CN101575311A - Method for preparing epiphysin - Google Patents
Method for preparing epiphysin Download PDFInfo
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- CN101575311A CN101575311A CNA2009100333969A CN200910033396A CN101575311A CN 101575311 A CN101575311 A CN 101575311A CN A2009100333969 A CNA2009100333969 A CN A2009100333969A CN 200910033396 A CN200910033396 A CN 200910033396A CN 101575311 A CN101575311 A CN 101575311A
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- 238000000034 method Methods 0.000 title claims abstract description 20
- 238000006243 chemical reaction Methods 0.000 claims abstract description 46
- 239000002994 raw material Substances 0.000 claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims description 49
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 45
- DRLFMBDRBRZALE-UHFFFAOYSA-N melatonin Chemical compound COC1=CC=C2NC=C(CCNC(C)=O)C2=C1 DRLFMBDRBRZALE-UHFFFAOYSA-N 0.000 claims description 32
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 30
- YJPIGAIKUZMOQA-UHFFFAOYSA-N Melatonin Natural products COC1=CC=C2N(C(C)=O)C=C(CCN)C2=C1 YJPIGAIKUZMOQA-UHFFFAOYSA-N 0.000 claims description 26
- 229960003987 melatonin Drugs 0.000 claims description 25
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 claims description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 22
- 239000003153 chemical reaction reagent Substances 0.000 claims description 18
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 17
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 11
- 229960003692 gamma aminobutyric acid Drugs 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 7
- 239000003810 Jones reagent Substances 0.000 claims description 6
- 230000021736 acetylation Effects 0.000 claims description 5
- 238000006640 acetylation reaction Methods 0.000 claims description 5
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims description 5
- 239000007810 chemical reaction solvent Substances 0.000 claims description 5
- 238000006646 Dess-Martin oxidation reaction Methods 0.000 claims description 4
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 claims description 4
- 229910000085 borane Inorganic materials 0.000 claims description 3
- 239000011259 mixed solution Substances 0.000 claims description 3
- AGBWAVXRUQFCEX-UHFFFAOYSA-N NN.C1(=CC=CC=C1)OC Chemical compound NN.C1(=CC=CC=C1)OC AGBWAVXRUQFCEX-UHFFFAOYSA-N 0.000 claims description 2
- 239000003638 chemical reducing agent Substances 0.000 claims description 2
- 150000004678 hydrides Chemical class 0.000 claims description 2
- 230000022244 formylation Effects 0.000 claims 1
- 238000006170 formylation reaction Methods 0.000 claims 1
- 125000003944 tolyl group Chemical group 0.000 claims 1
- 150000002475 indoles Chemical class 0.000 abstract description 2
- 229930195212 Fischerindole Natural products 0.000 abstract 1
- 230000006229 amino acid addition Effects 0.000 abstract 1
- 229940054051 antipsychotic indole derivative Drugs 0.000 abstract 1
- 230000032050 esterification Effects 0.000 abstract 1
- 238000005886 esterification reaction Methods 0.000 abstract 1
- 150000002148 esters Chemical class 0.000 abstract 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract 1
- 230000003647 oxidation Effects 0.000 abstract 1
- 238000007254 oxidation reaction Methods 0.000 abstract 1
- 238000007363 ring formation reaction Methods 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 28
- 239000007788 liquid Substances 0.000 description 25
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
- -1 tetracol phenixin Chemical compound 0.000 description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- 238000003756 stirring Methods 0.000 description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- 230000002829 reductive effect Effects 0.000 description 13
- 238000001035 drying Methods 0.000 description 12
- WPGPRLVPWACBHW-UHFFFAOYSA-N (4-methoxy-4-oxobutyl)azanium;chloride Chemical compound Cl.COC(=O)CCCN WPGPRLVPWACBHW-UHFFFAOYSA-N 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- PWLNAUNEAKQYLH-UHFFFAOYSA-N butyric acid octyl ester Natural products CCCCCCCCOC(=O)CCC PWLNAUNEAKQYLH-UHFFFAOYSA-N 0.000 description 10
- ZTQSAGDEMFDKMZ-UHFFFAOYSA-N butyric aldehyde Natural products CCCC=O ZTQSAGDEMFDKMZ-UHFFFAOYSA-N 0.000 description 10
- 229960000935 dehydrated alcohol Drugs 0.000 description 10
- 239000005457 ice water Substances 0.000 description 10
- UUIQMZJEGPQKFD-UHFFFAOYSA-N n-butyric acid methyl ester Natural products CCCC(=O)OC UUIQMZJEGPQKFD-UHFFFAOYSA-N 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- HGBOYTHUEUWSSQ-UHFFFAOYSA-N valeric aldehyde Natural products CCCCC=O HGBOYTHUEUWSSQ-UHFFFAOYSA-N 0.000 description 10
- 238000005481 NMR spectroscopy Methods 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 7
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 7
- 239000012280 lithium aluminium hydride Substances 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 7
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 6
