CN111732734A - Sulfur-containing polyethylene glycol modified resin - Google Patents

Sulfur-containing polyethylene glycol modified resin Download PDF

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CN111732734A
CN111732734A CN202010769695.5A CN202010769695A CN111732734A CN 111732734 A CN111732734 A CN 111732734A CN 202010769695 A CN202010769695 A CN 202010769695A CN 111732734 A CN111732734 A CN 111732734A
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resin
polyethylene glycol
peg
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向双春
高峰
李云平
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Dalian Alaning Biotechnology Co ltd
Suzhou Jinding Biological Co ltd
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Suzhou Jinding Biological Co ltd
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Abstract

The invention obtains the polyethylene glycol containing sulfur element by the reaction of polyethylene glycol monoallyl ether and sulfhydryl compound containing amino or carboxyl, and the structural general formula is as follows:
Figure DEST_PATH_IMAGE002
simultaneously, amino or carboxyl is introduced into polyethylene glycol, so that the modified polyethylene glycol is very convenientIntroduced into the resin to obtain polyethylene glycol resin with different efficacies.

Description

Sulfur-containing polyethylene glycol modified resin
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to sulfur-containing polyethylene glycol modified resin.
Background
Merrifield et al reported the concept of solid phase polypeptide synthesis as early as 1960, cross-linking styrene to different types of chloromethylated polystyrene [ Wu M, Yang G, Chen Z. Polymer supported peroxidisefailure: A mil and clean oxidation of organic compounds and indirect polymers, reaction function Polymer, 2000, 44: 97-100; HariA, Miller BL., expands differentiation in soluble vs. soluble-supported reactivity for the synthesis of sulfonic acid derivatives, Org Lett, 1999, 1: 2109-2111 ] as a carrier resin for solid phase synthesis of polypeptides (Merrifield resin, see below). Since then, polymeric solid supports have become more and more popular for use in the synthesis and purification of products.
Figure 665936DEST_PATH_IMAGE001
Merrifield resin and polyethylene glycol (PEG) structure
Despite the many known advantages of crosslinked polystyrene support resins, in solid phase synthesis of polypeptides, the polymers are mixed with polar solvents used in conventional polypeptide synthesis, such as Dimethylformamide (DMF) [ Santini R, Griffith MC, Qi M.A measure of solvent effects on drying of resins for soluble phase organic synthesis. Tetrahedron Lett, 1998, 39: 8951-8954; the compatibility of Vaino AR, Goodin DB, JandaKD, inquiring resins for solid phase organic synthesis, The relative sensitivity of The spinning and microscopic as probe by EPR and fluorescence spectroscopy, J Comb Chem, 2000, 2: 330-336, is poor, as well as The absorption and swelling properties of The solvent. Furthermore, in heterogeneous synthesis, the poorly soluble polymer changes the traditional liquid phase synthesis into solid phase synthesis, the reaction becomes more complicated, the reaction kinetics is non-linear, and it is difficult to evaluate the completion of the reaction and the purity of the synthesized product on the support. To overcome the drawbacks of Merrifield et al resins, polyethylene glycol (PEG, shown in formula (a) below) such as TentaGel (formula (a) below) and formula (b) below) have been grafted onto a hydrophobic polystyrene core, which resins have good swelling in both non-polar and polar solvents [ Becker H, Lucas HW, Maul J, Pilai VNR, Anzier H, Mutter M. PEG-PS resins having descriptions for soluble-phase peptide synthesis, Macromol Chem Rapid Commun.1982, 3: 217-223; wan LS, Ke BB, Li XK. Honeycomb-patterned films of polystyrene/poly (ethylene glycol), Preparation, surface aggregation and polyethylene adsorption, Sci China Ser B-Chem, 2009, 52: 969-974 ]. Currently, modified polystyrene resins have been greatly developed in research and development and commercialization.
Figure 114235DEST_PATH_IMAGE002
Structures of TentaGel resin and ArgoGel resin, wherein the spherical resin portion is crosslinked polystyrene, and X represents a functional group
Polyethylene glycol and the like having good swelling properties can be introduced into the resin by various methods. The first method is that polyethylene glycol forms an ether bond with the resin. TentaGel resin and ArgoGel resin. The preparation method is to form a polyethylene glycol chain by polymerizing the resin with hydroxyl and ethylene oxide under the catalysis of alkali and high pressure. The length of the polyethylene glycol On the surface of the Resin obtained by the method is within 600, and the molecular weight is smaller, so that the method cannot meet the Synthesis of most of polypeptides [ Owen W. Gooding, Sylvee Baudart, Tracy L. Deegan, On the Development of New Poly (styrene-oxy-ethylene) Graft Copolymer Resin Supports for Solid-Phase Organic Synthesis J. comb. chem. 1999, 1, 113-122 ].
The second is the introduction of polyethylene glycol to the resin surface through a lipid group. The resin containing lipid group is easy to hydrolyze or aminolyze in the process of polypeptide synthesis, and has no practical application.
The third method is to introduce polyethylene glycol through an amide bond. The method can be realized by the reaction of resin with carboxyl and polyethylene glycol containing amido. Because it is difficult to introduce carboxyl groups on the resin surface, carboxyl groups are introduced through succinic anhydride and then reacted with Polyethylene Glycol containing amino groups [ High-Load "Polyethylene Glycol-Polystyrene (PEG-PS) graftSupports for Solid-Phase Synthesis, Kates et al biopolymers (PeptideSec.), Vol. 47, 365-. For example, the structural formula shown in the following figure.
Figure 441442DEST_PATH_IMAGE003
Resin formed by reaction of carboxyl resin and polyethylene glycol containing amino
Another popular method is to react carboxyl-containing polyethylene glycol with an amine-based resin to produce a polyethylene glycol resin. The method is exemplified as follows:
Figure 367810DEST_PATH_IMAGE005
resin formed by reaction of carboxyl-containing polyethylene glycol and resin with amino
The amino-containing polyethylene glycol can also react with resin with benzenesulfonyl chloride, isocyanate and isothiocyanate to prepare modified resin with polyethylene glycol on the surface.
The method for introducing polyethylene glycol into resin generally has the problems of poor resin effect or high production cost of modified polyethylene glycol. The invention obtains the polyethylene glycol containing sulfur element by the reaction of polyethylene glycol monoallyl ether and sulfhydryl compound containing amino or carboxyl, and introduces the amino or carboxyl into the polyethylene glycol, thus conveniently introducing the polyethylene glycol into resin and obtaining the polyethylene glycol resin with good performance.
Disclosure of Invention
Aiming at the problems that the modified polyethylene glycol resin does not reach the standard or is difficult to prepare, the invention provides the sulfur-containing polyethylene glycol modified resin and the preparation method thereof.
A sulfur-containing polyethylene glycol modified resin has a chemical structural general formula as follows:
Figure 978919DEST_PATH_IMAGE006
（Ⅰ）
a and B are one of the following chemical structure fragments:
a is
Figure 581808DEST_PATH_IMAGE007
B is
Figure 380000DEST_PATH_IMAGE008
Either, or,
a is
Figure 375638DEST_PATH_IMAGE009
B is
Figure 575675DEST_PATH_IMAGE010
Either, or,
a is
Figure 116509DEST_PATH_IMAGE011
B is
Figure 401996DEST_PATH_IMAGE012
Either, or,
a is
Figure 935746DEST_PATH_IMAGE013
B is
Figure 239557DEST_PATH_IMAGE014
Either, or,
a is
Figure 466139DEST_PATH_IMAGE015
B is
Figure 238923DEST_PATH_IMAGE016
Either, or,
a is
Figure 61517DEST_PATH_IMAGE017
B is
Figure 236146DEST_PATH_IMAGE018
；
Wherein X is an S atom or a sulfone (SO2),
W1a resin of the structure:
Figure 368050DEST_PATH_IMAGE019
W2a resin of the structure:
Figure 877398DEST_PATH_IMAGE020
、
Figure 487371DEST_PATH_IMAGE021
、
Figure 782086DEST_PATH_IMAGE022
、
Figure 101203DEST_PATH_IMAGE023
one of (1); w is matrix resin, and the matrix resin is one of polystyrene resin, polyacrylamide resin and polymethacrylate resin;
n is 5-120, q1 and q2 are respectively 1-5, m1 and m2 are both 1-2, R1 is hydrogen, methyl, carboxy methyl ester, carboxy tert-butyl ester, carboxy benzyl ester, -CH2OCH3、-CH2OCH2CH3One of (1); r2 is one of hydrogen, methyl, ethyl and benzyl; r3 represents one of hydrogen, methyl, dimethylamino, diethylamino and dibenzylamino; r4 represents one of hydrogen, methyl, ethyl and benzyl; r5 represents one of hydrogen, methyl, ethyl and benzyl;
the K1 is one of the following structural formulas:
Figure 583000DEST_PATH_IMAGE024
；
Figure 996664DEST_PATH_IMAGE025
；
Figure 880306DEST_PATH_IMAGE026
；
Figure 868859DEST_PATH_IMAGE027
；
Figure 837952DEST_PATH_IMAGE028
；
the K is one of the following structural formulas:
Figure 55307DEST_PATH_IMAGE029
；
Figure 809768DEST_PATH_IMAGE030
；
Figure 454376DEST_PATH_IMAGE031
；
Figure 176344DEST_PATH_IMAGE032
；
Figure 931810DEST_PATH_IMAGE033
。
further, the matrix resin is polystyrene resin.
