US20220017480A1 - Nonionic polyether surfactants - Google Patents
Nonionic polyether surfactants Download PDFInfo
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- US20220017480A1 US20220017480A1 US17/374,509 US202117374509A US2022017480A1 US 20220017480 A1 US20220017480 A1 US 20220017480A1 US 202117374509 A US202117374509 A US 202117374509A US 2022017480 A1 US2022017480 A1 US 2022017480A1
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- 239000004094 surface-active agent Substances 0.000 title claims abstract description 5
- 239000004721 Polyphenylene oxide Substances 0.000 title claims abstract 3
- 229920000570 polyether Polymers 0.000 title claims abstract 3
- 150000001875 compounds Chemical class 0.000 claims description 49
- -1 n-decyl Chemical group 0.000 claims description 25
- 238000000034 method Methods 0.000 claims description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- 239000012453 solvate Substances 0.000 claims description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 12
- 125000003342 alkenyl group Chemical group 0.000 claims description 11
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 11
- 239000003638 chemical reducing agent Substances 0.000 claims description 10
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical group C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 claims description 9
- KWEKXPWNFQBJAY-UHFFFAOYSA-N (dimethyl-$l^{3}-silanyl)oxy-dimethylsilicon Chemical group C[Si](C)O[Si](C)C KWEKXPWNFQBJAY-UHFFFAOYSA-N 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- GYHNNYVSQQEPJS-UHFFFAOYSA-N Gallium Chemical compound [Ga] GYHNNYVSQQEPJS-UHFFFAOYSA-N 0.000 claims description 6
- GPWHDDKQSYOYBF-UHFFFAOYSA-N ac1l2u0q Chemical compound Br[Br-]Br GPWHDDKQSYOYBF-UHFFFAOYSA-N 0.000 claims description 6
- 229910052733 gallium Inorganic materials 0.000 claims description 6
- 230000007062 hydrolysis Effects 0.000 abstract description 7
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 7
- 239000000243 solution Substances 0.000 description 20
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 229920000136 polysorbate Polymers 0.000 description 15
- 229920001213 Polysorbate 20 Polymers 0.000 description 13
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 13
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 13
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 13
- 229920000053 polysorbate 80 Polymers 0.000 description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- 229950008882 polysorbate Drugs 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 8
- 229940125782 compound 2 Drugs 0.000 description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 229940125904 compound 1 Drugs 0.000 description 6
- VQXVDWAHOYMHCW-UHFFFAOYSA-N CCOCCOCC(OCCO)C1OCC(OCCO)C1OCCO Chemical compound CCOCCOCC(OCCO)C1OCC(OCCO)C1OCCO VQXVDWAHOYMHCW-UHFFFAOYSA-N 0.000 description 5
- 235000014113 dietary fatty acids Nutrition 0.000 description 5
- 239000000194 fatty acid Substances 0.000 description 5
- 229930195729 fatty acid Natural products 0.000 description 5
- 239000002736 nonionic surfactant Substances 0.000 description 5
- 229940068965 polysorbates Drugs 0.000 description 5
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- 108090000371 Esterases Proteins 0.000 description 4
- 108090001060 Lipase Proteins 0.000 description 4
- 102000004882 Lipase Human genes 0.000 description 4
- 239000004367 Lipase Substances 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 239000001110 calcium chloride Substances 0.000 description 4
- 229910001628 calcium chloride Inorganic materials 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 125000004404 heteroalkyl group Chemical group 0.000 description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 4
- 235000019421 lipase Nutrition 0.000 description 4
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 4
- 238000001556 precipitation Methods 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 description 3
- 125000000041 C6-C10 aryl group Chemical group 0.000 description 3
- XKMLPZHKGVYINO-UHFFFAOYSA-N CC(=O)OCCOCC(OCCO)C1OCC(OCCO)C1OCCO Chemical compound CC(=O)OCCOCC(OCCO)C1OCC(OCCO)C1OCCO XKMLPZHKGVYINO-UHFFFAOYSA-N 0.000 description 3
- VQXVDWAHOYMHCW-WTXIUTQJSA-N CCOCCOCC(OCCO)[C@H]1OC[C@@H](OCCO)[C@@H]1OCCO Chemical compound CCOCCOCC(OCCO)[C@H]1OC[C@@H](OCCO)[C@@H]1OCCO VQXVDWAHOYMHCW-WTXIUTQJSA-N 0.000 description 3
- 229910005258 GaBr3 Inorganic materials 0.000 description 3
- 229920001214 Polysorbate 60 Polymers 0.000 description 3
- 125000002252 acyl group Chemical group 0.000 description 3
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 3
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 3