- 239000012346 acetyl chloride Substances 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 230000006837 decompression Effects 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 238000012544 monitoring process Methods 0.000 description 5
- OLKOIWQNCSVBCU-UHFFFAOYSA-N n-(4-hydroxybutyl)acetamide Chemical class CC(=O)NCCCCO OLKOIWQNCSVBCU-UHFFFAOYSA-N 0.000 description 5
- HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 description 5
- 229940067157 phenylhydrazine Drugs 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 238000001953 recrystallisation Methods 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229960001866 silicon dioxide Drugs 0.000 description 5
- 159000000000 sodium salts Chemical class 0.000 description 5
- 230000002459 sustained effect Effects 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 229910052783 alkali metal Inorganic materials 0.000 description 4
- 229940117975 chromium trioxide Drugs 0.000 description 4
- WGLPBDUCMAPZCE-UHFFFAOYSA-N chromium trioxide Inorganic materials O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 4
- GAMDZJFZMJECOS-UHFFFAOYSA-N chromium(6+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[Cr+6] GAMDZJFZMJECOS-UHFFFAOYSA-N 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 125000001041 indolyl group Chemical group 0.000 description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- 235000002639 sodium chloride Nutrition 0.000 description 3
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 235000017550 sodium carbonate Nutrition 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 1
- 238000006783 Fischer indole synthesis reaction Methods 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 230000002060 circadian Effects 0.000 description 1
- 230000000536 complexating effect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 229960004756 ethanol Drugs 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 230000036737 immune function Effects 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 150000002497 iodine compounds Chemical class 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 238000005502 peroxidation Methods 0.000 description 1
- 210000004560 pineal gland Anatomy 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 230000033764 rhythmic process Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 230000036299 sexual function Effects 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
Images
Abstract
The invention discloses a novel method for preparing epiphysin, which uses low-cost 4-propalanine as a raw material to prepare the epiphysin through steps of carboxylic esterification, amino acylation, ester reduction, hydroxyl oxidation, fischer indole cyclization and the like. The method for preparing the epiphysin uses the raw material of the 4-propalanine which has wide sources and low cost; besides, the method has high total yield and simple reaction conditions and reaction processes, avoids using expensive indole derivatives as initial raw materials in the previous documents, and provides a new choice for preparing and producing the epiphysin.
Description
Technical field
The present invention relates to a kind of preparation method of medicine, be specifically related to a kind of method for preparing melatonin.
Background technology
Melatonin is a kind of indoles hormone that the secretion of human brain pineal gland produces, its main acting body is safeguarded the circadian diel rhythm of human body self now, help sleep, it has the enhancing immune function of human body, suppress the growth of tumour cell, melatonin also may have restraining effect to central nervous system; Be a kind of than the more effective peroxidation base of vitamin-E scavenging agent, it plays regulating effect to production growth, sexual function and many organs in addition.
Its chemistry is by name: N-ethanoyl-5-methoxytryptamine
English by name: N-Acetyl-5-Methoxytryptamine
Molecular formula: C
13H
16N
2O
2
Molecular weight: 232.27
Outward appearance: white powder
About the preparation method of melatonin, existing bibliographical information: EP 0330625 A2, J.Am.Chem.Soc.1959,81:8084, J.Org.Chem.1960,25:857 etc.Be raw material with expensive indole ring derivative all in above-mentioned bibliographical information, the Lithium Aluminium Hydride of inevitably having used again simultaneously is as reductive agent, and the suitability for industrialized production that this has just limited melatonin greatly influenced its popularization.
The 4-aminobutyric acid that our use cost is cheap in this patent is a raw material, made up indole ring by the Fischer indole synthesis, per step reaction raw materials all is simple and easy to, the yield height, and avoided shortcomings such as the more expensive raw material such as Lithium Aluminium Hydride reductive agent, indole ring derivative of patent before this or bibliographical information and purification inconvenience.For the preparation and the production of melatonin provides new selection.
