Note: Descriptions are shown in the official language in which they were submitted.
1023-ll Z~ L6~2
P~QSESS FOR THE PRQDUCTION_OF ;-
ALPHA-6-DEOXYTETRA~YC~INES
This inYention relates to a process for the
preparation of alpha-6-deoxytétracyclines and to the
use of a heterogeneous rhodium catalyst thereinj and
more particularly to such a process useful in the
production of the antibiotic do~ycycline, viz.,
alpha-6-deoxy-5-oxytetracycline.
~ACKGROUND OF ~HE INVENTION
The preparation o doxycycline and other
alpha-6-deo~ytetracyclines was first described in
Blackwood et al. U.S. Patent No. 3,200,149 granted
August 10, 1965. That patent described their
preparation by the catalytic hydroge~ation of a
corresponding 6-methylene intermediate, e.g., in the
case of do~ycycline, lla-chloro-6-deoxy-6-demethyl- ~;
6-methylene-5-oxytetracycline (lla-chloro
methacycline) or 6-deo~y-6-demethyl-6-methylene-
5-oxytetracycline (methacycline), in the presence of
a heterogeneous noble metal catalyst, e.g. palladium
on carbon. The Blackwood patent disclosed the
production, in yields of up to about 50fi, of
equimolar proportions of the diastereoisomers
(epimers) of the 6-deo~ytetracyclines. In the case
of do~ycycline, the patent disclosed the
co-production of the corresponding beta epimer,
beta-6-deo~y-5-o~ytetracycline.
Subsequent efforts have been directed to
the development of syntheses for producing the
6 deo~ytetracyclines in greater yields and with
SUBSTl~UTE SHEET
. . ~ . . . .......... ` : ,............... ... , ` . :
: ~ . `; ~, .` :.
204~6~
greater stereoselectivity of formation of the
desired alpha epimers, e.g., doxycycline. Thus,
Korst U.S. Patent No. 3,444,198 granted May 13,
1969, disclosed that the stereoselectivity of
formation of the alpha epimers may be increased when
the noble metal hydrogenation catalyst is poisoned
The Korst patent described the formation of epimeric
mixtures of the 6-deoxytetracyclines in total yields
of up to about 60%, with the stereoselective
production of the alpha epimers in amounts of up to ~ .
about 90~ of the epimeric product mi~tures.
The use of rhodium chloride/triphenylphos-
phine and similar complexes as homogeneous,
stereospecific hydrogenation catalysts in the
production of doxycycline and other alpha-6-deo~y~5
oxytetracyclines has also been extensively discussed
in the patent literature. See, for example,
U.S. Patents Nos. 3,907,B90; 3,962,331; 4,001,3219
4,207,258; 4,550,096; 4,743,699; and French Patent
No. 2,216,268.
Other noble m~tal or noble metal salt
heterogeneous hydrogenation catalysts for
6-methylenetetracyclines have also been disclosed in
the literatu~e. For example, Faubl et al. in U.S.
Patent No. 3,962,131 describes a heterogeneous
catalyst for use in hydrogenating methacycline. The ~
Faubl catalyst is produced by reacting rhodium ~-
trichloride and sodium acetate in methanol at
temperatures in excess of 50OC, and reacting this
system with triphenylphosphine. The Faubl catalyst
is reported to exhibit stereoselectivity for the
alpha epimers by a factor of at least 9:1 versus the
beta epimer with a yield o~ 98.8% reported in the
sole Faubl example.
SUBSTITlJTE SHEE~
.. . :. :. . ,. , - , . .
- . - . ... - . ,
~ : , :, .
.. , : , ;: ... ,, ;.. , . , .. ;, .
-. . ...... .. ., . . .. ~.
w~
:
Zt~6~2
-3- -
Catalytic hydrogenation of methacycline
using a catalytic amount of rhodium metal together
wi~h a phosphine, prefera~ly triphe~ylphosphine, and
a promoter, e.g., excess acid (over that required to
form an acid addition salt with methacycline), is
disclosed by Morris, Jr. in U.S. Patent No.
3,959,862. The heterogen~ous rhodium metal catalyst
may be of the non-supported or supported type, eOg~,
supported by car~on, silica, alumina or ~arium
sulfate.
