CN117800852A - Synthetic method of natural product salt spike grass alkali - Google Patents
Synthetic method of natural product salt spike grass alkali Download PDFInfo
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- 239000003513 alkali Substances 0.000 title claims abstract description 27
- 150000003839 salts Chemical class 0.000 title claims abstract description 25
- 240000007492 Uniola paniculata Species 0.000 title claims abstract description 23
- 229930014626 natural product Natural products 0.000 title claims abstract description 21
- 238000010189 synthetic method Methods 0.000 title description 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 56
- 238000000034 method Methods 0.000 claims abstract description 35
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 claims abstract description 18
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 17
- IHIJFQRUYCEKCZ-UHFFFAOYSA-N n-methyl-4-nitrobenzenesulfonamide Chemical compound CNS(=O)(=O)C1=CC=C([N+]([O-])=O)C=C1 IHIJFQRUYCEKCZ-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000001308 synthesis method Methods 0.000 claims abstract description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 60
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 20
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 17
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 10
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 claims description 9
- 238000001514 detection method Methods 0.000 claims description 8
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 7
- -1 1, 8-dibutyl-1, 5, 7-triazacyclodecane Chemical compound 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- MCZDHTKJGDCTAE-UHFFFAOYSA-M tetrabutylazanium;acetate Chemical compound CC([O-])=O.CCCC[N+](CCCC)(CCCC)CCCC MCZDHTKJGDCTAE-UHFFFAOYSA-M 0.000 claims description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 5
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 239000001632 sodium acetate Substances 0.000 claims description 5
- 235000017281 sodium acetate Nutrition 0.000 claims description 5
- 238000005868 electrolysis reaction Methods 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 239000012044 organic layer Substances 0.000 claims description 4
- 229940049953 phenylacetate Drugs 0.000 claims description 4
- 238000004440 column chromatography Methods 0.000 claims description 3
- 239000012299 nitrogen atmosphere Substances 0.000 claims description 3
- 229910052697 platinum Inorganic materials 0.000 claims description 3
- 244000025254 Cannabis sativa Species 0.000 claims description 2
- 239000012295 chemical reaction liquid Substances 0.000 claims description 2
- 239000001875 1-phenylethyl acetate Substances 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 21
- 230000015572 biosynthetic process Effects 0.000 abstract description 15
- 239000006227 byproduct Substances 0.000 abstract description 9
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 9
- 239000001257 hydrogen Substances 0.000 abstract description 9
- 239000002994 raw material Substances 0.000 abstract description 9
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 7
- 238000009776 industrial production Methods 0.000 abstract description 4
- 238000006114 decarboxylation reaction Methods 0.000 abstract description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract 1
- 239000010902 straw Substances 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 description 29
- 239000000243 solution Substances 0.000 description 11
- ZCTYHONEGJTYQV-UHFFFAOYSA-N N-methylphenylethanolamine Chemical compound CNCC(O)C1=CC=CC=C1 ZCTYHONEGJTYQV-UHFFFAOYSA-N 0.000 description 7
- 230000008569 process Effects 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 150000003254 radicals Chemical class 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- CWERGRDVMFNCDR-UHFFFAOYSA-N thioglycolic acid Chemical compound OC(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-N 0.000 description 4
- QKDPDTZVDBRIFG-UHFFFAOYSA-N 1-(methylamino)-3-phenylpropan-2-ol Chemical compound CNCC(O)CC1=CC=CC=C1 QKDPDTZVDBRIFG-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 241000784794 Halostachys Species 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000010511 deprotection reaction Methods 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- 235000011181 potassium carbonates Nutrition 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 241000201895 Salicornia Species 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 150000001336 alkenes Chemical class 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 description 2