A synthetic method of sulfur-containing polyethylene glycol modified resin comprises the following steps:
in the first step, sulfur-containing polyethylene glycol is synthesized.
According to the difference of the structural general formula, the synthesis method of the sulfur-containing polyethylene glycol is divided into the following methods:
the synthesis method 1:
the structural general formula (I) is as follows:
Figure 773733DEST_PATH_IMAGE034
and
Figure 854822DEST_PATH_IMAGE035
the sulfur-containing polyethylene glycol modified resin is represented by the structural formula
Figure 798507DEST_PATH_IMAGE036
The sulfur-containing polyethylene glycol is obtained by reacting with resin,
the specific reaction steps of the sulfur-containing polyethylene glycol when X is S are as follows:
step 1, condensing polyethylene glycol monoallyl ether 1 with a mercapto tert-butyl ester compound 2 under the catalysis of AIBN in a solvent, evaporating the solvent under reduced pressure to remove the solvent to obtain a reaction concentrated liquid, adding water, extracting the unreacted mercapto tert-butyl ester compound 2 with petroleum ether, extracting the water layer with the solvent, and evaporating the solvent under reduced pressure to obtain polyethylene glycol-R6 ester compound thioether 3.
And 2, mixing an acid-binding agent, the polyethylene glycol-R6 ester compound thioether 3 and p-toluenesulfonyl chloride in a solvent for reaction, evaporating the solvent under reduced pressure, washing with acid water for a plurality of times, directly purifying by using a silica gel column to remove unreacted p-toluenesulfonyl chloride after a dichloromethane layer is dried, and evaporating the eluent under reduced pressure to obtain the Tos ester 4 of the polyethylene glycol-R6 ester compound thioether.
Step 3, reacting Tos ester 4 of polyethylene glycol-tert-butyl ester compound thioether with sodium azide in a proper solvent, evaporating under reduced pressure to remove the solvent to obtain a thick liquid, dissolving the thick liquid with dichloromethane, washing with water to remove the sodium azide, and evaporating the dichloromethane under reduced pressure to obtain polyethylene glycol-R6Ester compound thioether azide compound 5.
Step 4, polyethylene glycol-R6Ester compound thioether azide compound 5 is reacted with triphenylphosphine in a suitable solvent for 2 to 12 hours. Adding water into the reaction solution, adjusting the pH value to 3-4 by using dilute acid, extracting triphenylphosphine and triphenylphosphine oxide from the obtained mixture by using ethyl acetate, basifying the water layer until the pH value is 8-9, extracting by using dichloromethane, drying, decompressing and rotary steaming to obtain amino-polyethylene glycol-R6An ester compound thioether 6.
Step 5, amino-polyethylene glycol-R6Removal of R from the ester Compound thioether 6 with an acid or base in a suitable solvent6And (4) a base. Then adjusting the pH to 7 with an acid or a base to obtain H2N-PEGn-CH2-CH2CH2-S-(CH2)q-(R3)CH-COOH7。
The acid for removing tert-butyl adopts: p-toluenesulfonic acid, methanesulfonic acid, hydrogen chloride ether solution and hydrogen chloride 1, 4 dioxane solution; removal of R6The base used in (1) is: sodium hydroxide, potassium hydroxide.
The method for synthesizing the compound 8-9 comprises the following specific steps:
step 1, amino compound and polyethylene glycol-R6Reacting Tos ester 4 of ester compound thioether for 1 to 5 hours, evaporating the solvent under reduced pressure, adding water, acidifying until the pH value is equal to 6-7, and evaporating under reduced pressure to obtain R amino-polyethylene glycol-R6An ester compound thioether 8.
Step 2, R amino-polyethylene glycol-R6Removal of R from the ester Compound thioether 8 with an acid or base in a suitable solvent6. Then adjusting pH to 7 with acid or base to obtain R-HN-PEGn-CH2CH2CH2-S-(CH2)q1-(R3) CH-COOH 9. The structural formulae of the above-mentioned compounds 1 to 9 are as follows:
Figure 373976DEST_PATH_IMAGE037
、
Figure 86717DEST_PATH_IMAGE038
、
Figure 807548DEST_PATH_IMAGE039
、
Figure 753377DEST_PATH_IMAGE040
、
Figure 850646DEST_PATH_IMAGE041
、
Figure 683472DEST_PATH_IMAGE042
、
Figure 840784DEST_PATH_IMAGE043
、
Figure 509794DEST_PATH_IMAGE044
、
Figure 676333DEST_PATH_IMAGE045
wherein R is5Is one of hydrogen, methyl, ethyl, benzyl and isopropyl, R6Is tert-butyl or benzyl.
When X is Sulfone (SO)2) When the compound 7 or 9 is oxidized by the following method, X is Sulfone (SO)2) Is/are as follows
Figure 98087DEST_PATH_IMAGE046
：
The sulfur-containing polyethylene glycol comprises the following specific reaction steps:
（1）R5-HN-PEGn-CH2CH2CH2-S-(CH2)q1-(R3) CH-COOH was dissolved in alkaline water and BOC anhydride was added. After the reaction, the aqueous solution was extracted with petroleum ether. Adjusting the pH of a water layer to 3-4 by using dilute acid, extracting by using dichloromethane, and removing the dichloromethane by reduced pressure distillation to obtain Boc-R5N-PEGn-CH2CH2CH2-S-(CH2)q1-(R3)CH-COOH10；
（2）Boc-R5N-PEGn-CH2CH2CH2-S-(CH2)q1-(R3) Dissolving CH-COOH10 in ethyl acetate, adding sodium tungstate aqueous solution and hydrogen peroxide, and heating to react until the thioether is completely converted into sulfone. Distilling off ethyl acetate under reduced pressure, extracting the obtained aqueous solution with dichloromethane, washing dichloromethane with water for several times, distilling off dichloromethane under reduced pressure to obtain Boc-R5N-PEGn-CH2CH2CH2-SO2-(CH2)q1-(R3)CH-COOH11；
（3）Boc-R5N-PEGn-CH2CH2CH2-SO2-(CH2)q1-(R3) The tert-butoxycarbonyl group was removed from CH-COOH11 with an acid in an appropriate solvent. After the reaction is finished for 3-24 hours, the solvent is evaporated to dryness under reduced pressure to obtain a viscous liquid, the viscous liquid is dissolved by methanol, and then the pH value is adjusted to be equal to 7 by alkali to obtain R5-HN-PEGn-CH2-CH2CH2-SO2-(CH2)q1-(R3) CH-COOH 12. The structural formulas of compounds 10-12 are as follows:
Figure 675568DEST_PATH_IMAGE047
、
Figure 81142DEST_PATH_IMAGE048
、
Figure 785792DEST_PATH_IMAGE049
R5is one of hydrogen, methyl, ethyl, benzyl and isopropyl.
