CN118324670A - Preparation method of dithiothreitol - Google Patents
Preparation method of dithiothreitol Download PDFInfo
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- CN118324670A CN118324670A CN202311822631.7A CN202311822631A CN118324670A CN 118324670 A CN118324670 A CN 118324670A CN 202311822631 A CN202311822631 A CN 202311822631A CN 118324670 A CN118324670 A CN 118324670A
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- dithiothreitol
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- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 117
- 238000006243 chemical reaction Methods 0.000 claims abstract description 59
- 238000000034 method Methods 0.000 claims abstract description 33
- SRRKNRDXURUMPP-UHFFFAOYSA-N sodium disulfide Chemical compound [Na+].[Na+].[S-][S-] SRRKNRDXURUMPP-UHFFFAOYSA-N 0.000 claims abstract description 27
- 239000012286 potassium permanganate Substances 0.000 claims abstract description 13
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims abstract description 12
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 27
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 26
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 5
- 230000009467 reduction Effects 0.000 claims description 5
- 235000009518 sodium iodide Nutrition 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 3
- 230000001590 oxidative effect Effects 0.000 claims description 3
- 239000011701 zinc Substances 0.000 claims description 3
- 229910052725 zinc Inorganic materials 0.000 claims description 3
- 238000009776 industrial production Methods 0.000 abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 18
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 10
- 238000001914 filtration Methods 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 239000007805 chemical reaction reactant Substances 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- 239000012362 glacial acetic acid Substances 0.000 description 4
- 230000007935 neutral effect Effects 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- 229910052698 phosphorus Inorganic materials 0.000 description 4
- 239000011574 phosphorus Substances 0.000 description 4
- -1 sulfonate compound Chemical class 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 238000004537 pulping Methods 0.000 description 3
- KOUKXHPPRFNWPP-UHFFFAOYSA-N pyrazine-2,5-dicarboxylic acid;hydrate Chemical compound O.OC(=O)C1=CN=C(C(O)=O)C=N1 KOUKXHPPRFNWPP-UHFFFAOYSA-N 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 239000004593 Epoxy Substances 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000001276 controlling effect Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000006471 dimerization reaction Methods 0.000 description 2
- ASQQEOXYFGEFKQ-UHFFFAOYSA-N dioxirane Chemical compound C1OO1 ASQQEOXYFGEFKQ-UHFFFAOYSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- 238000010907 mechanical stirring Methods 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 229940048181 sodium sulfide nonahydrate Drugs 0.000 description 2
- WMDLZMCDBSJMTM-UHFFFAOYSA-M sodium;sulfanide;nonahydrate Chemical compound O.O.O.O.O.O.O.O.O.[Na+].[SH-] WMDLZMCDBSJMTM-UHFFFAOYSA-M 0.000 description 2
- FQDIANVAWVHZIR-OWOJBTEDSA-N trans-1,4-Dichlorobutene Chemical compound ClC\C=C\CCl FQDIANVAWVHZIR-OWOJBTEDSA-N 0.000 description 2
- LJVHJHLTRBXGMH-HNQUOIGGSA-N (e)-1,4-dibromobut-1-ene Chemical compound BrCC\C=C\Br LJVHJHLTRBXGMH-HNQUOIGGSA-N 0.000 description 1
- HEWZVZIVELJPQZ-UHFFFAOYSA-N 2,2-dimethoxypropane Chemical compound COC(C)(C)OC HEWZVZIVELJPQZ-UHFFFAOYSA-N 0.000 description 1
- JYWKEVKEKOTYEX-UHFFFAOYSA-N 2,6-dibromo-4-chloroiminocyclohexa-2,5-dien-1-one Chemical compound ClN=C1C=C(Br)C(=O)C(Br)=C1 JYWKEVKEKOTYEX-UHFFFAOYSA-N 0.000 description 1
- BWGRDBSNKQABCB-UHFFFAOYSA-N 4,4-difluoro-N-[3-[3-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-thiophen-2-ylpropyl]cyclohexane-1-carboxamide Chemical compound CC(C)C1=NN=C(C)N1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)C1=CC=CS1 BWGRDBSNKQABCB-UHFFFAOYSA-N 0.000 description 1
