A process for the preparation of bisguaiacol based compounds

Abstract

The present invention relates to synthetic aromatic / monomeric compounds specifically bisguaiacol based compounds. The invention relates to a process for preparation of said Bisguaiacol-F based compounds of Formula I and / or one or more of Formula IA, Formula IB or Formula IC thereof, or stereoisomer, racemate, and pharmaceutically acceptable salts thereof. Further, the compounds prepared and disclosed herein are useful for production of water treatment membranes, biomedical devices, household products, automation component, fuel cell membrane, printed circuit board, and production of polymers such as polycarbonates, polyesters, polysufonates, and epoxy resins Formula(I).

Description

[0001] A PROCESS FOR THE PREPARATION OF BISGUAIACOL BASED COMPOUNDS

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to a process for preparation of the Bisguaiacol based compound of Formula I and / or one or more of Formula IA, Formula IB or Formula IC thereof, or stereoisomer, racemate, and pharmaceutically acceptable salts thereof. Particularly, the present invention relates to the Bisguaiacol based compound of Formula I and / or one or more of Formula IA, Formula IB or Formula IC thereof, or stereoisomer, racemate, and pharmaceutically acceptable salts thereof. More particularly, present invention relates to compound of Formula I, useful for production of water treatment membranes, biomedical devices, household products, automation component, fuel cell membrane, printed circuit board, and production of polymers such as polycarbonates, polyesters, polysufonates, and epoxy resins. It is submitted that said compounds of Formula I are greener alternative to bisphenol based compounds for said applications and industries.

[0004] BACKGROUND OF THE INVENTION

[0005] Currently, polycarbonates, epoxy resins, and plastics are synthesized by bisphenol-A in various industries. These materials are optically transparent and have excellent mechanical and electrical properties. In addition, polycarbonates are heat and water resistant, have neither taste nor odor, impermeable to oils, fats, and bacteria, and are physiologically inert. Bisphenol-A based plastics are very hard, clean and tough so it is used to make waterbottles and sports equipment. BPA containing epoxy resins are used in food and beverage cans, water pipeline etc. (Thirukumaran Periyasamy et al., New J. Chem., 2016, 40, 9313). Therefore, global demand of bisphenol-A is very high. In presence of Bronsted acid catalyst, condensation reaction of phenol with acetone gives Bisphenol-A and phenol with formaldehyde gives Bisphenol-F Steven-Friso Koelewijn et al., Green Chem., 2019, 00, 1-12). However, Bisphenol-A is banned in baby bottles and other food packaging materials because it is harmful to childrens and pregnant women. Bisphenol-A plays vital role in disrupting our normal hormones like estrogen and shows adverse effect on endocrine system. Endocrine mediated toxicity causes diabetes, obesity, reproductive disorders, birth defects, breast cancer and chronic respiratory diseases etc. (Rezg, R. et al., Environ. Int. 2014, 64, 83 90). From recent decades primary challenge before the scientists and technologists is to find greener options for energy, fuels, chemicals and materials. From last two decades, biomass has emerged as one of sustainable alternatives for chemicals and material synthesis. Biomass is composed of lignin, cellulose and hemicellulose. The vanillin, Vanillyl alcohol, guaiacol are some of lignin derived molecules which is used for synthesis of polycarbonates. Guaiacol is common product of pyrolysis of wood and it is also derived from guaiacum or wood creosote. It is also found in essentials oils from celery seeds, tobacco leaves, orange leaves and lemon peels. Bisguaiacol-F is green alternative to Bisphenol-A. It is used for synthesis of household products, automation components, fuel cell membrane, water treatment membrane, food packaging, printed circuit board and biomedical devices. However, it is environmentally friendly and it doesn’t show any adverse effect on human health. Currently Bisguaiacol-F (BGF) is synthesized by electrophilic aromatic condensation of vanillyl alcohol with guaiacol and vanillin with guaiacol in presence of acid catalysts. Homogeneous H2SO4 catalyst (F. Cavani et al., Journal of Molecular Catalysis A: Chemical, 2002, 447 453). sulphonic acid functionalized resin like Amberlyst-15 Steven-Friso Koelewijn et al., Green Chem., 2019, 21, 6622) was used for Bisguaiacol-F synthesis. However, said known methods have limitations e.g. high cost of vanilyl alcohol, higher impurities, low scale production, lesser yields, etc. making it unreliable / non-preferable for high scale production of BGF.

[0006] Therefore, there is an unmet need to provide effective and alternative materials / compounds to bisphenol with high scale production and less impurities. Addressing all these problems, inventors of present application provide effective way for formation of bisguaiacol based compounds of Formula I / IA / IB / IC or mixture therof with low cost and high scale production, mixture of bisguaiacol F (BGF), bisguaiacol A (BGA), bisguaiacol E (BGE) and their other different analogues / isomeric forms in single reaction, efficient alternative to toxic and non-preferred bisphenol A, simple, easy to process, scalable, tunable, higher conversion rates and selectivity of upto 80- 85%, higher yields of upto 80%, etc.

[0007] OBJECTIVE OF THE INVENTION

[0008] Main objective of the present invention is to provide a process for the preparation of the Bisguaiacol based compound of Formula I and / or one or more of Formula IA, Formula IB or Formula IC thereof, or stereoisomer, racemate, and pharmaceutically acceptable salts thereof.

[0009] Another objective of the present invention is to provide the Bisguaiacol based compound of Formula I and / or one or more of Formula IA, Formula IB or Formula IC thereof, or stereoisomer, racemate, and pharmaceutically acceptable salts thereof.

[0010] Yet another objective of the present invention is to provide a process for preparation of the Bisguaiacol based compound of Formula I and / or one or more of Formula IA, Formula IB or Formula IC thereof, or stereoisomer, racemate, and pharmaceutically acceptable salts thereof, using simple biomass derived reactants such as (un) substituted guaiacol and formaldehyde.

[0011] Still another objective of the present invention is to provide the Bisguaiacol based compounds of Formula I, IA, IB, IC or mixture thereof, useful for preparation of water treatment membranes, biomedical devices, household products, automation component, fuel cell membrane, printed circuit board, and production of polymers such as polycarbonates, polyesters, polysufonates, and epoxy resins.

[0012] SUMMARY OF THE INVENTION

[0013] Accordingly, present invention provides a process of preparation of Bisguaiacol based compounds of formula I and / or one or more of formula IA, formula IB or formula IC thereof, or stereoisomer, racemate, and pharmaceutically acceptable salts thereof, wherein

[0014] A, B, B’, B”, B’” and B”” are independently selected from -O-, -N-, or absent; Rl, R2, R3, R4 and R5 are independently selected from hydrogen, (un)substituted alkyl (Cl to C21), (un)substituted alkoxy (Cl to C21), (un)substituted aryl (C5-C11), (un)substituted heteroaryl, silyl, alkylsilyl, (un)substituted alkylether, (un) substituted arylether, (un)substituted heteroarylether, (un)substituted alkynyl (C2-C12), (un)substituted alkylene (C2-C12), (un)substituted allyl (C2-C12), (un) substituted cyclic ring (C3-C12), (un)substituted cycloalkyl (C3-C12), heteroalkylene, arylalkyl, heteroarylalkyl, halo, nitro, (un)substitutedalkyl-ether-(un)substitutedaryl, (un)substitutedalkyl-ether-(un)substitutedheteroaryl, (un)substitutedalkyl-ether- (un)substitutedalkyl, (un)substitutedalkyl-thio-(un)substitutedaryl,

[0015] (un)substitutedalkyl-thio-(un)substitutedheteroaryl, (un)substitutedalkyl-thio-

[0016] (un)substitutedalkyl, alkylaryl, alkylheteroaryl, alkylalkenyl, alkylalkenylalkyl, arylalkenyl, arylalkenylaryl, heterocycloalkyl, haloalkyl, heteroalkyl, alkylamino, alkoxycarbonyl, alkylcarbonyl, alkylcarbonylamino, alkylsulfonylamino, aminosulfonyl, alkylaminosulfonyl, dialkylamino sulfonyl, aminosulfonylamino, aminocarbonylamino, alkylaminosulfonylamino, dialkylamino sulfonylamino, alkylaminocarbonylamino, alkylcarbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, carbamyl, cyano-alkyl, alkoxyalkyl, dialkylamino, dialkylcarbamyl, haloalkoxy, haloalkyl, ester, ether, acetal, thioacetal, ketal, thioketal, carbamate or carbonate;

