CN112979625A - Synthesis method and application of piperlongumine - Google Patents
Synthesis method and application of piperlongumine Download PDFInfo
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- CN112979625A CN112979625A CN202110148259.0A CN202110148259A CN112979625A CN 112979625 A CN112979625 A CN 112979625A CN 202110148259 A CN202110148259 A CN 202110148259A CN 112979625 A CN112979625 A CN 112979625A
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- benzodioxole
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- piperlongumine
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- VABYUUZNAVQNPG-BQYQJAHWSA-N Piplartine Chemical compound COC1=C(OC)C(OC)=CC(\C=C\C(=O)N2C(C=CCC2)=O)=C1 VABYUUZNAVQNPG-BQYQJAHWSA-N 0.000 title claims abstract description 32
- VABYUUZNAVQNPG-UHFFFAOYSA-N Piperlongumine Natural products COC1=C(OC)C(OC)=CC(C=CC(=O)N2C(C=CCC2)=O)=C1 VABYUUZNAVQNPG-UHFFFAOYSA-N 0.000 title claims abstract description 31
- WHAAPCGHVWVUEX-UHFFFAOYSA-N Piperlonguminine Natural products CC(C)CNC(=O)C=CC=CC1=CC=C2OCOC2=C1 WHAAPCGHVWVUEX-UHFFFAOYSA-N 0.000 title claims abstract description 31
- 238000001308 synthesis method Methods 0.000 title claims abstract description 15
- -1 bromopropyl Chemical group 0.000 claims abstract description 35
- DIYWRNLYKJKHAM-MDOVXXIYSA-N (-)-cubebin Chemical compound C1=C2OCOC2=CC(C[C@@H]2[C@@H](CC=3C=C4OCOC4=CC=3)CO[C@@H]2O)=C1 DIYWRNLYKJKHAM-MDOVXXIYSA-N 0.000 claims abstract description 16
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims abstract description 16
- 230000000147 hypnotic effect Effects 0.000 claims abstract description 16
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims abstract description 16
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 15
- UIYJGLLTSVRSBM-UHFFFAOYSA-N 3-(1,3-benzodioxol-5-yl)propanoic acid Chemical compound OC(=O)CCC1=CC=C2OCOC2=C1 UIYJGLLTSVRSBM-UHFFFAOYSA-N 0.000 claims abstract description 14
- 150000001336 alkenes Chemical class 0.000 claims abstract description 14
- XUEHVOLRMXNRKQ-KHMAMNHCSA-N alpha cubebene Natural products CC(C)[C@@H]([C@H]12)CC[C@@H](C)[C@]32[C@@H]1C(C)=CC3 XUEHVOLRMXNRKQ-KHMAMNHCSA-N 0.000 claims abstract description 14
- 150000001408 amides Chemical class 0.000 claims abstract description 14
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 claims abstract description 14
- 206010039897 Sedation Diseases 0.000 claims abstract description 13
- 230000001590 oxidative effect Effects 0.000 claims abstract description 13
- 230000036280 sedation Effects 0.000 claims abstract description 13
- 150000001728 carbonyl compounds Chemical class 0.000 claims abstract description 12
- 239000007800 oxidant agent Substances 0.000 claims abstract description 12
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 9
- SATCULPHIDQDRE-UHFFFAOYSA-N piperonal Chemical compound O=CC1=CC=C2OCOC2=C1 SATCULPHIDQDRE-UHFFFAOYSA-N 0.000 claims abstract description 9
- OJOFMLDBXPDXLQ-VIFPVBQESA-N (4s)-4-benzyl-1,3-oxazolidin-2-one Chemical compound C1OC(=O)N[C@H]1CC1=CC=CC=C1 OJOFMLDBXPDXLQ-VIFPVBQESA-N 0.000 claims abstract description 8
- 125000005997 bromomethyl group Chemical group 0.000 claims abstract description 8
- 239000007858 starting material Substances 0.000 claims abstract description 7
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 claims abstract description 5
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 18
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims description 15
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 14
- 230000009471 action Effects 0.000 claims description 14
- LFTLOKWAGJYHHR-UHFFFAOYSA-N N-methylmorpholine N-oxide Chemical compound CN1(=O)CCOCC1 LFTLOKWAGJYHHR-UHFFFAOYSA-N 0.000 claims description 13
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims description 13
- 238000006467 substitution reaction Methods 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 11
- 229910000489 osmium tetroxide Inorganic materials 0.000 claims description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 239000003446 ligand Substances 0.000 claims description 7
- 238000007254 oxidation reaction Methods 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- 230000009467 reduction Effects 0.000 claims description 7
