CN116514684A - Preparation method of O-sulfo-L-tyrosine sodium salt - Google Patents
Preparation method of O-sulfo-L-tyrosine sodium salt Download PDFInfo
- Publication number
- CN116514684A CN116514684A CN202310492767.XA CN202310492767A CN116514684A CN 116514684 A CN116514684 A CN 116514684A CN 202310492767 A CN202310492767 A CN 202310492767A CN 116514684 A CN116514684 A CN 116514684A
- Authority
- CN
- China
- Prior art keywords
- compound
- group
- reaction
- pyridine
- solvent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- BSGUVYQJXDWSSQ-QRPNPIFTSA-M sodium;(2s)-2-amino-3-(4-sulfooxyphenyl)propanoate Chemical compound [Na+].OC(=O)[C@@H](N)CC1=CC=C(OS([O-])(=O)=O)C=C1 BSGUVYQJXDWSSQ-QRPNPIFTSA-M 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 99
- 238000006243 chemical reaction Methods 0.000 claims abstract description 53
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 28
- 238000000034 method Methods 0.000 claims abstract description 26
- 239000003513 alkali Substances 0.000 claims abstract description 23
- 239000002904 solvent Substances 0.000 claims abstract description 22
- 239000012442 inert solvent Substances 0.000 claims abstract description 20
- 239000002253 acid Substances 0.000 claims abstract description 12
- 239000002585 base Substances 0.000 claims abstract description 9
- 125000006239 protecting group Chemical group 0.000 claims abstract description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 6
- 150000003839 salts Chemical class 0.000 claims abstract description 4
- 239000011734 sodium Substances 0.000 claims abstract description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 40
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 33
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 30
- 239000007787 solid Substances 0.000 claims description 30
- 239000000243 solution Substances 0.000 claims description 26
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 25
- 238000001914 filtration Methods 0.000 claims description 22
- 238000003756 stirring Methods 0.000 claims description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 20
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 17
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- 239000000706 filtrate Substances 0.000 claims description 14
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 13
- UDYFLDICVHJSOY-UHFFFAOYSA-N sulfur trioxide pyridine complex Chemical compound O=S(=O)=O.C1=CC=NC=C1 UDYFLDICVHJSOY-UHFFFAOYSA-N 0.000 claims description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- 230000003197 catalytic effect Effects 0.000 claims description 5
- 239000012295 chemical reaction liquid Substances 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 4
- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical compound Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 4
- 239000011593 sulfur Substances 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 3
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 3
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 claims description 3
- 239000012670 alkaline solution Substances 0.000 claims description 3
- 125000003277 amino group Chemical group 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- 230000001105 regulatory effect Effects 0.000 claims description 3
- DZGCGKFAPXFTNM-UHFFFAOYSA-N ethanol;hydron;chloride Chemical compound Cl.CCO DZGCGKFAPXFTNM-UHFFFAOYSA-N 0.000 claims description 2
- LBAQSKZHMLAFHH-UHFFFAOYSA-N ethoxyethane;hydron;chloride Chemical compound Cl.CCOCC LBAQSKZHMLAFHH-UHFFFAOYSA-N 0.000 claims description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 12
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 239000008213 purified water Substances 0.000 description 6
- 239000002994 raw material Substances 0.000 description 5
- 229960004441 tyrosine Drugs 0.000 description 5
- 239000003814 drug Substances 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 229920001184 polypeptide Polymers 0.000 description 4
- 102000004196 processed proteins & peptides Human genes 0.000 description 4
- 108090000765 processed proteins & peptides Proteins 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000011031 large-scale manufacturing process Methods 0.000 description 3
- 238000004537 pulping Methods 0.000 description 3
- SWZCTMTWRHEBIN-QFIPXVFZSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-(4-hydroxyphenyl)propanoic acid Chemical compound C([C@@H](C(=O)O)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21)C1=CC=C(O)C=C1 SWZCTMTWRHEBIN-QFIPXVFZSA-N 0.000 description 2
- 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 description 2
- 230000003113 alkalizing effect Effects 0.000 description 2
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000006277 sulfonation reaction Methods 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- -1 amino acid compound Chemical class 0.000 description 1
- 238000010009 beating Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011403 purification operation Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000014616 translation Effects 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
- C07C303/24—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfuric acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
- C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
- C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
- C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
- C07C2603/18—Fluorenes; Hydrogenated fluorenes
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention provides a preparation method of O-sulfo-L-tyrosine sodium salt. Specifically, the method comprises the following steps: (i) In a solvent, in the presence of alkali, reacting the compound S2 with a sulfonating reagent to obtain a compound S3; (ii) In an inert solvent, under alkaline conditions, the compound S3 and Na + Generating a salt reaction to obtain a compound S4; and (iii) removing the amino protecting group from compound S4 in an inert solvent in the presence of an acid or a base to give compound S1 (O-sulfo-L-tyrosine sodium salt).