- 235000011130 ammonium sulphate Nutrition 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- SRVXDMYFQIODQI-UHFFFAOYSA-K gallium(iii) bromide Chemical compound Br[Ga](Br)Br SRVXDMYFQIODQI-UHFFFAOYSA-K 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical class 0.000 description 3
- 229940068977 polysorbate 20 Drugs 0.000 description 3
- 229940068968 polysorbate 80 Drugs 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 2
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 description 2
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 2
- 108010073361 BioXtra Proteins 0.000 description 2
- 0 C*(CO*(C)C1C(C(CC(C)(C)OC*(C)OC*)C(C)(C)OC*(C)O)OCC1C(C)(C)OC*(C)O)O Chemical compound C*(CO*(C)C1C(C(CC(C)(C)OC*(C)OC*)C(C)(C)OC*(C)O)OCC1C(C)(C)OC*(C)O)O 0.000 description 2
- RTVSWTDQADYUFV-VAHSSUGTSA-N CCCCCCCC/C=C\CCCCCCCCOCCOCC(OCCO)[C@H]1OC[C@@H](OCCO)[C@@H]1OCCO Chemical compound CCCCCCCC/C=C\CCCCCCCCOCCOCC(OCCO)[C@H]1OC[C@@H](OCCO)[C@@H]1OCCO RTVSWTDQADYUFV-VAHSSUGTSA-N 0.000 description 2
- AGRFDIJOWZMEAU-SBZWWDHJSA-N CCCCCCCCCCCCOCCOCC(OCCO)[C@H]1OC[C@@H](OCCO)[C@@H]1OCCO Chemical compound CCCCCCCCCCCCOCCOCC(OCCO)[C@H]1OC[C@@H](OCCO)[C@@H]1OCCO AGRFDIJOWZMEAU-SBZWWDHJSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 159000000007 calcium salts Chemical class 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 125000004185 ester group Chemical group 0.000 description 2
- 125000001033 ether group Chemical group 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 239000000295 fuel oil Substances 0.000 description 2
- 230000003301 hydrolyzing effect Effects 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000003456 ion exchange resin Substances 0.000 description 2
- 229920003303 ion-exchange polymer Polymers 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 210000000496 pancreas Anatomy 0.000 description 2
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical class OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 description 1
- 125000004649 C2-C8 alkynyl group Chemical group 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 101000968511 Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv) Triacylglycerol lipase Proteins 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 235000011148 calcium chloride Nutrition 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000007515 enzymatic degradation Effects 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000002366 lipolytic effect Effects 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 235000010483 polyoxyethylene sorbitan monopalmitate Nutrition 0.000 description 1
- 239000000249 polyoxyethylene sorbitan monopalmitate Substances 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members 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
- C07D307/20—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
- C11D—DETERGENT COMPOSITIONS; USE OF SINGLE SUBSTANCES AS DETERGENTS; SOAP OR SOAP-MAKING; RESIN SOAPS; RECOVERY OF GLYCEROL
- C11D1/00—Detergent compositions based essentially on surface-active compounds; Use of these compounds as a detergent
- C11D1/66—Non-ionic compounds
- C11D1/72—Ethers of polyoxyalkylene glycols
Definitions
- Polysorbates are amphiphilic, nonionic surfactants comprising fatty acid esters of polyoxyethylene sorbitan. Polysorbates are widely as research reagents and in protein pharmaceuticals to stabilize the proteins against interface-induced aggregation and to minimize surface adsorption of proteins.
- the main disadvantage of polysorbates is their susceptibility to hydrolysis due to the presence of an ester bond. Acid- and base-promoted hydrolytic degradation as well as enzymatic degradation of polysorbates is well-documented, limiting their use in applications that require basic or acidic pH conditions.
- the disclosure provides a compound of Formula (I):
- R is a an optionally substituted C6-C70 alkyl or optionally substituted C6-C70 alkenyl
- w is an integer ranging from 0 to 20
- x is an integer ranging from 0 to 20,
- y is an integer ranging from 0 to 20
- z is an integer ranging from 0 to 20.
- R is an unsubstituted C6-C70 alkyl or unsubstituted C6-C70 alkenyl. In certain embodiments, R is an unsubstituted C10-C25 alkyl or unsubstituted C10-C25 alkenyl. In certain embodiments, the sum of w, x, y, and z is 20.
- the compound is represented by Formula (IA):
- R, w, x, y, and z are as defined for compound of Formula (I).
- R is n-decyl, n-undecyl, n-dodecyl, n-hexadecyl, or n-heptadecyl.
- the disclosure provides a method of preparing a compound of Formula (I):
- R is a an optionally substituted C6-C70 alkyl or optionally substituted C6-C70 alkenyl
- w is an integer ranging from 0 to 20
- x is an integer ranging from 0 to 20,
- y is an integer ranging from 0 to 20
- z is an integer ranging from 1 to 20,
- forming a trimethylsilyl derivative of compound of Formula (II) is done by contacting a compound of Formula (II) with a silylating agent in a suitable solvent.
