WO2005102976A1 - Process for preparing nonaethylene glycol monomethyl ether - Google Patents
Process for preparing nonaethylene glycol monomethyl ether Download PDFInfo
- Publication number
- WO2005102976A1 WO2005102976A1 PCT/US2005/013392 US2005013392W WO2005102976A1 WO 2005102976 A1 WO2005102976 A1 WO 2005102976A1 US 2005013392 W US2005013392 W US 2005013392W WO 2005102976 A1 WO2005102976 A1 WO 2005102976A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- monomethyl ether
- glycol monomethyl
- ether
- process according
- coupling agent
- Prior art date
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- 238000004519 manufacturing process Methods 0.000 title claims abstract description 11
- VVHAVLIDQNWEKF-UHFFFAOYSA-N nonaethylene glycol monomethyl ether Chemical compound COCCOCCOCCOCCOCCOCCOCCOCCOCCO VVHAVLIDQNWEKF-UHFFFAOYSA-N 0.000 title claims description 20
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 38
- 238000000034 method Methods 0.000 claims description 33
- 230000008569 process Effects 0.000 claims description 29
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 19
- 150000001875 compounds Chemical class 0.000 claims description 18
- 239000007822 coupling agent Substances 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 18
- 238000005984 hydrogenation reaction Methods 0.000 claims description 14
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 12
- WGKYSFRFMQHMOF-UHFFFAOYSA-N 3-bromo-5-methylpyridine-2-carbonitrile Chemical compound CC1=CN=C(C#N)C(Br)=C1 WGKYSFRFMQHMOF-UHFFFAOYSA-N 0.000 claims description 11
- 229920000847 nonoxynol Polymers 0.000 claims description 11
- YWQONRFGUUDRMP-UHFFFAOYSA-N 2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxymethylbenzene Chemical compound COCCOCCOCCOCCOCCOCCOCC1=CC=CC=C1 YWQONRFGUUDRMP-UHFFFAOYSA-N 0.000 claims description 10
- FHHGCKHKTAJLOM-UHFFFAOYSA-N hexaethylene glycol monomethyl ether Chemical compound COCCOCCOCCOCCOCCOCCO FHHGCKHKTAJLOM-UHFFFAOYSA-N 0.000 claims description 10
- GQKZBCPTCWJTAS-UHFFFAOYSA-N methoxymethylbenzene Chemical compound COCC1=CC=CC=C1 GQKZBCPTCWJTAS-UHFFFAOYSA-N 0.000 claims description 10
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 9
- 239000011591 potassium Substances 0.000 claims description 9
- JLGLQAWTXXGVEM-UHFFFAOYSA-N triethylene glycol monomethyl ether Chemical compound COCCOCCOCCO JLGLQAWTXXGVEM-UHFFFAOYSA-N 0.000 claims description 9
- 229960005235 piperonyl butoxide Drugs 0.000 claims description 8
- 229910052700 potassium Inorganic materials 0.000 claims description 8
- SULYUXLJHONROP-UHFFFAOYSA-N 2-[2-(2-phenylmethoxyethoxy)ethoxy]ethyl 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OCCOCCOCCOCC1=CC=CC=C1 SULYUXLJHONROP-UHFFFAOYSA-N 0.000 claims description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 4
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 claims description 4
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 claims description 4
- 229910000105 potassium hydride Inorganic materials 0.000 claims description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 3
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 claims description 3
- 229910052763 palladium Inorganic materials 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- MEUSATKDKDWEPY-UHFFFAOYSA-N 2-[2-(2-phenylmethoxyethoxy)ethoxy]ethyl methanesulfonate Chemical compound CS(=O)(=O)OCCOCCOCCOCC1=CC=CC=C1 MEUSATKDKDWEPY-UHFFFAOYSA-N 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 claims description 2
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 abstract description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 12
- 238000005859 coupling reaction Methods 0.000 description 9
- 239000010410 layer Substances 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 229920001223 polyethylene glycol Polymers 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- KVPHZILZNXDCNH-UHFFFAOYSA-N 2-[2-(2-phenylmethoxyethoxy)ethoxy]ethanol Chemical compound OCCOCCOCCOCC1=CC=CC=C1 KVPHZILZNXDCNH-UHFFFAOYSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 5
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 239000000654 additive Substances 0.000 description 4
- 230000008878 coupling Effects 0.000 description 4
- 238000010168 coupling process Methods 0.000 description 4
- -1 softeners Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000000996 additive effect Effects 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- 235000019341 magnesium sulphate Nutrition 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- QCOJKZNIMJQFAI-UHFFFAOYSA-N 2-[2-(2-chloroethoxy)ethoxy]ethoxymethylbenzene Chemical compound ClCCOCCOCCOCC1=CC=CC=C1 QCOJKZNIMJQFAI-UHFFFAOYSA-N 0.000 description 2