The synthesis method 2 comprises the following steps:
the structural general formula (I) is as follows:
Figure 343944DEST_PATH_IMAGE050
and
Figure 843058DEST_PATH_IMAGE051
the sulfur-containing polyethylene glycol modified resin is represented by the structural formula
Figure 470349DEST_PATH_IMAGE052
The sulfur-containing polyethylene glycol is obtained by reacting with resin,
the specific reaction steps of the sulfur-containing polyethylene glycol when X is S are as follows:
(1) polyethylene glycol monoallyl ether 1 was condensed with a mercapto Boc amide group-containing compound 13 in a solvent under AIBN catalysis. Evaporating the solvent under reduced pressure to obtain a reaction thick liquid, adding water, extracting the unreacted Boc acylamino-containing compound 13 by using petroleum ether, extracting a water layer by using the solvent, and evaporating the solvent under reduced pressure to obtain a polyethylene glycol-thioether-Boc acylamino compound 14;
(2) dissolving the polyethylene glycol-thioether-Boc acylamino compound 14 and tert-butyl acrylate in an organic solvent, and adding alkaline water for reaction. After the reaction, water was added and stirred uniformly, and the aqueous layer was removed by layering. Drying the organic layer, and then decompressing and evaporating to dryness to obtain Boc-R2-N-(R1)CH-(CH2)q2-S-CH2CH2CH2-PEGn-CH2CH2COOtBu15；
(3) Removing Boc and tert-butyl from tert-butyl propionate-polyethylene glycol-thioether-Boc amide compound 15 with acid in appropriate solvent, reacting, evaporating solvent under reduced pressure after reaction to obtain viscous liquid, dissolving with methanol, and adjusting pH to 7 with alkali to obtain R2-NH- (R)1)CH-(CH2)q2-S-CH2CH2CH2-PEGn-CH2CH2COOH16。
The synthesis of 16-1 comprises the following specific steps:
(1) dissolving the polyethylene glycol-thioether-Boc amido compound 14 and tert-butyl bromoacetate in an organic solvent, and adding sodium hydride in batches for reaction. After the reaction, the reaction mixture was slowly poured into a saturated ammonium chloride solution, and the aqueous layer was removed by separation. Drying the organic layer, and then decompressing and evaporating to dryness to obtain Boc-R2-N-(R1)CH-(CH2)q2-S-CH2CH2CH2-PEGn-CH2COOtBu15-1；
(2) Removing Boc and tert-butyl by acid in proper solvent for reaction, evaporating solvent under reduced pressure after reaction, dissolving viscous liquid with methanol, and adjusting pH to 7 with alkali to obtain R2-NH-(R1)CH-(CH2)q2-S-CH2CH2CH2-PEGn-CH2COOH 16-1. The specific structural formulas of the compounds 13-16 and the compounds 15-1 and 16-1 are as follows:
Figure 713111DEST_PATH_IMAGE053
、
Figure 624304DEST_PATH_IMAGE054
、
Figure 294320DEST_PATH_IMAGE055
、
Figure 408907DEST_PATH_IMAGE056
、
Figure 206092DEST_PATH_IMAGE057
、
Figure 722524DEST_PATH_IMAGE058
R2is one of hydrogen, methyl, ethyl, benzyl and isopropyl.
II, when X is Sulfone (SO)2) In this case, compound 15 or 15-1 is oxidized by the following method, and the protecting group is removed to give X as Sulfone (SO)2) Is/are as follows
Figure 829021DEST_PATH_IMAGE059
：
The specific reaction steps are as follows:
(1) dissolving tert-butyl propionate-polyethylene glycol-thioether-Boc amide compound 15 in ethyl acetate, adding sodium tungstate aqueous solution and hydrogen peroxide, and heating for reaction until thioether is completely converted into sulfone. Distilling off ethyl acetate under reduced pressure, extracting the obtained aqueous solution with dichloromethane, washing dichloromethane with water for several times, distilling off dichloromethane under reduced pressure to obtain Boc-R2-N-(R1)CH2-(CH2)q2-SO2-CH2CH2CH2-PEGn-CH2CH2COOtBu17；
（2）Boc-R2-N-(R1)CH2-(CH2)q2-SO2-CH2CH2CH2-PEGn-CH2CH2COOtBu17 Boc and t-butyl were removed with acid in a suitable solvent. After the reaction is finished for 3-24 hours, the solvent is evaporated to dryness under reduced pressure to obtain a viscous liquid, the viscous liquid is dissolved by methanol, then the pH value is adjusted to be 7 by alkali,to obtain R2-NH-(R1)CH-(CH2)q2-SO2-CH2CH2CH2-PEGn-CH2CH2COOH 18. The compound Boc-R2-N-(R1)CH2-(CH2)q2-SO2-CH2CH2CH2-PEGn-CH2CH2COOtBu17 and R2-NH-(R1)CH-(CH2)q2-SO2-CH2CH2CH2-PEGn-CH2CH2The structural formula of COOH18 is as follows:
Figure 430903DEST_PATH_IMAGE060
、
Figure 264736DEST_PATH_IMAGE061
thirdly, the structural general formula (I) is as follows:
Figure 635674DEST_PATH_IMAGE062
and
Figure 913072DEST_PATH_IMAGE063
the sulfur-containing polyethylene glycol modified resin is characterized in that the structural formula is as follows:
Figure 487404DEST_PATH_IMAGE064
the specific synthetic steps of the sulfur-containing polyethylene glycol are as follows:
the synthesis method 3:
when X is S, according to K and m2Different structure of value, sulfur-containing polyethylene glycol R2-NH-(R1)CH2-(CH2)q2-S-CH2CH2CH2-PEGn-(CH2)m2The specific structure of PH-K is as follows:
Figure 141239DEST_PATH_IMAGE065
Figure 366684DEST_PATH_IMAGE066
Figure 549404DEST_PATH_IMAGE067
Figure 640725DEST_PATH_IMAGE068
Figure 567093DEST_PATH_IMAGE069
Figure 647045DEST_PATH_IMAGE070
Figure 282556DEST_PATH_IMAGE071
Figure 80748DEST_PATH_IMAGE072
Figure 76386DEST_PATH_IMAGE073
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。
the method comprises the following specific steps:
1. preparation of Compounds 19, 21, 23, 25, 27
(1) Dissolving the polyethylene glycol-thioether-Boc amido compound 14 in an anhydrous solvent, slowly adding alkali, and then adding tBu-CP1-Tos. After the reaction is finished, slowly pouring the reaction liquid into saturated ammonium chloride solution, and extracting the obtained mixed liquid with petroleum to remove the residual tBu-CP1-Tos. Aqueous layer with dichloro-benzeneExtracting with methane for several times, washing dichloromethane layer with saturated sodium chloride aqueous solution for several times, drying with anhydrous sodium sulfate, and distilling under reduced pressure to remove dichloromethane to obtain tBu-CP1-polyethylene glycol-thioether-Boc amide compound 39.
The polyethylene glycol-thioether-Boc amido compound 14, alkali and tBu-CP1-molar ratio of Tos of 1: (3-8): (2-5);
the reaction temperature was controlled at 0 ℃ to 50 ℃.
The alkali is one of sodium hydride and potassium hydride.
（2）tBu-CP1-polyethylene glycol-thioether-Boc amide compound 39 Boc and tert-butyl are removed with acid in a suitable solvent. And after the reaction is finished for 3-24 hours, evaporating the solvent to dryness under reduced pressure to obtain a viscous liquid, dissolving the viscous liquid with methanol, and then adjusting the pH to be equal to 7 with alkali to obtain compounds 19, 21, 23, 25 and 27.
The acid, tBu-CP1The molar ratio of the polyethylene glycol-thioether-Boc amido compound 39 is (1-5): 1
The reaction solvent adopts: one or more of chloroform, dichloromethane, 1, 4 dioxane, ethyl acetate and toluene.
The reaction temperature was controlled at-10 ℃ to 30 ℃.
The acid for removing tert-butyl adopts: one or more of p-toluenesulfonic acid, methanesulfonic acid, hydrogen chloride ether solution and hydrogen chloride 1, 4 dioxane solution.
The tBu-CP1The specific structural formula of the compound corresponding to Tos is as follows:
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、
Figure 335701DEST_PATH_IMAGE076
、
Figure 869450DEST_PATH_IMAGE077
、
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、
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2. preparation of Compounds 20, 22, 24, 26, 28
(1) Polyethylene glycol-thioether-Boc amido compound 14, tBu-CP2Dissolving triphenylphosphine in a proper solvent, slowly dropwise adding an azo catalyst, reacting for 12-48 hours, washing the reaction solution for several times by using water, drying by using anhydrous sodium sulfate, purifying by using a silica gel column to remove triphenylphosphine and triphenylphosphine oxide, and performing reduced pressure spin drying on the eluent to obtain tBu-CP1-polyethylene glycol-thioether-Boc amide compound 40.
The polyethylene glycol-thioether-Boc amido compound 14, tBu-CP2The molar ratio of-OH, azo catalyst and triphenylphosphine is 1: (1-3): (1-4): (1 to 4)
The reaction temperature was controlled at 10 ℃ to 70 ℃.