- 229960002179 ephedrine Drugs 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 150000002431 hydrogen Chemical group 0.000 description 2
- WVDDGKGOMKODPV-UHFFFAOYSA-N hydroxymethyl benzene Natural products OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 230000001590 oxidative effect Effects 0.000 description 2
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- URDXYWDQNDKHLS-UHFFFAOYSA-N 1-oxa-3-azaspiro[4.5]decane Chemical compound O1CNCC11CCCCC1 URDXYWDQNDKHLS-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- LZTWMDUXAADMLF-UHFFFAOYSA-N 2-(methylamino)-1-phenylethanone;hydrochloride Chemical compound Cl.CNCC(=O)C1=CC=CC=C1 LZTWMDUXAADMLF-UHFFFAOYSA-N 0.000 description 1
- JTDTYGHSVYMKMH-UHFFFAOYSA-N 2-chloro-n-methyl-2-phenylethanamine Chemical compound CNCC(Cl)C1=CC=CC=C1 JTDTYGHSVYMKMH-UHFFFAOYSA-N 0.000 description 1
- KVRWKUUAOATUGG-UHFFFAOYSA-N 2-methyl-4-nitrobenzenesulfonamide Chemical compound CC1=CC([N+]([O-])=O)=CC=C1S(N)(=O)=O KVRWKUUAOATUGG-UHFFFAOYSA-N 0.000 description 1
- RZVHIXYEVGDQDX-UHFFFAOYSA-N 9,10-anthraquinone Chemical group C1=CC=C2C(=O)C3=CC=CC=C3C(=O)C2=C1 RZVHIXYEVGDQDX-UHFFFAOYSA-N 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- ZCTYHONEGJTYQV-VIFPVBQESA-N Halostachine Chemical compound CNC[C@H](O)C1=CC=CC=C1 ZCTYHONEGJTYQV-VIFPVBQESA-N 0.000 description 1
- 238000006434 Ritter amidation reaction Methods 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000010306 acid treatment Methods 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- XLJMAIOERFSOGZ-UHFFFAOYSA-N anhydrous cyanic acid Natural products OC#N XLJMAIOERFSOGZ-UHFFFAOYSA-N 0.000 description 1
- 239000003957 anion exchange resin Substances 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 238000005260 corrosion Methods 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
- 230000007423 decrease Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000002848 electrochemical method Methods 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000007046 ethoxylation reaction Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- BCQZXOMGPXTTIC-UHFFFAOYSA-N halothane Chemical compound FC(F)(F)C(Cl)Br BCQZXOMGPXTTIC-UHFFFAOYSA-N 0.000 description 1
- 229960003132 halothane Drugs 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 description 1
- 230000026045 iodination Effects 0.000 description 1
- 238000006192 iodination reaction Methods 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 150000002831 nitrogen free-radicals Chemical class 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 238000010405 reoxidation reaction Methods 0.000 description 1
- 230000027756 respiratory electron transport chain Effects 0.000 description 1
- 239000002455 scale inhibitor Substances 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 125000003011 styrenyl group Chemical group [H]\C(*)=C(/[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 239000004753 textile Substances 0.000 description 1
- 238000006257 total synthesis reaction Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing a natural product salt spike grass alkali. According to the method, firstly, N-methyl-4-nitrobenzenesulfonamide and styrene are used for synthesizing 2- (N-methyl-4-nitrobenzenesulfonamide) -1-phenylacetic acid ethyl ester under electrochemical conditions, then decarboxylation is carried out to obtain N- (2) -hydroxy-2-phenethyl) -N-methyl-4-nitrobenzenesulfonamide, and finally, the salt spike straw alkali is obtained through Ns protection. The method for synthesizing the salt spike grass alkali has the advantages that the raw materials used in the method are low in price and easy to obtain, the used reagents are conventional reagents with low price, the synthesis cost is low, the reaction conditions are mild, particularly, the electrochemical synthesis method is introduced, the byproduct is hydrogen, the reaction is controllable, the environment-friendly concept is met, and the potential industrial production is realized.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing a natural product salt spike grass alkali.
