WO2014174397A2 - Method of synthesis molecules using catalyst and composites thereof - Google Patents
Method of synthesis molecules using catalyst and composites thereof Download PDFInfo
- Publication number
- WO2014174397A2 WO2014174397A2 PCT/IB2014/060537 IB2014060537W WO2014174397A2 WO 2014174397 A2 WO2014174397 A2 WO 2014174397A2 IB 2014060537 W IB2014060537 W IB 2014060537W WO 2014174397 A2 WO2014174397 A2 WO 2014174397A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- catalyst
- molecule
- ing
- coupling
- graphite oxide
- Prior art date
Links
- 239000003054 catalyst Substances 0.000 title claims abstract description 90
- 238000000034 method Methods 0.000 title claims abstract description 66
- 238000003786 synthesis reaction Methods 0.000 title abstract description 23
- 230000015572 biosynthetic process Effects 0.000 title abstract description 22
- 239000002131 composite material Substances 0.000 title description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 36
- 150000005347 biaryls Chemical group 0.000 claims abstract description 30
- 229910002804 graphite Inorganic materials 0.000 claims abstract description 28
- 239000010439 graphite Substances 0.000 claims abstract description 28
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 26
- 238000010168 coupling process Methods 0.000 claims abstract description 26
- 238000005859 coupling reaction Methods 0.000 claims abstract description 26
- 238000010438 heat treatment Methods 0.000 claims abstract description 26
- 230000008878 coupling Effects 0.000 claims abstract description 25
- 239000002904 solvent Substances 0.000 claims abstract description 22
- 239000005740 Boscalid Substances 0.000 claims abstract description 20
- WYEMLYFITZORAB-UHFFFAOYSA-N boscalid Chemical compound C1=CC(Cl)=CC=C1C1=CC=CC=C1NC(=O)C1=CC=CN=C1Cl WYEMLYFITZORAB-UHFFFAOYSA-N 0.000 claims abstract description 20
- 229940118790 boscalid Drugs 0.000 claims abstract description 20
- RMMXLENWKUUMAY-UHFFFAOYSA-N telmisartan Chemical compound CCCC1=NC2=C(C)C=C(C=3N(C4=CC=CC=C4N=3)C)C=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C(O)=O RMMXLENWKUUMAY-UHFFFAOYSA-N 0.000 claims abstract description 16
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 claims abstract description 15
- 150000004820 halides Chemical class 0.000 claims abstract description 15
- 239000002105 nanoparticle Substances 0.000 claims abstract description 13
- 229910052763 palladium Inorganic materials 0.000 claims abstract description 13
- 239000004072 C09CA03 - Valsartan Substances 0.000 claims abstract description 9
- 239000005537 C09CA07 - Telmisartan Substances 0.000 claims abstract description 8
- 229960005187 telmisartan Drugs 0.000 claims abstract description 8
- 229960004699 valsartan Drugs 0.000 claims abstract description 8
- SJSNUMAYCRRIOM-QFIPXVFZSA-N valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SJSNUMAYCRRIOM-QFIPXVFZSA-N 0.000 claims abstract 3
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 claims description 20
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 16
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 16
- -1 haloaryl amine Chemical class 0.000 claims description 15
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 14
- 150000001502 aryl halides Chemical class 0.000 claims description 11
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 8
- 150000002940 palladium Chemical class 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- 150000001412 amines Chemical class 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 2
- 238000006880 cross-coupling reaction Methods 0.000 abstract description 34
- 239000000203 mixture Substances 0.000 description 40
- 239000000758 substrate Substances 0.000 description 19
- 150000001875 compounds Chemical class 0.000 description 11
- 229940079593 drug Drugs 0.000 description 11
- 239000003814 drug Substances 0.000 description 11
- 239000003153 chemical reaction reagent Substances 0.000 description 10
- 239000003638 chemical reducing agent Substances 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 9
- 229940000425 combination drug Drugs 0.000 description 9
- 229910052799 carbon Inorganic materials 0.000 description 8
- 150000002500 ions Chemical class 0.000 description 8
- 239000004094 surface-active agent Substances 0.000 description 8
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 7
- 230000008569 process Effects 0.000 description 7
- 230000002194 synthesizing effect Effects 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 125000003277 amino group Chemical group 0.000 description 6
- 125000000524 functional group Chemical group 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- ACWBQPMHZXGDFX-QFIPXVFZSA-N valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=NN1 ACWBQPMHZXGDFX-QFIPXVFZSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 5
- 125000003118 aryl group Chemical group 0.000 description 5
- 238000006555 catalytic reaction Methods 0.000 description 5
- 230000002411 adverse Effects 0.000 description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 4
- 235000011181 potassium carbonates Nutrition 0.000 description 4
- 238000006069 Suzuki reaction reaction Methods 0.000 description 3
- 230000004075 alteration Effects 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 150000001721 carbon Chemical class 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 230000036647 reaction Effects 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000009834 vaporization Methods 0.000 description 3
- 230000008016 vaporization Effects 0.000 description 3
- YOJKKXRJMXIKSR-UHFFFAOYSA-N 1-nitro-2-phenylbenzene Chemical group [O-][N+](=O)C1=CC=CC=C1C1=CC=CC=C1 YOJKKXRJMXIKSR-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 101100234002 Drosophila melanogaster Shal gene Proteins 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- 235000015076 Shorea robusta Nutrition 0.000 description 2
- 244000166071 Shorea robusta Species 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 229940000406 drug candidate Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 239000011261 inert gas Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000005055 short column chromatography Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- OMNWKPZIFZJANV-UHFFFAOYSA-N 1-(4-chlorophenyl)-2-nitrobenzene Chemical group [O-][N+](=O)C1=CC=CC=C1C1=CC=C(Cl)C=C1 OMNWKPZIFZJANV-UHFFFAOYSA-N 0.000 description 1
- JPBWZIPCMDZOPM-UHFFFAOYSA-N 2-(4-chlorophenyl)aniline Chemical compound NC1=CC=CC=C1C1=CC=C(Cl)C=C1 JPBWZIPCMDZOPM-UHFFFAOYSA-N 0.000 description 1
- ISDBWOPVZKNQDW-UHFFFAOYSA-N 4-phenylbenzaldehyde Chemical compound C1=CC(C=O)=CC=C1C1=CC=CC=C1 ISDBWOPVZKNQDW-UHFFFAOYSA-N 0.000 description 1
- 244000118350 Andrographis paniculata Species 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 238000004873 anchoring Methods 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- QARVLSVVCXYDNA-IDEBNGHGSA-N bromobenzene Chemical group Br[13C]1=[13CH][13CH]=[13CH][13CH]=[13CH]1 QARVLSVVCXYDNA-IDEBNGHGSA-N 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 229940074619 diovan Drugs 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- HQKRONTYTFHUAU-UHFFFAOYSA-N ethyl 3-(4-tert-butylphenyl)-1h-indole-2-carboxylate Chemical compound CCOC(=O)C=1NC2=CC=CC=C2C=1C1=CC=C(C(C)(C)C)C=C1 HQKRONTYTFHUAU-UHFFFAOYSA-N 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- RUZLIIJDZBWWSA-INIZCTEOSA-N methyl 2-[[(1s)-1-(7-methyl-2-morpholin-4-yl-4-oxopyrido[1,2-a]pyrimidin-9-yl)ethyl]amino]benzoate Chemical group COC(=O)C1=CC=CC=C1N[C@@H](C)C1=CC(C)=CN2C(=O)C=C(N3CCOCC3)N=C12 RUZLIIJDZBWWSA-INIZCTEOSA-N 0.000 description 1
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Substances [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 230000001473 noxious effect Effects 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- QARVLSVVCXYDNA-UHFFFAOYSA-N phenyl bromide Natural products BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 239000010970 precious metal Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000009877 rendering Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 238000006276 transfer reaction Methods 0.000 description 1
- 229910052724 xenon Inorganic materials 0.000 description 1
- FHNFHKCVQCLJFQ-UHFFFAOYSA-N xenon atom Chemical compound [Xe] FHNFHKCVQCLJFQ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J23/00—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00
- B01J23/38—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of noble metals
- B01J23/40—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of noble metals of the platinum group metals
- B01J23/44—Palladium
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B37/00—Reactions without formation or introduction of functional groups containing hetero atoms, involving either the formation of a carbon-to-carbon bond between two carbon atoms not directly linked already or the disconnection of two directly linked carbon atoms
- C07B37/04—Substitution
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C1/00—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon
- C07C1/32—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon starting from compounds containing hetero-atoms other than or in addition to oxygen or halogen
- C07C1/321—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon starting from compounds containing hetero-atoms other than or in addition to oxygen or halogen the hetero-atom being a non-metal atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/26—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton
- C07C17/263—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton by condensation reactions
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C25/00—Compounds containing at least one halogen atom bound to a six-membered aromatic ring
- C07C25/18—Polycyclic aromatic halogenated hydrocarbons
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
-
- 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
- C07C37/11—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by reactions increasing the number of carbon atoms
- C07C37/18—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by reactions increasing the number of carbon atoms by condensation involving halogen atoms of halogenated compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/30—Preparation of ethers by reactions not forming ether-oxygen bonds by increasing the number of carbon atoms, e.g. by oligomerisation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/353—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by isomerisation; by change of size of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
- C07D213/16—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing only one pyridine ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/30—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/04—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/08—Radicals containing only hydrogen and carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/08—Hydrogen atoms or radicals containing only hydrogen and carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/22—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains four or more hetero rings
Definitions
- the present subject matter relates to a method of synthesis of molecules using catalyst. More specif ically the subject matter relates to the method of synthesis of molecules through cross-coupling reaction that employs catalyst. The present subject matter further relates to the molecules and composites thereof.