Summary of the invention:
Goal of the invention: the objective of the invention is provides a kind of starting raw material low price in order to solve the deficiencies in the prior art, and reaction is simple, the novel method of the preparation melatonin that productive rate is high.
Technical scheme: in order to realize above purpose, the method for preparing melatonin provided by the invention comprises the steps:
(1) with 4-aminobutyric acid (I) be raw material in the presence of methyl alcohol and thionyl chloride, reaction obtains compound (II); Wherein the amount ranges of thionyl chloride is: the 2-6 equivalent;
(2) get the compound (II) that step (1) obtains and in the presence of alkaline reagents, obtain compound (III) with the acetylation reagent reaction;
(3) compound (III) also can be by being obtained in the presence of methyl alcohol and thionyl chloride by compound (IV); Wherein the amount ranges of thionyl chloride is: the 2-6 equivalent;
(4) in the presence of alkaline reagents, obtain compound (IV) for raw material by 4-aminobutyric acid (I) with the acetylation reagent reaction;
(5) get the compound (III) and borane reducing agent hydride reaction that step (2) obtains, obtain compound (V);
(6) get compound (V) that step (5) obtains in the presence of Jones reagent or Sha Ruite reagent or Dess-martin oxygenant, obtain compound (VI);
(7) get compound (VI) that step (6) obtains with to the anisole hydrazine reaction, methyl alcohol and water mixed solution obtain compound (VII) as solvent, promptly obtain melatonin;
The method for preparing melatonin provided by the invention, wherein the amount of the used thionyl chloride of step (1) is the 2-6 equivalent.Wherein step (1) reaction solvent is a methyl alcohol, and temperature of reaction can be 10 ℃-25 ℃ as preferable reaction temperature at-10 ℃-30 ℃, and the reaction times is as the criterion to react completely, and can be 30 minutes to 24 hours.
The method for preparing melatonin provided by the invention, wherein the used alkaline reagents of step (2) is one of following reagent: alkali-metal carbonate, as salt of wormwood, yellow soda ash; Alkali-metal supercarbonate is as saleratus, sodium bicarbonate; Alkali-metal oxyhydroxide is as the organic bases of sodium hydroxide, potassium hydroxide or Ammonia, as triethylamine, pyridine, as preferably being sodium bicarbonate or yellow soda ash; Used acetylation reagent is preferably: Acetyl Chloride 98Min., diacetyl oxide.Wherein step (2) reaction solvent can be acetone, butanone, tetrahydrofuran (THF), dioxane, methyl tertiary butyl ether, amides, N, dinethylformamide, N,N-dimethylacetamide; The mixed solvent of methylene dichloride, ethylene dichloride, chloroform, tetracol phenixin, benzene, toluene or multiple above-mentioned organic solvent.The temperature of step (2) reaction can be 0 ℃-25 ℃ as preferable reaction temperature between 0 ℃-60 ℃, and the reaction times is as the criterion to react completely, and can be 1 hour to 10 hours.
The method for preparing melatonin provided by the invention, the wherein same step of step (3) (1).
The method for preparing melatonin provided by the invention, the wherein same step of step (4) (2)
The method for preparing melatonin provided by the invention, wherein step (5) used hydroborate can be an alkali metal salt of hydroborate, as sodium borohydride, POTASSIUM BOROHYDRIDE, sodium cyanoborohydride; An alkali metal salt of hydroborate and lewis acidic mixed system are as the system of sodium borohydride and iodine; Organo-borane as diborane or organosilicon reagent, as triethyl silicon hydrogen, triphenyl silicon hydrogen, is sodium borohydride or POTASSIUM BOROHYDRIDE as preferred alkaline reagents.Wherein step (5) reaction solvent can be methyl alcohol, ethanol, tetrahydrofuran (THF), ether.The temperature of step (5) reaction is 0 ℃-100 ℃, and as being preferably 30 ℃-100 ℃, the reaction times is as the criterion to react completely, and can be 30 minutes to 10 hours.