[0017] Rl’, R2’, R3’, R4’ and R5’ are independently selected from hydrogen, (un) substituted alkyl (Cl to C21), (un)substituted alkoxy (Cl to C21), (un)substituted aryl (C5-C11), (un)substituted heteroaryl, silyl, alkylsilyl, (un)substituted alkylether, (un)substituted arylether, (un)substituted heteroarylether, (un)substituted alkynyl (C2-C12), (un)substituted alkylene (C2-C12), (un)substituted allyl (C2-C12), (un) substituted cyclic ring (C3-C12), (un)substituted cycloalkyl (C3-C12), heteroalkylene, arylalkyl, heteroarylalkyl, halo, nitro, (un)substitutedalkyl-ether-(un)substitutedaryl, (un)substitutedalkyl-ether-(un)substitutedheteroaryl, (un)substitutedalkyl-ether- (un)substitutedalkyl, (un)substitutedalkyl-thio-(un)substitutedaryl,

[0018] (un)substitutedalkyl-thio-(un)substitutedheteroaryl, (un)substitutedalkyl-thio-

[0019] (un)substitutedalkyl, alkylaryl, alkylheteroaryl, alkylalkenyl, alkylalkenylalkyl, arylalkenyl, arylalkenylaryl, heterocycloalkyl, haloalkyl, heteroalkyl, alkylamino, alkoxycarbonyl, alkylcarbonyl, alkylcarbonylamino, alkylsulfonylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, aminosulfonylamino, aminocarbonylamino, alkylaminosulfonylamino, dialkylamino sulfonylamino, alkylaminocarbonylamino, alkylcarbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, carbamyl, cyano-alkyl, alkoxyalkyl, dialkylamino, dialkylcarbamyl, haloalkoxy, haloalkyl, ester, ether, acetal, thioacetal, ketal, thioketal, carbamate or carbonate; and

[0020] R and R’ are independently selected from hydrogen, (un)substituted alkyl (Cl to C21), (un)substituted alkoxy (Cl to C21), (un) substituted aryl (C5-C11), (un)substituted heteroaryl, silyl, alkylsilyl, (un)substituted alkylether, (un)substituted arylether, (un)substituted heteroarylether, (un)substituted alkynyl (C2-C12), (un)substituted alkylene (C2-C12), (un)substituted allyl (C2-C12), (un)substituted cyclic ring (C3- C12), (un) substituted cycloalkyl (C3-C12), heteroalkylene, arylalkyl, heteroarylalkyl, halo, nitro, (un)substitutedalkyl-ether-(un)substitutedaryl, (un)substitutedalkyl-ether- (un)substitutedheteroaryl, (un)substitutedalkyl-ether-(un)substitutedalkyl,

[0021] (un)substitutedalkyl-thio-(un)substitutedaryl, (un)substitutedalkyl-thio-

[0022] (un)substitutedheteroaryl, (un)substitutedalkyl-thio-(un)substitutedalkyl, alkylaryl, alkylheteroaryl, alkylalkenyl, alkylalkenylalkyl, arylalkenyl, arylalkenylaryl, heterocycloalkyl, haloalkyl, heteroalkyl, alkylamino, alkoxycarbonyl, alkylcarbonyl, alkylcarbonylamino, alkylsulfonylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, aminosulfonylamino, aminocarbonylamino, alkylamino sulfonylamino , dialkylamino sulfonylamino , alkylaminoc arbonylamino , alkylcarbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, carbamyl, cyano-alkyl, alkoxyalkyl, dialkylamino, dialkylcarbamyl, haloalkoxy, haloalkyl, ester, ether, acetal, thioacetal, ketal, thioketal, carbamate or carbonate; optionally R1 with R2 or R2 with R3 or R3 with R4 or R4 with R5 or R with R’ forms together a cyclic ring which may be further substituted; or optionally Rl’ with R2’ or R2’ with R3’ or R3’ with R4’ or R4’ with R5’ forms together a cyclic ring which may be further substituted. wherein the process comprising the steps of:

[0023] I. stirring and reacting (un)substituted Guaiacol based compound(s) of formula A and / or B with aldehyde / ketone compound of formula C in a solvent and optionally under nitrogen pressure in the range of 5 to 15 bar, in presence of a heterogenous catalyst at a speed in the range of 300 to 1000 RPM, and a temperature in the range of 35-105 °C, for a time period of 1-8 hrs to obtain compound of formula I, IA, IB, IC or mixture thereof,

[0024] Formula A Formula B Formula C wherein the heterogeneous catalyst is selected from Lanxess KI 13 IS and Lanxess K2649 and LanxessK2629; wherein Lanxess KI 13 IS is a strongly acidic, gel-type, and polymer- based resin in spherical bead form with a very narrow bead size distribution with particle size in the range of 0.80-1.25 mm; and wherein the Lanxess K2649 is a strongly acidic, macroporous, polymer-based resin in spherical bead form, and with particle size in the range of 0.40- 1.25 mm; and

[0025] II. optionally separating and purifying the compound of formula I, IA, IB, IC or mixture thereof of step (I) to obtain pure compounds of formula I, IA, IB and / or IC.

[0026] In an embodiment of the present invention, the compound of formula A and / or B is

[0027] In another embodiment of the present invention, the compound of formula C is selected from formaldehyde, acetone and acetaldehyde.

[0028] In yet another embodiment of the present invention, the solvent is selected from methanol, acetonitrile, 1,4-dioxane, ethanol, water, and isopropyl alcohol or mixture thereof. In yet another embodiment of the present invention, the molar ratio of formula A or B: formula C is in range of 1:0.5 to 4:2 and wherein the amount of catalyst is in the range between 5-20% w / w with respect to guaiacol.

[0029] In yet another embodiment of the present invention, the compound of formula I, IA, IB and / or IC is selected from the group consisting of:

[0030] In yet another embodiment of the present invention, the yield of compound of formula I, IA, IB and / or IC alone or in mixture form is in range of 40 to 85% and wherein the selectivity of formation of compounds of formula I, IA, IB and / or IC alone or in mixture form is in range of 90-98%.

[0031] In yet another embodiment of the present invention, the conversion rate of both reactants formula A and B is of about 100%.

[0032] In yet another embodiment of the present invention, the compound obtained by the process provides single isomeric compound (ee) or mixture of isomeric forms / compounds from a single reaction / process.

[0033] In yet another embodiment of the present invention, the process may be done in batch mode or in continuous mode.

[0034] BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Fig. la shows effect of molar ratio for the preparation of compounds of bisguaiacol F which falls under the Formula(s) I, IA, IB and / or IC of the present invention. Reaction conditions: Guaiacol (Imol), Formaldehyde (0.5-2 mol), catalyst- 10 w / w%, solvent (6ml), temperature- 90° C, and time- 6 h.

[0036] Fig. lb shows effect of molar ratio for the preparation of compounds of bisguaiacol F which falls under the Formula(s) I, IA, IB and / or IC of the present invention. Reaction conditions: Guaiacol (1-4 mol), Formaldehyde (1 mol), catalyst- 10 w / w%, solvent (6ml), temperature- 90° C, and time- 6 h.

[0037] DETAILED DESCRIPTION OF THE INVENTION

[0038] “Membered ring” or “cyclic ring” as used herein means any cyclic structure with carbon, hydrogen and heteroatom (N, O, S, P, Si, B, etc.) in saturated or unsaturated cyclic ring form e.g. cyclic ring may be 4 to 10-membered ring. Thus, by way of example and not limitation, those membered rings include cyclohexyl, pyridinyl, pyranyl, thiopyranyl, etc. which are 6-membered rings, cyclopentyl, pyrrolyl, furanyl, thienyl, pyrrolidine, pyrrole, tetrahydrofuran, furan, phospholane, phosphole, silacyclopentane, silole, tetrahydrothiophene, thiophene, etc.

