U.S. patent application number 15/351700 was filed with the patent office on 2017-10-05 for methods for synthesizing substituted tetracycline compounds.
The applicant listed for this patent is Paratek Pharmaceuticals, Inc.. Invention is credited to Mark Grier, Farzaneh Seyedi, Tadeusz Warchol.
Application Number | 20170283368 15/351700 |
Document ID | / |
Family ID | 39926392 |
Filed Date | 2017-10-05 |
United States Patent
Application |
20170283368 |
Kind Code |
A1 |
Seyedi; Farzaneh ; et
al. |
October 5, 2017 |
METHODS FOR SYNTHESIZING SUBSTITUTED TETRACYCLINE COMPOUNDS
Abstract
Methods of synthesizing substituted tetracycline compounds are
provided.
Inventors: |
Seyedi; Farzaneh;
(Mansfield, MA) ; Warchol; Tadeusz; (Northborough,
MA) ; Grier; Mark; (Midvale, UT) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Paratek Pharmaceuticals, Inc. |
Boston |
MA |
US |
|
|
Family ID: |
39926392 |
Appl. No.: |
15/351700 |
Filed: |
November 15, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12217709 |
Jul 7, 2008 |
9522872 |
|
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15351700 |
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61060351 |
Jun 10, 2008 |
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60948385 |
Jul 6, 2007 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07C 231/12 20130101;
C07C 2603/44 20170501; C07C 237/26 20130101; C07C 231/12
20130101 |
International
Class: |
C07C 231/12 20060101
C07C231/12; C07C 237/26 20060101 C07C237/26 |
Claims
1-20. (canceled)
21. A method for synthesizing a 9-substituted tetracycline
compound, the method comprising: a) reacting a 9-halogenated
tetracycline compound with carbon monoxide, a first palladium
catalyst, a silane and a base to generate a 9-carboxaldehyde
substituted tetracycline compound; and b) reacting said
9-carboxaldehyde substituted tetracycline compound with a primary
or secondary amine under hydrogenolysis or reductive amination
conditions to generate said 9-substituted tetracycline compound, or
a pharmaceutically acceptable salt or ester thereof.
22. The method of claim 21, wherein said 9-halogenated tetracycline
compound is 9-halogenated minocycline.
23. The method of claim 22, wherein said 9-halogenated minocycline
is a 9-iodine substituted minocycline, a 9-chlorine substituted
minocycline, or a 9-bromine substituted minocycline.
24. The method of claim 23, wherein said 9-halogenated minocycline
is a 9-iodine substituted minocycline.
25. The method of claim 21, wherein said hydrogenolysis conditions
comprise a second palladium catalyst, an ammonium compound and one
or more solvents; and wherein said reductive amination conditions
comprise a reducing agent and a solvent.
26. The method of claim 21, wherein said first palladium catalyst
is Pd(OAc).sub.2, PdCl(tBu.sub.2PhP).sub.2
[dichlorobis(di-tert-butylphenylphosphine palladium (II)] or
PdCl.sub.2(DPEPhos) [bis(diphenylphosphinophenyl)ether palladium
(II) chloride].
27. The method of claim 26, wherein said first palladium catalyst
is Pd(OAc).sub.2 or PdCl.sub.2(tBu.sub.2PhP).sub.2.
28. The method of claim 21, wherein the silane is a compound
represented by the chemical formula R.sub.2SiH.sub.2 or R.sub.3SiH,
wherein each R is independently C.sub.1-C.sub.10 branched or
straight chain alkyl or C.sub.5-C.sub.14 aryl.
29. The method of claim 28, wherein the silane is selected from the
group consisting of tripropylsilane (Pr.sub.3SiH),
triisopropylsilane (iPr.sub.3SiH), benzyldimethylsilane,
di-tert-butylsilane (tBu.sub.2SiH.sub.2), triethylsilane
(Et.sub.3SiH), cyclohexyldimethylsilane, dimethylphenylsilane,
diethylisopropylsilane, methylphenylsilane,
dimethylisopropylsilane, diethylmethylsilane, dimethylethylsilane,
diethylsilane (Et.sub.2SiH.sub.2), trioctylsilane,
dimethyloctadecylsilane, trihexylsilane, triphenylsilane
(Ph.sub.3SiH), diisopropyloctylsilane, methyldiphenylsilane,
triisobutylsilane (iBu.sub.3SiH), tributylsilane (Bu.sub.3SiH),
diphenylsilane (Ph.sub.2SiH.sub.2) and dimethylphenethylsilane.
30. The method of claim 29, wherein the silane is Et.sub.3SiH.
31. The method of claim 21, wherein the base is a carbonate
base.
32. The method of claim 31, wherein the carbonate base is selected
from the group consisting of lithium carbonate, sodium carbonate,
potassium carbonate, magnesium carbonate, calcium carbonate,
strontium carbonate and lanthanum carbonate.
33. The method of claim 32, wherein the base is sodium
carbonate.
34. The method of claim 21, wherein the base is a
trialkylamine.
35. The method of claim 34, wherein the base is selected from the
group consisting of trimethylamine, triethylamine, tributylamine,
triisopropylamine, dimethylethylamine, diisopropylethylamine,
diethylmethylamine, dimethylisopropylamine and
dimethylbutylamine.
36. The method of claim 32, wherein the base is
diisopropylethylamine.
37. The method of claim 21, wherein the reaction in step a)
comprises a Lewis acid.
38. The method of claim 37, wherein the Lewis acid is InCl.sub.3.
Description
RELATED APPLICATIONS
[0001] This non-provisional patent application claims priority
under 35 U.S.C. .sctn.119(e) to the following provisional
applications: U.S. Provisional Patent Application Ser. No.
60/948,385, filed Jul. 6, 2007, and U.S. Provisional Patent
Application Ser. No. 61/060,351, filed Jun. 10, 2008, each of which
is herein incorporated by reference in its entirety.
BACKGROUND OF THE INVENTION
[0002] The development of the tetracycline antibiotics was the
direct result of a systematic screening of soil specimens collected
from many parts of the world for evidence of microorganisms capable
of producing bacteriocidal and/or bacteriostatic compositions. The
first of these novel compounds was introduced in 1948 under the
name chlortetracycline. Two years later, oxytetracycline became
available. The elucidation of the chemical structure of these
compounds confirmed their similarity and furnished the analytical
basis for the production of a third member of this group in 1952,
tetracycline. A new family of tetracycline compounds, without the
ring-attached methyl group present in earlier tetracyclines, was
prepared in 1957 and became publicly available in 1967; and
minocycline was in use by 1972.
[0003] Recently, research efforts have focused on developing new
tetracycline antibiotic compositions effective under varying
therapeutic conditions and routes of administration. New
tetracycline analogues have also been investigated which may prove
to be equal to or more effective than the originally introduced
tetracycline compounds. Examples include U.S. Pat. Nos. 2,980,584;
2,990,331; 3,062,717; 3,165,531; 3,454,697; 3,557,280; 3,674,859;
3,957,980; 4,018,889; 4,024,272; and 4,126,680. These patents are
representative of the range of pharmaceutically active tetracycline
and tetracycline analogue compositions.
[0004] Historically, soon after their initial development and
introduction, the tetracyclines were found to be highly effective
pharmacologically against rickettsiae; a number of gram-positive
and gram-negative bacteria; and the agents responsible for
lymphogranuloma venereum, inclusion conjunctivitis, and
psittacosis. Hence, tetracyclines became known as "broad spectrum"
antibiotics. With the subsequent establishment of their in vitro
antimicrobial activity, effectiveness in experimental infections,
and pharmacological properties, the tetracyclines as a class
rapidly became widely used for therapeutic purposes. However, this
widespread use of tetracyclines for both major and minor illnesses
and diseases led directly to the emergence of resistance to these
antibiotics even among highly susceptible bacterial species both
commensal and pathogenic (e.g., pneumococci and Salmonella). The
rise of tetracycline-resistant organisms has resulted in a general
decline in use of tetracyclines and tetracycline analogue
compositions as antibiotics of choice.
SUMMARY OF THE INVENTION
[0005] The invention generally pertains to methods for synthesizing
substituted tetracycline compounds. In one embodiment, the
invention pertains, at least in part, to a method for synthesizing
a carboxaldehyde substituted tetracycline compound by reacting a
tetracycline reactive intermediate under appropriate conditions
with carbon monoxide, a palladium catalyst, a phosphine ligand, a
silane and a base, such that the carboxaldehyde substituted
tetracycline compound is synthesized. In some embodiments, the
carboxaldehyde substituted tetracycline compound is a 7-, 9- and/or
10-carboxaldehyde substituted tetracycline compound.
[0006] For example, the tetracycline reactive intermediate is a
halogenated tetracycline intermediate or a triflate substituted
tetracycline intermediate. Examples include an iodine substituted
tetracycline intermediate, a chlorine substituted tetracycline
intermediate, a bromine substituted tetracycline intermediate, an
iodine and chlorine substituted tetracycline intermediate or a
bromine and iodine substituted tetracycline intermediate. In one
embodiment, the compound is a 10-triflate substituted tetracycline
intermediate. Other typical intermediates include 7-iodosancycline,
9-iododoxycycline, 7-chloro-9-iodosancycline or
7-bromo-9-iodosancycline.
[0007] In one embodiment, the method further comprises the step of
precipitating the carboxaldehyde substituted tetracycline compound
in a solvent, such as a non-polar solvent. Examples of non-polar
solvents include diethyl ether, MBTE, heptane and combinations
thereof.
[0008] In some embodiments, the method also includes further
reacting the carboxaldehyde substituted tetracycline compound under
palladium catalyzed coupling conditions, hydrogenolysis conditions
or reductive amination conditions.
[0009] In another embodiment, the invention pertains, at least in
part, to a method for synthesizing a substituted tetracycline
compound comprising reacting a reactive tetracycline intermediate
with carbon monoxide, a palladium catalyst, a phosphine ligand, a
silane and a base under appropriate conditions, wherein the
reactive tetracycline intermediate is substituted at a first
position with a first reactive moiety and substituted at a second
position with a second reactive moiety, such that the first
reactive moiety is replaced with a carboxaldehyde substituent and
the second reactive moiety is unreacted. Typically, the first and
second reactive moieties are selected from halogens and triflates.
For example, the first reactive moiety is iodine and the second
reactive moiety is bromine. In one embodiment, the reactive
tetracycline intermediate is 7-bromo-9-iodosancycline.
[0010] In one embodiment, the method further comprises the step of
precipitating the carboxaldehyde substituted tetracycline compound
in a solvent, such as a non-polar solvent. Examples of non-polar
solvents include diethyl ether, MBTE, heptane and combinations
thereof.
[0011] In some embodiments, the method further comprises the step
of reacting the second reactive moiety under hydrogenolysis
conditions or palladium catalyzed coupling conditions.