- 238000006722 reduction reaction Methods 0.000 claims description 7
- 230000002194 synthesizing effect Effects 0.000 claims description 7
- 230000000049 anti-anxiety effect Effects 0.000 claims description 6
- 239000002249 anxiolytic agent Substances 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 6
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 5
- 229940079593 drug Drugs 0.000 claims description 5
- 239000012285 osmium tetroxide Substances 0.000 claims description 5
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 claims description 5
- 239000003638 chemical reducing agent Substances 0.000 claims description 4
- 230000007062 hydrolysis Effects 0.000 claims description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims description 4
- 150000002440 hydroxy compounds Chemical class 0.000 claims description 4
- OVEHNNQXLPJPPL-UHFFFAOYSA-N lithium;n-propan-2-ylpropan-2-amine Chemical compound [Li].CC(C)NC(C)C OVEHNNQXLPJPPL-UHFFFAOYSA-N 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- 238000006479 redox reaction Methods 0.000 claims description 4
- 238000011160 research Methods 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 229910010084 LiAlH4 Inorganic materials 0.000 claims description 3
- 241000872931 Myoporum sandwicense Species 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 230000003647 oxidation Effects 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- 238000007039 two-step reaction Methods 0.000 claims description 3
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 2
- 229940126585 therapeutic drug Drugs 0.000 abstract description 2
- 241000699670 Mus sp. Species 0.000 description 15
- QGMRQYFBGABWDR-UHFFFAOYSA-M Pentobarbital sodium Chemical compound [Na+].CCCC(C)C1(CC)C(=O)NC(=O)[N-]C1=O QGMRQYFBGABWDR-UHFFFAOYSA-M 0.000 description 9
- 229960001412 pentobarbital Drugs 0.000 description 7
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- 238000002474 experimental method Methods 0.000 description 5
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- 240000003731 Piper cubeba Species 0.000 description 4
- 235000002711 Piper cubeba Nutrition 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 235000013399 edible fruits Nutrition 0.000 description 3
- 239000000932 sedative agent Substances 0.000 description 3
- 230000001624 sedative effect Effects 0.000 description 3
- 230000003860 sleep quality Effects 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 241000722363 Piper Species 0.000 description 2
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
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- 150000002596 lactones Chemical class 0.000 description 2
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- 239000011734 sodium Substances 0.000 description 2
- 210000000952 spleen Anatomy 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 235000008534 Capsicum annuum var annuum Nutrition 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 206010062717 Increased upper airway secretion Diseases 0.000 description 1
- 229910010082 LiAlH Inorganic materials 0.000 description 1
- 235000019510 Long pepper Nutrition 0.000 description 1
- 240000003455 Piper longum Species 0.000 description 1
- 206010041349 Somnolence Diseases 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- RXVGBQCEAQZMLW-UHFFFAOYSA-N alpha-solanine Natural products CC1CCC2C(C)C3C(CC4C5CC=C6CC(CCC6(C)C5CCC34C)OC7OC(CO)C(O)C(OC8OC(CO)C(O)C(O)C8O)C7OC9OC(CO)C(O)C(O)C9O)N2C1 RXVGBQCEAQZMLW-UHFFFAOYSA-N 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000000941 bile Anatomy 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 230000001989 choleretic effect Effects 0.000 description 1
- 235000013409 condiments Nutrition 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- AAOVKJBEBIDNHE-UHFFFAOYSA-N diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 description 1
- 229960003529 diazepam Drugs 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 208000002173 dizziness Diseases 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 229940000406 drug candidate Drugs 0.000 description 1
- 239000012259 ether extract Substances 0.000 description 1