[0039] “Alkyl” as used herein is collection of carbon atoms that are covalently linked together in normal, secondary, tertiary or cyclic arrangements, i.e., in linear, branched, cyclic arrangement or some combination thereof. An alkyl substituent to structure is chain of carbon atoms that is covalently attached to structure through sp3carbon of substituent. The alkyl substituents, as used herein, contains one or more saturated moieties or groups and may additionally contain unsaturated alkyl moieties or groups, i.e., substituent may comprise one, two, three or more independently selected double bonds or triple bonds of combination thereof, typically one double or one triple bond if such unsaturated alkyl moieties or groups are present.

[0040] Unsaturated alkyl moieties or groups include moieties or groups as described below for alkenyl, alkynyl, cycloalkyl, and aryl moieties. Saturated alkyl moieties contain saturated carbon atoms (sp3) and no aromatic, sp2or sp carbon atoms. The number of carbon atoms in an alkyl moiety or group can vary and typically is 1 to about 50, e.g., about 1-30 or about 1-20, unless otherwise specified, e.g., Ci-8 alkyl or Ci-Cs alkyl means an alkyl moiety containing 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms and Ci-6 alkyl or Ci-C6means an alkyl moiety containing 1, 2, 3, 4, 5 or 6 carbon atoms.

[0041] Cycloalkyl as used here is a monocyclic, bicyclic or tricyclic ring system composed of only carbon atoms. The term “cycloalkyl” encompasses a monocyclic or polycyclic aliphatic, non-aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom. The number of carbon atoms in an cycloalkyl substituent, moiety or group can vary and typically is 3 to about 50, e.g., about 1-30 or about 1-20, unless otherwise specified, e.g., C3-8 alkyl or C3-C8 alkyl means an cycloalkyl substituent, moiety or group containing 3, 4, 5, 6, 7 or 8 carbon atoms and C3-6 alkyl or C3-C6 means an cycloalkyl substituent, moiety or group containing 3, 4, 5 or 6 carbon atoms. Cycloalkyl substituents, moieties or groups will typically have 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms and may contain exo or endo- cyclic double bonds or endo-cyclic triple bonds or a combination of both wherein the endo-cyclic double or triple bonds, or the combination of both, do not form a cyclic conjugated system of 4n+2 electrons; wherein the bicyclic ring system may share one (i.e., spiro ring system) or two carbon atoms and the tricyclic ring system may share a total of 2, 3 or 4 carbon atoms, typically 2 or 3.

[0042] Unless otherwise specified, cycloalkyl substituents, moieties or groups can contain moieties and groups described for alkenyl, alkynyl, aryl, arylalkyl, alkylaryl and the like and can contain one or more other cycloalkyl moieties. Thus, cycloalkyls may be saturated, or partially unsaturated. Cycloalkyls may be fused with an aromatic ring, and the points of attachment to the aromatic ring are at a carbon or carbons of the cycloalkyl substituent, moiety or group that is not an aromatic ring carbon atom. Cycloalkyl groups include groups having from 3 to 10 ring atoms.

[0043] “Alkylamine” as used herein means an — N(alkyl)xHygroup, moiety or substituent where x and y are independently selected from the group x=l, y=l and x=2, y=0. Alkylamine includes those — N(alkyl)xHygroups wherein x=2 and y=0 and the alkyl groups taken together with the nitrogen atom to which they are attached form a cyclic ring system.

[0044] “Heteroalkylene” as used herein means alkylene (i.e. alkanediyl) group, moiety or substituent in which one or more skeletal atoms of alkyl are selected from atom other than carbon, e.g. oxygen, nitrogen, sulfur, phosphorus or combinations thereof.

[0045] “Alkenyl” as used herein means a substituent, moiety or group that comprises one or more double bond moities (e.g., — CH=CH — ) or 1, 2, 3, 4, 5 or 6 or more, typically 1, 2 or 3 such moieties and can include an aryl moiety or group such as benzene, and additionally comprises linked normal, secondary, tertiary or cyclic carbon atoms, i.e., linear, branched, cyclic or any combination thereof unless the alkenyl moiety is a vinyl moiety (e.g., — CH=CH2).

[0046] “Alkynyl” as used herein means substituent, moiety or group that comprises one or more triple bond moieties (i.e., — C=C — ) e.g., 1, 2, 3, 4, 5, 6 or more, typically 1 or 2 triple bonds, optionally comprising 1, 2, 3, 4, 5, 6 or more double bonds, with remaining bonds (if present) being single bonds and comprising linked normal, secondary, tertiary or cyclic carbon atoms, i.e., linear, branched, cyclic or any combination thereof, unless the alkynyl moiety is ethynyl. The number of carbon atoms in an alkenyl moiety or group can vary and typically is 2 to about 50, e.g., about 2-30 or about 2-20, unless otherwise specified, e.g., C2-8 alkynyl or C2-8 alkynyl means an alkynyl moiety containing 2, 3, 4, 5, 6, 7 or 8 carbon atoms. Alkynyl groups will typically have 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms. “Aromatic” as used herein refers to a planar ring having a delocalized pi-electron system containing 4n+2 pi electrons, where n is a positive integer. Aromatic rings can be formed from five, six, seven, eight, nine, ten, or more than ten atoms. Aromatics are optionally substituted.

[0047] “Aryl” as used here means an aromatic ring system or a fused ring system with no ring heteroatoms comprising 1, 2, 3 or 4 to 6 rings, typically 1 to 3 rings, wherein the rings are composed of only carbon atoms; and refers to a cyclically conjugated system of 4n+2 electrons (Huckel rule), typically 6, 10 or 14 electrons some of which may additionally participate in exocyclic conjugation (cross-conjugated (e.g., quinone).

[0048] “Arylalkyl” as used herein means a substituent, moiety or group where an aryl moiety is bonded to an alkyl moiety, i.e., -alkyl-aryl, where alkyl and aryl groups are as described above, e.g., — CH2 — CeHs or — CHiCHiCHs) — CeHs. When arylalkyl is used as a Markush group (i.e., a substituent) the alkyl moiety of the arylalkyl is attached to a Markush Formula with which it is associated through a sp3carbon of the alkyl moiety.

[0049] “Alkylaryl” as used herein means substituent, moiety or group where alkyl moiety is bonded to aryl moiety i.e. -aryl-alkyl, where aryl and alkyl groups are as described above, e.g. -CeFU-CFF or -C6H4-CH2CH(CH3).Whenalkylaryl is used as Markush group (substituent), aryl moiety of alkylaryl is attached to Markush with which it is associated through sp2carbon of aryl moiety.

[0050] “Optionally substituted” covers “Optionally substituted alkyl”, “optionally substituted alkenyl”, “optionally substituted alkynyl”, “optionally substituted alkylaryl”, “optionally substituted arylalkyl”, “optionally substituted heterocycle”, “optionally substituted aryl”, “optionally substituted heteroaryl”, “optionally substituted alkylheteroaryl”, “optionally substituted heteroaryl alkyl” and the like as used herein mean an alkyl, alkenyl, alkynyl, alkylaryl, arylalkyl heterocycle, aryl, heteroaryl, alkylheteroaryl, heteroarylalkyl, or other substituent, moiety or group as defined or disclosed herein that has a substituent(s) that optionally replaces hydrogen atom(s) or substituent(s) that interrupts carbon atom chain. Such substituents are as described herein. For phenyl moiety, arrangement of any two substituents present on aromatic ring can be ortho(o), meta(m), or para(p). Optionally substituted fluoroalkyl is alkyl or cycloalkyl moiety, typically linear alkyl, wherein one or more hydrogen atoms is replaced by fluorine and at least one other atom other than carbon and fluorine. An optionally substituted or substituted substituent, moiety or group includes those having one or more additional group(s) that replace its hydrogen atom(s) individually and independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, cyano, halo, nitro, haloalkyl, fluoroalkyl, fluoroalkoxy, and amino, including mono- and di-substituted amino groups, and the protected derivatives thereof.

