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.

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 3 -etherate, BF 3 -methanol, AlCl 3 , CsCl, SmCl 3 -6H 2 O, InCl 3 , CrF 3 , AlF 3 , Sc(OTf) 3 , YTiF 4 , BEt 3 , GeCl 4 , EuCl 3 -nH 2 O, LaCl 3 , and Ln(OTf) 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.