CN114524795A - Improved preparation method of Rhodomyrtone - Google Patents
Improved preparation method of Rhodomyrtone Download PDFInfo
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- CN114524795A CN114524795A CN202210262070.9A CN202210262070A CN114524795A CN 114524795 A CN114524795 A CN 114524795A CN 202210262070 A CN202210262070 A CN 202210262070A CN 114524795 A CN114524795 A CN 114524795A
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- TYDBFNAOFZIICW-UHFFFAOYSA-N rhodomyrtone Natural products OC1=C(C(=O)CC(C)C)C(O)=C2C(CC(C)C)C(C(C(C)(C)C(=O)C3(C)C)=O)=C3OC2=C1 TYDBFNAOFZIICW-UHFFFAOYSA-N 0.000 title claims abstract description 39
- TYDBFNAOFZIICW-CQSZACIVSA-N (9r)-6,8-dihydroxy-2,2,4,4-tetramethyl-7-(3-methylbutanoyl)-9-(2-methylpropyl)-9h-xanthene-1,3-dione Chemical compound OC1=C(C(=O)CC(C)C)C(O)=C2[C@@H](CC(C)C)C(C(C(C)(C)C(=O)C3(C)C)=O)=C3OC2=C1 TYDBFNAOFZIICW-CQSZACIVSA-N 0.000 title claims abstract description 38
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 238000006243 chemical reaction Methods 0.000 claims abstract description 32
- 238000000034 method Methods 0.000 claims abstract description 18
- 239000002253 acid Substances 0.000 claims abstract description 17
- 239000002904 solvent Substances 0.000 claims abstract description 14
- 230000001404 mediated effect Effects 0.000 claims abstract description 11
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 11
- 238000005618 Fries rearrangement reaction Methods 0.000 claims abstract description 9
- 238000006845 Michael addition reaction Methods 0.000 claims abstract description 9
- 238000007069 methylation reaction Methods 0.000 claims abstract description 7
- 230000008569 process Effects 0.000 claims abstract description 6
- 238000006722 reduction reaction Methods 0.000 claims abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 54
- 239000000243 solution Substances 0.000 claims description 51
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 33
- 150000001875 compounds Chemical class 0.000 claims description 32
- 239000012074 organic phase Substances 0.000 claims description 25
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- 239000000543 intermediate Substances 0.000 claims description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- 238000003756 stirring Methods 0.000 claims description 17
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 16
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 230000035484 reaction time Effects 0.000 claims description 12
- 238000005406 washing Methods 0.000 claims description 12
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- 239000012046 mixed solvent Substances 0.000 claims description 9
- 239000003208 petroleum Substances 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 8
- 229910052723 transition metal Inorganic materials 0.000 claims description 8
- 150000003624 transition metals Chemical class 0.000 claims description 8
- JPYHHZQJCSQRJY-UHFFFAOYSA-N Phloroglucinol Natural products CCC=CCC=CCC=CCC=CCCCCC(=O)C1=C(O)C=C(O)C=C1O JPYHHZQJCSQRJY-UHFFFAOYSA-N 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 claims description 7
- 229960001553 phloroglucinol Drugs 0.000 claims description 7
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 claims description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
- 239000005457 ice water Substances 0.000 claims description 6
- 239000011259 mixed solution Substances 0.000 claims description 6
- QCDYQQDYXPDABM-UHFFFAOYSA-N phloroglucinol Chemical compound OC1=CC(O)=CC(O)=C1 QCDYQQDYXPDABM-UHFFFAOYSA-N 0.000 claims description 6
- LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical class [Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O LJCNRYVRMXRIQR-OLXYHTOASA-L 0.000 claims description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 6
- 230000009471 action Effects 0.000 claims description 5
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 5
- 238000010791 quenching Methods 0.000 claims description 5
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 claims description 5
- 229910015900 BF3 Inorganic materials 0.000 claims description 4
- 239000002841 Lewis acid Substances 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- 230000002378 acidificating effect Effects 0.000 claims description 4
- 238000009835 boiling Methods 0.000 claims description 4
- 239000003638 chemical reducing agent Substances 0.000 claims description 4
- 150000007517 lewis acids Chemical class 0.000 claims description 4
- 239000011780 sodium chloride Substances 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 3
- WHGYCGOFTBFDLW-UHFFFAOYSA-L nickel(2+);diperchlorate;hexahydrate Chemical compound O.O.O.O.O.O.[Ni+2].[O-]Cl(=O)(=O)=O.[O-]Cl(=O)(=O)=O WHGYCGOFTBFDLW-UHFFFAOYSA-L 0.000 claims description 3
- 230000000171 quenching effect Effects 0.000 claims description 3
- 238000002390 rotary evaporation Methods 0.000 claims description 3
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical class [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 3
- 239000007858 starting material Substances 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 2