- 239000003777 experimental drug Substances 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 201000005917 gastric ulcer Diseases 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 229920005610 lignin Polymers 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 208000026435 phlegm Diseases 0.000 description 1
- 239000001086 piper cubeba l. Substances 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- IIQJBVZYLIIMND-UHFFFAOYSA-J potassium;antimony(3+);2,3-dihydroxybutanedioate Chemical compound [K+].[Sb+3].[O-]C(=O)C(O)C(O)C([O-])=O.[O-]C(=O)C(O)C(O)C([O-])=O IIQJBVZYLIIMND-UHFFFAOYSA-J 0.000 description 1
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- 230000028327 secretion Effects 0.000 description 1
- 208000019116 sleep disease Diseases 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- ZGVSETXHNHBTRK-OTYSSXIJSA-N solanine Chemical compound O([C@H]1[C@@H](O)[C@@H](CO)O[C@H]([C@@H]1O[C@@H]1[C@@H]([C@H](O)[C@@H](O)[C@H](C)O1)O)O[C@@H]1CC2=CC[C@H]3[C@@H]4C[C@@H]5N6C[C@@H](C)CC[C@@H]6[C@H]([C@@H]5[C@@]4(C)CC[C@@H]3[C@@]2(C)CC1)C)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O ZGVSETXHNHBTRK-OTYSSXIJSA-N 0.000 description 1
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Images
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
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- Health & Medical Sciences (AREA)
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- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
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- Biomedical Technology (AREA)
- Chemical Kinetics & Catalysis (AREA)
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- Medicinal Chemistry (AREA)
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- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a synthesis method of piper longumine, which comprises the following steps: 1, 3-benzodioxole-5-formaldehyde and malonic acid are used as starting materials to generate 1, 3-benzodioxole-5-propionic acid, the 1, 3-benzodioxole-5-propionyl chloride is reacted with oxalyl chloride to generate 1, 3-benzodioxole-5-propionyl chloride, then the corresponding amide is generated with (S) -4-benzyl-2-oxazolidinone, then the product is reacted with bromopropyl to generate corresponding olefin, and an oxidant OsO is combined to generate4Producing corresponding carbonyl compound under the catalysis of/NMO, preparing the carbonyl compound into corresponding hydroxyl compound, oxidizing the hydroxyl compound into lactone compound by using Fetizon reagent, reacting the lactone compound with 5- (bromomethyl) -1, 3-benzodiocene, and finally using diisobutylaluminium hydrideReducing to obtain the cubebin. The invention also discloses application of the piperlongumine in sedation and hypnosis. The invention provides a potential therapeutic drug for sedation and hypnosis.
Description
Technical Field
The invention belongs to the technical field of lignin application, relates to a synthesis method of piper cubebine, and particularly relates to application of piper cubebine.
Background
The cubebin is extracted and separated from dry mature fruit of Litsea cubeba (Lour.) Pers. The cubeberry fruit contains cubebin, and components such as cubebic acid and cubebelactone are also found. The cubeb litsea cubeba fruit has the effects of warming spleen and kidney, invigorating stomach and promoting digestion, and belongs to aromatic appetizing condiment. It is mainly used for treating deficiency and fullness of spleen and stomach, cold qi attacking heart, stabbing pain in heart and abdomen, pain in hypochondrium, dizziness and limb drowsiness. Modern pharmacological research shows that the cubeb litsea cubeba has the function of protecting the cardiovascular system; has therapeutic effect on gastric diseases such as gastric ulcer and diarrhea, and also has choleretic effect, so that bile secretion is increased remarkably; has certain phlegm eliminating effect, and can prolong the latent period of initial cough; in addition, the cubeb litsea cubeba decoction can inhibit the mouse writhing reaction caused by the potassium antimony tartrate and prolong the thermal pain reaction time; the ether extract can obviously inhibit the writhing reaction of mice caused by acetic acid; the water extract can obviously prolong the latency of the mouse to the response of the heat stimulus.