- Cross-coupling reactions are used to synthesize molecules. Some cross coupling reactions produce core molecules such as biaryl cores and other core moieties. Pharmaceutical industry is spending tremendous amount of money for developing such core moieties as multiple billions of dollars of business is observed per year around drug candidates such as valsartan, telmisartan, agrochemical agent boscalid and selective PPARy modulator (SPPARMy) that involve such core moieties.
- SPPARMy selective PPARy modulator
- Presently the use of noxious phosphine based palladium catalyst is considered as a viable route for preparation of core moieties of a number of drug molecules.
- Cross-coupling reaction that employs a catalyst for synthesizing a molecule is generally homogeneous catalytic reaction that takes place in a reaction mixture. Because, the catalyst is homogeneously mixed in the reaction mixture, separating the catalyst from the reaction mixture is difficult thereby making it difficult to claim and employ the catalyst for further cross-coupling. Furthermore, both the molecules as well as the catalysts used in such reactions often get contaminated during the reactions and therefore, the reaction renders the catalyst unusable for further cross-coupling reactions and produce a poor quality molecule. This is a big disadvantage especially when the catalysts are employed to obtain pharmaceutically important molecules, which require the molecules to be substantially free of any impurities.
- the present subject matter provides solut ion to the above and other problems.
- the subject matter provides a method of synthesis of molecules.
- the method provides a cross-coupling reaction that results into a substantially heterogeneous reaction mixture and therefore, the molecule and the catalyst remain substantially separable and substantially non-contaminated after the synthesis. Therefore, the catalyst claimed after the synthesis of the molecules may be reusably employed in further synthesis.
- the present subject matter provides a method for obtaining a catalyst that is substant ial ly free of any surfactants, reagents, and/or reducing agents.
- the catalyst has carbon derivat ive and anchored nanopart icles on the carbon derivat ive.
- the catalyst is developed without introducing any surfactants, reagents and/or reducing agents. Therefore, undesired effects on the structure and characterist ics of the catalyst caused due to introduct ion of surfactants, reagents and/or reducing agents are substant ial ly avoided.
- the catalyst has demonstrated its reusability across mult iple the cross-coupling react ions.
- the environment and temperature at which the cross-coupl ing react ion takes place are selected such that the catalyst retains its most of the characterist ics and therefore, renders itself reusable in further cross-coupling react ions.
- a method to synthesize a molecule employs a catalyst for a cross-coupling react ion.
- the catalyst is obtained by d ispersing a carbon derivat ive and a second compound in a solvent to obtain a mixture, wherein the second compound is a salt of a metal; and heat ing the mixture to alter chemical nature of the second compound and to form the catalyst, wherein the catalyst includes nanopart icles of the metal anchored with the carbon derivate.
- the temperature to heat the mixture is selected from a range of temperature, wherein the range has a f irst temperature and a second temperature. The f irst temperature is higher than a temperature at which chemical nature of the second compound is altered begins and the second temperature is lower than the temperature at which the carbon derivat ive begins to deform. The first temperature is lower than the second temperature.
- a method provides: mixing boronic acid, hal ide, a catalyst having graphite oxide supported pal lad ium nanopart icles, a solvent and a base and coupling boronic acid and halide by heat ing, wherein, heat ing includes heat ing at a temperature lower than the temperature at which the graphite oxide deforms and the coupling is substant ial ly heterogeneous catalyt ic coupl ing and wherein the coupl ing provides a biaryl core.
- the catalyst is formed by heat ing graphite oxide and pal lad ium salt at a temperature that alters chemical nature of the pal lad ium salt, while maintaining structural order of the graphite oxide substant ial ly unaltered.
- the catalyst employs graphite oxide and pal lad ium salt in the rat io of 2:1.
- the halide is an aryl hal ide and the boronic acid is phenyl boronic acid.
- the solvent is any one of d ioxane and isopropanol.
- the base is any one of sod ium methoxide and potassium carbonate.
- the method comprises subject ing the biaryl core to further coupling to obtain any one of boscalid, telmisartan, valsartan, and SPPARMy molecule.
- the hal ide is a haloaryl amine and the biaryl core has an amine group.
- the method further comprises, subject ing the biaryl core with amine to amine-acid chloride coupl ing using 2-nicot inyl chloride to obtain boscalid.
- the present subject matter provides a molecule obtained by coupl ing boronic acid and hal ide in presence of a catalyst having graphite oxide supported pal lad ium nanopart icles, a solvent and a base and by heat ing, wherein, heat ing includes heat ing at a temperature lower than the temperature at which the graphite oxide deforms, and wherein the coupl ing is substant ial ly heterogeneous catalyt ic coupling, wherein the molecule is a biaryl core.
- the hal ide is an aryl halide and the boronic acid is phenyl boronic acid.
- the solvent is any one of d ioxane and isopropanol.
- the base is any one of sod ium methoxide and potassium carbonate.
- the method further comprises subject ing the biaryl core to further coupling to obtain any one of boscalid, telmisartan, valsartan, and SPPARMy molecule.
- the halide is a haloaryl amine and coupling provides a biaryl core having an amine group.
- the method further comprises, subject ing the biaryl core to amine-acid chloride coupl ing using 2-nicot inyl chloride to obtain boscalid.
- the catalyst and a substrate are combined.
- the substrate may include more than one compound.
- the catalyst and the substrates are further provided with a base.
- the combinat ion is then suppl ied with a solvent to obtain a first mixture.
- the first mixture is then heated. Heat ing the first mixture init iates the cross-coupl ing react ion.
- the heat ing of the first mixture is control led such that the temperature of the first mixture is raised high enough to begin the cross- coupling react ion, but is kept lower than a temperature at which the carbon derivat ive of the catalyst deforms.
- the environment for the cross-coupling react ion is selected in such a way that the molecule is synthesized without adversely affect ing the catalyst and therefore, the catalyst retains most of its characterist ics and therefore may be reused in further cross- coupling react ions as catalyst.
- the environment has nitrogen, in some other examples, the environment has inert environment, and in some further examples, the environment has air.
- Cross-coupled molecule and the catalyst may be then separated.
- the catalyst may be separated through a membrane paper.
- the separated catalyst may be used for further cross-coupling react ions.