- 229910052782 aluminium Inorganic materials 0.000 claims description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 2
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 2
- 239000011592 zinc chloride Substances 0.000 claims description 2
- 235000005074 zinc chloride Nutrition 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 10
- 238000010898 silica gel chromatography Methods 0.000 abstract description 8
- 238000000926 separation method Methods 0.000 abstract description 7
- 239000002360 explosive Substances 0.000 abstract description 4
- 231100000331 toxic Toxicity 0.000 abstract description 3
- 230000002588 toxic effect Effects 0.000 abstract description 3
- 230000011987 methylation Effects 0.000 abstract description 2
- 230000010933 acylation Effects 0.000 abstract 1
- 238000005917 acylation reaction Methods 0.000 abstract 1
- 238000001308 synthesis method Methods 0.000 abstract 1
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 8
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 7
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 238000002114 high-resolution electrospray ionisation mass spectrometry Methods 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 238000011020 pilot scale process Methods 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 2
- ISULZYQDGYXDFW-UHFFFAOYSA-N 3-methylbutanoyl chloride Chemical compound CC(C)CC(Cl)=O ISULZYQDGYXDFW-UHFFFAOYSA-N 0.000 description 2
- 230000000840 anti-viral effect Effects 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000011031 large-scale manufacturing process Methods 0.000 description 2
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- 239000002994 raw material Substances 0.000 description 2
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- 238000001228 spectrum Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- 208000002874 Acne Vulgaris Diseases 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 241000701022 Cytomegalovirus Species 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 241000701074 Human alphaherpesvirus 2 Species 0.000 description 1
- 241000701085 Human alphaherpesvirus 3 Species 0.000 description 1
- 238000006000 Knoevenagel condensation reaction Methods 0.000 description 1
- 240000005125 Myrtus communis Species 0.000 description 1
- 235000013418 Myrtus communis Nutrition 0.000 description 1
- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 1
- 240000007994 Rhodomyrtus tomentosa Species 0.000 description 1
- 235000007234 Rhodomyrtus tomentosa Nutrition 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 241000700584 Simplexvirus Species 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- MKUXAQIIEYXACX-UHFFFAOYSA-N aciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCO)C=N2 MKUXAQIIEYXACX-UHFFFAOYSA-N 0.000 description 1
- 229960004150 aciclovir Drugs 0.000 description 1
- 206010000496 acne Diseases 0.000 description 1
- -1 acyl phloroglucinol compound Chemical class 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229940125810 compound 20 Drugs 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000003381 deacetylation reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- CDHICTNQMQYRSM-UHFFFAOYSA-N di(propan-2-yl)alumane Chemical compound CC(C)[AlH]C(C)C CDHICTNQMQYRSM-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 1
- 241000411851 herbal medicine Species 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
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- 238000003541 multi-stage reaction Methods 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
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- 238000006467 substitution reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
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Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/78—Ring systems having three or more relevant rings
- C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
- C07D311/82—Xanthenes
- C07D311/84—Xanthenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 9
- C07D311/86—Oxygen atoms, e.g. xanthones
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses an improved preparation method of Rhodomyrtone, which relates to the technical field of chemical synthesis, and effectively optimizes the conditions of each reaction and the subsequent treatment mode in the processes of Fries rearrangement reaction, Fries acylation, methylation, reduction reaction, Michael addition and acid-mediated cyclization reaction, thereby overcoming the problems that the prior synthesis method needs silica gel column chromatography separation, uses a large amount of explosive and toxic solvents, has low total yield, is only suitable for preparation in dozens or hundreds of milligrams scales and the like, and leading the obtained Rhodomyrtone to have no need of silica gel column chromatography separation, high total yield (34.6 percent), high purity (99.8 percent) and is suitable for large-scale preparation.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to an improved preparation method of Rhodomyrtone.