With the modern fast-paced lifestyle and the increase of social pressure, more and more people have insomnia with different degrees. The sleep quality problem not only affects the daily living state of people, but also increases the risk of suffering from mental diseases along with the deepening of the insomnia degree. Therefore, improving sleep state, improving sleep quality level, and solving a series of sleep disorders become problems to be urgently needed to be solved in modern clinical medicine, and effective improvement of sleep conditions will bring positive social significance. The applicant has conducted an intensive study on whether piper cubeba su can improve sleep.
Disclosure of Invention
An object of the present invention is to solve at least the above problems and/or disadvantages and to provide at least the advantages described hereinafter.
The invention also aims to provide a method for synthesizing the piper longumine.
Still another object of the present invention is to provide the use of cubebin.
Therefore, the technical scheme provided by the invention is as follows:
the synthesis method of the piper longumine comprises the following steps:
1, 3-benzodioxole-5-formaldehyde and malonic acid are used as starting materials to generate 1, 3-benzodioxole-5-propionic acid through oxidation-reduction reaction,
carrying out halogen substitution reaction on 1, 3-benzodioxole-5-propionic acid and oxalyl chloride to generate 1, 3-benzodioxole-5-propionyl chloride, carrying out nucleophilic substitution reaction on the propionyl chloride and (S) -4-benzyl-2-oxazolidinone under the catalysis of n-butyl lithium to generate corresponding amide,
the amide generated at the same time and bromopropyl group generate nucleophilic substitution reaction under the action of ligand bis (trimethylsilyl) amido lithium LiHMDS to generate corresponding olefin, and the corresponding olefin is oxidized in a combined oxidant osmium tetroxide/N-methylmorpholine oxide OsO4The corresponding carbonyl compound is generated through reduction, hydrolysis and oxidation reaction under the catalysis of NMO,
followed by the use of a strong reducing agent lithium aluminium hydride LiAlH4And sodium periodate NaIO as oxidant4The carbonyl compound is subjected to two-step reaction of reduction and oxidation to prepare a corresponding hydroxyl compound,
and selectively oxidizing the hydroxy compound to a lactone compound with a Fetizon reagent,
the lactone compound and 5- (bromomethyl) -1, 3-benzodicyclopentadiene produce substitution reaction under the action of diisopropylamine lithium LDA, and the product is finally reduced with diisobutyl aluminium hydride to obtain the cubebin.
Preferably, in the synthesis method of the piperlongumine, 1, 3-benzodioxole-5-formaldehyde and malonic acid are used as starting materials and react for 1 hour in the presence of a catalyst of 10% of carbon palladium, hydrogen and methanol to generate the 1, 3-benzodioxole-5-propionic acid.
Preferably, in the synthesis method of the piperlongumine, 1, 3-benzodioxole-5-propionic acid and oxalyl chloride are subjected to halogen substitution reaction for 4 hours to generate 1, 3-benzodioxole-5-propionyl chloride, and are subjected to nucleophilic substitution reaction with (S) -4-benzyl-2-oxazolidinone under the catalysis of n-butyl lithium to generate corresponding amide for 17 hours.
Preferably, in the synthesis method of the piperlongumine, the amide and bromopropyl group undergo nucleophilic substitution reaction for 17 hours under the action of ligand bis (trimethylsilyl) amino lithium LiHMDS to generate corresponding olefin, and the corresponding olefin is oxidized by a combined oxidant tetraOsmium oxide/N-methylmorpholine oxide OsO4The reaction is carried out for 3 days under the catalysis of/NMO to generate the corresponding carbonyl compound.
