CN117466782A - Preparation process of N, N-bis (2-hydroxyethyl) -2-aminoethanesulfonic acid - Google Patents
Preparation process of N, N-bis (2-hydroxyethyl) -2-aminoethanesulfonic acid Download PDFInfo
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- CN117466782A CN117466782A CN202210865064.2A CN202210865064A CN117466782A CN 117466782 A CN117466782 A CN 117466782A CN 202210865064 A CN202210865064 A CN 202210865064A CN 117466782 A CN117466782 A CN 117466782A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 79
- AJTVSSFTXWNIRG-UHFFFAOYSA-N 2-[bis(2-hydroxyethyl)amino]ethanesulfonic acid Chemical compound OCC[NH+](CCO)CCS([O-])(=O)=O AJTVSSFTXWNIRG-UHFFFAOYSA-N 0.000 title claims abstract description 48
- 238000006243 chemical reaction Methods 0.000 claims abstract description 75
- 229940125782 compound 2 Drugs 0.000 claims abstract description 27
- 229940125904 compound 1 Drugs 0.000 claims abstract description 19
- 229940126214 compound 3 Drugs 0.000 claims abstract description 18
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 17
- 239000002253 acid Substances 0.000 claims abstract description 7
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 6
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 5
- 239000003513 alkali Substances 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 39
- 239000002904 solvent Substances 0.000 claims description 30
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 27
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 27
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 27
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 26
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 22
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 16
- 238000000746 purification Methods 0.000 claims description 16
- 230000035484 reaction time Effects 0.000 claims description 16
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- 239000007810 chemical reaction solvent Substances 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 10
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 claims description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- 230000008569 process Effects 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 150000002367 halogens Chemical group 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Chemical group OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 5
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 4
- 150000004820 halides Chemical class 0.000 claims description 4
- 230000002140 halogenating effect Effects 0.000 claims description 4
- 229910052751 metal Inorganic materials 0.000 claims description 4
- 239000002184 metal Substances 0.000 claims description 4
- AKEJUJNQAAGONA-UHFFFAOYSA-N sulfur trioxide Chemical compound O=S(=O)=O AKEJUJNQAAGONA-UHFFFAOYSA-N 0.000 claims description 4
- 239000011541 reaction mixture Substances 0.000 claims description 3
- 238000006277 sulfonation reaction Methods 0.000 claims description 3
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 claims description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical group OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 2
- 239000004215 Carbon black (E152) Substances 0.000 claims description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical group OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 claims description 2
- 150000001340 alkali metals Chemical group 0.000 claims description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 2
- 150000001342 alkaline earth metals Chemical class 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 claims description 2
- 238000005886 esterification reaction Methods 0.000 claims description 2
- 125000005842 heteroatom Chemical group 0.000 claims description 2
- 229930195733 hydrocarbon Natural products 0.000 claims description 2
- 239000012433 hydrogen halide Substances 0.000 claims description 2
- 229910000039 hydrogen halide Inorganic materials 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 2
- 229910052698 phosphorus Inorganic materials 0.000 claims description 2
- 239000011574 phosphorus Substances 0.000 claims description 2
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 239000011593 sulfur Substances 0.000 claims description 2
- HIFJUMGIHIZEPX-UHFFFAOYSA-N sulfuric acid;sulfur trioxide Chemical compound O=S(=O)=O.OS(O)(=O)=O HIFJUMGIHIZEPX-UHFFFAOYSA-N 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims 1
- 239000006177 biological buffer Substances 0.000 abstract description 10
- 239000002994 raw material Substances 0.000 abstract description 9
- 239000012535 impurity Substances 0.000 abstract description 5
- 238000009776 industrial production Methods 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 19
- 238000009987 spinning Methods 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 238000001035 drying Methods 0.000 description 8
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000012512 characterization method Methods 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 230000020477 pH reduction Effects 0.000 description 5
- 238000001953 recrystallisation Methods 0.000 description 5
- 238000000967 suction filtration Methods 0.000 description 5
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 4
- 235000010265 sodium sulphite Nutrition 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 2
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 2
- 239000012346 acetyl chloride Substances 0.000 description 2