Description
Technical Field
The invention relates to the field of chemical synthesis, in particular to a preparation method of 0-sulfo-L-tyrosine sodium salt.
Background
The structural formula of the O-sulfo-L-tyrosine sodium salt is as follows:
the O-sulfo-L-tyrosine sodium salt is an amino acid compound used for proteomics research, tyrosine is sulfonated in organisms, has wider application in polypeptide and protein synthesis, and greatly improves the hydrophilicity of the tyrosine by introducing the strong acid group sulfonic acid, so that if the O-sulfo-L-tyrosine sodium salt is introduced in polypeptide synthesis, the water solubility of the polypeptide can be improved to a certain extent, and the subsequent synthesis and purification work of the polypeptide are facilitated.
The synthetic routes of O-sulfo-L-tyrosine sodium salt reported at present mainly comprise the following steps:
the first synthetic route is: l-tyrosine is used as an initial raw material, concentrated sulfuric acid is used as a sulfonating reagent, and sodium hydroxide or sodium carbonate is used for alkalizing, so that O-sulfo-L-tyrosine sodium salt is obtained, and the flow is as follows:
the route reports that the yield is only about 20%, the post-treatment is complex, the product with higher purity is difficult to obtain, the concentrated sulfuric acid used in the reaction is a tube product easy to prepare, the alkali amount required by alkali adjustment is also larger, and the large-scale production is not facilitated at all.
The second synthetic route is: l-tyrosine is used as a starting material, chlorosulfonic acid is used as a sulfonating reagent, and sodium hydroxide is used for alkalizing, so that O-sulfo-L-tyrosine sodium salt is obtained, and the flow is as follows:
the chlorosulfonic acid used in the route has higher activity, has larger problems in the aspect of safety, needs anhydrous and anaerobic operation, has obvious reaction temperature rise, and has corrosion action on byproduct hydrochloric acid gas generated by the reaction, and is easy to damage equipment, so that the method has high requirements on the equipment of the reaction, is not beneficial to the enlarged production, simultaneously has larger alkali amount, and the product has partial hydrolysis, so that the content of L-tyrosine is larger, and is difficult to obtain pure products.
The third synthetic route is: l-tyrosine is used as a starting material, a sulfur trioxide-DMF complex is used as a sulfonating reagent, sulfonation is carried out in a mixed solvent of DMF and 1, 4-dioxane, and then sodium carbonate or sodium bicarbonate is used for alkalization, so that O-sulfo-L-tyrosine sodium salt is obtained, and the flow is as follows:
the method requires a large amount of solvent, because the solubility of L-tyrosine in DMF and 1, 4-dioxane is not ideal, the post-treatment is troublesome, the pure product can be obtained by the complicated operations such as freeze-drying, column chromatography and the like, and the method is also unfavorable for the large-scale production.
Therefore, the technical need in the art is to provide a method for synthesizing O-sulfo-L-tyrosine sodium salt, which has the advantages of simple operation, easily available raw materials, simple post-treatment, high purity and small single impurity.
Disclosure of Invention
The invention aims to provide the preparation method of the O-sulfo-L-tyrosine sodium salt, which is simple and convenient to operate, easy to obtain raw materials, simple in post-treatment, high in purity and small in single impurity.
The invention provides a preparation method of O-sulfo-L-tyrosine sodium salt, which comprises the following steps:
(i) In an inert solvent, in the presence of alkali, reacting the compound S2 with a sulfonating reagent to obtain a compound S3;
(ii) In an inert solvent, under alkaline conditions, the compound S3 and Na + Generating a salt reaction to obtain a compound S4; and
(iii) Removing amino protecting groups from the compound S4 in an inert solvent in the presence of acid or alkali to obtain a compound S1;
wherein R is 1 Is a group selected from the group consisting of:
and in step (i), the sulphonation reagent is selected from the group consisting of: sulfur trioxide-DMF, sulfur trioxide-pyridine, or a combination thereof.
