发明名称 Neutral zwitterionic displacer molecules for hydrophobic displacement chromatography
摘要 A process for separating organic compounds from a mixture by reverse-phase displacement chromatography, including providing a hydrophobic stationary phase; applying to the hydrophobic stationary phase a mixture comprising organic compounds to be separated; displacing the organic compounds from the hydrophobic stationary phase by applying thereto an aqueous composition comprising a non-surface active hydrophobic neutral zwitterionic displacer molecule and optionally an organic solvent; and collecting a plurality of fractions eluted from the hydrophobic stationary phase containing the separated organic compounds; in which the non-surface active hydrophobic neutral zwitterionic displacer molecule comprises a hydrophobic zwitterion having the general formula, as defined in the disclosure: [CM-R*—CM′].
申请公布号 US9120846(B2) 申请公布日期 2015.09.01
申请号 US201214349102 申请日期 2012.10.03
申请人 Sachem, Inc. 发明人 Haymore Barry L.
分类号 A61K38/00;C07K5/00;C07K7/00;C07K16/00;C07K17/00;C07K1/20;B01D15/32;B01D15/42 主分类号 A61K38/00
代理机构 Renner, Otto, Boisselle & Sklar, LLP 代理人 Renner, Otto, Boisselle & Sklar, LLP
主权项 1. A process for separating organic compounds from a mixture by reverse-phase displacement chromatography, comprising: providing a hydrophobic stationary phase; applying to the hydrophobic stationary phase a mixture comprising organic compounds to be separated; displacing the organic compounds from the hydrophobic stationary phase by applying thereto an aqueous composition comprising a non-surface active hydrophobic neutral zwitterionic displacer molecule; and collecting a plurality of fractions eluted from the hydrophobic stationary phase containing the separated organic compounds; wherein the non-surface active hydrophobic neutral zwitterionic displacer molecule comprises a hydrophobic neutral zwitterion having the general formula: [CM-R*—CM′] wherein in the general formula, CM is an independent hydrophobic chemical moiety with a formal positive (+) charge selected from: quaternary ammonium (I), quaternary phosphonium (II), sulfonium (III), sulfoxonium (IV), imidazolinium (amidinium) (V), guanidinium (VI), imidazolium (VII), 1,2,3,4-tetrahydroisoquinolinium (VIII), 1,2,3,4-tetrahydroquinolinium (IX), isoindolinium (X), indolinium (XI), benzimidazolium (XII), pyridinium (XIIIa, XIIIb, XIIIc, XIIId), quinolinium (XIV), isoquinolinium (XV), and CM′ is an independent hydrophobic chemical moiety with a formal negative (−) charge selected from: carboxylate (XVI), N-acyl-α-amino acid (XVII), sulfonate (XVIII), sulfate monoester (XIX), phosphate monoester (XX), phosphate diester (XXI), phosphonate monoester (XXII), phosphonate (XXIII), tetraaryl borate (XXIV), boronate (XXV), boronate ester (XXVI); wherein the chemical moieties (I)-(XXVI) have the following chemical structures: wherein in the general formula, CM and CM′ are independent charged chemical moieties having the opposite formal charge such that the molecule as a whole is an electrically neutral zwitterion having zero formal charge at operational pH and CM and CM′ are chemically attached to each other by a doubly connected chemical moiety, R*, which replaces one R1, R2(if present), R3 (if present) or R4 (if present) chemical moiety on CM and replaces one R1′, R2′ (if present), R3′ (if present) or R4′ (if present) chemical moiety on CM′, wherein, when any R1, R2, R3, and R4 is present on CM′, it is designated R1′, R2′, R3′, and R4′; wherein each of R1, R1′, R2, R2′, R3, R3′, R4 and R4′ is a linear or branched chemical moiety independently defined by the formula, —CxX2x-2r—AR1—CuX2u-2s—AR2,R* is a direct chemical bond or is a doubly connected, linear or branched chemical moiety defined by the formula, —CxX2x-2r—AR1-CuX2u-2s—,and R5 is a linear or branched chemical moiety defined by the formula, —CxX2x-2r—AR2; wherein each AR1 independently is a doubly connected methylene moiety (—CX1X2—, from methane), a doubly connected phenylene moiety (—C6G4-, from benzene), a doubly connected naphthylene moiety (—C10G6—, from naphthalene) or a doubly connected biphenylene moiety (—C12G8-, from biphenyl); wherein AR2 independently is hydrogen (—H), fluorine (—F), a phenyl group (—C6G5), a naphthyl group (—C10G7) or a biphenyl group (—C12G9); wherein each X, X1 and X2 is individually