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 2
- FRYHCSODNHYDPU-UHFFFAOYSA-N ethanesulfonyl chloride Chemical compound CCS(Cl)(=O)=O FRYHCSODNHYDPU-UHFFFAOYSA-N 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000003456 ion exchange resin Substances 0.000 description 2
- 229920003303 ion-exchange polymer Polymers 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 2
- 239000010865 sewage Substances 0.000 description 2
- BVIXLMYIFZGRBH-UHFFFAOYSA-M sodium;2-chloroethanesulfonate Chemical compound [Na+].[O-]S(=O)(=O)CCCl BVIXLMYIFZGRBH-UHFFFAOYSA-M 0.000 description 2
- VWUDFVFHUCCEJX-UHFFFAOYSA-M sodium;but-1-ene-1-sulfonate Chemical compound [Na+].CCC=CS([O-])(=O)=O VWUDFVFHUCCEJX-UHFFFAOYSA-M 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- 238000001994 activation Methods 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 125000000532 dioxanyl group Chemical group 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000010850 salt effect Methods 0.000 description 1
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-M sulfamate Chemical compound NS([O-])(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-M 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/32—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of salts of sulfonic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
- C07C209/74—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton by halogenation, hydrohalogenation, dehalogenation, or dehydrohalogenation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/06—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton from hydroxy amines by reactions involving the etherification or esterification of hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/02—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/02—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof
- C07C303/22—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof from sulfonic acids, by reactions not involving the formation of sulfo or halosulfonyl groups; from sulfonic halides by reactions not involving the formation of halosulfonyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
- C07C303/28—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
Abstract
The invention relates to the technical field of biological buffer reagent synthesis, and discloses a preparation process of N, N-bis (2-hydroxyethyl) -2-aminoethanesulfonic acid, which comprises the following preparation steps: reacting the compound 1 with a reagent A to obtain a compound 2; reacting the compound 2 with a sulfonating agent B to obtain a compound 3; the compound 3 is subjected to at least one of reaction with acid or alkali and hydrolysis reaction to prepare N, N-bis (2-hydroxyethyl) -2-aminoethanesulfonic acid; the preparation method provided by the invention has the advantages that the cost of raw materials used in the preparation method is low, the operation is simple, the purity of the obtained product is higher, the yield of the product is improved, the application cost of the product is reduced, the preparation method is suitable for industrial production, and the obtained product can meet the requirements of the biological buffer field on the purity, the impurity content and the cost of the product.
Description
Technical Field
The invention belongs to the technical field of biological buffering agents, and relates to a preparation process of N, N-bis (2-hydroxyethyl) -2-aminoethanesulfonic acid.
Background
In biological studies, the subject is usually cultivated in a medium, and when the chemical reaction occurs, the medium, tissue space and biomacromolecule of the subject are reacted with [ H ] in the medium + ]There is a certain requirement for concentration, so that a suitable biological buffer with a relatively stable pH is required. In addition to the pKa values being suitable, biological buffers are generally required to be chemically inert, readily soluble in water and poorly soluble in organic solventsThe method has the characteristics of small influence on temperature and small salt effect, and is easy to synthesize.
The isethionate is a better biological buffer, the traditional synthetic route is to use diethanolamine and sodium butenesulfonate or sodium chloroethyl sulfonate as reactants, the reaction yield is lower by about 60%, so that the production efficiency is lower, the raw materials are more expensive, and the energy consumption is high, thereby bringing about the problem of discharge of a large amount of sewage. The Chinese patent CN2015138904. X discloses a preparation method of a biological buffer, breaks through the traditional step method of reacting diethanolamine with sodium butene sulfonate or sodium chloroethyl sulfonate as raw materials, obtains isethionate through the reaction of ethylene oxide and sulfamate, greatly improves the reaction yield and efficiency, and overcomes the problems of low yield and low efficiency in the prior art. And the synthesis process has the advantages of less solvent amount, less sewage, high reaction efficiency, simple and easily obtained raw materials and easy industrialization. However, in the patent, BES is prepared by removing sodium ions through the strong acid ion exchange resin, the activation process of the strong acid ion exchange resin is complex, a large amount of three wastes can be generated, the efficiency is low, and the flow is long; the commercialization cost is high and the operability is low.