- VVBQKDDPSXBMMZ-UHFFFAOYSA-N 2-[2-[2-[2-[2-(2-phenylmethoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethanol Chemical class OCCOCCOCCOCCOCCOCCOCC1=CC=CC=C1 VVBQKDDPSXBMMZ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- IIRDTKBZINWQAW-UHFFFAOYSA-N hexaethylene glycol Chemical compound OCCOCCOCCOCCOCCOCCO IIRDTKBZINWQAW-UHFFFAOYSA-N 0.000 description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 2
- 238000009434 installation Methods 0.000 description 2
- 239000003607 modifier Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- SZGNWRSFHADOMY-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol Chemical compound COCCOCCOCCOCCOCCOCCOCCOCCO SZGNWRSFHADOMY-UHFFFAOYSA-N 0.000 description 1
- MFGOFGRYDNHJTA-UHFFFAOYSA-N 2-amino-1-(2-fluorophenyl)ethanol Chemical compound NCC(O)C1=CC=CC=C1F MFGOFGRYDNHJTA-UHFFFAOYSA-N 0.000 description 1
- ACCCXSZCOGNLFL-UHFFFAOYSA-N 8-phenyl-3,7-dihydropurine-2,6-dione Chemical class N1C=2C(=O)NC(=O)NC=2N=C1C1=CC=CC=C1 ACCCXSZCOGNLFL-UHFFFAOYSA-N 0.000 description 1
- FIPWRIJSWJWJAI-UHFFFAOYSA-N Butyl carbitol 6-propylpiperonyl ether Chemical compound C1=C(CCC)C(COCCOCCOCCCC)=CC2=C1OCO2 FIPWRIJSWJWJAI-UHFFFAOYSA-N 0.000 description 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
- ZQZPJPHAPLBNCN-UHFFFAOYSA-N NCCOCCOCCOCc1ccccc1 Chemical compound NCCOCCOCCOCc1ccccc1 ZQZPJPHAPLBNCN-UHFFFAOYSA-N 0.000 description 1
- 239000005456 alcohol based solvent Substances 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- OVHDZBAFUMEXCX-UHFFFAOYSA-N benzyl 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OCC1=CC=CC=C1 OVHDZBAFUMEXCX-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000002051 biphasic effect Effects 0.000 description 1
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Inorganic materials [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical compound C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000002778 food additive Substances 0.000 description 1
- 235000013373 food additive Nutrition 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 125000003827 glycol group Chemical group 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 238000005192 partition Methods 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- 239000003444 phase transfer catalyst Substances 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010057 rubber processing Methods 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Classifications
-
- 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
- C07C41/16—Preparation of ethers by reaction of esters of mineral or organic acids with hydroxy or O-metal groups
-
- 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
- C07C41/26—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of hydroxy or O-metal groups
Definitions
- the present invention relates to a novel process for preparing nonaethylene glycol. More specifically, the present invention relates to a process for preparing nonaethylene glycol monomethyl ether.
- the present invention provides a novel process for preparing nonaethylene glycol monomethyl ether.
- the process comprises the steps of: a) reacting a compound of formula (I):
- LG is a suitable leaving group, with triethylene glycol monomethyl ether in the presence of a coupling agent, to prepare hexaethylene glycol monobenzyl monomethyl ether; b) hydrogenating hexaethylene glycol monobenzyl monomethyl ether to prepare hexaethylene glycol monomethyl ether; c) reacting hexaethylene glycol monomethyl ether with a compound of formula (I) in the presence of a coupling agent to prepare nonaethylene glycol monobenzyl monomethyl ether; and d) hydrogenating nonaethylene glycol monobenzyl monomethyl ether to prepare nonaethylene glycol monomethyl ether.
- Polyethylene glycols such as nonaethylene glycol monomethyl ether, are useful in a number of areas, including for example, as plasticizers, softeners, humectants, ointments, polishes, paper coatings, mold lubricants, bases for cosmetics and pharmaceuticals, solvents, binders, metal and rubber processing, food additives, chemical intermediates, phase transfer catalysts, polymer-bound reagents, reagents for binding assays, processes for protein and cell purification, peptide synthesis and as modifiers for a variety of substrates, including pharmaceutically active agents.
- plasticizers such as plasticizers, softeners, humectants, ointments, polishes, paper coatings, mold lubricants, bases for cosmetics and pharmaceuticals, solvents, binders, metal and rubber processing, food additives, chemical intermediates, phase transfer catalysts, polymer-bound reagents, reagents for binding assays, processes for protein and cell purification, peptide
- polyethylene glycols have been used as covalent modifiers of both low molecular weight compounds and biological macromolecules, predominantly to allow for the alteration of one or more of the properties of the substrate.
