CN116769154A - Preparation method of monomethoxy polyethylene glycol sulfhydryl - Google Patents
Preparation method of monomethoxy polyethylene glycol sulfhydryl Download PDFInfo
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- CN116769154A CN116769154A CN202310822761.4A CN202310822761A CN116769154A CN 116769154 A CN116769154 A CN 116769154A CN 202310822761 A CN202310822761 A CN 202310822761A CN 116769154 A CN116769154 A CN 116769154A
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- polyethylene glycol
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- monomethoxy polyethylene
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- 239000002202 Polyethylene glycol Substances 0.000 title claims abstract description 27
- 229920001223 polyethylene glycol Polymers 0.000 title claims abstract description 27
- 125000003396 thiol group Chemical group [H]S* 0.000 title claims description 19
- 238000002360 preparation method Methods 0.000 title abstract description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 57
- 238000006243 chemical reaction Methods 0.000 claims abstract description 39
- NULDEVQACXJZLL-UHFFFAOYSA-N 2-(2-aminoethyldisulfanyl)ethylazanium;chloride Chemical compound Cl.NCCSSCCN NULDEVQACXJZLL-UHFFFAOYSA-N 0.000 claims abstract description 22
- PZBFGYYEXUXCOF-UHFFFAOYSA-N TCEP Chemical compound OC(=O)CCP(CCC(O)=O)CCC(O)=O PZBFGYYEXUXCOF-UHFFFAOYSA-N 0.000 claims abstract description 21
- 239000007853 buffer solution Substances 0.000 claims abstract description 21
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 14
- 235000010354 butylated hydroxytoluene Nutrition 0.000 claims abstract description 12
- 238000002156 mixing Methods 0.000 claims abstract description 4
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims abstract 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 39
- 229920001427 mPEG Polymers 0.000 claims description 14
- -1 ester compound Chemical class 0.000 claims description 11
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 6
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 6
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 238000005520 cutting process Methods 0.000 abstract description 5
- 239000003795 chemical substances by application Substances 0.000 abstract description 2
- 150000001875 compounds Chemical class 0.000 abstract description 2
- 238000001308 synthesis method Methods 0.000 abstract description 2
- 230000000694 effects Effects 0.000 abstract 1
- 231100000331 toxic Toxicity 0.000 abstract 1
- 230000002588 toxic effect Effects 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 description 38
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 20
- 238000003756 stirring Methods 0.000 description 17
- 239000000047 product Substances 0.000 description 15
- 239000000243 solution Substances 0.000 description 12
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 10
- 238000000967 suction filtration Methods 0.000 description 10
- 238000001914 filtration Methods 0.000 description 9
- 230000001376 precipitating effect Effects 0.000 description 9
- 238000001291 vacuum drying Methods 0.000 description 9
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 238000005303 weighing Methods 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 229910019142 PO4 Inorganic materials 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 4
- 239000010452 phosphate Substances 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- MWZBTMXISMOMAE-AATRIKPKSA-N (E)-ethyl 3-(2-furyl)acrylate Chemical compound CCOC(=O)\C=C\C1=CC=CO1 MWZBTMXISMOMAE-AATRIKPKSA-N 0.000 description 3
- 239000003638 chemical reducing agent Substances 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- DNJIEGIFACGWOD-UHFFFAOYSA-N ethyl mercaptane Natural products CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 238000002390 rotary evaporation Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 2
- ZJIFDEVVTPEXDL-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) hydrogen carbonate Chemical compound OC(=O)ON1C(=O)CCC1=O ZJIFDEVVTPEXDL-UHFFFAOYSA-N 0.000 description 1
- KIUMMUBSPKGMOY-UHFFFAOYSA-N 3,3'-Dithiobis(6-nitrobenzoic acid) Chemical compound C1=C([N+]([O-])=O)C(C(=O)O)=CC(SSC=2C=C(C(=CC=2)[N+]([O-])=O)C(O)=O)=C1 KIUMMUBSPKGMOY-UHFFFAOYSA-N 0.000 description 1
- QXZGLTYKKZKGLN-UHFFFAOYSA-N 4-(2,5-dioxopyrrolidin-1-yl)oxy-4-oxobutanoic acid Chemical compound OC(=O)CCC(=O)ON1C(=O)CCC1=O QXZGLTYKKZKGLN-UHFFFAOYSA-N 0.000 description 1
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/32—Polymers modified by chemical after-treatment
- C08G65/329—Polymers modified by chemical after-treatment with organic compounds
- C08G65/334—Polymers modified by chemical after-treatment with organic compounds containing sulfur
- C08G65/3348—Polymers modified by chemical after-treatment with organic compounds containing sulfur containing nitrogen in addition to sulfur
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/32—Polymers modified by chemical after-treatment
Landscapes
- Chemical & Material Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Polymers & Plastics (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a preparation method of monomethoxy polyethylene glycol mercapto, belonging to the technical field of compound synthesis methods. Mixing cystamine hydrochloride, triethylamine and mPEG-SCM for reaction to obtain an SH intermediate; and then adding tri (2-carboxyethyl) phosphine, SH intermediate and 2, 6-di-tert-butyl-p-cresol into the buffer solution to react so as to obtain the monomethoxy polyethylene glycol mercapto. The intermediate preparation of the invention is added with excessive cystamine hydrochloride, so the conversion rate of mPEG-SCM can be close to 100%, meanwhile, TCEP is selected as a disulfide bond cutting agent, the TECP has stronger reducing capability and selectivity, and compared with the existing DTT, the method has smaller and safer toxic and side effects on human bodies.