Another process for the heterogeneous
hydrogenation of methacycline is disclosed by Page
in U.S. Patent No. 4,597,904. Page employs a
rhodium salt catalyst wherein the rhodium is bonded
to a polysiloxane carrier, generally an aminopoly~
siloxane. The methacycline hydrogenation is
accomplished in the presence of a tertiary
phosphine, e.g., triphenylphosphine. The Page 3
hydrogenation process is reported to be
sterospecific, typically yielding less than 0~2%
beta epimer. However, polysilo~ane materials are
known to be sensitive to elevated temperatures,
e.g., greater than 90C, and any breakdown of the
polysiloxane carrier would adversely impact the
functionality and the recylability of the Page
rhodium salt catalyst.
The present invention is directed to an
improved process for the production of doxycycline
and other alpha-6-deoxytetracyclines, wherein the
desired alpha epimer is produced in both high yield
and stereospecificity, and the noble metal
constituent of the hydrogenation catalyst may be
utilized in smaller proportions than herétofore
required and is readily recoverable from the
SUBSmUTE Sl IEET
, . ............... , . , . .: , ... ,. `. ` : `~:
~ : ,, ; ~ . .
~' :
2~4~
_4_
reaction mixture for reuse. Other objects and advantages of
this invention will be apparent from the following description
~f preferred embodiments thereof.
SUMMARY OF THE INVENTION
This invention comprises an impro~ed process for the
preparation of alpha-6-deoxy-tetracyclines by the hydrogenation
of the corresponding 6-methyl-enetetracyclines in the presence
of a heterogeneous rhodium catalyst wherein the rhodium is
complexed and bound to a silica gel support.
':
. , :. . . , , . , .: , ,, . ~ . .
20~
-5-
Silica-supported rhodium complex catalysts
of this type have been disclosed for the
halogenation of alkenes. Czakova et al., ~ Q
~tal. II, 313-322 (19al). See also ~artley,
~up~Qrted Met~l ~omplex~s, D. Reidel Publishing Co.,
pages 150 et seq. (1985); Kochloe~1 et al., ~
~h~L~ mm~ 1977, 510-11; Conan et al., J. M~l.
Catal. I, 375-382 (1976).
It has been found that when an appropriate
6-methylene-tetracycline substrate is hydrogenated
in the presence of a heterogeneous rhodium catalyst
of the preceding type, the corresponding
alpha-6-deogytetracycline is produced in greater
than about 95% yield and with the co-production of
negligible amounts of the corresponding
beta-6-deo~ytetracycline epimer. The heterogeneous
rhodium catalyst is also easily recovered from the
reaction system, e.g., by filtration, thereby
allowi~g for the efficient reuse of catalyst in
subsequent hydrogenation reactions, and for the
elimination of e~pensive purification operations
generally required for separation of the undesired
beta epimers.
Moreover, it has been found that the a~ove
heterogeneous rhodium catalyst may be used to
stereospecifically hydrogenate methacycline to form
the alpha epimer do~ycycline at signi~icantly lower
rhodium metal levels as compared to prior art
heterogeneous catalyst systems. According to the
present invention, stereospecific formation of
do~ycycline is achieved at rhodium metal levels of
as low as O.lS mg per gram ll-a chloro methacycline,
without sacrificing product yield. Indeed, yields
well above 90~ and as high as 99.3% are achieved at
S~JB~T Tl JTE SHIE~ET
`,.. ... . ...
,... . . .. .. . ...
2C)4L4612
rhodium metal levels no higher than 0.2 mg/g
methacycline. By way of comparison, the lowest
reported rhodium metal methacycline ratio for the
Page heterogeneous catalyst was 0.~5 mgfgram
(Example 1) with a yield of only 87.4~. Similarly,
at a rhodium metal ll-a chloro methacycline ratio of ~-
0.19 mg/gram (E~ample 6) a yield of only 89.9~ was
achieved using a Page heterogeneous catalyst. Still
higher rhodium metal levels are reported for the
Morris, Jr. heterogeneous catalyst system (2.3 and
23 mg/gram). Thus, dramatic reductions in the amount
of rhodium metal required to selectively form
alpha-6-deoxytetracyclines may be achieved at high
yields with the attendant cost advantages.
Comparisons of the no~le metal levels in prior ar~
hydrogenation catalysts and their respective yields
and stereospecificities as compared to the process ;~
of the present invention are presented in the
following Table (prior art data taken from U.S.
Patent No. 4,597,904 to Page; Table I).