[0051] “Heterocycle” or “heterocyclic” as used herein means a cycloalkyl or aromatic ring system wherein one or more, typically 1, 2 or 3, but not all of the carbon atoms comprising the ring system are replaced by a heteroatom which is an atom other than carbon, including, N, O, S, Se, B, Si, P, typically N, O or S wherein two or more heteroatoms may be adjacent to each other or separated by one or more carbon atoms, typically 1-17 carbon atoms, 1-7 atoms or 1-3 atoms. Heterocycles include heteroaromatic rings (also known as heteroaryls) and heterocycloalkyl rings (also known as heteroalicyclic groups) containing one to four heteroatoms in the ring(s), where each heteroatom in the ring(s) is selected from O, S and N, wherein each heterocyclic group has from 4 to 10 atoms in its ring system, and with the proviso that the any ring does not contain two adjacent O or S atoms.

[0052] Non-aromatic heterocyclic, substituents, moieties or groups (also known as heterocycloalkyls) have at least 3 atoms in their ring system and aromatic heterocyclic groups have at least 5 atoms in their ring system and include benzo-fused ring systems. Heterocyclics with 3, 4, 5, 6 and 10 atoms include aziridinylazetidinyl, thiazolyl, pyridyl and quinolinyl, respectively.

[0053] When heterocycle is used as a Markush group (i.e., a substituent) the heterocycle is attached to a Markush Formula with which it is associated through a carbon or a heteroatom of the heterocycle, where such an attachment does not result in an unstable or disallowed formal oxidation state of that carbon or heteroatom. A heterocycle that is C-linked is bonded to a molecule through carbon atom include moieties such as — (CHi),,- heterocycle where n is 1, 2 or 3 or — C<heterocycle where C< represents a carbon atom in a heterocycle ring. Heterocycle that is N-linked is nitrogen containing heterocycle that is bonded a heterocycle ring nitrogen sometimes described as — N<heterocycle where N<represents nitrogen atom in heterocycle ring. Thus, nitrogencontaining heterocycles may be C-linked or N-linked and include pyrrole substituents, which may be pyrrol- 1-yl (N-linked) or pyrrol-3-yl (C-linked), imidazole substituents, which may be imidazol-l-yl or imidazol-3-yl (both N-linked) or imidazol-2-yl, imidazol-4-yl or imidazol-5-yl (all C-linked).

[0054] “Heteroaryl” as used herein means an aryl ring system wherein one or more, typically 1, 2 or 3, but not all of the carbon atoms comprising the aryl ring system are replaced by a heteroatom which is an atom other than carbon, including, N, O, S, Se, B, Si, P, typically, oxygen ( — O — ), nitrogen ( — NX — ) or sulfur ( — S — ) where X is — H, protecting group or Ci-6 optionally substituted alkyl, wherein heteroatom participates in conjugated system either through pi-bonding with adjacent atom in ring system or through lone pair of electrons on heteroatom and may be optionally substituted on one or more carbons or heteroatoms, or combination of both, in manner which retains cyclically conjugated system.

[0055] Monocyclic heteroaryls include, by way of example and not limitation, pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Heteroaryls include those substituents, moieties or groups containing 0-3 N atoms, 1-3 N atoms or 0-3 N atoms, 0-1 0 atoms and 0-1 S atoms. A heteroaryl may be monocyclic or bicyclic. The ring system of a heteroaryls ring typically contains 1-9 carbons (i.e., C1-C9 heteroaryl). Monocyclic heteroaryls include C1-C5 heteroaryls. Monocyclic heteroaryls include those having 5- membered or 6-membered ring systems. Bicyclic heteroaryls include C6-C9 heteroaryls. Depending on the structure, a heteroaryl group can be a monoradical or a diradical (i.e., a heteroarylene group).

[0056] “Heterocycloalkyl” or “heteroalicyclic” as used herein means cycloalkyl group or substituent wherein at least on carbon of cycloalkyl chain is replaces with heteroatom selected from nitrogen, oxygen and sulfur. The heterocycloalkyl may be fused with aryl or heteroaryl.

[0057] “Heteroarylalkyl” as used herein means a substituent, moiety or group where a heteroaryl moiety is bonded to an alkyl moiety, i.e., -alkyl-heteroaryl, where alkyl and heteroaryl groups are as described above. When heteroarylalkyl is used as a Markush group (i.e., a substituent) the alkyl moiety of the heteroarylalkyl is attached to a Markush Formula with which it is associated through a sp3carbon of the alkyl moiety.

[0058] “Alkylheteroaryl” as used herein means substituent, moiety or group where heteroaryl moiety is bonded to alkyl moiety, i.e., heteroaryl-alkyl, where heteroaryl and alkyl groups are as described above. When heteroarylalkylis used as Markush group (substituent), heteroaryl moiety of heteroarylalkyl is attached to Markush Formula with which it is associated through sp2carbon or heteroatom of alkyl moiety.

[0059] “Haloalkyl” as used herein means an alkyl substituent moiety or group in which one or more of its hydrogen atoms are replaced by one or more independently selected halide atoms. Haloalkyl includes C1-C4 haloalkyl.

[0060] The term “heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus or combinations thereof. In one aspect, a heteroalkyl is a Ci-Ce heteroalkyl. “Ester” as used herein means a substituent, moiety or group that contains a — C(O) — O — structure (i.e., ester functional group) wherein the carbon atom of the structure is not directly connected to another heteroatom and is directly connected to — H or another carbon atom.

[0061] “Acetal”, “thioacetal”, “ketal”, “thioketal” and the like as used herein means a moiety, group or substituent comprising or consisting of a carbon to which is bonded two of the same or different heteroatoms wherein the heteroatoms are independently selected S and O. For acetal the carbon has two bonded oxygen atoms, a hydrogen atom and an organic moiety. For ketal, the carbon has two bonded oxygen atoms and two independently selected organic moieties where the organic moiety is as described herein alkyl or optionally substituted alkyl group. For thioacetals and thioketals one or both of the oxygen atoms in acetal or ketal, respectively, is replaced by sulfur.

[0062] “Ether” as used herein means an organic moiety, group or substituent that comprises or consists of 1, 2, 3, 4 or more — O — moieties, usually 1 or 2, wherein no two — O — moieties are immediately adjacent (i.e., directly attached) to each other.

[0063] “Carbonate” as used here means a substituent, moiety or group that contains a — O — C(=O) — O — structure (i.e., carbonate functional group).

[0064] “Carbamate” or “urethane” as used here means a substituent, moiety or group that contains a — O — C(=O)N(RPR) — , — O — C(=0)N(RPR)2, — O — C(=O)NH(optionally substituted alkyl) or — O — C(=O)N (optionally substituted alkyl)2- structure (i.e., carbamate functional group) where RPRand optionally substituted alkyl are independently selected and RPRare independently — H, a protecting group or an organic moiety as described for ester, alkyl or optionally substituted alkyl.

[0065] As used herein, the term “alkylene”, employed alone or in combination with other terms, refers to a divalent alkyl linking group. As used herein, the term “alkoxy”, employed alone or in combination with other terms, refers to a group of Formula — O-alkyl, wherein the alkyl group as defined above.

[0066] As used herein, the term “alkylamino” refers to a group of Formula — NH(alkyl), wherein the alkyl group is as defined above.

[0067] As used herein, the term “alkoxycarbonyl” refers to a group of Formula — C(O)O-alkyl, wherein the alkyl group is as defined above.

[0068] As used herein, the term “alkylcarbonyl” refers to a group of Formula — C(O)-alkyl, wherein the alkyl group is as defined above.

[0069] As used herein, the term “alkylcarbonylamino” refers to a group of Formula — NHC(O)-alkyl, wherein the alkyl group is as defined above.

[0070] As used herein, the term “alkylsulfonylamino” refers to a group of Formula — NHS(O)2-alkyl, wherein the alkyl group is as defined above.

[0071] As used herein, the term “aminosulfonyl” refers to a group of Formula — S(O)2NH2.

[0072] As used herein, the term “alkylaminosulfonyl” refers to a group of Formula — S(O)2NH(alkyl), wherein the alkyl group is as defined above.

[0073] As used herein, the term “dialkylaminosulfonyl” refers to a group of Formula — S(O)2N(alkyl)2, wherein each alkyl group independently is as defined above.