Description
Technical Field
The invention belongs to the technical field of compound synthesis methods, and particularly relates to a preparation method of monomethoxy polyethylene glycol mercapto.
Background
The existing method for preparing the monomethoxy polyethylene glycol sulfhydryl group comprises the following specific steps:
the first step: the intermediate connecting the two ends was prepared using mPEG-SCM (monomethoxy polyethylene glycol succinimidyl acetate) with cystamine hydrochloride in DCM (dichloromethane) as solvent under triethylamine conditions, the reaction procedure was as follows:
the yields of such intermediates prepared are known from the prior art (U.S. Pat. No. 3,182A) to be about 98%;
and a second step of: cleavage with TCEP, DTT, mercaptoethanol, etc
The method requires strict control of the molar quantity ratio of the feed in the preparation process of the first step intermediate to be 1:0.5, but at the same time, because the molecular weight of the mPEG-SCM (monomethoxypolyethylene glycol succinimidyl acetate) used is difficult to determine precisely, it is almost impossible to control strictly the molar quantity ratio of the charges to 1:0.5, thereby making it difficult to achieve 100% conversion, and there are cases where a polymerization intermediate is present together with the raw material. Resulting in less than expected conversion of the intermediate when cut into finished products.
Disclosure of Invention
The invention aims to provide a preparation method of monomethoxy polyethylene glycol mercapto, which can achieve the intermediate conversion rate of nearly 100%, and adopts TCEP as a disulfide bond cutting reducing agent, so that the conversion rate is improved.
The invention provides a preparation method of monomethoxy polyethylene glycol sulfhydryl, which comprises the following steps:
step one: mixing and reacting cystamine hydrochloride, triethylamine and an ester compound of mPEG to obtain an SH intermediate;
step two: adding tris (2-carboxyethyl) phosphine (TCEP), the SH intermediate in the first step and 2, 6-di-tert-butyl-p-cresol (BHT) into a buffer solution for reaction to obtain monomethoxy polyethylene glycol sulfhydryl.
Preferably, the mass ratio of the cystamine hydrochloride, the triethylamine and the mPEG ester compound in the step one is (1-2): 6 (0.8-1).
Preferably, the ratio of the cystamine hydrochloride, triethylamine and mPEG esters in the step one is 1:6:1.
Preferably, the esters of mPEG in step one are mPEG-SCM, mPEG-SC or mPEG-SS.
Preferably, the reaction temperature in the first step is room temperature, and the reaction time is 2-4h.
Preferably, the solvent in the first reaction is methylene chloride.
Preferably, the mass ratio of SH intermediate, tris (2-carboxyethyl) phosphine and 2, 6-di-tert-butyl-p-cresol in step two is 1:1.1:0.233.
preferably, the reaction temperature in the second step is 25 ℃ at room temperature, and the reaction time is 1h.
Preferably, the buffer solution in the second step is an aqueous solution prepared by sodium dihydrogen phosphate and sodium dihydrogen phosphate.
