CN112624956A - Novel process for preparing 3-indolesulfonic acid derivatives - Google Patents
Novel process for preparing 3-indolesulfonic acid derivatives Download PDFInfo
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- CN112624956A CN112624956A CN201910951188.0A CN201910951188A CN112624956A CN 112624956 A CN112624956 A CN 112624956A CN 201910951188 A CN201910951188 A CN 201910951188A CN 112624956 A CN112624956 A CN 112624956A
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- indolesulfonic
- indolesulfonic acid
- acid derivative
- acid derivatives
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- MBGDTSHOGKMEKH-UHFFFAOYSA-N 1h-indole-3-sulfonic acid Chemical class C1=CC=C2C(S(=O)(=O)O)=CNC2=C1 MBGDTSHOGKMEKH-UHFFFAOYSA-N 0.000 title claims abstract description 21
- 238000004519 manufacturing process Methods 0.000 title abstract description 4
- 238000002360 preparation method Methods 0.000 claims abstract description 12
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 10
- 238000000746 purification Methods 0.000 claims abstract description 10
- 238000000034 method Methods 0.000 claims abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 5
- 238000005580 one pot reaction Methods 0.000 claims abstract description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 150000001875 compounds Chemical group 0.000 claims description 10
- 150000002500 ions Chemical class 0.000 claims description 7
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 claims description 6
- 239000002994 raw material Substances 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 5
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 claims description 4
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 4
- 238000004949 mass spectrometry Methods 0.000 claims description 4
- 229910021529 ammonia Inorganic materials 0.000 claims description 3
- -1 potassium 3-indolesulfonic acid Chemical compound 0.000 claims description 3
- 238000010791 quenching Methods 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- 125000003277 amino group Chemical group 0.000 claims description 2
- 229910000069 nitrogen hydride Inorganic materials 0.000 claims 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 2
- 230000008034 disappearance Effects 0.000 claims 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims 1
- 235000011114 ammonium hydroxide Nutrition 0.000 claims 1
- 239000012038 nucleophile Substances 0.000 claims 1
- 230000000269 nucleophilic effect Effects 0.000 claims 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 1
- 208000037157 Azotemia Diseases 0.000 abstract description 5
- 238000001514 detection method Methods 0.000 abstract description 5
- 208000009852 uremia Diseases 0.000 abstract description 5
- 239000000463 material Substances 0.000 abstract description 2
- 238000000926 separation method Methods 0.000 abstract description 2
- 102000014914 Carrier Proteins Human genes 0.000 abstract 1
- 108010078791 Carrier Proteins Proteins 0.000 abstract 1
- 239000002253 acid Substances 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 208000020832 chronic kidney disease Diseases 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 208000022831 chronic renal failure syndrome Diseases 0.000 description 2
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 description 2
- 150000002475 indoles Chemical class 0.000 description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- 150000002989 phenols Chemical class 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- 238000007789 sealing Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- MXALRLXMXCYNGF-UHFFFAOYSA-N 1h-indole-2-sulfonic acid Chemical class C1=CC=C2NC(S(=O)(=O)O)=CC2=C1 MXALRLXMXCYNGF-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 208000035850 clinical syndrome Diseases 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
- 229940109239 creatinine Drugs 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 208000028208 end stage renal disease Diseases 0.000 description 1
- 201000000523 end stage renal failure Diseases 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 150000002357 guanidines Chemical class 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000011895 specific detection Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 108700012359 toxins Proteins 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 239000002441 uremic toxin Substances 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/36—Oxygen atoms in position 3, e.g. adrenochrome
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
Abstract
本发明提供了3‑吲哚磺酸衍生物新型制备方法，通过改变技术路线，实现了一锅一次纯化的方法，高产率的得到了1位修饰的3‑吲哚磺酸衍生物。此方法操作简单，反应条件温和，试剂廉价易得，产率高，一次性分离提纯，适合大量生产，合成的目标产物，可与载体蛋白偶联，表达特异性抗体识别3‑吲哚磺酸，为检测尿毒症提供了物质基础和技术路线。The present invention provides a novel preparation method of 3-indole sulfonic acid derivatives. By changing the technical route, a one-pot purification method is realized, and the 1-position modified 3-indole sulfonic acid derivatives are obtained in high yield. This method is simple in operation, mild in reaction conditions, cheap and easy to obtain reagents, high in yield, one-time separation and purification, suitable for mass production, and the synthesized target product can be coupled with carrier protein to express specific antibodies that recognize 3-indolesulfonic acid , provides the material basis and technical route for the detection of uremia.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of a 3-indolsulfonic acid derivative.