[0012] In some embodiments, the carboxaldehyde substituent is
further reacted under reductive amination conditions to produce an
aminomethyl substituted tetracycline compound; and the second
reactive moiety is further reacted under palladium coupling
conditions or under hydrogenolysis conditions. For example, the
aminomethyl substituted tetracycline compound is a 7- or
9-aminomethyl substituted tetracycline compound.
[0013] The invention also relates to methods for synthesizing an
aminomethyl substituted tetracycline compound comprising the steps
of: a) reacting reactive tetracycline intermediate with carbon
monoxide, a palladium catalyst, a phosphine ligand, a silane and a
base under appropriate conditions, wherein the reactive
tetracycline intermediate is substituted at a first position with a
first reactive moiety and at a second position substituted with a
second reactive moiety, wherein the first reactive moiety is
replaced with a carboxaldehyde substituent; b) reacting the
carboxaldehyde substituent under reductive amination conditions;
and c) reacting the second reactive moiety under palladium coupling
conditions or under hydrogenolysis conditions.
[0014] For example, the first reactive moiety is iodine and the
second reactive moiety is bromine. In one embodiment, the reactive
tetracycline intermediate is 7-bromo-9-iodosancycline. For example,
the aminomethyl substituted tetracycline compound is a 7- or
9-aminomethyl substituted tetracycline compound.
[0015] In one embodiment, the method further comprises the step of
precipitating the carboxaldehyde substituted tetracycline compound
in a solvent, such as a non-polar solvent. Examples of non-polar
solvents include diethyl ether, MBTE, heptane and combinations
thereof.
[0016] In some embodiments, the method of the invention, further
includes adding a Lewis acid with the carbon monoxide, the
palladium catalyst, the phosphine ligand, the silane and the base.
For example, the Lewis acid is InCl.sub.3. In some embodiments, a
Lewis acid is used in the presence of a trialkylamine base.
[0017] One example of a palladium catalyst is Pd(OAc).sub.2. One
example of a phosphine ligand is a xantphos ligand, such as
xantphos. Examples of the silane include Ph.sub.2SiH.sub.2 and
Et.sub.3SiH. Examples of the base include carbonate bases and
trialkylamine bases. For example, the base can be sodium carbonate
or diisopropylethylamine.
[0018] In various embodiments of the invention, the substituted
tetracycline compound is synthesized in at least about 90% yield.
In other examples, the substituted tetracycline compound is
synthesized in about 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%
yield.
[0019] The invention generally pertains to methods for synthesizing
substituted minocycline compounds. In one embodiment, the invention
pertains, at least in part, to a method for synthesizing a
carboxaldehyde substituted minocycline compound by reacting a
minocycline reactive intermediate under appropriate conditions with
carbon monoxide, a palladium catalyst, a silane and a base, such
that the carboxaldehyde substituted minocycline compound is
synthesized.
[0020] For example, the palladium catalyst is
PdCl.sub.2(tBu.sub.2PhP).sub.2
dichlorobis(di-tert-butylphenylphosphine palladium (II)] or
PdCl.sub.2(DPEPhos) [bis(diphenylphosphinophenyl)ether palladium
(II) chloride].
[0021] In one embodiment, the silane is Et.sub.3SiH. In one
embodiment, the base is a carbonate base, for example, sodium
carbonate.
[0022] In one embodiment, the method further comprises the step of
precipitating the carboxaldehyde substituted minocycline compound
in a solvent, such as a non-polar solvent. Examples of non-polar
solvents include diethyl ether, MBTE, heptane and combinations
thereof.
[0023] For example, the minocycline reactive intermediate is a
halogenated minocycline intermediate, such as an iodine substituted
minocycline intermediate, a chlorine substituted minocycline
intermediate, or a bromine substituted minocycline intermediate.
For example, the compound is a 9-halogenated minocycline. One
example is 9-iodo minocycline.
[0024] For example, the palladium catalyst is
PdCl.sub.2(tBu.sub.2PhP).sub.2
dichlorobis(di-tert-butylphenylphosphine palladium (II)] or
PdCl.sub.2(DPEPhos) [bis(diphenylphosphinophenyl)ether palladium
(II) chloride].
[0025] In one embodiment, the silane is Et.sub.3SiH. In one
embodiment, the base is a carbonate base, for example, sodium
carbonate.
[0026] In yet another embodiment, the invention pertains, at least
in part, to a method for synthesizing a substituted minocycline
compound by reacting a carboxaldehyde substituted minocycline
compound under palladium catalyzed coupling conditions,
hydrogenolysis conditions or reductive amination conditions.
[0027] The invention also pertains, at least in part, to a method
for synthesizing an aminomethyl substituted minocycline compound
comprising the steps of: a) reacting a reactive minocycline
intermediate with carbon monoxide, a palladium catalyst, a silane
and a base under appropriate conditions, to form a carboxaldehyde
substituted minocycline, and b) reacting the carboxaldehyde
substituted minocycline under reductive amination conditions to
form an aminomethyl substituted minocycline compound.
[0028] In one embodiment, the aminomethyl substituted minocycline
compound is a 9-aminomethyl substituted minocycline compound.
[0029] For example, the palladium catalyst is
PdCl.sub.2(tBu.sub.2PhP).sub.2
dichlorobis(di-tert-butylphenylphosphine palladium (II)] or
PdCl.sub.2(DPEPhos) [bis(diphenylphosphinophenyl)ether palladium
(II) chloride].
[0030] In one embodiment, the silane is Et.sub.3SiH. In one
embodiment, the base is a carbonate base, for example, sodium
carbonate.
[0031] In one embodiment, the method further comprises the step of
precipitating the carboxaldehyde substituted minocycline compound
in a solvent, such as a non-polar solvent. Examples of non-polar
solvents include diethyl ether, MBTE, heptane and combinations
thereof.
[0032] In one embodiment, the substituted minocycline compound is
at least about 51% pure. For example, the substituted minocycline
compound is about 55%, 60%, 65%, 69%, or 70% pure.
[0033] This invention identifies an efficient route for the
synthesis of 9-amino-methyl-substituted minocyclines, such as, for
example, Compound 1:
##STR00001##
DETAILED DESCRIPTION OF THE INVENTION
[0034] The regioselective functionalization of the D-ring site in
the tetracycline class of therapeutic agents has been a significant
hurdle to overcome in the development of practical synthetic
methodology. The chemical diversity that can be achieved through
selective functionalization can have a major impact in the
discovery of novel compounds of pharmaceutical interest.
Conventional techniques in the installment of regioselective
chemical "handles" on positions C7 and C9 of the D-ring of
tetracyclines typically entail the use of temporary blocking groups
or other functionality (e.g., a NH.sub.2 group), which can have
major drawbacks in terms of regioselectivity, yield and
practicality. In that regard, the need for a methodology that can
overcome these problems and complement well-established
transformations would greatly benefit the development of new
chemically diverse tetracycline compounds.
[0035] The advancement in the development of palladium coupling
reactions has made a major impact on practical tetracycline
derivatization, particularly at positions C7 and C9 on the D-ring.
Practical large-scale carboxaldehyde functionalization of
tetracyclines has been faced with significant hurdles as the
current method is not conducive on a process scale. Since
tetracycline compounds substituted with a carboxaldehyde at
positions C7 and C9 are important intermediates in the synthesis of
a broad scope of libraries, the need for an improved methodology
that is conducive for a process scale is paramount. The traditional
carbonylation of tetracyclines utilizes Bu.sub.3SnH as a reducing
agent, but this methodology has significant drawbacks on a process
scale and typically its use is avoided in the synthesis of
pharmaceuticals. In that regard, developing processes that utilize
alternative reducing reagents, palladium catalysts and additives
that can overcome the inherent problems with tin based reagents is
important.
[0036] The use of silicon based reducing reagents in palladium
catalyzed carbonylations is a viable alternative to organotin
reducing agents. In terms of cost, a silicon based reducing reagent
is an attractive substitute for Bu.sub.3SnH and has proved to be
satisfactory in carboxaldehyde formation with the tetracycline
compounds. Using similar conditions as that of the Bu.sub.3SnH
methodology, the desired carboxaldehyde tetracycline compounds may
be obtained in high yields. The silicon based reducing agents
display good qualities in comparison to Bu.sub.3SnH where the
formation of the desired carboxaldehyde was highly favored over the
premature reduced byproduct, which is observed to a significant
extent in the Bu.sub.3SnH reaction. Moreover, the incidence of
epimerization of position C4 has been a major problem in
tetracycline derivatization and can have a profound effect in
reducing the overall yield. The use of a chelating Lewis acid as an
additive may prevent epimerization and exhibits protective
effects.
[0037] The conventional aqueous workup in the Bu.sub.3SnH method
typically results in some decomposition and rapid epimerization
further compounding the deleterious effect in reducing the overall
yield. Therefore, another improved development in the use of
silicon based reducing agents compared to the traditional organotin
methodology is in the ease of isolating the desired product in a
non-polar solvent, thereby circumventing time consuming
chromatography.
[0038] This new method for synthesizing substituted tetracyclines
utilizes a less toxic reducing agent, as well as a low catalyst
loading, and provides the product in desirable epimer purity and
yield. The combination of improved yields, better toxicity profile
and reduced labor costs should have a profound effect on the
process scale synthesis of substituted tetracyclines.
[0039] An alternative reducing reagent was investigated that can
overcome the inherent problems with tin based reagents. The easily
accessible iodotetracyclines are substrates for conversion into
tetracycline carboxaldehydes. Through the C10 triflate
intermediate, the C10 position is transformed to a carboxaldehyde
functionality using the same catalytic carbonylation reaction.
[0040] For example, the catalyst derived from Pd(OAc.sub.2) and the
ligand xantphos are used in the formylation process with several
common silanes. A variety of silicon reagents can be used under
similar conditions as in the tin method, to produce the desired
carboxaldehyde tetracycline in high yields with simple workup. The
attribute of favored formation of the carboxaldehyde results in a
significant improvement in the yield and the reaction times are
shorter, which avoids epimerization of the desired product. The
product can be easily isolated in acceptable purity by
precipitating the product in a mixture MTBE and heptane. This work
up avoids tedious filtration and chromatography, and aqueous workup
results in less decomposition and epimerization than in the
Bu.sub.3SnH method (thereby improving the yield). The combination
of improved yields, better toxicity profile and reduced labor costs
profoundly affect the process synthesis of carboxaldehyde
tetracyclines.
[0041] A palladium catalyzed carbonylation reaction was performed
on 9-iodominocycline, which resulted in high yield with little if
any epimerization. A multitude of other carboxaldehyde
tetracyclines can also be produced from the following
iodotetracyclines, which include 7-iodosacycline,
9-iododoxycycline, 7-chloro-9-iodosancycline,
7-bromo-9-iodosancycline and other C7 and or C9 combination
tetracyclines. In the 7-bromo-9-iodosancycline case, the C9 iodo
group is regioselectively carbonylated where the C7 bromo group is
unreactive under the indicated conditions. The reaction proceeds in
excellent yield generating the 7-bromo-9-carboxaldehydesancycline
compound, which is a useful intermediate in the preparation of a
variety of novel compounds of pharmaceutical interest.