The method of the present invention thus
stereospecifically produces the alpha epimer at
significantly higher yields than those reported for
prior art processes with the e~ception of Page
example 4. However, in the case of Page e2ample 9,
the ratio of rhodium to methacycline HCl was more
than twice th~t employed according to the present
invention. Accordingly, the present invention is
more efficient than prior art processes for
preparing alpha-6-deo~ycyclines.
PREF~RRED EM~QEIMENTS OF T~E INVE~TION
The catalysts useful in the hydrogenation
proces of the invention are preferably prepared by
reacting silica gel with a compound having one or
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more groups capable of functioning as ligands which
bon~ rhodium complexes thereto. It is believed that
the length and mobility of the ligands influence the
degree to which catalytic intermediates interact,
thereby reducing hydrogenation activity. Compounds
having suitable groups include alkoxysilyl-
substituted alkyldiphenyl phosphines such as the
following:
(EtO)3SiCHzPPh2
(EtO)3Si(c~l2)2pph2
(Eto)3si(cHz)3pph2
(EtO)3Si(CH2)qPPh2
(EtO)3Si(CH2)5PPh2
(EtO)3Si(CH2)6PPh2
(EtO)2MeSiCH2PPh2
(EtO)2MeSi(cH2)2Pph2
(EtO)2MeSi(cH2)3pph2
(Eto)Me2sicH2pph2
wherein Et is ethyl and Ph is phenyl. Alter
natively, ligands may be formed in ~i~ with the
silica gel, e.g., by reacting chloromethyl ether and
diphenylphosphi~e lithium.
The silica gel used in preparing the
catalyst generally has a particle size of 0.063 to
0.2 mm and a pore diameter of 20 to 100 Angctroms,
e.g., Kieselgel 100 (Merck). Preferably, the silica
gel has a particle size of 0.063 to 0.090 mm and a
pore size of 40 to 60 An~stroms.
The silica gel is generally dried, e.g., in
a vacuum oven at 180C, before being reacted with an
alkoxysilyl-substituted alkyldiphenyl phosphine.
The reaction of the silica gel with the
alkyldiphenyl phosphines is generally accomplished
in an aromatic solvent, e.g., benzene, xylene or
SlJBSTmJlE SHEF~
~0~L~6~l2
toluene, at a temperature of from 60 to 115C. For example,
the dried silica gel may be added to the aromatic solvent under
an inert gas blanket, e.g., nitrogen, together with 2-diphenyl
phosphine-ethyltriethoxysilane to attach suitable ligands to
the silica gel. The reaction mixture is generally refluxed ~or
about one to six hours to allow the ligands to attach to the ~ -
silica gel.
The reaction mixture is then azeotropically distilled
to remove ethanol formed by interaction between the
alkoxysilane group of the ligand compound and the surface
hydroxyl groups of the gel support. Distillation conditions
depend on the solvent employed and whether the reaction is done ~;
under ambient pressures or under vacuum, as will be readily
apparent to one of ordinary skill in the art.
Typically, after the distillate is removed, fresh
make-up solvent is added to the reaction mixture and the system
is agitated under an inert atmosphere, e.g., nitrogen, while
cooling to 20- to 30 C. The reaction mixture is then filtered
and the recovered cake is washed with solvent. The filter cake
comprises silica gel with a plurality of ligands attached
thereto, the free ends of the ligands being suita~le for
attachment to a rhodium complex.
The filter cake is reslurried in an aromatic solvent
and a rhodium complex is added thereto. For example suitable
rhodium complex~s include Rh2C12(C2H4)4,
. . . :, :. . ,
2~46~2
1~--
Rh2C12 (cyclooctene)4, Rh~12(PPh3), Wilkinson s
Catalyst ~Rh(PPh3)3Cl].
The rhodium complex containing system is lightly
refluxed under an inert atmosphere to allow the rhodium complex
to react with the free ends of the ligand groups, e.g~, for 12
to 16 hours. The reaction mixture is then cooled to 20~40~C
and filtered to recover the heterogeneous rhodium catalys~ of
the invention. The catalyst generally has from 0.3 to 006%
rhodium metaL per gram of catalyst.
In accordance with the in~ention, the heterogeneous
rhodium catalyst is utilized in the production o~ any of the
known alpha-6-deoxytetracyclin~s, preferably those having the
formula:
3 R1 NMe~
~ C O NH 2
wherein R and R2 are each hydrogen or chloro and Rl is
hydrogen or hydroxyl. ;;
The preceding compounds are produced by hydrogenatio~
of the corresponding 6-methylene tetracycline compounds of the
formula:
; , :; . , : ... ,. . ~ " . . . . . . .