- FIG. 1 shows a schemat ic d iagram of a graphite oxide structure
- FIG. 2 shows representat ive core molecules and drug complexes thereof
- FIG. 3a and FIG. 3b show a TABLE 1 and TABLE 2 respect ively;
- FIG. ⁇ shows a schemat ic d iagram accord ing an embod iment of a method of the present subject matter
- FIG. a and FIG. b shows more detailed d iagrams of the method of the present subject matter
- FIG. 5 shows a l ist of solvents, bases, environment cond it ions and temperatures accord ing to an aspect of the present subject matter
- FIG. 6a and FIG. 6b show TABLE and TABLE 5 respect ively that l ist various combinat ions of molecules that may be obtained by the method of present subject matter;
- FIG. 7a and FIG. 7b show TABLE 6 and TABLE 7 respect ively that l ist various combinat ions of molecules that may be obtained by the method of present subject matter.
- FIG. 8a, FIG. 8b and FIG. 8c show graphs of percentage isolated yield obtained upon employing the catalyst recyclably accord ing to the present subject matter
- FIG. 9 shows a TABLE 8 that lists a number of examples accord ing to which intermed iate molecules of some top sel l ing drug cand idates may be obtained accord ing to present subject matter.
- FIG. 10 shows a route normal ly adapted by the industry for synthesizing boscalid and the route accord ing to the present subject matter.
- FIG. 1 shows a schemat ic d iagram of structure of a graphite oxide.
- FIG. 1 shows representat ive funct ion groups 101, 103, 105, 107 and 109.
- the funct ional groups 103 and 107 demonstrate somewhat similar behavior.
- FIG. 2 shows some core molecules and drug complexes thereof.
- the core molecule 2'-(4,4-d imethyl-4,5-d i hydrooxazol-2-yl)biphenyl-4-carbaldehyde is used to form drug complex telmisartan.
- the core molecule (S)-methyl 2-((2'-(iH-tetrazol-5-yl)biphenyl-4- yl)methylamino)-3-methyl butanoate may be used to form drug complex valsartan.
- the core molecule 4'-chloro-2-nitrobiphenyl may be used to form the drug complex boscalid.
- the core molecule ethyl 3-(4-tert-butylphenyl)-iH-indole-2-carboxylate may be used to form the drug complex SPPARMy etc.
- the drug complex telmisartan is being developed by a company Boehringer under brand name Micard is.
- the drug complex valsartan is developed by company Novart is under brand name Diovan.
- the drug complex boscalid is developed by company BASF.
- the drug complex SPPARMy is being developed by company GlaxoSmithKl ine etc.
- FIG. 3a and FIG. 3b show TABLE 1 and TABLE 2, respect ively.
- FIG. ⁇ shows a schematic diagram according an embodiment of a method 400 of the present subject matter.
- the method 400 provides obtaining a catalyst substantially free of surfactants, reagents and/or reducing agents.
- the method 400 provides synthesizing a molecule using the catalyst.
- FIG a shows the block 401 of the method 400 in more details.
- the carbon derivative and a second compound is dispersed in a solventto obtain a mixture.
- the second compound is a salt of the metal.
- the carbon derivative is graphite oxide and second compound is palladium acetate.
- the block 91 is performed in the substantially inert environment.
- the block 91 may include a block 411, a block 421, a block 31, and a block 93.
- the graphite oxide and palladium acetate are mixed in a substantially inert environment.
- the substantially inert environment removes active or reactive elements.
- elements such as oxygen and moisture are removed from the substantially inert environment.
- the substantially inert environment comprises any one or more of vacuum, nitrogen, argon, xenon and a substantially inert gas.
- graphite oxide and palladium acetate are dispersed in a solvent to obtain the mixture.
- the solvent is toluene.
- the mixture is exposed to ultrasonic exposure to substantially uniformly distribute the graphite oxide and palladium acetate.
- some part of the palladium acetate may get dissolved in the toluene.
- the block 401 includes a block 93.
- the block 93 may be included with the block 91.
- the mixture is heated to alter the chemical nature of the palladium acetate.
- the alteration is performed by introducing reagents and/or reducing agents, however, according to the method 401 the alteration is performed by heating the mixture. This ensures that structure and the characteristics of the catalyst are not adversely affected by the reagents and/or reducing agents, which often degrade the quality of the catalyst by affecting adversely the functional groups (101, 103, 105, 107 and 109 shown in
- a temperature for heating the mixture is selected from a range of temperature, wherein the temperature is between a first temperature and the second temperature.
- the first temperature is higher than the temperature at which the chemical alteration of the second compound takes place and the second temperature is lower than the temperature at which the carbon derivat ive deforms.
- the catalyst is formed by heat ing the mixture for a predetermined t ime, the t ime is determined based on the volume of the mixture.
- the catalyst which may be Graphite Oxide having anchored Pal lad ium Nanopart icles GO-PdNPs, at block 95, is extracted from the mixture.
- FIG. shows block 403 of FIG. in more details.
- the block 03 comprises a block 13, at block 13 the catalyst and a substrate are combined to obtain a combinat ion.
- the substrate may include more than one compound or component.
- the catalyst and the substrates are further provided with a base to obtain a combinat ion.
- the combinat ion is suppl ied to a solvent to obtain a f irst mixture.
- the f irst mixture is then heated. Heat ing the first mixture init iates the cross- coupling react ion.
- the heat ing of the first mixture is control led such that the temperature of the first mixture is raised high enough to begin the cross-coupl ing react ion, but is kept lower than a temperature at which the carbon derivat ive of the catalyst deforms. Heat ing is performed for a predetermined t ime, the t ime is determined based on the volume of the mixture at the above selected temperature.
- the cross-coupled molecule and the catalyst are separated from the first mixture.
- the separated catalyst may be employed in synthesis of further molecules.
- the method 400 or a part thereof is performed in a vacuum or nitrogenous environment, or a substant ial ly inert environment to remove oxygen and moisture and other react ive elements from the combinat ion.
- the catalyst is reusably employed in the cross-coupling react ion.
- the method 400 is performed in a control led environment.
- the controlled environment is nitrogenous.
- the control led environment has an inert gas.
- the control led environment has air.
- the substrate is aryl halide.
- the substrate is bromobenzene.
- the other substrate is a boronic acid.
- the other substrate is phenyl boronic acid.
- the base is sod ium methoxide.
- the substrate is a combinat ion of aryl halide, phenyl boronic acid.
- the base is potassium carbonate, K 2 C0 3 .
- the solvent is isopropanol.
- the solvent is d ioxane.
- FIG. 5 shows TABLE 3 which l ists a number of solvents and bases with respect ive environment cond it ions and temperature that may be employed for cross coupling react ion accord ing to an aspect of the present subject matter.
- the catalyst may be resuably employed for many cycles for obtaining the molecule using cross-coupling react ions.
- the catalyst is developed without introducing any surfactants, reagents and/or reducing agents. Should the surfactants, reagents and/or reducing agents be introduced during the synthesis of the catalyst, a number of funct ional groups of the graphite oxide gets consumed by the surfactants, reagents and/or reducing agents therefore, reducing the number of funct ional groups available for anchoring the pal lad ium nanopart icles.
- the present subject matter provides that the object ive of introducing surfactants, reagents and/or reducing agents may be achieved without introducing them by control l ing the environment and the temperature during the synthesis of the catalyst. Thereby obtaining a higher quality catalyst.
- the quality of the catalyst remains substant ial ly unaffected because of availabil ity of a large number of funct ional groups. That is during the cross-coupling react ions, a number of bond that anchor the pal lad ium nanopart icles to the graphite oxide may break, however, because a large number of funct ional groups are available, new bonds may form to anchor the pal lad ium nanopart icles and therefore creat ing a macro-cycl ic effect and leaving the catalyst substant ial ly unaffected in terms of quality beyond the cross-coupl ing react ion and hence enabling reuse of the catalyst for further react ions. Furthermore, because the catalyst of the present subject matter does not get d issolved in the solvent during the cross-coupling react ion, it becomes relat ively easy to extract the catalyst after the react ion is complete and the molecule is formed.
- the method of the present subject matter shal l be described in more details.
- the method may be employed to obtain a molecule of biaryl using aryl hal ide and phenyl boronic acid as substrates, sod ium methoxide as base and d ioxane as solvent and GO-PdNPs as catalyst.