[0042] The invention generally pertains to methods of synthesizing
substituted tetracycline compounds. In one embodiment, the
invention pertains, at least in part, to a method for synthesizing
a carboxaldehyde substituted tetracycline compound.
[0043] The invention generally pertains to methods of synthesizing
substituted minocycline compounds. In one embodiment, the invention
pertains, at least in part, to a method for synthesizing a
carboxaldehyde substituted minocycline compound.
[0044] The term "tetracycline compound" includes substituted or
unsubstituted tetracycline compounds or compounds with a similar
ring structure to tetracycline. Examples of tetracycline compounds
include: chlortetracycline, oxytetracycline, demeclocycline,
methacycline, sancycline, chelocardin, rolitetracycline,
lymecycline, apicycline; clomocycline, guamecycline, meglucycline,
mepylcycline, minocycline, penimepicycline, pipacycline,
etamocycline, penimocycline, etc. Other derivatives and analogues
comprising a similar four ring structure are also included (See
Rogalski, "Chemical Modifications of Tetracyclines," the entire
contents of which are hereby incorporated herein by reference).
Table 1 depicts tetracycline and several known other tetracycline
derivatives.
TABLE-US-00001 TABLE 1 ##STR00002## ##STR00003## ##STR00004##
##STR00005## ##STR00006## ##STR00007## ##STR00008## ##STR00009##
##STR00010##
[0045] Other tetracycline compounds which may be modified using the
methods of the invention include, but are not limited to,
6-demethyl-6-deoxy-4-dedimethylaminotetracycline;
tetracyclino-pyrazole; 7-chloro-4-dedimethylaminotetracycline;
4-hydroxy-4-dedimethylaminotetracycline;
12.alpha.-deoxy-4-dedimethylaminotetracycline;
5-hydroxy-6.alpha.-deoxy-4-dedimethylaminotetracycline;
4-dedimethylamino-12.alpha.-deoxyanhydrotetracycline;
dimethylamino-6-demethyl-6-deoxy-4-dedimethylaminotetracycline;
tetracyclinonitrile; 4-oxo-4-dedimethylaminotetracycline
4,6-hemiketal; 4-oxo-11a
Cl-4-dedimethylaminotetracycline-4,6-hemiketal;
5a,6-anhydro-4-hydrazon-4-dedimethylamino tetracycline;
4-hydroxyimino-4-dedimethylamino tetracyclines;
4-hydroxyimino-4-dedimethylamino 5a,6-anhydrotetracyclines;
4-amino-4-dedimethylamino-5a, 6 anhydrotetracycline;
4-methylamino-4-dedimethylamino tetracycline;
4-hydrazono-11a-chloro-6-deoxy-6-demethyl-6-methylene-4-dedimethylamino
tetracycline; tetracycline quaternary ammonium compounds;
anhydrotetracycline betaines; 4-hydroxy-6-methyl pretetramides;
4-keto tetracyclines; 5-keto tetracyclines; 5a, 11a dehydro
tetracyclines; 11a Cl-6, 12 hemiketal tetracyclines; 11a
Cl-6-methylene tetracyclines; 6, 13 diol tetracyclines;
6-benzylthiomethylene tetracyclines; 7,
11a-dichloro-6-fluoro-methyl-6-deoxy tetracyclines; 6-fluoro
(.alpha.)-6-demethyl-6-deoxy tetracyclines; 6-fluoro
(.beta.)6-demethyl-6-deoxy tetracyclines; 6-.alpha.
acetoxy-6-demethyl tetracyclines; 6-.beta. acetoxy-6-demethyl
tetracyclines; 7, 13-epithiotetracyclines; oxytetracyclines;
pyrazolotetracyclines; 11a halogens of tetracyclines; 12a formyl
and other esters of tetracyclines; 5, 12a esters of tetracyclines;
10, 12a-diesters of tetracyclines; isotetracycline;
12-a-deoxyanhydro tetracyclines;
6-demethyl-12a-deoxy-7-chloroanhydrotetracyclines;
B-nortetracyclines; 7-methoxy-6-demethyl-6-deoxytetracyclines;
6-demethyl-6-deoxy-5a-epitetracyclines;
8-hydroxy-6-demethyl-6-deoxy tetracyclines; monardene;
chromocycline; 5a methyl-6-demethyl-6-deoxy tetracyclines; 6-oxa
tetracyclines, and 6 thia tetracyclines.
[0046] The term "substituted tetracycline compound" includes
tetracycline compounds with one or more additional substituents,
e.g., at the 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 11a, 12, 12a or 13
position or at any other position which allows the substituted
tetracycline compound of the invention to perform its intended
function.
[0047] The term "carboxaldehyde substituted tetracycline compound"
includes tetracycline compounds that are substituted with one or
more aldehyde moieties (e.g. --C(O)H) at the 1, 2, 3, 4, 5, 6, 7,
8, 9, 10, 11, 11a, 12, 12a or 13 position or at any other position
which allows the substituted tetracycline compound of the invention
to perform its intended function. In one embodiment, the
carboxaldehyde substituted tetracycline compound is a 7-, 9- and/or
10-carboxaldehyde substituted tetracycline compound.
[0048] In one embodiment, the invention pertains to methods for
synthesizing a carboxaldehyde substituted tetracycline by reacting
a tetracycline reactive intermediate under appropriate conditions.
The term "appropriate conditions" includes any conditions that are
suitable for carrying out the reaction of converting the
tetracycline reactive intermediate to the carboxaldehyde
substituted tetracycline. Appropriate conditions include any
suitable solvents, temperature, catalysts and reagents. A skilled
artisan would readily be able to determine appropriate conditions
for carrying out the methods of the invention.
[0049] The term "tetracycline reactive intermediate" includes
tetracycline compounds that are chemically reactive and undergo the
desired reaction to form the substituted tetracycline compounds of
the invention. In one embodiment, the tetracycline reactive
intermediate is a halogenated tetracycline intermediate, including
an iodine substituted tetracycline intermediate (e.g.,
7-iodosancycline, 9-iododoxycycline), a chlorine substituted
tetracycline intermediate, a bromine substituted tetracycline
intermediate, an iodine and chlorine substituted tetracycline
intermediate (e.g., 7-chloro-9-iodosancycline) or a bromine and
iodine substituted tetracycline intermediate (e.g.,
7-bromo-9-iodosancycline). In another embodiment, the tetracycline
reactive intermediate is a triflate substituted tetracycline
intermediate (e.g., a 10-triflate substituted tetracycline
intermediate). The term triflate includes the
trifluoromethanesulfonate moiety and has the structure
CF.sub.3SO.sub.3--. In another embodiment, the tetracycline
reactive intermediate is a halogenated minocycline intermediate,
including an iodine, chlorine, or bromine substituted tetracycline
intermediate (e.g., 9-iodominocycline).
[0050] In one embodiment, the invention pertains to methods for
synthesizing a carboxaldehyde substituted tetracycline by reacting
a tetracycline reactive intermediate under appropriate conditions
with carbon monoxide, a palladium catalyst, a phosphine ligand, a
silane and a base; such that the carboxaldehyde substituted
tetracycline compound is synthesized.
[0051] In one embodiment, the invention pertains to methods for
synthesizing a carboxaldehyde substituted tetracycline by reacting
a tetracycline reactive intermediate under appropriate conditions
with carbon monoxide, a palladium catalyst, a silane and a base;
such that the carboxaldehyde substituted tetracycline compound is
synthesized.
[0052] The term "palladium catalyst" includes palladium (II)
chloride (PdCl.sub.2), bis(acetonitrile)dichloropalladium,
palladium (II) acetate (Pd(OAc).sub.2),
2-(dicyclohexylphosphino)biphenyl,
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)
complex, bis(triphenylphosphine)palladium(II) dichloride,
dichlorobis(tricyclohexylphosphine)palladium(II),
bis(triphenylphosphine)palladium(II) diacetate,
tris(dibenzylideneacetone)dipalladium(0), allylpalladium chloride
dimer, tetrakis(triphenylphosphine)palladium(0),
bis[tris(4-(heptadecafluorooctyl)phenyl)phosphine]palladium(II)
dichloride or
bis[tris(3-(1H,1H,2H,2H-perfluorodecyl)phenyl)phosphine]palladium(II)
dichloride. The term "palladium catalyst" also includes any
palladium catalyst that may be suitable for catalyzing the
conversion of the tetracycline reactive intermediate to the
carboxaldehyde substituted tetracycline compound. In one particular
embodiment, the palladium catalyst is palladium (II) acetate
(Pd(OAc).sub.2).
[0053] The term "palladium catalyst" also includes
phosphine-containing palladium (II) catalysts such as
PdCl.sub.2(tBu.sub.2PhP).sub.2
dichlorobis(di-tert-butylphenylphosphine palladium (II)] and
PdCl.sub.2(DPEPhos) [bis(diphenylphosphinophenyl)ether palladium
(II) chloride]. The term "palladium catalyst" also includes any
palladium catalyst that may be suitable for catalyzing the
conversion of the minocycline reactive intermediate to the
carboxaldehyde substituted minocycline compound.
[0054] The term "phosphine ligand" includes chelating non-chiral
and chiral phosphine ligands that contain one or more phosphorus
atoms trivalently bonded to an alkyl, alkenyl, alkynyl or aryl
group. The term "phosphine ligand" also includes any phosphine
ligand that may be suitable for use in the conversion of the
tetracycline reactive intermediate to the carboxaldehyde
substituted tetracycline compounds. In one embodiment, the
phosphine ligand is a xantphos ligand. Examples of xantphos ligands
are shown in Table 2. In one particular embodiment, the xantphos
ligand is xantphos.
TABLE-US-00002 TABLE 2 ##STR00011## ##STR00012## ##STR00013##
##STR00014## ##STR00015## ##STR00016## ##STR00017## ##STR00018##
##STR00019##
[0055] The term "silane" includes compounds with the chemical
formula R.sub.2SiH.sub.2 or R.sub.3SiH, in which each R is
independently C.sub.1-C.sub.10 branched or straight chain alkyl or
C.sub.5-C.sub.14 aryl. Examples of silanes include, for example,
tripropylsilane (Pr.sub.3SiH), triisopropylsilane (iPr.sub.3SiH),
benzyldimethylsilane, di-tert-butylsilane (tBu.sub.2SiH.sub.2),
triethylsilane (Et.sub.3SiH), cyclohexyldimethylsilane,
dimethylphenylsilane, diethylisopropylsilane, methylphenylsilane,
dimethylisopropylsilane, diethylmethylsilane, dimethylethylsilane,
diethylsilane (Et.sub.2SiH.sub.2), trioctylsilane,
dimethyloctadecylsilane, trihexylsilane, triphenylsilane
(Ph.sub.3SiH), diisopropyloctylsilane, methyldiphenylsilane,
triisobutylsilane (iBu.sub.3SiH), tributylsilane (Bu.sub.3SiH),
diphenylsilane (Ph.sub.2SiH.sub.2) and dimethylphenethylsilane. In
one particular embodiment, the silane is Ph.sub.2SiH.sub.2 or
Et.sub.3SiH.