Background
Rhodomyrtone, chemical name: 6, 8-dihydroxy-7- (3-methylbutyryl) -9-isobutyl-2, 2, 4, 4-tetramethyl-4, 9-dihydro-1H-xanthene-1, 3(2H) -dione, which is an acyl phloroglucinol compound separated from traditional Chinese herbal medicine myrtle (Rhodomyrtus tomentosa). The report in the literature shows that Rhodomyrtone is a novel natural antibiotic, has remarkable and broad-spectrum antibacterial activity, and has a mechanism of action different from that of the existing antibiotic drugs on the market. Currently, this compound has entered the clinical research stage for the treatment of acne vulgaris (Antibiotics, 2021, 10, 108). Meanwhile, the inventor and other earlier researches found that Rhodomyrtone can remarkably inhibit diseases caused by herpes simplex virus I, herpes simplex virus II, varicella-zoster virus and cytomegalovirus (CN 110279688A). Compared with antiviral drugs such as acyclovir and the like on the market, Rhodomyrtone has the same antiviral activity, but has different antiviral action mechanisms, and is expected to solve the drug resistance problem of the existing drugs on the market. Therefore, the Rhodomyrtone has good application prospect in treating related diseases caused by bacterial and viral infection. However, the Rhodomyrtone derived from natural sources has a low content, and there are problems in that separation is difficult and the period is long. Therefore, the development of a chemical synthesis method for preparing Rhodomyrtone has important application value.
Currently, there are few documents and patents on the method for synthesizing Rhodomyrtone. In 2013, Maier et al disclosed a synthetic route of Rhodomyrtone for the first time (Tetrahedron, 2013, 69, 8559). As shown in a synthetic route 1, the route takes phloroglucinol 2 as a starting material, and an intermediate 6 is obtained through acetylation, methylation and deacetylation reactions. Subsequently, compound 6 was subjected to Knoevenagel condensation, Michael addition and acid-mediated cyclization reaction in sequence to give intermediate 9. Finally, the compound 9 is separated by silica gel column chromatography under the action of titanium tetrachloride and dichloromethane as a solvent in a yield of 40% to obtain the Rhodomyrtone (1). This route requires a total of 8 reactions, with the longest linear step being 7, and an overall yield of only 0.033%. In addition, the route uses a large amount of explosive solvent nitromethane and toxic solvent benzene, and partial steps need to be separated and purified by silica gel column chromatography, which are all beneficial to large-scale production.
Scheme 1:
in 2015, Maier et al developed two new synthetic routes for Rhodomyrtone based on the above routes, as shown in synthetic routes 2 and 3. Unfortunately, neither of these routes has significantly improved the synthetic steps and yields over the first generation synthetic routes. Wherein, the synthetic route 1 needs 8 steps of reaction in total, and the total yield is 0.037%; scheme 2 requires a total of 10 reactions with an overall yield of only 0.025%. In addition, the multistep reactions in the synthetic routes 1 and 2 are separated by silica gel column chromatography, and even the preparative thin layer chromatography is adopted for separation and purification, so that the application limitation is large.
Scheme 2:
scheme 3:
in 2019, the inventor discloses a new synthetic route (CN 110279688A) of Rhodomyrtone, as shown in synthetic route 4, the route uses phloroglucinol 2 as a starting material, and performs isovalerylation and methylation reaction to obtain an intermediate 20, and the intermediate 9 is obtained by performing reduction, Michael addition and acid-mediated cyclization reaction on the compound 20. Referring to the synthetic work of Maier et al, Rhodomyrtone was obtained from Compound 9 in 35% yield. The synthetic steps of the route only need 5 steps of reaction, and the total yield is 12%. However, the route still has the problems of using a large amount of nitromethane which is an explosive solvent, needing to adopt silica gel column chromatography for separation and purification and the like, and is not beneficial to pilot scale production and industrial scale production.
Scheme 4:
in 2020, Tan et al optimized a new synthetic route for Rhodomyrtone based on the above route (org. Lett.2020, 22, 8007). As shown in scheme 5, this scheme starts with intermediate 3 and requires 6 reactions in a total yield of 27.9%. However, each step of the reaction in the route needs to be separated and purified by column chromatography, and the final 3 steps of reaction only complete preparation in a scale of dozens of milligrams, so that the difficulty of application to pilot scale amplification and industrial scale production is large.
