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WO2000047031A2 - Agents de separation chimique, et methodes d'utilisation desdits agents - Google Patents

Agents de separation chimique, et methodes d'utilisation desdits agents Download PDF

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Publication number
WO2000047031A2
WO2000047031A2 PCT/US2000/003523 US0003523W WO0047031A2 WO 2000047031 A2 WO2000047031 A2 WO 2000047031A2 US 0003523 W US0003523 W US 0003523W WO 0047031 A2 WO0047031 A2 WO 0047031A2
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Prior art keywords
precipiton
product
reactant
isomer
compound
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PCT/US2000/003523
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English (en)
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WO2000047031A3 (fr
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Craig Stephens Wilcox
Jaemoon Yang
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University Of Pittsburgh
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Priority to EP00910145A priority Critical patent/EP1165222A4/fr
Priority to AU32287/00A priority patent/AU3228700A/en
Priority to US09/913,231 priority patent/US6706839B1/en
Publication of WO2000047031A2 publication Critical patent/WO2000047031A2/fr
Publication of WO2000047031A3 publication Critical patent/WO2000047031A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/215—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring having unsaturation outside the six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B63/00—Purification; Separation; Stabilisation; Use of additives
    • C07B63/02—Purification; Separation; Stabilisation; Use of additives by treatment giving rise to a chemical modification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/82—Purification; Separation; Stabilisation; Use of additives
    • C07C209/86—Separation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/26—Separation; Purification; Stabilisation; Use of additives
    • C07C319/28—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
    • C07C37/01—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis
    • C07C37/055—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis the substituted group being bound to oxygen, e.g. ether group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
    • C07C37/01—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis
    • C07C37/055—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis the substituted group being bound to oxygen, e.g. ether group
    • C07C37/0555—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis the substituted group being bound to oxygen, e.g. ether group being esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
    • C07C39/205—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing only six-membered aromatic rings as cyclic parts with unsaturation outside the rings
    • C07C39/21—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing only six-membered aromatic rings as cyclic parts with unsaturation outside the rings with at least one hydroxy group on a non-condensed ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
    • C07C39/205—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing only six-membered aromatic rings as cyclic parts with unsaturation outside the rings
    • C07C39/225—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing only six-membered aromatic rings as cyclic parts with unsaturation outside the rings with at least one hydroxy group on a condensed ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/09—Geometrical isomers

Definitions

  • the present invention relates generally to agents useful in partitioning and/or puri ication of reactants, intermediate products, and final products from a phase as well as methods of using partitioning agents to selectively separate active agents (either reactant or product) from a phase.
  • the present invention may also be described as being directed to chemical product isolation, separation, phase transfer, and/or purification as well as agents or compounds useful therefor.
  • solid phase synthesis does not have universal applicability.
  • One disadvantage of solid phase synthesis is that reactions at the solid-liquid interface are not always readily controlled. Additionally, not all chemical reactions are compatible with this method, and since solid phase separation is substantially heterogeneous, the use of solid phase synthesis runs contrary to a more preferred homogenous reaction mixture.
  • homogeneous reaction mixtures are desirable because reaction conditions can be reliably controlled.
  • a primary disadvantage of homogeneous reactions, and one that solid phase synthesis attempts to avoid, is that contaminants are in the same phase and intimately mingled with desired products or intermediate materials.
  • Products, whether they be final or intermediate stage products, have traditionally been precipitated by removing solvent or by changing solvent, and by covalent or ionic modifications of the product through addition of more chemicals (for example, acids, bases, or metals). Changes in solubility caused by salt formation or protonation or deprotonation can support liquid-liquid extraction approaches to product separation.
  • phase separation techniques Four phases are commonly used in standard laboratory separation methods: a gas phase, a solid phase, and two liquid phases - organic and aqueous.
  • a third liquid phase known as a "fluorous" phase has recently found applicability in organic synthesis.