[0056] The term "base," includes chemical species that accept
protons, such as carbonate bases and trialkylamines. Examples of
carbonate bases include, for example, lithium carbonate, sodium
carbonate, potassium carbonate, magnesium carbonate, calcium
carbonate, strontium carbonate and lanthanum carbonate. In one
embodiment, the carbonate base is sodium carbonate. Examples of
trialkylamines include, for example, trimethylamine, triethylamine,
tributylamine, triisopropylamine, dimethylethylamine,
diisopropylethylamine, diethylmethylamine, dimethylisopropylamine
and dimethylbutylamine. In one embodiment, the trialkylamine is
diisopropylethylamine.
[0057] The invention also pertains, at least in part, to methods
for synthesizing a substituted tetracycline compound by reacting
the carboxaldehyde substituted tetracycline compound under
palladium catalyzed coupling conditions, hydrogenolysis conditions
or reductive amination conditions.
[0058] For example, the C9 position of 7-bromo-9-iodosancycline can
be selectively converted to a carboxaldehyde group selectively in a
palladium catalyzed reductive carbonylation reaction. The reaction
has excellent regioselectivity where the C9 iodo group reacts
preferentially with Pd(PPh.sub.3).sub.4, Bu.sub.3SnH, and CO in NMP
at 70.degree. C. The reaction proceeds in good yield generating the
7-bromo-9-carboxaldehydesancycline compound that is a useful
intermediate in the preparation of a variety of novel
compounds.
[0059] The 7-bromo-9-carboxaldehydesancycline compound can
participate in a reductive alkylation reaction to furnish C9
position aminomethyl derivatives. In another sequence, the C7 bromo
group can then either be reduced under hydrogenolysis or the bromo
group can participate in a variety of palladium catalyzed coupling
processes to afford a multitude of C7 functionalized, C9
aminomethyl sancycline derivatives.
[0060] In using palladium catalyzed coupling reactions, the C9
position can be selectively coupled with an appropriate
regioselective catalyst to furnish a 9 position alkyl, aryl,
heterocycle, carbonyl or other type of functional groups. As stated
above, the C7 bromo group can either be reduced or coupled to
generate a variety of C7 substituted sancycline derivatives. In
subjecting the bromo group of a 7-bromo-9-carboxaldehydesancycline
compound to a coupling process, a variety of C7 and C9 position
combination substituted compounds can be produced.
[0061] In one embodiment, the invention pertains a method for
synthesizing a 9-substituted minocycline compound by reacting a
reactive minocycline intermediate with carbon monoxide, a palladium
catalyst, a silane and a base under appropriate conditions, wherein
the reactive minocycline intermediate is substituted at the
9-position with a reactive moiety such that the reactive moiety is
replaced with a carboxaldehyde substituent.
[0062] The phrase "palladium catalyzed coupling conditions" refers
to reaction conditions that include a palladium catalyst and
converts a tetracycline compound of the invention to a substituted
tetracycline compound by the formation of a carbon-carbon bond at
the 7, 8, 9 and/or 10 position of the tetracycline compound or at
any other position which allows the substituted tetracycline
compound of the invention to perform its intended function.
Examples of palladium catalyzed coupling conditions include
reductive aminations, Stille reactions, Suzuki coupling reactions
and Heck reactions. A skilled artisan would be able to readily
determine other applicable palladium catalyzed coupling conditions
for the conversion of a tetracycline compound of the invention to a
substituted tetracycline compound. In one embodiment, the palladium
catalyzed coupling conditions includes an organotin compound (e.g.,
Bu.sub.3SnR', wherein R' is a C.sub.1-C.sub.10 straight or branched
chain alkyl, a C.sub.2-C.sub.10 branched or straight chain alkenyl
or alkynyl, or a C.sub.5-C.sub.14 aryl group), a halogen or
triflate substituted compound (e.g., a halogen substituted
tetracycline compound or a triflate substituted tetracycline
compound), a palladium catalyst (e.g., Pd/C, Pd(PPh.sub.3).sub.4,
Pd(OAc).sub.2 or Pd.sub.2(dba).sub.3) and a solvent. In another
embodiment, the palladium catalyzed coupling conditions include an
alkene (e.g., R.sup.1C.dbd.CR.sup.2, wherein R.sup.1 and R.sup.2
are each independently hydrogen, a C.sub.1-C.sub.10 straight or
branched chain alkyl, a C.sub.2-C.sub.10 branched or straight chain
alkenyl or alkynyl, or a C.sub.5-C.sub.14 aryl group), a halogen or
triflate substituted compound (e.g., aryl, benzyl, or vinyl halogen
or triflate compound, such as, for example, a halogen substituted
tetracycline compound or a triflate substituted tetracycline
compound), a palladium catalyst (e.g., Pd/C, Pd(PPh.sub.3).sub.4,
PdCl.sub.2 or Pd(OAc).sub.2), a phosphine ligand (e.g.,
triphenylphosphine or 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl
(BINAP)), a base (e.g., triethylamine, potassium carbonate or
sodium acetate) and a solvent. In yet another embodiment, the
palladium catalyzed coupling reaction includes an aryl or vinyl
boronic acid (e.g., a compound of the formula R.sup.3B(OH).sub.2 in
which R.sup.3 may be, for example, a C.sub.2-C.sub.10 branched or
straight chain alkenyl or alkynyl, or a C.sub.5-C.sub.14 aryl
group), an aryl or vinyl halide or triflate (e.g., a halide or
triflate substituted C.sub.2-C.sub.10 branched or straight chain
alkenyl, halide or triflate substituted C.sub.5-C.sub.14 aryl group
or a halogen substituted tetracycline compound or a triflate
substituted tetracycline compound), a palladium catalyst (e.g.,
Pd(PPh.sub.3).sub.4) and a solvent.
[0063] The phrase "hydrogenolysis conditions" refers to reaction
conditions that convert a tetracycline compound of the invention to
a substituted tetracycline compound by the addition of a molecule
of hydrogen at the 7, 8, 9 and/or 10 position of the tetracycline
compound or at any other position which allows the substituted
tetracycline compound of the invention to perform its intended
function. A skilled artisan would be able to readily determine
other applicable hydrogenolysis conditions for the conversion of a
tetracycline compound of the invention to a substituted
tetracycline compound. In one embodiment, hydrogenolysis conditions
include a palladium catalyst (e.g.,
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex
(Cl.sub.2Pd(dppf))), an ammonium compound (e.g., ammonium formate)
and one or more solvents (e.g., 1-methyl-2-pyrrolidinone (NMP) and
water). In some examples, palladium on carbon (Pd/C) is the
hydrogenolysis catalyst. In other examples, a borohydride agent is
the hydrogenolysis catalyst.
[0064] The phrase "reductive amination conditions" refers to
reaction conditions that involve the conversion of a carbonyl group
(e.g., a carboxaldehyde moiety) to an amine at the 7, 8, 9 and/or
10 position of the tetracycline compound or at any other position
which allows the substituted tetracycline compound of the invention
to perform its intended function. A skilled artisan would be able
to readily determine other applicable reductive amination
conditions for the conversion of a tetracycline compound of the
invention to a substituted tetracycline compound. In one
embodiment, the reductive amination conditions include a reducing
agent (e.g., sodium cyanoborohydride or sodium triacetate
borohydride), a primary or secondary amine, wherein the amine is a
C.sub.1-C.sub.10 branched or straight chain alkyl amine (e.g.,
methylamine, dimethylamine, ethylamine, diethylamine,
isopropylamine, diisopropylamine, t-butylamine, propylamine,
butylamine and the like) or C.sub.5-C.sub.14 aryl amine (e.g.,
phenylamine, diphenylamine and the like), and a solvent (e.g.,
dimethylformamide (DMF) or 1,2-dichloroethane). In some
embodiments, the reductive amination is performed in the presence
of Pd/C. In some reactions, Pd/C is not included in the reductive
amination reaction.
[0065] In one embodiment, the invention pertains a method for
synthesizing a substituted tetracycline compound by reacting a
reactive tetracycline intermediate with carbon monoxide, a
palladium catalyst, a phosphine ligand, a silane and a base under
appropriate conditions, wherein the reactive tetracycline
intermediate is substituted at a first position with a first
reactive moiety and substituted at a second position with a second
reactive moiety, such that one of the first reactive moiety is
replaced with a carboxaldehyde substituent and the second reactive
moiety is unreacted.
[0066] In one embodiment, the invention pertains a method for
synthesizing a 9-substituted minocycline compound by reacting a
reactive minocycline intermediate with carbon monoxide, a palladium
catalyst, a silane and a base under appropriate conditions, wherein
the reactive minocycline intermediate is substituted at the
9-position with a reactive moiety such that the reactive moiety is
replaced with a carboxaldehyde substituent.
[0067] In one embodiment, the method for synthesizing substituted
tetracycline compounds provides the desired substituted
tetracycline compounds in high yield. For example, the yield is at
least about 90%, at least about 91%, at least about 92%, at least
about 93%, at least about 94%, at least about 95%, at least about
96%, at least about 97%, at least about 98%, or at least about 99%.
In another embodiment, the desired substituted tetracycline is
synthesized in about quantitative yields.
[0068] In one embodiment, the method for synthesizing substituted
minocycline compounds provides the desired substituted tetracycline
compounds in high yield. For example, the yield is at least about
90%, at least about 91%, at least about 92%, at least about 93%, at
least about 94%, at least about 95%, at least about 96%, at least
about 97%, at least about 98%, or at least about 99%. In another
embodiment, the desired substituted tetracycline is synthesized in
about quantitative yields.
[0069] In another embodiment, the invention pertains to a method
for synthesizing an aminomethyl substituted tetracycline compound
comprising the steps of: a) reacting a reactive tetracycline
intermediate with carbon monoxide, a palladium catalyst, a silane
and a base under appropriate conditions, wherein reactive
tetracycline intermediate is substituted at the 9-position with a
reactive moiety, wherein the reactive moiety is replaced with a
carboxaldehyde substituent; b) reacting the carboxaldehyde
substituent under reductive amination conditions.
[0070] For example, the aminomethyl substituted tetracycline
compound is a 9-aminomethyl substituted minocycline compound.
[0071] In one embodiment, the 9-aminomethyl minocycline compound
synthesized by the method of the invention is substantially pure.
For example, the purity is greater than 50%, at least about 55%, at
least about 60%, at least about 65%, at least about 69%, at least
about 70%, at least about 75%, at least about 80%, at least about
85%, at least about 90%, or at least about 99%.