- the fol lowing equat ion shows the react ion.
- the method may be performed in a Schlenk flask.
- GO-PdNPs catalyst of about 10 mg is taken.
- the GO-PdNPs is obtained by the method described above.
- the GO-PdNPs is mixed with substrates, aryl haiide (1 mmol) and phenyl boronic acid (1.5 mmol); and base NaOMe (2 mmol).
- the mixture is subjected to high vacuum. The vacuum removes oxygen, moisture and other volat ile react ive elements from the mixture.
- the mixture may be subjected to vacuum for about one hour; the t ime however may be decided based on the quant ity of the mixture.
- the dry d ioxane (5 mL) is added to the mixture under N2 atmosphere fol lowed by the add it ion of l iquid substrates (if any) in the requisite amounts.
- the d ioxane d issolves aryl haiide, phenyl boronic acid and part ial ly d issolves sod ium methoxide. Nitrogen creates substant ial ly inert environment.
- l iquid substrates may be added to the mixture after a nitrogenous environment is created.
- the mixture is then heated at about 100 degree Celsius for about 24 hours under nitrogenous environment.
- the t ime for heat ing the mixture may be determined based on quant ity of the mixture.
- the temperature at which the mixture is heated is determined based on the temperature at which cross-coupl ing react ion starts but the temperature is kept below the temperature at which the structure of the catalyst deforms.
- the catalyst and biaryl molecule are extracted, by cooling the mixture at room temperature, filtrat ion using a membrane paper and washing of the react ion mixture and the desired biaryl molecule is then purified employing vaporizat ion under reduced pressure and short column chromatography (silica gel 100-200 mesh) etc.
- FIG. 6a and FIG. 6b show TABLE and TABLE 5 respect ively.
- the method may be employed to obtain a molecule of biaryl using aryl haiide and phenyl boronic acid as substrates, potassium carbonate as base, isopropanol as solvent and GO-PdNPs as cata
- the following equation shows the reaction.
- the catalyst (GO-PdNPs) (10 mg), aryl halide (1 mmol), boronic acid (1.5 mmol), K2CO3 (2 mmol) and isopropanol (5 mL) are combined to obtain a mixture and refluxed at about 90 °C for 24 hour.
- the time for boiling may be determined based on the quantity of the mixture.
- isopropanol boils and initiates the catalytic reaction.
- the mixture is then cooled at room temperature.
- the catalyst may be extracted employing filtration through a membrane paper and washing of the reaction mixture and the desired biaryl molecule may be then purified employing vaporization under reduced pressure and short column chromatography (silica gel 100-200 mesh).
- FIG.7a and FIG.7b show TABLE 6 and TABLE 7, respectively.
- the TABLE 6 and TABLE 7 list various combinations of molecules that may be obtained by the method of present subject matter.
- catalyst may be recyclably employed to obtain the molecule.
- FIG.8a, FIG.8b and FIG.8c show graphs of the percentage isolated yield obtained upon employing the catalyst recyclably in the cross-coupling reaction. The graphs demonstrate that the catalyst remains active for a number of cycles.
- FIG.8a corresponds to the following catalytic reaction.
- FIG.8b corresponds to the following catalytic reaction.
- FIG.8c corresponds to the following catalytic reaction.
- the subject matter may be employed for obtaining active intermediate molecules.
- FIG. 9 shows TABLE 8 that lists a number of examples according to which intermediate molecules may be obtained according to present subject matter.
- the subject matter provides a method of synthesis of boscalid.
- the method according to this aspect takes advantage of the robustness of the catalysts and provides a cost effective and safe solution for synthesis of boscalid.
- FIG.10 shows a route normally adapted by the industry for synthesizing boscalid and the route according to the present subject matter.
- haloaryl amine instead of using haloaryl amine, the industry employs mult i step processes for synthesis of molecules such as boscal id avoid ing haloaryl amine as substrate for the cross-coupl ing.
- the haloaryl nitrobenzene is used instead of haloaryl amine for the Suzuki coupl ing react ion to obtain nitrobiphenyl.
- the nitrobiphenyl is then hydrogenated to obtain the respect ive biaryl that has an amine group as shown above.
- the hydrogenat ion process is expensive and environmental ly unfriend ly.
- the biaryl containing the amine group is subjected to amine-acid chloride coupl ing react ion with 2-nicot inyl chloride. Further this process is cumbersome, mult i-step and mult i- pot process.
- the catalyst of the present subject matter shows robustness even with haloaryl amine and therefore may produce the boscalid d irectly by employing the haloaryl amine in the Suzuki coupling react ion removing the requirement of the expensive and hazardous step of hydrogenat ion as shown in the above react ion.
- the catalyst of the present subject matter not only remains substant ial ly unaltered during the coupling process even with aryls such as haloaryl amines but also shows reusabil ity.
- the one-pot synthesis of boscalid may be accomplished by introducing 2-nicot inyl chloride after the cross-coupling react ion is complete.
- the method may yield about 67% of isolated boscalid.
- the GO-PdNPs may be used for number of consecut ive cycles in cross-coupling react ion of haloaryl amine and boronic acid to achieve quant itat ive yield of 4'- chlorobiphenyl-2-amine. The result of which are shown in FIG. 8c.
- yield -I represent yield from reaction condition: Pd(OAc)2 (2.2 mg), aryl halide (1 mmol), boronic acid (1.5 mmol) and base (2 mmol) reacted in 5 mL of solvent under appropriate condition. And yield -II show yields according to present subject matter. It clears from the above table that the present subject matter results in better yields.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Catalysts (AREA)
Abstract
A method to synthesis molecules is provided. The method employs a catalyst for a cross- coupling react ion to obtain the molecule. The method comprises coupling boronic acid and halide in presence of the catalyst having graphite oxide supported palladium nanoparticles, a solvent and a base by heating. The heating is performed at a temperature lower than the temperature at which the graphite oxide deforms. The molecule is a biaryl. The method further provides obtaining complexs such as boscalid, telmisartan, valsartan, and SPPARMγ.
Description
"METHOD OF SYNTHESIS OF MOLECULES USING CATALYST AND COMPOSITES
THEREOF"
CROSS-REFERENCE
[001] The subject matter of the research article Dr. Swadhin Mandal et.al, Palladium Nanoparticles on Graphite Oxide: A Recyclable Catalyst for the Synthesis of Biaryl Cores published in ACS Catal., 2013, 3 (12), pp 2776-2789 is incorporated in this specification by reference. The subject matter of Indian Patent Application Number 464/KOL/2013 and corresponding International Patent Application number PCT/IB2014/060463 are incorporated in this specification by reference.
TECHNICAL FIELD
[002] The present subject matter relates to a method of synthesis of molecules using catalyst. More specif ically the subject matter relates to the method of synthesis of molecules through cross-coupling reaction that employs catalyst. The present subject matter further relates to the molecules and composites thereof.
BACKGROUND
[003] Cross-coupling reactions are used to synthesize molecules. Some cross coupling reactions produce core molecules such as biaryl cores and other core moieties. Pharmaceutical industry is spending tremendous amount of money for developing such core moieties as multiple billions of dollars of business is observed per year around drug candidates such as valsartan, telmisartan, agrochemical agent boscalid and selective PPARy modulator (SPPARMy) that involve such core moieties. Presently the use of noxious phosphine based palladium catalyst is considered as a viable route for preparation of core moieties of a number of drug molecules. However, syntheses of such core moieties with the conventional catalysts have hassles like the contamination of precious metals with the product as well as the "use and throw" nature of the catalyst. Thereby adversely affecting the environment. Therefore, there is a need to obviate the above and other disadvantages.
SUMMARY
[004] For the purpose of illustration, following discussion uses a method of synthesis of molecules and composite thereof employing cross-coupling reaction such as Suzuki coupling, only as example. Further, for illustration the discussion uses synthesis of graphite oxide having palladium nanoparticles anchored on it. However, it shall become clear, after reading this specification, that the subject matter may be practiced, without departing from the spirit of the present subject matter, in other cross-coupling reactions.