Overall, the number of patents for N, N-bis (2-hydroxyethyl) -2-aminoethanesulfonic acid and its sodium salt products is relatively small, and there are a number of problems associated with the prior art processes, such as: the raw materials of the product are not easy to obtain, the manufacturing cost is high, the yield is low, the three wastes are more, the preparation method is complex, and the like. The above problems, if not resolved, will prevent their large-scale application, especially their use as materials in the biological buffer field.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention aims at a preparation process of N, N-bis (2-hydroxyethyl) -2-aminoethanesulfonic acid, and a high-purity product is obtained and the yield is improved by optimizing the initial raw materials, the preparation method and the purification process; the preparation process of the invention has the advantages of simplicity, low cost, suitability for industrial production and suitability for application in the field of biological buffers.
The aim of the invention can be achieved by adopting the following technical scheme:
a preparation process of N, N-bis (2-hydroxyethyl) -2-aminoethanesulfonic acid, comprising the following steps:
preparation step S1: the compound 1 reacts with a reagent A to prepare a compound 2;
preparation step S2: the compound 2 reacts with a sulfonating reagent B to prepare a compound 3;
preparation step S3: the compound 3 is subjected to at least one of reaction with acid or alkali and hydrolysis reaction to prepare N, N-bis (2-hydroxyethyl) -2-aminoethanesulfonic acid;
wherein, the structural formula of the compound 1 is shown as formula I:
the structural formula of the compound 2 is shown as a formula II:
the reaction equation of the preparation step S1 is shown in the following formula (1):
the structural formula of the compound 3 is shown in a formula III:
the reaction equation of the preparation step S2 is shown in the following formula (2):
the reaction equation of the preparation step S3 is shown in the following formula (3):
wherein the reagent A is a halogenating reagent, RCOOH, RCOX, RSO 3 H、RSO 2 At least one of X; x is halogen;
X 1 、X 2 、X 3 is halogen, OH, OSO 2 R, OCOR; and X is 1 、X 2 、X 3 Not all OH;
m is a group IA metal or a group IIA metal, NH 4 + At least one of (a) and (b);
r is saturated or unsaturated, straight-chain or branched, heteroatom-containing or heteroatom-free C 1 -C 30 Hydrocarbon radicals, C 1 -C 30 One of the aromatic ring groups.
Further, compound 1 in the preparation step S1 is reacted with reagent a, and then subjected to at least one of hydrolysis reaction and esterification reaction to prepare compound 2.
Further, the sulfonation reagent B is sulfite, bisulfite, concentrated sulfuric acid, fuming sulfuric acid, chlorosulfonic acid, sulfur trioxide and SO 2 At least one of the reaction mixtures with an oxide or hydroxide of an alkali metal group IA or group IIA alkaline earth metal.
Further, the halogenating agent is at least one of halogen, hydrogen halide, hydrohalic acid, sulfur-containing halide, and phosphorus-containing halide.
Further, the reaction temperature of the reaction in the preparation step S1 is-50-200 ℃, the reaction pressure is-0.05-1 MPa, and the reaction time is 0.1-72 hours;
the reaction temperature of the reaction in the preparation step S2 is-50-200 ℃, the reaction pressure is-0.05-1 MPa, and the reaction time is 0.1-72 hours;
the reaction temperature of the reaction in the preparation step S3 is-50-200 ℃, the reaction pressure is-0.05-1 MPa, and the reaction time is 0.1-72 hours.