（2）tBu-CP2-polyethylene glycol-thioether-Boc amido compound 40 Boc and tert-butyl are removed with acid in a suitable solvent. And after the reaction is finished for 3-24 hours, evaporating the solvent to dryness under reduced pressure to obtain a viscous liquid, dissolving the viscous liquid with methanol, and then adjusting the pH to be equal to 7 with alkali to obtain compounds 20, 22, 24, 26 and 28.
The acid, tBu-CP2The molar ratio of the polyethylene glycol-thioether-Boc amido compound 40 is (1-5): 1.
the reaction solvent adopts: one or more of chloroform, dichloromethane, 1, 4 dioxane, ethyl acetate and toluene.
The reaction temperature was controlled at-10 ℃ to 30 ℃.
The acid for removing tert-butyl adopts: one or more of p-toluenesulfonic acid, methanesulfonic acid, hydrogen chloride ether solution and hydrogen chloride 1, 4 dioxane solution. The tBu-CP2The specific structure of-OH is shown below:
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、
Figure 729642DEST_PATH_IMAGE081
、
Figure 169851DEST_PATH_IMAGE082
、
Figure 36175DEST_PATH_IMAGE083
、
Figure 296255DEST_PATH_IMAGE084
when X is Sulfone (SO)2) When, according to the structure of K and m2Different structures of value, R2-NH-(R1)CH2-(CH2)q-SO2-CH2CH2CH2-PEGn-(CH2)m1The specific structure of PH-K is as follows:
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Figure 951676DEST_PATH_IMAGE086
Figure 988902DEST_PATH_IMAGE087
Figure 251125DEST_PATH_IMAGE088
Figure 664789DEST_PATH_IMAGE089
Figure 814010DEST_PATH_IMAGE090
Figure 38449DEST_PATH_IMAGE091
Figure 7542DEST_PATH_IMAGE092
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the specific synthesis method comprises the following steps: reference compound 18 was prepared by oxidation and deprotection using compound 39 or 40 as starting material.
And step two, reacting the sulfur-containing polyethylene glycol synthesized in the step one with different types of resins to synthesize the resin modified by the sulfur-containing polyethylene glycol:
the preparation method comprises the following steps:
the method comprises the following steps:
1) and (3) reacting sulfur-containing polyethylene glycol and Fmoc-OSu in an organic water mixed solvent by using alkali as an acid-binding agent to obtain the Fmoc-sulfur-containing polyethylene glycol.
The reaction solvent is one of acetone/water, tetrahydrofuran/water, 1, 4 dioxane/water and acetonitrile/water.
The acid-binding agent is selected from one of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, etc.
2) Fmoc-sulfur-containing polyethylene glycol corresponding to the resin, a polypeptide condensing agent, an organic base, and PS1 (aminomethyl resin or substituted aminomethyl resin) are subjected to coupling reaction in a proper solvent, and the Fmoc-sulfur-containing polyethylene glycol is introduced into the resin.
The molar ratio of the reaction feeding materials is Fmoc-sulfur-containing polyethylene glycol: polypeptide condensing agent: an organic base and an aminomethyl resin or a substituted aminomethyl resin = (2 to 4): (2-4): (3-6): 1;
the polypeptide condensing agent includes one of common reagents such as DIC, HBTU, HATU and COMU.
The organic base is one of IDEA, triethylamine and N-methylmorpholine.
The solvent used in the synthesis adopts one of DMF, NMP and dichloromethane.
3) Fmoc-sulfur-containing polyethylene glycol resin is synthesized by using a common Fmoc removal solvent to remove Fmoc protecting groups, so that the sulfur-containing polyethylene glycol modified resin is obtained.
The Fmoc removal solution is a 20% piperidine solution, 1-5%/1-5% DBU/1-octyl mercaptan solution or 1-5%/19-15% DBU/piperidine solution, and the solvent adopted by the solution comprises one or more of DMF, NMP, tetrahydrofuran, dimethyl tetrahydrofuran, 1, 4 dioxane and acetonitrile.
The method 2 comprises the following steps:
reacting sulfur-containing polyethylene glycol with one of sulfonyl chloride resin, isocyanate resin or isothiocyanate resin and organic base in proper solvent at 5-40 deg.c for several hr. And after the reaction is finished, draining the reaction solution, and washing the obtained resin with the solvent for several times to obtain the target resin.
The molar ratio of the reaction feeding materials is that the sulfur-containing polyethylene glycol: organic base: sulfonyl chloride resin = (2-4): (3-6): 1;
the organic base is one of triethylamine, nitrogen methyl morpholine and the like.
The reaction solvent is one of dichloromethane, ethyl acetate, DMF, NMP, tetrahydrofuran, dimethyl tetrahydrofuran, etc.
The method 3 comprises the following steps:
carboxyl resin, polypeptide condensation reagent and organic alkali react for half an hour at room temperature in proper solvent, then sulfur-containing polyethylene glycol corresponding to the resin is added for reaction for hours at room temperature, reaction liquid is drained, and the obtained resin is washed for a plurality of times by the solvent, so that the target resin is obtained.
The molar ratio of the reaction feeding materials is sulfur-containing polyethylene glycol, a polypeptide condensing agent, organic alkali and carboxyl resin = (2-4): (2-4): (3-6): 1
The polypeptide condensing agent is one of N, N' -disuccinimidyl carbonate, DIC, HBTU, HATU, COMU, TBTU, HOBt and the like.
The organic base adopts one or more of DIEA, DBU, triethylamine and N-methyl morpholine.
The solvent used in the synthesis adopts one or more of DMF, NMP and dichloromethane.
The invention has the beneficial effects that:
the invention obtains the polyethylene glycol containing sulfur element by the reaction of polyethylene glycol monoallyl ether and sulfhydryl compound containing amido or carboxyl, and the polyethylene glycol is very conveniently introduced onto resin by amido bond, thiourea, urea and sulfamide, thus the obtained polyethylene glycol chain has stable chemical property. Secondly, long-chain polyethylene glycol can be introduced into the resin by the method, and the obtained polyethylene glycol resin is more suitable for synthesizing long peptide and difficult peptide. Third, the introduction of terminal amine and carboxyl groups of polyethylene glycol onto the resin facilitates the introduction of different polypeptide synthesis linkers onto the resin relative to other groups, and thus can be used to synthesize different types of polypeptides.
Abbreviations used in the present invention and meanings corresponding to English
TFA Trifluoroacetic acid
DMF N, N-dimethylformamide
NMP N-methyl pyrrolidone
Fmoc 9-fluorenylmethoxycarbonyl group
Fmoc-Osu 9-fluorenylmethyl-N-succinimidyl carbonate
DBU
1, 8-diazabicycloundec-7-enes
DIC N, N' -diisopropylcarbodiimide
HOBt 1-hydroxybenzotriazoles
HATU 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate
HBTU benzotriazole-N, N, N ', N' -tetramethyluronium hexafluorophosphate
TBTU O- (IH-benzotriazol-1-yl) -N, N, N ', N' -tetramethylisourea boron tetrafluoride
COMU (2-oximino-cyanoacetic acid ethyl ester) -N, N-dimethyl-morpholinyl urea hexafluorophosphate
TEA Triethylamine
DIEA N, N-diisopropylethylamine
NMM N-methylmorpholine
tBu Tert-butyl ester
Boc Tert-butyloxycarbonyl radical
PEG Polyethylene glycol
APEG Polyethylene glycol monoallyl ether
Tos P-methylbenzenesulfonic acid group
DEAD Azodicarboxylic acid diethyl ester
AIBN Azobisisobutyronitrile
Drawings
FIG. 1 is the scheme showing the example 8Fmoc-NH-CH2CH2-S-CH2CH2CH2-PEG30-40-CH2CH2COOH nuclear magnetic spectrum.
FIG. 2 shows Fmoc-NH-CH of example 82CH2-S-CH2CH2CH2-PEG30-40-CH2CH2COOH mass spectrum.
FIG. 3 shows example 8NH2-CH2CH2-S-CH2CH2CH2-PEG30-40-CH2CH2CO-AM-polystyrene resin 4 IR spectrum.
FIG. 4 shows example 8NH2-CH2CH2-S-CH2CH2CH2-PEG30-40-CH2CH2CO-AM-polystyrene resin 4 appearance.
Detailed Description
The invention discloses a sulfur-containing polyethylene glycol modified resin and a preparation method thereof, and the embodiment is only a part of embodiment of the invention, but not all embodiments. The embodiments are only for illustrating the technical concept and features of the present invention, and the purpose of the embodiments is to enable those skilled in the art to understand the contents of the present invention and implement the present invention, and not to limit the protection scope of the present invention. All equivalent changes and modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.
The invention is further illustrated by the following examples.