[005] Cross-coupling reaction that employs a catalyst for synthesizing a molecule is generally homogeneous catalytic reaction that takes place in a reaction mixture. Because, the catalyst is homogeneously mixed in the reaction mixture, separating the catalyst from the reaction mixture is difficult thereby making it difficult to claim and employ the catalyst for further cross-coupling. Furthermore, both the molecules as well as the catalysts used in such reactions often get contaminated during the reactions and therefore, the reaction renders the catalyst unusable for further cross-coupling reactions and produce a poor quality molecule. This is a big disadvantage especially when the catalysts are employed to obtain pharmaceutically important molecules, which require the molecules to be substantially free of any impurities. Furthermore, often the industry observes that employs different catalysts for synthesizing different cross coupled molecules, such as biaryl cores. It may be advantageous and cost effective if a single catalyst enables the synthesis of most varieties of cross-coupled molecules. Further, these methods are often multi-pot, multi-step methods. That is, these method require transfer reaction solution/mixture in many pots and involve a large number of steps. This makes the process of synthesizing these molecules expensive and time consuming.
[006] The present subject matter provides solut ion to the above and other problems. The subject matter provides a method of synthesis of molecules. The method provides a cross-coupling reaction that results into a substantially heterogeneous reaction mixture and therefore, the molecule and the catalyst remain substantially separable and substantially non-contaminated after the synthesis. Therefore, the catalyst claimed after the synthesis of the molecules may be reusably employed in further synthesis.
[007] To achieve above and other objectives, according to one aspect of the present
subject matter provides a method for obtaining a catalyst that is substant ial ly free of any surfactants, reagents, and/or reducing agents. The catalyst has carbon derivat ive and anchored nanopart icles on the carbon derivat ive. Accord ing to one aspect, the catalyst is developed without introducing any surfactants, reagents and/or reducing agents. Therefore, undesired effects on the structure and characterist ics of the catalyst caused due to introduct ion of surfactants, reagents and/or reducing agents are substant ial ly avoided. The catalyst has demonstrated its reusability across mult iple the cross-coupling react ions. Accord ing to an aspect of the subject matter, the environment and temperature at which the cross-coupl ing react ion takes place are selected such that the catalyst retains its most of the characterist ics and therefore, renders itself reusable in further cross-coupling react ions.
[008] Accord ing to an aspect of the present subject matter, a method to synthesize a molecule is provided. The method employs a catalyst for a cross-coupling react ion. The catalyst is obtained by d ispersing a carbon derivat ive and a second compound in a solvent to obtain a mixture, wherein the second compound is a salt of a metal; and heat ing the mixture to alter chemical nature of the second compound and to form the catalyst, wherein the catalyst includes nanopart icles of the metal anchored with the carbon derivate. Accord ing to one aspect, the temperature to heat the mixture is selected from a range of temperature, wherein the range has a f irst temperature and a second temperature. The f irst temperature is higher than a temperature at which chemical nature of the second compound is altered begins and the second temperature is lower than the temperature at which the carbon derivat ive begins to deform. The first temperature is lower than the second temperature.
[009] Accord ing to one aspect, a method provides: mixing boronic acid, hal ide, a catalyst having graphite oxide supported pal lad ium nanopart icles, a solvent and a base and coupling boronic acid and halide by heat ing, wherein, heat ing includes heat ing at a temperature lower than the temperature at which the graphite oxide deforms and the coupling is substant ial ly heterogeneous catalyt ic coupl ing and wherein the coupl ing provides a biaryl core. Accord ing to a further aspect, the catalyst is formed by heat ing graphite oxide and pal lad ium salt at a temperature that alters chemical nature of the pal lad ium salt, while maintaining structural order of the graphite oxide substant ial ly unaltered. Accord ing to yet a further aspect, the catalyst employs graphite oxide and pal lad ium salt in the rat io of 2:1. Accord ing to another aspect, the halide is an aryl hal ide and the boronic acid is phenyl boronic
acid. Accord ing to yet another aspect, the solvent is any one of d ioxane and isopropanol. Accord ing to a further aspect, the base is any one of sod ium methoxide and potassium carbonate. Accord ing to yet a further aspect, the method comprises subject ing the biaryl core to further coupling to obtain any one of boscalid, telmisartan, valsartan, and SPPARMy molecule. Accord ing to yet another further aspect, the hal ide is a haloaryl amine and the biaryl core has an amine group. Accord ing to further aspect, the method further comprises, subject ing the biaryl core with amine to amine-acid chloride coupl ing using 2-nicot inyl chloride to obtain boscalid.
[0010] In another embod iment, the present subject matter provides a molecule obtained by coupl ing boronic acid and hal ide in presence of a catalyst having graphite oxide supported pal lad ium nanopart icles, a solvent and a base and by heat ing, wherein, heat ing includes heat ing at a temperature lower than the temperature at which the graphite oxide deforms, and wherein the coupl ing is substant ial ly heterogeneous catalyt ic coupling, wherein the molecule is a biaryl core. In an aspect, the hal ide is an aryl halide and the boronic acid is phenyl boronic acid. In yet an aspect, the solvent is any one of d ioxane and isopropanol. In another aspect, the base is any one of sod ium methoxide and potassium carbonate. In yet another aspect, the method further comprises subject ing the biaryl core to further coupling to obtain any one of boscalid, telmisartan, valsartan, and SPPARMy molecule. Accord ing to a further aspect, the halide is a haloaryl amine and coupling provides a biaryl core having an amine group. Accord ing to further aspect, the method further comprises, subject ing the biaryl core to amine-acid chloride coupl ing using 2-nicot inyl chloride to obtain boscalid.
[0011] Accord ing to the method, the catalyst and a substrate are combined. In another example, the substrate may include more than one compound. In one opt ion, the catalyst and the substrates are further provided with a base. The combinat ion is then suppl ied with a solvent to obtain a first mixture. The first mixture is then heated. Heat ing the first mixture init iates the cross-coupl ing react ion. The heat ing of the first mixture is control led such that the temperature of the first mixture is raised high enough to begin the cross- coupling react ion, but is kept lower than a temperature at which the carbon derivat ive of the catalyst deforms. The environment for the cross-coupling react ion is selected in such a way that the molecule is synthesized without adversely affect ing the catalyst and therefore, the catalyst retains most of its characterist ics and therefore may be reused in further cross-
coupling react ions as catalyst. In one possibil ity the environment has nitrogen, in some other examples, the environment has inert environment, and in some further examples, the environment has air.
[0012] Cross-coupled molecule and the catalyst may be then separated. In one example, the catalyst may be separated through a membrane paper. The separated catalyst may be used for further cross-coupling react ions.
BRIEF DESCRIPTION OF DRAWINGS
[0013] The subject matter shal l now be described with reference to the accompanying f igures, wherein:
[001 ] FIG. 1 shows a schemat ic d iagram of a graphite oxide structure;
[0015] FIG. 2 shows representat ive core molecules and drug complexes thereof;
[0016] FIG. 3a and FIG. 3b show a TABLE 1 and TABLE 2 respect ively;
[0017] FIG. ^ shows a schemat ic d iagram accord ing an embod iment of a method of the present subject matter;
[0018] FIG. a and FIG. b shows more detailed d iagrams of the method of the present subject matter;
[0019] FIG. 5 shows a l ist of solvents, bases, environment cond it ions and temperatures accord ing to an aspect of the present subject matter;
[0020] FIG. 6a and FIG. 6b show TABLE and TABLE 5 respect ively that l ist various combinat ions of molecules that may be obtained by the method of present subject matter;
[0021] FIG. 7a and FIG. 7b show TABLE 6 and TABLE 7 respect ively that l ist various combinat ions of molecules that may be obtained by the method of present subject matter.
[0022] . FIG. 8a, FIG. 8b and FIG. 8c show graphs of percentage isolated yield obtained upon employing the catalyst recyclably accord ing to the present subject matter;
[0023] FIG. 9 shows a TABLE 8 that lists a number of examples accord ing to which
intermed iate molecules of some top sel l ing drug cand idates may be obtained accord ing to present subject matter; and
[002 ] FIG. 10 shows a route normal ly adapted by the industry for synthesizing boscalid and the route accord ing to the present subject matter.