Further, the molar ratio of the compound 1 to the reagent A in the preparation step S1 is 1 (0.1-10);
the molar ratio of the compound 2 to the sulfonating agent B in the preparation step S2 is 1 (0.1-10).
Further, the preparation step S1 is carried out in a reaction solvent A, wherein the reaction solvent A is one or a combination of more than two of acetone, dichloromethane, chloroform, dichloroethane, tetrahydrofuran, ethyl acetate, dimethyl carbonate, diethyl ether, acetonitrile, dioxane, N-dimethylformamide and dimethyl sulfoxide;
the preparation step S2 is carried out in a reaction solvent B, wherein the reaction solvent B is one or a combination of more than two of methanol, ethanol, acetone, tetrahydrofuran, ethyl acetate, dimethyl carbonate, diethyl ether, acetonitrile, dioxane, N-dimethylformamide and dimethyl sulfoxide;
the preparation step S3 is carried out in a reaction solvent C, wherein the reaction solvent C is one or a combination of more than two of methanol, ethanol, acetone, methylene dichloride, chloroform, dichloroethane, tetrahydrofuran, ethyl acetate, dimethyl carbonate, diethyl ether, acetonitrile, dioxane, N-dimethylformamide and dimethyl sulfoxide.
Further, the preparation process of the N, N-bis (2-hydroxyethyl) -2-aminoethanesulfonic acid further comprises the following preparation steps: recrystallizing the obtained N, N-bis (2-hydroxyethyl) -2-aminoethanesulfonic acid with a purification solvent to obtain refined N, N-bis (2-hydroxyethyl) -2-aminoethanesulfonic acid.
Further, the purifying solvent is one or more of methanol, ethanol, acetone, tetrahydrofuran, ethyl acetate, dimethyl carbonate, diethyl ether, acetonitrile, dioxane, N-dimethylformamide and dimethyl sulfoxide.
Compared with the prior art, the invention has the beneficial effects that:
1. the preparation method of the N, N-bis (2-hydroxyethyl) -2-aminoethanesulfonic acid improves the yield of the product by optimizing the initial raw materials and optimizing the preparation and purification steps, is simple, reduces the cost of the product, is suitable for industrial production, and the prepared N, N-bis (2-hydroxyethyl) -2-aminoethanesulfonic acid has high purity, meets the requirements of the biological buffer field on the purity, the impurity content, the cost and the like, and is suitable for application in the biological buffer field.
2. The byproducts and impurities generated by the preparation method are easy to purify and separate, the impurities in the product can reach the actual application standard of high purity without complex purification process, the preparation flow of the product is simplified, the product purity is high, and the requirements on the yield and quality of large-scale application can be met.
Detailed Description
The invention will now be further described with reference to the following detailed description, which is a few non-limiting examples, but is not intended to limit the invention to the examples and descriptions which follow, but are merely illustrative of the principles of the invention; that is, the following description is only a part of preferred embodiments of the present invention and should not be construed as limiting the scope of the invention, and it will be apparent to those skilled in the art that various changes, modifications and alterations can be made therein without departing from the spirit, principle and scope of the invention, and that these additional features may be taken alone or in any combination thereof should be considered as within the scope of the invention as claimed. In addition, the raw materials used in the present invention are generally common commercial products, and therefore, the sources thereof are not particularly limited.
Nuclear magnetic analysis test, using Bruker (Bruker) company AVANCE 400 meganuclear magnetic resonance spectrometer.
Purity was analytically tested by high performance liquid chromatography HPLC.
The pressure values mentioned in this patent application, unless specified otherwise, refer to the gauge pressure, which refers to the number of total absolute pressures exceeding the ambient atmospheric pressure or the pressure in the liquid at a point above atmospheric pressure.
The reaction temperature refers generally to the temperature of the oil bath for the reaction unless otherwise specified.
The yield is calculated as the percentage ratio of the actual product mass to the theoretical product mass, calculated as the raw material in the reaction equation that is not excessive.