Background
The salt spike grass alkali has the chemical name of alpha- (methyl) benzyl alcohol or N-methyl phenylethanolamine, and the English name: halostachine was isolated for the first time from Chenopodiaceae Halostachys caspia. The structure is similar to that of ephedrine, and has the pharmacological activity of ephedrine. Besides being used as a medical intermediate, the dye can be widely applied to intermediates in various fields, such as textile auxiliary agents, corrosion and scale inhibitors and dye synthesis intermediates; can also be used for synthesizing anion exchange resin, water treatment cation flocculant and the like. Meanwhile, many chiral amino alcohol compounds or derivatives also often play an important role in asymmetric catalytic reactions in the form of chiral ligands or chiral auxiliaries. Therefore, efficient synthesis of spica base (especially chiral α -aminoalcohol compounds) by chemical methods is one of the focus of attention of chemists.
In the prior art, the method in the patent with publication number CN 106831453A and the name N-methylbenzyl ethanolamine and the hydrochloride synthesis method (N-methyl phenylethanolamine and its hydrochloride synthesis method) takes styrene as a raw material, and sequentially adds sulfuric acid aqueous solution and sodium periodate at-5 ℃, after the heating and stirring reaction is finished, adds sodium thiosulfate aqueous solution to quench the reaction, adjusts the pH value to 8, extracts and concentrates the reaction product to obtain an intermediate, adds methylamine aqueous solution into a reaction bottle, slowly drops the intermediate into the reaction bottle, stirs the reaction bottle at room temperature overnight after the dropping, and decompresses and concentrates the reaction product to obtain N-methylbenzyl ethanolamine after the HPLC detection reaction is finished. The specific synthetic reaction formula is as follows:
the method uses strong acid and strong oxidant in the operation process, heats, uses highly toxic methylamine solution, and has the characteristics of long reaction time, etc. The key is that the amplification has the characteristics of potential danger and the like. (2) Reagents for Storage and Regeneration of Nonstabilized Azomethine Ylides spirothreseneoxazolidines, org. Lett. 2016, 18, 8, 1764-1767, arylethanolamines in Ritter reaction Synthesis of 2,4-Diarylimidazole Core; asian Journal of Organic Chemistry, vol 12, issue 2 (2023) doi.org/10.1002/ajoc.202200656 all relate to the synthesis of spicine, which is characterized in that unstable azomethine ylide and anthraquinone form stable spiro-oxazolidine, and then react with benzaldehyde at high temperature by microwave treatment and hydrochloric acid treatment to open loops to obtain alpha- (methylaminomethyl) benzyl hydrochloride, wherein the specific synthesis reaction formula is as follows:
(3) catalytic-Free Visible-Light-Mediated Iodoamination of Olefins and Synthetic Applications; org. Lett. 2021, 23, 14, 5581-5586. Involve the synthesis of spica base using Visible Light mediated iodination followed by alcoholization and Ns removal to synthesize alpha- (methylaminomethyl) benzyl alcohol. The specific synthetic reaction formula is as follows:
(4) European Journal of Medicinal Chemistry, vol 13, issue 3, (1978), P277-288, chemistry-A European Journal, vol 13, issue 27, (2007), P7780-7784 all relate to the synthesis of halothane, sodium borohydride reduction is carried out on raw material methylaminoacetophenone hydrochloride to obtain alpha- (methylaminomethyl) benzyl alcohol, and the specific synthesis reaction formula is as follows:
(5) Angewandte Chemie-International Edition, vol:42, issue:27 (2003), P3133-3136, which relates to the synthesis of halostachys, the specific synthesis reaction formula is as follows:
sodium borohydride is used in the methods, however, sodium borohydride is inflammable, and is easy to generate dangers when meeting water and alcohols, so that the raw material cost, the equipment loss and the post-treatment cost are greatly increased.