- ZAXMKKSKBGKALJ-UHFFFAOYSA-N [3-acetyloxy-1,4-bis(acetylsulfanyl)butan-2-yl] acetate Chemical compound CC(=O)SCC(OC(=O)C)C(CSC(C)=O)OC(C)=O ZAXMKKSKBGKALJ-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- WERYXYBDKMZEQL-UHFFFAOYSA-N butane-1,4-diol Chemical compound OCCCCO WERYXYBDKMZEQL-UHFFFAOYSA-N 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- PVRATXCXJDHJJN-UHFFFAOYSA-N dimethyl 2,3-dihydroxybutanedioate Chemical compound COC(=O)C(O)C(O)C(=O)OC PVRATXCXJDHJJN-UHFFFAOYSA-N 0.000 description 1
- VDQVEACBQKUUSU-UHFFFAOYSA-M disodium;sulfanide Chemical compound [Na+].[Na+].[SH-] VDQVEACBQKUUSU-UHFFFAOYSA-M 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- XCRBXWCUXJNEFX-UHFFFAOYSA-N peroxybenzoic acid Chemical compound OOC(=O)C1=CC=CC=C1 XCRBXWCUXJNEFX-UHFFFAOYSA-N 0.000 description 1
- 229910001392 phosphorus oxide Inorganic materials 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229910052979 sodium sulfide Inorganic materials 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- VSAISIQCTGDGPU-UHFFFAOYSA-N tetraphosphorus hexaoxide Chemical compound O1P(O2)OP3OP1OP2O3 VSAISIQCTGDGPU-UHFFFAOYSA-N 0.000 description 1
- DUYAAUVXQSMXQP-UHFFFAOYSA-M thioacetate Chemical compound CC([S-])=O DUYAAUVXQSMXQP-UHFFFAOYSA-M 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- CMPGARWFYBADJI-UHFFFAOYSA-L tungstic acid Chemical compound O[W](O)(=O)=O CMPGARWFYBADJI-UHFFFAOYSA-L 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of dithiothreitol (a compound of formula 1), which is shown in the following reaction scheme. In the method, the compound of formula 2 is oxidized under potassium permanganate to generate a compound of formula 3, the compound of formula 3 is reacted with sodium disulfide to generate a compound of formula 4, and finally the compound of formula 4 is reduced with zinc powder to generate a compound of formula 1. The preparation method is simple, mild in reaction condition, high in reaction yield and convenient for industrial production.
Description
Technical Field
The present invention relates to the field of chemical synthesis. In particular, the invention relates to a method for synthesizing dithiothreitol.
Background
One of the uses of dithiothreitol is as a reducing agent and deprotection agent for thiolated DNA. The terminal sulphur atoms of thiolated DNA tend to form dimers in solution, especially in the presence of oxygen. This dimerization greatly reduces the efficiency of some coupling experiments (e.g., immobilization of DNA in a biosensor); and dithiothreitol is added into the DNA solution, and the DNA is removed after a period of reaction, so that dimerization of the DNA can be reduced.
Currently, the following literature reports on the synthesis of dithiothreitol:
Heteromyces (2003), 60 (1), 47-56 report: the compound of formula 4 reacts with trialkyl phosphorus and then hydrolyzes to obtain the compound of formula 1 (dithiothreitol) and trialkyl phosphorus oxide, and the yield is 65-70%.
The dithiothreitol yield of the method is not high (65% -70%), and the use of phosphorus-containing compounds in the reaction process can pollute the environment.
2. Chinese patent document CN101503384a (2009-08-12) reports a synthetic method of dithiothreitol (formula 1), and the specific synthetic route is shown below:
In the method, after 1, 4-butylene glycol is added with liquid bromine, the mixture is hydrolyzed under alkaline condition to obtain dioxirane, then the dioxirane is added with thioacetic acid to obtain dithiothreitol diacetate, and finally the dithiothreitol (formula 1) is hydrolyzed under alkaline condition, and the total yield is 35.4-36.4%. In the first step of the method, liquid bromine with high toxicity and inconvenient operation is utilized, and in the third step, malodorous thioacetic acid is utilized, so that the production environment and the danger are high.