Background
Uremia is the terminal stage of chronic renal failure and is a common clinical syndrome of various end-stage renal diseases. In clinical manifestations of patients, metabolic disorders are generally manifested by accumulation of protein metabolites, including urea, guanidine compounds, creatinine, amines, indoles, phenols, and middle molecular weight substances. Indoles, amines and phenols are toxins produced by the metabolism of uremic bacteria. The indolesulfonic acid compounds are considered to be one of the major causes of uremia, and the content of indolesulfuric acid in serum of patients with chronic renal failure has increased by about 60-fold. Therefore, the determination of the concentration of 3-indolesulfonic acid in serum is of great significance for the examination and diagnosis of uremia. Traditionally, serum uremic toxins have been monitored and analyzed primarily by gas chromatography and high performance liquid chromatography. Although these methods are excellent in both sensitivity and accuracy, they have high requirements for instrumentation and equipment and high dependence on instrumentation and analysis. Therefore, the preparation of the 3-indonesulfonic acid compound with 1-position derivatization of a specific functional group, the coupling of the 3-indonesulfonic acid compound with an antibody and the preparation of a specific detection 3-indonesulfonic acid antibody have important significance.
Structure of 3-indolesulfonic acid derivative:
the technical route previously reported for 3-indolesulfonic acid derivatives:
the preparation of the derivative is carried out by the technical route of the prior patent (JPH 10265457A): the method of three-pot and three-time purification is adopted, the steps are long, and the introduction of amine functional groups adopts a protection-deprotection strategy.
The preparation of the derivative, the reagent used in the prior patent (JPH10265457A) comprises: toxic benzylamine, expensive transition metal reagent palladium carbon and flammable and explosive hazardous gas hydrogen.
The preparation of the derivative is complicated in the process used in the prior patent (JPH 10265457A): the post-treatment is complex, three steps of purification are needed, not only the loss of compounds but also the waste of solvents are caused, and the environmental pollution and the cost are increased; at the same time, the hydrogenation operation is strictly complicated.
The total yield of the derivative in the prior patent (JPH 10265457A): because the polarity of the compounds is large, silica gel columns and palladium carbon are seriously adsorbed, the compound loss is caused by purification, and the total yield in three steps is only 23 percent.
Disclosure of Invention
The technical route for synthesizing the 3-indolesulfonic acid derivative adopted by the invention is as follows:
the specific operation for synthesizing the 3-indolesulfonic acid derivative adopted by the invention is as follows: dissolving 3-indolsulfonic acid potassium salt (50.3mg,0.2 mmol,1.0 equivalent) in 1mL DMF, adding 60% NaH (16mg,0.4mmol,2.0 equivalent) at zero degree, stirring at zero degree for half an hour, adding epichlorohydrin (16 uL, 0.4mmol,2.0 equivalent), stirring at room temperature for three hours, allowing LC-MS detection raw material to disappear (mass spectrum negative ion absorption, M-H ═ 268.0), adding water for quenching, removing DMF under reduced pressure, directly adding ammonia reagent group, sealing for reaction overnight, and allowing LC-MS detection raw material to reactThe material disappeared and the product formed (ms anion M-H285.0), HPLC (C18, 10% -75% MeOH/H)2O) purification to give the title compound (29mg, 51% yield).
The specific operation for synthesizing the 3-indolesulfonic acid derivative adopted by the invention is as follows: dissolving 3-indolsulfonic acid potassium salt (1.06g,4mmol, 1.0 equivalent) in 15mL DMF, adding 60% NaH (320mg,8mmol,2.0 equivalent) at zero degree, stirring at zero degree for half an hour, adding epichlorohydrin (320 uL, 8mmol,2.0 equivalent), stirring at room temperature for three hours later, allowing LC-MS detection raw material to disappear (mass spectrometry negative ion absorption, M-H ═ 268.0), adding water for quenching, removing DMF under reduced pressure, directly adding ammonia reagent group, sealing for reaction overnight, allowing LC-MS detection raw material to disappear, and generating a product (mass spectrometry negative ion M-H ═ 285.0), and performing HPLC (C18, 10% -75% MeOH/H)2O) purification to give the title compound (585mg, 51% yield).