- the silylating agent is hexamethyldisilazane (HMDS).
- the reducing agent is 1,1,3,3-tetramethyldisiloxane.
- step (b) is performed at a temperature ranging from about 25° C. to about 80° C. In certain embodiments, step (b) is performed at a room temperature. In some embodiments, step (b) does not require a solvent.
- the method further comprises contacting the product of step (b) with water.
- a surfactant composition comprising a compound of Formula (I) or (IA).
- FIG. 1A is an NMR spectrum of Polysorbate 20 (Tween 20®) and FIG. 1B is an NMR spectrum of an exemplary polysorbate ether (Compound 1).
- FIG. 2A is an NMR spectrum of Polysorbate 80 (Tween 80®) and FIG. 2B is an NMR spectrum of an exemplary polysorbate ether (Compound 2).
- polysorbate ether compounds that can be useful as nonionic surfactants in applications where nonionic surfactants such as polysorbate 20 or polysorbate 80 are employed.
- nonionic surfactants such as polysorbate 20 or polysorbate 80 are employed.
- R is an optionally substituted C6-C70 alkyl or optionally substituted C6-C70 alkenyl
- w is an integer ranging from 0 to 20
- x is an integer ranging from 0 to 20,
- y is an integer ranging from 0 to 20
- z is an integer ranging from 0 to 20.
- R is an unsubstituted C6-C50 alkyl. In other embodiments, R is an unsubstituted C10-C25 alkyl.
- the sum of w, x, y, and z is 20.
- the compound is represented by Formula (IA):
- R is n-decyl, n-undecyl, n-dodecyl, n-hexadecyl, or n-heptadecyl.
- the compound is Compound 1:
- the compound is Compound 2:
- alkyl and “alkenyl” include straight-chain, branched-chain, and cyclic monovalent hydrocarbyl radicals, and combinations of these, which contain only C and H when they are unsubstituted.
- the total number of carbon atoms in each such group is sometimes described herein, e.g., when the group can contain up to ten carbon atoms it can be represented as 1-10C, as C 1 -C 10 , C—C10, or C1-10.
- Alkyl and alkenyl groups can be optionally substituted to the extent that such substitution makes sense chemically.
- Typical substituents include, but are not limited to, halogens (F, Cl, Br, I), ⁇ O, ⁇ N—CN, ⁇ N—OR, ⁇ NR, OR, NR 2 , SR, SO 2 R, SO 2 NR 2 , NRSO 2 R, NRCONR 2 , NRC(O)OR, NRC(O)R, CN, C(O)OR, C(O)NR 2 , OC(O)R, C(O)R, and NO 2 , wherein each R is independently H, C1-C8 alkyl, C2-C8 heteroalkyl, C1-C8 acyl, C2-C8 heteroacyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C6-C10 aryl, or C5-C
- Alkyl and alkenyl groups can also be substituted by C1-C8 acyl, C2-C8 heteroacyl, C6-C10 aryl or C5-C10 heteroaryl, each of which can be substituted by the substituents that are appropriate for the particular group.
- Optionally substituted indicates that the particular group being described may have one or more hydrogen substituents replaced by a non-hydrogen substituent. In some optionally substituted groups or moieties, all hydrogen substituents are replaced by a non-hydrogen substituent, e.g., C1-C6 alkyl, C2-C6 heteroalkyl, alkynyl, halogens (F, Cl, Br, N 3 , OR, NR 2 , SR, SO 2 R, SO 2 NR 2 , NRSO 2 R, NRCONR 2 , NRC(O)OR, NRC(O)R, CN, C(O)OR, C(O)NR 2 , OC(O)R, C(O)R, oxo, and NO 2 , wherein each R is independently H, C1-C6 alkyl, or C2-C6 heteroalkyl.
- a non-hydrogen substituent e.g., C1-C6 alkyl, C2-C6 heteroalky
- an optional substituent is attached via a double bond, such as a carbonyl oxygen or oxo ( ⁇ O)
- the group takes up two available valences, so the total number of substituents that may be included is reduced according to the number of available valences.
- stereoisomer or “stereoisomers” refer to compounds that differ in the chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers.
- tautomer refers to alternate forms of a compound that differ in the position of a proton, such as enol-keto and imine-enamine tautomers.
- nonionic surfactant composition comprising one or more compounds of Formula (I) or Formula (IA).
- the disclosure provides a method of synthesis of a compound of Formula (I), comprising the steps of contacting a protected derivative of a compound of Formula (II):
- R is an optionally substituted C6-C70 alkyl or optionally substituted C6-C70 alkenyl
- w is an integer ranging from 0 to 20
- x is an integer ranging from 0 to 20,
- y is an integer ranging from 0 to 20
- z is an integer ranging from 0 to 20, with a suitable reducing agent thereby reducing the ester group of the compound of Formula (II) to the corresponding ether group.