Scheme 5:
in summary, the Rhodomyrtone synthesis routes reported in the literature and the patent at present have the problems of silica gel column chromatography separation, large use of explosive and toxic solvents, low total yield and the like, and are only suitable for preparation on a scale of dozens or hundreds of milligrams, but are difficult to be applied to pilot scale or industrial preparation.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention provides an improved preparation method of Rhodomyrtone, which has the characteristics of simple and convenient operation, low production cost, no need of silica gel column chromatography separation and purification, and mild reaction conditions, and is suitable for large-scale and industrial production.
In order to solve the problems, the invention adopts the following technical scheme:
an improved preparation method of Rhodomyrtone shown in formula I, which is characterized in that the method comprises the following steps:
(1) taking phloroglucinol as an initial raw material, carrying out Friedel-crafts acylation reaction under the action of Lewis acid, and carrying out post-treatment on A to obtain a compound shown as a formula II; the Friedel-crafts acylation reaction is carried out in a mixed solvent of dichloroethane and nitromethane.
(2) And (2) carrying out methylation reaction on the compound shown in the formula II prepared in the step (1) and methyl iodide under an alkaline condition, and carrying out aftertreatment B to obtain the compound shown in the formula III.
(3) And (3) carrying out a reduction reaction on the compound shown in the formula III prepared in the step (2) under the condition of a reducing agent, and carrying out post-treatment C to obtain the compound shown in the formula IV.
(4) Carrying out transition metal catalyzed Michael addition and acid mediated cyclization reaction on the compound shown in the formula IV prepared in the step (3), and carrying out aftertreatment on the compound D to obtain a compound shown in the formula V; the transition metal catalyzed Michael addition and acid mediated cyclization reactions are carried out in an acidic mixed solvent.
(5) Carrying out Fries rearrangement reaction on the compound shown in the formula V prepared in the step (4) under the action of Lewis acid, and carrying out post-treatment on the compound E to obtain a target compound shown in the formula I; the Fries rearrangement reaction is carried out in a high boiling point solvent of toluene or dichloroethane.
The Lweis acid in the step (1) is one or a combination of more than one of aluminum trichloride, zinc chloride and boron trifluoride, and is preferably aluminum trichloride as the preferred material of the invention; the Friedel-crafts acylation reaction temperature is 40-80 ℃, and the reaction time is 5-10 hours; the ratio of the dichloroethane to the nitromethane mixed solvent is 5: 1-10: 1, preferably 10: 1.
The alkali in the step (2) is sodium methoxide or sodium hydroxide; the methylation reaction temperature is 40-60 ℃, and the reaction time is 2-8 hours.
The reducing agent in the step (3) is diisobutyl aluminum hydride or red aluminum; the reduction reaction temperature is-30 to-10 ℃, and the reaction time is 1 to 2 hours.
The transition metal catalyst in the step (4) is a nickel catalyst, preferably Ni (PPh3)4、Ni(PPh3)2Cl2、Ni(OAc)2Nickel perchlorate hexahydrate; the temperature of the transition metal catalyzed Michael addition reaction is 35-45 ℃, and the reaction time is 5-8 hours; the acid of the acid-mediated cyclization reaction is p-toluenesulfonic acid or methanesulfonic acid; the temperature of the acid-mediated cyclization reaction is 60-70 ℃, and the reaction time is 8-10 hours; the acidic mixed solvent is tetrahydrofuran and anhydrous acetic acid, and the ratio is 4: 1-6: 1.
The Lweis acid in the step (5) is titanium tetrachloride or boron trifluoride, and is preferably titanium tetrachloride; the Fries rearrangement reaction temperature is 80-100 ℃, and the reaction time is 2-3 hours; the high boiling point solvent of the Fries rearrangement reaction is dichloroethane or toluene, and toluene is preferred.
The preparation method of the Rhodomyrtone and the key intermediate thereof shown in the formula I is characterized by comprising the following steps:
the post-treatment A comprises the following steps: the reaction solution was slowly added to a mixed solution of saturated sodium potassium tartrate and ice water to quench, stirred vigorously, extracted with ethyl acetate, and the organic phases were combined. The organic phase is washed successively with hot water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Dissolving the obtained concentrated solution in ethyl acetate, dropwise adding petroleum ether under the stirring condition, and slowly crystallizing after the addition is finished to obtain the corresponding target product.