(6) Journal of Molecular Catalysis B enzymic, vol: 122, (2015), P29-34, which relates to the synthesis of halostachys, wherein the specific synthesis reaction formula is as follows:
the method needs to take the virulent ethylene oxide as the raw material for reaction, and the yield of the method is only 34 percent.
(7) Tetrahedron Asymmetry, vol 8, issue 3, (1997), P459-467, tetrahedron, vol 48, issue 19, (1992) P3977-3982. A chiral N-methylbenzylethanolamine is synthesized according to the following reaction formula:
in the method, the virulent sodium cyanide is used as a reactant, and reacts with benzaldehyde to obtain the cyano alcohol benzene ring substrate, so that the method has dangerousness and is not suitable for industrial production. Therefore, it is very necessary to develop a simple, efficient, green method for synthesizing salicornia.
Disclosure of Invention
The invention aims to solve the defects of the prior art and provides a synthesis method of natural product salt spike grass alkali, which adopts the following technical scheme:
the synthesis method of the natural product salt spike grass alkali comprises the following steps:
s1: inserting a carbon rod and a platinum electrode into a three-port electric reaction tube, sequentially adding N-methyl-4-nitro-benzenesulfonamide, tetrabutylammonium acetate and sodium acetate, then adding dichloromethane, 2, 2, 2-trifluoroethanol, 36% acetic acid solution and styrene under the nitrogen atmosphere, and carrying out electrolysis on an organic layer of the product after 5h under the conditions of room temperature, stirring and constant current of 2.0 mA-6.0 mA, concentrating and carrying out column chromatography to obtain 2- (N-methyl-4-nitrophenyl) sulfonamide) -1-ethyl phenylacetate;
s2: placing 2- (N-methyl-4-nitrophenyl) sulfamido) -1-ethyl phenylacetate and potassium carbonate into a reaction bottle, adding dichloromethane and methanol, stirring at room temperature for 4 hours, and concentrating the reaction liquid under reduced pressure after TLC detection reaction is finished to obtain N- (2) -hydroxy-2-phenethyl) -N-methyl-4-nitrobenzenesulfonamide;
s3: DBU (1, 8-dibutyl-1, 5, 7-triazacyclodecane) and 2-thioglycollic acid are sequentially added into DMF (dimethylformamide) solution to be dissolved to obtain a reaction solution, then DMF solution of N- (2) -hydroxy-2-phenethyl) -N-methyl-4-nitrobenzenesulfonamide is dripped into the reaction solution, stirring is carried out at room temperature for overnight, and the reaction solution is decompressed and concentrated after TLC detection reaction is finished, thus obtaining the spica et grass alkali finally.
The invention is realized byNAnd (3) taking methyl-4-nitrobenzenesulfonamide as a raw material, carrying out electroinitiation on the raw material and styrene under electrochemical conditions to generate nitrogen free radicals to attack unsaturated olefin, further oxidizing a benzyl free radical intermediate formed by addition into benzyl carbocation at an anode, combining the benzyl carbocation with oxyanion acetate to synthesize a key intermediate (I) 2- (N-methyl-4-nitrophenyl) sulfamido) -1-phenylacetic acid ethyl ester, and then sequentially carrying out decarboxylation to obtain an intermediate II (N- (2) -hydroxy-2-phenethyl) -N-methyl-4-nitrobenzenesulfonamide) and carrying out Ns protection to obtain the halofop-butyl (alpha- (methylaminomethyl) benzyl alcohol). The method for synthesizing the salt spike grass alkali has the advantages that the raw materials used in the method are low in price and easy to obtain, the used reagents are conventional reagents with low price, the synthesis cost is low, the reaction conditions are mild, particularly, the electrochemical synthesis method is introduced, the byproduct is hydrogen, the reaction is controllable, the environment-friendly concept is met, and the potential industrial production is realized.