3. Patent document CN103073462a (2013-05-01) reports a synthetic method of the compound of formula 1. The specific synthetic route is as follows:
Dimethyl tartrate is used as a raw material, the raw material reacts with 2, 2-dimethoxy propane to generate 2, 3-O-isopropylidene dimethyl tartrate, sodium borohydride is used for reduction to obtain 2, 3-O-isopropylidene threitol, the compound reacts with sulfonyl chloride under the action of sodium hydrogen to generate 2, 3-O-isopropylidene threitol sulfonate, the obtained sulfonate compound reacts with thioacetate to generate 2, 3-O-isopropylidene dithiothreitol diacetate, and finally alkaline hydrolysis is used to obtain the compound of the formula 1. The method has the advantages that the reaction steps are too long, dangerous and flammable sodium hydrogen is used in the third step of synthesis, malodorous thioacetic acid is used in the fourth step, and the production environment and the danger are high.
4. Patent document CN112028799a (2020-12-04) reports a synthetic method of the compound of formula 1. The specific synthetic route is as follows:
The 1, 4-disulfonic acid-2-butene is oxidized with peroxybenzoic acid or tungstic acid/hydrogen peroxide to obtain an epoxy compound, and then the epoxy compound is reduced by lithium aluminum hydride and sodium borohydride to obtain the compound of the formula 1, wherein the yield is 78-79%. The method uses dangerous inflammable lithium aluminum hydride, and has high production risk.
5. Patent document CN115093352a (2022-09-23) reports the reaction method shown in the following scheme:
The method comprises the steps of (1, 4-dibromobutene and pyridine are formed into quaternary ammonium salt, potassium permanganate is used for oxidation to form glycol, acetic anhydride is used for protecting glycol to form ester, the glycol reacts with potassium thioacetate to obtain 1, 4-diacetylthio-2, 3-diacetyloxy butane, sulfuric acid is added into methanol for reflux reaction, and dithiothreitol is obtained, and the total yield is 55%. In the method, the malodorous reagent pyridine is needed to be utilized, so that the production environment is poor, and the solvent DMF wastewater is difficult to treat and the like.
Therefore, there is an urgent need in the art for a dithiothreitol synthesis method that is simple to operate, safe, environmentally friendly, high in yield, and advantageous for industrial production.
Disclosure of Invention
The invention aims to provide a brand-new dithiothreitol synthesis method which has the advantages of simplicity and convenience in operation, safety, environmental friendliness, high yield, contribution to industrial production and the like.
The invention provides a preparation method of dithiothreitol shown in a formula 1, which is shown in the following reaction scheme:
The method comprises the following steps:
1) Oxidizing the compound of formula 2 to produce a compound of formula 3;
2) Reacting a compound of formula 3 with sodium disulfide to produce a compound of formula 4;
3) The compound of formula 4 is reduced to obtain the compound of formula 1.
In a specific embodiment, in step 3), the compound of formula 4 is reduced with zinc to give the compound of formula 1.
In a specific embodiment, in step 3), the compound of formula 4 is reduced with zinc powder to give the compound of formula 1.
In a specific embodiment, in step 1), the compound of formula 2 is oxidized using potassium permanganate to produce the compound of formula 3.
In a specific embodiment, the compound of formula 2 is oxidized to the compound of formula 3 using potassium permanganate at a temperature of-20 ℃ to 40 ℃, preferably 5 ℃ to 10 ℃.
In a specific embodiment, in step 2), the molar ratio of the compound of formula 3 to sodium disulphide is from 1:1 to 1:3; preferably 1:1.5.
In a specific embodiment, in step 2), the reaction of the compound of formula 3 with sodium disulphide to form the compound of formula 4 is carried out in a solvent selected from the group consisting of N, N dimethylformamide, N dimethylacetamide, dimethylsulfoxide, THF or a mixed solvent thereof; n, N dimethylformamide is preferred.