The method for preparing melatonin provided by the invention, wherein the used Jones reagent of step (6) is the aqueous solution that chromium trioxide, sulfuric acid and water are made into; Used Sha Ruite reagent is pyridine and the complexing salt of chromium trioxide in hydrochloric acid soln; Used Dess-martin oxygenant is the high price iodine compound.Wherein step (2) reaction solvent can be acetone, butanone, tetrahydrofuran (THF), dioxane, methyl tertiary butyl ether, amides, N, dinethylformamide, N,N-dimethylacetamide; The mixed solvent of methylene dichloride, ethylene dichloride, chloroform, tetracol phenixin, benzene, toluene or multiple above-mentioned organic solvent.The temperature of step (2) reaction can be 20 ℃-60 ℃ as preferable reaction temperature between 0 ℃-60 ℃, and the reaction times is as the criterion to react completely, and can be 1 hour to 15 hours.
Beneficial effect: the method for preparing left side melatonin provided by the invention compared with prior art has the following advantages:
1, the used initial raw material of the present invention is the 4-aminobutyric acid, and raw material sources are wide, and are cheap.
2, the method total recovery height for preparing melatonin provided by the invention, the required condition of reaction and reaction process simple, reduced cost, simplified existing technology, for the preparation and the production of melatonin provides new selection.
Description of drawings
Accompanying drawing prepares the schema of melatonin for the present invention.
Embodiment:
Below in conjunction with specific embodiment, further illustrate the present invention, should understand these embodiment only is used to the present invention is described and is not used in and limit the scope of the invention, after having read the present invention, those skilled in the art all fall within the application's claims institute restricted portion to the modification of the various equivalent form of values of the present invention.
Embodiment 1
(1) compound (II) is the synthetic of 4-aminobutyric acid methyl ester hydrochloride
Get 4-aminobutyric acid 10.3g, be dissolved in the 150ml anhydrous methanol, be cooled to 0-5 ℃ with ice-water bath, slowly drip thionyl chloride (8ml), drip off half an hour.React 72h under the room temperature.Decompression is steamed and is slipped when being left the 20ml solvent, adds anhydrous diethyl ether 60ml.Stir half an hour, filter white solid, behind the drying under reduced pressure white crystal 13.6g, productive rate 89%.MS：m/z＝118(M+1)；
1H?NMR(D
2O)：1.7-1.8(2H，CH
2CH
2CH
2)，2.34-2.39(2H，CH
2CH
2CO)，3.12-3.16(2H，NH
2CH
2)，3.64(3H，OCH
3)。
(2) compound (III) is the synthetic of N-ethanoyl methyl-butyrate
Get 4-aminobutyric acid methyl ester hydrochloride (15.3g), be dissolved in the 500ml methylene dichloride, add anhydrous sodium carbonate 80g, stir 0.5h, be cooled to 0-5 ℃, slowly drip the 9ml Acetyl Chloride 98Min., stirred 3 hours down at 5 ℃-10 ℃ with ice-water bath.Cross the sodium salt of filtrable volume, concentrating under reduced pressure obtains water white transparency thick liquid 14.6g, productive rate 92%.MS：m/z＝160(M+1)；
1HNMR(DMSO)：1.6-1.7(2H，CH
2CH
2CH
2)，1.84(3H，CH
3CO)，2.30-2.34(2H，CH
2CO)，3.03-3.07(2H，NHCH
2)，3.59(3H，OCH
3)，8.2(1H，NH)。
(3) compound (V) is the synthetic of 4-acetylamino butanols
Get N-ethanoyl methyl-butyrate (15.9g), be dissolved in the 200ml dehydrated alcohol, repeatedly add the 4.94g lithium aluminum hydride in batches, added in 45 minutes, 25 ℃ were stirred 4.5 hours down.The slowly Dropwise 5 ml shrend reaction of going out, the tetrahydrofuran (THF) extraction, saturated common salt water washing three times, the anhydrous magnesium sulfate drying organic layer filters, and obtains water white liquid 10.6g, productive rate 81% after filtrate is concentrated.MS：m/z＝132(M+1)；
1H?NMR(D
2O)：1.445(4H，CH
2CH
2)，1.87(3H，CH
3CO)，3.07(2H，NHCH
2)，3.5(2H，CH
2OH)，3.64(1H，OH)，7.94(1H，NHCO)。
(4) compound (VI) is the synthetic of N-ethanoyl butyraldehyde
Get 28.0gPCC, be dissolved in the 150ml methylene dichloride, slowly drip the dichloromethane solution 100ml that contains 13.1g N-ethanoyl butanols, react 2h under the room temperature, TLC monitoring reaction process.Reaction solution leaves standstill 0.5h, and upper strata liquid is crossed silicagel column, and concentrated methylene chloride solution obtains yellow liquid 9.29g, productive rate 72%.
(5) compound (VII) is the synthetic of N-ethanoyl-5-methoxytryptamine
Get N-ethanoyl butyraldehyde 6.45g, be dissolved in the 80ml dehydrated alcohol, get, be dissolved among the 40ml 2N HCl, under stirring ethanolic soln slowly is added drop-wise in the hydrochloric acid soln, keep reacting liquid temperature at 20 ℃-30 ℃, sustained reaction 3 hours methoxyl group phenylhydrazine 6.9g.Filter, obtain pale brown look solid.Use the acetone-water recrystallization, obtain white powder 4.6g, productive rate 40%.Mp：117.2-117.9℃；MS：233(M+1)，174；
1H?NMR：1.93(s，3H，CH
3)，2.94(t，2H，CH
2CH
2NH)，3.59(dd，2H，CH
2CH
2NH)，3.86(s，3H，OCH
3)，5.58(s，1H，NH)，6.86-7.26(m，4H，Ph-H&Indol-H)，8.02(s，1H，Indol-NH)。
Embodiment 2
(1) compound (II) is the synthetic of 4-aminobutyric acid methyl ester hydrochloride
Get 4-aminobutyric acid 10.3g, be dissolved in the 150ml anhydrous methanol, be cooled to 0-5 ℃, slowly drip thionyl chloride (8ml), dripped off in one hour with ice-water bath.React 54h under the room temperature.Decompression is steamed and is slipped when being left the 20ml solvent, adds anhydrous diethyl ether 60ml.Stir 0.5h, filter white solid, behind the drying under reduced pressure white crystal 11.5g, productive rate 75%.MS：m/z＝118(M+1)；
1H?NMR(D
2O)：1.7-1.8(2H，CH
2CH
2CH
2)，2.34-2.39(2H，CH
2CH
2CO)，3.12-3.16(2H，NH
2CH
2)，3.64(3H，OCH
3)。
(2) compound (III) is the synthetic of N-ethanoyl methyl-butyrate
Get 4-aminobutyric acid methyl ester hydrochloride 15.3g, be dissolved in the 500ml methylene dichloride, add anhydrous sodium carbonate 80g, stir 0.5h, be cooled to 0-5 ℃, slowly drip the 9ml Acetyl Chloride 98Min., stirred 3 hours down at 10 ℃-15 ℃ with ice-water bath.Cross the sodium salt of filtrable volume, concentrating under reduced pressure obtains water white transparency thick liquid 11.9g, productive rate 75%.MS：m/z＝160(M+1)；
1H?NMR(DMSO)：1.6-1.7(2H，CH
2CH
2CH
2)，1.84(3H，CH
3CO)，2.30-2.34(2H，CH
2CO)，3.03-3.07(2H，NHCH
2)，3.59(3H，OCH
3)，8.2(1H，NH)。
(3) compound (V) is the synthetic of 4-acetylamino butanols
Get N-ethanoyl methyl-butyrate 15.9g, be dissolved in the 200ml dehydrated alcohol, repeatedly add the 3.6g lithium aluminum hydride in batches, added in 45 minutes, 25 ℃ were stirred 4.5 hours down.The slowly Dropwise 5 ml shrend reaction of going out, the tetrahydrofuran (THF) extraction, saturated common salt water washing three times, the anhydrous magnesium sulfate drying organic layer filters, and obtains water white liquid 9.7g, productive rate 74% after filtrate is concentrated.MS：m/z＝132(M+1)；
1HNMR(D
2O)：1.445(4H，CH
2CH
2)，1.87(3H，CH
3CO)，3.07(2H，NHCH
2)，3.5(2H，CH
2OH)，3.64(1H，OH)，7.94(1H，NHCO)。
(4) compound (VI) is the synthetic of N-ethanoyl butyraldehyde
Get 32gPCC, be dissolved in the 150ml methylene dichloride, slowly drip the dichloromethane solution 100ml that contains 13.1gN-ethanoyl butanols, react 2h under the room temperature, TLC monitoring reaction process.Reaction solution leaves standstill 0.5h, and upper strata liquid is crossed silicagel column, and concentrated methylene chloride solution obtains yellow liquid 9.54g, productive rate 74%.