In another preferred embodiment, the method further comprises a post-treatment step: (iv) Filtering the reaction liquid obtained in the step (iii), collecting solids, adding the solids into water, stirring, filtering, collecting filtrate, and concentrating to dryness; and (3) obtaining a solid, adding the solid into a poor solvent, stirring, and filtering to obtain the compound S1.
In another preferred embodiment, in step (i), the sulphonation reagent is sulphur trioxide-pyridine.
In another preferred embodiment, in step (i), one or more technical features selected from the group consisting of:
the solvent is selected from the group consisting of: n, N-dimethylformamide, N-dimethylacetamide, pyridine, N-methylmorpholine, dichloromethane, acetonitrile, or a combination thereof, preferably N, N-dimethylformamide or pyridine;
the base is selected from the group consisting of: pyridine, triethylamine, N-diisopropylethylamine, N-dimethylaniline, or a combination thereof, preferably pyridine.
The molar ratio of the compound S2 to the sulfonation reagent is 1:1-2.5, preferably 1:1-1.5;
the temperature of the reaction is 20-50 ℃, preferably 20-40 ℃; and/or
The reaction time is 1 to 24 hours, preferably 6 to 12 hours.
In another preferred embodiment, in step (i), pyridine is used as solvent and base simultaneously, preferably the ratio of compound S2 to pyridine is 1g:4-10mL, preferably 1g:4-5mL.
In another preferred embodiment, in step (ii), one or more technical features selected from the group consisting of:
the alkaline condition means a pH of 8 to 14, preferably a pH of 8 to 10, more preferably a pH of 9;
the inert solvent is selected from the group consisting of: water, or a mixture of water and one or more of methanol, ethanol, N-propanol, isopropanol, acetone, acetonitrile, 1, 4-dioxane, tetrahydrofuran, N-dimethylformamide and N, N-dimethylacetamide; preferably, the volume ratio of water to organic solvent in the mixture is 1:1-10), more preferably 1:5;
the temperature of the reaction is 0-20 ℃, preferably 5-10 ℃; and/or
The reaction time is 1 to 24 hours, preferably 6 to 12 hours.
In another preferred embodiment, in step (ii), the alkaline conditions are obtained by alkaline adjustment of: sodium hydroxide, sodium carbonate, sodium bicarbonate; preferably, the base is in the form of an alkaline solution, preferably 3-5mol/L aqueous sodium hydroxide.
In another preferred embodiment, step (ii) further comprises the steps of: (ii-1) mixing the reaction solution of step (ii) with an organic solvent, stirring, filtering, collecting filtrate, concentrating to dryness to obtain the S4 compound, and using in the next step.
In another preferred embodiment, in the step (ii-1), after the reaction solution of the step (ii) is mixed with the organic solvent, the volume ratio of water to the organic solvent is 1: (2-10), preferably 1:3-5.
In another preferred embodiment, in step (iii), one or more technical features selected from the group consisting of:
the inert solvent is selected from the group consisting of: methanol, ethanol, methylene chloride, or a combination thereof;
the acid stripping is selected from the group consisting of: hydrochloric acid-methanol, hydrochloric acid-ethanol, hydrochloric acid-diethyl ether, preferably hydrochloric acid-methanol;
the alkaline stripping is selected from the group consisting of: piperidine, piperazine, or combinations thereof, preferably piperazine;
the temperature of the reaction is 20-50 ℃, preferably 20-40 ℃; and/or
The reaction time is 1 to 24 hours, preferably 6 to 12 hours.
In another preferred embodiment, in step (iv), the poor solvent is selected from the group consisting of: methanol, ethanol, ethyl acetate, dichloromethane, 1, 2-dichloroethane, tetrahydrofuran, acetonitrile, or a combination thereof, preferably ethyl acetate.