- the compounds disclosed herein are prepared by reduction of a polysorbate compound with a suitable reducing agent, for example, 1,1,3,3-tetramethyldisiloxane in the presence of gallium tribromide.
- a suitable reducing agent for example, 1,1,3,3-tetramethyldisiloxane in the presence of gallium tribromide.
- the synthesis of a compound of Formula (I) is performed according to the synthetic route depicted in Scheme 1.
- the methods disclosed herein comprise forming a trimethylsilyl protected derivative of compound of Formula (II) and contacting the trimethylsilyl derivative of compound of Formula (II) with a suitable reducing agent and gallium tribromide.
- contacting the trimethylsilyl derivative of compound of formula (II) with a suitable reducing agent and gallium tribromide is done in a suitable solvent.
- a suitable solvent can be used in the steps described above.
- a trimethylsilyl protected derivative of compound of Formula (II) can be formed by contacting a compound of Formula (II) with a suitable silylating agent.
- a suitable silylating agent Silylating agents and methods of their use are known in the art. Any suitable silylating agent can be used to form a trimethylsilyl-protected compound of Formula (II).
- the silylating agent is hexamethyldisilazane (HMDS).
- any suitable reducing agent can be used to for the reduction the ester group of the compound of Formula (II) to the corresponding ether group.
- the reducing agent is 1,1,3,3-tetramethyldisiloxane.
- the reduction step involves contacting a protected derivative of compound of Formula (II) with 1,1,3,3-tetramethyldisiloxane and gallium tribromide.
- the reduction can be performed at any suitable temperature, for example, at a temperature ranging from about 25° C. to about 80° C. In some embodiments, the reduction step does not require a solvent.
- the methods further include a hydrolysis step, for example the method comprises contacting the product of the reduction step with water, thereby removing the protecting groups (e.g., trimethylsilyl groups).
- the protecting groups e.g., trimethylsilyl groups.
- the compound of Formula (II) is a polysorbate or polyethyleneglycol sorbitan ester.
- suitable polyethyleneglycol sorbitan esters include especially polyoxyethylene sorbitan monolaurate (e.g. polysorbate 20 or Tween 20®), polyoxyethylene sorbitan monooleate (e.g. polysorbate 80 or Tween 80®), polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monoelaidate, polyoxyethylene sorbitan monomyristoleate, and polyoxyethylene sorbitan monopalmitate.
- the term “about” indicates that the subject value can be modified by plus or minus 5% and still fall within the disclosed embodiment.
- Neat dry Tween 20® (11.4 g, 9 mmol) was dissolved in HMDS (23 mL) and THF (46 mL). Ammonium sulfate (0.06 g, 0.45 mmol) was added and mixture was stirred overnight at ambient temperature. The mixture was evaporated in vacuo, co-evaporated twice with 20 mL toluene and dried 1 h under high vacuum, giving 13.4 g of heavy oil. The oil was heated to 50° C., and GaBr 3 (310 mg, 1 mmol) was added followed by dropwise addition of 1,1,3,3-tetramethyldisiloxane (5.0 mL, 28 mmol). Mixture was stirred at 60° C.
- Neat dry Tween 20® (13.3 g, 11 mmol) was dissolved in HMDS (26 mL) and THF (52 mL). Ammonium sulfate (0.054 g, 0.41 mmol) was added and mixture was stirred overnight at ambient temperature. The mixture was evaporated in vacuo, co-evaporated twice with 25 mL toluene and dried 1 h under high vacuum. The resulting oil was heated to 50° C., and GaBr 3 (415 mg, 1.3 mmol) was added followed by dropwise addition of 1,1,3,3-tetramethyldisiloxane (6.9 mL, 39 mmol). The mixture was stirred at 60° C.
- Compound 2 was prepared from Tween 80® by the procedure described above for the preparation of Compound 1.
- Neat dry Tween 80® (10.6 g, 8 mmol) was dissolved in HMDS (20 mL) and THF (40 mL). Ammonium sulfate (0.05 g, 0.4 mmol) was added, and mixture was stirred overnight at ambient temperature. The mixture was evaporated in vacuo, co-evaporated twice with 20 mL toluene and dried 1 h under high vacuum, giving 12.5 g of heavy oil. The oil was heated to 50° C., and GaBr3 (360 mg, 1.2 mmol) was added followed by dropwise addition of 1,1,3,3-tetramethyldisiloxane (5.0 mL, 28 mmol). The mixture was stirred at 60° C.
- Tween 80® and Compound 2 demonstrated similar differences in stability when subjected to Lipase hydrolysis conditions as described above.
- Tween 80® and Compound 2 demonstrated similar differences in stability when subjected to Esterase hydrolysis conditions as described above.