In a specific embodiment, in step 2), the reaction of the compound of formula 3 with sodium disulphide to form the compound of formula 4 is carried out in the presence of a catalyst selected from potassium iodide, sodium iodide, potassium bromide or mixtures thereof; potassium iodide is preferred.
In a specific embodiment, in step 3), the reduction of the compound of formula 4 to give the compound of formula 1 is carried out at a temperature of 20℃to 120℃and preferably 60℃to 65 ℃.
In a specific embodiment, the yield of the compound of formula 1 is 90% or more, preferably 95% or more, more preferably 96% or more.
It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. And are limited to a space, and are not described in detail herein.
Detailed Description
The inventors have conducted extensive and intensive studies and have unexpectedly found a synthesis method for industrially advantageously producing dithiothreitol (compound of formula 1) with safety using a compound of formula 2 as a starting material, on the basis of which the present invention has been completed.
The method of the invention
The synthetic route reaction formula of the method is shown as follows:
in the method of the invention, the compound of the formula 2 is reacted with potassium permanganate to generate the compound of the formula 3, and then the compound of the formula 4 is reacted with sodium disulfide to generate the compound of the formula 1 under the condition of reducing zinc powder. The method has short synthetic route, adopts cheap and easily available sodium disulfide as a thio reagent to construct a disulfide compound formula 4, and finally uses zinc powder for reduction to obtain the compound of the formula 1.
In a specific embodiment, the preparation method of dithiothreitol according to the present invention comprises the steps of:
1) Oxidizing the compound of formula 2 to produce a compound of formula 3;
2) Reacting a compound of formula 3 with sodium disulfide to produce a compound of formula 4;
3) The compound of formula 4 is reduced to obtain the compound of formula 1.
Based on the teachings of the present invention, one skilled in the art knows how to oxidize a compound of formula 2 to a compound of formula 3. For example, oxidation of a compound of formula 2 with potassium permanganate yields a compound of formula 3. The oxidation of the compound of formula 2 by potassium permanganate to the compound of formula 3 may be carried out at a suitable temperature, for example at a temperature of-20 ℃ to 40 ℃, preferably 5 ℃ to 10 ℃.
In particular embodiments, reacting the compound of formula 3 with sodium disulfide to produce the compound of formula 4 may be performed at a suitable molar ratio of the compound of formula 3 to sodium disulfide. For example, the molar ratio of the compound of formula 3 to sodium disulfide may be from 1:1 to 1:3; preferably 1:1.5.
In particular embodiments, the reaction of the compound of formula 3 with sodium disulfide to form the compound of formula 4 may be carried out in a suitable solvent. The solvent can be N, N dimethylformamide, N dimethylacetamide, dimethyl sulfoxide, THF or a mixed solvent thereof; but N, N dimethylformamide is preferred.
In a specific embodiment, the reaction of the compound of formula 3 with sodium disulfide to form the compound of formula 4 is carried out in the presence of a catalyst. The catalyst may be potassium iodide, sodium iodide, potassium bromide or mixtures thereof; but potassium iodide is preferred.
Based on the teachings of the present invention, one skilled in the art knows how to reduce the compound of formula 4 to give the compound of formula 1. For example, zinc may be used to reduce the compound of formula 4 to give the compound of formula 1; preferably, zinc dust is used to reduce the compound of formula 4 to give the compound of formula 1.
In a specific embodiment, the reduction of the compound of formula 4 to give the compound of formula 1 is carried out at a suitable temperature, for example at a temperature of 20 ℃ to 120 ℃, preferably 60 ℃ to 65 ℃.
The preparation method of dithiothreitol is simple and safe to operate, is suitable for industrial mass production, and has high yield of the obtained dithiothreitol. In a specific embodiment, the yield of dithiothreitol prepared by the method of the present invention may be up to 90% or more, preferably 95% or more, more preferably 96% or more.