DETAILED DESCRIPTION
[0025] Before the present subject matter is described in further detail, it is to be understood that the subject matter is not l imited to the part icular embod iments described, and may vary as such. It is also to be understood that the terminology used throughout the preced ing and forthcoming d iscussion is for the purpose of describing part icular embod iments only, and is not intended to be l imit ing. It must be noted that as used herein, the singular forms "a", "an", and "the" include plural references unless the context clearly d ictates otherwise.
[0026] FIG. 1 shows a schemat ic d iagram of structure of a graphite oxide. FIG. 1 shows representat ive funct ion groups 101, 103, 105, 107 and 109. The funct ional groups 103 and 107 demonstrate somewhat similar behavior.
[0027] FIG. 2 shows some core molecules and drug complexes thereof. The core molecule 2'-(4,4-d imethyl-4,5-d i hydrooxazol-2-yl)biphenyl-4-carbaldehyde is used to form drug complex telmisartan. The core molecule (S)-methyl 2-((2'-(iH-tetrazol-5-yl)biphenyl-4- yl)methylamino)-3-methyl butanoate may be used to form drug complex valsartan. The core molecule 4'-chloro-2-nitrobiphenyl may be used to form the drug complex boscalid. The core molecule ethyl 3-(4-tert-butylphenyl)-iH-indole-2-carboxylate may be used to form the drug complex SPPARMy etc. The drug complex telmisartan is being developed by a company Boehringer under brand name Micard is. The drug complex valsartan is developed by company Novart is under brand name Diovan. The drug complex boscalid is developed by company BASF. The drug complex SPPARMy is being developed by company GlaxoSmithKl ine etc.
[0028] FIG. 3a and FIG. 3b show TABLE 1 and TABLE 2, respect ively. The TABLE 1 and
TABLE 2 l ist some of the synthesis processes of molecules and catalysts, synthet ic procedures adapted for synthesizing the respect ive molecules. However the issue of reusabil ity of the catalysts in these examples has not been appropriately addressed.
[0029] FIG. ^ shows a schematic diagram according an embodiment of a method 400 of the present subject matter. According to one aspect, at block 401, the method 400 provides obtaining a catalyst substantially free of surfactants, reagents and/or reducing agents. According to a further aspect of the present subject matter at block 403, the method 400 provides synthesizing a molecule using the catalyst.
[0030] FIG a shows the block 401 of the method 400 in more details. According to one aspect of the block 401, at block 91, the carbon derivative and a second compound is dispersed in a solventto obtain a mixture. The second compound is a salt of the metal. Forthe purpose of this discussion, the carbon derivative is graphite oxide and second compound is palladium acetate. In some embodiments, the block 91 is performed in the substantially inert environment. The block 91, may include a block 411, a block 421, a block 31, and a block 93. At block 411, the graphite oxide and palladium acetate are mixed in a substantially inert environment. Subjecting the mixed carbon derivative and the second compound to the substantially inert environment removes active or reactive elements. In some examples, elements such as oxygen and moisture are removed from the substantially inert environment. In some other examples, the substantially inert environment comprises any one or more of vacuum, nitrogen, argon, xenon and a substantially inert gas. Atthe block 21 graphite oxide and palladium acetate are dispersed in a solvent to obtain the mixture.
Forthe purpose of this discussion, the solvent is toluene. At block 31, the mixture is exposed to ultrasonic exposure to substantially uniformly distribute the graphite oxide and palladium acetate. At block 31, some part of the palladium acetate may get dissolved in the toluene.
The block 401 includes a block 93. In some examples, the block 93 may be included with the block 91. At block 93 the mixture is heated to alter the chemical nature of the palladium acetate. Generally, the alteration is performed by introducing reagents and/or reducing agents, however, according to the method 401 the alteration is performed by heating the mixture. This ensures that structure and the characteristics of the catalyst are not adversely affected by the reagents and/or reducing agents, which often degrade the quality of the catalyst by affecting adversely the functional groups (101, 103, 105, 107 and 109 shown in
FIG.1) of the graphite oxide. Further, a temperature for heating the mixture is selected from a range of temperature, wherein the temperature is between a first temperature and the second temperature. The first temperature is higher than the temperature at which the chemical alteration of the second compound takes place and the second temperature is lower
than the temperature at which the carbon derivat ive deforms. The catalyst is formed by heat ing the mixture for a predetermined t ime, the t ime is determined based on the volume of the mixture. The catalyst, which may be Graphite Oxide having anchored Pal lad ium Nanopart icles GO-PdNPs, at block 95, is extracted from the mixture.
[0031] FIG. shows block 403 of FIG. in more details. The block 03 comprises a block 13, at block 13 the catalyst and a substrate are combined to obtain a combinat ion. In another example, the substrate may include more than one compound or component. In one opt ion, the catalyst and the substrates are further provided with a base to obtain a combinat ion. At block 23 the combinat ion is suppl ied to a solvent to obtain a f irst mixture. At block 33 the f irst mixture is then heated. Heat ing the first mixture init iates the cross- coupling react ion. The heat ing of the first mixture is control led such that the temperature of the first mixture is raised high enough to begin the cross-coupl ing react ion, but is kept lower than a temperature at which the carbon derivat ive of the catalyst deforms. Heat ing is performed for a predetermined t ime, the t ime is determined based on the volume of the mixture at the above selected temperature. At block 3, the cross-coupled molecule and the catalyst are separated from the first mixture. The separated catalyst may be employed in synthesis of further molecules. In some embod iments, the method 400 or a part thereof is performed in a vacuum or nitrogenous environment, or a substant ial ly inert environment to remove oxygen and moisture and other react ive elements from the combinat ion.
[0032] Accord ing to one aspect of the present subject matter, the catalyst is reusably employed in the cross-coupling react ion. Accord ing to a further aspect, the method 400 is performed in a control led environment. In one example, the controlled environment is nitrogenous. In a further example, the control led environment has an inert gas. In some other example, the control led environment has air.
[0033] Accord ing to a further aspect, the substrate is aryl halide. In one example, the substrate is bromobenzene. Accord ing to a further aspect, the other substrate is a boronic acid. In one example, the other substrate is phenyl boronic acid. In one example, the base is sod ium methoxide. In some other example, the substrate is a combinat ion of aryl halide, phenyl boronic acid. In an example, the base is potassium carbonate, K2C03. In one example, the solvent is isopropanol. In some other example, the solvent is d ioxane. FIG. 5 shows TABLE 3 which l ists a number of solvents and bases with respect ive environment cond it ions and
temperature that may be employed for cross coupling react ion accord ing to an aspect of the present subject matter.
[003 ] Accord ing to one aspect of the present subject matter, the catalyst may be resuably employed for many cycles for obtaining the molecule using cross-coupling react ions. The catalyst is developed without introducing any surfactants, reagents and/or reducing agents. Should the surfactants, reagents and/or reducing agents be introduced during the synthesis of the catalyst, a number of funct ional groups of the graphite oxide gets consumed by the surfactants, reagents and/or reducing agents therefore, reducing the number of funct ional groups available for anchoring the pal lad ium nanopart icles. The present subject matter provides that the object ive of introducing surfactants, reagents and/or reducing agents may be achieved without introducing them by control l ing the environment and the temperature during the synthesis of the catalyst. Thereby obtaining a higher quality catalyst.
[0035] During the cross-coupl ing react ion, the quality of the catalyst remains substant ial ly unaffected because of availabil ity of a large number of funct ional groups. That is during the cross-coupling react ions, a number of bond that anchor the pal lad ium nanopart icles to the graphite oxide may break, however, because a large number of funct ional groups are available, new bonds may form to anchor the pal lad ium nanopart icles and therefore creat ing a macro-cycl ic effect and leaving the catalyst substant ial ly unaffected in terms of quality beyond the cross-coupl ing react ion and hence enabling reuse of the catalyst for further react ions. Furthermore, because the catalyst of the present subject matter does not get d issolved in the solvent during the cross-coupling react ion, it becomes relat ively easy to extract the catalyst after the react ion is complete and the molecule is formed.