'~', ' 3 ~
~. .,
2~6~;~
-13-
R CH Q NM~
2 _1
~ CoNH2 (II~
wherein R, Rl and R2 are as defined above.
6 methylenetetracyclines which are thus reacted may be
prepared in the manner known in the art, e.g., as described in
Blac~wood U.S. Patent No~ 2,984,986 granted May 16, 1961 or
Villax U.S. Patent No. 3,848,491 granted November 19, 1974~ ;
Preferably, the catalytic hydrogenation is utilized ~o
prepare doxycycline (wherein R is hydroge~ and R1 is
hydroxyl) from methacyline (wherein R is hydrogen, Rl is
hydroxyl and R2 is hydrogen) or from lla-chloro methacycline
twherein R is hydrogen, Rl is hydroxyl, and R2 is chloro).
When lla-chloro methacycline is utilized as the starting
material, an equimolar quantity of triphenyl phosphine is also
typica~ly included in the hydrogenation system~
The hydrogenation reaction i5 carried out in one of
the manners known in the art, with the stereospecific formatiQn
of the desired alpha epimer in yields in excess of 94%. HPLC
analyses of the hydrogenation products generally indicate
;
2~6~2
-13/1-
negligible beta epimer contents. The hydrogenation is e~fected
in the preseince of from about 0.05 to 0.2 grams of catalyst per
gram of 6-methylenetetracycline reacted, which corresponds, for
example in the production of doxycycline, to a rhodium metal to
methacycline ratio of 0.15 to 1.2 mg per gram. The amount of
rhodium required for reduction of methacycline to doxycycline
may thus be significantly
' -,, i :. ,` : ,
~ O90l07492 PCT/US90/00~
2~ 6~2
-14-
reduced as compared to prior art hydrogenation
processes. The catalytic hydrogenation of the
present invention therefore pro~ides superior yields
and purities of the desired alpha-6-deoxytetra-
cyclines, with substantially improved efficiencies
in the operation.
The reaction is suitably carried out in a
lower alkanolic solvent. Preferably methanol or
ethanol is employed. The solvents are typically
degassed with nitrogen prior to use.
The reaction time depends on the amount of
catalyst and the type of autoclave used for
hydrogenation. Normally, to obtain high yields and
purities, reaction times of from about 6 to 12 hours
are utilized. It is preferred, but not critical, to
carry out the reaction under pressures ranging from
about 60 to 130 psig, and at temperatures of from
about 90 to 100C. At temperatures lower than
about asoc the reaction may be unacceptably slow,
and at higher temperatures decomposition can occur.
Addition of a small amount of
triphenylphosphine, e.g., from about 4 to 8 mg per
gram of the 6-methylenetetracycline substrate, to
the reaction mixture prior to hydrogenation
promotes and accelerates the rate of hydrogen
absorption, thus facilitating completion of the
reaction. The optimum quantity of
triphenylphosphine for a given catalyst is
determined empirically. A small amount of acid,
e.g., hydrochloric acid, may also be added to
promote the hydrogenation reaction.
The do~ycycline or other alpha-epimer is
typically crystallized as an acid addition salt from
the reaction mi~ture, e.g., in the form of the
S~IBS~TUTE~ SHEET
? ~
. , ~, : ,
~3:~'h11~
~04~6~L2
-15-
p-toluene sulfonate, sulfosalicylate, or
hydrochloride salt. The purity is more than 99.5~O
by HPLC. The doxycycline acid addition salt is
thereafter convertPd directly to doxycycline hyclate
(the hemiethanolate hemihydrate~ in stoichiometric
yield by procedurPs known in the art.
The catalytic hydrogenation may be utilized
in a single step to effect both the reductive
dehalogenation and reduction of the 6-methylene
group of a~ lla-halo-6-deoxy-6-demethyl-6-
methylenetetracycline, e.g., lla-chloro
methacycline. The corresponding alpha-6-deoxytetra-
cycline, e.g., doxycycline, is directly produced in
improved yield and purity, and with decreased
rhodium consumption.