In another preferred embodiment, the method comprises the steps of:
(i) In pyridine, the compound S2 reacts with sulfur trioxide-pyridine until the compound S2 reacts completely, and the reaction solution is concentrated and dried to obtain a compound S3;
(ii) Dissolving a compound S3 in an inert solvent, cooling a system to 5-10 ℃, then regulating the pH value of a reaction solution to be alkaline by using alkali, naturally heating to room temperature for reaction, concentrating and drying the reaction solution after the compound S3 is completely reacted to obtain a compound S4;
(iii) Dissolving the compound S4 in an inert solvent, adding a catalytic amount of alkali or acid, and removing the protecting group of the amino group to obtain the compound S1.
In another preferred embodiment, the method comprises the steps of:
(i) Adding the compound S2 into a solvent, adding alkali and a sulfonating reagent at 25-30 ℃, wherein the mol ratio of the compound S2 to the sulfonating reagent is 1:1-1:2.5, stirring overnight at 25-30 ℃, carrying out HPLC tracking reaction until the compound S2 is completely reacted, and concentrating to dryness to obtain a compound S3;
(ii) Adding the compound S3 into a solvent, cooling the system to 10 ℃, then adjusting the pH value of the reaction liquid to be alkaline by using alkali, naturally heating to room temperature, stirring overnight, carrying out HPLC tracking reaction until the compound S3 is completely reacted, and concentrating to dryness to obtain a compound S4;
(iii) Adding the compound S4 into a solvent, adding a catalytic amount of alkali or acid, removing the protecting group of the amino, and tracking the reaction by HPLC until the compound S4 is completely reacted; and
(iv) Filtering the reaction solution in the step (iii), collecting solids, adding the solids into water, stirring, filtering, collecting filtrate, and concentrating to dryness; and (3) obtaining a solid, adding the solid into a poor solvent, stirring, and filtering to obtain the compound S1.
In another preferred embodiment, the O-sulfo-L-tyrosine sodium salt obtained by the method has a purity of 95% or more, preferably 97% or more, more preferably 99% 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
Through extensive and intensive research, the inventor provides a preparation method of O-sulfo-L-tyrosine sodium salt through a large number of screening and testing, and the method is simple and convenient to operate, easy to obtain raw materials, simple in post-treatment, high in product purity and very suitable for large-scale industrial production. The present invention has been completed on the basis of this finding.
Terminology
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
As used herein, the term "comprising" or "including" can be open, semi-closed, and closed. In other words, the term also includes "consisting essentially of …," or "consisting of ….
As used herein, the term "room temperature" or "normal temperature" refers to a temperature of 4-40 ℃, preferably 25±5 ℃.
Preparation method
The invention provides a preparation method of O-sulfo-L-tyrosine sodium salt, which comprises the following steps:
(i) In an inert solvent, in the presence of alkali, reacting the compound S2 with a sulfonating reagent to obtain a compound S3;
(ii) In an inert solvent, under alkaline conditions, the compound S3 and Na + Generating a salt reaction to obtain a compound S4;
(iii) Removing amino protecting groups from the compound S4 in an inert solvent in the presence of acid or alkali to obtain a compound S1;
wherein R is 1 Is a group selected from the group consisting of:
and in step (i), the sulphonation reagent is selected from the group consisting of: sulfur trioxide-DMF, sulfur trioxide-pyridine, or a combination thereof.
Preferably, in step (i), the sulphonation reagent is sulphur trioxide-pyridine.
Preferably, in step (i), the base is selected from the group consisting of: pyridine, triethylamine, N-diisopropylethylamine, N-dimethylaniline, or a combination thereof, preferably pyridine.
Preferably, in step (i), pyridine is used as both solvent and base, preferably the ratio of compound S2 to pyridine is 1g:1-5mL, preferably 1g:3-4mL.
Preferably, in step (ii), the alkaline conditions are obtained by alkaline adjustment of: sodium hydroxide, sodium carbonate, sodium bicarbonate; preferably, the base is in the form of an alkaline solution, preferably 5mol/L aqueous sodium hydroxide.
In another preferred embodiment, step (ii) further comprises the steps of: (ii-1) mixing the reaction solution of step (ii) with an organic solvent, stirring, filtering, collecting filtrate, concentrating to dryness to obtain the S4 compound, and using in the next step.