Example 1H2N-PEG(8~12)-CH2CH2CH2-S-CH2CH2-COOH (Compound 7, R)3=H）
1）HO-PEG(8~12)-CH2CH2CH2-S-CH2CH2-COOtBu Synthesis
1200g (about 2.4mol) of APEG500 is dissolved in 7L of 1, 4 dioxane, under the protection of nitrogen, 889g (6mol) of tert-butyl 2-mercaptoacetate is added, the temperature is raised to 55 ℃, 93.5g (0.3mol) of AIBN is added, when the temperature is stabilized to 55 ℃, the nitrogen protection is removed, the reaction is carried out for 13h at 55 ℃, and the reaction is detected to be complete by MS.
Removing about 4L of 1, 4 dioxane under reduced pressure by rotary evaporation, adding 10L of water, extracting a large amount of unreacted tert-butyl 2-mercaptoacetate by using petroleum ether (5L × 3), adjusting the pH of a water layer to be 4 (a small amount of acid is used for extraction) by using 40% phosphoric acid, extracting dichloromethane (5L 2), washing once by using water, drying a dichloromethane solution by using anhydrous sodium sulfate, and drying by reduced pressure to obtain HO-PEG (8-12) -CH2CH2CH2-S-CH2CH2-COOtBu1.16kg。
2）Tos-O-PEG(8~12)-CH2CH2CH2-S-CH2CH2-COOtBu Synthesis
Under ice-bath conditions, 1.1kg (1.7mol) of HO-PEG(8~12)-CH2CH2CH2-S-CH2-COOtBu was dissolved in 6L of methylene chloride, and 450g (2.3mol) of p-toluenesulfonyl chloride was added. 287g (2.8mol) of triethylamine are added in portions. After the addition, the temperature naturally rises to room temperature, and the reaction lasts for 3 hours. The dichloromethane reaction solution was washed with water, diluted phosphoric acid and saturated brine respectivelyThe dichloromethane layer was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to give 1.04kg of a brown oil.
3)N3-PEG(8~12)-CH2CH2CH2-S-CH2CH2-COOtBu Synthesis
0.9kg (1.4mol) of Tos-O-PEG(8~12)-CH2CH2CH2-S-CH2-COOtBu, 160g (2.5mol) of sodium azide, mixed with 7L of DMF, heated to 60 ℃, stirred overnight, 10L of water was added to the reaction mixture, the mixture was extracted with ethyl acetate (1L × 7), the ethyl acetate was washed with water (1L × 7), and then washed once with 8L of saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to give 0.71kg of a yellow oil.
4）NH2-PEG(8~12)-CH2CH2CH2-S-CH2CH2-COOtBu Synthesis
770g (1.29mol) of N are added under ice bath3-PEG(8~12)-CH2CH2CH2-S-CH2CH2COOtBu was dissolved in 6L of toluene, 847g (3.23mol) of triphenylphosphine was added in portions, the mixture was allowed to warm up naturally, stirred overnight, filtered to remove most of the triphenylphosphine oxide produced, 10L of diluted acid water was added, the layers were separated, the aqueous phase was extracted 3 times with ethyl acetate until the triphenylphosphine oxide was completely extracted, the aqueous phase was adjusted to pH =8 with sodium carbonate, extracted with ethyl acetate (5L of × 2), washed with water and saturated brine, and after drying, dried by spin-drying to obtain 710g of a pale yellow oil.
5）NH2-PEG(8~12)-CH2CH2CH2-S-CH2CH2-COOH synthesis
680g(1.14mol)NH2-PEG(20~30)-CH2CH2CH2-S-CH2CH2COOtBu was dissolved in 2.5L of methylene chloride, and 2.5L of trifluoroacetic acid was added to react at room temperature for 3 hours. Spin-drying the solvent under reduced pressure, adding 500ml water into the concentrate, adjusting pH to 7.0 with sodium hydroxide aqueous solution, and evaporating under reduced pressure to remove water to obtain NH2-PEG(8~12)-CH2CH2CH2-S-CH2-CH2COOH570g。
H1NMR(400MHz，DMSO-d6)：1.71~1.75(m，2H)，2.34~2.36(m，2H)，2.47~2.58(m，4H)，2.59~2.61(m，2H)，2.64~2.71(m，4H)，3.41~3.60(m，32H)，7.93(s，1H)。
Example 2Me-HN-PEG(8~12)-CH2CH2CH2-S-CH2CH2COOH (Compound 9, R3= hydrogen, R5= methyl group)
1）Me-NH-PEG(8~12)-CH2CH2CH2-S-CH2CH2-COOtBu
70g (0.1mol) of Tos-O-PEG(8~12)-CH2CH2CH2-S-CH2CH2-COOtBu is dissolved in 400ml tetrahydrofuran, cooled to-60 ℃, 100ml of 3M methylamine tetrahydrofuran solution is dripped, after the dripping is finished, the temperature is kept at-60 ℃ and the stirring is carried out for 3 hours, the solvent is evaporated to dryness under reduced pressure to obtain light yellow oily substance, 400ml of water is added to dissolve the oily substance, the water phase is extracted by ethyl acetate (200ml × 3), the acetic acid is washed once by 200ml of saturated saline solution, dried by anhydrous sodium sulfate and evaporated to dryness under reduced pressure to obtain 53g yellow oily substance.
2)Me-NH-PEG(8~12)-CH2CH2CH2-S-CH2CH2-COOH
35g(52mmol)NH2-PEG(20~30)-CH2CH2CH2-S-CH2CH2COOtBu was dissolved in a mixed solution of 150ml of methylene chloride and 150ml of trifluoroacetic acid, and reacted at room temperature for 5 hours. The solvent was spin-dried under reduced pressure, the obtained oily substance was dissolved in 150ml of water, the obtained aqueous layer was adjusted to pH 7.0 with aqueous sodium hydroxide solution, and finally water was distilled off under reduced pressure to obtain Me-NH-PEG containing sodium trifluoroacetate(20~30)-CH2CH2CH2-S-CH2CH2-COOH27g。
H1NMR(400MHz，DMSO-d6)：1.70~1.74(m，2H)，2.33~2.35(m，2H)，2.47~2.58(m，4H)，2.59~2.61(m，2H)，2.64~2.71(m，4H)，3.31~3.53(m，35H)，7.91(s，1H)。
Example 3
NH2-CH2-CH2-S-CH2CH2CH2-PEG (30 to 40) -CH2CH2COOH (Compound 16, R1= H, R2= H)
1) Boc-NH-CH2-CH2-S-CH2CH2CH2-PEG (30-40) -OH (compound 14) synthesis
150g (about 0.1mol) of APEG1500 was dissolved in 600ml of 1, 4-dioxane, 106g (0.6mol) of Boc-cysteamine (compound 13) was added under nitrogen protection, the temperature was raised to 55 ℃, 3.3g (0.02mol) of AIBN was added, and when the temperature stabilized to 55 ℃, the nitrogen protection was removed, the reaction was reacted at 55 ℃ for 9 hours, and the reaction was detected to be complete by MS.