Example 1
A preparation process of N, N-bis (2-hydroxyethyl) -2-aminoethanesulfonic acid comprises the following preparation steps:
(1) Preparation step 1:
reacting 1 mole of compound 1 with thionyl chloride in a reactor; the mass ratio of the compound 1 to the thionyl chloride is 1:1.1, the solvent is methylene dichloride, the reaction temperature is 40 ℃, the reaction pressure is normal pressure, the reaction time is 4 hours, and the compound 2 is obtained after the reaction is completed and the spinning is performed.
(2) And (2) preparation step:
reacting 1 mole of compound 2 of the above formula with sodium sulfite in a reactor; the mass ratio of the compound 2 to sodium sulfite is 1:1.1; the solvent is DMF, the reaction temperature is 110 ℃, the reaction pressure is normal pressure, the reaction time is 1 hour, and the solvent is dried by spinning after the reaction is completed, thus obtaining the compound 3.
(3) And (3) preparation step:
in a reactor, 1 mole of compound 3 in the formula is dissolved in methanol, excessive hydrochloric acid solution is added, acidification reaction is carried out under normal pressure for 1 hour, after the reaction is finished, the solvent is dried by spinning, and the N, N-bis (2-hydroxyethyl) -2-aminoethanesulfonic acid is obtained, and the crude product yield is 92%.
(4) And (3) purification:
in a reactor, 1 mole of N, N-bis (2-hydroxyethyl) -2-aminoethanesulfonic acid is dissolved in methanol, ethyl acetate serving as a purifying solvent is added for recrystallization, insoluble matters are obtained through suction filtration, and refined N, N-bis (2-hydroxyethyl) -2-aminoethanesulfonic acid is obtained after drying, the purification yield is 90%, and the purity of the product is 99.2%.
The nmr characterization data were as follows:
1 HNMR(400MHz,D 2 O):3.883(4H),3.664(2H),3.402(4H),3.317(2H)。
example 2
A preparation process of N, N-bis (2-hydroxyethyl) -2-aminoethanesulfonic acid comprises the following preparation steps:
(1) Preparation step 1:
in a reactor, 1 mole of compound 1 is reacted with propionic acid; adding a small amount of sulfuric acid to remove water generated by the reaction, wherein the mass ratio of the compound 1 to the propionic acid is 1:1.2, the solvent is tetrahydrofuran, the reaction temperature is 50 ℃, the reaction pressure is normal pressure, the reaction time is 3 hours, and the compound 2 is obtained after the reaction is completed and spin-dried.
(2) And (2) preparation step:
in a reactor, 1 mole of compound 2 in the above formula is reacted with a sulfonating agent B, which is SO 2 A reaction mixture with sodium hydroxide; the mass ratio of the compound 2 to the sulfonation reagent B is 1:1.05; the solvent is tetrahydrofuran, the reaction temperature is 65 ℃, the reaction pressure is normal pressure, the reaction time is 2 hours, and the solvent is dried by spinning after the reaction is completed, so that the compound 3 is obtained.
(3) And (3) preparation step:
in a reactor, 1 mole of compound 3 in the formula is dissolved in ethanol, then excessive hydrochloric acid solution is added, acidification reaction is carried out under normal pressure for 1 hour, after the reaction is finished, the solvent is dried by spinning, and crude N, N-bis (2-hydroxyethyl) -2-aminoethanesulfonic acid is obtained, and the yield of the crude product is 93%.
(4) And (3) purification:
in a reactor, 1 mole of crude N, N-bis (2-hydroxyethyl) -2-aminoethanesulfonic acid is dissolved in ethanol, purified solvent dimethyl carbonate is added for recrystallization, insoluble matters are obtained by suction filtration, and refined N, N-bis (2-hydroxyethyl) -2-aminoethanesulfonic acid is obtained by drying, the purification yield is 92%, and the purity of the product is 99.1%.