- polyethylene glycol may be used to improve solubility, increase molecular weight or change a substrate's partition properties in a biphasic system. S. Zalipsky, Id.
- the present invention provides a process for preparing nonaethylene glycol monomethyl ether, as illustrated in Scheme 1 below.
- Scheme 1
- Me refers to methyl and Ph refers to phenyl.
- the process comprises the steps of: a) reacting a compound of formula (1):
- LG is a suitable leaving group, with triethylene glycol monomethyl ether in the presence of a coupling agent, to prepare hexaethylene glycol monobenzyl monomethyl ether; b) hydrogenating hexaethylene glycol monobenzyl monomethyl ether to prepare hexaethylene glycol monomethyl ether; c) reacting hexaethylene glycol monomethyl ether with a compound of formula (I) in the presence of a coupling agent to prepare nonaethylene glycol monobenzyl monomethyl ether; and d) hydrogenating nonaethylene glycol monobenzyl monomethyl ether to prepare nonaethylene glycol monomethyl ether.
- a triethylene glycol monobenzyl ether compound of formula (I) is reacted with triethylene glycol monomethyl ether.
- the leaving group in the compound of formula (I) may be any suitable leaving group known to those skilled in the art of organic chemistry to be useful in such synthesis. Suitable leaving groups include activated esters. Specific examples of suitable leaving groups including but are not limited to tosyl; mesylate; and tresylate. In one embodiment, the leaving group is tosyl.
- Suitable coupling agents are known in the art.
- suitable coupling agents include bases.
- suitable coupling agents include but are not limited to potassium tert- butoxide, sodium te/ butoxide, sodium hydride, potassium hydride, potassium hydroxide, sodium metal, sodium hexamethyldisilazide, potassium hexamethyldisilazide and the like.
- the coupling agent for the reaction of step (a) is potassium tert- butoxide.
- the coupling reaction of step (a) preferably carried out in a polar aprotic solvent at reduced temperature (e.g., below room temperature).
- suitable solvents include, but are not limited to tetrahydrofuran, /V, ⁇ dimethylformamide, N,N- dimethylacetamide, hexamethylphosphoramide and_dioxane.
- the coupling reaction of step (a) is carried out using tetrahydrofuran as the solvent.
- the preparation of the compound of formula (I) involves the installation of the leaving group on commercially available triethylene glycol monobenzyl ether. Methods for the installation of such leaving groups are "known in the art. See, e.g., A.
- a tosyl leaving group may be installed on triethylene glycol monobenzyl ether by reacting triethylene glycol monobenzyl ether with 4-toluenesulfonyl chloride in a suitable solvent and basic additive.
- suitable solvents and basic additives for installing the tosylate or mesylate include pyridine (as both solvent and basic additive), dichloromethane and triethylamine, dichloromethane and pyridine, and sodium, potassium or cesium hydroxide in dioxane.
- the leaving group is tosyl and the solvent and basic additive are both pyridine.
- Examples of compounds of formula (I) which are useful in the process of the present invention include but are not limited to triethylene glycol benzyl tosyl ether, triethylene glycol benzyl mesyl ether.
- the coupling reaction of step (a) produces hexaethylene glycol monobenzyl monomethyl ether.
- This compound is then subjected to hydrogenation conditions to yield hexaethylene glycol monomethyl ether.
- Suitable techniques for the hydrogenation of hexaethylene glycol monobenzyl monomethyl ether are analogous to techniques for the hydrogenation of similar compounds. See, e.g., C. Selve, et al., J. Chem. Soc. Chem. Commun. 1990, 911-912; and E. Weber, LiebigsAnn. Chem. 1983, 770-801.
- the hydrogenation step (b) is carried out using palladium catalyzed hydrogenation in a hydrogen atmosphere.
- Suitable palladium catalysts include palladium on carbon.
- Suitable solvents for the hydrogenation step (b) include the solvents described above for use in step (a) of the process as well as alcohol solvents. In one embodiment, the process is conveniently carried out using the same solvent for botht the couplings step (a) and the hydrogenation step (b).
- step (c) The hydrogenation of step (b) yields hexaethylene glycol monomethyl ether. Conveniently, hexaethylene glycol monomethyl ether is then reacted with the compound of formula (I).
- This coupling reaction (step (c)) may conveniently be carried out using the same reaction conditions as described above for the reaction of step (a).
- the coupling agent in step (c) is selected from potassium te/ ⁇ -butoxide, potassium hydride and potassium hexamethyldisilazide.
- the same coupling agent may be employed for both step (a) and step (c) of the process of the present invention.
- the coupling agent for both step (a) and step (c) is potassium f ⁇ /?-butoxide.