The mechanism of the invention is as follows:
as can be seen from the above, in the first step of the process, N-methyl-4-nitro-benzenesulfonamide (1 a) and AcO-are firstly subjected to proton coupling electron transfer to generate a free radical intermediate (II), styrene is attacked to generate an intermediate free radical (III), a carbocation Intermediate (IV) is generated by reoxidation at an anode, and the matched cathode is electrolyzed to generate hydrogen and acetate ions, and the hydrogen and acetate ions and the acetate ions in tetrabutylammonium acetate electrolyte participate in the reaction of the carbocation Intermediate (IV) together to generate a target product 4a (namely an intermediate (I), and 2- (N-methyl-4-nitrophenyl) sulfonamide) -1-ethyl phenylacetate.
The invention adopts an electrochemical method to skillfully introduce the protected functional groups containing O and N on the styrene functional groups, has accurate reaction sites and high regioselectivity, and more importantly, has controllable reaction, mild conditions and hydrogen as a byproduct. And the second step and the third step are sequentially deprotected, and acetate ions and p-nitrobenzenesulfonyl are removed to obtain an intermediate (II) and salicornia. The second and third steps of reactions belong to common functional group deprotection processes, the operation is simple, harsh conditions are not needed, and the yield is high; the above products are purified by silica gel flash chromatography, wherein the developing agent is petroleum ether and ethyl acetate.
As a further preferred embodiment, the constant current in S1 is 6.0. 6.0 mA. In the step S1, a carbon rod is adopted as an anode, a Pt sheet is adopted as a cathode, the constant current is in a range of 2-8 mA, and the time is correspondingly prolonged as the constant current is smaller; most preferably a constant current of 6 mA, 5h.
As a further preferred embodiment, the molar ratio of N-methyl-4-nitro-benzenesulfonamide, tetrabutylammonium acetate, sodium acetate and styrene in S1 is 1:2:4:3. In the present invention, if the amount of acetate is too low, the reaction yield is lowered because the stable existence time in the system is short in relation to the carbocation Intermediate (IV) shown in the reaction mechanism of the figure, and the increased solubility of AcO-is favorable for rapidly generating stable products with the carbocation Intermediate (IV).
As a further preferred embodiment, the volume ratio of dichloromethane, 2, 2, 2-trifluoroethanol and 36% acetic acid solution in S1 is 10:1:2. In the invention, dichloromethane, 2, 2, 2-trifluoroethanol and 36% acetic acid solution are used as mixed solvents, wherein, trifluoroethanol (TFE) can stabilize N free radicals, but excessive TFE can generate trifluoro ethoxylation anions in cathode electrolysis to participate in carbocation Intermediate (IV) reaction, which is unfavorable for the generation of products; the reaction system became very clean with significantly less byproducts after the addition of 36% AcOH solution, due to the matching of the cathodic and anodic electrolysis phases.
As a further preferred embodiment, the ratio of N-methyl-4-nitro-benzenesulfonamide to dichloromethane in S1 is 0.2:5 in mmol/mL. The reaction effect is poor, the reaction is incomplete, byproducts are generated, the byproducts are related to the solubility of the substrate, and the byproducts with too large proportion are obviously increased.
As a further preferred embodiment, the molar ratio of ethyl 2- (N-methyl-4-nitrophenyl) sulfonamide) -1-phenylacetate to potassium carbonate in S2 is 2:3. increasing the amount of potassium carbonate can eliminate the reaction between hydroxyl and ortho-hydrogen, and the reaction time is prolonged or even eliminated.
As a further preferred embodiment, the volume ratio of methylene chloride to methanol in S2 is 3:1. In the selection of the solvent, methylene chloride is selected: methanol is used as a mixed solvent, single-component dichloromethane or single-component methane is used as a solvent, the reaction does not occur, and only under the condition of the mixed solvent, the reaction can be carried out, and dichloromethane: the ratio of methanol is too large or too small, and the side reactions have various degrees of increased yield drop.