The beneficial effects of the invention are that
The invention provides a preparation method of monomethoxy polyethylene glycol sulfhydryl, which comprises the steps of mixing excessive cystamine hydrochloride, triethylamine and mPEG ester compounds for reaction to obtain an SH intermediate; then adding TCEP, the SH intermediate and BHT into the buffer solution to react, thus obtaining the monomethoxy polyethylene glycol sulfhydryl. Compared with the prior art, the conversion rate of the ester compound of mPEG can be nearly 100% because the intermediate preparation is added with excessive cystamine hydrochloride, meanwhile, the disulfide bond cutting step is replaced by TCEP compared with the traditional DTT or mercaptoethanol cutting agent, and if the DTT is used as the cutting reducing agent in the prior art, the residual DTT in the product can react with the reagent DTNB added in the detection link to generate other byproduct substances, so that the authenticity of the detection data is influenced. However, this does not occur with TCEP; in addition, compared with DTT, TECP has stronger reducing capability and better selectivity. TCEP is more stable in both acidic and basic conditions, is itself not charged, does not affect subsequent experiments, is not only a highly effective disulfide reducing agent, but also does not need to be removed in some thiol crosslinking reactions.
The method has higher yield, does not need to react in an argon environment, and has simpler conditions; the intermediate target is selected to be a single-ended product, and the addition ratio of other raw materials can be adjusted to increase the conversion rate of SCM.
Drawings
FIG. 1 is a nuclear magnetic resonance spectrum of an intermediate of example 1;
FIG. 2 is a nuclear magnetic resonance spectrum of the finished product of example 1.
Detailed Description
The invention provides a preparation method of monomethoxy polyethylene glycol sulfhydryl, which comprises the following steps:
step one: weighing cystamine hydrochloride, preferably adding 5 times of solvent into a round bottom flask, stirring and dissolving, adding triethylamine oil bath, stirring, preferably at 25 ℃, for 1-2 hours, then adding an ester compound of mPEG, stirring and reacting, preferably at 25 ℃, for 1-2 hours, preferably performing G3 suction filtration on the obtained reaction liquid, performing rotary evaporation on the filtrate, precipitating the rotary evaporation liquid by using 20 times of MTBE, performing G2 suction filtration, and performing vacuum drying to obtain an SH intermediate; the solvent is preferably dichloromethane; the esters of mPEG are preferably mPEG-SCM (monomethoxy polyethylene glycol succinimidyl acetate), mPEG-SC (monomethoxy polyethylene glycol succinimidyl carbonate) or mPEG-SS (monomethoxy polyethylene glycol succinimidyl succinate), more preferably mPEG-SCM.
The ratio of the amount of the cystamine hydrochloride, the triethylamine and the mPEG ester compounds is preferably (1-2) 6 (0.8-1), more preferably 1:6:1; the single-ended intermediate preparation is added into excessive cystamine hydrochloride, so that the conversion rate of the ester compound of mPEG can be close to 100%. The reaction process of this step is as follows:
step two: adding TCEP into a buffer solution, stirring and dissolving (pH=4-5), adding ethanol into BHT, stirring and dissolving, adding the SH intermediate in the first step into the buffer solution, adding BHT ethanol, reacting, wherein the reaction temperature is preferably 25 ℃ at room temperature, the reaction time is preferably 1h, extracting, adding anhydrous sodium sulfate for drying, performing suction filtration on G3, precipitating filtrate by using MTBE, performing suction filtration on G2, and performing vacuum drying to obtain monomethoxy polyethylene glycol mercapto; the ratio of the amounts of the substances of the SH intermediate, TCEP and BHT is preferably 1:1.1:0.233; the buffer solution is preferably an aqueous solution of sodium dihydrogen phosphate and sodium dihydrogen phosphate with a pH of about 7, and the reaction process is as follows:
the invention is described in further detail below with reference to the specific examples, wherein the starting materials are commercially available.