The post-treatment B comprises the following steps: and (3) adjusting the pH value of the reaction solution to 5-6 by using 1mol/L hydrochloric acid, removing the solvent methanol by reduced pressure rotary evaporation, adding a saturated sodium sulfite solution, extracting by using ethyl acetate, and combining organic phases. And washing the organic phase by a 1mol/L sodium hydroxide solution, washing by a saturated sodium chloride solution, drying by anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain a corresponding target product.
The post-treatment C comprises the following steps: and (3) adjusting the pH value of the reaction solution to 5-6 by using 1mol/L hydrochloric acid, heating to room temperature, adding water and ethyl acetate, violently stirring until the mixture is layered, extracting by using ethyl acetate, and combining organic phases. Drying the organic phase by anhydrous sodium sulfate, filtering, decompressing and concentrating to obtain the corresponding target product.
The post-treatment D is as follows: and (3) adjusting the pH value of the reaction solution to 5-6 by using a saturated sodium bicarbonate solution, extracting by using ethyl acetate, washing by using hot water, washing by using a saturated sodium chloride solution, drying by using anhydrous sodium sulfate, filtering, and concentrating under reduced pressure. Dissolving the obtained concentrated solution in dichloromethane, dropwise adding petroleum ether under stirring, and crystallizing to obtain the target product.
The post-treatment E is as follows: slowly adding the reaction solution into a mixed solution of saturated sodium potassium tartrate and ice water, quenching, vigorously stirring, extracting with dichloromethane, and combining organic phases. The organic phase is washed successively with 1mol/L sodium hydroxide solution, sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Dissolving the obtained concentrated solution in dichloromethane, dropwise adding petroleum ether under stirring, and slowly crystallizing after adding to obtain the target product.
The invention has the beneficial effects that:
the method for preparing the compound Rhodomyrtone shown in the formula I has one or more of the following advantages:
1) the raw materials and the solvent used in the method are cheap and easy to obtain;
2) the synthesis process of the method is easy to operate, does not need silica gel chromatographic purification, and is easy for large-scale preparation;
3) the method has high synthesis yield, and the total yield is about 34.6%;
4) the Rhodomyrtone prepared by the method has high purity, and the purity can reach more than 99.8%;
5) the method is suitable for pilot plant or large-scale preparation.
Drawings
FIG. 1 shows Rhodomyrtone of the present invention1H-NMR nuclear magnetic spectrum.
FIG. 2 shows Rhodomyrtone of the present invention13C-NMR nuclear magnetic spectrum.
FIG. 3 is an HPLC analysis chromatogram of Rhodomyrtone of the present invention.
Detailed Description
In order to further illustrate the technical effects of the present invention, the present invention is specifically described below by way of examples. The examples provided are merely illustrative of the methods of the present invention and do not limit the disclosure in any way.
The reagents, methods and apparatus employed in the present invention are conventional in the art, unless otherwise indicated. The compound shown in the formula I is called compound I for short, the compound shown in the formula II is called compound II for short, and the like.
In the following examples, the purity of the compounds II to IV as intermediates was determined to be greater than 90% and close to 100%, so that the amounts of the substances were calculated as 100% purity.
Example preparation of Rhodomyrtone
The synthetic route of the compound shown in formula I of the embodiment of the invention, namely Rhodomyrtone, is as follows:
1) synthesis of Compound II intermediates