The nmr characterization data were as follows:
1 H NMR(400MHz,D 2 O):3.883(4H),3.664(2H),3.402(4H),3.317(2H)。
example 3
A preparation process of N, N-bis (2-hydroxyethyl) -2-aminoethanesulfonic acid comprises the following preparation steps:
(1) Preparation step 1:
reacting 1 mole of compound 1 with acetyl chloride in a reactor; the mass ratio of the compound 1 to the acetyl chloride is 1:1.2, the solvent is acetonitrile, the reaction temperature is 40 ℃, the reaction pressure is normal pressure, the reaction time is 4 hours, and the compound 2 is obtained after the reaction is completed and spin-drying is carried out.
(2) And (2) preparation step:
reacting 1 mole of compound 2 of the above formula with sodium bisulfite in a reactor; the mass ratio of the compound 2 to the sodium bisulfite is 1:1.05; the solvent is tetrahydrofuran, the reaction temperature is 45 ℃, the reaction pressure is normal pressure, the reaction time is 3 hours, and the solvent is dried by spinning after the reaction is completed, so that the compound 3 is obtained.
(3) And (3) preparation step:
in a reactor, 1 mole of compound 3 in the formula is dissolved in DMF, then excessive hydrochloric acid solution is added, acidification reaction is carried out under normal pressure for 2 hours, after the reaction is finished, the solvent is dried by spinning, and crude N, N-bis (2-hydroxyethyl) -2-aminoethanesulfonic acid is obtained, and the yield of the crude product is 90%.
(4) And (3) purification:
in a reactor, 1 mole of crude N, N-bis (2-hydroxyethyl) -2-aminoethanesulfonic acid is dissolved in methanol, diethyl ether serving as a purifying solvent is added for recrystallization, insoluble matters are obtained through suction filtration, and the refined N, N-bis (2-hydroxyethyl) -2-aminoethanesulfonic acid is obtained after drying, the purification yield is 91%, and the purity of the product is 99.3%.
The nmr characterization data were as follows:
1 H NMR(400MHz,D 2 O):3.883(4H),3.664(2H),3.402(4H),3.317(2H)。
example 4
A preparation process of N, N-bis (2-hydroxyethyl) -2-aminoethanesulfonic acid comprises the following preparation steps:
(1) Preparation step 1:
in a reactor, 1 mole of compound 1 was reacted with ethylsulfonyl chloride; the mass ratio of the compound 1 to the ethyl sulfonyl chloride is 1:1.2, the solvent is DMF, the reaction temperature is 80 ℃, the reaction pressure is normal pressure, the reaction time is 1 hour, and the compound 2 is obtained after the reaction is completed and spin-drying is carried out.
(2) And (2) preparation step:
reacting 1 mole of compound 2 of the above formula with sodium sulfite in a reactor; the mass ratio of the compound 2 to sodium sulfite is 1:1.1; the solvent is tetrahydrofuran, the reaction temperature is 60 ℃, the reaction pressure is normal pressure, the reaction time is 1 hour, and the solvent is dried by spinning after the reaction is completed, so that the compound 3 is obtained.
(3) And (3) preparation step:
in a reactor, 1 mole of compound 3 in the formula is dissolved in methanol, then excessive hydrochloric acid solution is added, acidification reaction is carried out under normal pressure for 1.5 hours, after the reaction is finished, the solvent is dried by spinning, and crude N, N-bis (2-hydroxyethyl) -2-aminoethanesulfonic acid is obtained, and the yield of the crude product is 87%.
(4) And (3) purification:
in a reactor, 1 mole of crude N, N-bis (2-hydroxyethyl) -2-aminoethanesulfonic acid is dissolved in methanol, purified solvent acetone is added for recrystallization, insoluble matters are obtained through suction filtration, and refined N, N-bis (2-hydroxyethyl) -2-aminoethanesulfonic acid is obtained after drying, the purification yield is 93%, and the purity of the product is 99.0%.