Example 1
Preparation of intermediate 5g
The feeding ratio is as follows: SCM (5 k): cystamine hydrochloride: triethylamine = 1:1:6
Weighing 0.225G of cystamine hydrochloride in a 25ml round bottom flask, adding 5ml of dichloromethane, 0.835ml of triethylamine and stirring for 1h in a 25-DEG oil bath, adding 5G of mPEG-SCM after complete dissolution, reacting for 1h, filtering the reaction solution by G3 suction to remove salt generated in the reaction after the reaction is finished, precipitating by using 100ml of MTBE, filtering by G2 suction, and vacuum drying a filter cake to obtain the middle; the intermediate purity was 100%. The nuclear magnetic hydrogen spectrum is shown in figure 1. In FIG. 1 a-CH 2 -, b-CH adjacent to carbon-oxygen bond 2 -，c:-CH 3 d-CH close to Sulfur 2 -。
Preparation of finished product 5g
SH intermediate (5 k): TCEP: bht=1: 1.1:0.233
Preparing a buffer solution: 5 times of phosphate solution (about ph=7) was prepared and Na was weighed 2 HPO 4 0.5625g of NaH in 7.7875ml of water 2 PO 4 0.53125g, dissolved in 17.125ml water, the two solutions were mixed well.
To the buffer solution, 0.197g of TCEP was dissolved with stirring (ph=between 4 and 5), and 0.031g of bht was dissolved with stirring by adding 5ml of ethanol. Weighing 5g of intermediate, adding buffer solution, adding BHT ethanol, completely dissolving, performing timing reaction for 1h,stopping the reaction, extracting for 2 times with DCM, adding anhydrous sodium sulfate, drying for 30min, suction-filtering with G3, precipitating filtrate with MTBE, suction-filtering with G2, and vacuum-drying to obtain the final product. The purity of the finished product is 99 percent. The nuclear magnetic hydrogen spectrum is shown in figure 2. In FIG. 2, a-CH 2 -，b:CH 3 ，c:-SH。
Example 2
Preparation of intermediate 5g
The feeding ratio is as follows: SCM (5 k): cystamine hydrochloride: triethylamine = 1:1.5:6
0.3378G of cystamine hydrochloride is weighed into a 100ml round bottom flask, 50ml of dichloromethane, 0.835ml of triethylamine and 25 ℃ oil bath are added for stirring for 1h, 5G of SCM is added after complete dissolution, reaction is carried out for 1h, after the reaction is completed, the reaction solution is filtered by G3 suction to remove salt generated in the reaction, 200ml of MTBE is used for precipitation, G2 suction is used for filtration, and a filter cake is dried in vacuum to obtain an intermediate. The intermediate purity was 100%.
Preparation of finished product 5g
SH intermediate (5 k): TCEP: bht=1: 1.1:0.233
Preparing a buffer solution: 5 times the amount of phosphate solution (approximately ph=7) was prepared, 40.5625g of na2hpo was dissolved in 7.7875ml of water, 40.53125g of nah2po was dissolved in 17.125ml of water, and the two solutions were mixed well.
To the buffer solution, 0.197g of TCEP was dissolved with stirring (ph=between 4 and 5), and 0.031g of bht was dissolved with stirring by adding 5ml of ethanol. Weighing 5G of intermediate, adding buffer solution, adding BHT ethanol, completely dissolving, timing to react for 1h, stopping the reaction, extracting with DCM for 2 times, adding anhydrous sodium sulfate, drying for 30min, performing G3 suction filtration, precipitating filtrate with MTBE, performing G2 suction filtration, and vacuum drying to obtain the finished product. The purity of the finished product is 99 percent
Example 3
Preparation of intermediate 5g
The feeding ratio is as follows: SCM (5 k): cystamine hydrochloride: triethylamine = 1:2:6
Weighing 0.45G of cystamine hydrochloride into a 100ml round bottom flask, adding 50ml of dichloromethane, 0.835ml of triethylamine, stirring for 1h in a 25-DEG oil bath, adding 5G of SCM after complete dissolution, reacting for 1h, filtering the reaction solution by G3 suction to remove salt generated in the reaction after the reaction is finished, precipitating by using 200ml of MTBE, filtering by G2 suction, and vacuum drying a filter cake to obtain an intermediate. The intermediate purity was 100%.
Preparation of finished product 5g
SH intermediate (5 k): TCEP: bht=1: 1.1:0.233
Preparing a buffer solution: 5 times the amount of phosphate solution (approximately ph=7) was prepared, 40.5625g of na2hpo was dissolved in 7.7875ml of water, 40.53125g of nah2po was dissolved in 17.125ml of water, and the two solutions were mixed well.