Phloroglucinol (100g, 793.0mmol) was dissolved in a mixed solvent of dichloroethane and nitromethane (10: 1, 2000mL) at room temperature. Subsequently, anhydrous aluminum chloride (317.2g, 2379mmol), isovaleryl chloride (106.3mL, 872.3mmol) were added sequentially. After stirring at room temperature for 30 minutes, the temperature was raised to 40 ℃ and the reaction was continued for 8 hours. The reaction solution was slowly added to a mixed solution (1000mL) of saturated sodium potassium tartrate and ice water, quenched, vigorously stirred for 3 hours, extracted 3 times with ethyl acetate (500 mL. times.3), and the organic phases were combined. The organic phase is washed with hot water, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Dissolving the obtained concentrated solution in ethyl acetate, dropwise adding petroleum ether under slow stirring, and slowly crystallizing after the addition to obtain intermediate II (135.0g, yield 86%).1H-NMR(400MHz，CD3OD)δ5.80(s，2H)，2.90(d，J＝6.8Hz，2H)，2.20(m，1H)，0.95(d，J＝6.7Hz，6H)；13C-NMR(100MHz，CD3OD)δ207.0，166.0，165.8，165.8，105.5，95.7，95.7，53.7，26.7，23.2，23.2；HR-ESI-MS m/z：[M+H]+calcd for C11H15O4：211.0965；Found：211.0963。
2) Synthesis of intermediates of Compound III
Intermediate II (50g, 237.9mmol) was dissolved in methanol (1500 mL). Sodium methoxide (89.9g, 1665.1mmol) was added under ice-bath conditions, and the reaction stirred for 30 min. Subsequently, methyl iodide (118.4mL, 190.29mmol) was added slowly and the reaction stirred for 30 minutes. After the temperature is raised to 55 ℃ and the reaction is continued for 2 hours, the pH value of the reaction solution is adjusted to 5-6 by using 1mol/L hydrochloric acid. Cooling to room temperature, and carrying out reduced pressure rotary evaporation to remove the solvent methanol. The resulting concentrate was added with a saturated sodium sulfite solution, extracted 3 times with ethyl acetate (500 mL. times.3), and the organic phases were combined. The organic phase was washed with 1mol/L sodium hydroxide solution, washed with sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give intermediate III (56.6g, 98% yield).1H-NMR(400MHz，CDCl3)δ18.28(s，OH)，2.77(d，J＝7.0Hz，2H)，2.07(m，1H)，1.34(s，6H)，1.25(s，6H)，0.88(d，J＝6.8Hz，3H)，0.88(d，J＝6.8Hz，3H)；13C-NMR(100MHz，CDCl3)δ 209.7，203.6，199.5，196.7，109.4，56.8，52.3，47.2，26.1，24.2，24.2，23.8，23.8，22.6，22.6；HR-ESI-MS m/z：[M+H]+calcd for C15H23O4：267.1591；Found：267.1588。
3) Synthesis of Compound IV intermediate
Intermediate III (50g, 87.5mmol) was dissolved in tetrahydrofuran (900mL) and diisopropylaluminum hydride (312.5mL, 468.8mmol, 1.0M, cyclohexane) was added slowly dropwise across the wall at-20 ℃. After stirring and reacting for 1 hour, adjusting the pH value of the reaction solution to 5-6 by using 1mol/L hydrochloric acid. After warming to room temperature, water and ethyl acetate were added, the mixture was vigorously stirred to separate layers, the reaction solution was extracted 3 times with ethyl acetate (300 mL. times.3), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give intermediate IV (44.6g, 95% yield) which was used in the next reaction without purification.
4) Synthesis of intermediate of compound V
Phloroglucinol (23.65g, 187.5mmol) was dissolved in tetrahydrofuran (1900mL) solution at room temperature. Subsequently, acetic acid (335mL), nickel perchlorate hexahydrate (6.855g, 18.75mmol), intermediate II (46.9g, 187.5mmol) were added in that order. After warming to 40 ℃ and reacting for 5 hours, p-toluenesulfonic acid (53.5g, 281.3mmol) was added and the reaction was continued for 8 hours. And cooling to room temperature, and adjusting the pH value of the reaction solution to 5-6 by using a saturated sodium bicarbonate solution. The reaction mixture was extracted 3 times with ethyl acetate (500 mL. times.3), and the organic phases were combined. The organic phase is washed by hot water, washed by sodium chloride solution, dried by anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was dissolved in methylene chloride, and petroleum ether was added dropwise with slow stirring to crystallize, whereby intermediate V (26.2g, yield 72%) was obtained.1H-NMR(500MHz，CD3OD)δ6.16(d，J＝2.3Hz，1H)，6.09(d，J＝2.3Hz，1H)，4.18(t，J＝5.8Hz，1H)，1.53(s，3H)，1.52-1.45(m，2H)，1.44(s，3H)，1.38(m，1H)，1.35(s，3H)，1.33(s，3H)，0.84(d，J＝6.5Hz，3H)，0.80(d，J＝6.5Hz，3H)；13C-NMR(125MHz，CD3OD)δ 213.7，199.6，169.9，158.1，157.1，153.7，114.9，106.0，100.1，95.3，56.8，48.4，47.0，26.8，26.1，25.3，25.2，25.0，24.7，24.3，23.7；HR-ESI-MS m/z：[M+H]+Calcd for C21H27O5：359.1853；Found 359.1851。
5) Preparation of the target product of Compound I