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- Medicinal Preparation (AREA)
Abstract
Description
- This application claims the benefit of U.S. Application No. 63/053,426, filed Jul. 17, 2020, expressly incorporated herein by reference in its entirety.
- Polysorbates are amphiphilic, nonionic surfactants comprising fatty acid esters of polyoxyethylene sorbitan. Polysorbates are widely as research reagents and in protein pharmaceuticals to stabilize the proteins against interface-induced aggregation and to minimize surface adsorption of proteins. The main disadvantage of polysorbates is their susceptibility to hydrolysis due to the presence of an ester bond. Acid- and base-promoted hydrolytic degradation as well as enzymatic degradation of polysorbates is well-documented, limiting their use in applications that require basic or acidic pH conditions.
- Thus, a need exists for a nonionic surfactant that would not be easily hydrolysable.
- In one aspect, the disclosure provides a compound of Formula (I):
- an isomer, a hydrate, a solvate, or a tautomer thereof,
- wherein:
- R is a an optionally substituted C6-C70 alkyl or optionally substituted C6-C70 alkenyl;
- w is an integer ranging from 0 to 20,
- x is an integer ranging from 0 to 20,
- y is an integer ranging from 0 to 20, and
- z is an integer ranging from 0 to 20.
- In some embodiments, R is an unsubstituted C6-C70 alkyl or unsubstituted C6-C70 alkenyl. In certain embodiments, R is an unsubstituted C10-C25 alkyl or unsubstituted C10-C25 alkenyl. In certain embodiments, the sum of w, x, y, and z is 20.
- In some embodiments, the compound is represented by Formula (IA):
- an isomer, a hydrate, a solvate, or a tautomer thereof,
- wherein R, w, x, y, and z are as defined for compound of Formula (I).
- In some embodiments of Formula (I) or Formula (IA), R is n-decyl, n-undecyl, n-dodecyl, n-hexadecyl, or n-heptadecyl.
- In another aspect, the disclosure provides a method of preparing a compound of Formula (I):
- an isomer, a hydrate, a solvate, or a tautomer thereof,
- wherein:
- R is a an optionally substituted C6-C70 alkyl or optionally substituted C6-C70 alkenyl;
- w is an integer ranging from 0 to 20,
- x is an integer ranging from 0 to 20,
- y is an integer ranging from 0 to 20, and
- z is an integer ranging from 1 to 20,
- comprising the steps of:
- forming a trimethylsilyl protected derivative of compound of formula (II):
- and
- (b) contacting the trimethylsilyl derivative of compound of formula (II) with a suitable reducing agent and gallium tribromide.
- In some embodiments, forming a trimethylsilyl derivative of compound of Formula (II) is done by contacting a compound of Formula (II) with a silylating agent in a suitable solvent. In some embodiments, the silylating agent is hexamethyldisilazane (HMDS). In some embodiments, the reducing agent is 1,1,3,3-tetramethyldisiloxane.
- In some embodiments, step (b) is performed at a temperature ranging from about 25° C. to about 80° C. In certain embodiments, step (b) is performed at a room temperature. In some embodiments, step (b) does not require a solvent.
- In some embodiments, the method further comprises contacting the product of step (b) with water.
- In a third aspect, provided herein is a surfactant composition comprising a compound of Formula (I) or (IA).
- The foregoing aspects and many of the attendant advantages of this invention will become more readily appreciated as the same become better understood by reference to the following detailed description, when taken in conjunction with the accompanying drawings, wherein:
-
FIG. 1A is an NMR spectrum of Polysorbate 20 (Tween 20®) andFIG. 1B is an NMR spectrum of an exemplary polysorbate ether (Compound 1). -
FIG. 2A is an NMR spectrum of Polysorbate 80 (Tween 80®) andFIG. 2B is an NMR spectrum of an exemplary polysorbate ether (Compound 2). - The disclosure provides polysorbate ether compounds that can be useful as nonionic surfactants in applications where nonionic surfactants such as polysorbate 20 or polysorbate 80 are employed. Thus, in one aspect, provided herein is a compound represented by Formula (I):
- or an isomer, a hydrate, a solvate, or a tautomer thereof, wherein:
- R is an optionally substituted C6-C70 alkyl or optionally substituted C6-C70 alkenyl;
- w is an integer ranging from 0 to 20,
- x is an integer ranging from 0 to 20,
- y is an integer ranging from 0 to 20, and
- z is an integer ranging from 0 to 20.
- In some embodiments of Formula (I), R is an unsubstituted C6-C50 alkyl. In other embodiments, R is an unsubstituted C10-C25 alkyl.
- In certain embodiments, the sum of w, x, y, and z is 20.
- In some embodiments, the compound is represented by Formula (IA):
- or an isomer, a hydrate, a solvate, or a tautomer thereof, wherein R, w, x, y, and z are as defined above for Formula (I).