In another preferred embodiment, the method further comprises a post-treatment step: (iv) Filtering the reaction liquid obtained in the step (iii), collecting solids, adding the solids into purified water, stirring, filtering, collecting filtrate, and concentrating to dryness; and (3) obtaining a solid, adding the solid into a poor solvent, stirring, and filtering to obtain the compound S1.
In another preferred embodiment, in step (iv), the poor solvent is selected from the group consisting of: methanol, ethanol, ethyl acetate, dichloromethane, 1, 2-dichloroethane, tetrahydrofuran, acetonitrile, or a combination thereof, preferably ethyl acetate.
In another preferred embodiment, the method comprises the steps of:
(i) In pyridine, the compound S2 reacts with sulfur trioxide-pyridine until the compound S2 reacts completely, and the reaction solution is concentrated and dried to obtain a compound S3;
(ii) Dissolving a compound S3 in an inert solvent, cooling a system to 5-10 ℃, then regulating the pH value of a reaction solution to be alkaline by using alkali, naturally heating to room temperature for reaction, concentrating and drying the reaction solution after the compound S3 is completely reacted to obtain a compound S4;
(iii) Dissolving the compound S4 in an inert solvent, adding a catalytic amount of alkali or acid, and removing the protecting group of the amino group to obtain the compound S1.
In another preferred embodiment, the method comprises the steps of:
(i) Adding the compound S2 into a solvent, adding alkali and a sulfonating reagent at 25-30 ℃, wherein the mol ratio of the compound S2 to the sulfonating reagent is 1:1-1:2.5, stirring overnight at 25-30 ℃, carrying out HPLC tracking reaction until the compound S2 is completely reacted, and concentrating to dryness to obtain a compound S3;
(ii) Adding the compound S3 into a solvent, cooling the system to 10 ℃, then adjusting the pH value of the reaction liquid to be alkaline by using alkali, naturally heating to room temperature, stirring overnight, carrying out HPLC tracking reaction until the compound S3 is completely reacted, and concentrating to dryness to obtain a compound S4;
(iii) Adding the compound S4 into a solvent, adding a catalytic amount of alkali or acid, removing the protecting group of the amino, and tracking the reaction by HPLC until the compound S4 is completely reacted; and
(iv) Filtering the reaction solution in the step (iii), collecting solids, adding the solids into purified water, stirring, filtering, collecting filtrate, and concentrating to dryness; and (3) obtaining a solid, adding the solid into the bad reagent ethyl acetate, stirring, and filtering to obtain the compound S1.
In another preferred embodiment, the O-sulfo-L-tyrosine sodium salt obtained by the method has a purity of 95% or more, preferably 97% or more, more preferably 99% or more.
The main advantages of the invention include:
compared with the prior art, the invention adopts Fmoc-L-tyrosine which is easy to obtain and has good solubility as the initial raw material, avoids the use of expensive reagent, high toxicity and high activity reagent and strict reaction condition thereof, difficult post-treatment process and environmental pollution, has convenient feeding in the whole process, uses the conventional simple operations of crystallization, beating and the like in post-treatment, is easy to purify, can obtain a product with higher purity, and is extremely easy for industrialized mass production.
The method of the invention has simple synthesis and convenient operation, and avoids the complicated operations such as high temperature and high pressure, distillation, freeze-drying, column chromatography and the like; meanwhile, the used reagents are conventional reagents, so that the purchase and the treatment are convenient, and the use of controlled reagents which are easy to make toxicity, explosion and the like is avoided; the post-treatment mainly adopts crystallization and pulping operation, greatly simplifies the purification operation, improves the purity of the product, has the comprehensive yield of about 75 percent and the purity higher than 99 percent, and is a method suitable for large-scale production, convenient to operate and high in product purity.
The invention is further described below in conjunction with the specific embodiments. It is to be understood that these examples are illustrative of the present invention and are not intended to limit 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.
The reagents used in the invention are as follows: fmoc-L-tyrosine, 99%, shanghai, available from pharmaceutical technologies Co., ltd; sulfur trioxide-pyridine complex, 97%, shanghai microphone Biochemical technologies Co., ltd; pyridine, AR, national drug group reagent limited; anhydrous methanol, AR, national drug group reagent limited; sodium hydroxide, 98%, shanghai microphone Lin Biochemical technology Co., ltd; anhydrous piperazine, 99%, shanghai Ala Biochemical technologies Co., ltd; ethyl acetate, AR, national drug group reagent limited; absolute ethanol, AR, national drug group reagent limited.