Intermediate V (20g, 55.8mmol) was dissolved in toluene (1000mL) solution and stirred for 30 min. Titanium tetrachloride (223.2mL, 223.2mmol, 1.0M, dichloromethane) was added and stirred for 30 minutes at 0 ℃. Subsequently, isovaleryl chloride (6.9mL, 55.8mmol) was added, warmed to room temperature and stirred for 30 min. The reaction system was heated to 80 ℃ and reacted for 2 hours. The reaction mixture was slowly added to a mixed solution of saturated sodium potassium tartrate and ice water (1000mL) to quench, and after vigorously stirring for 1 hour, the reaction mixture was extracted 3 times with dichloromethane (300 mL. times.3). The organic phase is washed by 1mol/L sodium hydroxide solution, washed by saturated sodium chloride solution, dried by anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was dissolved in methylene chloride, and petroleum ether was added dropwise with slow stirring, followed by slow crystallization after the addition to give Rhodomyrtone (14.8g, yield 60%).1H-NMR(400MHz，CDCl3)：δ13.54(s，OH)，8.32(s，OH)，6.22(s，1H)，4.30(t，J＝5.6Hz，1H)，3.04(dd，J＝15.6，6.8Hz，1H)，2.97(dd，J＝15.6，6.8Hz，1H)，2.28(m，1H)，1.56(s，3H)，1.48(m，2H)，1.44(s，3H)，1.43(s，3H)，1.41(m，1H)，1.39(s，3H)，0.97(d，J＝6.4Hz，3H)，0.97(d，J＝6.4Hz，3H)，0.86(d，J＝6.0Hz，3H)，0.84(d，J＝6.0Hz，3H)；13C-NMR(100MHz，CDCl3)：δ 212.3，207.0，198.9，167.9，163.1，158.9，155.8，114.4，107.8，106.3，94.8，56.2，53.3，47.4，46.0，25.4，25.3，25.3，24.9，24.7，24.7，24.4，23.7，23.3，23.0，22.9；HR-ESI-MS m/z：[M+H]+Calcd for C26H35O6：443.2428；Found443.2424。
It should be noted that the above embodiments are only for illustrating the technical solutions of the present invention and not for limiting, and although the technical solutions of the present invention are described in detail with reference to the best embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made on the technical solutions of the present invention without departing from the spirit and scope of the present invention, which are all covered by the protection scope of the present invention.
Claims (7)
1. An improved process for the preparation of rhodomyrtone (i), characterized in that said process comprises the following steps:
(1) taking phloroglucinol as a starting material, carrying out Friedel-crafts acylation reaction under the action of Lewis acid, and carrying out aftertreatment on A to obtain a compound shown in a formula II; the Friedel-crafts acylation reaction is carried out in a mixed solvent of dichloroethane and nitromethane;
(2) carrying out methylation reaction on the compound shown in the formula II prepared in the step (1) and methyl iodide under an alkaline condition, and carrying out aftertreatment B to obtain a compound shown in a formula III;
(3) and (3) carrying out a reduction reaction on the compound shown in the formula III prepared in the step (2) under the condition of a reducing agent, and carrying out post-treatment C to obtain the compound shown in the formula IV. The reaction temperature is between-30 and-10 ℃;
(4) carrying out transition metal catalyzed Michael addition and acid mediated cyclization reaction on the compound shown in the formula IV prepared in the step (3), and carrying out aftertreatment on the compound D to obtain a compound shown in the formula V; the transition metal catalyzed Michael addition and the acid mediated cyclization reaction are carried out in an acidic mixed solvent;
(5) carrying out Fries rearrangement reaction on the compound shown in the formula V prepared in the step (4) under the action of Lewis acid, and carrying out post-treatment on the compound E to obtain a target compound shown in the formula I; the Fries rearrangement reaction is carried out in a high boiling point solvent of toluene or dichloroethane.
2. The process for the preparation of a Rhodomyrtone key intermediate of formula II according to claim 1, wherein: the Lweis acid in the step (1) is one or a combination of more than one of aluminum trichloride, zinc chloride and boron trifluoride; the Friedel-crafts acylation reaction temperature is 40-80 ℃, and the reaction time is 5-10 hours; the ratio of the dichloroethane and the nitromethane mixed solvent is 5: 1-10: 1.
3. The process for preparing a Rhodomyrtone key intermediate of formula III according to claim 1, wherein: the alkali in the step (2) is sodium methoxide or sodium hydroxide; the methylation reaction temperature is 40-60 ℃, and the reaction time is 2-8 hours.