The nmr characterization data were as follows:
1 H NMR(400MHz,D 2 O):3.883(4H),3.664(2H),3.402(4H),3.317(2H)。
example 5
A preparation process of N, N-bis (2-hydroxyethyl) -2-aminoethanesulfonic acid comprises the following preparation steps:
(1) Preparation step 1:
reacting 1 mole of compound 1 with phosphorus tribromide in a reactor; the mass ratio of the compound 1 to the phosphorus tribromide is 1:3.15, the solvent is dioxane, the reaction temperature is 70 ℃, the reaction pressure is normal pressure, the reaction time is 1.5 hours, and the compound 2 is obtained after the reaction is completed and the spin-drying is carried out.
(2) And (2) preparation step:
reacting 1 mole of compound 2 of the above formula with sodium bisulfite in a reactor; the mass ratio of the compound 2 to the sodium bisulfite is 1:1.25; the solvent is DMF, the reaction temperature is 80 ℃, the reaction pressure is normal pressure, the reaction time is 0.5 hour, and the solvent is dried by spinning after the reaction is completed, thus obtaining the compound 3.
(3) And (3) preparation step:
in a reactor, 1 mole of compound 3 in the formula is dissolved in methanol, 2.1 moles of aqueous solution of sodium hydroxide is added, stirring reaction is carried out until the reaction is complete, then excessive hydrochloric acid is added for acidification reaction under normal pressure for 2 hours, after the reaction is completed, the solvent is dried by spinning, and crude N, N-bis (2-hydroxyethyl) -2-aminoethanesulfonic acid is obtained, and the crude product yield is 90%.
(4) And (3) purification:
in a reactor, 1 mole of crude N, N-bis (2-hydroxyethyl) -2-aminoethanesulfonic acid is dissolved in methanol, a purification solvent tetrahydrofuran is added for recrystallization, insoluble matters are obtained by suction filtration, and the refined N, N-bis (2-hydroxyethyl) -2-aminoethanesulfonic acid is obtained by drying, the purification yield is 92%, and the purity of the product is 99.5%.
The nmr characterization data were as follows:
1 H NMR(400MHz,D 2 O):3.883(4H),3.664(2H),3.402(4H),3.317(2H)。
the experiment shows that the N, N-bis (2-hydroxyethyl) -2-aminoethanesulfonic acid prepared in the embodiment has high purity and low impurity content, can meet the requirements of application fields, and the preparation method has the highest product yield of 93 percent, improves the product yield and has the highest product purity of 99.5 percent.
The above embodiments are only preferred embodiments of the present invention, and the scope of the present invention is not limited thereto, but any insubstantial changes and substitutions made by those skilled in the art on the basis of the present invention are intended to be within the scope of the present invention as claimed.
Claims (9)
1. A process for the preparation of N, N-bis (2-hydroxyethyl) -2-aminoethanesulfonic acid, comprising the steps of:
preparation step S1: the compound 1 reacts with a reagent A to prepare a compound 2;
preparation step S2: the compound 2 reacts with a sulfonating reagent B to prepare a compound 3;
preparation step S3: the compound 3 is subjected to at least one of reaction with acid or alkali and hydrolysis reaction to prepare N, N-bis (2-hydroxyethyl) -2-aminoethanesulfonic acid;
wherein, the structural formula of the compound 1 is shown as formula I:
the structural formula of the compound 2 is shown as a formula II:
the structural formula of the compound 3 is shown in a formula III:
wherein the reagent A is a halogenating reagent, RCOOH, RCOX, RSO 3 H、RSO 2 At least one of X; x is halogen;
X 1 、X 2 、X 3 is halogen, OH, OSO 2 R, OCOR; and X is 1 、X 2 、X 3 Not all OH;
m is a group IA metal or a group IIA metal, NH 4 + At least one of (a) and (b);
r is saturated or unsaturated, straight-chain or branched, heteroatom-containing or heteroatom-free C 1 -C 30 Hydrocarbon radicals, C 1 -C 30 One of the aromatic ring groups.