The synthetic method of the 3-indonesulfonic acid derivative has the advantages of simple operation, one-pot method, mild reaction conditions, no toxic reagent, cheap and easily-obtained reagent, high yield of the target product, easy separation and purification, one-time purification and suitability for mass production. The efficient selective synthesis of the 3-indolesulfonic acid derivative has great significance for detecting, diagnosing and treating uremia.
The hydrogen spectrum characterization of the synthesized 3-indole sulfonic acid derivative is as follows:1h NMR (300MHz, DMSO-d6) δ 7.50 (d, J ═ 7.8Hz,1H),7.43(d, J ═ 8.3Hz,1H),7.18(s,1H),7.10(t, J ═ 7.6Hz,1H),6.97(t, J ═ 7.4 Hz,1H),5.76(bs,2H), 4.25-4.05 (m,2H), 4.04-3.91 (m,1H),2.83(dd, J ═ 12.8,3.2Hz,1H), 2.67(dd, J ═ 12.8,9.0Hz,1H) calculated: [ M-H ]]-,C11H13N2O5S285.0, actual negative ion peak: [ M-H ]]-， C11H13N2O5S＝285.0
Drawings
FIG. 1 is a hydrogen spectrum of the synthesized 3-indolesulfonic acid derivative.
FIG. 2 is a mass spectrum-negative ion absorption of the synthesized 3-indolesulfonic acid derivative.
Claims (4)
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| CN201910951188.0A CN112624956A (en) | 2019-10-08 | 2019-10-08 | Novel process for preparing 3-indolesulfonic acid derivatives |
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH10265457A (en) * | 1997-03-19 | 1998-10-06 | Kureha Chem Ind Co Ltd | Indoxyl sulfate derivative, antigen, antibody and detection of indoxyl sulfate using the same |
| CN101434571A (en) * | 2007-11-13 | 2009-05-20 | 杭州容立医药科技有限公司 | Cycloalkano [1,2-b] indole sulfonic acid amide, and method for synthesizing isomer or salt thereof |
| CN102272128A (en) * | 2008-11-06 | 2011-12-07 | 弗特克斯药品有限公司 | Modulators of ATP-binding cassette transporters |
| US20120035346A1 (en) * | 2009-01-15 | 2012-02-09 | Terpetschnig Ewald A | Luminescent compounds |
| CN105348268A (en) * | 2015-09-24 | 2016-02-24 | 四川大学 | Substituted carbazole-indole sulfonate derivative, and preparation method therefor and use thereof |
| CN106946758A (en) * | 2017-03-07 | 2017-07-14 | 丽水学院 | A kind of synthetic method of 3 (trifluoroacetyl) indole derivativeses |
-
2019
- 2019-10-08 CN CN201910951188.0A patent/CN112624956A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH10265457A (en) * | 1997-03-19 | 1998-10-06 | Kureha Chem Ind Co Ltd | Indoxyl sulfate derivative, antigen, antibody and detection of indoxyl sulfate using the same |
| CN101434571A (en) * | 2007-11-13 | 2009-05-20 | 杭州容立医药科技有限公司 | Cycloalkano [1,2-b] indole sulfonic acid amide, and method for synthesizing isomer or salt thereof |
| CN102272128A (en) * | 2008-11-06 | 2011-12-07 | 弗特克斯药品有限公司 | Modulators of ATP-binding cassette transporters |
| US20120035346A1 (en) * | 2009-01-15 | 2012-02-09 | Terpetschnig Ewald A | Luminescent compounds |
| CN105348268A (en) * | 2015-09-24 | 2016-02-24 | 四川大学 | Substituted carbazole-indole sulfonate derivative, and preparation method therefor and use thereof |
| CN106946758A (en) * | 2017-03-07 | 2017-07-14 | 丽水学院 | A kind of synthetic method of 3 (trifluoroacetyl) indole derivativeses |
Non-Patent Citations (2)
| Title |
|---|
| YONG-LIANG ZHAO，等: "Identification of Racemic and Chiral Carbazole Derivatives Containing an Isopropanolamine Linker as Prospective Surrogates against Plant Pathogenic Bacteria: In Vitro and In Vivo Assays and Quantitative Proteomics", 《JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY》 * |
| 花林: "Fischer法合成吲哚磺酸类化合物的研究", 《中国优秀博硕士学位论文全文数据库(硕士) 工程科技Ⅰ辑》 * |
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Application publication date: 20210409 |