The invention has the advantages that:
1. according to the method, the sodium disulfide is used for constructing the sulfhydryl, so that the use of malodorous vulcanizing agents is avoided, and the production environment is good;
2. In the method, zinc powder is used for replacing the trialkyl phosphorus to reduce the disulfide bond in the formula 4, so that the use of phosphorus-containing compounds to pollute the environment is avoided;
3. the reaction process conditions of the method are optimized, and the reaction yield is high; and
4. The method has mild reaction conditions, is easy to operate and is favorable for industrial production.
The technical solutions of the present invention are further described below with reference to specific embodiments, but the following examples are not to be construed as limiting the present invention, and all the various methods of application adopted according to the principles and technical means of the present invention are within the scope of the present invention. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. Percentages and parts are by weight unless otherwise indicated.
Example 1: synthesis of Compound of formula 3 (different reaction temperature Studies)
Three reaction bottles were taken, and 16.25 g (0.13 mol) of 1, 4-dichloro-2-butene (formula 2) and 300 g of isopropyl alcohol were added thereto, respectively, and after the addition was completed, they were dissolved by stirring. The temperature of the No. 1 reaction bottle is controlled to be minus 15 ℃ to minus 10 ℃, 411 g of 5 percent potassium permanganate neutral liquid is added dropwise, after the dripping is finished, the pH value is regulated by dilute sulfuric acid to be 3 to 4, and the temperature is controlled to react for 2 hours; adding 411 g of 5% potassium permanganate neutral solution dropwise into a No. 2 reaction bottle at a temperature of 5-10 ℃, adjusting the pH value to be 3-4 with dilute sulfuric acid after the dripping is finished, and continuously controlling the temperature to react for 2 hours; 411 g of 5% potassium permanganate neutral solution is added dropwise into a No. 3 reaction bottle at 15-20 ℃ and the pH value is regulated by dilute sulfuric acid=3-4 after the dripping is finished, and the temperature is controlled continuously for 2 hours for reaction. TLC detects that three reaction starting materials were reacted. Filtering, washing the filter cake with isopropanol, concentrating the filtrate under reduced pressure to 110 g for crystallization, filtering and drying to obtain the compound of the formula 3. The yields and purities of the three compounds of formula 3 were calculated as shown in the following table.
TABLE 1
| Experimental group | Reaction solvent | Reaction temperature | Yield is good | HPLC |
| 1 | Isopropyl alcohol | -15～-10℃ | 83.9％ | 98.7％ |
| 2 | Isopropyl alcohol | 5～10℃ | 92.1％ | 99.1％ |
| 3 | Isopropyl alcohol | 15～20℃ | 88.3％ | 98.5％ |
Example 2: synthesis of Compound 3
65 G (0.52 mol) of 1, 4-dichloro-2-butene (formula 2) and 1200 g of isopropanol were added to the flask, and after the addition, the mixture was dissolved by stirring. Then the temperature of the reaction bottle is controlled to be 5-10 ℃, 1650 g of 5% potassium permanganate neutral solution is added dropwise, the pH value is regulated to be 3-4 by dilute sulfuric acid after the dripping is finished, and the reaction is continued for 2 hours by controlling the temperature (TLC detects that the raw materials are reacted). Filtering, washing the filter cake with isopropanol, concentrating the filtrate under reduced pressure until the concentration reaches 450 g for crystallization, filtering and drying to obtain 76.5 g of the compound of the formula 3, wherein the yield is 92.5%, and the HPLC is 99.2%.
Example 3: synthesis of Compound 4 (different feed ratio study)
Preparation of sodium disulfide solution:
Na2S+S→Na2S2
240.2g of sodium sulfide nonahydrate and 250ml of purified water are added into a 1000ml single-port bottle, the temperature is slowly raised to 60 ℃ through mechanical stirring until the solid of the raw material is fully dissolved, then 32g of sulfur powder is added, the temperature is continuously raised to 80 ℃ until the solid of the sulfur powder is fully dissolved, the temperature is kept for 60 minutes after the solid of the sulfur powder is dissolved, and the temperature is cooled to room temperature for standby.