Preferably, in the synthesis method of the piperlongumine, the hydroxyl compound is selectively oxidized into a lactone compound by using a Fetizon reagent, and the lactone compound is obtained by refluxing for 1.5 hours by using toluene.
Preferably, in the synthesis method of the piperlongumine, the reaction time of the substitution reaction of the lactone compound and the 5- (bromomethyl) -1, 3-benzodicyclopentadiene under the action of the diisopropylamine lithium LDA is 23 hours.
The application of the piperlongumine in sedation and hypnosis, or in the preparation of drugs with sedation, hypnosis, anti-depression and/or anti-anxiety functions, or in the preparation of kits with sedation, hypnosis, anti-depression and/or anti-anxiety functions, or in scientific research.
The invention at least comprises the following beneficial effects:
the method can quickly synthesize a large amount of cubebin, has low cost, and has obvious sedative and hypnotic effects from a sedative and hypnotic activity test. Therefore, the preparation method and the application of the cubebin provided by the invention can ensure that the cubebin is applied to sedation and hypnosis, and provide a potential therapeutic drug for sedation and hypnosis.
Additional advantages, objects, and features of the invention will be set forth in part in the description which follows and in part will become apparent to those having ordinary skill in the art upon examination of the following or may be learned from practice of the invention.
Drawings
Fig. 1 is a schematic flow diagram of a synthesis method of piperlongumine of the present invention.
Detailed Description
The present invention is further described in detail below with reference to the attached drawings so that those skilled in the art can implement the invention by referring to the description text.
It will be understood that terms such as "having," "including," and "comprising," as used herein, do not preclude the presence or addition of one or more other elements or groups thereof.
No cubeb fruit or cubebin has been found to have sedative and hypnotic effects. According to the invention, a sufficient amount of cubebin is synthesized by a semi-synthesis method, and a sedative-hypnotic activity test is carried out on the cubebin, and the result shows that the cubebin has an obvious sedative-hypnotic effect.
As shown in fig. 1, the invention provides a method for synthesizing piperlongumine, comprising the following steps:
the synthesis method of the piper longumine comprises the following steps:
1, 3-benzodioxole-5-formaldehyde and malonic acid are used as starting materials to generate 1, 3-benzodioxole-5-propionic acid through oxidation-reduction reaction,
carrying out halogen substitution reaction on 1, 3-benzodioxole-5-propionic acid and oxalyl chloride to generate 1, 3-benzodioxole-5-propionyl chloride, carrying out nucleophilic substitution reaction on the propionyl chloride and (S) -4-benzyl-2-oxazolidinone under the catalysis of n-butyl lithium to generate corresponding amide,
the amide generated at the same time and bromopropyl group generate nucleophilic substitution reaction under the action of ligand bis (trimethylsilyl) amido lithium LiHMDS to generate corresponding olefin, and the corresponding olefin is oxidized in a combined oxidant osmium tetroxide/N-methylmorpholine oxide OsO4The corresponding carbonyl compound is generated through reduction, hydrolysis and oxidation reaction under the catalysis of NMO,
followed by the use of a strong reducing agent lithium aluminium hydride LiAlH4And sodium periodate NaIO as oxidant4The carbonyl compound is subjected to two-step reaction of reduction and oxidation to prepare a corresponding hydroxyl compound,
and selectively oxidizing the hydroxy compound to a lactone compound with a Fetizon reagent,
the lactone compound and 5- (bromomethyl) -1, 3-benzodicyclopentadiene produce substitution reaction under the action of diisopropylamine lithium LDA, and the product is finally reduced with diisobutyl aluminium hydride to obtain the cubebin.
In one embodiment of the present invention, 1, 3-benzodioxole-5-carbaldehyde and malonic acid are preferably reacted in the presence of a catalyst of 10% palladium on carbon, hydrogen and methanol for 1 hour to produce 1, 3-benzodioxole-5-propionic acid.