Example 1
Preparation of compound S3:
pyridine is used as a solvent and alkali, 400mL of pyridine and 100.0g of compound S2 are added into a 1L three-necked flask, the solution is stirred at 30 ℃, 78.9g of sulfur trioxide-pyridine complex is added into the reaction system in batches, the solution is stirred, and stirring is started overnight at room temperature. The reaction was followed by HPLC until compound S2 was complete.
The reaction solution was concentrated in vacuo at 50℃to give 98.9g of Compound S3, which was used directly in the next reaction.
Example 2
Preparation of compound S4:
98.9g of Compound S3 was added to a 1L three-necked flask, 50mL of purified water was added at 30℃and the solution was stirred and dissolved, the system was cooled to 10℃and 135.6mL of 5mol/L sodium hydroxide solution was added dropwise, pH=9, and the mixture was allowed to naturally warm to room temperature and stirred overnight after the completion of the addition. The reaction was followed by HPLC until compound S3 was complete.
700mL of absolute methanol was added to the reaction mixture, stirred for 0.5h, filtered, and the filtrate was collected and concentrated in vacuo at 50℃to give 245.7g of Compound 4, which was used directly in the next reaction.
Example 3
Preparation of compound S1:
into a 1L three-necked flask, 245.7g of Compound S4 was charged, 700mL of anhydrous methanol and 20.0g of anhydrous piperazine were added at 30℃and stirring was started overnight at room temperature. The reaction was followed by HPLC until compound S4 was complete.
The solid was filtered, collected, added to 200mL of purified water and stirred for 0.5h. Filtering, collecting filtrate, concentrating the filtrate at 50deg.C under vacuum to dryness to obtain solid, adding the solid into 300mL ethyl acetate, pulping for 0.5h, filtering, and collecting the solid to obtain 55.98g white solid compound S1, wherein the total yield of three steps is 74%, and the purity is more than 99%.
Example 4
200mL of N, N-dimethylformamide, 40mL of triethylamine and 20.0g of compound S2 were added to a 500mL three-necked flask with triethylamine as a solvent, and the solution was stirred at 30℃to prepare a solution, after which 15.5g of a sulfur trioxide-pyridine complex was added to the reaction system in portions, followed by stirring, cloudiness of the system, and stirring at room temperature overnight. The reaction was followed by HPLC, and about 14% of compound S2 was unreacted. The reaction solution was concentrated in vacuo at 50℃to give 20.6g of Compound S3, which was used directly in the next reaction.
Into a 500mL three-necked flask, 20.6g of compound S3 was added, 10mL of purified water was added at 30℃and the solution was stirred and dissolved, the system was cooled to 10℃and 21.8mL of 5mol/L sodium hydroxide solution was added dropwise, pH=8-9, and the mixture was naturally warmed to room temperature and stirred overnight after the completion of the addition. The reaction was followed by HPLC until compound S3 was complete. 140mL of absolute methanol was added to the reaction mixture, stirred for 0.5h, filtered, and the filtrate was collected and concentrated in vacuo at 50℃to give 40.8g of Compound 4, which was used directly in the next reaction.
In a 500mL three-necked flask, 40.8g of Compound S4 was added, 140mL of anhydrous methanol and 4.0g of anhydrous piperazine were added at 30℃and stirring was started overnight at room temperature. The reaction was followed by HPLC until compound S4 was complete. The solid was filtered, collected, added to 40mL of purified water and stirred for 0.5h. Filtering, collecting filtrate, concentrating the filtrate at 50deg.C under vacuum to dryness to obtain solid, adding the solid into 60mL ethyl acetate, pulping for 0.5h, filtering, and collecting the solid to obtain 6.51g white solid compound S1 with total three steps yield of 43% and purity of 82.5%.
All documents mentioned in this application are incorporated by reference 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 claims appended hereto.