- In some embodiments, R is n-decyl, n-undecyl, n-dodecyl, n-hexadecyl, or n-heptadecyl.
- In some embodiments, the compound is Compound 1:
- or an isomer, solvate, hydrate, or a tautomer thereof,
wherein x+y+x=20. - In some embodiments, the compound is Compound 2:
- or an isomer, solvate, hydrate, or a tautomer thereof, wherein x+y+x=20.
- As used herein, the terms “alkyl,” and “alkenyl” include straight-chain, branched-chain, and cyclic monovalent hydrocarbyl radicals, and combinations of these, which contain only C and H when they are unsubstituted. The total number of carbon atoms in each such group is sometimes described herein, e.g., when the group can contain up to ten carbon atoms it can be represented as 1-10C, as C1-C10, C—C10, or C1-10.
- Alkyl and alkenyl groups can be optionally substituted to the extent that such substitution makes sense chemically. Typical substituents include, but are not limited to, halogens (F, Cl, Br, I), ═O, ═N—CN, ═N—OR, ═NR, OR, NR2, SR, SO2R, SO2NR2, NRSO2R, NRCONR2, NRC(O)OR, NRC(O)R, CN, C(O)OR, C(O)NR2, OC(O)R, C(O)R, and NO2, wherein each R is independently H, C1-C8 alkyl, C2-C8 heteroalkyl, C1-C8 acyl, C2-C8 heteroacyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C6-C10 aryl, or C5-C10 heteroaryl, and each R is optionally substituted with halogens (F, Cl, Br, I), ═O, ═N—CN, ═N—OR′, ═NR, OR, NR′2, SR, SO2R′, SO2NR′2, NR′SO2R′, NR′CONR′2, NR′C(O)OR′, NR′C(O)R′, CN, C(O)OR′, C(O)NR′2, OC(O)R′, C(O)R′, and NO2, wherein each R is independently H, C1-C8 alkyl, C2-C8 heteroalkyl, C1-C8 acyl, C2-C8 heteroacyl, C6-C10 aryl or C5-C10 heteroaryl. Alkyl and alkenyl groups can also be substituted by C1-C8 acyl, C2-C8 heteroacyl, C6-C10 aryl or C5-C10 heteroaryl, each of which can be substituted by the substituents that are appropriate for the particular group.
- “Optionally substituted,” as used herein, indicates that the particular group being described may have one or more hydrogen substituents replaced by a non-hydrogen substituent. In some optionally substituted groups or moieties, all hydrogen substituents are replaced by a non-hydrogen substituent, e.g., C1-C6 alkyl, C2-C6 heteroalkyl, alkynyl, halogens (F, Cl, Br, N3, OR, NR2, SR, SO2R, SO2NR2, NRSO2R, NRCONR2, NRC(O)OR, NRC(O)R, CN, C(O)OR, C(O)NR2, OC(O)R, C(O)R, oxo, and NO2, wherein each R is independently H, C1-C6 alkyl, or C2-C6 heteroalkyl. Where an optional substituent is attached via a double bond, such as a carbonyl oxygen or oxo (═O), the group takes up two available valences, so the total number of substituents that may be included is reduced according to the number of available valences.
- Isomers, e.g., stereoisomers, and tautomers of the compounds disclosed herein are also within the scope of this disclosure. As used herein, “stereoisomer” or “stereoisomers” refer to compounds that differ in the chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers. As used herein, “tautomer” refers to alternate forms of a compound that differ in the position of a proton, such as enol-keto and imine-enamine tautomers.
- In another aspect, provided herein is a nonionic surfactant composition comprising one or more compounds of Formula (I) or Formula (IA).
- In yet another aspect, the disclosure provides a method of synthesis of a compound of Formula (I), comprising the steps of contacting a protected derivative of a compound of Formula (II):
- or an isomer, a hydrate, a solvate, or a tautomer thereof, wherein:
- R is an optionally substituted C6-C70 alkyl or optionally substituted C6-C70 alkenyl;
- w is an integer ranging from 0 to 20,
- x is an integer ranging from 0 to 20,
- y is an integer ranging from 0 to 20, and
- z is an integer ranging from 0 to 20, with a suitable reducing agent thereby reducing the ester group of the compound of Formula (II) to the corresponding ether group.
- In certain embodiments, the compounds disclosed herein are prepared by reduction of a polysorbate compound with a suitable reducing agent, for example, 1,1,3,3-tetramethyldisiloxane in the presence of gallium tribromide.
- In some embodiments, the synthesis of a compound of Formula (I) is performed according to the synthetic route depicted in Scheme 1.
- In some embodiments, the methods disclosed herein comprise forming a trimethylsilyl protected derivative of compound of Formula (II) and contacting the trimethylsilyl derivative of compound of Formula (II) with a suitable reducing agent and gallium tribromide.
