U.S. patent application number 13/291742 was filed with the patent office on 2012-06-21 for methods, compositions, and apparatuses for forming macrocyclic compounds.
Invention is credited to Billy T. Fowler, Thomas E. Johnson.
Application Number | 20120157658 13/291742 |
Document ID | / |
Family ID | 36000462 |
Filed Date | 2012-06-21 |
United States Patent
Application |
20120157658 |
Kind Code |
A1 |
Johnson; Thomas E. ; et
al. |
June 21, 2012 |
METHODS, COMPOSITIONS, AND APPARATUSES FOR FORMING MACROCYCLIC
COMPOUNDS
Abstract
This invention relates to methods, compositions, and apparatuses
for producing macrocyclic compounds. First, one or more reactants
are provided in a reaction medium, which are capable of forming the
macrocyclic compound through a desired reaction pathway that
includes at least cyclization, and which are further capable of
forming undesired oligomers through a undesired reaction pathway
that includes undesirable oligomerization. Oligomerization of such
reactions in the reaction medium is modulated to reduce formation
of undesired oligomers and/or to reduce separation of the undesired
oligomers from the reaction medium, relative to a corresponding
unmodulated oligomerization reaction, thereby maximizing yields of
the macrocyclic compound. The macrocyclic compound so formed is
then recovered from the reaction medium. Preferably, the
macrocyclic compound spontaneously separates from the reaction
medium via phase separation. More preferably, the macrocyclic
compound spontaneous precipitates from the reaction medium and
therefore can be easily recovered by simple filtration.
Inventors: |
Johnson; Thomas E.; (Athens,
GA) ; Fowler; Billy T.; (Hull, GA) |
Family ID: |
36000462 |
Appl. No.: |
13/291742 |
Filed: |
November 8, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12772749 |
May 3, 2010 |
8053571 |
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13291742 |
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11059796 |
Feb 17, 2005 |
7709632 |
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12772749 |
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60545131 |
Feb 17, 2004 |
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Current U.S.
Class: |
530/323 ;
540/145; 540/469; 546/13; 548/314.4; 548/518; 549/348; 556/90;
560/190; 564/16; 564/273; 568/29; 568/309; 568/718; 568/719;
585/25; 585/27 |
Current CPC
Class: |
C07D 291/08 20130101;
C07D 323/00 20130101; C07D 313/00 20130101 |
Class at
Publication: |
530/323 ;
540/145; 540/469; 546/13; 548/314.4; 548/518; 549/348; 556/90;
560/190; 564/16; 564/273; 568/29; 568/309; 568/718; 568/719;
585/25; 585/27 |
International
Class: |
C07K 2/00 20060101
C07K002/00; C07D 513/22 20060101 C07D513/22; C07F 5/02 20060101
C07F005/02; C07D 403/14 20060101 C07D403/14; C07D 409/14 20060101
C07D409/14; C07D 493/22 20060101 C07D493/22; C07F 7/00 20060101
C07F007/00; C07C 69/52 20060101 C07C069/52; C07F 9/28 20060101
C07F009/28; C07C 249/00 20060101 C07C249/00; C07C 315/00 20060101
C07C315/00; C07C 45/00 20060101 C07C045/00; C07C 39/15 20060101
C07C039/15; C07C 39/17 20060101 C07C039/17; C07C 15/18 20060101
C07C015/18; C07C 13/64 20060101 C07C013/64; C07D 487/22 20060101
C07D487/22 |
Claims
1. A cyclization process, comprising: a) providing a reaction
system comprising one or more reactants in a reaction medium,
wherein: (i) at least one of the reactants participates in both
cyclization and oligomerization reactions, (ii) at least one of the
reactants comprises a linear precursor, (iii) the cyclization
process involves one or more reactions that produce oligomerization
byproducts, and (iv) cyclization is desired and oligomerization is
undesired; b) adding one or more extraneous oligomerization
byproducts into the reaction medium, so as to reduce formation of
undesired oligomers in said reaction medium, relative to formation
of undesired oligomers in a corresponding reaction medium to which
said one or more extraneous oligomerization byproducts is not
added; and c) forming a desired cyclic reaction product.
2. The process of claim 1, wherein said one or more reactions
include a reaction selected from the group consisting of
condensation reactions, oligomerization reactions, cyclization
reactions, substitution reactions, and metathesis reactions.
3. The process of claim 1, wherein said desired cyclic reaction
product comprises a product selected from the group consisting of
calix[n]pyrroles, calix[n]erines, cycloalkanes, cycloalkenes,
cycloalkynes, piperidines, morpholines, pyrrolidines, aziridines,
anilines, thiophenes, quinolines, isoquinolines, naphthalenes,
pyrimidines, purines, benzofurans, oxiranes, pyrroles, thiazides,
ozazoles, imidazoles, indoles, furans, benzothiophenes,
polyazamacrocycles, carbohydrates, acetals, crown ethers, cyclic
anhydrides, lactams, lactones, cyclic peptides,
phenylthiohydantoins, thiazolinones, succinimides, coronenes,
macrolides, carbocyclics, cyclodextrins, squalene oxides, ionophore
antibiotics, cyclic bis-N,O-acetals, cyclic disulfides, terpenoids,
spirocycles, resorcinarene macrocycles, cyclic oligo(siloxane)s,
stannylated cyclic oligo(ethyleneoxide)s, cyclic
poly(dibutyltindicarboxylate)s, cyclic poly(pyrrole), cyclic
poly(thiophene)s, cyclic poly(amide)s, cyclic poly(ether)s, cyclic
poly(carbonate)s, cyclic poly(ethersulfone)s, cyclic
poly(etherketone)s, cyclic poly(urethane)s, cyclic poly(imide)s,
cyclic poly(decamethylene fumarate)s, and cyclic
poly(decamethylethylene maleate)s.
4. The process of claim 1, wherein said one or more reactions
comprise at least one condensation reaction.
5. The process of claim 1, wherein said one or more extraneous
oligomerization byproducts comprise water.
6. The process of claim 1, wherein said one or more extraneous
oligomerization byproducts comprise a byproduct selected from the
group consisting of adenosine 5'-monophosphate (AMP), cytidine
5'-monophosphate (CMP), guanosine 5'-monophosphate (GMP), thymidine
5'-monophosphate (TMP), uridine 5'-monophosphate (UMP), adenosine
di-phosphate (ADP), cytidine di-phosphate (CDP), guanosine
di-phosphate (GDP), thymidine di-phosphate (TDP), uridine
di-phosphate (UDP), pyrophosphoric acid, alkyl pyrophosphates,
pyridine, aniline, benzyl alcohol, water, dihydrogen sulfide,
methanol, ethanol, propanol, butanol, bromide, alkylthiol,
thiophenol, 2-butyne, acetic acid, acetone, carbon dioxide, carbon
monoxide, deuterium oxide, fructose, galactose, gallic acid,
glycerol, glucose, hydrochloric acid, hydrogen cyanide, hydrobromic
acid, hydroiodic acid, iodoform, lactic acid, nitrogen, nitrous
acid, ammonia, methyl amine, ethyl amine, propyl amine, butyl
amine, dimethyl amine, diethyl amine, dipropyl amine, trimethyl
amine, triethyl amine, hydrogen, phenol, sulfur dioxide, phosphoric
acid, ethylene, sulfuric acid, silanes, silylethers, sulfonic
acids, sulfite esters, sulfenic acids, sulfinic acids, disulfides,
peroxides, boronic acids, borate ethers, triflates, mesylates,
sulfates, alkyl halides, perchloric acid, periodic acid, sulfones,
sulfoxides, succinimide, N,N-diisopropylurea, amino acids, methyl
thiocyanate, and N-hydroxysuccinimide.
7. The process of claim 1, further comprising recovering the
desired cyclic reaction product by selectively separating the
desired cyclic reaction product from the reaction medium.
8. The process of claim 7, wherein the desired cyclic reaction
product is selectively separated from the reaction medium using a
semi-permeable membrane.
9. The process of claim 7, wherein the desired cyclic reaction
product is selectively separated from the reaction medium using an
affinity column.
10. The process of claim 1, wherein the reaction medium comprises:
(1) one or more solvents in which one or more reactants are
soluble, and (2) one or more co-solvents for effectuating
spontaneous separation of the desired cyclic reaction product from
the reaction medium.
11. The process of claim 10, wherein said one or more co-solvents
comprise a solvent selected from the group consisting of water,
methanol, ethanol, isopropanol, tert-butanol, n-propanol,
iso-butanol, n-butanol, ethylene glycol, propylene glycol, formic
acid, limonene, dipropylene glycol, monomethyl ether, diethylene
glycol, ethyl ether, tripropylene glycol, monomethyl ether,
dimethyl sulfoxide, phenol, polypropylene glycol,
N-methyl-2-pyrrolidone, acetone, ethyl acetate, glycolfurol,
solketal, glycerol, formol, formamide, nitrobenzene,
tetrahydrofuryl alcohol, polyethylene glycol, dimethyl isosorbide,
dimethyl acetamide, methyl ethyl ketone, 1,4-dioxane, hydrosols,
acetonitrile, ammonia, methyl amine, ethyl amine, propyl amine,
butyl amine, dimethyl amine, diethyl amine, dipropyl amine,
trimethyl amine, triethyl amine, dimethylformamide,
tetrahydrofuran, glycol ethers, methyl cellosolve, cellosolve,
butyl cellosolve, hexyl cellosolve, methyl carbitol, carbitol,
butyl carbitol, hexyl carbitol, propasol solvent B, propasol
solvent P, propasol solvent M, propasol solvent DM,
methoxytriglycol, ethoxytriglycol, butoxytriglycol,
1-butoxyethoxy-2-propanol, phenyl glycol ether, glymes, monoglyme,
ethylglyme, diglyme, ethyl diglyme, triglyme, butyl diglyme,
tetraglyme, aminoalcohols, sulfolane, hexamethylphosphorictriamide
(HMPA), nitromethane, methyl ethylether, carbon disulfide, methale
chloride, chloroform, tetrahydrofuran, toluene, and benzene.
12. The process of claim 1, wherein a stabilizing agent is used to
stabilize the desired cyclic reaction product, wherein the
stabilizing agent comprises a salt with metallic or inorganic ions
that bind to the desired cyclic reaction product.
13. The process of claim 1, wherein a cyclization agent is used to
facilitate cyclization, wherein the cyclization agent comprises a
template material that pre-organizes reactive ends of desired
oligomers for cyclization or a material with microporous
structure.
14. The process of claim 1, wherein at least one catalyst is used
to catalyze cyclization, wherein the catalyst comprises a protic
acid selected from the group consisting of hydrochloric acid,
hydrobromic acid, sulfuric acid, boron trifluoride etherate, acetic
acid, propionic acid, benzoic acid, methane sulfonic acid,
trichloroacetic acid, trifluoroacetic acid, triflic acid, sulfonic
acid, benezenesulfonic acid, p-toluenesulfonic acid, camphor
sulfonic acid, and trifluoromethane sulfonic acid, or a Lewis acid
selected from the group consisting of BF.sub.3-etherate,
BF.sub.3-methanol, AlCl.sub.3, CsCl, SmCl.sub.3-6H.sub.2O,
InCl.sub.3, CrF.sub.3, AlF.sub.3, Sc(OTf).sub.3, YTiF.sub.4,
BEt.sub.3, GeCl.sub.4, EuCl.sub.3-nH.sub.2O, LaCl.sub.3, and
Ln(OTf).sub.3, where Ln is a lanthanide.
15. The process of claim 1, further comprising modifying the
desired cyclic reaction product, using one or more processing
operations selected from the group consisting of (i) oxidation,
(ii) reduction, (iii) further cyclization, (iv) isomeric
rearrangement, and (v) purification.
16. A process for forming a macrocyclic polypyrrole compound,
comprising: (a) providing a reaction system comprising i) a pyrrole
reactant, ii) a second reactant that reacts with a pyrrole to form
an oligomeric product and a cyclic product, and iii) a reaction
medium, wherein the reactants are capable of forming the
macrocyclic polypyrrole in the reaction medium through at least one
desired reaction pathway that includes at least cyclization
reaction(s), and wherein said reactants are further capable of
forming undesired oligomers through at least one undesired reaction
pathway that includes undesired oligomerization reactions; and (b)
adding an extraneous oligomerization by-product to the reaction
medium, so as to reduce formation of the undesired oligomers by the
reactants and/or to reduce separation of the undesired oligomers
from the reaction medium, relative to a corresponding reaction
medium to which said extraneous oligomerization by-product has not
been added.
17. The process of claim 16, wherein the macrocyclic polypyrrole
compound comprises a compound selected from the group consisting of
porphyrinogens, porphyrins, saphyrins, texaphyrins,
bacteriochlorins, chlorins, coproporphyrin I, corrins, corroles,
cytoporphyrins, deuteroporphyrins, etioporphyrin I, etioporphyrin
III, hematoporphyrins, pheophorbide a, pheophorbide b, phorbines,
phthalocyanines, phyllochlorins, phylloporphyrins, phytochlorins,
phytoporphyrins, protoporphyrins, pyrrochlorins, pyrroporphyrins,
rhodochlorins, rhodoporphyrins, and uroporphyrin I.