[0072] In yet another embodiment, the method for synthesizing the
tetracycline compounds of the invention further comprises the step
of precipitating the substituted tetracycline compound in a
solvent, such as, for example, a non-polar solvent. The term
"non-polar solvent" includes those solvents that have a dielectric
constant of less than about 15. Examples of non-polar solvents
include, for example, hexanes, heptane, benzene, toluene, diethyl
ether (Et.sub.2O), chloroform, ethyl acetate, dichloromethane and
methyl t-butyl ether (MBTE, or TMBE) or combinations thereof. In
one embodiment, the solvent is Et.sub.2O, MBTE, heptane or a
combination thereof.
[0073] This invention identifies an efficient route for the
synthesis of 9-amino-methyl-substituted minocyclines, such as, for
example, Compound 1:
##STR00020##
[0074] The method of the invention employs a selective
palladium-phosphine catalyst, such as
PdCl.sub.2(tBu.sub.2PhP).sub.2 or PdCl.sub.2(DPEPhos) for
converting the 9-iodo compound to the 9-formyl compound. This
method results in a much higher and selective conversion of
iodominocycline to formylminocycline relative to previously
described syntheses. The high quality of the formylminocycline that
is produced by these methods leads to corresponding improvement in
the quality and yield of the subsequent reductive amination. The
reductive amination can be performed with a variety of amines, for
example, the neopentyl amine can be used to generate Compound
1.
[0075] In one embodiment, the substituted tetracycline compound is
of formula (I):
##STR00021##
wherein:
[0076] X is CHC(R.sup.13Y'Y), CR.sup.6'R.sup.6, S, NR.sup.6, or
O;
[0077] R.sup.2, R.sup.2', R.sup.4', and R.sup.4'' are each
independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio,
alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl,
heterocyclic, heteroaromatic or a prodrug moiety;
[0078] R.sup.4 is NR.sup.4'R.sup.4'', alkyl, alkenyl, alkynyl,
hydroxyl, halogen, or hydrogen;
[0079] R.sup.3, R.sup.11 and R.sup.12 are each hydrogen or a
pro-drug moiety;
[0080] R.sup.5 is hydroxyl, hydrogen, thiol, alkanoyl, aroyl,
alkaroyl, aryl, heteroaromatic, alkyl, alkenyl, alkynyl, alkoxy,
alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl,
alkyl carbonyloxy, or aryl carbonyloxy;
[0081] R.sup.6 and R.sup.6' are each independently hydrogen,
methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl,
alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl,
alkylamino, or an arylalkyl;
[0082] R.sup.8 is alkyl, alkenyl, alkynyl, aryl, arylalkyl,
arylalkenyl or arylalkynyl, formyl or carbonyl;
[0083] R.sup.7 is alkyl, alkenyl, alkynyl, aryl, arylalkyl,
arylalkenyl or arylalkynyl, formyl or carbonyl;
[0084] R.sup.9 is alkyl, alkenyl, alkynyl, aryl, arylalkyl,
arylalkenyl or arylalkynyl, formyl or carbonyl;
[0085] R.sup.10 is hydroxyl, alkoxyl, alkyl, alkenyl, alkynyl,
aryl, arylalkyl, arylalkenyl, arylalkynyl, formyl or carbonyl;
[0086] R.sup.13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl,
alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl; and
[0087] Y' and Y are each independently hydrogen, halogen, hydroxyl,
cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy,
alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl, and pharmaceutically acceptable salts thereof.
[0088] In another embodiment, the invention pertains to a method
for synthesizing an aminomethyl substituted tetracycline compound
comprising the steps of: a) reacting a reactive tetracycline
intermediate with carbon monoxide, a palladium catalyst, a
phosphine ligand, a silane and a base under appropriate conditions,
wherein reactive tetracycline intermediate is substituted at a
first position with a first reactive moiety and substituted at a
second position with a second reactive moiety, wherein the first
reactive moiety is replaced with a carboxaldehyde substituent; b)
reacting the carboxaldehyde substituent under reductive amination
conditions; and c) reacting the second reactive moiety under
palladium coupling conditions or under hydrogenolysis
conditions.
[0089] In one embodiment, the aminomethyl substituted tetracycline
compound is a 9-aminomethyl substituted compound of formula
(II):
##STR00022##
wherein:
[0090] J.sup.5 and J.sup.6 are each independently hydrogen, alkyl,
alkenyl, alkynyl, aryl, sulfonyl, acyl, alkoxycarbonyl,
alkaminocarbonyl, alkaminothiocarbonyl, substituted thiocarbonyl,
substituted carbonyl, alkoxythiocarbonyl, or linked to form a
ring;
[0091] J.sup.7 and J.sup.8 are each alkyl, halogen, or
hydrogen;
[0092] X is CHC(R.sup.13Y'Y), CR.sup.6'R.sup.6,
C.dbd.CR.sup.6'R.sup.6, S, NR.sup.6, or O;
[0093] R.sup.2, R.sup.2', R.sup.4', and R.sup.4'' are each
independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio,
alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl,
heterocyclic, heteroaromatic or a prodrug moiety;
[0094] R.sup.4 is NR.sup.4'R.sup.4'', alkyl, alkenyl, alkynyl,
aryl, hydroxyl, halogen, or hydrogen;
[0095] R.sup.3, R.sup.11 and R.sup.12 are each hydrogen or a
pro-drug moiety;
[0096] R.sup.5 is hydroxyl, hydrogen, thiol, alkanoyl, aroyl,
alkaroyl, aryl, heteroaromatic, alkyl, alkenyl, alkynyl, alkoxy,
alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl,
alkyl carbonyloxy, or aryl carbonyloxy;
[0097] R.sup.6 and R.sup.6' are each independently hydrogen,
methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl,
alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl,
alkylamino, or an arylalkyl;
[0098] R.sup.8 is alkyl, alkenyl, alkynyl, aryl, arylalkyl,
arylalkenyl or arylalkynyl, formyl or carbonyl;
[0099] R.sup.7 is alkyl, alkenyl, alkynyl, aryl, arylalkyl,
arylalkenyl or arylalkynyl, formyl or carbonyl;
[0100] R.sup.10 is hydroxyl, alkoxyl, alkyl, alkenyl, alkynyl,
aryl, arylalkyl, arylalkenyl, arylalkynyl, formyl or carbonyl;
[0101] R.sup.13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl,
alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl; and
[0102] Y' and Y are each independently hydrogen, halogen, hydroxyl,
cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy,
alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl, and pharmaceutically acceptable salts thereof.
[0103] In another embodiment, the aminomethyl substituted
tetracycline compound is a 7-aminomethyl substituted compound of
formula (III):
##STR00023##
wherein:
[0104] J.sup.1 and J.sup.2 are each independently each
independently hydrogen, alkyl, alkenyl, alkynyl, aryl, sulfonyl,
acyl, alkoxycarbonyl, alkaminocarbonyl, alkaminothiocarbonyl,
substituted thiocarbonyl, substituted carbonyl, alkoxythiocarbonyl,
or linked to form a ring;
[0105] J.sup.3 and J.sup.4 are each alkyl, halogen, or
hydrogen;
[0106] X is CHC(R.sup.13Y'Y), CR.sup.6'R.sup.6,
C.dbd.CR.sup.6'R.sup.6, S, NR.sup.6, or O;
[0107] R.sup.2, R.sup.2', R.sup.4', and R.sup.4'' are each
independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio,
alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl,
heterocyclic, heteroaromatic or a prodrug moiety;
[0108] R.sup.4 is NR.sup.4'R.sup.4'', alkyl, alkenyl, alkynyl,
aryl, hydroxyl, halogen, or hydrogen;
[0109] R.sup.3, R.sup.11 and R.sup.12 are each hydrogen or a
pro-drug moiety;
[0110] R.sup.5 is hydroxyl, hydrogen, thiol, alkanoyl, aroyl,
alkaroyl, aryl, heteroaromatic, alkyl, alkenyl, alkynyl, alkoxy,
alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl,
alkyl carbonyloxy, or aryl carbonyloxy;
[0111] R.sup.6 and R.sup.6' are each independently hydrogen,
methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl,
alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl,
alkylamino, or an arylalkyl;
[0112] R.sup.8 is alkyl, alkenyl, alkynyl, aryl, arylalkyl,
arylalkenyl or arylalkynyl, formyl or carbonyl;
[0113] R.sup.9 is alkyl, alkenyl, alkynyl, aryl, arylalkyl,
arylalkenyl or arylalkynyl, formyl or carbonyl;
[0114] R.sup.10 is hydroxyl, alkoxyl, alkyl, alkenyl, alkynyl,
aryl, arylalkyl, arylalkenyl, arylalkynyl, formyl or carbonyl;
[0115] R.sup.13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl,
alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl; and
[0116] Y' and Y are each independently hydrogen, halogen, hydroxyl,
cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy,
alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl, and pharmaceutically acceptable salts, esters, and
prodrugs thereof.
[0117] Examples of the substituted tetracycline compounds that may
be synthesized by the methods disclosed herein can be found in U.S.
Pat. Nos. 6,818,634; 6,642,270; 6,500,812; 6,849,615; 6,818,635;
6,683,068; 6,846,939; 7,208,482; 7,001,918; 6,617,318; 7,067,681;
7,202,235; 6,833,365; 6,624,168 and 7,094,806; and U.S. Patent
Publication Nos. 20040176334; 2006-0148765; 20050143353;
2007-0072834; 20040138183; 20040214801; 2005-0288262; 2006-0084634;
20040266740; 20050026875; 20050038002; 20050026876; 20050143352;
2006-0003971; 20050137174; 2006-0166945; 2006-0166944;
2006-0281717; 2007-0093455; 20040157807; 20050250744; 20050187198;
20050119235; 2006-0234988; 2006-0229282; 2006-0205698; the entire
contents of each of these patents and patent applications are
hereby incorporated by reference.
[0118] In one embodiment, the method for synthesizing the
tetracycline compounds of the invention further comprises adding a
Lewis acid with the carbon monoxide, the palladium catalyst, the
phosphine ligand, the silane and a base. The term "Lewis acid"
includes aluminum (III) bromide (AlBr.sub.3), aluminum (III)
chloride (AlCl.sub.3), boron (III) chloride (BCl.sub.3), boron
(III) fluoride (BF.sub.3), iron (III) bromide, iron (III) chloride,
tin (IV) chloride (SnCl.sub.4), titanium (IV) chloride (TiCl.sub.4)
or indium (III) chloride (InCl.sub.3). In one embodiment, the Lewis
acid is InCl.sub.3. In another embodiment, the Lewis acid is used
when the base is a trialkylamine (e.g., diisopropylethylamine).