In a preferred embodiment, a methanolic
mi~ture containing a 6-deoxy-6-demethyl-6-
methylenetetracycline, preferably the hydrochloric
acid addition salt thereof, triphenylphosphine,
hydrochloric acid, and a heterogeneous rhodium
catalyst o~ the invention, is subjected to agitation
in a stainless steel autoclave, and hydrogenated at
about 90C under a hydrogen pressure of about 100
psig. The reaction mixture is cooled to about 60C
and pumped through a filter to recover the
catalyst. To the filtrate is added p-tolune
sulfonic acid and the system is stirred at 50-60C
for one hour. Thereafter, the system is cooled to
5C for at least two hours. The alpha-6-deo~y-5-
oxytetracyline p-toluene sulfonate thus obtained is
filtered, washed with methanol and then with acetone.
Alternatively, the reductive dehalogenation
and hydrogenation can be carried out with a two-step
process initially effecting lla-dehalogenation with
3TIIT~ ITr~
~ . . _ ' . I ~ . .1 .
', ' ;'' ' ~ ;, ; , ' ` '' " '-, . '. '.,
.' . ,;~, ' '` . ' , ' , '," "' '
"1. . ~'~ .. ., '~......... .
~ 9~/07492 PCT/US90/00~
20~6~2
-16-
a conventional catalyst, e.g., S~O Rh/C or 5% Pd/C in
methanol. The initial catalyst is then removed by
filtration, and the solution is again subjected to
hydrogenation in the presence of a heterogeneous
rhodium catalyst of the invention.
In the following examples, particularly
preferred embodiments of the process for the
preparation of alpha-6-deoxytetracyclines are
described. In the examples, all temperatures are
given in Degrees Celsius and all parts and
percentages by weight, unless otherwise specified.
EXAMPLE 1
prepar~tiQ~LQf Heteroqeneou ~ ~,Qdium CatalY~.
Silica gel (20.0 kg) was dried in a vacuum
oven at 180C for 5 to 6 hours. While stirring, the
dried silica gel was added to toluene (100 liters)
under a nitrogen ~lanket. In a separate 15 gallon
polypropylene carboy vessel, ethyltrietho~ysilyl-~-
diphenylphosphine (960 grams) was added to toluene
(50 liters) and agitated. The contents of the
carboy vessel was then added to the silica
gel-containing system and agitated under nitrogen.
The system was gently refluxed at 113C for 5 hours.
After refluxing, the system was
atmosphericall~ distilled (azeotropic) at 110-115
to remove distillate (100 liters) containing
ethanol. Fresh toluene (100 liters) was added to
the s~stem with agitation to replace the distillate
while cooling to 20-30C. The system was filtered
to recover a toluene wet cake that was washed with
additional toluene.
The cake was added to fresh toluene (140
liters) while agitating under a nitrogen blanket.
The mi~ture was warmed to 55-70C and Wilkinson's
~5 W ~3 ~3T IT ~ 9 T e~
:, , . , ` :: . . ~ .
': ': '.
,L6~
-17-
Catalyst (~80 grams) was added. The system was
lightly re1uxed at 113~C under nitrogen for 12 to
16 hours, then cooled to 20-40C. The system was
filtered to recover the catalyst (23-24 kg) which
was washed with toluene and vacuum dried at 45Co
PreParation o nQ~Yc~cline P-Toluene Sul~honate
from MethacYcline HC~
Methacycline HCl (13.44 kilograms) was
added to methanol (63.0 liters) under a nitrogen -~
blanket. Triphenylphosphine (42 grams) and
hydrochloric acid (14 mls.) were added to the system
and the system was warmed to 50C for about one-half
hour. Heterogeneous rhodium catalyst (2.1
kilograms) of Example 1 was added to the system
which was pressurized with hydrogen to a pressure of
100 psig. The system was warmed to 90C (+ SC)
and maintained at this temperature for 24 hours.
The system was cooled to 60C and pumped to a filter
to recover the heterogeneous rhodium catalyst.
p-Toluene sulfonic acid (6.16 kilgrams~ was added to
the system and stirred at 50-60C for one hour.
The system was allowed to cool overnight at room
temperature and was then cooled to 5C for two
hours. Do~ycycline p-tolune sulfonate was recovered
from the system by filtering and was washed with
cold methanol (3 liters) and cold acetone (3
liters). The product was dried at about 40C. The
resulting product weighed about 16.0 kilograms (94%
theoretical yield). HPLC analysis showed the
product to be 99~ pure alpha-deo~ycycline p-toluene
sulfonate with no beta epimer present. A second
crop of Q.94 kg as sulfosalicylate salt was
recovered. The total yield was therefore 99%.