4. The process for preparing a Rhodomyrtone key intermediate of formula IV according to claim 1, wherein: the reducing agent in the step (3) is diisobutyl aluminum hydride or red aluminum; the reaction time is 1-2 hours.
5. The process according to claim 1 for the preparation of a key intermediate of Rhodomyrtone of formula V, wherein: the transition metal catalyst in the step (4) is a nickel catalyst, preferably Ni (PPh)3)4、Ni(PPh3)2Cl2、Ni(OAc)2Nickel perchlorate hexahydrate; the temperature of the transition metal catalyzed Michael addition reaction is 35-45 ℃, and the reaction time is 5-8 hours; the acid of the acid-mediated cyclization reaction is p-toluenesulfonic acid or methanesulfonic acid; the temperature of the acid-mediated cyclization reaction is 60-70 ℃, and the reaction time is 8-10 hours; the acidic mixed solvent is tetrahydrofuran and anhydrous acetic acid, and the ratio is 4: 1-6: 1.
6. The process for preparing Rhodomyrtone of formula I according to claim 1, wherein: the Lweis acid in the step (5) is titanium tetrachloride or boron trifluoride; the Fries rearrangement reaction temperature is 80-100 ℃, and the reaction time is 2-3 hours; the high boiling point solvent of Fries rearrangement reaction is dichloroethane or toluene.
7. The method for preparing Rhodomyrtone and key intermediates thereof according to claim 1 to 6, wherein:
the post-treatment A comprises the following steps: slowly adding the reaction solution into a mixed solution of saturated sodium potassium tartrate and ice water for quenching, violently stirring, extracting by using ethyl acetate, combining organic phases, washing the organic phases by using hot water, washing by using a saturated sodium chloride solution, drying by using anhydrous sodium sulfate, filtering, and concentrating under reduced pressure, dissolving the obtained concentrated solution in ethyl acetate, dropwise adding petroleum ether under the condition of stirring, and slowly crystallizing after the addition is finished to obtain a corresponding target product;
the post-treatment B comprises the following steps: and (3) adjusting the pH value of the reaction solution to 5-6 by using 1mol/L hydrochloric acid, removing the solvent methanol by reduced pressure rotary evaporation, adding a saturated sodium sulfite solution, extracting by using ethyl acetate, and combining organic phases. Washing the organic phase by a 1mol/L sodium hydroxide solution, washing by a saturated sodium chloride solution, drying by anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain a corresponding target product;
the post-treatment C comprises the following steps: adjusting the pH value of the reaction solution to 5-6 by using 1mol/L hydrochloric acid, heating to room temperature, adding water and ethyl acetate, violently stirring until layering, extracting by using ethyl acetate, combining organic phases, drying the organic phases by using anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain corresponding target products;
the post-treatment D is as follows: adjusting the pH value of the reaction solution to 5-6 with a saturated sodium bicarbonate solution, extracting with ethyl acetate, sequentially washing with hot water, washing with a saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, dissolving the obtained concentrated solution in dichloromethane, dropwise adding petroleum ether under stirring, and crystallizing to obtain a target product;
the post-treatment E is as follows: slowly adding the reaction solution into a mixed solution of saturated sodium potassium tartrate and ice water, quenching, vigorously stirring, extracting with dichloromethane, and combining organic phases. And washing the organic phase by using a 1mol/L sodium hydroxide solution, washing by using a sodium chloride solution, drying by using anhydrous sodium sulfate, filtering, concentrating under reduced pressure, dissolving the obtained concentrated solution in dichloromethane, dropwise adding petroleum ether under stirring, and slowly crystallizing after the addition is finished to obtain the target product.
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| CN115710245A (en) * | 2022-10-25 | 2023-02-24 | 中国科学院华南植物园 | Myrtle ketone industrial extraction method and myrtle ketone microcapsule preparation method |
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| CN115710245A (en) * | 2022-10-25 | 2023-02-24 | 中国科学院华南植物园 | Myrtle ketone industrial extraction method and myrtle ketone microcapsule preparation method |
| CN115710245B (en) * | 2022-10-25 | 2023-08-08 | 中国科学院华南植物园 | Industrial extraction method of myrtle ketone and preparation method of myrtle ketone microcapsule |
| CN115626906B (en) * | 2022-10-25 | 2023-08-22 | 中国科学院华南植物园 | Industrial extraction method of high-purity myrtle ketone |
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