[0119] In yet another embodiment, the method for synthesizing the
tetracycline compounds of the invention further comprises the step
of precipitating the substituted tetracycline compound in a
solvent, such as, for example, a non-polar solvent. The term
"non-polar solvent" includes those solvents that have a dielectric
constant of less than about 15. Examples of non-polar solvents
include, for example, hexanes, heptane, benzene, toluene, diethyl
ether (Et.sub.2O), chloroform, ethyl acetate, dichloromethane and
methyl t-butyl ether (MBTE) or combinations thereof. In one
embodiment, the solvent is Et.sub.2O, MBTE, heptane or a
combination thereof.
[0120] The term "alkyl" includes saturated aliphatic groups,
including straight-chain alkyl groups (e.g., methyl, ethyl, propyl,
butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.),
branched-chain alkyl groups (isopropyl, tert-butyl, isobutyl,
etc.), cycloalkyl (alicyclic) groups (cyclopropyl, cyclopentyl,
cyclohexyl, cycloheptyl, cyclooctyl), alkyl substituted cycloalkyl
groups, and cycloalkyl substituted alkyl groups. The term alkyl
further includes alkyl groups, which can further include oxygen,
nitrogen, sulfur or phosphorous atoms replacing one or more carbons
of the hydrocarbon backbone. In certain embodiments, a straight
chain or branched chain alkyl has 10 or fewer carbon atoms in its
backbone (e.g., C.sub.1-C.sub.10 for straight chain,
C.sub.3-C.sub.10 for branched chain). The term C.sub.1-C.sub.10
includes alkyl groups containing 1 to 10 carbon atoms.
[0121] The term substituted alkyl includes alkyl moieties having
substituents replacing a hydrogen on one or more carbons of the
hydrocarbon backbone. Such substituents can include, for example,
alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy,
arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy,
carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl,
aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,
alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato,
cyano, amino (including alkyl amino, dialkylamino, arylamino,
diarylamino, and alkylarylamino), acylamino (including
alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido),
amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,
sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,
trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an
aromatic or heteroaromatic moiety. Cycloalkyls can be further
substituted, e.g., with the substituents described above. An
"alkylaryl" or an "arylalkyl" moiety is an alkyl substituted with
an aryl (e.g., phenylmethyl (benzyl)). The term "alkyl" also
includes the side chains of natural and unnatural amino acids.
[0122] The term "aryl" includes groups, including 5- and 6-membered
single-ring aromatic groups that may include from zero to four
heteroatoms, for example, benzene, phenyl, pyrrole, furan,
thiophene, thiazole, isothiaozole, imidazole, triazole, tetrazole,
pyrazole, oxazole, isooxazole, pyridine, pyrazine, pyridazine, and
pyrimidine, and the like. Furthermore, the term "aryl" includes
multicyclic aryl groups, e.g., tricyclic, bicyclic, e.g.,
naphthalene, benzoxazole, benzodioxazole, benzothiazole,
benzoimidazole, benzothiophene, methylenedioxyphenyl, quinoline,
isoquinoline, napthridine, indole, benzofuran, purine, benzofuran,
deazapurine, or indolizine. Those aryl groups having heteroatoms in
the ring structure may also be referred to as "aryl heterocycles,"
"heterocycles," "heteroaryls" or "heteroaromatics." The aromatic
ring can be substituted at one or more ring positions with such
substituents as described above, as for example, halogen, hydroxyl,
alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,
aryloxycarbonyloxy, carboxylate, alkylcarbonyl,
alkylaminoacarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl,
alkylcarbonyl, arylcarbonyl, arylalkylcarbonyl, alkenylcarbonyl,
alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate,
phosphonato, phosphinato, cyano, amino (including alkyl amino,
dialkylamino, arylamino, diarylamino, and alkylarylamino),
acylamino (including alkylcarbonylamino, arylcarbonylamino,
carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio,
arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato,
sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido,
heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.
Aryl groups can also be fused or bridged with alicyclic or
heterocyclic rings which are not aromatic so as to form a polycycle
(e.g., tetralin).
[0123] The term "alkenyl" includes unsaturated aliphatic groups
analogous in length and possible substitution to the alkyls
described above, but that contain at least one double bond.
[0124] For example, the term "alkenyl" includes straight-chain
alkenyl groups (e.g., ethylenyl, propenyl, butenyl, pentenyl,
hexenyl, heptenyl, octenyl, nonenyl, decenyl, etc.), branched-chain
alkenyl groups, cycloalkenyl (alicyclic) groups (cyclopropenyl,
cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl), alkyl or
alkenyl substituted cycloalkenyl groups, and cycloalkyl or
cycloalkenyl substituted alkenyl groups. The term alkenyl further
includes alkenyl groups which include oxygen, nitrogen, sulfur or
phosphorous atoms replacing one or more carbons of the hydrocarbon
backbone. In certain embodiments, a straight chain or branched
chain alkenyl group has 10 or fewer carbon atoms in its backbone
(e.g., C.sub.2-C.sub.10 or straight chain, C.sub.3-C.sub.10 for
branched chain). Likewise, cycloalkenyl groups may have from 3-10
carbon atoms in their ring structure. The term C.sub.2-C.sub.10
includes alkenyl groups containing 2 to 10 carbon atoms.
[0125] The term substituted alkenyl includes alkenyl moieties
having substituents replacing a hydrogen on one or more carbons of
the hydrocarbon backbone. Such substituents can include, for
example, alkyl groups, alkynyl groups, halogens, hydroxyl,
alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,
aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl,
alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,
dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate,
phosphonato, phosphinato, cyano, amino (including alkyl amino,
dialkylamino, arylamino, diarylamino, and alkylarylamino),
acylamino (including alkylcarbonylamino, arylcarbonylamino,
carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio,
arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato,
sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido,
heterocyclyl, alkylaryl, or an aromatic or heteroaromatic
moiety.
[0126] The term "acyl" includes compounds and moieties which
contain the acyl radical (CH.sub.3CO--) or a carbonyl group. It
includes substituted acyl moieties. The term "substituted acyl"
includes acyl groups where one or more of the hydrogen atoms are
replaced by for example, alkyl groups, alkynyl groups, halogens,
hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,
aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl,
alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,
dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate,
phosphonato, phosphinato, cyano, amino (including alkyl amino,
dialkylamino, arylamino, diarylamino, and alkylarylamino),
acylamino (including alkylcarbonylamino, arylcarbonylamino,
carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio,
arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato,
sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido,
heterocyclyl, alkylaryl, or an aromatic or heteroaromatic
moiety.
[0127] The term "acylamino" includes moieties wherein an acyl
moiety is bonded to an amino group. For example, the term includes
alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido
groups.
[0128] The term "aroyl" includes compounds and moieties with an
aryl or heteroaromatic moiety bound to a carbonyl group. Examples
of aroyl groups include phenylcarboxy, naphthyl carboxy, etc.
[0129] The terms "alkoxyalkyl," "alkylaminoalkyl" and
"thioalkoxyalkyl" include alkyl groups, as described above, which
further include oxygen, nitrogen or sulfur atoms replacing one or
more carbons of the hydrocarbon backbone, e.g., oxygen, nitrogen or
sulfur atoms.
[0130] The term "alkoxy" includes substituted and unsubstituted
alkyl, alkenyl, and alkynyl groups covalently linked to an oxygen
atom. Examples of alkoxy groups include methoxy, ethoxy,
isopropyloxy, propoxy, butoxy, and pentoxy groups. Examples of
substituted alkoxy groups include halogenated alkoxy groups. The
alkoxy groups can be substituted with groups such as alkenyl,
alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy,
alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl,
arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,
dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate,
phosphonato, phosphinato, cyano, amino (including alkyl amino,
dialkylamino, arylamino, diarylamino, and alkylarylamino),
acylamino (including alkylcarbonylamino, arylcarbonylamino,
carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio,
arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato,
sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido,
heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moieties.
Examples of halogen substituted alkoxy groups include, but are not
limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy,
chloromethoxy, dichloromethoxy, trichloromethoxy, etc.
[0131] The term "amine" or "amino" includes compounds where a
nitrogen atom is covalently bonded to at least one carbon or
heteroatom. The term "alkyl amino" includes groups and compounds
wherein the nitrogen is bound to at least one additional alkyl
group. The term "dialkyl amino" includes groups wherein the
nitrogen atom is bound to at least two additional alkyl groups. The
term "arylamino" and "diarylamino" include groups wherein the
nitrogen is bound to at least one or two aryl groups, respectively.
The term "alkylarylamino," "alkylaminoaryl" or "arylaminoalkyl"
refers to an amino group which is bound to at least one alkyl group
and at least one aryl group. The term "alkaminoalkyl" refers to an
alkyl, alkenyl, or alkynyl group bound to a nitrogen atom which is
also bound to an alkyl group.
[0132] The term "amide" or "aminocarbonyl" includes compounds or
moieties which contain a nitrogen atom which is bound to the carbon
of a carbonyl or a thiocarbonyl group. The term includes
"alkaminocarbonyl" or "alkylaminocarbonyl" groups which include
alkyl, alkenyl, aryl or alkynyl groups bound to an amino group
bound to a carbonyl group. It includes arylaminocarbonyl groups
which include aryl or heteroaryl moieties bound to an amino group
which is bound to the carbon of a carbonyl or thiocarbonyl group.
The terms "alkylaminocarbonyl," "alkenylaminocarbonyl,"
"alkynylaminocarbonyl," "arylaminocarbonyl," "alkylcarbonylamino,"
"alkenylcarbonylamino," "alkynylcarbonylamino," and
"arylcarbonylamino" are included in term "amide." Amides also
include urea groups (aminocarbonylamino) and carbamates
(oxycarbonylamino).
[0133] The term "carbonyl" or "carboxy" includes compounds and
moieties which contain a carbon connected with a double bond to an
oxygen atom. The carbonyl can be further substituted with any
moiety which allows the compounds of the invention to perform its
intended function. For example, carbonyl moieties may be
substituted with alkyls, alkenyls, alkynyls, aryls, alkoxy, aminos,
etc. Examples of moieties which contain a carbonyl include
aldehydes, ketones, carboxylic acids, amides, esters, anhydrides,
etc. The term "formyl" includes compounds with the formula
--C(O)H.
[0134] The term "thiocarbonyl" or "thiocarboxy" includes compounds
and moieties which contain a carbon connected with a double bond to
a sulfur atom.
[0135] The term "ether" includes compounds or moieties which
contain an oxygen bonded to two different carbon atoms or
heteroatoms. For example, the term includes "alkoxyalkyl" which
refers to an alkyl, alkenyl, or alkynyl group covalently bonded to
an oxygen atom which is covalently bonded to another alkyl
group.
[0136] The term "ester" includes compounds and moieties which
contain a carbon or a heteroatom bound to an oxygen atom which is
bonded to the carbon of a carbonyl group. The term "ester" includes
alkoxycarboxy groups such as methoxycarbonyl, ethoxycarbonyl,
propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, etc. The alkyl,
alkenyl, or alkynyl groups are as defined above.