(II) synthesizing a compound of formula 4:
Taking three reaction bottles, respectively adding 31.8 g (0.2 mol) of tetrahydrofuran in formula 3 and 150 g of sodium iodide in 1.6 g, stirring and dissolving after the addition, and adding 104.4 g (0.2 mol) of prepared sodium disulfide solution in a No. 1 reaction bottle; 156.6 g (0.3 mol) of the prepared sodium disulfide solution is added into a No. 2 reaction flask; 261.0 g (0.5 mol) of the prepared sodium disulfide solution is added into a reaction flask No. 3; after the addition, the three reaction flasks were reacted at 55-60℃for 3 hours (TLC detected that the three reaction starting materials were reacted). Adding ethyl acetate, washing and layering, extracting the water layer with ethyl acetate once, combining the organic layers, drying, filtering, and concentrating the filtrate to obtain a residual liquid. Pulping the raffinate by petroleum ether to obtain the compound of formula 4. The yields of the three reactions were calculated as follows.
TABLE 2
Example 4: synthesis of Compound of formula 4 (comparative study of different catalysts)
Taking three reaction bottles, respectively adding 31.8 g (0.2 mol) of tetrahydrofuran in formula 3 and 150 g, 156.6 g (0.3 mol) of prepared sodium disulfide solution, and adding 1.6 g of sodium iodide into the reaction bottle 1 after the addition is finished; 1.6 g of potassium iodide is added into a No. 2 reaction bottle; 1.6 g of potassium bromide is added into a reaction bottle No. 3; after the addition, the three reaction flasks were reacted at 55-60℃for 3 hours (TLC detected that the three reaction starting materials were reacted). Adding ethyl acetate, washing and layering, extracting the water layer with ethyl acetate once, combining the organic layers, drying, filtering, and concentrating the filtrate to obtain a residual liquid. Pulping the raffinate by petroleum ether to obtain the compound of formula 4. The yields of the three reactions were calculated as follows.
TABLE 3 Table 3
Example 5: synthesis of Compound of formula 4 (comparative study of different reaction solvents)
Three reaction vials were taken and 31.8 g (0.2 mole) of formula 3, 156.6 g (0.3 mole) of the prepared sodium disulfide solution, and 1.6 g of potassium iodide were added, respectively. 150 g of tetrahydrofuran is added into a No. 1 reaction bottle after the addition is finished; 150 g of N, N dimethylformamide is added into a No. 2 reaction flask; 150 g of dimethyl sulfoxide is added into a reaction flask No. 3; after the addition, the three reaction flasks were reacted at 55-60℃for 3 hours (TLC detected that the three reaction starting materials were reacted). Adding ethyl acetate, washing and layering, extracting the water layer with ethyl acetate once, combining the organic layers, drying, filtering, and concentrating the filtrate to obtain a residual liquid. Pulping the raffinate by petroleum ether to obtain the compound of formula 4. The yields of the three reactions were calculated as follows.
TABLE 4 Table 4
Example 6: synthesis of Compounds of formula 4
Preparation of sodium disulfide solution:
240.2g of sodium sulfide nonahydrate and 250ml of purified water are added into a 1000ml single-port bottle, the temperature is slowly raised to 60 ℃ through mechanical stirring until the solid of the raw material is fully dissolved, then 32g of sulfur powder is added, the temperature is continuously raised to 80 ℃ until the solid of the sulfur powder is fully dissolved, the temperature is kept for 60 minutes after the solid of the sulfur powder is dissolved, and the temperature is cooled to room temperature for standby.
(II) synthesizing a compound of formula 4:
159.0 g (1 mol) of the compound of formula 3, 750 g of N, N dimethylformamide and 8g of potassium iodide were added to the reaction flask. The sodium disulfide solution prepared above was added and reacted at 55-60℃for 3 hours (TLC detection of the completion of the reaction of the starting material). Ethyl acetate was added, the layers were separated by washing with water, the aqueous layer was extracted once with ethyl acetate, and the combined organic layers were dried. Filtering, and concentrating the filtrate to obtain residual liquid. The raffinate was slurried with petroleum ether to give 143.9 g of the compound of formula 4 in 94.5% yield.