In one embodiment of the present invention, 1, 3-benzodioxole-5-propionic acid is preferably subjected to a halogen substitution reaction with oxalyl chloride for 4 hours to produce 1, 3-benzodioxole-5-propionyl chloride, and subjected to a nucleophilic substitution reaction with (S) -4-benzyl-2-oxazolidinone under the catalysis of n-butyllithium for 17 hours to produce the corresponding amide.
In one embodiment of the present invention, preferably, the amide is subjected to nucleophilic substitution reaction with bromopropyl under the action of ligand bis (trimethylsilyl) aminolithium LiHMDS for 17 hours to generate corresponding olefin, and the corresponding olefin is subjected to nucleophilic substitution reaction with bromopropyl under the action of a combined oxidant osmium tetroxide/N-methylmorpholine oxide OsO4The reaction is carried out for 3 days under the catalysis of/NMO to generate the corresponding carbonyl compound.
In one embodiment of the present invention, the hydroxyl compound is preferably selectively oxidized to a lactone compound using a Fetizon reagent, and the lactone compound is obtained by refluxing with toluene for 1.5 hours.
In one embodiment of the present invention, the reaction time of the substitution reaction of the lactone compound with 5- (bromomethyl) -1, 3-benzodiocene by lithium diisopropylamide LDA is preferably 23 hours.
The application of the piperlongumine in sedation and hypnosis, or in the preparation of drugs with sedation, hypnosis, anti-depression and/or anti-anxiety functions, or in the preparation of kits with sedation, hypnosis, anti-depression and/or anti-anxiety functions, or in scientific research.
In order to make the technical solution of the present invention better understood by those skilled in the art, the following examples are now provided for illustration:
the method synthesizes the piperlongumine by using a synthesis method, and observes the influence of the piperlongumine on the sleep quality of the mice by using a model which is cooperated with the effect of the sodium pentobarbital subliminal on the sleep of the mice. The results show that compared with a blank control group, the positive medicine group, the high-dosage and medium-dosage piperlongumine group can obviously increase the number of sleeping animals, has statistical significance (p is less than 0.01), and induces mice to sleep to present a dose dependence relationship.
First, experiment purpose
The effect of piperlongumine in combination with sodium pentobarbital threshold on the latency to fall asleep and the duration of sleep in mice was observed.
Second, Experimental materials
Synthesis of piperlongumine:
1, 3-benzodioxole-5-formaldehyde and malonic acid are used as starting materials, 1, 3-benzodioxole-5-propionic acid is generated through simple redox reaction, then halogen displacement reaction is carried out on oxalyl chloride to generate 1, 3-benzodioxole-5-propionyl chloride, nucleophilic substitution reaction is carried out on the propionyl chloride and (S) -4-benzyl-2-oxazolidinone under the catalysis of n-butyl lithium to generate corresponding amide, nucleophilic substitution reaction is carried out on the propionyl chloride and bromopropyl under the action of ligand LiHMDS to generate corresponding olefin, and the combination oxidant OsO4The corresponding product is generated through reduction, hydrolysis and oxidation reaction under the catalysis of/NMO, and then a strong reducing agent LiAlH is used4And oxidant NaIO4The carbonyl compound is reduced and oxidized to prepare a corresponding hydroxyl compound, the hydroxyl compound is selectively oxidized to be lactone by a Fetizon reagent, the lactone and 5- (bromomethyl) -1, 3-benzodicyclopentadiene are subjected to substitution reaction under the action of LDA, and finally a product is reduced by diisobutylaluminum hydride to obtain the product.
1. Experimental animals: kunming mice (KM mice), 110, male and female halves, weight 20-22g, purchased from Schleickzeda laboratory animals Co., Ltd, Hunan, license number: SCXK (Xiang) 2019-.
2. Experimental drugs and reagents: the long pepper solanine, the sodium pentobarbital, the sodium carboxymethylcellulose and the pure water.