- In some embodiments, contacting the trimethylsilyl derivative of compound of formula (II) with a suitable reducing agent and gallium tribromide is done in a suitable solvent. Any suitable solvent can be used in the steps described above.
- In some embodiments, a trimethylsilyl protected derivative of compound of Formula (II) can be formed by contacting a compound of Formula (II) with a suitable silylating agent. Silylating agents and methods of their use are known in the art. Any suitable silylating agent can be used to form a trimethylsilyl-protected compound of Formula (II). In some embodiments, the silylating agent is hexamethyldisilazane (HMDS).
- Any suitable reducing agent can be used to for the reduction the ester group of the compound of Formula (II) to the corresponding ether group. In some embodiments, the reducing agent is 1,1,3,3-tetramethyldisiloxane. In some embodiments, the reduction step involves contacting a protected derivative of compound of Formula (II) with 1,1,3,3-tetramethyldisiloxane and gallium tribromide. The reduction can be performed at any suitable temperature, for example, at a temperature ranging from about 25° C. to about 80° C. In some embodiments, the reduction step does not require a solvent.
- In some embodiments, the methods further include a hydrolysis step, for example the method comprises contacting the product of the reduction step with water, thereby removing the protecting groups (e.g., trimethylsilyl groups).
- In some embodiments, the compound of Formula (II) is a polysorbate or polyethyleneglycol sorbitan ester. Examples of suitable polyethyleneglycol sorbitan esters include especially polyoxyethylene sorbitan monolaurate (e.g. polysorbate 20 or Tween 20®), polyoxyethylene sorbitan monooleate (e.g. polysorbate 80 or Tween 80®), polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monoelaidate, polyoxyethylene sorbitan monomyristoleate, and polyoxyethylene sorbitan monopalmitate.
- As used herein, the term “about” indicates that the subject value can be modified by plus or minus 5% and still fall within the disclosed embodiment.
- While each of the elements of the present disclosure is described herein as containing multiple embodiments, it should be understood that, unless indicated otherwise, each of the embodiments of a given element of the present invention is capable of being used with each of the embodiments of the other elements of the present invention and each such use is intended to form a distinct embodiment of the present invention.
- The referenced patents, patent applications, and scientific literature referred to herein are hereby incorporated by reference in their entirety as if each individual publication, patent or patent application were specifically and individually indicated to be incorporated by reference.
- While illustrative embodiments have been illustrated and described, it will be appreciated that various changes can be made therein without departing from the spirit and scope of the invention.
- As can be appreciated from the disclosure above, the present invention has a wide variety of applications. The invention is further illustrated by the following examples, which are only illustrative and are not intended to limit the definition and scope of the invention in any way.
- Neat dry Tween 20® (11.4 g, 9 mmol) was dissolved in HMDS (23 mL) and THF (46 mL). Ammonium sulfate (0.06 g, 0.45 mmol) was added and mixture was stirred overnight at ambient temperature. The mixture was evaporated in vacuo, co-evaporated twice with 20 mL toluene and dried 1 h under high vacuum, giving 13.4 g of heavy oil. The oil was heated to 50° C., and GaBr3 (310 mg, 1 mmol) was added followed by dropwise addition of 1,1,3,3-tetramethyldisiloxane (5.0 mL, 28 mmol). Mixture was stirred at 60° C. for 8 h, cooled, dissolved in 20 mL toluene and evaporated to dryness. Oily residue was mixed with 30 mL water, stirred 1 h and evaporated to dryness, then co-evaporated with additional 30 mL water. The crude product was dissolved in 200 mL water and filtered via Dowex 50 WX8-400 ion exchange resin (100 g). The filtrate was diluted with water to 220 mL total volume, and the pH of the solution was adjusted to 9-10 using aqueous NH3.
- Neat dry Tween 20® (13.3 g, 11 mmol) was dissolved in HMDS (26 mL) and THF (52 mL). Ammonium sulfate (0.054 g, 0.41 mmol) was added and mixture was stirred overnight at ambient temperature. The mixture was evaporated in vacuo, co-evaporated twice with 25 mL toluene and dried 1 h under high vacuum. The resulting oil was heated to 50° C., and GaBr3 (415 mg, 1.3 mmol) was added followed by dropwise addition of 1,1,3,3-tetramethyldisiloxane (6.9 mL, 39 mmol). The mixture was stirred at 60° C. for 8 h, cooled, dissolved in 26 mL toluene and evaporated to dryness. The oily residue was mixed with 39 mL water, stirred 15 h and evaporated to dryness, then co-evaporated with additional 39 mL water. The crude product was dissolved in 100 mL 5% MeOH in CH2Cl2 and filtered via 20 g silica. Silica pad was washed with 150 mL 5% MeOH in CH2Cl2. The filtrate was evaporated to dryness and dissolved in 70 mL water and 70 mL heptane. The aqueous layer was separated, and the organic layer was extracted with 35 mL water. The combined aqueous layers were evaporated giving 11.5 g (88%) of the exemplary polysorbate ether as viscous clear oil.