[0074] As used herein, the term “aminosulfonylamino” refers to a group of Formula — NHS(O)2NH2.

[0075] As used herein, the term “alkylaminosulfonylamino” refers to a group of Formula — NHS(O)2NH(alkyl), wherein the alkyl group is as defined above.

[0076] As used herein, the term “dialkylaminosulfonylamino” refers to a group of Formula — NHS(O)2N(alkyl)2, wherein each alkyl group independently is as defined above.

[0077] As used herein, the term “aminocarbonylamino”, employed alone or in combination with other terms, refers to a group of Formula — NHC(0)NH2.

[0078] As used herein, the term “alkylaminocarbonylamino” refers to a group of Formula — NHC(O)NH(alkyl), wherein the alkyl group is as defined above.

[0079] As used herein, the term “dialkylaminocarbonylamino” refers to a group of Formula — NHC(O)N(alkyl)2, wherein each alkyl group independently is as defined above.

[0080] As used herein, the term “alkylcarbamoyl” refers to a group of Formula — C(O) — NH(alkyl), wherein the alkyl group is as defined above.

[0081] As used herein, the term “thio” refers to a group of Formula — SH.

[0082] As used herein, the term “alkylthio” refers to a group of Formula — S-alkyl, wherein the alkyl group is as defined above. As used herein, the term “alkylsulfinyl” refers to a group of Formula — S(O)-alkyl, wherein the alkyl group is as defined above.

[0083] As used herein, the term “alkylsulfonyl” refers to a group of Formula — S(O)2-alkyl, wherein the alkyl group is as defined above.

[0084] As used herein, the term “carbamyl” to a group of Formula — C(0)NH2.

[0085] As used herein, the term “carbonyl”, employed alone or in combination with other terms, refers to a — C(O) — group.

[0086] As used herein, the term “carboxy” refers to a group of Formula — C(O)OH.

[0087] As used herein, the term “dialkylamino” refers to a group of Formula — N(alkyl)2, wherein the two alkyl groups each is as defined above.

[0088] As used herein, the term “dialkylcarbamyl” refers to a group of Formula — C(O)N(alkyl)2, wherein the two alkyl groups each is as defined above.

[0089] The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the present invention that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. In some embodiments, the compound has the (R)-configuration. In some embodiment, compound has (S)-configuration.

[0090] Resolution of racemic mixture of compounds is carried out by any of numerous methods known in the art. Example method includes fractional recrystallization using chiral resolving acid which is optically active, salt-forming organic acid.

[0091] Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent composition can be determined by one skilled in the art.

[0092] Compounds of the invention also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropictautomers which are isomeric protonation states having the same empirical Formula and total charge. Example prototropictautomers include ketone — enol pairs, amide — imidic acid pairs, lactam — lactim pairs, enamine — imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H — and 3H- imidazole, 1H — , 2H — and 4H-l,2,4-triazole, 1H — and 2H — isoindole, and 1H — and 2H-pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.Compounds of invention can also include all isotopes of atoms occurring in intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

[0093] The term, “compound,” used herein is meant to include all stereoisomers, geometric iosomers, tautomers, and isotopes of structures depicted. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.

[0094] All compounds, and pharmaceutically acceptable salts thereof, can be found together with other substances such as water and solvents (e.g. hydrates and solvates) or can be isolated.

[0095] The expressions, “ambient temperature” and “room temperature” or “rt” as used herein, are understood in the art, and refer generally to a temperature, e.g. a reaction temperature, that is about the temperature of the room in which the reaction is carried out, for example, a temperature from about 20° C. to about 30° C.

[0096] The present invention relates to a Bisguaiacol based compounds of Formula I, or stereoisomer, racemate, and pharmaceutically acceptable salts thereof, represented as:

[0097] Formula I wherein

[0098] A, B, B’, B”, B’” and B”” are independently selected from -O-, -N-, or absent;

[0099] Rl, R2, R3, R4 and R5are independently selected from the group consisting of hydrogen, (un)substituted alkyl (Cl to C21), (un)substituted alkoxy (Cl to C21), (un)substituted aryl (C5-C11), (un)substituted heteroaryl, silyl, alkylsilyl, (un)substituted alkylether, (un)substituted arylether, (un)substituted heteroarylether, (un)substituted alkynyl (C2-C12), (un)substituted alkylene (C2-C12), (un)substituted allyl (C2-C12), (un)substituted cyclic ring (C3-C12), (un)substituted cycloalkyl (C3- C12), heteroalkylene, arylalkyl, heteroarylalkyl, halo, nitro, (un)substitutedalkyl-ether- (un)substitutedaryl, (un)substitutedalkyl-ether-(un)substitutedheteroaryl,

[0100] (un)substitutedalkyl-ether-(un)substitutedalkyl, (un)substitutedalkyl-thio-

[0101] (un)substitutedaryl, (un)substitutedalkyl-thio-(un)substitutedheteroaryl,

[0102] (un)substitutedalkyl-thio-(un)substitutedalkyl, alkylaryl, alkylheteroaryl, alkylalkenyl, alkylalkenylalkyl, arylalkenyl, arylalkenylaryl, heterocycloalkyl, haloalkyl, heteroalkyl, alkylamino, alkoxycarbonyl, alkylcarbonyl, alkylcarbonylamino, alkylsulfonylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, amino sulfonylamino, aminocarbonylamino, alkylaminosulfonylamino, dialkylamino sulfonylamino, alkylaminocarbonylamino, alkylcarbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, carbamyl, cyano-alkyl, alkoxyalkyl, dialkylamino, dialkylcarbamyl, haloalkoxy, haloalkyl, ester, ether, acetal, thioacetal, ketal, thioketal, carbamate or carbonate;

[0103] Rl’, R2’, R3’, R4’ and R5’ are independently selected from the group consisting of hydrogen, (un)substituted alkyl (Cl to C21), (un)substituted alkoxy (Cl to C21), (un)substituted aryl (C5-C11), (un)substituted heteroaryl, silyl, alkylsilyl, (un)substituted alkylether, (un)substituted arylether, (un)substituted heteroarylether, (un)substituted alkynyl (C2-C12), (un)substituted alkylene (C2-C12), (un)substituted allyl (C2-C12), (un)substituted cyclic ring (C3-C12), (un)substituted cycloalkyl (C3- C12), heteroalkylene, arylalkyl, heteroarylalkyl, halo, nitro, (un)substitutedalkyl-ether- (un)substitutedaryl, (un)substitutedalkyl-ether-(un)substitutedheteroaryl,

[0104] (un)substitutedalkyl-ether-(un)substitutedalkyl, (un)substitutedalkyl-thio-

[0105] (un)substitutedaryl, (un)substitutedalkyl-thio-(un)substitutedheteroaryl,

[0106] (un)substitutedalkyl-thio-(un)substitutedalkyl, alkylaryl, alkylheteroaryl, alkylalkenyl, alkylalkenylalkyl, arylalkenyl, arylalkenylaryl, heterocycloalkyl, haloalkyl, heteroalkyl, alkylamino, alkoxycarbonyl, alkylcarbonyl, alkylcarbonylamino, alkylsulfonylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, amino sulfonylamino, aminocarbonylamino, alkylaminosulfonylamino, dialkylamino sulfonylamino, alkylaminocarbonylamino, alkylcarbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, carbamyl, cyano-alkyl, alkoxyalkyl, dialkylamino, dialkylcarbamyl, haloalkoxy, haloalkyl, ester, ether, acetal, thioacetal, ketal, thioketal, carbamate or carbonate; and

[0107] Rand R’ are independently selected from hydrogen, (un)substituted alkyl (Cl to C21), (un)substituted alkoxy (Cl to C21), (un)substituted aryl (C5-C11), (un)substituted heteroaryl, silyl, alkylsilyl, (un)substituted alkylether, (un)substituted arylether, (un)substituted heteroarylether, (un)substituted alkynyl (C2-C12), (un)substituted alkylene (C2-C12), (un)substituted allyl (C2-C12), (un)substituted cyclic ring (C3- C12), (un) substituted cycloalkyl (C3-C12), heteroalkylene, arylalkyl, heteroarylalkyl, halo, nitro, (un)substitutedalkyl-ether-(un)substitutedaryl, (un)substitutedalkyl-ether- (un)substitutedheteroaryl, (un)substitutedalkyl-ether-(un)substitutedalkyl,