Removing about 400ml of 1, 4-dioxane by reduced pressure rotary evaporation, adding 400ml of water, extracting a large amount of unreacted Boc-cysteamine by petroleum ether (400ml of × 3), adjusting the pH value of a water layer to be =4 by 40% phosphoric acid, extracting dichloromethane (300ml of × 2), washing once by water, drying a dichloromethane solution by anhydrous sodium sulfate, and evaporating to dryness under reduced pressure to obtain Boc-NH-CH2-CH2-S-CH2CH2CH2-PEG(30~40)-OH103g。
2）Boc-NH-CH2-CH2-S-CH2CH2CH2-PEG(30~40)-CH2CH2COOtBu (Compound 15) Synthesis
80g (ca. 50mmol) Boc-NH-CH2-CH2-S-CH2CH2CH2-PEG(30~40)-OH is dissolved in 400ml dichloromethane, cooled to-5 ℃, 14.8g (116mmol) of tert-butyrolactylate and 1.87g (5.8mmol) of tetrabutylammonium fluoride are added, 30ml20% NaOH aqueous solution is added, reaction is carried out overnight at 25 ℃, MS detects that the reaction is complete, 400ml water is added, the pH of the aqueous phase is adjusted to 3-4 by 40% phosphoric acid, the layers are separated, the obtained DCM is washed by water (200ml × 2), dried by anhydrous sodium sulfate and finally evaporated to dryness under reduced pressure to obtain 73g pale yellow Boc-NH-CH2-CH2-S-CH2CH2CH2-PEG(20~30)-CH2CH2COOtBu。
3)NH2-CH2-CH2-S-CH2CH2CH2-PEG(30~40)-CH2CH2Synthesis of COOH (Compound 16)
70g(44mol)Boc-NH-CH2-CH2-S-CH2CH2CH2-PEG(20~30)-CH2CH2COOtBu was dissolved in 800ml of methylene chloride, and 17.6g (92.8mmol) of p-toluenesulfonic acid was added to the solution to react at room temperature for 3 hours. Adding 500ml of water into the reaction solution, layering, adjusting the pH of the obtained water layer to 7.0 by using sodium hydroxide water solution, and finally removing water by reduced pressure distillation to obtain NH containing p-toluenesulfonic acid sodium salt2-CH2-CH2-S-CH2CH2CH2-PEG(30~40)-CH2CH2COOH57g。
H1NMR(400MHz，DMSO-d6)：1.74~1.76(m，2H)，2.39~2.42(m，2H)，2.49~2.53(m，2H)，3.13~3.14(m，2H)，3.50~3.67(m，163H)，7.82(s，2H)，10.17(s，1H)。
Example 4:
NH2-CH2-CH2-SO2-CH2CH2CH2-PEG(20~30)-CH2COOH (Compound 18, R1=H，R2=H，m=1）
Figure 122501DEST_PATH_IMAGE095
1）Boc-NH-CH2-CH2-SO2-CH2CH2CH2-PEG(20~30)-CH2COOtBu (Compound 15-1) Synthesis
138g(100mmol)Boc-NH-CH2CH2-S-CH2CH2CH2-PEG(20~30)Adding 0.5L of anhydrous tetrahydrofuran into-OH (compound 14) and 40g (1mol) of 60% sodium hydride, cooling to 0 ℃, adding 117g (600mmol) of tert-butyl bromoacetate, reacting at 0-5 ℃ for 72 hours, slowly pouring the reaction liquid into 1L of saturated ammonium chloride solution, extracting the obtained mixed liquid with petroleum ether to remove the unreacted tert-butyl bromoacetate (600mlx2), extracting the product (300mlx3) with dichloromethane, drying with anhydrous sodium sulfate, and evaporating to dryness under reduced pressure to obtain 69g of light yellow viscous liquid.
2）NH2-CH2-CH2-SO2-CH2CH2CH2-PEG(20~30)-CH2COOtBu
58gBoc-NH-CH2-CH2-S-CH2CH2CH2-PEG(20~30)-CH2COOtBu was dissolved in 250ml of ethyl acetate, and 25ml of an aqueous solution containing 2.4g of sodium tungstate and 20ml of 27% hydrogen peroxide were added, followed by heating to react until the thioether was completely converted into sulfone. The ethyl acetate was distilled off under reduced pressure, the resulting aqueous solution was extracted with dichloromethane (100 mlx2), the dichloromethane was washed with water several times, and the dichloromethane was distilled off under reduced pressure to give NH2-CH2-CH2-SO2-CH2CH2CH2-PEG(20~30)-CH2COOtBu53g
3)NH2-CH2-CH2-SO2-CH2CH2CH2-PEG(20~30)-CH2COOH
50g(33mmol)Boc-NH-CH2CH2-SO2-CH2CH2CH2-PEG(20~30)-CH2COOtBu was dissolved in 200ml of methylene chloride, and 12.5g (66mmol) of p-toluenesulfonic acid was added to the solution to react at room temperature for 3 hours. Adding 2L of water into the reaction solution, layering, adjusting the pH of the obtained water layer to 7.0 by using sodium hydroxide aqueous solution, and finally removing water by reduced pressure distillation to obtain 43gNH containing p-toluenesulfonic acid sodium salt2-CH2-CH2-S-CH2CH2CH2-PEG(20~30)-COOH
H1NMR(400MHz，DMSO-d6)：1.74~1.76(m，2H)，2.54~2.58(m，2H)，2.67~2.70(m，2H)，2.96~2.98(m，2H)，3.45~3.56(m，124H)，4.01~4.08(m，2H)，7.82(s，2H)。
Example 5: compound 19 was synthesized (h =0, n = 20-30, q =1, R1=H，R2=H）
Figure 578890DEST_PATH_IMAGE096
1) P-methylene benzoic acid tBu ester-PEG(20~30)-CH2-CH2-CH2-S-CH2CH2-NH-Boc (Compound 39) Synthesis
138g(100mmol)Boc-NH-CH2CH2-S-CH2CH2CH2Adding PEG (20-30) -OH (compound 14) and 120g (0.5mol) of sodium hydride into 1 liter of anhydrous tetrahydrofuran, cooling to-5 ℃, dropwise adding 135.5g (0.5mol) of p-bromomethylbenzoic acid tert-butyl ester, reacting at 0-5 ℃ for 40 hours, slowly pouring a reaction solution into 2L of saturated ammonium chloride solution, extracting the obtained mixed solution with petroleum ether to remove the unreacted p-bromomethylbenzoic acid tert-butyl ester (800mlx2), extracting a product (500mlx3) with dichloromethane, drying with anhydrous sodium sulfate, and evaporating to dryness under reduced pressure to obtain 42g of light yellow viscous liquid.
2) Synthesis of Compound 19
30g (19 mmol) of tBu ester-PEG of p-methylenebenzoic acid(20~30)-CH2CH2CH2-S-CH2CH2-NH-Boc was dissolved in 50ml of dichloromethane, and 50ml of trifluoroacetic acid was added to react at room temperature for 1 hour. Evaporating the reaction solution under reduced pressure to dryness, dissolving the obtained concentrate with 60ml of water, adjusting pH to 7.0 with sodium hydroxide water solution, and evaporating under reduced pressure to remove water to obtain 26g p-methylenebenzoic acid-PEG containing trifluoroacetic acid sodium salt(20~30)-CH2-CH2-CH2-S-CH2CH2-NH2(Compound 19)
H1NMR(400MHz，DMSO-d6)：1.76~1.78(m，2H)，2.52~2.56(m，2H)，2.67~2.70(m，2H)，2.96~2.98(m，2H)，3.46~3.62(m，124H)，4.11~4.13(s，2H)，7.47~7.49(d，2H)，7.78~7.80(d，2H)，7.82(s，2H)，13.92(s，1H)。
Example 6: benzyl acetate-PEG(20~30)-CH2-CH2-CH2-S-CH2CH2-NH2Compound 22 was synthesized (h =1, n = 20-30, q =1, R1=H，R2=H）
Figure 334356DEST_PATH_IMAGE097
1) Tert-butyl acetate benzyl ether-PEG(20~30)-CH2-CH2-CH2-S-CH2CH2-NH-Boc
138g(100mmol)Boc-NH-CH2CH2-S-CH2CH2CH2-PEG (20-30) -OH (Compound 40), 47.6g (200mmol) of tert-butyl acetate p-hydroxybenzyl ether (tBu-CP)2-OH =35), 78.6g (300mmol) of triphenylphosphine was dissolved in dichloromethane, 52g (300mmol) of DEAD was slowly added dropwise, reaction was carried out at 50 ℃ for 16 hours, the reaction was completed, the reaction solution was washed with water several times, dried over anhydrous sodium sulfate, purified by silica gel column to remove triphenylphosphine and triphenylphosphine oxide, and the eluate was dried under reduced pressure to obtain 61g of tert-butyl acetate benzyl ether-PEG(20~30)-CH2-CH2-CH2-S-CH2CH2-NH-Boc。
2) 42g (26.2mmol) of tert-butyl acetate benzyl ether-PEG(20~30)-CH2-CH2-CH2-S-CH2CH2The solution of-NH-Boc was dissolved in 80ml of dichloromethane, and 9.9g (52.4mmol) of p-toluenesulfonic acid was added to the solution to react at room temperature for 6 hours. Evaporating the reaction solution under reduced pressure to dryness, dissolving the obtained concentrate with 60ml of water, adjusting pH to 7.0 with sodium hydroxide water solution, and evaporating under reduced pressure to remove water to obtain 24g of benzyl acetate-PEG containing p-toluenesulfonate(20~30)-CH2-CH2-CH2-S-CH2CH2-NH2
H1NMR(400MHz，DMSO-d6)：1.76~1.78(m，2H)，2.52~2.56(m，2H)，2.67~2.70(m，2H)，2.96~2.98(m，2H)，3.46~3.62(m，124H)，4.50~4.52(s，2H)，4.70~4.72(s，2H)，6.87~6.89(d，2H)，6.97~6.99(d，2H)，7.82(s，2H)，13.90(s，1H)。
Example 7
H2N-PEG(8~12)-CH2CH2CH2-S-CH2CH[N(CH3)2]-COOH (Compound 7, R)3= dimethylamino group)
Figure 943323DEST_PATH_IMAGE098
1）HO-PEG(8~12)-CH2CH2CH2-S-CH2CH[N(CH3)2]-COOBzl Synthesis
120g (about 0.24mol) of APEG500 is dissolved in 7L1, 4 dioxane, 143g (0.6mol) of N, N' -dimethyl cysteine benzyl ester is added under the protection of nitrogen, the temperature is raised to 55 ℃, 9.4g (0.3mol) of AIBN is added, the temperature is stabilized to 55 ℃, the protection of nitrogen is removed, the reaction is carried out for 17 hours at 55 ℃, and the reaction is detected to be complete by MS.