- Compound 2 was prepared from Tween 80® by the procedure described above for the preparation of Compound 1.
- Neat dry Tween 80® (10.6 g, 8 mmol) was dissolved in HMDS (20 mL) and THF (40 mL). Ammonium sulfate (0.05 g, 0.4 mmol) was added, and mixture was stirred overnight at ambient temperature. The mixture was evaporated in vacuo, co-evaporated twice with 20 mL toluene and dried 1 h under high vacuum, giving 12.5 g of heavy oil. The oil was heated to 50° C., and GaBr3 (360 mg, 1.2 mmol) was added followed by dropwise addition of 1,1,3,3-tetramethyldisiloxane (5.0 mL, 28 mmol). The mixture was stirred at 60° C. for 8 h, cooled, dissolved in 20 mL toluene and evaporated to dryness. Oily residue was mixed with 30 mL water, stirred 1 h and evaporated to dryness, then co-evaporated with additional 30 mL water. Crude product was dissolved in 150 mL water and filtered via Dowex 50 WX8-400 ion exchange resin (50 g). Filtrate was diluted with water to 200 mL total volume, pH of the solution was adjusted to 9-10 using aqueous NH3. A small sample was evaporated for 1H NMR analysis (
FIG. 2 ). - In the following experiments, the properties of exemplary reduced polysorbates were compared with the starting materials purchased from Sigma: Tween 20® BioXtra, Cat No P7949 and Tween 80® BioXtra, Cat No P8074
- A. Stability in 2M NaOH
- The following solutions are prepared in two vials: (A) 1% Tween 20® in 2M NaOH; (B) 1% Compound 2 in 2M NaOH. Both solutions were left at room temperature and the changes were observed visually. The solution A (initially clear) became non-transparent within one hour and turned into stiff gel the next day due to precipitation of the fatty acid salt. Solution B remained clear for at least one month.
- Similarly, hydrolytic stability of (A) Tween 80® and (B) Compound 2 were compared. The solution A became cloudy within one hour and turned into a stiff gel the next day due to precipitation of the fatty acid salt. Solution B remained clear for at least one month.
- B. Enzymatic Stability
- Stability of surfactants in the presence of hydrolyzing enzymes was tested according to a simplified literature procedure (Francisco J. Plou, Manuel Ferrer, Oscar M. Nuero, Maria V. Calvo, Miguel Alcalde, Fuensanta Reyes, Antonio Ballesteros. Analysis of Tween 80 as an esterase/lipase substrate for lipolytic activity assay. Biotechnology Techniques, Vol 12, No 3, March 1998, pp. 183-186.)
- B1. Resistance to Lipase Hydrolysis
- The following solutions are prepared in two vials: (A) to 20 mL of 1% Tween 20® in 10 mM tris-HCl (pH 8.0) is added 1 mL of 5% CaCl2 followed by 2 mL of 2 mg/mL solution of Lipase from porcine pancreas (Sigma L3126) in 10 μM tris-HCl (pH 8.0); (B) to 20 mL of 1% Compound 1 in 10 mM tris-HCl (pH 8.0) is added 1 mL of 5% CaCl2 followed by 2 mL of 2 mg/mL solution of Lipase from porcine pancreas (Sigma L3126) in 10 μM tris-HCl (pH 8.0). Both solutions were left at room temperature, and changes were observed visually. The solution A became cloudy within one hour and became non-transparent the next day due to precipitation the calcium salt of the fatty acid. Solution B remained clear for at least one month.
- Tween 80® and Compound 2 demonstrated similar differences in stability when subjected to Lipase hydrolysis conditions as described above.
- B2. Resistance to Esterase Hydrolysis
- The following solutions were prepared in two vials: (A) to 20 mL of 1% Tween 20® in 10 mM tris-HCl (pH 8.0) is added 1 mL of 5% CaCl2 followed by 40 μL of 100 UN/mL solution of Esterase from porcine liver (Sigma E2884) in 10 μM tris-HCl (pH 8.0); (B) to 20 mL of 1% Compound 1 in 10 mM tris-HCl (pH 8.0) is added 1 mL of 5% CaCl2 followed by 40 μL of 100 UN/mL solution of Esterase from porcine liver in 10 μM tris-HCl (pH 8.0). Both solutions were left at room temperature and changes were observed visually. The solution A became cloudy within one hour and became non-transparent the next day due to precipitation the calcium salt of the fatty acid. Solution B remained clear for at least one month.
- Tween 80® and Compound 2 demonstrated similar differences in stability when subjected to Esterase hydrolysis conditions as described above.
Claims (17)
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