[0108] (un)substitutedalkyl-thio-(un)substitutedaryl, (un)substitutedalkyl-thio-

[0109] (un)substitutedheteroaryl, (un)substitutedalkyl-thio-(un)substitutedalkyl, alkylaryl, alkylheteroaryl, alkylalkenyl, alkylalkenylalkyl, arylalkenyl, arylalkenylaryl, heterocycloalkyl, haloalkyl, heteroalkyl, alkylamino, alkoxycarbonyl, alkylcarbonyl, alkylcarbonylamino, alkylsulfonylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, aminosulfonylamino, aminocarbonylamino, alkylamino sulfonylamino , dialkylamino sulfonylamino , alkylaminocarbonylamino , alkylcarbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, carbamyl, cyano-alkyl, alkoxyalkyl, dialkylamino, dialkylcarbamyl, haloalkoxy, haloalkyl, ester, ether, acetal, thioacetal, ketal, thioketal, carbamate or carbonate; optionally R1 with R2 or R2 with R3 or R3 with R4 or R4 with R5 or R with R’ forms together a cyclic ring which may be further substituted; or optionally Rl’ with R2’ or R2’ with R3’ or R3’ with R4’ or R4’ with R5’ forms together a cyclic ring which may be further substituted.

[0110] The present invention relates to a Bisguaiacol based compound of Formula IA, or stereoisomer, racemate, and pharmaceutically acceptable salts thereof, represented as:

[0111] Formula IA wherein Rl, R2, R4, R5, Rl’, R2’, R4’, R5’, R &R’are same as defined above.

[0112] The present invention relates to a Bisguaiacol based compound of Formula IB, or stereoisomer, racemate, and pharmaceutically acceptable salts thereof, represented as:

[0113] Formula IB wherein Rl, R2, R4, R5, Rl’, R2’, R3’, R5’, R & R’ are same as defined above. The present invention relates to a Bisguaiacol based compound of Formula IC, or stereoisomer, racemate, and pharmaceutically acceptable salts thereof, represented as:

[0114] Formula IC wherein Rl, R2, R4, R5, Rl’, R2’, R3’, R4’, R & R’ are same as defined above.

[0115] The present invention relates to a process for the preparation of said Bisguaiacol based compound of Formula I and / or one or more of Formula IA, Formula IB or Formula IC thereof, or stereoisomer, racemate, and pharmaceutically acceptable salts thereof, the process comprising the steps of: a) stirring and reacting (un)substituted Guaiacol based compound(s) of Formula A and / or B with aldehyde / ketone compound of Formula C in a solvent and optionally under pressure in the range of 5 to 15 bar,

[0116] 9 9

[0117] Formula A Formula B Formula e in presence of a heterogenous catalyst at aspeed in the range of 300 to 1000 RPM, and a temperature in the range of 35-105°C, for a time period of 1-8 hrs to obtain compound of Formula I, IA, IB, IC or mixture thereof, and b) optionally separating and purifying the compound of Formula I, IA, IB, IC or mixture thereof of step (I) to obtain pure compounds of Formula I, IA, IB and / or IC; wherein the Rl, R2, R3, R4, R5, Rl’, R2’, R3’, R4’, R5’, A, B, B’, B”, B’”, B””, R & R’ are same as defined above.

[0118] The compound of Formula I, IA, IB and / or IC is selected from the group consisting of:

[0119]

[0120] The yield of compound of Formula I, IA, IB and / or IC alone or in mixture form is in range of 40 to 85%.

[0121] The conversion rate of both reactants Formula A and Bis of about 100%.

[0122] The selectivity of formation of compounds of Formula I, IA, IB and / or IC alone or in mixture form is in range of 90-98%.

[0123] The compound of Formula A and / or B is selected from guaiacol or substituted guaiacol with substitutions Rl, R2, R3, R4, R5, Rl’, R2’, R3’, R4’, R5’, A, B, B’, B”, B’”, and B””where the substitutions of Formula A and Bare same as defined above.

[0124] Specifically, the compound of Formula A and / or Formula B is

[0125] The compound of Formula C is selected from aldehyde and ketone with substitutions R and R’ where the substitution R and R’ of Formula C is same as defined above.

[0126] The compound of Formula C is formaldehyde, acetone and acetaldehyde.

[0127] The heterogenous catalyst is selected from 5% w / v of H2SO4, cation exchange resin, anion exchange resin, a macro-porous sulfonic ion exchange acid resin (Amberlyst-15), a strongly acidic cation exchange resin of the sulfonated polystyrene type (Amerlyte IR-120), uniform particle size macroporous anion exchange resins (Dowex 50WX8), Lanxess KI 13 IS, Sn-Mont (montmorillonite clay combined with aqueous solutions of tin salt), Ionic solid, and Lanxess K2649, or mixture thereof.

[0128] The compound of Formula I, IA or IB as synthesized herein is optionally purified by literature methods known to a person skilled in the art e.g. drying, evaporation, concentration methods, chromatographic techniques (conventional or advanced such as column chromatography, flash chromatography, HPLC, etc.) and so on.

[0129] The compound obtained by the process provides single isomeric compound (ee) or mixture of isomeric forms / compounds from a single reaction / process.

[0130] The process for synthesis of compound of Formula I may be done in batch mode or in continuous mode.

[0131] The Lanxess KI 13 IS is a strongly acidic, gel-type, and polymer-based resin in spherical bead form with a very narrow bead size distribution. It is a sulphonic acid functionalized styrenic translucent gel. The particle size of resin is 0.80-1.25 mm.

[0132] The Ionic solid is composed of cation and anion held together by electrostatic force. Here, ionic solid is prepared by using isonicotinic acid treated with chloro sulphonic acid (SO3H-INA).

[0133] The Lanxess K 2649 is a strongly acidic, macroporous, polymer-based resin in spherical bead form, and with sulfonic acid groups. The particle size of resin is 0.40-1.25 mm. Its physical appearance is beige, and opaque.

[0134] The solvent is selected from methanol, acetonitrile, 1,4-dioxane, ethanol, water, and isopropyl alcohol or mixture thereof.

[0135] Specifically, the solvent is acetonitrile.

[0136] Specifically, the temperature of said process is in range of 40-100 °C. More specifically, the temperature of said process is 60 or 90 °C.

[0137] Specifically, the time period covered in said process is in range of 2-8 hrs. More specifically, the time period covered in said process is in range of 5 to 7 hrs. Even more specifically, the time period covered in said process is 6 hrs.

[0138] The pressure in said process is kept in the range of 5 to 15 bars or 5 to 10 bars.

[0139] The amount of catalyst is in the range between 5-20% w / w with respect to guaiacol.

[0140] The process provides mixture of bisguaiacol based compounds with hydroxy substitutions at para-para’ position, para-meta’ position and para-ortho’ position in said Formula I, IA, IB or IC.

[0141] The selectivity of bisguaiacol based compounds of Formula I, IA, IB or IC with parapara’ position is in range of 30-65%, with para-meta’ position is in range of 5-30%, and with para-ortho’ position is in range of 4-10%.

[0142] Specifically, the process covers Lanxess K2649 ion exchange resin as heterogenous catalyst with best results, providing 97% conversion of guaiacol and 100% conversion of formaldehyde with 60% pp-BGF (para-para’), 15% mp-BGF (para-meta’), and 6% op-BGF (para-ortho’).

[0143] The process covers guaiacol and formaldehyde as reactants for synthesis of Bisguaiacol-F based compounds where both the reactants are very cheap with 100% conversion of formaldehyde and 97% conversion of guaiacol at temperature of 90 °C within 6 hrs reaction time, and with 60% pp’-BGF, 15% mp,-BGF, and 6% op,-BGF selectivity.

[0144] It is submitted that the literarure known methods disclose excess guaiacol with vanillin or vanillyl alcohol for their reaction. After reaction that unreacted excess guaiacol separated by vacuum distillation. Guaiacol has high boiling point than other solvents. Therefore, the processing cost is also high. However, in present invention, the inventors have used stoichiometrically required guaiacol and formaldehyde amounts, and they all almost 100% converted to products, in which acetonitrile as a solvent in lesser amount which can be easily separated after reaction.

[0145] The molar ratio ofFormula A or B: Formula C is in range of 1:0.5 to 4:2. Specifically, the ratio is in range of 1:0.5 to 1:2 or 1: 1 to 4: 1.

[0146] The molar ratio of guaiacol: aldehyde / ketone is in range of 1:0.5 to 4:2. Specifically, the ratio is in range of 1:0.5 to 1:2 or 1: 1 to 4:1.

[0147] The predetermined molar ratio of Guaiacol, aldehyde or ketoneand solvent is in the range of 0.5:0.5:0.5 and 4:4:5.

[0148] The present disclosure, the predetermined molar ratio of Guaiacol, aldehyde or kotone and solvent is 1: 1: 1.5.

[0149] The amount / loading of the heterogenous catalyst is in range of 5-20% with respect to the amount ofFormula A (guaiacol).

[0150] The general synthetic scheme for preparation of Formula I is provided herein: wherein Rl, R2, R3, R4, R5, Rl’, R2’, R3’, R4’, R5’, A, B, B’, B”, B’”, B””, R & R’ are same as defined in above embodiment(s).

[0151] The Bisguaiacol-F based compounds of Formula I, IA, IB, IC or mixture thereof are useful or possess application in preparation of various water treatment membranes, biomedical devices, household products, automation component, fuel cell membrane, printed cicuit board, and production of polymers such as polycarbonates, polyesters, polysufonates, and epoxy resins. EXAMPLES

[0152] The following examples are given as a way of illustration only and should not be construed to limit the scope of the present invention.

[0153] Guaiacol and 37 wt% aqueous formaldehyde purchased from Loba Chemie. Resins such as Amberlyst-15, Amberlyte IR-120, Thermax resin, Dowex 50WX8, Lanxess KI 131 IS and Lanxess K2649 were obtained from Sigma- Aldrich, India. Solvents such as methanol, acetonitrile, ethanol, ethyl acetate and petroleum ether and silica gel (230- 400 mesh) were purchased from Chem Labs, India.

[0154] Example 1: General synthesis of compounds of Bisguaiacol F (falls under Formula I, IA, IB and / or IC) in batch mode:

[0155] A mixture of guaiacol (10g, 0.080 mole), formaldehyde (6.5g 0.080 mole) and acetonitrile as a solvent (6ml) with acidic catalyst (1g) stirred for 6 h at 90 °C in autoclave reactor. The reaction mixture was filtered and catalyst was separated. Extract the reaction mixture in ethyl acetate and washed by water and brine solution. Separated organic layer dried over sodium sulphate and evaporate on Rota evaporator. The obtained crude reaction products were separated and purified by column chromatography using petroleum ether and ethyl acetate mixture (v / v) as an eluent.

[0156] Table 1: Optimization and preference of catalysts

[0157] Table 2: Optimization and preference of solvents

[0158] Reaction optimization for synthesis of Bisguaiacol-F (falls under Formula I, IA, IB and / or IC of the present invention):

[0159] 1) Effect of molar ratio: The effect of molar ratio was studied in two different mode.

[0160] In first case, inventors used guaiacol 1 mole and formaldehyde concentration varies between 0.5 - 2 moles (Figure la). In other case, inventors used formaldehyde 1 mole and guaiacol concentration varies between 1-4 moles (Figure lb). From this study, it is revealed that maximum conversion of reactants as well as product selectivity obtained by taking guaiacol: Ibnnaldchydc (1:1) molar ratio.

[0161] Example 2: General synthesis of compounds of Bisguaiacol A (falls under Formula I, IA, IB and / or IC) in batch mode:

[0162] A mixture of guaiacol (15g, 0.120 mol), acetone (13.93g, 0.240 mol), nitrogen pressure (5 bar) and acidic catalyst (1.5g) stirred for 7 h at 60 °C in autoclave reactor. The reaction mixture was filtered and catalyst was separated. Extract the reaction mixture in ethyl acetate and washed by water and brine solution. Separated organic layer dried over sodium sulphate and evaporate on Rota evaporator.

[0163] Example 3: General synthesis of compounds of Bisguaiacol E:

[0164] A mixture of guaiacol (15g, 0.120 mol), acetaldehyde (5.286g, 0.120 mol), nitrogen pressure (5 bar) and acidic catalyst (1.5g) stirred for 6 h at 90 °C in autoclave reactor. The reaction mixture was filtered and catalyst was separated. Extract the reaction mixture in ethyl acetate and washed by water and brine solution. Separated organic layer dried over sodium sulphate and evaporate on Rota evaporator.

[0165] 5

[0166] Example 4: General synthesis of compounds of Bisguaiacol P:

[0167] A mixture of guaiacol (15g, 0.120 mol), propionaldehyde (6.96g, 0.120 mol), nitrogen pressure (5 bar) and acidic catalyst (1.5g) stirred for 6 h at 90 °C in autoclave reactor. The reaction mixture was filtered and catalyst was separated. Extract the reaction mixture in ethyl acetate and washed by water and brine solution. Separated organic layer dried over sodium sulphate and evaporate on Rota evaporator.

[0168] Example 5: General synthesis of compounds of Bisguaiacol B: A mixture of guaiacol (15g, 0.120 mol), butyraldehyde (8.65g, 0.120 mol), nitrogen pressure (5 bar) and acidic catalyst (1.5g) stirred for 6 h at 90 °C in autoclave reactor. The reaction mixture was filtered and catalyst was separated. Extract the reaction mixture in ethyl acetate and washed by water and brine solution. Separated organic layer dried over sodium sulphate and evaporate on Rota evaporator.

[0169] Reaction optimization for synthesis of Bisguaiacol- A (falls under Formula I, IA, IB and / or IC):

[0170] 1) Effect of molar ratio: The effect of molar ratio was studied by using guaiacol Imole and acetoneconcentration varies between 1-3 moles (Figure 2). From this study, it is confirmed that maximum conversion of both reactants obtained by taking guaiacol: acetone (1:2) molar ratio.

[0171] 2) Effect of Catalyst loading:To find out the maximum catalyst amount needed to reach maximum conversion of guaiacol and acetone, the effect of catalyst amount in the range between 5-20% w / w with respect to guaiacol was studied (Figure3). With 15% w / w of catalyst, guaiacol conversion reached to 47% and acetone conversion reached to 59%. More than 15% w / w catalyst amount didn’t affect the conversion of guaiacol and acetone. From this study, it is confirmed that maximum 15% w / w catalyst amount is required to reach the maximum conversion of both reactants.

[0172] 3) Effect of Nitrogen pressure: Condensation reaction of guaiacol with acetone was performed in presence of nitrogen pressure.Without nitrogen pressure guaiacol and acetone showed very less conversion. Therefore, we used nitrogen pressure ranging between 5-15 bar. At 5 bar N2 pressure guaiacol and acetone gave maximum conversion (Figure 4).

[0173] Example 5: Characterization data for all synthesized compounds

[0174] Compound Characterization data

[0175] ADVANTAGES OF THE INVENTION:

[0176] • Provide effective preparation of said Bisguaicolbasedcompounds of Formula I, IA, IB, IC or mixture thereof achievinghigher conversion rates and selectivity of upto80-85%, higher yields of upto75-80%.

[0177] • Provides low cost preparation along with high scale production of BGF, mixture of BGF and their different analogues / isomeric forms in a single reaction.

[0178] • Provides process with compounds alternative to toxic and non-preferred bisphenol - A, in a simple and easy manner with higher scalability and tenability.