Claims (10)
1. The preparation method of the O-sulfo-L-tyrosine sodium salt is characterized by comprising the following steps:
(i) In a solvent, in the presence of alkali, reacting the compound S2 with a sulfonating reagent to obtain a compound S3;
(ii) In an inert solvent, under alkaline conditions, the compound S3 and Na + Generating a salt reaction to obtain a compound S4; and
(iii) Removing amino protecting groups from the compound S4 in an inert solvent in the presence of acid or alkali to obtain a compound S1;
wherein R is 1 Is a group selected from the group consisting of:
and in step (i), the sulphonation reagent is selected from the group consisting of: sulfur trioxide-DMF, sulfur trioxide-pyridine, or a combination thereof.
2. The method of manufacturing according to claim 1, further comprising the step of post-treatment: (iv) Filtering the reaction liquid obtained in the step (iii), collecting solids, adding the solids into water, stirring, filtering, collecting filtrate, and concentrating to dryness; and (3) obtaining a solid, adding the solid into a poor solvent, stirring, and filtering to obtain the compound S1.
3. The method of claim 1, wherein in step (i), the sulfonating agent is sulfur trioxide-pyridine.
4. The method of claim 1, wherein step (i) comprises one or more features selected from the group consisting of:
the solvent is selected from the group consisting of: n, N-dimethylformamide, N-dimethylacetamide, pyridine, N-methylmorpholine, dichloromethane, acetonitrile, or a combination thereof, preferably N, N-dimethylformamide or pyridine;
the base is selected from the group consisting of: pyridine, triethylamine, N-diisopropylethylamine, N-dimethylaniline, or a combination thereof, preferably pyridine;
the molar ratio of the compound S2 to the sulphonating agent is 1: (1-2.5), preferably 1: (1-1.5);
the temperature of the reaction is 20-50 ℃, preferably 20-40 ℃;
the reaction time is 1 to 24 hours, preferably 6 to 12 hours.
5. The method of claim 1, wherein in step (ii) one or more features selected from the group consisting of:
the alkaline condition means a pH of 8 to 14, preferably a pH of 8 to 10, more preferably a pH of 9;
the inert solvent is selected from the group consisting of: water, or a mixture of water and one or more of methanol, ethanol, N-propanol, isopropanol, acetone, acetonitrile, 1, 4-dioxane, tetrahydrofuran, N-dimethylformamide and N, N-dimethylacetamide; preferably, in the mixture, the volume ratio of water to organic solvent is 1: 1-10), more preferably 1:5;
the temperature of the reaction is 0-20 ℃, preferably 5-10 ℃; and/or
The reaction time is 1 to 24 hours, preferably 6 to 12 hours.
6. The method of claim 1, wherein in step (ii), the alkaline conditions are adjusted by: sodium hydroxide, sodium carbonate, sodium bicarbonate; preferably, the base is in the form of an alkaline solution, preferably 3-5mol/L aqueous sodium hydroxide.
7. The method of preparing as claimed in claim 1, wherein step (ii) further comprises the steps of: (ii-1) mixing the reaction solution of step (ii) with an organic solvent, stirring, filtering, collecting filtrate, concentrating to dryness to obtain the S4 compound, and using in the next step.
8. The method of claim 1, wherein step (iii) comprises one or more features selected from the group consisting of:
the inert solvent is selected from the group consisting of: methanol, ethanol, methylene chloride, or a combination thereof;
the acid stripping is selected from the group consisting of: hydrochloric acid-methanol, hydrochloric acid-ethanol, hydrochloric acid-diethyl ether, preferably hydrochloric acid-methanol;
the alkaline stripping is selected from the group consisting of: piperidine, piperazine, or combinations thereof, preferably piperazine;
the temperature of the reaction is 20-50 ℃, preferably 20-40 ℃; and/or
The reaction time is 1 to 24 hours, preferably 6 to 12 hours.
9. The method of claim 2, wherein in step (iv), the poor solvent is selected from the group consisting of: methanol, ethanol, ethyl acetate, dichloromethane, 1, 2-dichloroethane, tetrahydrofuran, acetonitrile, or a combination thereof, preferably ethyl acetate.