18. A cyclization process, comprising: a) providing a reaction
system comprising one or more reactants in a reaction medium,
wherein: (i) at least one of the reactants is a linear precursor
that participates in an oligomerization process, which
oligomerization process produces, in addition to oligomers, one or
more oligomerization byproducts, (ii) the oligomerization process
proceeds to a desired degree of oligomerization to form a desired
oligomer before the desired oligomer can be either cyclized to form
a desired cyclic product, or undergo further oligomerization to
form one or more undesired oligomers, and (iii) the degree of
oligomerization can be controlled in such a manner as to increase
yields of the desired oligomer, and decrease yields of said one or
more undesired oligomers, by adding a first amount of said one or
more extraneous reaction byproducts, and can increase yields of at
least one of said one or more undesired oligomers, and decrease
yields of said desired oligomer, by adding a second amount of said
one or more extraneous reaction byproducts, b) adding said first
amount of said one or more extraneous oligomerization byproducts
into the reaction medium, so as to increase oligomerization to said
desired degree to form said desired oligomer, and decrease further
oligomerization to form said undesired oligomer(s), relative to the
amount of further oligomerization that would be observed in a
corresponding reaction medium to which said one or more extraneous
oligomerization byproducts is not added, or said second amount of
said one or more oligomerization byproducts is added; and c)
cyclizing the desired oligomer to form a desired cyclic reaction
product.
19. The process of claim 18 wherein one of the reactants comprises
a pyrrole.
20. The process of claim 18, wherein the product comprises a
compound selected from the group consisting of porphyrinogens,
porphyrins, saphyrins, texaphyrins, bacteriochlorins, chlorins,
coproporphyrin I, corrins, corroles, cytoporphyrins,
deuteroporphyrins, etioporphyrin I, etioporphyrin III,
hematoporphyrins, pheophorbide a, pheophorbide b, phorbines,
phthalocyanines, phyllochlorins, phylloporphyrins, phytochlorins,
phytoporphyrins, protoporphyrins, pyrrochlorins, pyrroporphyrins,
rhodochlorins, rhodoporphyrins, and uroporphyrin I.
21. The process of claim 18, wherein the product comprises a cyclic
peptide.
22. The process of claim 18, wherein the product comprises a
macrocyclic lactone.
23. The process of claim 18, wherein the product comprises a
macrolide.
24. The process of claim 18, further comprising: d) modifying the
desired cyclic reaction product, using one or more processing
operations selected from the group consisting of (i) oxidation,
(ii) reduction, (iii) further cyclization, (iv) isomeric
rearrangement, and (v) purification.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 11/059,796 filed Feb. 17, 2005, issuing as
U.S. Pat. No. 7,709,632 on May 4, 2010, which claims priority to
U.S. Provisional Patent Application No. 60/545,131 filed Feb. 17,
2004. The disclosures of all of the foregoing applications are
hereby incorporated herein by reference in their respective
entireties, for all purposes, and the priority of all such
applications is hereby claimed under the provisions of 35 U.S.C.
.sctn.120.
FIELD OF THE INVENTION
[0002] The present invention relates generally to methods,
compositions, and apparatuses for synthesizing a wide variety of
macrocyclic compounds.
BACKGROUND OF THE INVENTION
[0003] At a time when the small-molecule pipeline of the
pharmaceutical industry is beginning to run dry, the number of
macrocycles has increased in an explosive manner. This fast-growing
phenomenon is due to the discovery of an impressive number of new
families of natural, semi-synthetic, and synthetic compounds, which
possess extraordinary properties. The macrocyclic structure is a
particularly desirable feature for the pharmaceutical industry. The
cyclic structure stabilizes the molecule against destruction by the
human body and increases its effectiveness in comparison with its
linear analog, by constraining it to a biologically active form.
Accordingly, macrocycles constitute a major class of pharmaceutical
agents that are currently under wide-spread clinical
investigation.
[0004] Moreover, macrocycles are key components in many other
fields, including nanotechnology. Nanoscale devices such as
chemical noses for the detection of land mines, sensors for the
detection of chemical weapons, light rods for solar energy
conversion, photovoltaic cells, light emitting diodes, magnetic
materials, multi-bit storage devices, and semi-conducting materials
have already been fashioned using macrocyclic compounds.
[0005] In spite of their great potential, however, macrocycles have
remained relatively under-explored and unexploited. Current methods
used for the preparation of macrocycles severely limit their use in
medicine and other important industries. While some of these
compounds are available from biological sources in quantities
sufficient for basic research or initial clinical studies, others
need to be produced by semi- or total synthesis, The present
methodologies for producing macrocycles require hundreds of
man-hours of work, produce large amounts of toxic waste, require
expensive manufacturing facilities, and still produce frustratingly
low quantities of the desired material. Low production yield
renders the profit margins of these molecules too small for
commercial production. Consequently, due to the high costs and low
profit margins associated with production of macrocycles by
conventional chemical manufacturing approaches, many important
discoveries are not commercialized. More importantly, the
staggering potential of macrocyclic research and development is
largely unrealized, as the result of the inability of the art to
provide a practicle method for making such compounds.
[0006] Thus, the inability to obtain large quantities of
macrocyclic molecules has been, and still is, the major stumbling
block for their commercial exploitation, as well as the stimulus
for efforts to improve existing methods or to discover new
ones.
[0007] Conceptually, the synthesis of cyclic molecules begins with
the preparation of open-chained starting materials which are
cyclized by a ring closure reaction. In contrast to the efficient
formation of five- or six-member rings, however, problems are
encountered when cyclization of compounds of other sizes, both
smaller and larger, is carried out in practice: yields of small
rings (3-4 atoms) are low and even lower for medium rings (8-12
carbon atoms) and macrocycles (>12 atoms). Due to ring strain
effects, small rings are less stable than five- or six-member
rings, and thus they are more difficult to obtain. However, most
macrocycles are unstrained and their enthalpy of formation is
comparable to that of five- or six-member rings. Thus, there are no
thermodynamic barriers to the formation of unstrained macrocycle.
Nonetheless, the kinetics of the formation of macrocycles greatly
complicates their formation. For entropic reasons, it is more
difficult to synthesize macrocycles than small and medium ring
compounds because macrocyclic ring formation involves a low
probability for coincident positioning of the two ends of the open
chain starting material, as required for cyclization to occur.
Further, intermolecular reactions of the reactive ends of the
linear precursor compete with the cyclization reaction. Such
intermolecular reactions lead to formation of undesired oligomers
and polymers.
[0008] In order to circumvent these undesirable oligomerization
reactions, cyclization is generally carried out under relatively
dilute conditions (typically less than 10 mM). The rationale for
the high dilution synthesis method is that if the concentration of
the reactants is sufficiently low, then the ring closure reaction
will be favored, since the reactive ends thereby are isolated from
the reactants and therefore more likely to react in an
intramolecular fashion to effect ring formation. However, the high
dilution principle is most effective if the cyclization reaction is
an irreversible reaction and the rate of cyclization is greater
than the rate of polymerization. In contrast to this kinetic
approach, in a thermodynamically controlled, reversible reaction,
the relative stabilities of all products, macrocyclic or acyclic,
determine the product distribution. If the macrocycle is the most
stable compound in such reversible reaction system, then the
macrocycle will be formed in good yield. Indeed, some examples
exist where macrocycles are in fact formed as the most stable
products in a reversible reaction. However, in most cyclization
reactions, macrocycles and undesired oligomers and polymers are of
comparable thermodynamic stabilities and therefore, all of them
will exist as a complex mixture, which requires extensive and
complicated purification procedures in order to obtain the desired
macrocyclic material. Furthermore, high dilution methods can only
provide limited quantities of the macrocyclic material and are
therefore inappropriate for high-volume commerical production.
[0009] In order to overcome or mediate the above-described
difficulties and complications, a wide variety of modifications and
improvements have been made to the high dilution methods, by
adapting such methods to the individual requirements of specific
target molecules. These approaches have achieved a wide variety of
levels of success, on a molecule by molecule basis. For example, it
is now possible to prepare modest quantities of certain macrocycles
by appropriate choice of starting material, solvent, temperature,
catalyst and dilution conditions, often with the assistance of
other effects, e.g., the template effect, the rigid group
principle, and other pseudo-dilution phenomenon.
[0010] In supramolecular chemistry, for example, the use of an
appropriate template can greatly improve cyclization steps. For
those examples where the building blocks for the macrocycle and its
oligomers are the same, an organic or inorganic guest material
(i.e., a template) may be found which binds complementarily into
the cavity formed by the macrocycle. Under reversible conditions,
the resulting supramolecular complex will be more stable than the
macrocyclic component and thus favored, which is known as the
template effect. In addition to mixtures in equilibrium, the
template effect can also be useful in kinetically controlled
reactions when the template facilitates the intramolecular reaction
by pre-organizing the reactive ends. Important features in high
yield template-assisted cyclization reactions include the geometry
of the template material, and the number of heteroatoms in the
interior cavity of the macrocycle that are available for
coordinating with the template.
[0011] In addition to template materials that bind to a cavity
formed by the macrocycle, other materials with microporous
structures can pre-organize the reactive ends of the reactants and
thereby facilitate the ring closure reaction, by providing a
localized environment defined by the microporous structure that is
highly favorable to the ring closure reaction. For example,
Smectite clays have been used to provide substantial improvements
in yield and/or selectivity of macrocyclic compounds. The
predetermined architectures of the microporous structures in the
clays can be effectively used to pre-organize the reactive
substances in a manner that controls the extent of oligomerization
and the geometry of the macrocycle so formed. Subsequently, the
final macrocyclic product can be removed from the clay
framework.
[0012] Further, some structural elements have emerged that show a
propensity to bend linear structures and form pre-organized ring
structures, suggesting that such pre-organization can be used to
favor intramolecular processes over the intermolecular ones and
provide simple routes for the preparation of macrocyclic
structures. This predisposition of certain molecules to bending or
folding has been widely studied, e.g., the Thorpe-Ingold effect,
and several structural elements, such as urea and proline residues,
have been identified as being associated with the formation of
U-turns in natural products. Consequently, sterically encumbering
groups can be added to acyclic precursors to effectuate bending
thereof and to facilitate ring closure, when the target macrocyclic
compound does not normally contain such sterically encumbering
groups.
[0013] Recent years have witnessed a renaissance in the field of
peptides. At present, more than 40 peptides are on the market, many
more are in registration processing, hundreds are in clinical
trials and more than 400 are in advanced preclinical studies. The
enhanced biological specificity, activity, and metabolic stability
of cyclopeptides in comparison with those of the linear peptides,
as a result of the constrained structural features of the cyclic
peptides, have attracted much attention. Cyclic peptidomimetic
scaffolds and templates have been widely used to assemble a wide
variety of spatially defined functional groups for molecular
recognition and drug discovery. There is a vigorous, on-going
effort to device and develop commercially applicable synthetic
methods for preparation of cyclic peptides and peptidomimetics.
[0014] Cyclic peptides can be synthesized from partially protected
linear precursors formed in solution or by solid-phase techniques
involving cyclization of such linear precursors in solution under
high or pseudo-dilution conditions. Alternatively, cyclic peptides
can be prepared by solid-phase assembly of the linear peptide
sequence, followed by cyclization while the peptide remains
anchored to a polymeric support. This method takes advantage of the
pseudo-dilution phenomenon attributed to the solid-phase, which
favors intramolecular reactions over intermolecular side reactions.
More recently, chemical ligation methods have also shown some
success in the formation of cyclic peptides, specifically in the
formation of backbone peptide bonds. Unlike other methods, chemical
ligation methods do not require coupling reagents or protection
schemes, but are achieved through a variable chemoselective capture
step followed by an invariable intramolecular acyl transfer
reaction.
[0015] Despite the development of the above-discussed synthesis
techniques and other high-dilution or pseudo-dilution methods,
however, the practical aspects of the synthesis principle, viz.,
the selection of starting materials and reaction parameters, still
have to be determined empirically, and the cyclization step still
remains as the fundamental synthetic challenge. The requirements
for complex multi-step processes, specific reaction conditions,
templates, selective protection/deprotection steps, and high
dilution of the reaction materials continue to restrict commercial
production of macrocyclic compounds, even after extensive
optimization, and the modified or improved methods still suffer
from many limitations of the original high-dilution procedure.
[0016] A general method that does not depend on high dilution of
the reaction materials or otherwise suffer the deficiencies of high
dilution techniques and is useful for synthesis of a wide variety
of macrocyclic compounds on a commercial scale would be of immense
value.
SUMMARY OF THE INVENTION
[0017] The present invention relates to a new method for producing
macrocyclic compounds, which can be generally applied to increase
the production yield and the volumetric production efficiency of a
wide variety of different classes of macrocyclic compounds.
[0018] The present invention also relates to new compositions and
to apparatuses for automated synthesis of a wide variety of
macrocyclic compounds for scale-up commercial production of
macrocyclic compounds at significantly reduced cost.
[0019] In one aspect, the present invention relates to a process
for manufacturing at least one macrocyclic compound, which
comprises the steps of: (a) providing a reaction system comprising
one or more reactants in a reaction medium, wherein such reactants
are capable of forming the macrocyclic compound in the reaction
medium at a first set of reaction conditions through at least one
desired reaction pathway that includes at least cyclization
reaction(s), and wherein such reactants are further capable of
forming undesired oligomers at the first set of reaction conditions
through at least one undesired reaction pathway that includes
undesirable oligomerization reactions; and (b) modulating
oligomerization reactions of such one or more reactants in the
reaction medium, so as to reduce formation of the undesired
oligomers by such one or more reactants and/or to reduce separation
of the undesired oligomers from the reaction medium, relative to
corresponding unmodulated oligomerization reactions.
[0020] The present invention in another aspect relates to a process
for manufacturing at least one macrocyclic compound, comprising the
steps of: (a) providing a reaction system comprising one or more
reactants in a reaction medium, wherein such reactants are capable
of forming an intermediate macrocyclic compound in the reaction
medium at a first set of reaction conditions through at least one
desired reaction pathway that includes at least cyclization
reaction(s), and wherein such reactants are further capable of
forming undesired oligomers at the first set of reaction conditions
through at least one undesired reaction pathway that includes
undesirable oligomerization reactions; and (b) modulating
oligomerization reactions of such one or more reactants in the
reaction medium, so as to reduce formation of undesired oligomers
by such one or more reactants and/or to reduce separation of the
undesired oligomers from the reaction medium, relative to
corresponding unmodulated oligomerization reactions; and (c)
modifying the intermediate macrocyclic compound to form a
macrocyclic compound of interest.
[0021] In a further aspect, the present invention relates to a
reaction composition for forming a macrocyclic compound,
comprising: [0022] (1) one or more reactants, wherein such
reactants are capable of forming the macrocyclic compound at a
first set of reaction conditions through at least one desired
reaction pathway that includes at least cyclization reaction(s),
and wherein such reactants are further capable of forming undesired
oligomers at the first set of reaction conditions through at least
one undesired reaction pathway that includes undesirable
oligomerization reactions; [0023] (2) one or more reacting solvents
for dissolving the reactants; and [0024] (3) one or more
oligomerization control additives that modulate oligomerization
reactions of such reactants by reducing formation of undesired
oligomers and/or separation of the undesired oligomers from such
reaction composition, relative to a corresponding reaction
composition lacking such oligomerization control additive(s).
[0025] In a still further aspect, the present invention relates to
a system for manufacturing at least one macrocyclic compound,
comprising at lease one reaction zone having: (1) one or more
supply vessels for supplying one or more reactants and/or one or
more solvents, wherein such reactants are capable of forming the
macrocyclic compound in a reaction medium comprising such one or
more solvents at a first set of reaction conditions through at
least one desired reaction pathway that includes at least
cyclization reaction(s), and wherein such reactants are further
capable of forming undesired oligomers at the first set of reaction
conditions through at least one undesired reaction pathway that
includes undesirable oligomerization reactions, (2) a reaction
chamber coupled with such supply vessels for receiving the
reactants and solvents and effectuating reactions of the reactants
therein to form the macrocyclic compound, and (3) an
oligomerization modulation unit for modulating oligomerization
reactions of such one or more reactants in the reaction chamber, so
as to reduce formation of undesired oligomers by such one or more
reactants or to reduce separation of the undesired oligomers from
the reaction medium, relative to corresponding unmodulated
oligomerization reactions.
[0026] Another aspect of the present invention relates to a process
for synthesizing a macrocyclic compound through cyclization
reaction(s), including the use of an oligomerization control agent
to control undesired oligomerization reactions that compete with
said cyclization reaction(s).
[0027] Other aspects, features and embodiments of the invention
will be more fully apparent from the ensuing disclosure and
appended claims.
Definitions
[0028] The words "a" and "an" as used herein are not limited to
their singular senses, but also covers the plural.
[0029] The phrases "macrocycles," "macrocyclic compounds," and
"cyclic compounds" are used interchangeably herein to refer to both
single cyclic and multi-cyclic compounds having one or more ring
structures. The total number of atoms on each of such ring
structures may be widely varied, e.g., in a range of from 3 to
about 100 or more. Such single cyclic or multi-cyclic compound may
further contain one or more linear functional groups, branched
functional groups, and/or arched functional groups that bridge
across a plane defined by a ring structure. In the case of
multi-cyclic compounds having two or more ring structures, any pair
of such ring structures may be separated from each another by a
non-cyclic spacing structure, or the rings can be in side-by-side
relationship to each another, sharing one chemical bond or one
atom, or alternatively, the rings may partially overlap with each
other, or one ring structure can be enclosed by or intertwined with
the other ring. The three-dimensional structures of such compounds
can be characterized by any geometric shape, either regular or
irregular, including, but not limited to, planar, cylindrical,
semispherical, spherical, ovoidal, helical, pyriamidyl, etc.
Specifically, such macrocyclic compounds may include, but are not
limited to porphyrinogens, porphyrins, saphyrins, texaphyrins,
bacteriochlorins, chlorins, coproporphyrin I, corrins, corroles,
cytoporphyrins, deuteroporphyrins, etioporphyrin I, etioporphyrin
III, hematoporphyrins, pheophorbide a, pheophorbide b, phorbines,
phthalocyanines, phyllochlorins, phylloporphyrins, phytochlorins,
phytoporphyrins, protoporphyrins, pyrrochlorins, pyrroporphyrins,
rhodochlorins, rhodoporphyrins, uroporphyrin I, calix[n]pyrroles,
calix[n]erines, cycloalkanes, cycloalkenes, cycloalkynes,
piperidines, morpholines, pyrrolidines, aziridines, anilines,
thiophenes, quinolines, isoquinolines, naphthalenes, pyrimidines,
purines, benzofurans, oxiranes, pyrroles, thiazides, ozazoles,
imidazoles, indoles, furans, benzothiophenes, polyazamacrocycles,
carbohydrates, acetals, crown ethers, cyclic anhydrides, lactams,
lactones, cyclic peptides, phenylthiohydantoins, thiazolinones,
succinimides, coronenes, macrolides, carbocyclics, cyclodextrins,
squalene oxides, ionophore antibiotics, cyclic bis-N,O-acetals,
cyclic disulfides, terpenoids, spirocycles, resorcinarene
macrocycles, cyclic oligo(siloxane)s, stannylated cyclic
oligo(ethyleneoxide)s, cyclic poly(dibutyltindicarboxylate)s,
cyclic poly(pyrrole), cyclic poly(thiophene)s, cyclic poly(amide)s,
cyclic poly(ether)s, cyclic poly(carbonate)s, cyclic
poly(ethersulfone)s, cyclic poly(etherketone)s, cyclic
poly(urethane)s, cyclic poly(imide)s, cyclic poly(decamethylene
fumarate)s, cyclic poly(decamethylethylene maleate)s, etc.
[0030] The phrase "desired oligomer" as used herein refers to the
oligomeric or polymeric compound formed by the reactants in the
reaction composition of the present invention, which has the
appropriate oligomer number (number of mer units) for forming the
desired macrocyclic compound by cyclization reaction.
[0031] The phrase "desired oligomerization" as used herein refers
to the oligomerization reaction(s) that form the desired
oligomers.
[0032] The phrase "undesired oligomers" as used herein refers to a
wide variety of oligomeric and/or polymeric compounds other than
the desired oligomer, which are also formed by the reactants in the
reaction composition of the present invention, and which have
oligomeric or polymeric numbers (number of mer units) that are
either smaller or larger than that of the desired oligomer.
[0033] The phrase "undesired oligomerization" as used herein refers
to the oligomerization reactions that form the undesired
oligomers.
[0034] The phrase "modulating" or "modulation" as used herein in
reference to oligomerization reactions is intended to be broadly
construed, to encompass any type of intervention affecting the
oligomerization reactions to cause reduction in formation of the
undesired oligomers and/or separation of the already formed
undesired oligomers from the reaction medium, relative to
corresponding oligomerization reactions carried out without such
intervention. Such intervention in specific embodiments of the
invention can include, for example, one or more of: addition of any
agent or additive; removal of any reaction byproduct; and change of
any reaction condition, whereby the oligomerization reactions takes
place with reduced formation of undesired oligomers and/or reduced
separation of the undesired oligomers from the reaction medium.
Conventional techniques, such as templating and other
pseudo-dilution techniques, while they may be additionally employed
in the overall process of the present invention to maximize yield
of desired macrocycle, form no part of modulation or modulating as
contemplated by the present invention.
[0035] The phrase "byproducts" and "reaction byproducts" are used
interchangeably herein to encompass any inorganic compounds,
organic compounds, organometallic compounds, chemical elements,
radicals, ions (cations/anions/Zwitterions), neutral particles,
energized particles, or other applicable species that are produced
by a specific reaction in the method of the present invention.
Specifically, reaction steps that may produce byproducts include,
but are not limited to, condensation reactions, oligomerization
reactions, cyclization reaction(s), substitution reaction(s),
metathesis reaction(s), etc.
[0036] The term "phase separation" as used herein broadly refers to
separation of material from its surrounding environment due to
physical and/or chemical differences between the material and its
environement, or otherwise as a result of differences in properties
between the material and its environment. Such term specifically
covers, but is not limited to, the spontaneous separation of an
insoluble or weakly soluble solid or gas from a liquid, or of an
immiscible liquid from another liquid, or of a liquid or solid from
a gas, due to a density differential therebetween. Such term, for
example, encompasses any separation based on differences in size,
shape, mass, density, solubility, volatility, permeability,
diffusion rate, charge distribution, mass/charge ratio, binding
affinity, adsorption/absorption potential, reactivity, or the
like.
[0037] The term "phase transfer" as used herein broadly refers to
transfer of material in a multi-phase environment (e.g., an
environmental that contains two or more distinct, immiscible
components as respect of phases), from one phase into another
phase. The phases thus differ from one another in one or more
physical and/or chemical characteristics, or in other
differentiating properties. Such term specifically encompasses, but
is not limited to, the transfer of one material from a first liquid
component into a second liquid component that is distinct from and
immiscible with such first liquid component. Such term further
encompasses any transfer of material from one phase component to
another based on differences in size, shape, mass, density,
solubility, volatility, permeability, diffusion rate, charge
distribution, mass/charge ratio, binding affinity,
adsorption/absorption potential, and/or reactivity between such
respective phase components.
[0038] The term "spontaneous" as used herein refers to a process
that proceeds under internal force(s) and requires no external
force(s) or intervention. A spontaneous process is not limited by
any specific time frame, i.e., it may occur instantaneously or over
a relatively long period of time.
BRIEF DESCRIPTION OF THE DRAWINGS
[0039] FIGS. 1A-1D illustrate a wide variety of generalized
reaction processes for forming macrocyclic compounds.
[0040] FIG. 2 is a graph of intensity as a function of average
oligomer length, showing shifts in oligomer distributions when
different concentrations of extraneous oligomerization byproduct
are introduced to the reaction system.
[0041] FIG. 3 shows a high-performance liquid chromatograph (HPLC)
of the products produced by reaction of benzaldehyde and pyrrole in
an absolute ethanol solution without oligomerization control.
[0042] FIGS. 4A and 4B show HPLC chromatographs of the products
produced by reaction of benzaldehyde and pyrrole in solutions
containing precipitating solvent and oligomerization control
additive species.
[0043] FIG. 4A shows a HPLC of the products produced by reaction of
benzaldehyde and pyrrole in a solution containing 50% methanol and
50% water by volume.
[0044] FIG. 4B shows a HPLC of the products produced by reaction of
benzaldehyde and pyrrole in a solution containing methanol and
water at a volume ratio of 3:5 with about 0.014 g/ml NaCl.
[0045] FIGS. 5-19 show processes for manufacturing a wide variety
of macrocyclic compounds, according to illustrative embodiments of
the present invention.
[0046] FIG. 20 is a schematic representation of a system for
manufacturing niacrocyche compounds, according to one embodiment of
the present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0047] The contents of U.S. Provisional Patent Application No.
60/545,131 filed Feb. 17, 2004 in the names of Thomas E. Johnson
and Billy T. Fowler for "METHODS AND COMPOSITIONS FOR FORMING
CYCLIC COMPOUNDS" are incorporated herein by reference in their
entirety for all purposes.
[0048] In general, synthesis of a macrocyclic compound involves
cyclization of a linear precursor. The linear precursor can either
be formed in situ from one or more starting materials, e.g., by
oligomerization reaction, or the linear precursor be provided
directly as the starting material for macrocyclic compound
synthesis.
[0049] FIG. 1A illustratively shows a process by which a
macrocyclic compound C can be formed by oligomerization and
cyclization reaction(s). Specifically, such process includes: (a)
condensation reaction of two or more reactants A and B, forming a
monomeric intermediate product AB; (b) reversible oligomerization
of such monomeric intermediate product AB, forming a desired
oligomer [AB].sub.n of length n, and (c) reversible cyclization of
such desired oligomer [AB].sub.n, forming the macrocyclic compound
C. The oligomerization of AB that forms the desired oligomer
[AB].sub.n necessary for subsequent cyclization and formation of
the compound C is the desired oligomerization. The condensation
reaction, the desired oligomerization reaction and the cyclization
reaction therefore define a desired reaction pathway 1 in which the
reactants A and B form the macrocyclic compound C. Further, the
desired oligomer [AB].sub.n is susceptible to further, undesired
oligomerization in forming undesired oligomers [AB].sub.n+k of
length (n+k). Such further oligomerization of the desired oligomer
[AB].sub.n defines an undesired reaction pathway 2, which directly
competes with the desired reaction pathway 1 by reducing
availability of the desired oligomer [AB].sub.n for the cyclization
reaction and causing significant reduction in the production yield
of the macrocyclic compound C.
[0050] FIG. 1B illustratively shows another process for forming a
macrocyclic compound C, which includes: (a) condensation reaction
of two or more reactants A and B, forming a linear intermediate
product AB; and (b) reversible cyclization of such linear
intermediate product AB, forming the macrocyclic compound C. No
oligomerization is required for formation of the macrocyclic
compound C in this process. Instead, the condensation reaction and
the cyclization reaction define the desired reaction pathway 1 in
which the reactants A and B form the desired macrocyclic compound
C. The linear intermediate product AB, however, is susceptible to
undesired oligomerization in forming undesired oligomers [AB].sub.m
of length m. Such undesired oligomerization of the linear
intermediate product therefore defines the undesired reaction
pathway 2, which directly competes with the desired reaction
pathway 1 by reducing availability of the linear intermediate
product AB for the cyclization reaction and causing significant
reduction in the production yield of the macrocyclic compound
C.
[0051] FIG. 1C illustratively shows a further process through which
a macrocyclic compound C can be formed through oligomerization and
cyclization. Specifically, such process includes: (a) reversible
oligomerization of a single reactant A, forming desired oligomer
A.sub.n of length n, and (b) reversible cyclization of such desired
oligomer A.sub.n, forming the macrocyclic compound C. The
oligomerization of A that forms the desired oligomer A.sub.n
necessary for subsequent cyclization and formation of the compound
C is the desired oligomerization. The desired oligomerization
reaction and the cyclization reaction therefore define the desired
reaction pathway 1 in which the reactant A forms the desired
macrocyclic compound C. In this reaction scheme, the desired
oligomer A.sub.n is susceptible to further, undesired
oligomerization in forming undesired oligomers A.sub.n+k of length
(n+k). Such further, undesired oligomerization of the desired
oligomer A.sub.n defines an undesired reaction pathway 2, which
directly competes with the desired reaction pathway 1 by reducing
availability of the desired oligomer A.sub.n for the cyclization
reaction and causing significant reduction in the production yield
of the macrocyclic compound C.
[0052] FIG. 1D illustratively shows another process for forming a
macrocyclic compound C, which includes only reversible cyclization
of a single reactant A, forming the macrocyclic compound C. No
condensation or oligomerization is required for formation of the
macrocyclic compound C in this process. Instead, the cyclization
reaction alone defines the desired reaction pathway 1 in which the
reactant A forms the desired macrocyclic compound C. The reactant
A, however, is susceptible to undesired oligomerization in forming
undesired oligomers A.sub.m of length m. Such undesired
oligomerization of the reactant A therefore defines the undesired
reaction pathway 2, which directly competes with the desired
reaction pathway 1 by reducing availability of the reactant A for
the cyclization reaction and causing significant reduction in the
production yield of the macrocyclic compound C.
[0053] The reactants as mentioned hereinabove may contain any
structure or functional groups, and they may incude, but are not
limited to, functional groups derived from methane, alkane primary,
alkane secondary, alkane tertiary, cycloaliphatic ring,
bicycloaliphatic ring, tricycloaliphatic ring, alkene, alkyne,
monocyclic aromatic hydrocarbon, polycyclic aromatic hydrocarbon,
biphenyl-type benzenoid ring, oxygen ether, thioether,
S-heterocyclic ring, N-heterocyclic ring, saturated, N-heterocyclic
ring, unsaturated, O-heterocyclic ring, epoxide, thioketone,
alcohol, thiol, amine primary, amine secondary, amine tertiary,
aldehyde, carboxylate ions, carboxylic acid, carboxylic acid ester,
carboxylic thioester, dicarboxylic and tricarboxylic acids, amide,
nitrile, oxime, thiocyanate, cyanamide, nitro, nitrate ester,
diazo, organohalide, organomercurial, organoarsenical,
organosilicon, organotin, organophosphate ester, thiophosphate
ester, phosphonic acid, phosphinic acid, sulfonic acid, sulfate
ester, peroxide, peracid, anhydride, alkaloids, grignard reagents,
ketone acetals, ylides, keto esters, keto acids, N-acylamino acids,
acychlorides, acylnitrenes, hydrazones, enamines, ketenes,
thiophens, furans, pyrides, allyllic alcohol, aromatic nitrogen,
aromatic alcohol, beta lactam fused, lactam, lactone, aromatic
ketone, aromatic oxygen, oxime ether, urea, urethane, trihalide,
cyclic ether, aryl halide, acetal ketal, sulfonamide, acyl halide,
bismaleimides, alditols, aldotetroses, alkadienes, amidomalonic
esters, alkatrienes, alkene oxides, alkenylbezenes, alkyl halides,
alkyl sulfates, alkyl tosylates, alkyl triflates, allenes, allylic
halides, and amine oxides.
[0054] Although the above-described processes of FIGS. 1A-1D differ
in the number of starting materials (i.e., reactants) and the
specific reaction steps, they share the following common features:
[0055] (1) all processes form the macrocyclic compound C through
cyclization of a linear precursor, e.g., the desired oligomer
[AB].sub.n in the process illustrated by FIG. 1A, the linear
intermediate AB in the process illustrated by FIG. 1B, the desired
oligomer A.sub.n in the process illustrated by FIG. 1C, and the
reactant A in the process illustrated by FIG. 1D; and [0056] (2)
such linear precursor is susceptible to undesired oligomerization
in forming undesired oligomers, e.g., [AB].sub.n+k in the process
illustrated by FIG. 1A, [AB].sub.m in the process illustrated by
FIG. 1B, A.sub.n+k in the process illustrated by FIG. 1C, and
[A].sub.m in the process illustrated by FIG. 1D.
[0057] The undesired oligomerization reaction competes with the
cyclization reaction, thus reducing the availability of the linear
precursor for cyclization reaction and causing reduction in the
production yield of the macrocyclic compound of interest. Moreover,
when the undesired oligomers reach certain critical length, they
may become insoluble or weakly soluble and will precipitate from
the reaction medium or otherwise separate from the reaction medium,
thereby converting the reversible oligomerization reaction into a
virtually irreversible reaction that dominates over the cyclization
reaction. In such event, the amount of undesired oligomers will far
exceed the amount of macrocycles in the product mixture.
[0058] The present invention provides a solution to such problem,
by modulating the oligomerization reaction, so as to reduce
formation of the undesired oligomers and/or to reduce separation of
the already-undesired oligomers from the reaction medium, relative
to an unmodulated oligomerization reaction.
[0059] In one embodiment of the present invention, such
oligomerization modulation is achieved by adding one or more
oligomerization control additives into the reaction medium. Such
oligomerization control additives can include any suitable
materials whose addition affects the oligomerization reactions in
such manner as to reduce formation of the undesired oligomers
and/or separation of the already undesired oligomers from the
reaction medium, relative to corresponding oligomerization
reactions carried out without addition of such oligomerization
control additives.
[0060] For example, for those oligomerization reactions in which an
oligomerization byproduct is also formed in addition to the
undesired oligomers, extraneous oligomerization byproduct can be
added into the reaction medium to increase the overall
oligomerization byproduct concentration in such reaction medium,
thereby directing the reaction away from production of the
undesired oligomers.
[0061] More importantly, the overall oligomerization byproduct
concentration in the reaction medium can be adjusted to provide a
product distribution of desired oligomers of selected lengths. In
general, the higher the oligomerization byproduct concentration,
the shorter the average length of the oligomers formed in the
reaction medium. FIG. 2 illustrates the shift in oligomer
distributions, when different amounts of extraneous oligomerization
byproduct are added. For example, when 14% extraneous
oligomerization byproduct (based on the total volume of the
reaction medium) is added, the distribution of the average oligomer
length peaks at about 5, which means that the oligomerization
reaction as thus modulated favors formation of pentamers. As
another example, when 8% (by volume) extraneous oligomerization
byproduct is added, the peak of the average oligomer length
distribution shifts to about 10, which means that the modulated
oligomerization reaction now favors formation of longer oligomers
of about length 10. As a still further example, when only 2% (by
volume) extraneous oligomerization byproduct is added, the peak of
the average oligomer length distribution further shifts to about
15, which means that the modulated oligomerization reaction now
favors formation of oligomers of about length 15.
[0062] Therefore, by adjusting the amount of added extraneous
oligomerization byproduct, the extent of the oligomerization
reaction can be controlled to favor formation of the desired
oligomers of a specific length (n) for cyclization to form the
macrocyclic compound.
[0063] The extraneous oligomerization byproduct used for modulating
the oligomerization reaction is selected based on the specific
oligomerization reaction involved. For example, suitable extraneous
oligomerization byproducts that can be used in specific instances
within the broad scope of the present invention include, but are
not limited to, adenosine 5'-monophosphate (AMP), cytidine
5'-monophosphate (CMP), guanosine 5'-monophosphate (GMP), thymidine
5'-monophosphate (TMP), uridine 5'-monophosphate (UMP), adenosine
di-phosphate (ADP), cytidine di-phosphate (CDP), guanosine
di-phosphate (GDP), thymidine di-phosphate (TDP), uridine
di-phosphate (UDP), pyrophosphoric acid, alkyl pyrophosphates,
pyridine, aniline, benzyl alcohol, water, dihydrogen sulfide,
methanol, ethanol, propanol, butanol, bromide, alkylthiol,
thiophenol, 2-butyne, acetic acid, acetone, carbon dioxide, carbon
monoxide, deuterium oxide, fructose, galactose, gallic acid,
glycerol, glucose, hydrochloric acid, hydrogen cyanide, hydrobromic
acid, hydroiodic acid, iodoform, lactic acid, nitrogen, nitrous
acid, ammonia, methyl amine, ethyl amine, propyl amine, butyl
amine, dimethyl amine, diethyl amine, dipropyl amine, trimethyl
amine, triethyl amine, hydrogen, phenol, sulfur dioxide, phosphoric
acid, ethylene, sulfuric acid, silanes, silylethers, sulfonic
acids, sulfite esters, sulfenic acids, sulfinic acids, disulfides,
peroxides, boronic acids, borate ethers, triflates, mesylates,
sulfates, alkyl halides, perchloric acid, periodic acid, sulfones,
sulfoxides, succinimide, N,N-diisopropylurea, amino acids, methyl
thiocyanate, and N-hydroxysuccinimide.
[0064] For those oligomerization reactions in which the undesired
oligomers formed are insoluble or weakly soluble in the reaction
medium, oligomerization modulation can be achieved by providing an
oligomerization control additive that includes one or more
solubilizing functional groups and functions as a solubilizing
agent. One or more oligomerization additives can be employed, as
necessary or desirable, in a specific application of the
methodology of the invention. The solubilizing agent participates
in the undesired oligomerization reaction to form modified
undesired oligomers that incorporate the solubilizing functional
group(s). Such modified undesired oligomers, due to incorporation
of the solubilizing functional group(s) therein, become more
soluble in the reaction medium and less susceptible to separation
therefrom. In this manner, the undesired oligomers are kept in the
reaction medium and may be reversibly converted to the desired
oligomers or other linear precursors for the cyclization
reaction.
[0065] Further, the oligomerization control additive may include a
compound or solvent species that interacts with the reactants or
one or more intermediate products of such reactants to affect the
oligomerization reactions in such a manner that formation of the
undesired oligomers is reduced.
[0066] In addition to the use of oligomerization control additives
as described hereinabove, oligomerization modulation within the
broad practice of the present invention may further include removal
of one or more reaction byproducts, to affect the oligomerization
reactions so that formation of the undesired oligomers is reduced,
and/or formation of the desired oligomer is favored, relative to a
corresponding reaction scheme lacking such byproduct removal.
[0067] Oligomerization modulation can also be achieved by changing
the reaction conditions in such a manner that the reaction
equilibria change to favor the desired reaction pathway over the
reaction pathway yielding undesired oligomers, thereby forming more
macrocyclic compound instead of undesired oligomers. For example,
by change of reaction temperature, pressure, pH value, energetic
state, magnetic state, and/or photonic state, the equilibria of the
oligomerization and cyclization reaction(s) can be changed to
stimulate formation of the macrocyclic compound and suppress
formation of the undesired oligomers. Such techniques can be used
either in conjunction with, or independent of, the use of
oligomerization control additives.
[0068] Modulation of the oligomerization reaction according to the
present invention can be used to effectively minimize or other
significantly reduce the impact of the undesired oligomerization,
and thereby achieve significantly increased yield of the
macrocyclic compound.
[0069] In certain reaction systems, multiple macrocyclic compounds
of different sizes can be formed via different reaction pathways
that include cyclization reaction(s) of different oligomers.
Suitable oligomerization modulation techniques can therefore be
selected to reduce formation of the undesired oligomers, thereby
reducing formation of those macrocyclic compounds that are
undesired and achieving improved product distribution that favors
the formation of one or more macrocyclic compound(s) of desired
size(s).
[0070] Macrocyclic compounds formed by the cyclization reaction(s)
under the influence of the above-mentioned oligomerization
modulation process can be recovered by any suitable methods or
techniques now known or hereinafter discovered in the art.
Preferably, such macrocyclic compound is selectively separated from
the reaction medium, based on differences in one or more physical
and/or chemical characteristics, or other material properties,
between such macrocyclic compound and other components of the
reaction medium.
[0071] For example, the macrocyclic compound can be selectively
separated from the reaction medium based on permeability difference
therebetween, by passing the reaction medium through a
semi-permeable membrane that is selectively permeable to such
macrocyclic compound but is impermeable to the starting materials,
the desired/undesired oligomers, and other components of the
reaction medium, or which, alternatively, is impermeable to the
macrocyclic compound but is permeable to all other components of
the reaction medium. As another example, the macrocyclic compound
can be selectively separated from the reaction medium based on
affinity difference therebetween, by passing the reaction medium
through an affinity column that has selective binding affinity for
the macrocyclic compound but not for the other components of the
reaction medium. As a further example, the macrocyclic compound can
be selectively separated from the reaction medium by application of
an electric field, if such macrocyclic compound carries a charge
that is different from those carried by the other components of the
reaction medium. As a still further example, the macrocyclic
compound can be selectively separated from the reaction medium by
application of a magnetic field, if the macrocyclic compound
exhibits a different magnetic state from those of the other
components of the reaction medium.
[0072] The physical and/or chemical characteristic differences that
can be used for separating the macrocyclic compound from the
reaction medium include, but are not limited to, differences in
size, shape, mass, density, solubility, volatility, permeability,
diffusion rate, charge distribution, mass/charge ratio, binding
affinity, adsorption/absorption potential, reactivity (e.g., metal
coordination, electrostatic interactions, hydrogen bonding,
donor-acceptor interactions, and covalent bond formation), etc.,
which have been widely used in a wide variety of well-known
separation methods, such as filtration, evaporation, flash
expansion, distillation, stripping, absorption, extraction,
crystallization, adsorption, ion exchanging, drying, leaching,
washing, clathration, osmosis, reverse osmosis, bubble
fractionation, magnetic separation, chromatography, freeze drying,
condensation, gel filtration, gaseous diffusion, sweep diffusion,
thermal diffusion, mass spectrometry, dialysis, electrodialysis,
electrophoresis, ultra-centrifugation, ultra-filtration, molecular
distillation, demisting, settling, centrifugation, cyclone flow
separation, electrostatic precipitation, etc.
[0073] It is to be emphasized that the above-listed physical and
chemical characteristic differences and separation techniques are
only illustrative of some of the vast numbers of separation
characteristics and techniques that can be usefully employed in the
broad practice of the present invention. Accordingly, the foregoing
should not be construed as an exhaustive listing and should not be
interpreted in any manner as limiting the broad scope of
applicability of the present invention.
[0074] In a preferred embodiment of the present invention, the
reaction medium composition and the reaction conditions are
adjusted so that the macrocyclic compound formed by the cyclization
reaction spontaneously separates from the reaction medium via phase
separation or phase transfer, without requirement for external
force or energy.
[0075] For example, when the reaction medium is in a liquid phase,
the reaction medium composition and the reaction conditions can be
selected to form the macrocyclic compound as a solid that is
insoluble or weakly soluble in such reaction medium, so that such
macrocyclic compound precipitates out of the reaction medium upon
formation. Such macrocyclic compound can alternatively be a liquid
phase material that is immiscible or weakly miscible in the
reaction medium, so that it spontaneously separates into a
different liquid layer, e.g., on top of or underneath the reaction
medium layer, depending on its specific gravity characteristics.
Such macrocyclic compound as a further alternative can be a gaseous
product that is insoluble or weakly soluble in said reaction
medium, so that it spontaneously bubbles out of the reaction medium
upon formation. As yet another alternative, the reaction medium can
be provided in a gaseous state, in which the macrocyclic compound
is formed as a liquid or alternatively a solid that spontaneously
separates from the gaseous reaction medium by condensation or
solidification, respectively.
[0076] Multiphase reaction systems can also be employed in the
present invention to achieve spontaneous separation of the
macrocyclic compound via phase transfer. For example, the reaction
medium can be provided as a first liquid phase component of a
multiphase reaction system, while a second liquid phase component
immiscible or weakly immiscible in such reaction medium is provided
as a liquid layer or volume adjacent to the reaction medium. The
macrocyclic compound to be formed is insoluble or weakly soluble in
the first liquid phase component defined by the reaction medium but
is soluble or moderately soluble in the second liquid phase
component. Therefore, macrocyclic compound that forms in the
reaction medium and contacts the liquid-liquid interface of these
two liquid phase components will spontaneously transfer from the
reaction medium into the adjacent second liquid phase component,
thereby separating from the reaction medium.
[0077] The spontaneous separation of the macrocyclic compound as
described hereinabove advantageously provides a driving force that
continuously drives the cyclization reaction toward the macrocyclic
compound, and such mode of reaction and separation therefore is a
particularly preferred approach in the practice of the present
invention.
[0078] The spontaneous separation of the macrocyclic compound from
the reaction medium can be effectuated by selecting suitable
solvents and/or additives, and/or by adjusting the reaction
conditions, to maximize the production of the macrocyclic compound.
Preferably, the composition of the reaction medium and the reaction
conditions are adjusted so that the reactants and at least the
desired oligomers are soluble in such reaction medium, and the
macrocyclic compound is insoluble or only weakly soluble in the
reaction medium, thereby selectively separating the macrocyclic
compound from the reaction medium.
[0079] In one specific embodiment of the present invention, the
reaction medium comprises a single solvent for dissolving the
reactants and selectively separating the macrocyclic component.
[0080] In an alternative embodiment, a reacting solvent and a
co-solvent are provided in the reaction medium, with the reacting
solvent functioning to dissolve the reactants, and the co-solvent
functioning to effectuate spontaneous separation of the macrocyclic
compound from the reaction medium. Preferably, such reacting
solvent and co-solvent operate to define a reaction medium in which
the reactants and the desired oligomers are soluble, and the
macrocyclic compound is insoluble or only weakly soluble.
[0081] As mentioned hereinabove, when the undesired oligomers reach
certain lengths, they may become insoluble or only weakly soluble
in the reaction medium and start to precipitate out of the reaction
medium. Such problem can be effectively dealt with by employing
suitable oligomerization control techniques as described
hereinabove to reduce formation of such undesired oligomers and/or
reduce separation of the undesired oligomers from the reaction
medium.
[0082] Suitable co-solvents that can be used in the broad practice
of the present invention for effectuating spontaneous separation of
the macrocyclic compound from the reaction medium include, but are
not limited to, water, methanol, ethanol, isopropanol,
tert-butanol, n-propanol, iso-butanol, n-butanol, ethylene glycol,
propylene glycol, formic acid, limonene, dipropylene glycol,
monomethyl ether, diethylene glycol, ethyl ether, tripropylene
glycol, monomethyl ether, dimethyl sulfoxide, phenol, polypropylene
glycol, N-methyl-2-pyrrolidone, acetone, ethyl acetate,
glycolfurol, solketal, glycerol, formol, formamide, nitrobenzene,
tetrahydrofuryl alcohol, polyethylene glycol, dimethyl isosorbide,
dimethyl acetamide, methyl ethyl ketone, 1,4-dioxane, hydrosolv,
acetonitrile, ammonia, methyl amine, ethyl amine, propyl amine,
butyl amine, dimethyl amine, diethyl amine, dipropyl amine,
trimethyl amine, triethyl amine, dimethylformamide,
tetrahydrofuran, glycol ethers, methyl cellosolve, cellosolve,
butyl cellosolve, hexyl cellosolve, methyl carbitol, carbitol,
butyl carbitol, hexyl carbitol, propasol solvent B, propasol
solvent P, propasol solvent M, propasol solvent DM,
methoxytriglycol, ethoxytriglycol, butoxytriglycol,
1-butoxyethoxy-2-propanol, phenyl glycol ether, glymes, monoglyme,
ethylglyme, diglyme, ethyl diglyme, triglyme, butyl diglyme,
tetraglyme, aminoalcohols, sulfolane, hexamethylphosphorictriamide
(HMPA), nitromethane, methyl ethylether, carbon disulfide, methale
chloride, chloroform, tetrahydrofuran, toluene, and benzene.
[0083] In addition to, or independent of, such co-solvent, one or
more separation additives can be provided in the reaction medium
for effectuating spontaneous separation of the macrocyclic compound
from the reaction medium.
[0084] For example, such separation additives may encompass salts
with cations selected from the group consisting of aluminum,
ammonium, barium, calcium, chromium(II), chromous, chromium(III),
chromic, copper(I), cuprous, copper(II), cupric, iron(II), ferrous,
iron(III), ferric hydrogen, hydronium, lead(II), lithium,
magnesium, manganese(II), manganous manganese(III), manganic,
mercury(I), mercurous, mercury(II), mercuric, nitronium, potassium,
silver, sodium, strontium, tin(II), stannous, tin(IV), stannic,
zinc oxonium, sulfonium, selenonium, chloronium, bromonium,
iodonium, tetramethylammonium, dimethyloxonium, diphenyliodonium,
ethylenebromonium, anilinium, guanidinium, 2-phenylhydrazinium,
1-methylhydrazinium, acetohydrazidium, benzamidium, acetonium,
1,4-dioxanium, ethylium or ethenium, phenylium,
2-cyclohexen-1-ylium, 9-anthrylium, neopentylium,
triphenylmethylium or triphenylcarbenium, methanediylium,
cyclopropenylium, ethane-1,1-diylium, ethane-1,2-diylium,
acetylium, methylsulfanylium or methanesulfenylium,
methanesulfonylium, benzylideneaminylium, quinolizinyum,
1,2,3-benzodithiazolylium, methyliumyl, ethan-2-ium-1-yl,
3-methyl-1-(trimethylsilyl)triaz-2-en-2-ium-1-id-2y1,
1,2,2,2-tetramethyldiazan-2-ium-1-ide, azanylium, aminylium,
nitrenium, phenylsulfanylium, tetramethyl-.lamda.5-phosphanylium,
tetramethylphosphoranylium, tetramethylphosphonium,
3-methyltriaz-1-en-1-ylium, heptamethyltrisilan-2-ylium,
4-cyclopropyltetrasulfan-1-ylium, cyclooct-3-en-1-ylium,
furan-2-ylium, 1,2-bis(4-methoxyphenyl)-2-phenylethen-1-ylium,
bicyclo [2.2.1] heptan-2-ylium, spiro [4.5] dec an-8-ylium,
propane-1,3-bis (ylium), 2,2-dimethyldiazane-1,1-bis(ylium),
2,2-dimethylhydrazine-1,1-bis(ylium), propane-2,2-bis (ylium)
1-methylethane-1,1-bis (ylium), cyclobut-3-ene-1,2-bis(ylium),
propane-1,2,3-tris(ylium), ammonium, methanediazonium,
methyldiazenylium, benzothiazole-2-diazonium,
benzothiazol-2-yldiazenylium, 2,4-dioxopentane-3-diazonium,
(2,4-dioxopentan-3-yl)diazenylium,
(1-acetyl-2-oxopropyl)diazenylium, benzene-1,4-bis (diazonium),
1,4-phenylenebis(diazenylium),
3,5-dimethyl-1,4-dihydropyridin-1-ylium,
3,5-dimethylpyridin-1(4h)-ylium, acetylium, hexanethioylium,
cyclohexanecarbonylium, ethenesulfonylium, dimethylphosphinoylium,
methylphosphonoylium, glutarylium, pentanedioylium,
pyridine-2,6-dicarbony.
[0085] Such separation additives may further encompass salts
including anions selected from the group consisting of hydride,
oxide, fluoride, sulfide, chloride, nitride, bromide, iodide,
nitrate, nitrite, chromate, chlorate, chlorite, dichromate,
sulfate, sulfite, phosphate, phosphite, carbonate, acetate,
hydroxide, cyanate, cyanide, hydrogen sulfate, hydrogen sulfite,
hydrogen carbonate, hydrogen phosphate, hypochlorite, dihydrogen
phosphate, perchlorate, oxalate, permanganate, silicate,
thiocyanate, iodate, Bromate, hypobromate, formate, amide,
hydroxide, peroxide, oxide, oxalate, arsenate, arsenite, hydride,
fluoride, chloride, bromide, iodide, sulfide, nitride, Hexanoate,
cyclohexanecarboxalyte, benzenesulfate, 1-butanide, 1-butyn-1-ide,
benzenide, triphenylmethanide, diphenylmethanediide,
cyclopentadienide, 1,4-dihydro-1,4-naphthalenediide, Ethylide or
ethene anion, Dihydronaphthylide or naphthalene anion,
p-benzosemiquinone anion, methanide, but-1-yn-1-ide, propan-2-ide,
diphenylmethanediide, tetramethylboranuide, benzenesulfonate,
dibenzylphosphinite, methanolate, benzene-1,4-bis(thiolate),
cyclohexaneselenolate, 3-hydroxybenzene-1,2-bis(olate),
carboxylato, phosphonato, sulfonato, oxido, methanidyl,
amidylidene, disulfanidyl, phosphanida, boranuida, methyl anion,
acetyl anion, phenyl anion, benzenesulfinyl anion, methanaminyl
anion, methylazanyl anion, cyclopenta-2,4-dien-1-yl anion,
diphenylmethylene dianion, 1,4-dihydronaphthalene-1,4-diyl dianion,
methylamide, methylazanide, dimethylphosphanide,
dimethylphosphinide, tributylstannanide, methylidynesilanide,
(diphenylboryl)methanide, tricyanomethanide, propan-2-ide,
but-1-yn-1-ide,
1,3-diphenylprop-2-en-1-ide1,1,2-tricyano-2-(3,4-dicyano-5-imino-1,5-dihy-
dro-2H-pyrrol-2-ylidene)ethan-1-ide, 4-chlorobenzen-1-ide,
cyclopenta-2,4-dien-1-ide, 7bH-indeno [1,2,3-jk]fluoren-7b-ide,
1,5-di-p-tolylpentaaza-1,4-dien-3-ide, 1H-benzotriazol-1-ide,
C.sub.6H.sub.5-N.sup.2-phenylimide, diphenylmethanediide,
9H-fluorene-9,9-diide, 1,4-dihydronaphthalene-1,4-diide,
1,1,1,5,5,5-hexamethyltrisilazane-2,4-diide,
1,3-diphenylpropane-1,2,3-triide,
1,4,6,9-tetrahydropyrene-1,4,6,9-tetraide.