Claims

We Claim1. A process for preparation of Bisguaiacol based compounds of formula I and / or one or more of formula IA, formula IB or formula IC thereof, or stereoisomer, racemate, and pharmaceutically acceptable salts thereof,Formula IB Formula IC whereinA, B, B’, B”, B’” and B”” are independently selected from -O-, -N-, or absent;Rl, R2, R3, R4 and R5 are independently selected from hydrogen, (un) substituted alkyl (Cl to C21), (un)substituted alkoxy (Cl to C21), (un)substituted aryl (C5-C11), (un)substituted heteroaryl, silyl, alkylsilyl, (un) substituted alkylether, (un)substituted arylether, (un)substituted heteroarylether, (un) substituted alkynyl (C2-C12), (un)substituted alkylene (C2-C12), (un)substituted allyl (C2-C12), (un) substituted cyclic ring (C3-C12), (un) substituted cycloalkyl (C3-C12), heteroalkylene, arylalkyl, heteroarylalkyl, halo, nitro, (un)substitutedalkyl-ether-(un)substitutedaryl, (un)substitutedalkyl- ether-(un)substitutedheteroaryl, (un)substitutedalkyl-ether-(un)substitutedalkyl, (un)substitutedalkyl-thio-(un)substitutedaryl,(un)substitutedalkyl-thio-(un)substitutedheteroaryl, (un)substitutedalkyl-thio- (un)substitutedalkyl, alkylaryl, alkylheteroaryl, alkylalkenyl, alkylalkenylalkyl, arylalkenyl, arylalkenylaryl, heterocycloalkyl, haloalkyl, heteroalkyl, alkylamino, alkoxycarbonyl, alkylcarbonyl, alkylcarbonylamino, alkylsulfonylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, amino sulfonylamino, aminocarbonylamino, alkylamino sulfonylamino,dialkylamino sulfonylamino, alkylaminocarbonylamino, alkylcarbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, carbamyl, cyano-alkyl, alkoxyalkyl, dialkylamino, dialkylcarbamyl, haloalkoxy, haloalkyl, ester, ether, acetal, thioacetal, ketal, thioketal, carbamate or carbonate;Rl’, R2’, R3’, R4’ and R5’ are independently selected from hydrogen, (un) substituted alkyl (Cl to C21), (un)substituted alkoxy (Cl to C21), (un) substituted aryl (C5-C11), (un)substituted heteroaryl, silyl, alkylsilyl, (un) substituted alkylether, (un) substituted arylether, (un)substituted heteroarylether, (un) substituted alkynyl (C2-C12), (un)substituted alkylene (C2-C12), (un)substituted allyl (C2-C12), (un) substituted cyclic ring (C3-C12), (un) substituted cycloalkyl (C3-C12), heteroalkylene, arylalkyl, heteroarylalkyl, halo, nitro, (un)substitutedalkyl-ether-(un)substitutedaryl, (un)substitutedalkyl- ether-(un)substitutedheteroaryl, (un)substitutedalkyl-ether-(un)substitutedalkyl, (un)substitutedalkyl-thio-(un)substitutedaryl,(un)substitutedalkyl-thio-(un)substitutedheteroaryl, (un)substitutedalkyl-thio- (un)substitutedalkyl, alkylaryl, alkylheteroaryl, alkylalkenyl, alkylalkenylalkyl, arylalkenyl, arylalkenylaryl, heterocycloalkyl, haloalkyl, heteroalkyl, alkylamino, alkoxycarbonyl, alkylcarbonyl, alkylcarbonylamino, alkylsulfonylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, amino sulfonylamino, aminocarbonylamino, alkylamino sulfonylamino, dialkylamino sulfonylamino, alkylaminocarbonylamino, alkylcarbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, carbamyl, cyano-alkyl, alkoxyalkyl, dialkylamino, dialkylcarbamyl, haloalkoxy, haloalkyl, ester, ether, acetal, thioacetal, ketal, thioketal, carbamate or carbonate; andR and R’ are independently selected from hydrogen, (un)substituted alkyl (Cl to C21), (un)substituted alkoxy (Cl to C21), (un)substituted aryl (C5-C11), (un) substituted heteroaryl, silyl, alkylsilyl, (un)substituted alkylether, (un) substituted arylether, (un)substituted heteroarylether, (un)substituted alkynyl (C2-C12), (un)substituted alkylene (C2-C12), (un)substituted allyl (C2- C12), (un)substituted cyclic ring (C3-C12), (un)substituted cycloalkyl (C3- C12), heteroalkylene, arylalkyl, heteroarylalkyl, halo, nitro, (un)substitutedalkyl-ether-(un)substitutedaryl, (un)substitutedalkyl-ether- (un)substitutedheteroaryl, (un)substitutedalkyl-ether-(un)substitutedalkyl,(un)substitutedalkyl-thio-(un)substitutedaryl, (un)substitutedalkyl-thio- (un)substitutedheteroaryl, (un)substitutedalkyl-thio-(un)substitutedalkyl, alkylaryl, alkylheteroaryl, alkylalkenyl, alkylalkenylalkyl, arylalkenyl, arylalkenylaryl, heterocycloalkyl, haloalkyl, heteroalkyl, alkylamino, alkoxycarbonyl, alkylcarbonyl, alkylcarbonylamino, alkylsulfonylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, amino sulfonylamino, aminocarbonylamino, alkylamino sulfonylamino, dialkylamino sulfonylamino, alkylaminocarbonylamino, alkylcarbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, carbamyl, cyano-alkyl, alkoxyalkyl, dialkylamino, dialkylcarbamyl, haloalkoxy, haloalkyl, ester, ether, acetal, thioacetal, ketal, thioketal, carbamate or carbonate; optionally R1 with R2 or R2 with R3 or R3 with R4 or R4 with R5 or R with R’ forms together a cyclic ring which may be further substituted; or optionally R1 ’ with R2’ or R2’ with R3’ or R3’ with R4’ or R4’ with R5’ forms together a cyclic ring which may be further substituted; wherein the process comprising the steps of: i. stirring and reacting (un)substituted Guaiacol based compound(s) of formula A and / or B with aldehyde / ketone compound of formula C in a solvent and optionally under nitrogen pressure in the range of 5 to 15 bar, in presence of a heterogenous catalyst at a speed in the range of 300 to 1000 rotation per minute (RPM), and a temperature in the range of 35-105 °C, for a time period of 1-8 hrs to obtain compound of formula I, IA, IB, IC or mixture thereof,Formula A Formula B FormulaCwherein the heterogeneous catalyst is selected from Lanxess KI 13 IS and Lanxess K2649 and LanxessK2629; wherein Lanxess KI 13 IS is a strongly acidic, gel-type, and polymer- based resin in spherical bead form with a very narrow bead size distribution with particle size in the range of 0.80-1.25 mm; and wherein the Lanxess K2649 is a strongly acidic, macroporous, polymer-based resin in spherical bead form, and with particle size in the range of 0.40- 1.25 mm; and optionally separating and purifying the compound of formula I, IA, IB, IC or mixture thereof of step (I) to obtain pure compounds of formula I, IA, IB and / or IC.

2. The process as claimed in claim 1, wherein the compound of formula A and / or B is guaiacol3. The process as claimed in claim 1, wherein the compound of formula C is selected from formaldehyde, acetone and acetaldehyde.

4. The process as claimed in claim 1, wherein the solvent is selected from methanol, acetonitrile, 1,4-dioxane, ethanol, water, and isopropyl alcohol or mixture thereof.

5. The process as claimed in claim 1, wherein the molar ratio of formula A or B: formula C is in range of 1:0.5 to 4:2 and wherein the amount of catalyst is in the range between 5-20% w / w with respect to guaiacol.

6. The process as claimed in claim 1, wherein the compound of formula I, IA, IB and / or IC is selected from the group consisting of:

7. The process as claimed in claim 1, wherein the yield of compound of formula I, IA, IB and / or IC alone or in mixture form is in range of 40 to 85% and wherein the selectivity of formation of compounds of formula I, IA, IB and / or IC alone or in mixture form is in range of 90-98%.

8. The process as claimed in the claim 1, wherein the conversion rate of both reactants formula A and B is 100%.

9. The process as claimed in claim 1, wherein the compound obtained by the process provides single isomeric compound (ee) or mixture of isomeric forms / compounds from a single reaction / process.

10. The process as claimed in claim 1, wherein the process may be done in batch mode or in continuous mode.

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