As a further preferred embodiment, the ratio of ethyl 2- (N-methyl-4-nitrophenyl) sulfonamide) -1-phenylacetate to methylene chloride in S2 is 0.2:1.5 in mmol/mL. The reaction ratio is too small, the reaction effect is poor, the lower the substrate solubility is, the reaction is slow, the reaction of the low-concentration free radical intermediate is not timely quenched, and the excessive ratio of byproducts is obviously increased.
As a further preferred embodiment, the molar ratio of DBU, 2-thioglycollic acid, N- (2) -hydroxy-2-phenethyl) -N-methyl-4-nitrobenzenesulfonamide in S3 is 6:6:1. DBU in this reaction: when the amount of 2-mercaptoacetic acid is too low, the reaction yield decreases, the reaction does not proceed to completion, and DBU: the 2-thioglycollic acid 6:6 is more beneficial to the reaction.
The beneficial effects of the invention are as follows: the invention adopts the electrochemical synthesis technology, the reaction condition is mild and controllable, the byproduct is hydrogen, the green synthesis concept is met, more importantly, the two elements are introduced into the one-step reaction, the site and the region selectivity are precisely controlled, and finally, the natural product salt spike grass alkali is synthesized by conventional deprotection; the method realizes one-step key reaction, two-step deprotection and three-step reaction to realize the total synthesis process of the natural product salt spike alkali, and mainly realizes efficient green synthesis, thereby having industrial production potential. In addition, the raw materials used in the method for fully synthesizing the natural product salt spike grass alkali are cheap and easy to obtain, the used reagents are cheap conventional reagents, and the synthesis cost is low.
Drawings
FIG. 1 shows a nuclear magnetic resonance hydrogen spectrum of intermediate (I);
FIG. 2 shows a nuclear magnetic resonance carbon spectrum of intermediate (I);
FIG. 3 shows a hydrogen nuclear magnetic resonance spectrum of intermediate (II);
FIG. 4 shows nuclear magnetic resonance spectra of intermediate (II).
Detailed Description
The conception, specific structure, and technical effects produced by the present invention will be clearly and completely described below with reference to the embodiments and the drawings to fully understand the objects, aspects, and effects of the present invention. It should be noted that, in the case of no conflict, the embodiments and features in the embodiments may be combined with each other.
Example 1
The synthesis method of the natural product salt spike grass alkali specifically comprises the following steps:
step 1: intermediate I (2- (N-methyl-4-nitrophenyl) sulphonamido) -1-phenylacetic acid ethyl ester) is synthesized, having the formula:
wherein during the synthesis processN-methyl-4-nitrobenzenesulfonamide has the formula:
the specific process is as follows: into a 10 mL-specification dry three-port electric reaction tube equipped with a stirrer was charged 0.2 mmolN-methyl-4-nitrobenzenesulfonamide, 0.4 mmol tetrabutylammonium acetate and 0.8 mmol sodium acetate, inserting a carbon rod (phi 6 mm) and a platinum electrode (1.5 cm x 1.5 cm x 0.3 mm) and then charging nitrogen; dichloromethane (DCM) (5.0 mL), 2, 2, 2-Trifluoroethanol (TFE) (0.5 mL), 36% aqueous acetic acid (1.0 mL) and styrene (1.2 mmol) were injected separately into the tubes by syringe under nitrogen atmosphere. The mixture was electrolyzed at room temperature using constant flow conditions (6.0 mA) under magnetic stirring for 5h, monitored by TLC plate, after the reaction was completed, the machine layer was concentrated and column chromatographed to give ethyl 2- (N-methyl-4-nitrophenyl) sulfonamide) -1-phenylacetate as a colorless liquid in 44% yield.