10. The method of manufacturing according to claim 2, characterized in that the method comprises the steps of:
(i) In pyridine, the compound S2 reacts with sulfur trioxide-pyridine until the compound S2 reacts completely, and the reaction solution is concentrated and dried to obtain a compound S3;
(ii) Dissolving a compound S3 in an inert solvent, cooling a system to 5-10 ℃, then regulating the pH value of a reaction solution to be alkaline by using alkali, naturally heating to room temperature for reaction, concentrating and drying the reaction solution after the compound S3 is completely reacted to obtain a compound S4;
(iii) Dissolving the compound S4 in an inert solvent, adding a catalytic amount of alkali or acid, and removing the protecting group of the amino group to obtain the compound S1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310492767.XA CN116514684A (en) | 2023-04-28 | 2023-04-28 | Preparation method of O-sulfo-L-tyrosine sodium salt |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310492767.XA CN116514684A (en) | 2023-04-28 | 2023-04-28 | Preparation method of O-sulfo-L-tyrosine sodium salt |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN116514684A true CN116514684A (en) | 2023-08-01 |
Family
ID=87398935
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310492767.XA Pending CN116514684A (en) | 2023-04-28 | 2023-04-28 | Preparation method of O-sulfo-L-tyrosine sodium salt |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116514684A (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4444682A (en) * | 1982-11-04 | 1984-04-24 | The Salk Institute For Biological Studies | Method of sulfation |
| CN106146360A (en) * | 2015-03-31 | 2016-11-23 | 深圳翰宇药业股份有限公司 | A kind of method preparing tyrosine-O-sulfonate |
-
2023
- 2023-04-28 CN CN202310492767.XA patent/CN116514684A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4444682A (en) * | 1982-11-04 | 1984-04-24 | The Salk Institute For Biological Studies | Method of sulfation |
| CN106146360A (en) * | 2015-03-31 | 2016-11-23 | 深圳翰宇药业股份有限公司 | A kind of method preparing tyrosine-O-sulfonate |
Non-Patent Citations (1)
| Title |
|---|
| FUTAKI, SHIROH等: "Use of dimethylformamide-sulfur trioxide complex as a sulfating agent of tyrosine", JOURNAL OF THE CHEMICAL SOCIETY, PERKIN TRANSACTIONS 1: ORGANIC AND BIO-ORGANIC CHEMISTRY, no. 6, pages 1739 - 1744 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN114805314B (en) | Synthesis method of Entecavir | |
| EP4212509A1 (en) | Method for preparing water-soluble magnolol derivative and honokiol derivative, methods for preparing intermediates of water-soluble magnolol derivative and honokiol derivative, and related monohydroxy protected intermediate | |
| CN117645636B (en) | Preparation method of adenine azide intermediate | |
| CN110305018A (en) | A kind of preparation method of the bromo- 2- fluoronitrobenzene of 3- | |
| CN110551144B (en) | Preparation method of amoxicillin | |
| CN112225647A (en) | Method for synthesizing 5-bromo-2-methoxyphenol | |
| CN116514684A (en) | Preparation method of O-sulfo-L-tyrosine sodium salt | |
| CN110922409A (en) | Method for preparing BTK inhibitor zebritinib | |
| CN115073458A (en) | Preparation method of avibactam sodium | |
| CN111574458B (en) | Synthetic method of ergothioneine | |
| CN114717280A (en) | Synthesis method of monopilavir | |
| CN109734757B (en) | Preparation method of related substance B of fondaparinux sodium injection | |
| CN108299466B (en) | Improved dolutegravir synthesis method | |
| CN112778189A (en) | (3R,4S) -N-substituent-3-carboxylic acid-4-ethyl pyrrolidine, intermediate and lapatinib | |
| CN112047896A (en) | Method for synthesizing aromatic ring group or aromatic heterocyclic group tetrazole | |
| CN111471085A (en) | Method for continuously preparing argatroban | |
| CN114409608B (en) | Synthetic method of ergothioneine | |
| CN115108933B (en) | Synthesis method of lacosamide | |
| CN115677599A (en) | Method for preparing 4- (p-acetamido benzene sulfonamide) -6-methoxy pyrimidine | |
| CN117466782A (en) | Preparation process of N, N-bis (2-hydroxyethyl) -2-aminoethanesulfonic acid | |
| CN115057898A (en) | Preparation method of fondaparinux sodium intermediate | |
| CN114524803A (en) | Synthesis method of quinoline compound intermediate | |
| CN115925636A (en) | Method for industrially producing 2-mercapto-5-methoxybenzimidazole | |
| CN116496180A (en) | Method for producing Lin Zage intermediate | |
| CN116396226A (en) | Preparation method of agoraphobia and intermediate compound thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |