 11, wherein R is methyl.
13. The process according to claim 11, wherein said
temperature is from about 40 to about 70°C.
14. The process of claim 11, wherein said catalytic
amount is about 0.1 to about 100 mol-per cent, based on said
tetracycline compound.
15. The process of claim 11, wherein said catalytic amount
is about 1 to about 10 mol-per cent, based on said tetra-
cycline compound.
16. The process of claim 11, wherein said reaction inert
solvent medium is selected from the group consisting of diethyl
ether, tetrahydrfuran, dioxan, 1,2-dimethoxy ethane, acetone,
methyl ethyl ketone, ethyl acetate, butyl acetate, methanol,
ethanol, isopropanol, ethylene glycol, propylene glycol,
diethylene glycol, 2-methoxyethanol, 2-(2-ethoxyethoxy)ethanol,
acetic acid, propionic acid, N,N-dimethylformamide, N,N-dimethyl-
acetamide, N-methylpyrrolidone, and mixtures thereof.
17. The process according to claim 11, wherein said
pressure is about 10 to about 100 psig.

Description

8~
U.S. Patent 3,200,149 discloses the production of ~-6-
;~ deoxytetracycline derivatives by a process which involves hydro- -
genation of ~in 6-deoxy-6-demethyl-6-methylenetetracycl ~ s-in the pre- -
sence of a catalytic amount o~ a noble metal catalyst such as
rhodium or palladium. The process coproduces ~ 6-deoxytetracy-
clines, as well as ~-6-deoxytetracyclines. One of the major ob-
jectives of the present invention was to improve upon that process
so as to produce a higher ~-isomer to ~-isomer ratio.
It has now been found that a higher ratio of ~-isomer
10 to ~ isomer can be achievad by hydrogenating a mixture prepared
from the 6-deoxy-6-demethyl-6-methylenetetracycline compound and
a specific, soluble rhodium tII) species, in a reaction-inert
, ~olvent. The specifi~ soluble rhodium (II) species is a dicar-
boxylato~triphenylphosphine~rhodium ~II) or dicarboxylato~
~ubstituted triphenylphosphine)rhodium ~II) species.
:J
~l~ West German Offenlegungsschrift 2,308,227 broadly dis-
close3 the use of soluble rhodium species for the stereoselective
reductlon o~ 6-deoxy-6-demethyl-6-methylenetetracyclines. How-
ever, the said Offenlegungs~chrift exemplifies only the use of
20~;rhodium~(I) species. Hui et al., Inorganic Chemistr~, 12, 757
(1973), and Journal of the Chemical Society (London), Part D,
., ~
95~ (1970), report t~at rhodium ~I~) diacetate i9 an effective
hydrogenation catalyst. However, use o~ rhodium ~ diacetate
in t~he~process o~ the presen~ invention does not not lead to a
25 ; ~favorable~ to~ ratio; approximately equal amounts o tho ~ - and
2-
! ` :

~- isomers are formed. The presence of the triphenylphosphine
or substituted triphenylphosphine ligand is essential to obtain
a stereoselective reduction. Although Legzdins et al~, Journal
of the Chemical Societ~ (London), Part D, 825 (1969) have reported
the use of rhodium diacetate in the presence of triphenylphos-
phine as a hydrogenation catalyst, their experiments were run in
the presence of a ~erystrong acid. The process of the present
invention is carried out under neutral conditions, or on a
weekly-acidic tetracycline acid-addition salt.
The present invention is based on the discovery that
hydrogenation of a mixture prepared from a 6-deoxy-6~demethyl-
6-methylenetetracycline and a specific rhodium species, in a
reaction-inert solvent, results in hydrogenation of the exocyc-
lic methylene group, and proceeds with a stereoselectivity which
favors the ~-isomers over the ~-isomers by a factor of at least
9:1. ,:.
According to the present invention there is provided
.. ..
a process for producing ~-6-deoxy-5~hydroxytetracycline which
' comprises introducing a catalytic amount of a compound of the
`} formula Rh(~COR)2(P~C6H513) and a tetracycline compound selected
`~ from the group consisting of
X fiH2 ~N(CH3~2
23 C , `~r ~ J ~ r J ~3~2
'1 E~ O 0~ -
j ~" :" ' '
~ 30 ~ NH2
~'~ -~ ' '' .'
,., ~ .