- step (c) may be carried out in a suitable solvent selected from those described above for the coupling step (a).
- step (a) and step (c) are carried out in the same solvent, e.g., tetrahydrofuran.
- step (c) yields nonaethylene glycol monobenzyl monomethyl ether, which is then subjected to hydrogenation to provide nonaethylene glycol monomethyl ether.
- the hydrogenation of step (d) may be carried out using the same reaction conditions described above for the hydrogenation of step (b). Conveniently, the hydrogenation may be carried out in the same solvent.
- the process of the present invention is carried out in solvent. Suitable solvents are selected from tetrahydrofuran, /V,/V-dimethylformamide, N,N- dimethylacetamide, hexamethylphosphoramide and dioxane. In one embodiment, the process of the invention is carried out using tetrahydrofuran as the solvent.
- the process of the present invention provides a number of unique advantages over conventional processes for preparing nonaethylene glycol monomethyl ether.
- the process of the present invention employs only two starting materials, both of which are available in high oligomeric purity, the compound of formula (1) and triethylene glycol monomethyl ether.
- Triethylene glycol monomethyl ether (which is employed to prepare the compounds of formula (I)) is commercially available in large quantities and at costs that permit commercial-scale synthesis of the desired nonaethylene glycol monomethyl ether product.
- the process of the present invention is carried out using only four steps and reaction conditions which are suitable for scale-up production of commercial quantities.
- This chain clipping side reaction produces higher quantities of ethylene glycol monomethyl ether chains of varying lengths, including the octaethylene glycol monomethyl ether, as side products. Such side products negatively impact production costs and increase risk particularly when the PEG chains are to be incorporated into pharmaceutically active agents for human use.
- the process of the present invention does not appear to initiate the chain clipping side reaction.
- the process of the present invention provides nonaethylene glycol monomethyl ether in a high level of oligomeric purity.
- Reagents are commercially available or are prepared according to procedures in the literature.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention provides a process for preparing nonethylene glycol monomethyl ether.
Description
PROCESS FOR PREPARING NONAETHYLENE GLYCOL MONOMETHYL ETHER
BACKGROUND OF THE INVENTION The present invention relates to a novel process for preparing nonaethylene glycol. More specifically, the present invention relates to a process for preparing nonaethylene glycol monomethyl ether.
Various processes are known for the synthsis of polyethylene glycols. See, for example, R.A. Bartsch et al, J. Org. Chem. 1989, 54:857-860; J.M. Harris, Macromol. J.Sci. Rev. Polymer Phys. Chem. 1985, C25 (3):325-373; and S. Zalipsky, Bioconjugate Chem. 1995, 6: 150-165.
U.S. Patent Nos. 6355646 and 6437124, both to Daluge et al., and PCT Publication No. WO 98/35966, published 20 Aug 1998 to Glaxo Group Limited, disclose a process for preparing nonaethylene glycol using hexaethyelene glycol as a starting material.
BRIEF SUMMARY OF THE INVENTION The present invention provides a novel process for preparing nonaethylene glycol monomethyl ether. The process comprises the steps of: a) reacting a compound of formula (I):
Additional aspects and advantages of the present invention will be apparent form the description and example which follow. DETAILED DESCRIPTION OF THE INVENTION
Polyethylene glycols, such as nonaethylene glycol monomethyl ether, are useful in a number of areas, including for example, as plasticizers, softeners, humectants, ointments, polishes, paper coatings, mold lubricants, bases for cosmetics and pharmaceuticals, solvents, binders, metal and rubber processing, food additives, chemical intermediates, phase transfer catalysts, polymer-bound reagents, reagents for binding assays, processes for protein and cell purification, peptide synthesis and as modifiers for a variety of substrates, including pharmaceutically active agents.
In particular, polyethylene glycols have been used as covalent modifiers of both low molecular weight compounds and biological macromolecules, predominantly to allow for the alteration of one or more of the properties of the substrate. For example, polyethylene glycol may be used to improve solubility, increase molecular weight or change a substrate's partition properties in a biphasic system. S. Zalipsky, Id.
U.S. Patent Nos. 6355646 and 6437124, both to Daluge et al., and PCT Publication No. WO 98/35966, published 20 Aug 1998 to Glaxo Group Limited, relate to substituted 1 ,3-Bis(cyclohexylmethyl)-1 ^.S.δ-tetrahydro^.δ-dioxo-ΘH-purin-δ- yl)phenyl polyethylene glycol derivatives. U.S. Patent No. 6608069 to Daluge et al., and PCT Publication No. WO 00/09507, published 24 Feb 2000 to Glaxo Group Limited, relate to phenyl xanthine derivatives which incorporate polyethylene glycol chains. The processes of the present invention are useful, among other things for
the preparation nonaethylene glycol monomethyl ether, which is useful for the synthesis of the compounds described in the foregoing patents and publications.
The present invention provides a process for preparing nonaethylene glycol monomethyl ether, as illustrated in Scheme 1 below. Scheme 1
Generally, the process comprises the steps of: a) reacting a compound of formula (1):
More specifically, a triethylene glycol monobenzyl ether compound of formula (I) is reacted with triethylene glycol monomethyl ether. The leaving group in the compound of formula (I) may be any suitable leaving group known to those skilled in the art of organic chemistry to be useful in such synthesis. Suitable leaving groups include activated esters. Specific examples of suitable leaving groups including but are not limited to tosyl; mesylate; and tresylate. In one embodiment, the leaving group is tosyl.
The reaction of the compound of formula (I) with triethylene glycol monomethyl ether is carried out in the presence of a coupling agent. Suitable coupling agents are known in the art. In particular, suitable coupling agents include bases. Specific examples of suitable coupling agents include but are not limited to potassium tert- butoxide, sodium te/ butoxide, sodium hydride, potassium hydride, potassium hydroxide, sodium metal, sodium hexamethyldisilazide, potassium hexamethyldisilazide and the like.
In one embodiment, the coupling agent for the reaction of step (a) is potassium tert- butoxide.
The coupling reaction of step (a) preferably carried out in a polar aprotic solvent at reduced temperature (e.g., below room temperature). Examples of suitable solvents include, but are not limited to tetrahydrofuran, /V,Λ dimethylformamide, N,N- dimethylacetamide, hexamethylphosphoramide and_dioxane. In one embodiment, the coupling reaction of step (a) is carried out using tetrahydrofuran as the solvent.
The preparation of the compound of formula (I) involves the installation of the leaving group on commercially available triethylene glycol monobenzyl ether. Methods for the installation of such leaving groups are "known in the art. See, e.g., A. Bouzide, et al., Tetrahedron LetterslOQ 42:8781 ; L. Jullien, et al., J. Chem Soc. Perkin Trans.2 9942:989-1002; A. M. Reichwein, et al., Reel. Trav. Ch/m. Pays- /5as 1993 112:595-608; A. M. Reichwein, e al. Reel. Trav. Chim. Pays-Bas 1993, 112:358-366; J. Ipaktschi, et al., LiebigsAnn. Chem. 1992, 1029-1032; W. Walkowiak, et al., Anal. Chem. 1992, 64:1685-1690; C. Selve, et al., Synth. Commun. 199020: 799-807; D. Bethell, et al., J. Chem. Soc. Perkin Trans. 1988 2:2035-2044; S. Svedhem, et al., J. Org. Chem. 2001 66: 4494-4503; G. Herve, Org. Biomol. Chem. 2003, 1:427-435; B. Mulley, J. Chem. Soc. A 1970 1459-1464; M. Carissimi, et al. J. Med. Chem. 19658: 542-545; Z. Grobelny, et al., J. Org. Chem. 199964:8990-8994; and C. Vitali, et al., Tetrahedron 198945: 2213-2222.
Optimal reaction conditions will depend upon the particular leaving group to be installed, and will be within the skill of the synthetic organic chemist. For example, a tosyl leaving group may be installed on triethylene glycol monobenzyl ether by reacting triethylene glycol monobenzyl ether with 4-toluenesulfonyl chloride in a suitable solvent and basic additive. Suitable solvents and basic additives for installing the tosylate or mesylate include pyridine (as both solvent and basic additive), dichloromethane and triethylamine, dichloromethane and pyridine, and sodium, potassium or cesium hydroxide in dioxane. In one embodiment, the the leaving group is tosyl and the solvent and basic additive are both pyridine.
Examples of compounds of formula (I) which are useful in the process of the present invention include but are not limited to triethylene glycol benzyl tosyl ether, triethylene glycol benzyl mesyl ether. The coupling reaction of step (a) produces hexaethylene glycol monobenzyl monomethyl ether. This compound is then subjected to hydrogenation conditions to yield hexaethylene glycol monomethyl ether. Suitable techniques for the
hydrogenation of hexaethylene glycol monobenzyl monomethyl ether are analogous to techniques for the hydrogenation of similar compounds. See, e.g., C. Selve, et al., J. Chem. Soc. Chem. Commun. 1990, 911-912; and E. Weber, LiebigsAnn. Chem. 1983, 770-801.
In one embodiment, the hydrogenation step (b) is carried out using palladium catalyzed hydrogenation in a hydrogen atmosphere. Suitable palladium catalysts include palladium on carbon. Suitable solvents for the hydrogenation step (b) include the solvents described above for use in step (a) of the process as well as alcohol solvents. In one embodiment, the process is conveniently carried out using the same solvent for botht the couplings step (a) and the hydrogenation step (b).