About 400ml of 1, 4-dioxane was removed by rotary evaporation under reduced pressure, 1L of water was added, and petroleum ether (0.5L. times.3) was added to extract a large amount of unreacted N, N' -dimethylcysteine benzyl ester. Adjusting pH of water layer to =4 with 40% phosphoric acid (small amount of acid), extracting with dichloromethane (5L 2), washing with water, drying dichloromethane solution with anhydrous sodium sulfate, and evaporating under reduced pressure to obtain HO-PEG (8-12) -CH2CH2CH2-S-CH2CH[N(CH3)2]-COOBzl104g。
2）Tos-O-PEG(8~12)-CH2CH2CH2-S-CH2CH[N(CH3)2]-COOBzl Synthesis
108g (170mmol) of HO-PEG (8-12) -CH2CH2CH2-S-CH2CH- [ N (CH3)2] -COOBzl are dissolved in 600ml of dichloromethane under the ice bath condition, and then 45g (0.23mol) of p-toluenesulfonyl chloride is added. 28g (0.28mol) of triethylamine are added in portions. After the addition, the temperature naturally rises to room temperature, and the reaction lasts for 3 hours. The dichloromethane reaction solution was washed with water, dilute phosphoric acid, and saturated brine, respectively, and the dichloromethane layer was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to give 94g of a brown oil.
3)N3-PEG(8~12)-CH2CH2CH2-S-CH2CH[N(CH3)2]-COOBzl Synthesis
90g (0.14mol) of Tos-O-PEG(8~12)-CH2CH2CH2-S-CH2CH[N(CH3)2]-COOBzl, 16g (0.25mol) sodium azide and 600ml DMF mixed, heated to 60 ℃, stirred overnight, to the reaction solution added with 1L water, the mixture with ethyl acetate (300ml × 7) extraction, ethyl acetate with water (300ml × 7) washing, and then 700ml saturated saline solution washing, anhydrous sodium sulfate drying, decompression evaporation to dryness, 68g yellow oily material.
4）NH2-PEG(8~12)-CH2CH2CH2-S-CH2CH[N(CH3)2]-COOBzl Synthesis
75g (0.13mol) N are added under ice-bath conditions3-PEG(8~12)-CH2CH2CH2-S-CH2CH[N(CH3)2]-COOBzl in 500ml toluene, adding in portions 85g (0.32mol) of triphenyl phosphine, adding natural temperature rise, stirring overnight, filtering to remove most of the generated triphenyl phosphine oxide, adding 1L of diluted acid water, layering, extracting the aqueous phase with ethyl acetate for 3 times until the triphenyl phosphine oxide is completely extracted, adjusting pH of the aqueous phase with sodium carbonate =8, extracting with ethyl acetate (500ml × 2), washing with water and saturated brine, drying, and spin-drying under reduced pressure to obtain 61g of light yellow oil.
5）NH2-PEG(8~12)-CH2CH2CH2-S-CH2CH[N(CH3)2]-COOH synthesis
66g(0.11mol)NH2-PEG(20~30)-CH2CH2CH2-S-CH2CH[N(CH3)2]-COOBzl was dissolved in 300ml of a methanol solution containing 12g of potassium hydroxide and reacted at room temperature for 3 hours. Adjusting the pH of the reaction solution to 7.0 by 6N hydrochloric acid, and finally removing the solvent by reduced pressure distillation to obtain NH2-PEG(8~12)-CH2CH2CH2-S-CH2CH[N(CH3)2]-COOH53g。
H1NMR(400MHz，DMSO-d6)：2.11~2.13(m，2H)，2.32(s，6H)，2.47~2.58(m，4H)，2.64~2.71(m，2H)，3.31~3.70(m，46H)，4.47~4.49(m，1H)，7.93(s，1H)。
Example 8
NH2-PEG8-12-CH2CH2CH2-S-CH2CH2-CO-AM-polystyrene resin preparation:
Figure 758833DEST_PATH_IMAGE099
1）Fmoc-NH-PEG8-12-CH2CH2CH2-S-CH2CH2-COOH
33.8gFmoc-OSu、50gH2N-PEG8-12-CH2CH2CH2-S-CH2CH2-COOH, 10.6g sodium carbonate, mixed in 200ml 1: 1 acetone/water mixed solution, and reacting at room temperature for 3 hours. 100ml of water was added, the reaction solution was extracted with petroleum ether (100 ml x3), then acidified to pH =2.0 with 6N hydrochloric acid, extracted with ethyl acetate (100 ml x2), and the resulting ethyl acetate solution was washed with saturated brine (100 ml x2), dried over anhydrous sodium sulfate, and dried under reduced pressure to give 59g of an oil.
2）Fmoc-NH-PEG8-12-CH2CH2CH2-S-CH2CH 2-CO-AM-polystyrene resin
70g of aminomethyl-polystyrene resin with a degree of substitution of 0.67 are soaked in 800ml of dichloromethane for 10 minutes, 60g of Fmoc-NH-PEG8-12-CH2CH2CH2-S-CH2CH2-COOH, 25.2g DIC, 27g HOBt and 35ml triethylamine were added to the aminomethyl-polystyrene resin and stirred mechanically for 3 hours, the ninhydrin color detection showed complete blocking of the amine groups on the resin. Filtration, resin with 800ml dichloromethane washing, repeated washing 3 times, the resin, air drying, and room temperature under reduced pressure drying, 91g resin, degree of substitution is 0.31.
3)NH2-PEG8-12-CH2CH2CH2-S-CH2CH 2-CO-AM-polystyrene resin
40gFmoc-NH-PEG8-12-CH2CH 2-S-CH2CH 2-CO-AM-resin 1 was soaked in 500ml DMF for 10 min, solvent was drained, Fmoc20 min was removed from the swollen resin with 500ml20% piperidine/DMF solution, reaction solution was drained, washed with DMF (500ml x2), dichloromethane (500ml x2), methanol (500ml x 1), air dried, and finally vacuum dried to obtain 38.2g of finished product.
Example 9
NH2-CH2CH2-S-CH2CH2CH2-PEG30-40-CH2CH2CO-AM-polystyrene resin
Figure 968097DEST_PATH_IMAGE100
1）Fmoc-NH-CH2CH2-S-CH2CH2CH2-PEG30-40-CH2CH2COOH
4.2gFmoc-OSu、14gH2N-CH2CH2-S-CH2CH2CH2-PEG25-35-CH2CH2COOH, 2.0g sodium carbonate, mixed in 80ml 1: 1 tetrahydrofuran/water mixed solution, and reacted at room temperature for 3 hours. 100ml of water was added, the reaction solution was extracted with petroleum ether (100 ml x3), then acidified to pH =2.0 with 6N hydrochloric acid, extracted with ethyl acetate (100 ml x2), and the resulting ethyl acetate solution was washed with saturated brine (100 ml x2), dried over anhydrous sodium sulfate, and dried under reduced pressure to give 15.5g of an oil.
The nuclear magnetism is shown in figure 1, and the mass spectrum is shown in figure 2.
2）Fmoc-NH-CH2CH2-S-CH2CH2CH2-PEG30-40-CH2CH2CO-AM-polystyrene resin
50g of aminomethyl-polystyrene resin with a degree of substitution of 0.67 are soaked for 10 minutes in 500ml of dichloromethane, 107g of Fmoc-NH-CH2CH2-S-CH2CH2CH2-PEG30-40-CH2CH2COOH, 25.4g HBTU, 9g HOBt and 11ml DIEA were added to the aminomethyl-polystyrene resin, respectively, and mechanically stirred for 3 hours, the ninhydrin color detection showed that the amine groups on the resin were completely blocked. Filtration, resin with 500ml dichloromethane washing, repeated washing 3 times, the resin, air drying, and room temperature under reduced pressure drying, 89g resin, degree of substitution is 0.44.
3)NH2-CH2CH2-S-CH2CH2CH2-PEG30-40-CH2CH2CO-AM-polystyrene resin
50gFmoc-NH-CH2CH2-S-CH2CH2CH2-PEG30-40-CH2CH2Soaking CO-AM-polystyrene resin in 600ml of DMF for 10 minutes, and draining to remove solventThe reagent and the swelled resin are subjected to Fmoc20 minutes removal by 600ml of 20% piperidine/DMF solution, reaction liquid is drained, DMF is used for washing (500mlx 2), dichloromethane is used for washing (500mlx 2), methanol is used for washing (500mlx 1), air drying is carried out, and finally vacuum drying is carried out to obtain 47g of finished product, wherein an infrared spectrum is shown in figure 3, and the appearance is shown in figure 4.
Example 10
HOOC-PH-PEG8-12-CH2CH2CH2-S-CH2CH2-NH-CO-polystyrene resin
Figure 776522DEST_PATH_IMAGE101
20g of carboxyl-polystyrene resin with a degree of substitution of 0.76 were soaked for 10 minutes in 200ml of DMF, 11.6g of N, N' -disuccinimidyl carbonate and 8ml of pyridine were added, stirred for 1 hour, filtered with suction and the resin was washed 2 times with DMF. Then 200ml DMF was added and 27g HOOC-PH-PEG was added8-12-CH2CH2CH2-S-CH2CH2-NH2And 11ml of triethylamine, stirred for 3 hours, filtered, and the resin was washed with 500ml of dichloromethane, and the washing was repeated 3 times, and the resulting resin was air-dried and then dried under reduced pressure at room temperature to obtain 26g of a resin having a degree of substitution of 0.23.
Example 11
HOOC-CH2CH2-PEG30-40-CH2CH2CH2-S-CH2CH2-Sulfamide-polystyrene resin
Figure 489263DEST_PATH_IMAGE102
40g of sulfonyl chloride resin with a degree of substitution of 0.72 were soaked in 300ml of dichloromethane for 10 minutes, 92g of HOOC-CH2CH2-PEG30-40-CH2CH2CH2-S-CH2CH2-NH2And 10ml of pyridine were mixed with the resin and stirred at room temperature for 4 hours. Suction filtering, washing the resin with 200ml dichloromethane, repeating washing for 2 times, washing with 1M p-toluenesulfonic acid dichloromethane for 1 time, air drying the obtained resinThe resin was dried and then dried under reduced pressure at room temperature to obtain 78g of a resin having a degree of substitution of 0.34.
Example 12
HOOC-CH2CH2-SO2-CH2CH2CH2-PEG8-12-CH2CH2-Urea-polystyrene resin
Figure 475674DEST_PATH_IMAGE103
18gHOOC-CH2CH2-SO2-CH2CH2CH2-PEG8-12-CH2CH2-NH225g of an isocyanate resin having a degree of substitution of 0.61 and 5.5ml of pyridine were mixed with 200ml of ethyl acetate and stirred at 60 ℃ for 4 hours.
Suction filtration, resin with 200ml ethyl acetate washing, repeated washing 3 times, then dichloromethane washing (200ml x2), the resin, air drying, and room temperature under reduced pressure drying, 32g resin, substitution degree of 0.44.
Example 13
HOOC-CH2-PEG8-12-CH2CH2CH2-S-CH2CH2-Thiourea-polystyrene resin
Figure 172234DEST_PATH_IMAGE104
15gHOOC-CH2-PEG8-12-CH2CH2CH2-S-CH2CH2-NH225g of an isothiocyanate resin having a degree of substitution of 0.63 and 5ml of triethylamine were mixed with 200ml of ethyl acetate, and the mixture was stirred at 70 ℃ for 4 hours.
Suction filtration, resin with 200ml ethyl acetate washing, repeated washing 3 times, then dichloromethane washing (200ml x2), the resin, air drying, and room temperature under reduced pressure drying, 29g resin, substitution degree of 0.28.
Example 14
HOOC-CH2CH2-PEG30-40-CH2CH2CH2-S-CH2CH2-NH-CO-polystyrene resin
Figure 20236DEST_PATH_IMAGE105
20g of carboxyl-polystyrene resin with a degree of substitution of 0.76 were soaked for 10 minutes in 200ml of DMF, 11.6g of N, N' -disuccinimidyl carbonate and 8ml of pyridine were added, stirred for 1 hour, filtered with suction and the resin was washed 2 times with DMF. Then 200ml DMF was added followed by 48g HOOC-CH2CH2-PEG30-40-CH2CH2CH2-S-CH2CH2-NH2And 11ml of triethylamine, stirred for 3 hours, filtered, and the resin was washed with 500ml of dichloromethane, and the washing was repeated 3 times, and the resulting resin was air-dried and then dried under reduced pressure at room temperature to obtain 38g of a resin having a degree of substitution of 0.29.
The technical means disclosed by the scheme of the invention are not limited to the technical means disclosed by the technical means, and also comprise the technical scheme formed by equivalent replacement of the technical features. The present invention is not limited to the details given herein, but is within the ordinary knowledge of those skilled in the art.

Claims (1)

1. A kind of resin modified by sulfur-containing polyethylene glycol is characterized in that the chemical structural general formula is as follows:
Figure 971756DEST_PATH_IMAGE001
（Ⅰ）
a and B are one of the following chemical structure fragments: a is
Figure 274562DEST_PATH_IMAGE002
B is
Figure 897304DEST_PATH_IMAGE003
Or, A is
Figure 451913DEST_PATH_IMAGE004
B is
Figure 601135DEST_PATH_IMAGE005
Or, A is
Figure 950208DEST_PATH_IMAGE006
B is
Figure 60246DEST_PATH_IMAGE007
Either, or,
a is
Figure 277601DEST_PATH_IMAGE008
B is
Figure 422275DEST_PATH_IMAGE009
Either, or,
a is
Figure 676669DEST_PATH_IMAGE010
B is
Figure 398638DEST_PATH_IMAGE011
Or, A is
Figure 29470DEST_PATH_IMAGE012
B is
Figure 887705DEST_PATH_IMAGE013
；
Wherein X is an S atom or a sulfone (SO2),
W1a resin of the structure:
Figure 844160DEST_PATH_IMAGE014
，
W2a resin of the structure:
Figure 663211DEST_PATH_IMAGE015
、
Figure 222368DEST_PATH_IMAGE016
、
Figure 76055DEST_PATH_IMAGE017
、
Figure 937832DEST_PATH_IMAGE018
one of (1); w is matrix resin, and the matrix resin is one of polystyrene resin, polyacrylamide resin and polymethacrylate resin;
n is 5-120, q1 and q2 are respectively 1-5, m1 and m2 are both 1-2, R1 is hydrogen, methyl, carboxy methyl ester, carboxy tert-butyl ester, carboxy benzyl ester, -CH2OCH3、-CH2OCH2CH3One of (1); r2 is one of hydrogen, methyl, ethyl and benzyl; r3 represents one of hydrogen, methyl, dimethylamino, diethylamino and dibenzylamino; r4 represents one of hydrogen, methyl, ethyl and benzyl; r5 represents one of hydrogen, methyl, ethyl and benzyl;
the K1 is one of the following structural formulas:
Figure 368813DEST_PATH_IMAGE019
；
Figure 341448DEST_PATH_IMAGE020
；
Figure 174275DEST_PATH_IMAGE021
；
Figure 206953DEST_PATH_IMAGE022
；
Figure 125231DEST_PATH_IMAGE023
(ii) a The K is one of the following structural formulas:
Figure 635978DEST_PATH_IMAGE024
；
Figure 464256DEST_PATH_IMAGE025
；
Figure 58049DEST_PATH_IMAGE026
；
Figure 338988DEST_PATH_IMAGE027
；
Figure 184585DEST_PATH_IMAGE028
。
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CN113234220A (en) * 2021-05-19 2021-08-10 浙江海洋大学 Flower-shaped structure Fe for photodegradation of ciprofloxacin3O4/Bi2WO6Process for preparing catalyst

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CN114736286A (en) * 2021-12-27 2022-07-12 杭州诺泰澳赛诺医药技术开发有限公司 Method for synthesizing polypeptide impurity monosulfide

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CN113234220A (en) * 2021-05-19 2021-08-10 浙江海洋大学 Flower-shaped structure Fe for photodegradation of ciprofloxacin3O4/Bi2WO6Process for preparing catalyst

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