[0137] The term "thioether" includes compounds and moieties which
contain a sulfur atom bonded to two different carbon or hetero
atoms. Examples of thioethers include, but are not limited to
alkthioalkyls, alkthioalkenyls, and alkthioalkynyls. The term
"alkthioalkyls" include compounds with an alkyl, alkenyl, or
alkynyl group bonded to a sulfur atom which is bonded to an alkyl
group. Similarly, the term "alkthioalkenyls" and alkthioalkynyls"
refer to compounds or moieties wherein an alkyl, alkenyl, or
alkynyl group is bonded to a sulfur atom which is covalently bonded
to an alkynyl group.
[0138] The term "hydroxy" or "hydroxyl" includes groups with an
--OH or --O.sup.-;
[0139] The term "halogen" includes fluorine, bromine, chlorine,
iodine, etc. The term "perhalogenated" generally refers to a moiety
wherein all hydrogens are replaced by halogen atoms.
[0140] The terms "polycyclyl" or "polycyclic radical" refer to two
or more cyclic rings (e.g., cycloalkyls, cycloalkenyls,
cycloalkynyls, aryls and/or heterocyclyls) in which two or more
carbons are common to two adjoining rings, e.g., the rings are
"fused rings". Rings that are joined through non-adjacent atoms are
termed "bridged" rings. Each of the rings of the polycycle can be
substituted with such substituents as described above, as for
example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy,
alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl,
alkoxycarbonyl, alkylaminoacarbonyl, arylalkylaminocarbonyl,
alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, arylalkyl
carbonyl, alkenylcarbonyl, aminocarbonyl, alkylthiocarbonyl,
alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino
(including alkyl amino, dialkylamino, arylamino, diarylamino, and
alkylarylamino), acylamino (including alkylcarbonylamino,
arylcarbonylamino, carbamoyl and ureido), amidino, imino,
sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates,
alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,
trifluoromethyl, cyano, azido, heterocyclyl, alkyl, alkylaryl, or
an aromatic or heteroaromatic moiety.
[0141] The term "heteroatom" includes atoms of any element other
than carbon or hydrogen. Preferred heteroatoms are nitrogen,
oxygen, sulfur and phosphorus.
Exemplification of the Invention
Example 1. Preparation of 9-Carboxaldehydeminocycline
##STR00024##
[0143] Method A.
[0144] A solution of anhydrous 9-iodominocycline freebase (14.6 g,
25.0 mmol), anhydrous InCl.sub.3 (11.1 g, 50.0 mmol), anhydrous
iPr.sub.2NEt (8.73 mL, 50.0 mmol), Pd(OAc).sub.2 (0.11 g, 0.50
mmol) and xantphos (0.29 g, 0.50 mmol) in anhydrous NMP (100 mL) in
a dried 3-neck flask with internal thermometer was purged with CO
to saturate the solution, then a large balloon of carbon monoxide
was affixed to the top of the flask to maintain a positive
pressure. The solution was heated to obtain an internal temperature
of 70.degree. C. at which time Et.sub.3SiH (4.44 mL, 27.5 mmol) was
added via syringe pump over a 90 minute period. After completion of
reaction, the reaction was cooled to ambient temperature and
diluted with CH.sub.3CN (50 mL). The solution was transferred to
another flask and while stirring vigorously Et.sub.2O (approx. 500
mL) was added slowly to precipitate the product. The resulting
suspension was collected on a fine fritted funnel rinsing with
Et.sub.2O. The product was further dried under high vacuum to
afford 12.1 g in 99% yield.
[0145] Method B.
[0146] A solution of anhydrous 9-iodominocycline freebase (14.6 g,
25.0 mmol), anhydrous Na.sub.2CO.sub.3 (10.6 g, 100.0 mmol),
Pd(OAc).sub.2 (0.11 g, 0.50 mmol) and xantphos (0.29 g, 0.50 mmol)
in anhydrous NMP (100 mL) in a dried 3-neck flask with internal
thermometer was purged with CO to saturate the solution, then a
large balloon of carbon monoxide was affixed to the top of the
flask to maintain a positive pressure. The solution was heated to
obtain an internal temperature of 70.degree. C. at which time
Et.sub.3SiH (4.44 mL, 27.5 mmol) was added via syringe pump over a
90 minute period. After completion of reaction, the reaction was
cooled to ambient temperature, diluted with CH.sub.3CN (50 mL) and
filtered through a fritted funnel. The solution was transferred to
another flask and while stirring vigorously 1:1 MTBE/heptane
(approx. 500 mL) was added slowly to precipitate the product. The
resulting suspension was collected on a fine fritted funnel rinsing
with 1:1 MTBE/heptane. The product was further dried under high
vacuum to afford 12.1 g in 99% yield.
Example 2. Synthesis of 9-Carboxaldehydesancycline
##STR00025##
[0148] Method A.
[0149] To a solution of anhydrous 9-iodosancycline freebase (13.5
g, 25.0 mmol), Pd(OAc).sub.2 (0.11 g, 0.50 mmol) and xantphos (0.29
g, 0.50 mmol) in anhydrous NMP (100 mL) in a dried 3-neck flask
with internal thermometer was purged with CO to saturate the
solution, then a large balloon of carbon monoxide was affixed to
the top of the flask to maintain a positive pressure. The solution
was heated to obtain an internal temperature of 70.degree. C. at
which time Et.sub.3SiH (4.44 mL, 27.5 mmol) was added via syringe
pump over a 90 minute period. After completion of reaction, the
reaction was cooled to ambient temperature and diluted with
CH.sub.3CN (50 mL). The solution was transferred to another flask
and while stirring vigorously Et.sub.2O (approx. 500 mL) was added
slowly to precipitate the product. The resulting suspension was
collected on a fine fritted funnel rinsing with Et.sub.2O. The
product was further dried under high vacuum to afford 11.1 g in 99%
yield.
[0150] Method B.
[0151] To a solution of anhydrous 9-iodosancycline freebase (13.5
g, 25.0 mmol), anhydrous Na.sub.2CO.sub.3 (10.6 g, 100.0 mmol),
Pd(OAc).sub.2 (0.11 g, 0.50 mmol) and xantphos (0.29 g, 0.50 mmol)
in anhydrous NMP (100 mL) in a dried 3-neck flask with internal
thermometer was purged with CO to saturate the solution, then a
large balloon of carbon monoxide was affixed to the top of the
flask to maintain a positive pressure. The solution was heated to
obtain an internal temperature of 70.degree. C. at which time
Et.sub.3SiH (4.44 mL, 27.5 mmol) was added via syringe pump over a
90 minute period. After completion of reaction, the reaction was
cooled to ambient temperature, diluted with CH.sub.3CN (50 mL) and
filtered through a fritted funnel. The solution was transferred to
another flask and while stirring vigorously 1:1 MTBE/heptane
(approx. 500 mL) was added slowly to precipitate the product. The
resulting suspension was collected on a fine fritted funnel rinsing
with 1:1 MTBE/heptane. The product was further dried under high
vacuum to afford 11.1 g in 99% yield.
Example 3. Preparation of 7-Bromo-9-Carboxaldehydesancycline
##STR00026##
[0153] Method A.
[0154] A solution of anhydrous 7-bromo-9-iodosancycline freebase
(15.5 g, 25.0 mmol), anhydrous InCl.sub.3 (11.1 g, 50.0 mmol),
anhydrous iPr.sub.2NEt (8.73 mL, 50.0 mmol), Pd(OAc).sub.2 (0.11 g,
0.50 mmol) and xantphos (0.58 g, 1.00 mmol) in anhydrous NMP (100
mL) in a dried 3-neck flask with internal thermometer was purged
with CO to saturate the solution, then a large balloon of carbon
monoxide was affixed to the top of the flask to maintain a positive
pressure. The solution was heated to obtain an internal temperature
of 70.degree. C. at which time Et.sub.3SiH (4.44 mL, 27.5 mmol) was
added via syringe pump over a 90 minute period. After completion of
reaction, the reaction was cooled to ambient temperature and
diluted with CH.sub.3CN (50 mL). The solution was transferred to
another flask and while stirring vigorously Et.sub.2O (approx. 500
mL) was added slowly to precipitate the product. The resulting
suspension was collected on a fine fritted funnel rinsing with
Et.sub.2O. The product was further dried under high vacuum to
afford 13.0 g in 99% yield.
[0155] Method B.
[0156] To a solution of anhydrous 7-bromo-9-iodosancycline freebase
(15.5 g, 25.0 mmol), anhydrous Na.sub.2CO.sub.3 (10.6 g, 100.0
mmol), Pd(OAc).sub.2 (0.11 g, 0.50 mmol) and xantphos (0.58 g, 1.00
mmol) in anhydrous NMP (100 mL) in a dried 3-neck flask with
internal thermometer was purged with CO to saturate the solution,
then a large balloon of carbon monoxide was affixed to the top of
the flask to maintain a positive pressure. The solution was heated
to obtain an internal temperature of 70.degree. C. at which time
Et.sub.3SiH (4.44 mL, 27.5 mmol) was added via syringe pump over a
90 minute period. After completion of reaction, the reaction was
cooled to ambient temperature, diluted with CH.sub.3CN (50 mL) and
filtered through a fitted funnel. The solution was transferred to
another flask and while stirring vigorously 1:1 MTBE/heptane
(approx. 500 mL) was added slowly to precipitate the product. The
resulting suspension was collected on a fine fritted funnel rinsing
with 1:1 MTBE/heptane. The product was further dried under high
vacuum to afford 13.0 g in 99% yield.
Example 4. Preparation of 9-Aminomethylsancycline Derivatives
##STR00027##
[0158] An amount of 9-carboxaldehyde-7-bromo tetracycline (1) is
reacted under reductive amination conditions (e.g., a primary or
secondary amine, DMF or 1,2-dichloroethane and NaCNBH.sub.3 or
Na(OAc).sub.2) to form a 9-aminomethyl-7-bromo tetracycline (2).
The brominated intermediate is subjected to palladium catalyzed
coupling conditions (an organotin reagent, a palladium catalyst and
a solvent; an alkene, a palladium catalyst, a phosphine ligand and
a base; or an aryl or vinyl boronic acid and a palladium catalyst)
and a solvent to form 9-aminomethyl-7-substituted tetracycline
compounds (3). Alternatively, the 9-aminomethyl-7-bromo
tetracycline (2) can be subjected to hydrogenolysis conditions
(e.g., a palladium catalyst, an ammonium formate and one or more
solvents) to form 9-aminomethyl sancycline compounds.
Example 5
Preparation of Compound 1
##STR00028##
[0159] Method A Procedure for Preparation of
9-Carboxaldehydeminocycline.