and independently —H, —F, —Cl or —OH; wherein any methylene moiety (—CX1X2—) within any —CxX2x-2r— or within any —CuX2u-2s- or within any —(CX1X2)p— may be individually and independently replaced with an independent ether-oxygen atom, —O—, an independent thioether-sulfur atom, —S—, or an independent ketone-carbonyl group, —C(O)—, in such a manner that each ether-oxygen atom, each thioether-sulfur atom or each ketone-carbonyl group is bonded on each side to an aliphatic carbon atom or an aromatic carbon atom; wherein not more than two ether-oxygen atoms, not more than two thioether-sulfur atoms and not more than two ketone-carbonyl groups may be replaced into any —CxX2x-2r— or into any —CuX2u-2s—; wherein mx, is the total number of methylene groups in each —CxX2x-2r— that are replaced with ether-oxygen atoms, thioether-sulfur atoms and ketone-carbonyl groups, and mu, is the total number of methylene groups in each —CuX2u-2s— that are replaced with ether-oxygen atoms, thioether-sulfur atoms and ketone-carbonyl groups; wherein G is individually and independently any combination of —H, —F, —Cl, —CH3, —OH, —OCH3, —N(CH3)2, —CF3, —CO2Me, —CO2NH2; —CO2NHMe, —CO2NMe2; wherein G* is individually and independently any combination of —F, —Cl, —R2, —OH, —OR2, —NR2R3, —CF3, —CO2Me, —CO2NH2; —CO2NHMe, —CO2NMe2; wherein a pair of R2, R2′, R3, R3′, R4 and R4′ may comprise a single chemical moiety such that R2/R3, R2/R4, R3/R4, R2′/R3′, R2,/R4′ or R3′/R4′ is individually and independently —(CX1X2)p- with p=3, 4, 5 or 6; wherein the integer values of each of x, r, u, s, mx, mu are independently selected for each R1, R1′, R2, R2′, R3, R3′, R4, R4′, R5 and R*, integer values r and s are the total number of contained, isolated cis/trans olefinic (alkene) groups plus the total number of contained simple monocyclic structures and fall in the ranges 0≦r≦2 and 0≦s≦2, the numeric quantity x+u−mx−mu falls in the range 0≦x+u−mx−mu≦11; wherein at least one aromatic chemical moiety, heterocyclic aromatic chemical moiety, imidazoline chemical moiety, amidine chemical moiety or guanidine chemical moiety is contained within CM or CM′; wherein a group-hydrophobic-index for each R-chemical-moiety (n) is numerically equal to the sum of the number of aliphatic carbon atoms plus the number of olefinic carbon atoms plus the number of thioether-sulfur atoms plus the number of chlorine atoms plus one-fifth the number of fluorine atoms plus one-half the number of ether-oxygen atoms plus one-half the number of ketone-carbon atoms plus one-half the number of aromatic carbon atoms beyond the number six minus the number of hydroxyl-oxygen atoms beyond the number one; wherein an overall-hydrophobic-index (N) for each [CM-R*-CM′] is numerically equal to the sum of the number of aliphatic carbon atoms plus the number of olefinic carbon atoms plus the number of thioether-sulfur atoms plus the number of chlorine atoms plus one-fifth the number of fluorine atoms plus one-half the number of ether-oxygen atoms plus one-half the number of ketone-carbon atoms plus one-half the number of aromatic carbon atoms beyond the number six minus the number of hydroxyl-oxygen atoms beyond the number one; wherein each of the group-hydrophobic-indices (1n and 1′n) for R1 and R1′ fall in the range 4.0<1n,1′n<12.0, each of the group-hydrophobic-indices (2n, 2′n, 3n, 3′n, 5n, 5′n and *n) for R2, R2′, R3, R3′, R5, R5′, R*, when present, fall in the range 0.0≦2n, 2′n, 3n, 3′n, 5n, 5′n, *n <12.0 and each of the group-hydrophobic-indices (4n and 4′n) for R4 and R4′, when present, fall in the range 0.0≦4n, 4′n≦5.0; wherein the overall-hydrophobic-index (N) falls in the range 10.0≦N<24.0; wherein the numeric value of the group-hydrophobic-index calculated for a cyclic chemical moiety is divided equally between the two respective R-chemical-moieties; wherein R1 is identified as that R-chemical-moiety when only one such chemical moiety is attached to CM or CM′; wherein R1 is identified as that R-chemical-moiety having the largest value of the group-hydrophobic-index when there are more than one such chemical moieties attached to CM or CM′; wherein R4 is identified as that R-chemical-moiety having the smallest value of the group-hydrophobic-index when there are more than three such chemical moieties attached to CM or CM′.
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