  • phase separation techniques liquid-liquid extractions play an important role in the purification of organic compounds. These extractions are almost always conducted with an organic solvent and water. Most frequently, they are used to separate organic compounds from inorganic compounds. A less frequent but still important application of organic-water extractions is an acid-base extraction.
  • chromotography Chromatographic methods of purification are enormous important, yet they are also expensive and time consuming.
  • a recent review of issues and approaches to product isolation and extraction is provided in "Strategy-Level Separations in Organic Synthesis: From Planning to Practice," D.P. Curran, Angewandte
  • the present invention is directed to a separation technique and agents useful therefor. As will be described more fully herein, the present invention allows for selective isomerization of a chemical moiety removably attached to a product or intermediate for selective separation of product or the intermediate by phase change or transfer.
  • compounds described herein comprise a reactant isomer functionalized for attachment to a reactant molecule, the reactant isomer capable of being isomerized into a separating isomer, the separating isomer having a different solubility than the reactant isomer.
  • the compound or compounds generally are of the following formula
  • Rll and R12 are each independently the same or different, a hydrogen, a halide, OR, OH, OOH, OORl, SRI, CN, NC, NR1R, a linear or branched alky group, an aryl group, a phenyl group, a substituted aryl, a substituted phenyl group, or other common functional group.
  • L is a linking group, the linking group being capable of isomerization and Rl, R2, R3, R4, R5, R6, R7, R8, R9, and R10 are, each independently, the same or different, a halide, OR, OH, OOH, OORl, SRI, CN, NC, NR1R, a linear or branched alky group, an aryl group, a phenyl group, a substituted aryl, a substituted phenyl group, or other common functional group.
  • the reactant isomer be a cis-alkene and the separating isomer be a trans alkene.
  • the separating isomer may also be a geometrical isomer, a stereoisomer and/or a structural isomer.
  • a method of separating a desired product from a reaction mixture is also disclosed wherein the method is comprised of covalently linking a separating agent to a reactant molecule, reacting the so formed reactant molecule to form a product with the separating agent being attached to the product, isomerizing the separating agent to thereby form a separable form of the product, and separating the product from the reaction mixture.
  • the method further includes the step of cleaving the separating agent from the product to thereby form a purified product. Isomerization may occur through geometrical isomerization, stereoisomerization, and/or structural isomerization.
  • the modified reactant molecule may be selectably transferred from one phase (e.g., hydrophobic) to another (e.g., hydrophilic) by isomerization.
  • phase partitioning agent may also be of the general formula:
  • L is a linking group, the linking group being capable of isomerization and Rl, R2, R3, R4, R5, R6, R7, R8, R9, and R10 are, each independently, the same of different, a halide, OR, OH, OOH, OORl, SRI, CN, NC, NR1R, a linear or branched alky group, an aryl group, a phenyl group, a substituted aryl, a substituted phenyl group, or other common functional group.
  • Some useful phase partitioning agents are represented below:
  • Another aspect of the present invention is a method of partitioning a reactant from a phase comprising isomerizing a precipiton covalently linked to the reactant.
  • the step of isomerizing the precipiton may include adding a chemical isomerizing agent and in a preferred embodiment irradiating the precipiton.
  • the reactant may have a plurality of precipitons attached to the reactant with each of the plurality of precipitons individually and selectively isomerizable.
  • reaction refers to a chemical entity that is required for a reaction but contributes either an invariant piece or no piece to the products of a synthesis.
  • agent includes a catalyst or any agent that is necessary to the chemical reaction but is itself substantially unchanged during the chemical reaction, whether or not it is used in substoichiometric quantities.
  • reactant refers generally to a type of molecule that contributes a variable piece to the products of a synthesis.
  • reactant and “reagent” in “common” (non-combinatorial) organic syntheses is vague, but those skilled in the art often refer to a reaction component as a reagent if it contributes no piece, a rather small piece, or a piece without carbon atoms therein to the target product.
  • Figure 1 is a schematic illustration of a typical reaction scheme utilizing a precipiton of the present invention.
  • Figure 2 is a schematic illustration of a reaction scheme wherein the precipiton is regenerated for further use.
  • Figure 3 is a schematic illustration of a more complicated reaction involving a precipiton.
  • Figure 4 is a schematic illustration of a Diels-Alder reaction utilizing an illustrative precipiton with resultant high yield of a desired 4.
  • Figure 5 is a schematic illustration of a biphasic reaction condition utilizing a precipiton of the present invention.
  • the present invention provides a novel approach to chemical product isolation and purification. Based on different solubilities between pairs or groups of isomers (e.g., geometrical, stereo, or structural isomers) can have very different solubilities.
  • a chemical moiety is preferably introduced into a synthesis via linkage to any component of a chemical reaction, preferably a reactant such as a starting material or intermediate product.
  • a reactant such as a starting material or intermediate product.
  • this chemical moiety is referred to herein as a
  • precipiton means any group of atoms (molecule or molecular fragment) that is purposefully added to a reactant molecule in order to facilitate phase transfer, separation or isolation of the intermediate or final product.
  • the term “precipiton” is used herein because the separation or isolation is usually precipitation based isolation. However, the term “precipiton” is by no means to be construed in such a limited sense.
  • the precipitons of the present invention preferably include an agent, which when isomerized, causes or initiates a phase transfer. This phase transfer characteristic preferably allows phase transfer of the molecule to which it is attached (conjugate system). The phase transfer is due to variable solubilities of respective groups of isomers.
  • the present invention is preferably directed to precipitons that are designed to be soluble under the conditions of the reaction and to become insoluble after isomerization. Stereoisomerization is the preferred isomerization technique because no atoms are added or removed from the precipiton.
  • One advantage of the present invention is the minimization of the need for chromatography, distillation, extraction, or other traditional means of product isolation are minimized and often eliminated.
  • Another advantage of the present invention is that an excess of reagents (to assure complete reaction progress) can be used in a reaction system with a minimal work-up comprised of the reaction mixture to a phase transfer initiator mechanism, for example, light (e.g., ultraviolet radiation) or a simple reagent, to induce precipitation of only the target molecule (e.g., depending on the stage of the work-up a reactant-precipiton complex).
  • a phase transfer initiator mechanism for example, light (e.g., ultraviolet radiation) or a simple reagent, to induce precipitation of only the target molecule (e.g., depending on the stage of the work-up a reactant-precipiton complex).
  • the use of the precipitons and/or the methods of the present invention in reactions and other bimolecular processes have resulted in products being isolated in greater than 95% purity - without recourse to extraction or chromatographic methods.
  • This present invention is useful in small and medium scale chemical syntheses and in large volume chemical production. The methods described herein are easily automated and can be incorporated into modern robotic approaches to parallel synthesis.
  • phase transfer agents are isomerizable precipitons which afford high solubility of the attached reactant, but yet have low chemical reactivity.
  • the precipiton preferably has a different, preferably very low, solubility in the reaction solvent.
  • This change in solubility may arise from changes in the inter- precipiton attractive forces and/or changes in precipiton-solvent interactions. For example, a change in geometry may lead to a change in dipole moment, causing aggregation of the more polar species that result from such isomerization.
  • changes in surface area of the precipiton may also affect inter-precipiton attraction, because a change in surface area influences both solute-solvent and solute-solute interactions.
  • Isomerization may also lead to exposure of hydrogen bonding groups and lead to alternative non-covalent association of precipitons.
  • the present invention is not to be limited to these approaches or to the above- described changes in solubility. Any precipiton in which geometrical change results in a change in phase partitioning is within the scope of the present invention.
  • Isomerization can be induced by light, by heat, or by added catalysts.
  • the present invention also embodies a method of selective isomerization of the precipiton which leads to a change in reactivity to promote salt formation or complexation to assist in phase separation.
  • the acidity or basicity of the reactants may be
  • solubility of a solid can be related to activity in the solid and the activity coefficient in the solution as follows:
  • solubility is expressed as mole fraction present in the saturated solution, a is activity in the solid, and g is the activity coefficient in the solution.
  • a preferred precipiton in its higher solubility form relies on isomerization to induce a change that will decrease a and increase g, and thereby convert the precipiton to a lower solubility form and favor precipitation.
  • useful changes in solubility may be in either direction, increasing or decreasing solubility in the medium (phase) or origin. Specific applications will define the desired or expected concentration of the soluble form and will provide a guide to the magnitude of the change that is needed.
  • Crystalline solids may have lower activity and might therefore be preferred on this basis, but amorphous solids have the advantage of greater rates of resolubilization. Therefore both crystalline and amorphous precipitons may find important uses.
  • the soluble form will usually be nonpolar, therefore relatively facile conversion or change to a polar form is very useful. It will decrease a and have little effect on g. Change to a polarizable form will have less effect, but may be useful. A change leading to a polar more symmetrical form with larger surface area is favorable. It would also be favorable to rely on specific interactions. H-bonds could be intramolecular but be broken on activation. This, too, greatly decreases a.
  • soluble form of the precipiton is polar and/or polarizable, a change leading to low polarity/polarizability would generally reduce solubility. Therefore a charged asymmetric molecule should become uncharged and symmetric. However, this will also increase activity in solid, in opposition to the desired effect.
  • a molecule that has capacity for intramolecular H-bonding may be considered non-polar.
  • the soluble form would be unable to intramolecularly H-bond. On activation, it would fold and become non-polar, diminishing solubility.
  • the solvent is nonpolar, a change to a polarizable environment is desirable.
  • the soluble form of the precipiton may be polar or nonpolar.
  • the H-bond effect is useful.
  • the dipole moment effect is useful.
  • change of the precipiton should be from polar to nonpolar, e.g., from extramolecular specific interactions to intramolecule interaction.
  • the changes in a given precipiton are preferably caused by isomerization of the precipiton. Isomerization is preferably reversible and either soluble or insoluble forms may be dominant depending on the conditions used for isomerization.
  • Many photochromic systems can be switched from one isomeric form to another by light. Application of such molecules to solubility control applied to chemical synthesis is without precedent. Whether light, heat, and/or a catalyst is preferred will depend on the application.
  • the -E-isomer was obtained pure in a 44% (51E) and 79% (52E) yield, respectively without any contamination of either Z-isomer or PI12S2.
  • the relatively lower yield for 51.E is due to the lower Z to E conversion and also to the bigger solubility of 51-B in Et 2 0 than 52- ⁇ in Et2 ⁇ (Table 26 and 27).
  • high-boiling solvents such as toluene and p-dioxane
  • the isomerization was faster than in THF and the reaction was completed in less than 3 h (Table 32).
  • a second catalytic method for isomerization/precipitation employs iodine and a radical initiator, for example dibenzoylperoxide. Irradiation of the cis-alkenes in the presence of 1-50 mol% iodine and OJ-25 mol% dibenzoylperoxide affords clean isomerization of the cis to trans alkene
  • Fig. 1 illustrates a simple reaction scheme utilizing a precipiton.
  • the soluble form 21a of a precipiton is shown as being in the same phase as reactant 23.
  • Reactant 23 which is a starting material that bears three functional groups - an alkene, a hydroxyl group, and a reactive group generalized as "X.” As illustrated, the OH or hydroxy group is used as an attaching group to precipiton 21a, however, any suitable functional group would suffice as an attachment site.
  • the reactant 23 is attached to the separating agent (precipiton) 21a through their OH groups (as, for example, may occur in ether or ester formation).
  • the conjugate of these two moieties is molecule 25.
  • Molecule 25 may be referred to herein as a reactant-precipiton complex or conjugate or a reactant molecule having a separating agent attached thereto.
  • Reactive group "X" is transformed to "Z” by Reaction 1.
  • the product of this transformation is intermediate-precipiton complex 27.
  • Treatment of intermediate-precipiton complex 27 with a catalyst or with light causes isomerization of the separation agent portion of the intermediate- precipiton complex 27 and results in separation of the product -precipiton conjugate 29 due to a reduced solubility or a change in phase affinity.
  • the separated product-precipiton complex 29 contains the transformed moiety 21b which can be cleaved from the precipiton to afford pure product (not shown).
  • Fig. 2 illustrates another aspect of the present invention wherein the precipitons may be recycled.
  • Fig. 2 demonstrates how waste products are separated by filtration from the solid reaction product.
  • the isolated precipitate 31 can be separated from waste products by filtration.
  • the precipitated product-precipiton complex 29 can be worked up so that the separation agent can be isolated (in this case the trans-form 21b of the precipiton) to afford pure product 31 and the insoluble form of precipiton 21b.
  • This insoluble form of precipiton 21 can be rendered soluble by reversing the isomerization to create a more soluble form of the precipiton 21a which may be used again in a reaction.
  • Fig. 3 illustrates another aspect of the present invention wherein the precipiton concept is used in a multi-step process.
  • the first reaction is carried out on a reactant 23 which is attached to the soluble form 21a of precipiton resulting in an intermediate-precipiton complex 27.
  • Intermediate-precipiton complex 27 is then the reactant for reaction 1 wherein the "X" functional group is transformed to a "Z" functional group.
  • This second intermediate-precipiton complex 27a is isomerized resulting in an insoluble intermediate product-precipiton complex 29a.
  • Product- precipiton complex 29a is dissolved in a second solvent and the precipiton portion of 29a is isomerized back into the soluble form of the precipiton and this resolubilized purified form of intermediate-precipiton complex 27a is utilized in reaction 2.
  • Intermediate-precipiton complex 27a is transformed via reaction by addition of the functional group "W" to the alkene of intermediate-precipiton complex 27a resulting in a second intermediate-precipiton complex 27b which is soluble in the reaction phase.
  • the soluble form of the second intermediate-precipiton complex 27b is isomerized to precipitate a second product-precipiton complex 29b.
  • This second product-precipiton complex 29b is then dissolved in a second solvent and the precipiton portion of product- precipiton complex 29b is cleaved resulting in product 31 which is easily isolatable from the precipiton (either in the form of soluble precipiton 21a or insoluble precipiton 21b).
  • the reaction process shown in Fig. 3 illustrates the utility of the present invention in a multi-step process whereby the many of the complicated separation or isolation techniques are eliminated due to the selectable control (e.g., through photoismerization) of the precipiton attached to the reactant.
  • stilbenes appear to be particularly suitable candidate molecules for a precipiton, primarily because of two very attractive properties: facile Z-E isomerization and an intrinsic low solubility of E-isomer.
  • the general features of the reaction scheme are shown below.
  • the photoisomerization reaction is preferably executed by irradiation with the use of ultraviolet light generated from UN emission equipment known to those skilled in the art.
  • the material subject to irradiation can be in the form of solution, melt, or solid.
  • Solvent can be employed, and the solvent will generally be one or more organic solvents. There are no particular limitations to the solvent provided that neither photoisomerization nor the practice of the invention are impaired.
  • Suitable solvents for the photoisomerization include hydrocarbons, including aromatic and acyclic hydrocarbons. Examples include the aromatic hydrocarbons toluene and xylene. Halogenated hydrocarbons can be used and examples include halobenzenes such as chlorobenzene.
  • Ethers can be used such as, for example, dioxane and tetrahydrofuran.
  • Alcohols can be used, and examples include alkanols such as the lower- alkanols exemplified by methanol, ethanol, propanol, butanol, pentanol, and hexanol.
  • Ketones can be used including, for example, methyl isobutyl ketone, methyl ethyl ketone, acetone, cyclopentanone, and cyclohexanone.
  • Aprotic polar solvents can be used such as, for example, dimethylsulfoxide, dimethylacetamide, dimethyformamide, and N-methylpyrolidone.
  • Glycols can be used such as, for example, ethylene glycol, propylene glycol, diethylene glycol, dipropylene glycol, ethylene glycol monomethyl ether, and propylene glycol monomethyl ether.
  • Acidic solvents can be used such as, for example, lower alkyl carbonic acids including acetic acid, chloroacetic acid, and butyric acid. The above solvents can be used singly or in a combination.
  • Suitable irradiation equipment for the photoisomerization reaction includes a low-pressure mercury lamp, a high-pressure mercury lamp, a Xenon lamp and lasers such as an excimer laser.
  • the efficiency of the absorption band of the compound and the wave length of emission lines of the light source may be chosen based on criteria commonly known to those skilled in the art. It is therefore preferable to select the light source by matching its UV emission to the wavelength range of the absorption band in ultra-violet and visible regions of the trans-isomer.
  • the region of the wavelength of the emission lines to be utilized is between about 200 nm and about 800 nm, more preferably between about 250 and about 550 nm, even more preferably 300-400 nm, and even more preferably about
  • the photoisomerization can be used to change the solubility of the irradiated compound. That is, isomerization may be used to change the solubility of a compound from soluble to less soluble and vice versa from less soluble to more soluble. Recovered isomerized precipiton may be recycled.
  • Several chemical and photochemical methods are available for transforming E-alkenes to Z-alkenes and Z-alkenes to E-alkenes. These methods, when applied to the recovered material, would provide the soluble precipiton form for reuse.
  • Some isomerizable precipitons can be readily changed from one form to another through irradiation with ultraviolet or visible light. This photon driven switching of solubility in fact is a preferred embodiment of the invention.
  • Volatile and non-volatile products, and targets that (after cleavage from the precipiton) are liquids, solids, or gases may be prepared by this method.
  • An advantage of the present invention is that the products are isolated in good yield often without resorting to liquid-liquid extraction, chromatography, distillation or recrystallization. Yield of the reactions described here are similar to that obtained using traditional methods, but costs of production as measured by time and materials can be significantly reduced.
  • Fig. 4 illustrates in a three-dimensional manner a multistage process like that shown in Fig. 3, but with even further potential elimination of physical separation steps (e.g., filtration may be avoided using two liquid phases to proceed with the reaction).
  • reactant 23 is functionalized by attachment of soluble form of precipiton 21a resulting in a reactant-precipiton complex or conjugate 25.
  • This reactant-precipiton complex 25 is processed in solvent A through reaction 1 where the "X" functional group is replaced by functional group "Z". If there are contaminants in solvent A the intermediate- precipiton 27a is isomerized to shift the intermediate-precipiton complex out of solvent A in the form of an insoluble product-precipiton complex 29a.
  • Insoluble product-precipiton complex 29a can be dissolved in a second solvent which may exist side-by-side in a two-phase system as shown in Fig. 3 or by liquid extraction.
  • Solvent B is used as a solvent for isomerization of product-precipiton complex 29a which results in transformation back to the first intermediate-precipiton complex 27a.
  • the value in this step is that any contaminants located in solvent A can be removed while the product-precipiton complex 29a is in solvent B.
  • product-precipiton complex 29a is isomerized back to the cis form resulting in intermediate-precipiton complex 27a which is utilized for reaction 2 wherein there is an alkene substitution of W on the alkene- functionalized portion of intermediate-precipiton complex 27a.
  • a second product-precipiton complex 29b which has a precipiton portion and includes the Z functional group as well as the W functional group can be isolated from solvent A. If the solvents exist side-by-side in a multi-phase system, phase shift or transfer can be used rather than collecting by filtration second product-precipiton complex 29b.
  • product-precipiton complex 29b can be directly dissolved into solvent B.
  • Second product-precipiton complex 29b can then be dissolved in solvent B and the precipiton portion of the product-precipiton complex 29b can be cleaved in solvent B resulting in the trans form of the precipiton being isolated in solvent B and the desired end product 31 being isolated in solvent A.
  • stilbenes appear to be particularly well suited as precipitons for purposes of the present invention. As will be described in greater detail below, a number of stilbenes were synthesized and tested for their suitability. Napthylstilbenes (Scheme 1)
  • TBS-protected 2,2-naphthylstilbene TBS-protected naphthaldehyde 55 was prepared from 6-bromo-2-naphthol by TBS protection (Wallimann, P.; Mattei, S.; Seiler, P.; Diederich, F. Helv. Chim. Acta. 1997, 80, 2368- 2390) followed by formylation using DMF as a formylating reagent in 81% overall yield over 2 steps.
  • Phenolic stilbene 57Z was obtained via a route employing a TBS-protecting group (Scheme 3).
  • Table 1 illustrates the observed UV spectra of stilbene compounds (56Z, 56E, 60Z, 60E).
  • the -E-stilbene isomer shows longer absorptiom maxima ( ⁇ m ax) and stronger absorption coefficient ( ⁇ ) than the corresponding Z-isomer.
  • the phenolic or naphtholic group can be functionalized by attaching an acryloyl group (see Scheme 4 below).
  • the biphenyl stilbene 57Z was treated with NaH followed by acryloyl chloride to give stilbene 61Z in 68% yield.
  • Naphthyl stilbene 62Z was prepared in 73% yield by desilylation followed by in-situ trapping of naphthoate anion with acryloyl chloride.
  • the target moieties may be separated from the precipiton by dissolving the precipitate in a better solvent and cleaving the precipiton from the target.
  • (E) norbene product can be treated in MeOH/K2C03 to provide the methyl ester. Evaporation of solvent and washing the residue with ether provide pure methyl ester (in solution) and recovered isomerized precipiton as a insoluble residue.
  • the trityl-ether connected polystyrene support (2% divinyl benzene- stryrene copolymer) with Michael acceptor reacted with thiophenols to give Michael addition products.
  • the products were isolated by formic acid treatment.
  • the 1,4-Michael addition of thiophenols into acyl stilbenes (61Z and 62Z) was also performed (Schemes 8 and 9).
  • the products can be, and in this case were isolated by methanolysis of the precipiton- attached products (68.E, 69.E, and 70E) (Scheme 34).
  • a suspension of starting materials (68- ⁇ , 69-E, and 70-E) in CHCI3 was treated with methanolic HC1 (generated in-situ from acetyl chloride with methanol).
  • methanolic HC1 generated in-situ from acetyl chloride with methanol.
  • the volatiles were evaporated.
  • precipitons 57.E or, 6SE
  • methyl ester 71 (Shi, D.; Lu, Z.; Mu, L.; Dai, G. Synth. Commun. 1998, 28, 1073-1078) (100% from 68-E, 61% from 70E) or, 72 (100%), respectively.

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  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne des agents de séparation et leurs méthodes d'utilisation, en vue de la séparation d'un réactif, d'un produit intermédiaire, et/ou d'un produit final d'un mélange de réaction, ce qui permet de réduire à leur minimum les cas de recours aux techniques de séparation ou d'isolation classiques.
PCT/US2000/003523 1999-02-10 2000-02-10 Agents de separation chimique, et methodes d'utilisation desdits agents WO2000047031A2 (fr)

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EP00910145A EP1165222A4 (fr) 1999-02-10 2000-02-10 Agents de separation chimique, et methodes d'utilisation desdits agents
AU32287/00A AU3228700A (en) 1999-02-10 2000-02-10 Chemical partitioning agents and methods of using same
US09/913,231 US6706839B1 (en) 1999-02-10 2000-02-10 Chemical partitioning agents and methods of using same

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JPH09219310A (ja) * 1996-02-09 1997-08-19 Sumitomo Bakelite Co Ltd プラスチック磁石用組成物
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