[0086] Preferably, such salts comprise an anion such as F,
Cl.sup.-, Br.sup.-, I.sup.-, SO.sub.4.sup.2-, HSO.sub.4,
Ph.sub.4B.sup.-, NO.sub.3.sup.-, SO.sub.3.sup.2-, and
BO.sub.2.sup.- or a cation such as ammonium, copper (II), iron
(III), magnesium, potassium, sodium, zinc, guanidinium,
triphenylmethylium, and tetramethylphosphonium.
[0087] Such salts can interact with the solvents contained in the
reaction medium, and/or interact with the macrocyclic compound, in
such a manner that the macrocyclic compound becomes less soluble in
such reaction medium and spontaneously separates from the reaction
medium upon its formation. Further, such salts may interact with
the other components of the reaction medium to reduce separation of
such components from the reaction medium.
[0088] By selecting the appropriate oligomerization control
additive(s), reacting solvent(s), co-solvent(s), and/or separation
additive(s), one can readily adjust the product distribution of the
oligomerization and/or cyclization reactions and improve the
production yield of the macrocyclic compound.
[0089] For example, FIG. 3 is a HPLC chromatograph for the products
formed by reacting benzaldehyde and pyrrole (which are used to form
tetraphenylporphyrinogen) in absolute ethanol (which functions as a
precipitating solvent for selectively precipitating the non-polar
tetraphenylporphyrinogen so formed), without any oligomerization
control. The lack of oligomerization control in such reaction
results in formation of a wide variety of reaction products, as
indicated by the Gaussian distribution. Majority of such reaction
products were linear extended oligomers that were formed and
precipitated out of the reaction solution concurrently with the
tetraphenylporphyrinogen, with only a small amount of
tetraphenylporphyrinogen (as represented by the peak at 29.153),
approximately less than 1%.
[0090] By reacting benzaldehyde and pyrrole in a reaction
composition that comprises ethanol (i.e., the precipitating
solvent) and water (i.e., the oligomerization control additive) at
a volumetric ratio of 1:1, approximately 30% of the reaction
products were tetraphenylporphyrinogen, as mixed with undesired
oligomers. FIG. 4A is a HPLC chromatograph for the products formed
by reacting benzaldehyde and pyrrole in a reaction composition that
comprises methanol (i.e., a different precipitating solvent) and
water (i.e., the oligomerization control additive) at a volumetric
ratio of 1:1. About 75% of the reaction products were
tetraphenylporphyrinogen (as represented by the peak at 29.261).
FIG. 4B is a HPLC chromatograph for the products formed by reacting
benzaldehyde and pyrrole in a reaction composition that contained
about 37.5% by volume of methanol (i.e., the precipitating
solvent), 62.5% by volume of water (i.e., the oligomerization
control additive), and 0.014 g/ml of NaCl (i.e., the separation
additive). The reaction composition used in FIG. 4B contained a
higher concentration of oligomerization control additive for more
effective modulation of the oligomerization reactions, and the
separation additive NaCl functioned to further adjust the solvent
strength of the reaction composition for more selective separation
of the macrocyclic compound. Consequently, the production yield of
the tetraphenylporphyrinogen (as represented by the peak at 29.004)
was further improved to about 85%. Addition of water in the
synthesis of non-polar porphyrinogens is completely opposite to the
teachings of the conventional wisdom, which advocates removal of
water instead, and it surprisingly and unexpectedly improves the
production yield of the non-polar porphyrinogen (e.g.,
tetraphenylporphyrinogen) by almost a hundred fold.
[0091] In another embodiment of the present invention, a
solid-phase substrate can be employed for immobilizing at least one
of the reactants and facilitating solid-phase reactions, to thereby
form a macrocyclic compound that is also immobilized on such
solid-phase substrate. In this circumstance, separation of the
macrocyclic compound can be carried out by removing the solid-phase
substrate from the reaction medium and subsequently releasing the
immobilized macrocyclic compound from such substrate. Such
solid-phase substrate technique is amenable to automation, and it
is particularly suitable for producing libraries of macrocycles in
the practice of the method of the present invention.
[0092] As mentioned hereinabove, in a thermodynamically controlled,
reversible reaction, the relative stabilities of all products,
macrocyclic or acyclic, determine the product distribution.
Therefore, the reaction medium of the present invention may further
comprise a stabilizing agent that selectively stabilizes the
macrocyclic compound, so as to increase the relative proportion of
the macrocyclic compound in the reaction end product mixture. Such
stabilizing agent can be of any suitable type, as for example
including, organic, inorganic, or organometallic compounds, ions,
or chemical elements. Preferably, the stabilizing agent is a salt
with metallic or inorganic ions that bind to the macrocyclic
compound and form a more stable complex than the macrocyclic
compound. Alternatively, the macrocyclic compound itself can be
engineered to undergo intramolecular rearrangement after the ring
closure reaction, thereby forming a different macrocyclic form that
is more stable than the original macrocyclic compound. Further, an
electric and/or magnetic field can be applied to the reaction
composition for selectively stabilizing the macrocyclic
compound.
[0093] The reaction medium of the present invention may further
comprise a cyclization agent that facilitates the ring closure or
cyclization reaction(s). For example, such cyclization agent can
include a template material, which pre-organizes the reactive ends
of the desired oligomers for more effective cyclization. A template
material, as mentioned hereinabove, can be employed to
complementarily bind to a cavity formed by the macrocyclic compound
and to form a more stable complex with such macrocyclic compound.
In such manner, the template material functions both as a
cyclization agent and a stabilizing agent. As another example, the
cyclization agent can include a material with microporous
structure, such as Smectite clay, which provides a localized
environment that is highly favorable to the ring closure reaction.
Further, the cyclization agent can include certain structural
elements that function to bend the linear structures of the desired
oligomers and form pre-organized ring structures, as discussed
hereinabove.
[0094] The reaction medium in the practice of the present invention
can further include any suitable catalyst materials now or
hereafter discovered for catalyzing one or more reactions in the
reaction medium.
[0095] The methodology of the present invention can also be used to
synthesize a macrocyclic compound of interest, by first forming a
macrocyclic intermediate compound through a desired reaction
pathway involving at least cyclization reaction(s) as described
hereinabove, and then modifying such macrocyclic intermediate
compound to form the macrocyclic compound of interest. The
modification of the macrocyclic intermediate compound may comprise
one or more steps such as oxidation, reduction, substitution of at
least one functional group, removal of at least one functional
group, addition of at least one functional group, further
cyclization, isomeric rearrangement, and/or purification. Such
modification can be carried out either in situ in the same reaction
medium as employed for the cyclization reaction(s), without
separation of the macrocyclic compound, or subsequently in a
different reaction medium, by first separating the macrocyclic
compound from the cyclization reaction medium.
[0096] The present invention in a further aspect provides a system
for manufacturing a macrocyclic compound, which may be employed to
carry out the synthesis methodology of the invention in a highly
effective manner.
[0097] FIG. 20 shows a schematic representation of one such system,
which includes a reaction zone having: (1) one or more supply
vessels for supplying one or more reactants and/or one or more
solvents that are needed for forming the macrocyclic compound, (2)
a reaction chamber coupled with such supply vessels for receiving
the reactants and solvents and effectuating reactions of the
reactants therein to form the macrocyclic compound, and (3) an
oligomerization modulation unit for modulating oligomerization
reactions of the reactants in the reaction chamber, so as to reduce
formation of undesired oligomers by the reactants and/or to reduce
separation of the undesired oligomers from the reaction medium,
relative to corresponding unmodulated oligomerization
reactions.
[0098] The reaction chamber may include one or more reactors of
suitable type(s), as for example selected from among: continuous
reactors, batch reactors, fixed-bed reactors, fluidized-bed
reactors, bubbling fluid reactors, circulating fluid bed reactors,
slurry-phase reactors, packed-bed reactors, trickle-bed reactors,
multi-tubular fixed-bed reactors, quench reactors, double-wall
heat-exchanging reactors, radial flow reactors, plug flow reactors,
continually stirred tank reactors, semi-batch reactors,
semi-continuous reactors, bypass reactors, differential reactors,
swing reactors, continuous regeneration reactors, multi-stage
reactors, and membrane-based reactors. The reaction chamber may
include a single reactor in which all the reactions are carried
out, or multiple reactors arranged in parallel or in series for
carrying out multiple processes.
[0099] The oligomerization modulation unit may include one or more
additive supply vessels for adding one or more oligomerization
control additives to the reaction chamber, or it may include one or
more process controllers for changing the reaction conditions in
the reaction chamber, consistent with the description
hereinabove.
[0100] Further, such reaction system of the present invention can
include a recovery zone, either downstream of or within the
reaction zone, which is arranged and constructed for either
subsequent or in situ recovery of the macrocyclic compound.
Alternatively, such reaction system may include multiple reaction
zones and multiple recovery zones that are arranged in series,
parallel, or combined forms for carrying out multi-stage
reaction/recovery processes.
[0101] The recovery zone may comprise one or more separation units
for selectively separating the macrocyclic compound from the
reaction medium, based on differences between the macrocyclic
compound and other components of the reaction medium, such as
differences in one or more physical and/or chemical characteristics
thereof, as for example size, shape, mass, density, solubility,
volatility, permeability, diffusion rate, charge distribution,
mass/charge ratio, binding affinity, adsorption/absorption
potential, magnetic state, and/or reactivity. A purification unit
may also be included in the recovery zone to further purify the
recovered macrocyclic compound.
[0102] Such separation and/or purification arrangement may include
one or more of evaporation units, flash expansion units,
distillation units, stripping units, absorption units, extraction
units, crystallization units, adsorption units, ion exchange units,
drying units, leaching units, washing units, clathration units,
osmosis units, reverse osmosis units, bubble fractionation units,
magnetic separation units, chromatography units, freeze drying
units, condensation units, gel filtration units, gaseous diffusion
units, sweep diffusion units, thermal diffusion units, mass
spectrometry units, dialysis units, electrodialysis units, gas
permeation units, electrophoresis units, ultra-centrifugation
units, ultra-filtration units, molecular distillation units,
filtration units, demisting units, settling units, centrifugation
units, cyclone flow units, and electrostatic precipitation
units.
[0103] Furthermore, a recycling unit may be coupled with the
reaction zone and the recovery zone, for recycling used reaction
medium by collecting at least a portion of the used reaction medium
from the recovery zone, treating the used reaction medium, and
recirculating the treated reaction medium back to the reaction
zone.
[0104] It may be desirable in some applications to further modify
the macrocyclic compound for subsequent processing or ultimate use,
such as by oxidation, reduction, substitution/addition/removal of
functional groups, further cyclization, and/or isomeric
rearrangement, and such modification can be carried out either in
situ in the reaction medium within the reaction chamber, in a
modification zone inside the reaction chamber, or subsequently in a
modification zone downstream of the reaction chamber.
[0105] The specific arrangement and configuration of the reaction
system depend on a wide variety of factors including requirements
imposed by the specific reactions and products involved, and are
readily determinable by a person ordinarily skilled in the art,
based on the disclosure herein without undue experimentation.
[0106] The present invention can be used for synthesis of a wide
variety of macrocyclic compounds, e.g., macrocyclic compounds that
fit the reaction profiles illustrated in FIGS. 1A-1D. Illustrated
examples of macrocyclic compounds that may be synthesized in
accordance with the method of the invention include, but are not
limited to, porphyrinogens, porphyrins, saphyrins, texaphyrins,
bacteriochlorins, chlorins, coproporphyrin I, corrins, corroles,
cytoporphyrins, deuteroporphyrins, etioporphyrin I, etioporphyrin
III, hematoporphyrins, pheophorbide a, pheophorbide b, phorbines,
phthalocyanines, phyllochlorins, phylloporphyrins, phytochlorins,
phytoporphyrins, protoporphyrins, pyrrochlorins, pyrroporphyrins,
rhodochlorins, rhodoporphyrins, uroporphyrin I, calix[n]pyrroles,
calix[n]erines, cycloalkanes, cycloalkenes, cycloalkynes,
piperidines, morpholines, pyrrolidines, aziridines, anilines,
thiophenes, quinolines, isoquinolines, naphthalenes, pyrimidines,
purines, benzofurans, oxiranes, pyrroles, thiazides, ozazoles,
imidazoles, indoles, furans, benzothiophenes, polyazamacrocycles,
carbohydrates, acetals, crown ethers, cyclic anhydrides, lactams,
lactones, cyclic peptides, phenylthiohydantoins, thiazolinones,
succinimides, coronenes, macrolides, carbocyclics, cyclodextrins,
squalene oxides, ionophore antibiotics, cyclic bis-N,O-acetals,
cyclic disulfides, terpenoids, spirocycles, resorcinarene
macrocycles, cyclic oligo(siloxane)s, stannylated cyclic
oligo(ethyleneoxide)s, cyclic poly(dibutyltindicarboxylate)s,
cyclic poly(pyrrole), cyclic poly(thiophene)s, cyclic poly(amide)s,
cyclic poly(ether)s, cyclic poly(carbonate)s, cyclic
poly(ethersulfone)s, cyclic poly(etherketone)s, cyclic
poly(urethane)s, cyclic poly(imide)s, cyclic poly(decamethylene
fumarate)s, cyclic poly(decamethylethylene maleate)s, etc.