Third, Experimental method
1. Sub-threshold dose of pentobarbital sodium was investigated: kunming mice (KM mice) 30 mice, each half of male and female, with a body weight of 20-22g, were divided into 3 groups, namely a sodium pentobarbital high dose group (35mg/kg), a sodium pentobarbital medium dose group (30mg/kg) and a sodium pentobarbital low dose group (25mg/kg), each group consisting of 10 mice. Mice were dosed by intraperitoneal injection according to the above doses, and the number of sleeping animals was recorded (sleep was indicated by disappearance of righting reflex for 1 min). The maximum dose at which 90% to 100% of the mice do not disappear from orthotropic reflex was chosen as the subthreshold dose.
2. Grouping experimental animals: 80 animals were randomly divided into 8 groups, each group consisting of a blank group, a positive group (diazepam tablets 2mg/kg), a high, medium and low dose group (100mg/kg,50mg/kg,25mg/kg) of piperlongumine, and 10 animals per group.
3. The administration method comprises the following steps: each drug was formulated as a suspension in 0.5% CMC-Na solution, and all animals were gavaged at a volume of 10ml/kg, and the blank group was given an equal volume of 0.5% CMC-Na solution.
4. The experimental method comprises the following steps: and (3) after the mice are administrated for 30min, injecting the pentobarbital sodium with subthreshold dose searched by the experiment into the abdominal cavity, wherein the administration volume is 10ml/kg, observing the mice, recording the occurrence of sleep when the righting reflex disappears for more than 1min, and recording the number of the mice falling asleep within 30 min.
Fourth, experimental results
As shown in Table 1, compared with the blank control group, the positive drug group, ZCX-1 high dose group, ZCX-2 high and medium dose groups all can significantly increase the number of sleeping animals, and have statistical significance (p is less than 0.01). zcx-2 induced mice to fall asleep and presented a dose dependent relationship.
TABLE 1 Effect of Piper longumine on subthreshold dose induced sleep in mice
Note: p <0.01 in comparison with blank
Fifth, experiment summary
The experimental result shows that the sleeping rate of the mice can be obviously increased by the cooperation of the piperlongumine and the subthreshold dose of the sodium pentobarbital, the efficacy is equivalent to that of a positive control, and the dose dependence is presented.
The scale of the processing described herein is intended to simplify the description of the invention. Modifications and variations to the methods of making and using the piperlongumine of the present invention will be apparent to those skilled in the art.
While embodiments of the invention have been described above, it is not limited to the applications set forth in the description and the embodiments, which are fully applicable in various fields of endeavor to which the invention pertains, and further modifications may readily be made by those skilled in the art, it being understood that the invention is not limited to the details shown and described herein without departing from the general concept defined by the appended claims and their equivalents.
Claims (7)
1. The synthesis method of the piper longumine is characterized by comprising the following steps:
1, 3-benzodioxole-5-formaldehyde and malonic acid are used as starting materials to generate 1, 3-benzodioxole-5-propionic acid through oxidation-reduction reaction,
carrying out halogen substitution reaction on 1, 3-benzodioxole-5-propionic acid and oxalyl chloride to generate 1, 3-benzodioxole-5-propionyl chloride, carrying out nucleophilic substitution reaction on the propionyl chloride and (S) -4-benzyl-2-oxazolidinone under the catalysis of n-butyl lithium to generate corresponding amide,
the amide generated at the same time and bromopropyl group generate nucleophilic substitution reaction under the action of ligand bis (trimethylsilyl) amido lithium LiHMDS to generate corresponding olefin, and the corresponding olefin is oxidized in a combined oxidant osmium tetroxide/N-methylmorpholine oxide OsO4The corresponding carbonyl compound is generated through reduction, hydrolysis and oxidation reaction under the catalysis of NMO,
followed by the use of a strong reducing agent lithium aluminium hydride LiAlH4And sodium periodate NaIO as oxidant4The carbonyl compound is subjected to two-step reaction of reduction and oxidation to prepare a corresponding hydroxyl compound,
and selectively oxidizing the hydroxy compound to a lactone compound with a Fetizon reagent,
the lactone compound and 5- (bromomethyl) -1, 3-benzodicyclopentadiene produce substitution reaction under the action of diisopropylamine lithium LDA, and the product is finally reduced with diisobutyl aluminium hydride to obtain the cubebin.