Example 7: synthesis of Compound of formula 1 (comparative study of different reaction temperatures)
Taking three reaction bottles, adding 76.0 g (0.5 mol) of a compound of formula 4, 250 g of glacial acetic acid and 98 g (1.5 mol) of zinc powder into each reaction bottle, and then reacting for 4 hours at 40-45 ℃ in a No. 1 reaction bottle; the reaction is carried out for 4 hours at 60-65 ℃ in a No. 2 reaction bottle; the reaction is carried out for 4 hours at 80-85 ℃ in a No. 3 reaction bottle. TLC detects that three reaction starting materials were reacted. Filtering, distilling the filtrate to recover glacial acetic acid, rectifying the residual liquid under high vacuum and reduced pressure at a vacuum degree of 400Pa, collecting the fraction at 90-95 ℃, naturally cooling the fraction to obtain white solid type 1 compound, and calculating the yields of the three reactions as shown in the table below.
TABLE 5
Example 8: synthesis of Compounds of formula 1
152.2 G (1 mol) of the compound of formula 4, 500 g of glacial acetic acid and 196.1 g (3 mol) of zinc powder are introduced into the reaction flask and reacted at 60-65℃for 4 hours after the addition (TLC detects that the starting material has reacted). Filtering, distilling the filtrate to recover glacial acetic acid, rectifying the residual liquid under high vacuum and reduced pressure at the vacuum degree of 400Pa, collecting the fraction at 90-95 ℃, and naturally cooling the fraction to obtain 148.5 g of white solid compound 1, wherein the yield is 96.3%.
All documents mentioned in this disclosure are incorporated by reference in this disclosure as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the application as defined in the appended claims.
Claims (10)
1. A process for the preparation of dithiothreitol of formula 1, said process being represented by the following reaction scheme:
The method comprises the following steps:
1) Oxidizing the compound of formula 2 to produce a compound of formula 3;
2) Reacting a compound of formula 3 with sodium disulfide to produce a compound of formula 4;
3) The compound of formula 4 is reduced to obtain the compound of formula 1.
2. The method of claim 1, wherein in step 3), the compound of formula 4 is reduced with zinc to yield the compound of formula 1.
3. The process of claim 2, wherein in step 3), the compound of formula 4 is reduced with zinc powder to give the compound of formula 1.
4. A process according to any one of claims 1 to 3, wherein in step 1) the compound of formula 2 is oxidised using potassium permanganate to form the compound of formula 3.
5. The process according to claim 4, wherein the compound of formula 2 is oxidized to the compound of formula 3 using potassium permanganate at a temperature of-20 ℃ to 40 ℃, preferably 5 ℃ to 10 ℃.
6. The method of any one of claims 1-5, wherein in step 2), the molar ratio of the compound of formula 3 to sodium disulfide is from 1:1 to 1:3; preferably 1:1.5.
7. The process according to any one of claims 1 to 6, wherein in step 2) the reaction of the compound of formula 3 with sodium disulphide to form the compound of formula 4 is carried out in a solvent selected from the group consisting of N, N dimethylformamide, N dimethylacetamide, dimethylsulfoxide, THF or a mixture thereof; n, N dimethylformamide is preferred.
8. The process of any one of claims 1-7, wherein in step 2) the reaction of the compound of formula 3 with sodium disulfide to form the compound of formula 4 is carried out in the presence of a catalyst selected from potassium iodide, sodium iodide, potassium bromide, or mixtures thereof; potassium iodide is preferred.
9. The process according to any one of claims 1 to 8, wherein in step 3) the reduction of the compound of formula 4 to the compound of formula 1 is carried out at a temperature of 20 ℃ to 120 ℃, preferably 60 ℃ to 65 ℃.
10. The process according to any one of claims 1 to 9, wherein the yield of the compound of formula 1 is above 90%, preferably above 95%, more preferably above 96%.
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