[0036] The method of the present subject matter shal l be described in more details. Accord ing to one aspect of the present subject matter, the method may be employed to obtain a molecule of biaryl using aryl hal ide and phenyl boronic acid as substrates, sod ium methoxide as base and d ioxane as solvent and GO-PdNPs as catalyst. The fol lowing equat ion shows the react ion.
aryl haiide biaryl
[0037] Accord ing to one aspect, the method may be performed in a Schlenk flask. Accord ing to the method to obtain the biaryl molecule, GO-PdNPs catalyst of about 10 mg is taken. The GO-PdNPs is obtained by the method described above. Accord ing to an aspect, the GO-PdNPs is mixed with substrates, aryl haiide (1 mmol) and phenyl boronic acid (1.5 mmol); and base NaOMe (2 mmol). The mixture is subjected to high vacuum. The vacuum removes oxygen, moisture and other volat ile react ive elements from the mixture. In one embod iment, the mixture may be subjected to vacuum for about one hour; the t ime however may be decided based on the quant ity of the mixture. Accord ing to a further aspect, the dry d ioxane (5 mL) is added to the mixture under N2 atmosphere fol lowed by the add it ion of l iquid substrates (if any) in the requisite amounts. The d ioxane d issolves aryl haiide, phenyl boronic acid and part ial ly d issolves sod ium methoxide. Nitrogen creates substant ial ly inert environment. Further, subject ing the mixture to high vacuum could result into vaporizat ion of l iquid aryl hal ides; therefore, l iquid substrates (aryl hal ides) may be added to the mixture after a nitrogenous environment is created. The mixture is then heated at about 100 degree Celsius for about 24 hours under nitrogenous environment. In some embod iments, the t ime for heat ing the mixture may be determined based on quant ity of the mixture. Furthermore, the temperature at which the mixture is heated is determined based on the temperature at which cross-coupl ing react ion starts but the temperature is kept below the temperature at which the structure of the catalyst deforms. The catalyst and biaryl molecule are extracted, by cooling the mixture at room temperature, filtrat ion using a membrane paper and washing of the react ion mixture and the desired biaryl molecule is then purified employing vaporizat ion under reduced pressure and short column chromatography (silica gel 100-200 mesh) etc.
[0038] FIG. 6a and FIG. 6b show TABLE and TABLE 5 respect ively. The TABLE and
TABLE 5 l ist various combinat ions of molecules that may be obtained by the method of present subject matter.
[0039] Accord ing to one aspect of the present subject matter, the method may be employed to obtain a molecule of biaryl using aryl haiide and phenyl boronic acid as
substrates, potassium carbonate as base, isopropanol as solvent and GO-PdNPs as cata The following equation shows the reaction.
carbonate
[00 0] According to a further embodiment, the catalyst (GO-PdNPs) (10 mg), aryl halide (1 mmol), boronic acid (1.5 mmol), K2CO3 (2 mmol) and isopropanol (5 mL) are combined to obtain a mixture and refluxed at about 90 °C for 24 hour. As discussed above the time for boiling may be determined based on the quantity of the mixture. At about 90 degree Celsius, isopropanol boils and initiates the catalytic reaction. The mixture is then cooled at room temperature. The catalyst may be extracted employing filtration through a membrane paper and washing of the reaction mixture and the desired biaryl molecule may be then purified employing vaporization under reduced pressure and short column chromatography (silica gel 100-200 mesh).
[00 1] FIG.7a and FIG.7b show TABLE 6 and TABLE 7, respectively. The TABLE 6 and TABLE 7 list various combinations of molecules that may be obtained by the method of present subject matter.
[00 2] According to an aspect, catalyst may be recyclably employed to obtain the molecule. FIG.8a, FIG.8b and FIG.8c show graphs of the percentage isolated yield obtained upon employing the catalyst recyclably in the cross-coupling reaction. The graphs demonstrate that the catalyst remains active for a number of cycles.
[00 3] FIG.8a corresponds to the following catalytic reaction.
O
[00 5] FIG.8c corresponds to the following catalytic reaction.
[00 6] According to an aspect of the present subject matter, the subject matter may be employed for obtaining active intermediate molecules.
[00 7] FIG. 9 shows TABLE 8 that lists a number of examples according to which intermediate molecules may be obtained according to present subject matter.
[00 8] According to a further aspect, the subject matter provides a method of synthesis of boscalid. The method according to this aspect, takes advantage of the robustness of the catalysts and provides a cost effective and safe solution for synthesis of boscalid. FIG.10 shows a route normally adapted by the industry for synthesizing boscalid and the route according to the present subject matter.
[00 9] Conventional industrial route for synthesis of boscalid does not employ haloaryl amine for the synthesis of the corresponding biaryl core. This is because, the amine group in haloaryl amine substrate tend to poison the catalyst in the cross-coupling reaction and therefore resulting an inactive catalyst. Therefore, in this process the catalyst is often becomes unusable for further catalytic purposes. This is because of the fact that the amine group of the haloaryl amine substrate preferably coordinates with the active palladium catalyst molecule and thereby rendering the catalyst unstable and also unusable for further
re-process. Therefore, instead of using haloaryl amine, the industry employs mult i step processes for synthesis of molecules such as boscal id avoid ing haloaryl amine as substrate for the cross-coupl ing. In this process, the haloaryl nitrobenzene is used instead of haloaryl amine for the Suzuki coupl ing react ion to obtain nitrobiphenyl. The nitrobiphenyl is then hydrogenated to obtain the respect ive biaryl that has an amine group as shown above. The hydrogenat ion process is expensive and environmental ly unfriend ly. To get the resultant boscalid, the biaryl containing the amine group is subjected to amine-acid chloride coupl ing react ion with 2-nicot inyl chloride. Further this process is cumbersome, mult i-step and mult i- pot process.
[0050] On the other hand, the catalyst of the present subject matter shows robustness even with haloaryl amine and therefore may produce the boscalid d irectly by employing the haloaryl amine in the Suzuki coupling react ion removing the requirement of the expensive and hazardous step of hydrogenat ion as shown in the above react ion. The catalyst of the present subject matter, not only remains substant ial ly unaltered during the coupling process even with aryls such as haloaryl amines but also shows reusabil ity. The one-pot synthesis of boscalid may be accomplished by introducing 2-nicot inyl chloride after the cross-coupling react ion is complete. Accord ing to an aspect, the method may yield about 67% of isolated boscalid. The GO-PdNPs may be used for number of consecut ive cycles in cross-coupling react ion of haloaryl amine and boronic acid to achieve quant itat ive yield of 4'- chlorobiphenyl-2-amine. The result of which are shown in FIG. 8c.
[0051] Further, the below table shows a comparison of yields obtained accord ing to present subject matter and convent ional methods.
[0052] The yield -I represent yield from reaction condition: Pd(OAc)2 (2.2 mg), aryl halide (1 mmol), boronic acid (1.5 mmol) and base (2 mmol) reacted in 5 mL of solvent under appropriate condition. And yield -II show yields according to present subject matter. It clears from the above table that the present subject matter results in better yields.
[0053] While the subject matter may be susceptible to various modifications and alternative forms, specific embodiments have been shown by way of example in the drawings and have been described herein. Alternate embodiments or modifications may be practiced without departing from the spirit of the subject matter. The drawings shown are schematic drawings and may not be to the scale. While the drawings show some features of the subject matter, some features may be omitted. In some other cases, some features may be emphasized while others are not. Further, the methods disclosed herein may be performed in manner and/or order in which the methods are explained. Alternatively, the methods may be performed in manner or order different than what is explained without departing from the spirit of the present subject matter. It should be understood that the subject matter is not intended to be limited to the particular forms disclosed. Rather, the subject matter is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the subject matter as described above.