and the acid-addition salts thereof into a reaction-inert sol-
vent, and maintaining h~drogen in contact with the reaction mix-
ture thus formed, at a temperature of from about 20 to about
100C., and at a pressure from about 1 to about 100 atmospheres
until reaction of from about 1 to about 2 moles of hydrogen
per mole of tetracycline compound occurs;
wherein R i5 selected from the group consisting of
hydrogen, alkyl having from 1 to 6 carbon atoms, chloromethyl,
dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl,
trifluoromethyl, phenyl, chlorophenyl, tolyl or anisyl;
X is selected from the group consisting of nydrogen
and chloro;
and Y is selected from the group consisting of
hydrogen, hydroxy and alkanoyl having from 2 to 7 carbon atoms.
Preparation of these starting materials is fully
disclosed and illustrated in U.S. Patent 3,200,149. In general,
the method of preparation involves treatment of a lla-chloro-6,
12-hemiketal of the appropriate tetracycline compound with a
strong acid of the dehydrating type such as sulfuric, trifluoro-
acetic, polyphosphoric, perchloric, hydrogen fluoride and the
like~ Of these, the preferred is hydrogen fluoride. Optimum
conditions are readily determined by routine experimentation.
~j Generally, the selected lla-chloroketal is merely added to the
selected acid and allowed to react, most appropriately at a
: .
temperature within the range o~ from 0 to 50C. and for a time
of up to several hours. After reaction is complete, the product ~ ;
is recovered in an appropriate manner, e.g., in the case o~
volatile acids by evaporation of the same to obtain the residual ~ -
`I product, and in other cases by standard procedure such as stir- -
ring with a non-solvent, e.g., diethyl ether, to precipitate
4~
~, :
.. ~
I
. ..
~` .. .. . .. ;,,. ,. . . . .. . .... ~. .. .. ;. . .

the product. ~hese 6-methylcne compounds may be converted
to acid addition salts or polyvalent metal salt complexes by
standard procedures prior to hydrogenation.
When the desired starting material is an lla-des-
chloro-6-deoxy-6-demethyl-6~methylenetetracycline, lla-de ;
chlorination may be accomplished by either chemical or catalytic
reduction using procedures well known to those skilled in the
~, art. Example XXXVII of U.S. Patent 3,200,149 illustrates hydro-
genation reduction of an lla-chloro-6~deoxy-6-deme~hyl-6-
methylenetetracycline hydrochloride to obtain the corresponding
lla-deschloro compound.
When Y of the starting materials for the present
invention is alkanoyloxy having from 2 to 7 carbon atoms, it
is appropriate to use the method of British Paten~ 1,287,493
1 15 for the preparation thereof. According to that method, the
appropriate lla-chloro-6-demethyl-6-deoxy-6-methylene-5-hydroxy-
tetracycline in the form of the free base or a poly~addition
~ salt is treated with a carboxylic acid having from 2 to 7 carbon
;l atoms in the molecule in the presence of methanesulfonic,
~, 20 ethanesulfonic or hydrofluoric acia, preferably at a tempera-
ture of from 20 to ~0C. for a period of time generally
-~ ranging from 2 to 20 hours. The resulting product may then be
"
reduced to the lla-deschloro compound by the procedure described
above.
The rhodium species of the formula Rh(OCOR)2Q are
either known in the art, or they are simple analogs or homo-
~' logs of compounds known in the art, and they can be prepared
by methods such as those discussed by Stephenson et al.,
~ . . . :.
;~ Journal of the Chemical Society (London), 3S32 (1965). Accord-
ing to these procedures, rhodium carbo~ylates are prep~red by ~ ;
~, -5-
'; ~, ., ' ' '
:,..