S3JBSmOTE SHEET
. . . . , . ~ . ~ . .
~ . ~
~"~90/07492 PCT/US90/00~
20~ 2 ~-
-18-
EXAMPLE 3
PrePar~tion o~ Do~c~line P-~QLuene SuLfonate
lla-chloro-6-deoxy-6-demethyl-6-methylene-5-
o~ytetracycline p-toluene sulfonate (25 grams~ and
triphenylphosphine (10.2 grams) were added to a
hydrogenation vessel. Methanol (75 mls.) was added
to the mixture, the reactants were warmed to 50C,
and heterogeneous rhodium catalyst of Example 1 (3.0
grams) was added. The reactants were hydrogenated
at 90C under a hydrogen pressure of 100 psig until
hydrogen upta~ce ceased. The system was cooled to
60C and the heterogeneous cataly~t was filtered
from the slurry. p-Toluene sulphonic acid (8.4 ~ ;
grams) was added to the ~iltrate at 50C and the
system was stirred for one hour. The system was
stored overnight at room temperature and then held
at 5C for two hours. Doxycycline p-toluene
sulfonate was then filtered from the system and
washed with cold methanol (20 mls.) and cold acetone
(20 mls.). The resulting product weighed 20.5 grams '~
(87%) and HPLC analysis showed: alpha isomer 99~;
beta isomer-negligible. A second crop of 1.9 grams
as sulfosalicylate salt was obtained. The total
yield was therefore 94%.
EX~MPLF~
PreP~ration_Qi~120:cYcy~lipe HYclatelFrom ' ~,
DoxvcYclin~ ~-Toluene ~ honat~
Doxycycline p-toluene sulphonate ~13 grams~
of E~ample 3 was mixed with acetone ~3B mls.) and
water (1.78 mls.) to obtain a solution at 35C.
Nuchar G-60 ~l gram) was added to the system and -~
stirred for one-half hour. The slurry was then
filtered through a celite pad. To the filtrate was
added ethanol (28.6 mls.) and 18% HCL in ethanol
SUE3STITUTE ~àHEET
"''1'1''~ ' ~ ;`
-19 -
( 19; 3 mls . ? . Within ten minutes seed began to
appear in the solution. The solution was stirred
for three hours at room temperature and then
filtered to obtain a cake. The cake was washed
first with ethanol (30 mls.), then with acetone (15
mls.) and then dried. The yield of doxycycline
hyclate from this first crop was 8.3 grams (76%)o
HPLC analysis showed the product to be 99.4% pure
alpha-do~ycycline hyclate with no detectable
beta-doxycycline hyclate. A second crop of '
doxycycline hyclate yielded an additional 2.04
grams, also essentially pure alpha-doxycycline
hyclate, giving a total yield of about 95%.
~a~
PreParation of Do~YG~cline P-Toluene Sulfonate from
Methac~cline HYdrochloride
Purified methacycline hydrochloride (5.0
grams), concentrated hydrochloric acid (37%; one
drop), and methanol (30 mls.) were added to a bomb.
The system was placed under a nitrogen atmosphere.
Triphenylphosphine (20 mgs.) and heterogeneous
rhodium catalyst of Example l (1.3 grams) were added
to the system. The system was heated to about 90%C
(ranging from 87.0 _ 95.0C) and hydrogenated under
a hydrogen pressure of ll9.0 psig at zero time. The
hydrogenation e~tended for 17 hours at which time
the hydrogen pressure was about 108.5 psig.
The system was then cooled to 55C and
decanted to separate a clear supernatant from the
silica-supported rhodium catalyst. p-Toluene
sulfonate acid hydrate (2.2 grams) was added to the
supernatant and the system was warmed to about
50C. The system was stirred for about two hours a~
room temperature, stirred in an ice bath for an
~& i~tllrtJTE 5~4El~T
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additional two hours, and then filtered. The
recovered cake was washed with cold acetone. T~e ~:
resulting do~ycycline p-toluene sulfonate (dry)
weighed about 6.2 grams (96.4~ yield) and analysis
by paper-gram showed only alpha isomer present. A
second crop of 2.1 grams was obtained as
sulfosalicylate salt. The total yield was thereore
99.3%
~ aving thus described the invention, what
is claimed is:
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SU8STITIJTE SHEET
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