The detection results are as follows:
1 H NMR (400 MHz, CDCl 3 ) δ 8.33 (d, J = 8.0 Hz, 2H), 7.91 (d, J = 8.0 Hz, 2H), 7.44 7.28 (m, 5H), 5.97 (dd, J = 8.0, 4.0 Hz, 1H), 3.60 (dd, J = 16.0, 8.0 Hz, 1H), 3.27 (dd, J = 16.0, 4.0 Hz, 1H), 2.82 (s, 3H), 2.12 (s, 3H)。
13 C NMR (101 MHz, CDCl 3 ) δ 170.01, 150.06, 143.96, 137.07, 128.86, 128.83, 128.46, 126.62, 124.43, 72.93, 54.95, 36.06, 21.14。
HRMS (ESI) calculated for C 17 H 18 N 2 NaO 6 S + , [M+Na] + : 401.07778; found: 401.07758。
step 2: intermediate II (N- (2) -hydroxy-2-phenethyl) -N-methyl-4-nitrobenzenesulfonamide is synthesized and has the following chemical formula:
the specific process is as follows: to a clean, 25 mL gauge single port round bottom flask equipped with stirrer was added 0.3 mmol of K2CO3 and 0.2 mmol of 2- (N-methyl-4-nitrophenyl) sulfonamide) -1-phenylacetic acid ethyl ester followed by sequential injection of Dichloromethane (DCM) (1.5 mL), methanol (MeOH) (0.5 mL), stirring at room temperature for 4h, monitoring by TLC plate, after completion of the reaction the organic layer was concentrated and column chromatographed to give N- (2) -hydroxy-2-phenethyl) -N-methyl-4-nitrobenzenesulfonamide as a colorless liquid in 66% yield.
The detection results are as follows:
1 H NMR (400 MHz, CDCl 3 ) δ 8.34 (d, J = 8.0 Hz, 2H), 7.96 (d, J = 8.0 Hz, 2H), 7.40 7.29 (m, 5H), 4.95 (dd, J = 8.0, 4.0 Hz, 1H), 3.34 (dd, J = 16.0, 8.0 Hz, 1H), 3.18 (dd, J = 16.0, 4.0 Hz, 1H), 2.89 (s, 3H)。
13 C NMR (101 MHz, CDCl 3 ) δ 150.11, 143.65, 140.82, 128.78, 128.54, 128.38, 125.96, 124.44, 72.72, 57.91, 36.68。
HRMS (ESI) calculated for C 15 H 17 N 2 O 5 S + , [M+H] + : 336.07799; found: 336.07771。
step 3: the chemical formula of the synthetic salt spike grass alkali is as follows:
the specific process is as follows; 1.2 mmol of DBU, 1.2 mmol of 2-mercaptoacetic acid and 2 mL of DMF were added in sequence to a clean 25 mL-gauge single port round bottom flask equipped with a stirrer, followed by dropwise addition of 1mL of a 0.2 mmol/mL DMF solution of N- (2) -hydroxy-2-phenethyl) -N-methyl-4-nitrobenzenesulfonamide to the reaction mixture slowly, stirring at room temperature for 12h, monitoring by TLC plate, after completion of the reaction, the organic layer was concentrated and column chromatography was carried out to give the natural product a- (methylaminomethyl) benzyl alcohol (spica. Alkaloid), a white solid in 76% yield.
The detection results are as follows:
1 H-NMR (300 MHz, CDCl3): δ 7.42 7.13 (m, 5H), 4.74 (dd, J = 8.1, 4.8 Hz, 1H), 3.81 (bs, 2H), 2.73 2.54 (m, 2H), 2.30 (s, 3H)。
13 C-NMR (75 MHz, CDCl3): δ 143.4, 128.3, 127.4, 125.8, 71.6, 59.3, 35。
HRMS (ESI) calculated for C 9 H 14 NO + , [M+H] + : 151.09971; found: 151.10012。
while the present invention has been described in considerable detail and with particularity with respect to several described embodiments, it is not intended to be limited to any such detail or embodiments or any particular embodiment, but is to be construed as providing broad interpretation of such claims by reference to the appended claims in view of the prior art so as to effectively encompass the intended scope of the invention. Furthermore, the foregoing description of the invention has been presented in its embodiments contemplated by the inventors for the purpose of providing a useful description, and for the purposes of providing a non-essential modification of the invention that may not be presently contemplated, may represent an equivalent modification of the invention.