To the buffer solution, 0.197g of TCEP was dissolved with stirring (ph=between 4 and 5), and 0.031g of bht was dissolved with stirring by adding 5ml of ethanol. Weighing 5G of intermediate, adding buffer solution, adding BHT ethanol, completely dissolving, timing to react for 1h, stopping the reaction, extracting with DCM for 2 times, adding anhydrous sodium sulfate, drying for 30min, performing G3 suction filtration, precipitating filtrate with MTBE, performing G2 suction filtration, and vacuum drying to obtain the finished product. The purity of the finished product is 99 percent
According to the results of the three examples, three excess feed ratios were achieved to 100% purity of the intermediate, analysis by synthesis, 1:1: the feed ratio of 6 saves raw materials, so that this ratio is selected to be most suitable.
Comparative example 1
Preparation of intermediate 5g
The feeding ratio is as follows: SCM (5 k): cystamine hydrochloride: triethylamine = 1:0.8:6
Weighing 0.18G of cystamine hydrochloride in a 25ml round bottom flask, adding 5ml of dichloromethane, 0.835ml of triethylamine and stirring for 1h in a 25-DEG oil bath, adding 5G of mPEG-SCM after complete dissolution, reacting for 1h, filtering the reaction solution by G3 suction to remove salt generated in the reaction after the reaction is finished, precipitating by using 100ml of MTBE, filtering by G2 suction, and vacuum drying a filter cake to obtain the middle; the intermediate purity was 79%.
Comparative example 2
Preparation of SH intermediate the same as in example 1
Preparation of finished product 5g
SH intermediate (5 k): DTT: bht=1: 1.1:0.233
Preparing a buffer solution: 5 times the amount of phosphate solution (approximately ph=7) was prepared, 40.5625g of na2hpo was dissolved in 7.7875ml of water, 40.53125g of nah2po was dissolved in 17.125ml of water, and the two solutions were mixed well.
To the buffer solution, 0.106g of DTT (dithiothreitol) was added and dissolved with stirring (ph=between 4 and 5), and 0.031g of BHT was added to 5ml of ethanol and dissolved with stirring. Weighing 5G of intermediate, adding buffer solution, adding BHT ethanol, completely dissolving, timing to react for 1h, stopping the reaction, extracting with DCM for 2 times, adding anhydrous sodium sulfate, drying for 30min, performing G3 suction filtration, precipitating filtrate with MTBE, performing G2 suction filtration, and vacuum drying to obtain the finished product. The purity of the finished product is 99 percent.
Claims (9)
1. A method for preparing a monomethoxy polyethylene glycol mercapto group, which is characterized by comprising the following steps:
step one: mixing and reacting cystamine hydrochloride, triethylamine and an ester compound of mPEG to obtain an SH intermediate;
step two: and (3) adding tri (2-carboxyethyl) phosphine, the SH intermediate in the first step and 2, 6-di-tert-butyl-p-cresol into a buffer solution to react to obtain the monomethoxy polyethylene glycol mercapto.
2. The method for preparing a monomethoxy polyethylene glycol mercapto group according to claim 1, wherein the mass ratio of the cystamine hydrochloride, triethylamine and mPEG ester compound in the step one is (1-2): 6 (0.8-1).
3. The method for preparing monomethoxy polyethylene glycol mercapto according to claim 1, wherein the mass ratio of the cystamine hydrochloride, triethylamine and mPEG ester compound in step one is 1:6:1.
4. The method for preparing a monomethoxy polyethylene glycol mercapto group according to claim 1, wherein the mPEG ester compound in the step one is mPEG-SCM, mPEG-SC or mPEG-SS.
5. The method for preparing the monomethoxy polyethylene glycol mercapto group according to claim 1, wherein the reaction temperature in the first step is room temperature and the reaction time is 2-4h.
6. The method for preparing a mercapto group of monomethoxy polyethylene glycol according to claim 1, wherein the solvent in the first step is methylene chloride.
7. The method for preparing the monomethoxy polyethylene glycol mercapto group according to claim 1, wherein the mass ratio of the SH intermediate, the tris (2-carboxyethyl) phosphine and the 2, 6-di-t-butyl-p-cresol in the second step is 1:1.1:0.233.
8. the method for preparing the monomethoxy polyethylene glycol mercapto group according to claim 1, wherein the reaction temperature in the second step is 25 ℃ at room temperature and the reaction time is 1h.
9. The method for preparing a monomethoxy polyethylene glycol mercapto group according to claim 1, wherein the buffer solution in the second step is an aqueous solution of sodium dihydrogen phosphate and sodium dihydrogen phosphate.
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