The hydrogenation of step (b) yields hexaethylene glycol monomethyl ether. Conveniently, hexaethylene glycol monomethyl ether is then reacted with the compound of formula (I). This coupling reaction (step (c)) may conveniently be carried out using the same reaction conditions as described above for the reaction of step (a). In one embodiment, the coupling agent in step (c) is selected from potassium te/ϊ-butoxide, potassium hydride and potassium hexamethyldisilazide. Advantageously, the same coupling agent may be employed for both step (a) and step (c) of the process of the present invention. In one embodiment, the coupling agent for both step (a) and step (c) is potassium fø/?-butoxide. The coupling step (c) may be carried out in a suitable solvent selected from those described above for the coupling step (a). In one convenient embodiment of the process of the present invention, step (a) and step (c) are carried out in the same solvent, e.g., tetrahydrofuran.
The coupling reaction of step (c) yields nonaethylene glycol monobenzyl monomethyl ether, which is then subjected to hydrogenation to provide nonaethylene glycol monomethyl ether. The hydrogenation of step (d) may be carried out using the same reaction conditions described above for the hydrogenation of step (b). Conveniently, the hydrogenation may be carried out in the same solvent.
In one embodiment, the process of the present invention is carried out in solvent. Suitable solvents are selected from tetrahydrofuran, /V,/V-dimethylformamide, N,N- dimethylacetamide, hexamethylphosphoramide and dioxane. In one embodiment, the process of the invention is carried out using tetrahydrofuran as the solvent.
The process of the present invention provides a number of unique advantages over conventional processes for preparing nonaethylene glycol monomethyl ether. In particular, the process of the present invention employs only two starting materials, both of which are available in high oligomeric purity, the compound of formula (1) and triethylene glycol monomethyl ether. Triethylene glycol monomethyl ether (which is employed to prepare the compounds of formula (I)) is commercially available in large quantities and at costs that permit commercial-scale synthesis of the desired nonaethylene glycol monomethyl ether product. Further the process of the present invention is carried out using only four steps and reaction conditions which are suitable for scale-up production of commercial quantities. Conventional processes employing hexaethylene glycol or hexaethylene glycol monobenzyl ethers suffer key disadvantages compared to the process of the present invention. In particular, availability of hexaethylene glycol in quantities suitable for synthesis of commercial quantities of the desired nonaethylene glycol monomethyl ether product is uncertain and the purchase of such quantities may be cost prohibative. Further it has been found that synthesis of nonaethylene glycol monomethyl ether by coupling hexaethylene glycol monobenzyl ether to triethylene glycol monomethyl ether results in a "chain clipping" reaction whereby one ethylene glycol unit is removed from the chain. This chain clipping side reaction produces higher quantities of ethylene glycol monomethyl ether chains of varying lengths, including the octaethylene glycol monomethyl ether, as side products. Such side products negatively impact production costs and increase risk particularly when the PEG chains are to be incorporated into pharmaceutically active agents for human use. The process of the present invention does not appear to initiate the chain clipping side reaction. Thus, the process of the present invention provides nonaethylene glycol monomethyl ether in a high level of oligomeric purity.
The following example is intended for illustration only and is not intended to limit the scope of the invention in any way, the invention being defined by the claims which follow.
Reagents are commercially available or are prepared according to procedures in the literature.
Example 1: Synthesis of Nonaethylene Glycol MonoMethyl Ether A. Triethylene Glycol MonoBenzyl Tosyl Ether
4-Toluenesulfonyl chloride (20.9 g, 0.11 mol) was added to a cold (0 SC) solution of triethylene glycol monobenzyl ether ("BnO-3EG-OH," 24.0 g, 0.1 mol) in pyridine (100 mL) in portions over a period of two minutes. A precipitate formed over 20 minutes. After 70 minutes the reaction mixture was allowed to warm to room temperature overnight. After 16 hours the reaction was diluted with ethyl acetate (100 mL) and quenched with water (50 mL) to dissolve the solids. The layers were separated and the organic layer was washed with aqueous hydrochloric acid till the aqueous layer was about pH 1. The organic solution was dried over magnesium sulfate and concentrated to dryness to give the title compound (28.94 g). 1H NMR (400 MHz, CDCI3, A10899) indicated an ca 4:1 mixture of desired triethylene glycol monobenzyl ether tosylate and undesired ({2-[2-(2-chloroethoxy)ethoxy]- ethoxy}methyl)benzene.
Triethylene glycol monobenzyl ether tosylate: 5H (CDCI3, ppm from TMS) 7.79 (2 H, d, J= 8.3 Hz, N-H), 7.4-7.2 (7 H, m, Ar-Λ), 4.55 (2 H, s, PhCΛfeO-), 4.15 (2 H, t, J= 4.7 Hz, CH2) 3.7-3.5 (10 H, m, C/V2 x 5), 2.43 (3 H, s, ArC/V3).