Claims (10)
1. The synthesis method of the natural product salt spike grass alkali is characterized by comprising the following steps of:
s1: inserting a carbon rod and a platinum electrode into a three-port electric reaction tube, sequentially adding N-methyl-4-nitro-benzenesulfonamide, tetrabutylammonium acetate and sodium acetate, then adding dichloromethane, 2, 2, 2-trifluoroethanol, 36% acetic acid solution and styrene under the nitrogen atmosphere, and carrying out electrolysis on an organic layer of the product after 5h under the conditions of room temperature, stirring and constant current of 2.0 mA-8.0 mA, concentrating and carrying out column chromatography to obtain 2- (N-methyl-4-nitrophenyl) sulfonamide) -1-ethyl phenylacetate;
s2: placing 2- (N-methyl-4-nitrophenyl) sulfamido) -1-ethyl phenylacetate and potassium carbonate into a reaction bottle, adding dichloromethane and methanol, stirring at room temperature for 4 hours, and concentrating the reaction liquid under reduced pressure after TLC detection reaction is finished to obtain N- (2) -hydroxy-2-phenethyl) -N-methyl-4-nitrobenzenesulfonamide;
s3: DBU (1, 8-dibutyl-1, 5, 7-triazacyclodecane) and 2-thioglycollic acid are sequentially added into DMF (dimethylformamide) solution to be dissolved to obtain a reaction solution, then DMF solution of N- (2) -hydroxy-2-phenethyl) -N-methyl-4-nitrobenzenesulfonamide is dripped into the reaction solution, stirring is carried out at room temperature for overnight, and the reaction solution is decompressed and concentrated after TLC detection reaction is finished, thus obtaining the spica et grass alkali finally.
2. The method for synthesizing the natural product salt spike grass alkali according to claim 1, wherein the constant current in S1 is 6.0 mA.
3. The method for synthesizing the natural product salt spike grass alkali according to claim 1, wherein the molar ratio of N-methyl-4-nitro-benzenesulfonamide, tetrabutylammonium acetate, sodium acetate and styrene in S1 is 1:2:4:3.
4. The method for synthesizing the natural product salt spike grass alkali according to claim 1, wherein the volume ratio of dichloromethane to 2 to 36 percent of acetic acid solution in S1 is 10:1:2.
5. The method for synthesizing the natural product salt spike grass alkali according to claim 1, wherein the ratio of the N-methyl-4-nitro-benzenesulfonamide to the dichloromethane in S1 is 0.2:5 in terms of mmol/mL.
6. The method for synthesizing the natural product salt spike grass alkali according to claim 1, wherein the molar ratio of the 2- (N-methyl-4-nitrophenyl) sulfonamide group) -1-phenyl ethyl acetate to the potassium carbonate in the S2 is 2:3.
7. the method for synthesizing natural product salt spike grass alkali according to claim 1, wherein the volume ratio of dichloromethane to methanol in S2 is 3:1.
8. The method for synthesizing the natural product salt spike grass alkali according to claim 1, wherein the ratio of the ethyl 2- (N-methyl-4-nitrophenyl) sulfonamide group) -1-phenylacetate to the dichloromethane in S2 is 0.2:1.5 in terms of mmol/mL.
9. The method for synthesizing the natural product salt spike grass alkali according to claim 1, wherein the molar ratio of DBU, 2-thioglycollic acid and N- (2) -hydroxy-2-phenethyl) -N-methyl-4-nitrobenzenesulfonamide in S3 is 6:6:1.
10. The method for synthesizing the natural product salt spike grass alkali according to claim 1, wherein the ratio of N- (2) -hydroxy-2-phenethyl) -N-methyl-4-nitrobenzenesulfonamide to DMF in S3 is 0.2:3 in mmol/mL.
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