2. The method for synthesizing piperlongumine of claim 1 wherein 1, 3-benzodioxole-5-formaldehyde and malonic acid are used as starting materials and react for 1 hour in the presence of catalyst 10% palladium carbon, hydrogen and methanol to produce 1, 3-benzodioxole-5-propionic acid.
3. The method for synthesizing piperlongumine of claim 1 wherein 1, 3-benzodioxole-5-propanoic acid and oxalyl chloride are subjected to halogen substitution reaction for 4 hours to generate 1, 3-benzodioxole-5-propanoyl chloride, and are subjected to nucleophilic substitution reaction with (S) -4-benzyl-2-oxazolidinone under the catalysis of n-butyl lithium to generate corresponding amide.
4. The method for synthesizing piperlongumine of claim 1 wherein the amide undergoes nucleophilic substitution reaction with bromopropyl under the action of ligand bis (trimethylsilyl) amino lithium LiHMDS for 17 hours to form corresponding olefin, and the corresponding olefin is oxidized in the presence of osmium tetroxide/N-methylmorpholine oxide OsO as combined oxidant4The reaction is carried out for 3 days under the catalysis of/NMO to generate the corresponding carbonyl compound.
5. The method of synthesizing piperlongumine of claim 1 wherein the lactone compound is obtained by selectively oxidizing the hydroxy compound to a lactone compound using Fetizon reagent and refluxing with toluene for 1.5 hours.
6. The method for synthesizing piperlongumine of claim 1 wherein the reaction time of substitution reaction between the lactone compound and 5- (bromomethyl) -1, 3-benzodicyclopentadiene under the action of lithium diisopropylamide LDA is 23 hours.
7. The application of the piperlongumine in sedation and hypnosis, or in the preparation of drugs with sedation, hypnosis, anti-depression and/or anti-anxiety functions, or in the preparation of kits with sedation, hypnosis, anti-depression and/or anti-anxiety functions, or in scientific research.
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| US20080194678A1 (en) * | 2005-07-15 | 2008-08-14 | Fundacao De Amparo A Pesquissa Do Estado De Aao Pa | Process To Obtain Synthetic And Semi-Synthetic Lignan Derivatives, Their Antiparasitic Activities And Corresponding Pharmaceutical Formulations, Including The Therapeutic Method Using Said Lignan For The Treatment Of Parasitosis |
| US20080214661A1 (en) * | 2005-04-28 | 2008-09-04 | Fundacado De Amparo A Pesquisa Do Estado De Sao Paulo | Process To Obtain Dibenzylbutyrolactonic, Tetrahydrofuranic Lignans And Their Synthetic And Semi-Synthetic Derivatives, Their Analgesic And Anti-Inflammatory Activities, Topical And/Or Systemic Formulations Containing Said Lignans And Their Respective Therapeutic Method |
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| US20080214661A1 (en) * | 2005-04-28 | 2008-09-04 | Fundacado De Amparo A Pesquisa Do Estado De Sao Paulo | Process To Obtain Dibenzylbutyrolactonic, Tetrahydrofuranic Lignans And Their Synthetic And Semi-Synthetic Derivatives, Their Analgesic And Anti-Inflammatory Activities, Topical And/Or Systemic Formulations Containing Said Lignans And Their Respective Therapeutic Method |
| US20080194678A1 (en) * | 2005-07-15 | 2008-08-14 | Fundacao De Amparo A Pesquissa Do Estado De Aao Pa | Process To Obtain Synthetic And Semi-Synthetic Lignan Derivatives, Their Antiparasitic Activities And Corresponding Pharmaceutical Formulations, Including The Therapeutic Method Using Said Lignan For The Treatment Of Parasitosis |
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