[0107] The following examples are provided to further illustrate
the broad applicability of the present invention, as applicable to
synthesis of a wide variety of macrocyclic compounds.
EXAMPLES
Example 1
Formation of Macrocyclic Aminomethylphosphine
[0108] As shown in FIG. 5, two reactants can be used for forming a
macrocyclic aminomethylphosphine compound. The first reactant
comprises a bis(hydroxymethyl)-organylphosphine 1, and the second
reactant comprises an aromatic diamine 2. The macrocyclic
aminomethylphosphine compound is formed through a desired reaction
pathway that comprises: (i) condensation reaction of four molecules
of 1 and two molecules of 2, forming a linear intermediate product
3 with oligomerization number of two (where n=1), and cyclization
of the linear intermediate product 3, forming a macrocyclic
aminomethylphosphine compound 4. The intermediate product 3 is also
susceptible to further undesired oligomerization in forming
undesirable oligomers (where n>1).
[0109] In the practice of the present invention, the
above-described reactions can be carried out in a solvent system
that contains: (1) dimethylforamide (DMF) as the reacting solvent
for dissolving the starting materials 1 and 2, (2) formamide as the
co-solvent for facilitating phase-separation of the cyclic end
product 4 from the starting materials 1 and 2, the linear
intermediate product 3 (where n=1), and undesirable oligomers
(where n>1), and (3) water as the oligomerization control
additive to modulate formation of the undesirable oligomers. The
concentrations of the starting materials 1 and 2 are preferably
higher than 0.25 M. The reaction temperature is preferably within a
range of from about -15.degree. C. to about 120.degree. C., and the
reaction duration is within a range of from about 4 hours to about
60 hours.
[0110] The identity of the R group, or any substituent for that
matter, may be hydrogen, aryl, phenyl, alkyl, cycloalkyl,
spiroalkyl, alkenyl, alkynyl, halogen, alkoxy, alkylthio,
perfluoroalkyl, perfluoroaryl, pyridyl, cyano, thiocyanato, nitro,
amino, alkylamino, acyl, sulfoxyl, sulfonyl, imido, amido, and
carbamoyl; or as a protected or unprotected reactive substituent
selected from the group consisting of hydroxy, thio, seleno,
telluro, ester, carboxylic acid, boronic acid, phenol, silane,
sulfonic acid, phosphonic acid, alkylthiol, formyl, halo, alkenyl,
alkynyl, haloalkyl, dialkyl phosphonate, alkyl sulfonate, alkyl
carboxylate, acetylacetone, and dialkyl boronate groups, or of any
suitable chemical moiety appropriate to the synthesis of the
macrocyclic product desired, while any two or more of R groups can
be further linked together to form a loop or other intramolecular
structure.
Example 2
Formation of Macrocyclic Imine
[0111] As shown in FIG. 6, two reactants 1 and 2 can be used for
formation of the macrocyclic imine. The first reactant 1 comprises
a diamine, and the second reactant 2 comprises a dialdehyde. Such
reactants 1 and 2 form the macrocyclic imine through a desired
reaction pathway that comprises: (i) condensation reaction of one
molecule of 1 and one molecule of 2, forming a linear intermediate
product (not shown), and (ii) cyclization of said linear
intermediate product, forming a macrocyclic imine compound 4 via
Schiff-base formation. The linear intermediate product is also
susceptible to further undesired oligomerization in forming
undesirable oligomers 3 (where n.gtoreq.1).
[0112] In the practice of the present invention, the
above-described reactions can be carried out in a solvent system
that contains: (1) ethanol as the reacting solvent for dissolving
the starting materials 1 and 2, (2) formamide as the co-solvent for
facilitating phase-separation of the cyclic end product 4 from the
starting materials, the linear intermediate product, and undesired
oligomers 3 (where n.gtoreq.1), and (3) water as the
oligomerization control additive to modulate formation of the
undesired oligomers 3. The concentrations of the starting materials
1 and 2 are preferably higher than 0.02 M. The reaction temperature
is preferably within a range of from about -15.degree. C. to about
80.degree. C., and the reaction duration is within a range of from
about 4 hours to about 60 hours. The identity of the R group is the
same as described hereinabove in Example 1.
Example 3
Formation of Macrocyclic Boronate Compound
[0113] As shown in FIG. 7A, two reactants 1 and 2 can be used for
forming a macrocyclic boronate compound. The first reactant 1
comprises an aryl boronic acid, and the second reactant 2 comprises
a 2,3-dihydroxy-pyridine. Such reacants 1 and 2 can form the
macrocyclic boronate compound through a desired reaction pathway
that comprises: (i) condensation reaction of one molecule of 1 and
one molecule of 2, forming a monomeric intermediate product 3, (ii)
desired oligomerization of such monomeric intermediate product 3,
forming a desired oligomer 4 with oligomerization number of four
(where n=3), and (iii) cyclization of said desired oligomer 4,
forming the desired boronate macrocyclic compound 5. Such desired
oligomer 4 is susceptible to further undesired oligomerization in
forming undesirable oligomers with n>3.
[0114] In practicing of the present invention, the above-described
reactions can be carried out in a solvent system that contains: (1)
dimethylacetamide as the reacting solvent for dissolving starting
materials 1 and 2, (2) formamide as the co-solvent for facilitating
phase-separation of the cyclic end product 5 from the starting
materials, monomeric intermediate product 3, the desired oligomer 4
(where n=3), and undesirable oligomers (where n>3), and (3)
water as the oligomerization control additive to modulate the
formation of undesirable oligomers. The concentrations of the
starting materials 1 and 2 are preferably higher than 0.03 M. The
reaction temperature is preferably within a range of from about
-15.degree. C. to about 120.degree. C., and the reaction duration
is within a range of from about 4 hours to about 60 hours. The
identity of the Ar group is the same as described hereinabove for
the R group in Example 1.
[0115] In this reaction, the added water breaks the boron-oxygen
bond in the oligomers 4 and therefore modulates the oligomerization
reactions.
Example 4
Alternative Process for Formation of Macrocyclic Boronate
Compound
[0116] FIG. 7B shows an alternative process for forming the
macrocyclic boronate compound in addition to the process described
in FIG. 7A, wherein the same reactants 1 and 2 can be used for
forming the macrocyclic boronate compound in the same manner as
described in Example 3, with the exception that pyridine, instead
of water, is used as the oligomerization control additive to
modulate formation of the undesirable oligomers. In this reaction,
the added pyridine interruptes formation of the boron-nitrogen
required for oligomerization and therefore modulates the
oligomerization reactions. Pyridine as used herein provides
additional control over the oligomerization reactions, which is not
available in FIG. 7A.
[0117] Further, a mixture of pyridine and water can be used as the
oligomerization control additives for more effective modulation of
the oligomerization reactions. It is also within the scope of the
present invention to add pyridine and remove water for controling
the oligomerization reactions. Removal of water drives the
condensation reaction and prevents decomposition of the monomeric
intermediate 3. Further, it prevents hydrolysis of the boron-oxygen
bonds in the oligomers and limits the oligomer decomposition to the
extent only caused by boron-nitrogen bond disruption.
Example 5
Formation of Macrocyclic Calix[4]Pyrrole Compound
[0118] As shown in FIG. 8A, two reactants 1 and 2 can be used for
forming the macrocyclic calix[4]pyrrole compound. Specifically, the
first reactant 1 comprises a ketone, and the second reactant 2
comprises a pyrrole, which can form the macrocyclic calix[4]pyrrole
compound through a desired reaction pathway that comprises: (i)
condensation reaction of 1 and 2, forming a monomeric intermediate
product (not shown); (2) desired oligomerization of such monomeric
intermediate, forming a desired oligomer 3 with oligomerization
number of four (where n=3); and (iii) cyclization of said desired
oligomer 3, forming the macrocyclic calix[4]pyrrole compound 4.
Such desired oligomer 3 is also susceptible to further undesired
oligomerization in forming undesirable oligomers with n>3.
[0119] In practicing of the present invention, the above-described
reactions can be carried out in a solvent system that contains: (1)
dimethylacetamide as the reacting solvent for dissolving starting
materials 1 and 2, (2) formamide as the co-solvent for facilitating
phase-separation of the cyclic end product 4 from the starting
materials 1 and 2, the desired oligomer 3 (where n=3), and
undesirable oligomers (where n>3), and (3) water as the
equilibrium control agent to modulate formation of the undesirable
oligomers. The concentrations of the starting materials 1 and 2 are
preferably higher than 0.01 M. The reaction temperature is
preferably within a range of from about -15.degree. C. to about
120.degree. C., and the reaction duration is within a range of from
about 4 hours to about 60 hours. The identity of the R group is the
same as described hereinabove in Example 1.
Example 6
Alternative Process for Formation of Macrocyclic Calix[4]pyrrole
Compound
[0120] FIG. 8B shows an alternative process for forming the
macrocyclic calix[4]pyrrole compound in addition to the process
described in FIG. 8A, wherein a different reactant 1 is used, which
causes generation of a different oligomerization byproduct (i.e.,
methanol instead of water). Consequently, methanol, instead of
water, is used as the oligomerization control additive to modulate
formation of the undesirable oligomers.
[0121] This example shows that by manipulating the starting
materials, different oligomerization byproducts can be generated,
enabling oligomerization control by different oligomerization
control additives, and one ordinarily skilled in the art can
readily select the suitable starting materials and the
oligomerization control additives for optimizing the macrocyclic
production, consistent with the principle and spirit of the present
invention.
Example 7
Formation of Macrocyclic Crown Ether
[0122] As shown in FIG. 9, two reactants 1 and 2 can be used for
formation of the macrocyclic crown ether. The first reactant 1
comprises a diacetal, and the second reactant 2 comprises a
diacetonide, which can form the macrocyclic crown ether through a
desired reaction pathway that comprises: (i) condensation reaction
of one molecule of 1 and one molecule of 2, forming a monomeric
intermediate product (not shown); (ii) oligomerization of such
monomeric intermediate product, forming a desired oligomer 3 with
oligomerization number of two (where n=2), and (iii) cyclization of
the desired oligomer 3, forming the macrocyclic crown ether
compound 4. Such desired oligomer 3 is also susceptible to further
undesired oligomerization in forming undesirable oligomers (wherein
n>2).
[0123] In practice of the present invention, the above-described
reactions can be carried out in a solvent system that contains: (1)
acetonitrile as the reacting solvent for dissolving the starting
materials 1 and 2, (2) formamide as the co-solvent for facilitating
phase-separation of the cyclic end product 4 from the starting
materials 1 and 2, the desired oligomer 3 (where n=2), and
undesirable oligomers (where n>2), and (3) a mixture of acetone
and methanol as the equilibrium control agents to modulate
formation of the undesirable oligomers. The concentrations of the
starting materials 1 and 2 are preferably higher than 0.04M. The
reaction temperature is preferably within a range of from about
-15.degree. C. to about 60.degree. C., and the reaction duration is
within a range of from about 4 hours to about 72 hours.
Example 8
Formation of Cyclic Peptide
[0124] As shown in FIG. 10, a single reactant 1 that comprises a
peptide chain flanked by a terminal thioester group and a terminal
thiol group is used for formation of a cyclic peptide 3 with a
thiolactone linker through cyclization of such reactant. The
reactant 1 is susceptible of undesired self-oligomerization in
forming undesirable oligomers 2 (where n.gtoreq.1).
[0125] In practice of the present invention, the above-described
reaction can be carried out in a solvent system that contains: (1)
an aqueous 0.2 M sodium phosphate pH 7.4 buffer as the reacting
solvent for dissolving the starting material 1, and (2) thiophenol
as the equilibrium control agent to modulate formation of undesired
oligomers 2. The concentration of the starting material 1 is
preferably higher than 0.001 M. The reaction temperature is
preferably within a range of from about -15.degree. C. to about
100.degree. C., and the reaction duration is within a range of from
about 2 hours to about 48 hours. No co-solvent is used herein.
Instead, solvent removal process is used for facilitating
phase-separation of the cyclic end product 3 from the starting
material 1 and the undesired oligomers 2. The identity of the R
group is --CH2CH2C(O)NHCH2COOH, but may it be any suitable chemical
moiety appropriate to the synthesis of the product desired.