({2-[2-(2-Chloroethoxy)ethoxy]ethoxy}methyl)benzene: δH (CDCI3, ppm from TMS) 7.4-7.2 (5 H, m, Ar-Λ), 4.57 (2 H, s, PhC/V2O-), 3.76 (2 H, t, J= 5.9 Hz, CA2CI) 3.7- 3.5 (10 H, m, C/V2 x 5). Mixture calculated to contain 88.4 wt% tosylate (25.58 g, 64.9% theory) and 11.6 wt% chloride (3.36 g, 13.0 % theory).
B. Triethylene Glvcol MonoBenzyl Tosyl Ether
4-Toluenesulfonyic anhydride (25 g, 76.6 mmol, 1.1 equiv) was added to a cold (5 SC) solution of triethylene glycol monobenzyl ether (BnO-3EG-OH, 24.0 g, 0.1 mol, 1 equiv) in pyridine (67 mL) in portions to control the exotherm. More pyridine (40 mL) was added to maintain stirring of the resultant slurry. After 5 hours the reaction was diluted with ethyl acetate (80 mL) and quenched with water (40 mL) to dissolve the solids. The layers were separated and the organic layer was washed with aqueous sulfuric acid till the aqueous layer was about pH 1. The organic solution was dried over magnesium sulfate and concentrated to dryness to give triethylene glycol monobenzyl ether tosylate (22.69 g, 83% theory). 1H NMR (400 MHz, CDCI3) consistent with above.
C. Hexaethylene Glycol MonoBenzyl Monomethyl Ether
A solution of potassium fø/7-butoxide in tetrahydrofuran (1 M, 17.5 mL, 17.5 mmol) was added to a solution of triethylene glycol monomethyl ether ("MeO-3EG-OH," 2.58 mL, 16.13 mmol) in tetrahydrofuran (20 mL) maintaining an internal temperature of less than 10 °C. After 15 minutes a solution of a mixture of triethylene glycol monobenzyl ether 4-toluenesuifonate ("BnO-3EG-OTs") and corresponding chloride (88.4 wt% tosylate; 5.00 g, 11.2 mmol of tosylate) in tetrahydrofuran (10 mL) was added. A colorless precipitate formed immediately. After 2 hours, the reaction was quenched with saturated aqueous sodium bicarbonate solution (25 mL) at a rate to control gas evolution. Water (20 mL) was added and the tetrahydrofuran was removed by distillation under reduced pressure. The resulting aqueous layer was washed with diisopropyl ether (50 mL) then ethyl acetate (50 mL). The ethyl acetate layer was dried over magnesium sulfate, filtered and concentrated to dryness to provide the coupled benzyl ether (2.66 g, 61.5% theory based on input tosylate). 1H NMR (400 MHz, CDCI3, A10919) δH (CDCI3, ppm from TMS) 7.4-7.2 (5 H, m, Ar-H), 4.57 (2 H, s, PhC /2O-), 3.7-3.6 (22 H, m, C/V2 x 11), 3.6-3.5 (2 H, m, CH2), 3.38 (3 H, s, OCH3).
P. Hexaethylene Glvcol Monomethyl Ether
A 50% wet paste of 10% palladium on carbon (0.71 g, 5 mol%) was charged to a nitrogen purged flask. A solution of hexaethylene glycol monomethyl monobenzyl
ether ("BnO-6EG-OMe"; 2.66g, 6.88 mmol) in tetrahydrofuran (26.6 mL) was added. The mixture was stirred under an atmosphere of hydrogen for 90 minutes. The mixture was filtered through celite to remove the catalyst. The solids were washed with tetrahydrofuran (20 mL). The filtrate was concentrated to dryness to give hexaethylene glycol monomethyl ether (2.01 g, 99% theory). 1H NMR (250 MHz, CDCI3, S44238) δH (CDCI3, ppm from TMS) 3.8-3.5 (24 H, m, CH2 x 12), 3.38 (3 H, s, OC 3), 2.08 (1 H, brs, OH).