refluxing rhodium hydrous oxide in, for example, an excess
of formic, acetic or propionic acid and ethanol. The yellow
solutions gradually turn amber and then green. The resulting
solutions are cooled and the dark green powders which precipi-
tate are filtered off and recrystallized from methanol orwater. These products are found to be stable at temperatures
up to 240C. The final catalyst complex is prepared by the
addition of triphenylphosphine, or the appropriately substi-
tuted triphenylphosphine, and diethyl ether to a cold ethanolic
solution of the rhodium carboxylate.
Appropriate reaction inert solven~s for the process
of the present invention include those which serve to substan-
, tially dissolve. the starting materials or the produck. Examples
of such solvents include ethers such as diethyl ether, tetra-
hydro~uran, dioxan, 1,2-dimethoxyethane; lower aliphatic ketones
such as acetone and methyl ethyl ~etone; low molecular weight
esters such as ethyl ac:etate and butyl acetate; mono- and poly-
"~ . ...
hydric lower alcohols such as methanol, ethanol, isopropanol,
ethylene glycol, propylene glycol and diethylene gIycol; lower
; 20 alkoxy substituted alkanols such as 2-methoxy-ethanol and 2-(2- ;~
i ethoxyethoxy) ethanol; lower alkanoic acids such as acetic acid ~ -~
and propionic acid; tertiary amides such as N,N-dime$hylformamide,
!
N,N,-dimethylacetamide and N-methylpyrrolidone and mixtures there-
~, of. ; ~-
i 25 Introduc~ion of the hydrogen gas into the reaction
inert solvent medium contai~ing the rhodium species and tetra-
cycline is generally accomplished by carrying out the rsaction
in a sealed vessel under an atmosphere of hydrog~n or o~ hydrogen
mixed with an inert diluent such as nitrogen or argon. The
pressure inside the reaction vessel may vary from ahout 1 to about ;
"j .
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,s,~
~" ^ ' .'

100 atmospheres. The preferred pressure range, when the -~
atmosphere in the reaction vessel is substantially pure hy-
drogen, is from about 10 ~o abou~ 100 psig.
The hydrogenation is generally run at a temperature
of from about 20 to about 100C., and preferably from about
40 to about 70C. Utilizing the preferred temperature and
pressure values, hydrogenation generally takes place in a few
hours, e.g., from about 2 hours to about 10 hours.
On hydrogenating a 7-halo substituted 6-methylene-6
deoxy-6-demethyl-tetracycline starting material in the process
of this invention, the 7-halo substituent remains substantially
intact. On the other hand, an lla-chloro substituent is removed.
The expression "catalytic amount" as used herein is
well understood by those skilled in the art of kno~n, tetracycline
~ 15 hydrogenations. Generally, this amount ranges from about 0.1 to ~-
; about 100 mol ~ based on the tetracycline substrate. The pre- `
ferred amount is from about 1 to about 10 mol %.
The reaction pxoduct of the present invention may be
isolated from the reaction medium by standard methods. For
example, the produet can often be induced ~o precipitate by ~he
addition of a non-solvent such as hexane or water or by the
addition of certain agents whish form insoluble salts with the
product. Alternatively, the crude product can be isolated by ~ ;
evaporation of the solvent or ~y dilution of the reaction mix-
ture with a large excess of water ~ollowed by extraction of the
~i product into a water-immisc~ble organic solvent and subsequent
evaporation of the water-immiscible solvent.
The following examples are ~or the purpose of
illustrating the present invention~
_
... . .
:, ~ .
:,:

8~3
EXAMPLE 1
Reduction of 6-~ethylene-6-demethyl-6-deoxy-5-
h~droxytetracycline using Diacetato(triphenylphosphine)rhodium(II)
A solution of 2.0 g. t4.18 mmol) of 6-methylene-6-de-
methyl-6-deoxy-5-hydroxy~etracycline hydrochlorlde and 0.088 g.
(4.4 mol-per cent) of diacetato(triphenylphosphine)rhodium(II)
in 30 mlO of degassed methanol was shaken under an atmosphere of
hydrogen, in a sealed vessel, at 60-70C., for 5.75 hours. The
hydrogen pressure in the rea~tion vessel was 66-71 psig. The
vessel was then opened and the reaction solution was filtered.
The filtrate was examined by high-pressure liquid chromatography
which indicated that it contained the required ~-6-deoxy-5-hy-
droxytetracycline, contaminated by 2-3% of its C-6 epimer.
i .. ~. . .. .
To the filtrate was then added a mi`xture of 20 ml.
of water and 30 ml. of 10~ aqueous sulfQ~alicyclic a~id, with
stirring. Stirring was continued overnight, and then the precipi-
tate was filtered o~f, ~iving 2.62 g. (95% yield) of ~-6-deoxy-
5-hydroxytetracycline a~ its sulfosalicylate salt. The product
l was shown to be 93% pure by ultraviolet spectroscopy.
I EXAMPLE 2
The procedure of Example I is repeated, except that
the 6-methylene-6-demethyl-6-deoxy-5-hydroxytetracycline used
therein i8 replaced by an equimolar amount of: -
6 methylene~6-demethyl-6-deoxytetracycline, ; ~
,~ 6-methylene-6-demethyl-6-deoxy-5-acetoxytetracycline, ~.
6-methylene-6-demethyl-6-deoxy-5-propionyloxytetracycline,
~, 6-methylena-6-demethyl-6-deoxy-5-bu~yryloxxtetracycline,
~, . . .
6-methylene-6-demethyl-6-deoxy-lla-chlorotetracycline,
6-methylene-~-demethyl-6-deoxy-S-hexanoyloxytetracycline,
6-methylene-6-demethyl-6-deoxy-7-chloro~et~acycline,
. . .
: ', :

6-methylene-6-demethyl-6-deoxy-7-chloro-5-hydroxytetracycline,
6-methylene-6-demethyl-6-deoxy-7-chloro-5-acetoxyte~racycline
6-methylene-6-demethyl-6-deoxy-7-chloro-5-isobutyryloxytetra-
: cyclin~,
6-methylene-6-demethyl-6-deoxy-7-chloro-5-lsovaleroyloxy-
tetracycline, and
6-methylene-6-demethyl-6-deoxy-7-chloro-5-heptanoyloxyte~ra-
cycline, respectively,
and the diacetato(triphenylphosphine)rhodiumtII~ used therein is
replaced by an equimolar amount o~:
; dipropionato(triphenylphosphine)rhodium~
dibenzoato(triphenylphosphine)rhodium~II), :
dibutyratottriphenylphosphine)rhodium~II), :
- dit~-chlorobenzoato)(triphenylphosphine)rhodium(II~
dibenzoato~triphenylphosphine)rhodium(II),
di~ormato(triphenylphosphine)rhodiumtII), ,:','
diacetato(triphenylphosphine)rhodium(II),
dibenzoatottriphenylphosphine)rhodium(II),
. I ~ . . .
di~m-toluato)~triphenylphosphine)rhodium~II), :- :.
i 20 dihexanoato(triphenylphosphine)rhodium~II),
~i diheptanoato(triphenylphosphine)rhodium~II), and
., , ~ . . .
~ di(~-methoxybenzoato)(triphenylphosphine)rhodium(I~
7, respectively. : :-
.1 ThiR a~ord~ the ~ollowing compounds, reRpectively:
~-6-deoxytetracyoline,
q~-6-deoxy-S-acetoxytetracycline,
6-deoxy-5-propionyloxytetracycline, -:
6-deoxy-5-butyryloxytetracycline,
6-deoxytetracycl~ne~
~-6-deoxy-S-hexanoyloxytetracycline;
~ -6-deoxy-7-chlortetracycline,
::: :
_ g _
. ', . .
, .'`1 .
, ~.'.1 , .