[0160] To a solution of anhydrous 9-iodominocycline freebase (14.6
g, 25.0 mmol), anhydrous InCl.sub.3 (11.1 g, 50.0 mmol), anhydrous
iPr.sub.2NEt (8.73 mL, 50.0 mmol), Pd(OAc).sub.2 (0.11 g, 0.50
mmol) and xantphos (0.29 g, 0.50 mmol) in anhydrous NMP (100 mL) in
a dried 3-neck flask with internal thermometer was purged with CO
to saturate the solution, then a large balloon of carbon monoxide
was affixed to the top of the flask to maintain a positive
pressure. The solution was heated to obtain an internal temperature
of 70.degree. C. at which time Et.sub.3SiH (4.44 mL, 27.5 mmol) was
added via syringe pump over a 90 min. period. After completion of
reaction, the reaction was cooled to ambient temperature and
diluted with CH.sub.3CN (50 mL). The solution was transferred to
another flask and while stirring vigorously Et.sub.2O (approx. 500
mL) was added slowly to precipitate the product. The resulting
suspension was collected on a fine fritted funnel rinsing with
Et.sub.2O. The product was further dried under high vacuum to
afford 12.1 g in 99% yield.
Method B Procedure for the Preparation of
9-Carboxaldehydeminocycline.
[0161] To a solution of anhydrous 9-iodominocycline freebase (14.6
g, 25.0 mmol), anhydrous Na.sub.2CO.sub.3 (10.6 g, 100.0 mmol),
Pd(OAc).sub.2 (0.11 g, 0.50 mmol) and xantphos (0.29 g, 0.50 mmol)
in anhydrous NMP (100 mL) in a dried 3-neck flask with internal
thermometer was purged with CO to saturate the solution, then a
large balloon of carbon monoxide was affixed to the top of the
flask to maintain a positive pressure. The solution was heated to
obtain an internal temperature of 70.degree. C. at which time
Et.sub.3SiH (4.44 mL, 27.5 mmol) was added via syringe pump over a
90 min. period. After completion of reaction, the reaction was
cooled to ambient temperature, diluted with CH.sub.3CN (50 mL) and
filtered through a fritted funnel. The solution was transferred to
another flask and while stirring vigorously 1:1 MTBE/heptane
(approx. 500 mL) was added slowly to precipitate the product. The
resulting suspension was collected on a fine fritted funnel rinsing
with 1:1 MTBE/heptane. The product was further dried under high
vacuum to afford 12.1 g in 99% yield.
Method A Procedure for the Preparation of
9-Carboxaldehydesancycline.
[0162] To a solution of anhydrous 9-iodosancycline freebase (13.5
g, 25.0 mmol), Pd(OAc).sub.2 (0.11 g, 0.50 mmol) and xantphos (0.29
g, 0.50 mmol) in anhydrous NMP (100 mL) in a dried 3-neck flask
with internal thermometer was purged with CO to saturate the
solution, then a large balloon of carbon monoxide was affixed to
the top of the flask to maintain a positive pressure. The solution
was heated to obtain an internal temperature of 70.degree. C. at
which time Et.sub.3SiH (4.44 mL, 27.5 mmol) was added via syringe
pump over a 90 min. period. After completion of reaction, the
reaction was cooled to ambient temperature and diluted with
CH.sub.3CN (50 mL). The solution was transferred to another flask
and while stirring vigorously Et.sub.2O (approx. 500 mL) was added
slowly to precipitate the product. The resulting suspension was
collected on a fine fritted funnel rinsing with Et.sub.2O. The
product was further dried under high vacuum to afford 11.1 g in 99%
yield.
Method B Procedure for the Preparation of
9-Carboxaldehydesancycline.
[0163] To a solution of anhydrous 9-iodosancycline freebase (13.5
g, 25.0 mmol), anhydrous Na.sub.2CO.sub.3 (10.6 g, 100.0 mmol),
Pd(OAc).sub.2 (0.11 g, 0.50 mmol) and xantphos (0.29 g, 0.50 mmol)
in anhydrous NMP (100 mL) in a dried 3-neck flask with internal
thermometer was purged with CO to saturate the solution, then a
large balloon of carbon monoxide was affixed to the top of the
flask to maintain a positive pressure. The solution was heated to
obtain an internal temperature of 70.degree. C. at which time
Et.sub.3SiH (4.44 mL, 27.5 mmol) was added via syringe pump over a
90 min. period. After completion of reaction, the reaction was
cooled to ambient temperature, diluted with CH.sub.3CN (50 mL) and
filtered through a fritted funnel. The solution was transferred to
another flask and while stirring vigorously 1:1 MTBE/heptane
(approx. 500 mL) was added slowly to precipitate the product. The
resulting suspension was collected on a fine fitted funnel rinsing
with 1:1 MTBE/heptane. The product was further dried under high
vacuum to afford 11.1 g in 99% yield.
Method A Procedure for the Preparation of
7-Bromo-9-Carboxaldehydesancycline.
[0164] To a solution of anhydrous 7-bromo-9-iodosancycline freebase
(15.5 g, 25.0 mmol), anhydrous InCl.sub.3 (11.1 g, 50.0 mmol),
anhydrous iPr.sub.2NEt (8.73 mL, 50.0 mmol), Pd(OAc).sub.2. (0.11
g, 0.50 mmol) and xantphos (0.58 g, 1.00 mmol) in anhydrous NMP
(100 mL) in a dried 3-neck flask with internal thermometer was
purged with CO to saturate the solution, then a large balloon of
carbon monoxide was affixed to the top of the flask to maintain a
positive pressure. The solution was heated to obtain an internal
temperature of 70.degree. C. at which time Et.sub.3SiH (4.44 mL,
27.5 mmol) was added via syringe pump over a 90 min. period. After
completion of reaction, the reaction was cooled to ambient
temperature and diluted with CH.sub.3CN (50 mL). The solution was
transferred to another flask and while stirring vigorously
Et.sub.2O (approx. 500 mL) was added slowly to precipitate the
product. The resulting suspension was collected on a fine fitted
funnel rinsing with Et.sub.2O. The product was further dried under
high vacuum to afford 13.0 g in 99% yield.
Method B Procedure for the Preparation of
7-Bromo-9-Carboxaldehydesancycline.
[0165] To a solution of anhydrous 7-bromo-9-iodosancycline freebase
(15.5 g, 25.0 mmol), anhydrous Na.sub.2CO.sub.3 (10.6 g, 100.0
mmol), Pd(OAc).sub.2 (0.11 g, 0.50 mmol) and xantphos (0.58 g, 1.00
mmol) in anhydrous NMP (100 mL) in a dried 3-neck flask with
internal thermometer was purged with CO to saturate the solution,
then a large balloon of carbon monoxide was affixed to the top of
the flask to maintain a positive pressure. The solution was heated
to obtain an internal temperature of 70.degree. C. at which time
Et.sub.3SiH (4.44 mL, 27.5 mmol) was added via syringe pump over a
90 min. period. After completion of reaction, the reaction was
cooled to ambient temperature, diluted with CH.sub.3CN (50 mL) and
filtered through a fritted funnel. The solution was transferred to
another flask and while stirring vigorously 1:1 MTBE/heptane
(approx. 500 mL) was added slowly to precipitate the product. The
resulting suspension was collected on a fine fitted funnel rinsing
with 1:1 MTBE/heptane. The product was further dried under high
vacuum to afford 13.0 g in 99% yield.
Example 6. Alternate Preparation of Compound 1
9-Carboxaldehydeminocycline
##STR00029##
[0167] A 2 L pressure reactor equipped with heating mantle,
mechanical stirring rod and stirrer bearing, temperature probe,
addition funnel, condenser and gas manifold inlet valve was purged
with CO (g). 625 mL 4/1 THF/DMF was charged to pressure reactor
followed by 9-iodominocycline 70 g (120 mmol), Na.sub.2CO.sub.3
24.18 g (228 mmol), and PdCl.sub.2[tBu.sub.2PhP].sub.2 0.76 g (1.2
mmol) and stirred with heavy agitation. Triethylsilane 15.32 g (132
mmol) was charged to the addition funnel and the reaction mixture
was purged with 30 psi CO (g) three times and then pressurized to
30 psi and heated to 70.degree. C. while stirring. Once the
temperature reached 70.degree. C., the addition funnel was opened
to allow triethylsilane addition dropwise over 2 hours and the
reaction was stirred overnight at 70.degree. C. under 30 psi
CO(g).
[0168] Reaction completion was verified by LCMS and the reaction
solution was allowed to gradually return to room temperature before
filtering over a bed of celite. The celite cake was washed with
1000 mL THF and the filtrate was slowly added to 8000 mL TBME (tert
butyl methyl ether) in a 12 L round bottom flask to precipitate
crude 9-formylminocycline. The solution was stirred and chilled
with an ice bath for 30 minutes before filtering. The filter cake
was rinsed with 1000 mL TBME and then drip dried on a Buchner
funnel with latex dental dam before drying in vacuum oven at room
temperature overnight. Theoretical Yield=58.2 g; Actual Yield=90.4
g; Purity=97% by AUC on LCMS.
Preparation of 9-Aminomethylminocycline Derivatives
##STR00030##
[0170] A mixture of 9-formylminocycline, neopentyl amine (9.34 mL),
5% Pd--C (Degussa E-196), wet (10 g) and methanol (100 mL) was
hydrogenated at 30 psi in Paar shaker. After 18 hrs and a
conversion of 13%, additional catalyst (5 g) was added and reaction
was continued for another 24 hrs. After this time conversion was
completed.
[0171] The reaction mixture was diluted with 10% Na.sub.2SO.sub.3
and filtered. The funnel was washed with MeOH and water giving
totally 300 mL of filtrate.
[0172] The pH of filtrate was adjusted to 4.5 and extracted with
dichloromethane (DCM) (2.times.100 mL) extracts were discarded and
pH of water phase was brought to 7.5.
[0173] This solution was extracted again with DCM (4.times.180 mL)
and the combined extracts were evaporated and dried to give
yellow-greenish solid (5.41 g). Part of this solid was redissolved
in DCM and precipitated from TBME/pentane, filtered, dried and
analyzed, purity (w/w %)=64.91%.
[0174] The application of this invention resulted in a yield of 59
g of crude Compound 1 from 100 g of minocycline compared to a yield
of 44 g of crude from the corresponding input of minocycline in the
known hydroxymethylphthalamide process. After correcting for assay
the output of Compound 1 is 38 g compared to 22 g in the
hydroxymethylphthalamide process.
[0175] The assay of the crude Compound 1 produced by this invention
was 69% compared to 50% from the hydroxymethylphthalamide
process.
##STR00031##
EQUIVALENTS
[0176] Those skilled in the art will recognize, or be able to
ascertain using no more than routine experimentation, numerous
equivalents to the specific procedures described herein. Such
equivalents are considered to be within the scope of the present
invention and are covered by the following claims. The contents of
all references, patents, and patent applications cited throughout
this application are hereby incorporated by reference. The
appropriate components, processes, and methods of those patents,
applications and other documents may be selected for the present
invention and embodiments thereof.
* * * * *