E. Nonaethylene Glycol Monobenzyl Monomethyl Ether A solution of potassium fe/?-butoxide (0.78 g, 6.8 mmol) in tetrahydrofuran (7.5 mL) was cooled to 5 °C. A solution of hexaethylene glycol monomethyl ("MeO-6EG-OH", 1.83 g, 6.19 mmol) in tetrahydrofuran (10 mL) was added dropwise over ten minutes. After 12 minutes, a solution of triethylene glycol monobenzyl ether 4- toluenesulfonate ("BnO-3EG-OTs", 3.17 g, 8.04 mmol) in tetrahydrofuran (7.5 mL) was added over four minutes. The mixture was allowed to warm to room temperature. After 19.5 hours, a solution of potassium fø/7-butoxide (0.45 g, 4.0 mmol) in tetrahydrofuran (5.0 mL) was added. After 90 minutes more the reaction was quenched with water (15 mL) and the tetrahydrofuran was removed by distillation under reduced pressure. The resulting aqueous layer was washed with diisopropyl ether (3 x 20 mL) then extracted with dichloromethane (2 x 20 mL). The dichloromethane layers were combined and washed with water (2 x 20 mL) then saturated aqueous sodium bicarbonate (4 x 20 mL) then concentrated to dryness to give nonethylene glycol monomethyl monobenzyl ether (2.52 g, 79% theory. 1H NMR (400 MHz, CDCI3, A11016) δH (CDCI3) ppm from TMS) 7.4-7.2 (5 H, m, Ar-/V), 4.57 (2 H, s, PhC /2O-), 3.7-3.6 (34 H, m, CH2 x 17), 3.6-3.5 (2 H, m, CH2), 3.38 (3 H, s, OC ).
F. Nonaethylene Glycol Monomethyl Ether
A 50% wet paste of 10% palladium on carbon (0.53 g, 5 mol%) was charged to a nitrogen purged flask. A solution of nonaethylene glycol monomethyl monobenzyl ether ("BnO-9EG-OMe;" 2.52g, 4.86 mmol) in tetrahydrofuran (25 mL) was added. The mixture was stirred under an atmosphere of hydrogen for 65 minutes. The
mixture was filtered through celite to remove the catalyst. The solids were washed with tetrahydrofuran (3 x 5 mL). The filtrate was concentrated to dryness to give nonaethylene glycol monomethyl ether (2.02 g, 97% theory). 1H NMR (400 MHz, CDCI3, A11021) δH (CDCI3, ppm from TMS) 3.8-3.6 (34 H, m, CH2 x 17), 3.6-3.5 (2 H, m, CH2), 3.38 (3 H, s, OC /3), 2.58 (1 H, t, J= 5.9 Hz, OH).
Claims
1. A process for preparing nonaethylene glycol monomethyl ether, said process comprising the steps of: a) reacting a compound of formula (I):
2. The process according to claim 1 , wherein said compound of formula (I) is selected from triethylene glycol benzyl tosyl ether and triethylene glycol benzyl mesyl ether.
3. The process according to claim 1 , wherein said coupling agent of step a) and step c) is the same.
4. The process according to claim 1 , wherein said coupling agent of step a) is selected from potassium tert-butoxϊde, sodium fe/7-butoxide, sodium hydride, potassium hydride, sodium metal, sodium hexamethyldisilazide, and potassium hexamethyldisilazide.
5. The process according to claim 1 , wherein said coupling agent of step c) is selected from potassium fe/?-butoxide, potassium hydride, potassium hexamethyldisilazide.
6. The process according to claim 1 , wherein said coupling agent for step a) and step c) is potassium tert-b Xox\de.
1. The process according to claim 1 , wherein said hydrogenation step b) and step d) is a palladium catalyzed hydrogenation.
8. The process according to claim 1 , wherein said steps (a), (b), (c), and (d) are carried out in a solvent.
9. The process according to claim 8, wherein said solvent is selected from tetrahydrofuran, /,ΛAdimethylformamide, /V,/V-dimethylacetamide, hexamethylphosphoramide and dioxane.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2858315A (en) * | 1956-04-25 | 1958-10-28 | Ciba Pharm Prod Inc | New isoquinolines and process for their manufacture |
| US6355646B1 (en) * | 1997-02-14 | 2002-03-12 | Glaxo Wellcome Inc. | Substituted (1,3-bis(cyclohexylmethyl)-1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl)phenyl derivatives, their preparation and their use in treatment of inflammatory conditions and immune disorders |
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2005
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2858315A (en) * | 1956-04-25 | 1958-10-28 | Ciba Pharm Prod Inc | New isoquinolines and process for their manufacture |
| US6355646B1 (en) * | 1997-02-14 | 2002-03-12 | Glaxo Wellcome Inc. | Substituted (1,3-bis(cyclohexylmethyl)-1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl)phenyl derivatives, their preparation and their use in treatment of inflammatory conditions and immune disorders |
Non-Patent Citations (1)
| Title |
|---|
| F. A. LOISEAU: "Multigram synthesis of well-defined extended bifunctional polyethylene glycol (PEG) chains", JOURNAL OF ORGANIC CHEMISTRY, vol. 69, no. 3, 6 February 2004 (2004-02-06), pages 639 - 647, XP002345040 * |
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