Example 9
Formation of Imidazolium-Linked Bicyclic Compound
[0126] As shown in FIG. 11, two reactants 1 and 2 can be used for
forming an imidazolium-linked bicyclic compound. Specifically, the
first reactant 1 comprises an (imidazol-1-ylmethyl)benzene, and the
second reactant 2 comprises a (bromomethyl)benzene, which can form
the imidazolium-linked bicyclic compound through a desired reaction
pathway that comprises: (i) condensation reaction of one molecule
of 1 and one molecule of 2, forming a linear intermediate product
(not shown); (ii) cyclization of said linear intermediate
production, forming a cyclic intermediate product with one ring
structure (not shown); and (iii) further cyclization of the cyclic
intermediate product to form the imidazolium-linked bicyclic
compound 4 with two ring structures. The linear intermediate
product is susceptible to undergo undesired oligomerization in
forming undesired linear oligomers 3 (where n>1), and the cyclic
intermediate product is also susceptible to undesired
oligomerization in forming undesired oligomers (not shown) with
ring structures.
[0127] In practicing the present invention, the above-described
reactions can be carried out in a solvent system that contains: (1)
dimethylformamide as the reacting solvent for dissolving the
starting materials 1 and 2, (2) acetone as the co-solvent for
facilitating phase-separation of the cyclic end product 4 from the
starting materials, the linear and cyclic intermediate products,
the undesired linear oligomers 3 (where n>1), and the
undesirable oligomers with ring structures, and (3) bromide as the
equilibrium control agent to modulate formation of the undesirable
oligomers, either linear or with ring structures. The
concentrations of the starting materials 1 and 2 are preferably
higher than 0.03 M. The reaction temperature is preferably within a
range of from about -15.degree. C. to about 120.degree. C., and the
reaction duration is within a range of from about 4 hours to about
168 hours. The identity of the R group is methyl, but it may be of
any suitable chemical moiety appropriate to the synthesis of the
product desired as listed in Example 1.
Example 10
Formation of Macrocyclic Lactone
[0128] As illustrated in FIG. 12, a single reactant 1 that
comprises a carboxylic acid terminal group and an ether terminal
group can be used for forming the macrocyclic lactone compound 2
through cyclization. Such reactant 1 is susceptible of undesired
self-oligomerization in forming undesirable oligomers 3. The
identity of the R group is the same as described hereinabove in
Example 1.
[0129] In practicing the present invention, the above-described
reaction can be carried out in a solvent system that contains: (1)
dimethylacetamide as the reacting solvent for dissolving the
starting material 1, (2) formamide as the co-solvent for
facilitating phase-separation of the cyclic end product 2 from the
starting material 1 and the undesirable oligomers 3 (where n>1),
and (3) methanol as the equilibrium control agent to modulate
formation of the oligomers. The concentration of the starting
material 1 is preferably higher than 0.1 M. The reaction
temperature is preferably within a range of from about -15.degree.
C. to about 120.degree. C., and the reaction duration is within a
range of from about 4 hours to about 72 hours.
Example 13
Formation of Arylene Ethynylene Macrocycle
[0130] As shown in FIG. 13, a single reactant 1 that comprises a
dialkyne can be used for forming the arylene ethynylene macrocyclic
compound 2 through a desired reaction pathway that comprises: (i)
oligomerization reaction of six molecules of 1, forming a desired
oligomer 3 with oligomerization number of six (where n=5) that is
susceptible to further undesired oligomerization in forming
undesirable oligomers with n>5, and (ii) cyclization of said
desired oligomer 3, forming an arylene ethynylene macrocyclic
compound.
[0131] In the present invention, this reaction can be carried out
in a solvent system that contains: (1) CCl.sub.4 as the reacting
solvent for dissolving the starting material 1 and catalyst system,
(2) nitrobenzene as the co-solvent for facilitating
phase-separation of the cyclic end product 2 from the starting
material 1, the desired oligomer 3 (where n=5), and the undesired
oligomers (where n>5), and (3) 2-butyne as the equilibrium
control agent to modulate formation of the undesired oligomers. The
concentration of the starting material 1 is preferably higher than
0.04 M. The reaction temperature is preferably within a range of
from about -15.degree. C. to about 80.degree. C., and the reaction
duration is within a range of from about 4 hours to about 24
hours.
[0132] Alternatively, this reaction can be carried out in a solvent
system that contains: (1) CH.sub.2Cl.sub.2 as the reacting solvent
for dissolving the starting material 1 and catalyst system, and (2)
2-butyne as the equilibrium control agent to modulate formation of
the undesirable oligomers. The concentration of the starting
material 1 is preferably higher than 0.04 M. The reaction
temperature is preferably within a range of from about -15.degree.
C. to about 80.degree. C., and the reaction duration is within a
range of from about 4 hours to about 24 hours. No co-solvent is
used. Instead, solvent removal method is used for facilitating
phase-separation of the cyclic end product 2 from the starting
materials, linear intermediate product 3, where n=5 and the
undesired oligomers 3, where n>5.
Example 14
Formation of the Macrocyclic Compound via Mixed Aldol Reaction
[0133] As shown in FIG. 14, two reactants 1 (a dialdehyde) and 2 (a
diketone) are used for forming a macrocyclic compound through a
desired reaction pathway that comprises: (i) condensation reaction
of one molecule of said first reactant and one molecule of said
second reactant, forming a linear intermediate product 3 with
oligomerization number of two that is susceptible to further
undesired oligomerization in forming undesirable oligomers, and
(ii) cyclization of said linear intermediate product, forming a
macrocyclic compound via a mixed Aldol reaction.
[0134] In the present invention, this reaction is carried out in a
solvent system that contains: (1) dimethylacetamide as the reacting
solvent for dissolving the starting materials 1 and 2, (2)
formamide as the co-solvent for facilitating phase-separation of
the cyclic end product 4 from the starting materials, linear
intermediate product 3, where n=0, and undesired oligomers where
n>0, and (3) water as the equilibrium control agent to modulate
formation of the undesirable oligomers where n>0. The
concentration of the starting materials 1 and 2 is preferably
higher than 0.1 M. The reaction temperature is preferably within a
range of from about -15.degree. C. to about 80.degree. C., and the
reaction duration is within a range of from about 4 hours to about
60 hours.
Example 15
Formation of Porphyrinogen
[0135] As shown in FIG. 15, a macrocyclic porphyrinogen can be
formed by using two reactants 1 (an aldehyde) and 2 (a pyrrole)
through a desired reaction pathway that comprises: (i) condensation
reaction of four molecules of 1 and four molecules of 2, forming a
linear intermediate product with oligomerization number of four
that is susceptible to further undesired oligomerization in forming
undesirable oligomers, and (ii) cyclization of said linear
intermediate product, forming a macrocyclic porphyrinogen
compound.
[0136] In the present invention, this reaction can be carried out
in a solvent system that contains: (1) dimethylacetamide as the
reacting solvent for dissolving starting materials 1 and 2, (2)
formamide as the co-solvent for facilitating phase-separation of
the cyclic end product 4 from the starting materials, linear
intermediate product 3, where n=3, and the undesired oligomers
where n>3, and (3) water as the equilibrium control agent to
modulate formation of the undesired oligomers 3, where n>3. The
concentration of the starting materials 1 and 2 is preferably
higher than 0.01 M. The reaction temperature is preferably within a
range of from about -15.degree. C. to about 120.degree. C., and the
reaction duration is within a range of from about 4 hours to about
60 hours. The identity of the Ar group is 4-(iodo)phenyl and the R
group is H, but, may be of any suitable chemical moiety appropriate
to the synthesis of the product desired.
Example 16
Formation of Resorcinarene
[0137] As shown in FIG. 16, a macrocyclic resorcinarene can be
formed by using two reactants 1 (an aldehyde) and 2 (a resorcinol)
through a desired reaction pathway that comprises: (i) condensation
reaction of four molecules of 1 and four molecules of 2, forming a
linear intermediate product with oligomerization number of four
that is susceptible to further undesired oligomerization in forming
undesirable oligomers, and (ii) cyclization of said linear
intermediate product, forming a macrocyclic resorcinarene
compound.
[0138] In the present invention, this reaction can be carried out
in a solvent system that contains: (1) dimethylacetamide as the
reacting solvent for dissolving starting materials 1 and 2, (2)
formamide as the co-solvent for facilitating phase-separation of
the cyclic end product 4 from the starting materials, linear
intermediate product 3, where n=3, and undesired oligomers 3, where
n>3, and (3) water as the equilibrium control agent to modulate
formation of the undesired oligomers 3, where n>3. The
concentration of the starting materials 1 and 2 is preferably
higher than 0.01 M. The reaction temperature is preferably within a
range of from about -15.degree. C. to about 120.degree. C., and the
reaction duration is within a range of from about 4 hours to about
60 hours. The identity of the Ar group is p-tolyl, but, may be of
any suitable chemical moiety appropriate to the synthesis of the
product desired as listed in Example 1.
Example 17
Formation of Macrocyclic Heteroheptaphyrin
[0139] As shown in FIG. 17, a macrocyclic heteroheptaphyrin
compound can be formed by two reactants 1 (a trithiophenediol) and
2 (a linear heterotetrapyrrole) through a desired reaction pathway
that comprises: (i) condensation reaction of one molecule of 1 and
one molecule of 2, forming a linear intermediate product with
oligomerization number of one that is susceptible to further
undesired oligomerization in forming undesirable oligomers, and
(ii) cyclization of said linear intermediate product, forming a
macrocyclic heteroheptaphyrin compound.
[0140] In the present invention, this reaction is carried out in a
solvent system that contains: (1) dimethylacetamide as the reacting
solvent for dissolving starting materials 1 and 2, (2) formamide as
the co-solvent for facilitating phase-separation of the cyclic end
product 4 from the starting materials, linear intermediate product
3, where n=1, and undesired oligomers 3, where n>1, and (3)
water as the equilibrium control agent to modulate formation of the
undesired oligomers 3, where n>1. The concentration of the
starting materials 1 and 2 is preferably higher than 0.01 M. The
reaction temperature is preferably within a range of from about
-15.degree. C. to about 120.degree. C., and the reaction duration
is within a range of from about 4 hours to about 60 hours. The
identity of the Ar group is Mesityl, but, may be of any suitable
chemical moiety appropriate to the synthesis of the product desired
as listed in Example 1.
Example 18
Formation of Macrocyclic Thioether Sulfone Compound
[0141] As shown in FIG. 18, a macrocyclic thioether sulfone
compound can be formed by using two reactants 1 (a bisthiophenol)
and 2 (a bisthiophenylether) through a desired reaction pathway
that comprises: (i) condensation reaction of two molecules of said
first reactant and two molecules of said second reactant, forming a
linear intermediate product with oligomerization number of two that
is susceptible to further undesired oligomerization in forming
undesirable oligomers, and (ii) cyclization of said linear
intermediate product, forming a macrocyclic aromatic thioether
sulfone compound via thioether exchange.
[0142] In the present invention, this reaction can be carried out
in a solvent system that contains: (1) benzene as the reacting
solvent for dissolving the starting materials 1 and 2, (2)
dimethylacetamide as the co-solvent for facilitating
phase-separation of the cyclic end product 4, where n=4, from the
starting materials, linear intermediate product 3, where n=3,
linear intermediate 5, where n.gtoreq.3, and the undesirable
oligomers 3, where n>3 and 5, where n>>3, and (3)
thiophenol as the equilibrium control agent to modulate formation
of the undesirable oligomers 3 and 5. The concentration of the
starting material 1 is preferably higher than 0.1 M. The reaction
temperature is preferably within a range of from about -15.degree.
C. to about 100.degree. C., and the reaction duration is within a
range of from about 4 hours to about 72 hours. The identity of the
Ar group is phenyl, but, may be of any suitable chemical moiety
appropriate to the synthesis of the product desired as listed in
Example 1.
Example 19
Formation of Macrocyclic Dibutyltin Dicarboxylate Compound
[0143] As shown in FIG. 19, a macrocyclic dibutyltin dicarboxylate
compound can be formed by using two reactants 1 (a dicarboxylic
acid) and 2 (a dibutyltin bisacetate) through a desired reaction
pathway that comprises: (i) condensation reaction of one molecule
of 1 and one molecule of 2, forming a linear intermediate product
with oligomerization number of one that is susceptible to further
undesired oligomerization in forming undesirable oligomers, and
(ii) cyclization of said linear intermediate product, forming a
macrocyclic dibutyltin dicarboxylate compound.
[0144] In the present invention, this reaction can be carried out
in a solvent system that contains: (1) chlorobenzene as the
reacting solvent for dissolving the starting materials 1 and 2, (2)
dimethylacetamide as the co-solvent for facilitating
phase-separation of the cyclic end product 4 from the starting
materials, linear intermediate product 3, where n=1, and undesired
oligomers 3, where n>1, and (3) acetic acid as the equilibrium
control agent to modulate formation of undesired oligomers 3, where
n>1. The concentration of the starting materials 1 and 2 is
preferably higher than 0.4 M. The reaction temperature is
preferably within a range of from about -15.degree. C. to about
120.degree. C., and the reaction duration is within a range of from
about 4 hours to about 72 hours.
[0145] While the invention has been described herein with reference
to a wide variety of specific embodiments, it will be appreciated
that the invention is not thus limited, and extends to and
encompasses a wide variety of other modifications and embodiments,
as will be appreciated by those ordinarily skilled in the art.
Accordingly, the invention is intended to be construed and
interpreted broadly, in accordance with the ensuing claims.
* * * * *