~4~
C'-6-deoxy-7-chloro-5-hydroxytetracycline,
~-6-deoxy-7-chloro-5-acetoxytetracycline,
~6-deoxy-7-chloro-5-isobutyryloxytetracycline,
C~-6-deoxy-7-chloro-5-isovaleroyloxytetracycline, and
~-6-deoxy-7-chloro-5-heptanoyloxytetracycline.
EXAMPLE 3_
Rhodium(II) Acetate_Dimer :: :
; A mixture of 1.72 g. o~' rhodium hydrous oxide (Rh[OH]3.-
H2O), 6 ml. of glacial acetic acid and 15 ml. of ethanol is
10 heated under reflux for 24 hours. The reaction mixture is cooled .
and ~he volatile components axe removed by evaporation ln vacuo
. to give the crude product. The crude product is purified by .: .-
dissolving it i~ acetone, allowing the solvent to evaporate
slowly and then filtering off the solid which precipitates.
EX~MPLE 4
Reaction of rhodium hydrous oxide with the appropri~
ate carboxylic acid, according to the procedure of Example III,
: ~,
produce the following rhodium~II) carboxylates: .
rhodium(II) propionate, .. .
~ . .
rhodium(II) benzoate,
i rhodium(II) butyrate,
rhodium(II) ~-chlorobenzoate, .
;~ rhodium~ ormate,
rhodium~II) m-toluate,
~ rhodium~I) hexanoate,
~ rhodlum~II) heptanoate, .
`' : rhodi~m(}I) ~ methoxybenzoate,
~:! rhodium(II) chloroacetate,
` ~7! ~ rhodium~ dichloroac tate,
. :30 rhodium(II3 trichloroacetate,
::
-:, . . .
~`! , . ~.: .

rhodium~II) fluoroacetate,
rhodium(II) difluoroacetate, and
rhodium(II) tri~luoroacetate D
EXAMPLE 5
.~ . .
Diacetatottriphenylphosphine)Rhodlum(II)
A mixture of 110 mg. of rhodium(II~ ~cetate dimer and
100 ml. o~ methanol is cooled to 17C. and a solution of 131 mg.
of triphenylphosphine in 5 ml. of ether is added with stirring.
Stirring is continued at ambient temperature for 2 hours and
then the precipitate is removed by filtration. This affords
219 mg. of the ~itle compound, m.p. 203-204C. -
EXAMP~E 6
: .
The ~rocedure of Example V is repeated, except that
i the rhodium(II) acetate dimer is replaced by the appropriate
rhodium(II) carboxylate, to produce the following congeners:
dipropionato(triphenylphosphine)rhodium~II),
1 dibenzoato~triphenylphosphine~rhodium~II),
'~ dibutyrato(triphenylphosphine)rhodium(II~
di(~-chlorobenzoato)ltriphenylphosphine)rhodium(II),
~` 20 diformato(triphenylphosphine)rhodium(II),
di(m-toluato)(triphenylphosphine)rhodium(II),
i dihexanato(triphenylphosphine)rhodium(II),
diheptanato(triphenylphosphine)rhodium(II),
. .
di(~-methoxybenzoato)(triphenylphosphine)rhodium(II),
Z5 di(chloroacetato)(triphenylphosphine)rhodium(II),
di~dichloroacetato)~triphenylphosphLne)rhodium(II)~
di(trichloroacetato)(triphenylphosphine)rhodium(II),
; ~ 1
di(fluo~oacetato)ttriphenylphosphine)rhodium(II)~
di~difluoroacetato)(trlphenylphosphine)rhodium(II), and
~; 30 di(trifluoroacetato~tripheny1p~osphine)rhodium~
, 1 1 1 ; '
~."~
,.:; ~ .. . :

; ~
_XAMPLE 7
Reduction of 6-Devxy-6-demeth~tl-6-methylene-
5-hydrox~tetrac~cline usinq Rhodlum~II) Diacetate
A solution of 2.0 g. (4.18 mmol.) of 6-deoxy-6-demethyl-
6-lnethylene~5-hyaroxytetracycline hydrochloride and 46 mg. ~5
mol-per cent~ of rhodium(II) diacetate in 30 ml. of de-gassed
~ methanol was shaken under an atmosphere of hydrogen at 65-70C. `~
for 5.25 hours. The hydrogen pressure in the reaction vessel m
was 65-70 psig. The cooled reaction vessel was then opened and
the contents were filtered. The filtrate was examined by high-
pressure liquid chromatography. This indicated that it contained
~-6-deoxy-5-hydroxytetracycline and ~ 6-deoxytetracycline, in
a ratio of about 2:3, together with a small amount of unreduced
starting material.
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