Claims
1. A method comprising: mixing boronic acid, halide, a catalyst having graphite oxide supported pal lad ium nanopart icles, a solvent and a base and coupling boronic acid and halide by heat ing, wherein, heat ing includes heat ing at a temperature lower than the temperature at which the graphite oxide deforms and the coupling is substant ial ly heterogeneous catalyt ic coupling and wherein the coupling provides a biaryl core.
2. The method of claim ι, wherein the catalyst is formed by heat ing graphite oxide and pal lad ium salt at a temperature that alters chemical nature of the pal lad ium salt, while maintaining structural order of the graphite oxide substant ial ly unaltered.
3. The method of claim 2, wherein the catalyst employs graphite oxide and pal lad ium salt in the rat io of 2:1.
it. The method of claim 1, wherein the hal ide is an aryl halide and the boronic acid is phenyl boronic acid.
5. The method of claim 1, wherein the solvent is any one of d ioxane and isopropanol.
6. The method of claim 1, wherein the base is any one of sod ium methoxide and potassium carbonate.
7. The method of claim 1, further comprising subject ing the biaryl core to further coupling to obtain any one of boscalid, telmisartan, valsartan, and SPPARMy molecule.
8. The method of claim 1, the halide is a haloaryl amine and the biaryl core has an amine.
9. The method of claim 8, further comprising, subject ing the biaryl core to amine-acid chloride coupling using 2-nicot inyl chloride to obtain boscal id.
10. A molecule obtained by coupl ing boronic acid and halide in presence of a catalyst having graphite oxide supported pal lad ium nanopart icles, a solvent and a base and by heat ing, wherein, heat ing includes heat ing at a temperature lower than the temperature at which the graphite oxide deforms, and wherein the coupl ing is substant ial ly heterogeneous catalyt ic coupling, wherein the molecule is a biaryl core.
11. The molecule of claim 10, wherein the hal ide is an aryl hal ide and the boronic acid is phenyl boronic acid.
12. The molecule of claim 10, wherein the solvent is any one of d ioxane and isopropanol.
13. The molecule of claim io, wherein the base is any one of sodium methoxide and potassium carbonate.
14. The molecule of claim io, further comprising subjecting the biaryl core to further coupling to obtain any one of boscalid, telmisartan, valsartan, and SPPARMy molecule.
15. The molecule of claim 10, the halide is a haloaryl amine and coupling provides a biaryl core having an amine.
16. The molecule of claim 10, further comprising, subjecting the biaryl core to amine-acid chloride coupling using 2-Nicotinyl chloride to obtain boscalid.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IN463KO2013 | 2013-04-25 | ||
IN463/KOL/2013 | 2013-04-25 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2014174397A2 true WO2014174397A2 (en) | 2014-10-30 |
WO2014174397A3 WO2014174397A3 (en) | 2015-04-02 |
Family
ID=51792451
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IB2014/060537 WO2014174397A2 (en) | 2013-04-25 | 2014-04-08 | Method of synthesis molecules using catalyst and composites thereof |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2014174397A2 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104478797A (en) * | 2014-12-09 | 2015-04-01 | 苏州至善化学有限公司 | Preparation method of nicotinamide fungicide namely boscalid |
GB2552697A (en) * | 2016-08-04 | 2018-02-07 | Rotam Agrochem Int Co Ltd | Process for the preparation of boscalid |
CN113336631A (en) * | 2021-06-10 | 2021-09-03 | 南开大学 | Application of artificial synthesis palladium nano-enzyme catalysis compound containing phenolic hydroxyl group connection |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
UA107804C2 (en) * | 2009-08-05 | 2015-02-25 | Du Pont | Mixtures of pesticides mezoionnyh |
CN103073489A (en) * | 2013-02-06 | 2013-05-01 | 利民化工股份有限公司 | Preparation method of Boscalid |
-
2014
- 2014-04-08 WO PCT/IB2014/060537 patent/WO2014174397A2/en active Application Filing
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104478797A (en) * | 2014-12-09 | 2015-04-01 | 苏州至善化学有限公司 | Preparation method of nicotinamide fungicide namely boscalid |
GB2552697A (en) * | 2016-08-04 | 2018-02-07 | Rotam Agrochem Int Co Ltd | Process for the preparation of boscalid |
GB2552697B (en) * | 2016-08-04 | 2021-03-10 | Rotam Agrochem Int Co Ltd | Process for the preparation of boscalid |
CN113336631A (en) * | 2021-06-10 | 2021-09-03 | 南开大学 | Application of artificial synthesis palladium nano-enzyme catalysis compound containing phenolic hydroxyl group connection |
CN113336631B (en) * | 2021-06-10 | 2022-12-02 | 南开大学 | Application of artificial synthesis palladium nano-enzyme catalysis compound containing phenolic hydroxyl group connection |
Also Published As
Publication number | Publication date |
---|---|
WO2014174397A3 (en) | 2015-04-02 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Islam et al. | A reusable polymer supported copper catalyst for the C–N and C–O bond cross-coupling reaction of aryl halides as well as arylboronic acids | |
Artok et al. | Heterogeneous Suzuki reactions catalyzed by Pd (0)–Y zeolite | |
Ayogu et al. | Recent advances in transition metal-catalysed cross-coupling of (hetero) aryl halides and analogues under ligand-free conditions | |
Miyamura et al. | Aerobic oxidation of amines catalyzed by polymer-incarcerated Au nanoclusters: Effect of cluster size and cooperative functional groups in the polymer | |
Evangelisti et al. | Palladium nanoparticles supported on polyvinylpyridine: Catalytic activity in Heck-type reactions and XPS structural studies | |
Sharghi et al. | Facile synthesis of 5-substituted-1H-tetrazoles and 1-substituted-1H-tetrazoles catalyzed by recyclable 4′-phenyl-2, 2′: 6′, 2 ″-terpyridine copper (II) complex immobilized onto activated multi-walled carbon nanotubes | |
Liu et al. | Palladium-catalyzed Heck-type domino cyclization and carboxylation to synthesize carboxylic acids by utilizing chloroform as the carbon monoxide source | |
Burgoyne et al. | Knoevenagel condensation reactions catalysed by metal-organic frameworks | |
Ma et al. | A water-soluble dilacunary silicotungstate as an effective catalyst for oxidation alcohols in water with hydrogen peroxide | |
CN107428695A (en) | Method for preparing androgen receptor antagonists and its intermediate | |
Ansari et al. | Cross‐couplings in Water–A Better Way to Assemble New Bonds | |
PT1937407E (en) | Solutions of anhydrous lanthanide salts and its preparation | |
CN104177388B (en) | A kind of bridging bisamide base ytterbium and its preparation method and application | |
WO2014174397A2 (en) | Method of synthesis molecules using catalyst and composites thereof | |
Shah et al. | Supported palladium nanoparticles: A general sustainable catalyst for microwave enhanced carbon-carbon coupling reactions | |
Varala et al. | Cesium salts in organic synthesis: A Review | |
Grant et al. | Synthesis of a hydrophilic naphthalimidedioxime | |
Liu et al. | A simple and novel amide ligand based on quinoline derivative used for palladium-catalyzed Suzuki coupling reaction | |
CN1803760A (en) | N-arylation process with hydrazone as ligand in aqueous phase system | |
JP2005238218A (en) | Palladium catalyst for carbon-carbon bond forming reaction and production method of olefin group-substituted aromatic compound using the palladium catalyst | |
An et al. | An Efficient and Solvent‐Free Reaction for Synthesis of Bis (indol‐3‐yl) methanes Catalyzed by Sulfamic Acid | |
Zhao et al. | Visible light-induced manganese-catalyzed aminocarbonylation of alkyl iodides under atmospheric pressure at room temperature | |
Funel et al. | Diastereospecific enolate addition and atom-efficient benzimidazole synthesis for the production of L/T calcium channel blocker ACT-280778 | |
WO2011020900A2 (en) | A process for preparing biaryl compounds in a suzuki type reaction allowing product isolation and catalyst recycling in one step | |
Yi et al. | Synthesis of RDX by nitrolysis of hexamethylenetetramine in fluorous media |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 14789005 Country of ref document: EP Kind code of ref document: A2 |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 14789005 Country of ref document: EP Kind code of ref document: A2 |