2. A process for the preparation of N, N-bis (2-hydroxyethyl) -2-aminoethanesulfonic acid according to claim 1, wherein,
and (2) after the compound 1 in the preparation step S1 reacts with the reagent A, carrying out at least one of hydrolysis reaction and esterification reaction to prepare the compound 2.
3. A process for the preparation of N, N-bis (2-hydroxyethyl) -2-aminoethanesulfonic acid according to claim 1, wherein,
the sulfonation reagent B is sulfite, bisulfite, concentrated sulfuric acid, fuming sulfuric acid, chlorosulfonic acid, sulfur trioxide and SO 2 At least one of the reaction mixtures with an oxide or hydroxide of an alkali metal group IA or group IIA alkaline earth metal.
4. The process for preparing N, N-bis (2-hydroxyethyl) -2-aminoethanesulfonic acid according to claim 1, wherein the halogenating agent is at least one of halogen, hydrogen halide, halogen acid, sulfur-containing halide and phosphorus-containing halide.
5. A process for the preparation of N, N-bis (2-hydroxyethyl) -2-aminoethanesulfonic acid according to claim 1, wherein,
the reaction temperature of the reaction in the preparation step S1 is-50-200 ℃, the reaction pressure is-0.05-1 MPa, and the reaction time is 0.1-72 hours;
the reaction temperature of the reaction in the preparation step S2 is-50-200 ℃, the reaction pressure is-0.05-1 MPa, and the reaction time is 0.1-72 hours;
the reaction temperature of the reaction in the preparation step S3 is-50-200 ℃, the reaction pressure is-0.05-1 MPa, and the reaction time is 0.1-72 hours.
6. A process for the preparation of N, N-bis (2-hydroxyethyl) -2-aminoethanesulfonic acid according to claim 1, wherein,
the molar ratio of the compound 1 to the reagent A in the preparation step S1 is 1 (0.1-10);
the molar ratio of the compound 2 to the sulfonating agent B in the preparation step S2 is 1 (0.1-10).
7. A process for the preparation of N, N-bis (2-hydroxyethyl) -2-aminoethanesulfonic acid according to claim 1, wherein,
the preparation method comprises the following steps of S1, reacting in a reaction solvent A, wherein the reaction solvent A is one or a composition of more than two of acetone, dichloromethane, chloroform, dichloroethane, tetrahydrofuran, ethyl acetate, dimethyl carbonate, diethyl ether, acetonitrile, dioxane, N-dimethylformamide and dimethyl sulfoxide;
the preparation step S2 is carried out in a reaction solvent B, wherein the reaction solvent B is one or a combination of more than two of methanol, ethanol, acetone, tetrahydrofuran, ethyl acetate, dimethyl carbonate, diethyl ether, acetonitrile, dioxane, N-dimethylformamide and dimethyl sulfoxide;
the preparation step S3 is carried out in a reaction solvent C, wherein the reaction solvent C is one or a combination of more than two of methanol, ethanol, acetone, methylene dichloride, chloroform, dichloroethane, tetrahydrofuran, ethyl acetate, dimethyl carbonate, diethyl ether, acetonitrile, dioxane, N-dimethylformamide and dimethyl sulfoxide.
8. The process for preparing N, N-bis (2-hydroxyethyl) -2-aminoethanesulfonic acid according to claim 1, further comprising the steps of:
recrystallizing the obtained N, N-bis (2-hydroxyethyl) -2-aminoethanesulfonic acid with a purification solvent to obtain refined N, N-bis (2-hydroxyethyl) -2-aminoethanesulfonic acid.
9. The process for preparing N, N-bis (2-hydroxyethyl) -2-aminoethanesulfonic acid according to claim 8, wherein the purifying solvent is one or more of methanol, ethanol, acetone, tetrahydrofuran, ethyl acetate, dimethyl carbonate, diethyl ether, acetonitrile, dioxane, N-dimethylformamide and dimethyl sulfoxide.
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