(5) compound (VII) is the synthetic of N-ethanoyl-5-methoxytryptamine
Get N-ethanoyl butyraldehyde 6.45g, be dissolved in the 70ml dehydrated alcohol, get, be dissolved among the 40ml 2N HCl, under stirring ethanolic soln slowly is added drop-wise in the hydrochloric acid soln, keep reacting liquid temperature at 20 ℃-30 ℃, sustained reaction 3 hours methoxyl group phenylhydrazine 6.9g.Filter, obtain pale brown look solid.Use the acetone-water recrystallization, obtain white powder 4.95g, productive rate 43%.Mp：117.2-117.9℃；MS：233(M+1)，174；
1HNMR：1.93(s，3H，CH
3)，2.94(t，2H，CH
2CH
2NH)，3.59(dd，2H，CH
2CH
2NH)，3.86(s，3H，OCH
3)，5.58(s，1H，NH)，6.86-7.26(m，4H，Ph-H&Indol-H)，8.02(s，1H，Indol-NH)。
Embodiment 3
(1) compound (II) is the synthetic of 4-aminobutyric acid methyl ester hydrochloride
Get 4-aminobutyric acid 10.3g, be dissolved in the 150ml anhydrous methanol, be cooled to 5-10 ℃ with ice-water bath, slowly drip thionyl chloride (6ml), drip off half an hour.React 24h under the room temperature.Decompression is steamed and is slipped when being left the 20ml solvent, adds anhydrous diethyl ether 60ml.Stir 0.5h, filter white solid, behind the drying under reduced pressure white crystal 9.8g, productive rate 62%.MS：m/z＝118(M+1)；
1H?NMR(D
2O)：1.7-1.8(2H，CH
2CH
2CH
2)，2.34-2.39(2H，CH
2CH
2CO)，3.12-3.16(2H，NH
2CH
2)，3.64(3H，OCH
3)。
(2) compound (III) is the synthetic of N-ethanoyl methyl-butyrate
Get 4-aminobutyric acid methyl ester hydrochloride (15.3g), be dissolved in the 500ml methylene dichloride, add anhydrous sodium carbonate 80g, stir 0.5h, be cooled to 0-5 ℃, slowly drip the 9ml Acetyl Chloride 98Min., stirred 9 hours down at 0 ℃-5 ℃ with ice-water bath.Cross the sodium salt of filtrable volume, concentrating under reduced pressure obtains water white transparency thick liquid 12.8g, productive rate 81%.MS：m/z＝160(M+1)；
1H?NMR(DMSO)：1.6-1.7(2H，CH
2CH
2CH
2)，1.84(3H，CH
3CO)，2.30-2.34(2H，CH
2CO)，3.03-3.07(2H，NHCH
2)，3.59(3H，OCH
3)，8.2(1H，NH)。
(3) compound (V) is the synthetic of 4-acetylamino butanols
Get N-ethanoyl methyl-butyrate (15.9g), be dissolved in the 200ml dehydrated alcohol, repeatedly add the 4.94g lithium aluminum hydride in batches, added in 45 minutes, 40 ℃ were stirred 4.5 hours down.The slowly Dropwise 5 ml shrend reaction of going out, the tetrahydrofuran (THF) extraction, saturated common salt water washing three times, the anhydrous magnesium sulfate drying organic layer filters, and obtains water white liquid 11.4g, productive rate 87% after filtrate is concentrated.MS：m/z＝132(M+1)；HNMR(D
2O)：1.445(4H，CH
2CH
2)，1.87(3H，CH
3CO)，3.07(2H，NHCH
2)，3.5(2H，CH
2OH)，3.64(1H，OH)，7.94(1H，NHCO)。
(4) compound (VI) is the synthetic of N-ethanoyl butyraldehyde
The 26.72g chromium trioxide is dissolved in the 23ml vitriol oil, is diluted to 100ml with water then and promptly gets Jones reagent.Under ice bath, slowly join the 100ml acetone soln of 13.1gN-ethanoyl butanols, react 2h under the room temperature, TLC monitoring reaction process.Reaction solution leaves standstill 0.5h, and upper strata liquid is crossed silicagel column, and anhydrous magnesium sulfate drying acetone concentrates organic layer, obtains yellow liquid 10.32g, productive rate 80%.
(5) compound (VII) is the synthetic of N-ethanoyl-5-methoxytryptamine
Get N-ethanoyl butyraldehyde 6.45g, be dissolved in the 80ml dehydrated alcohol, get, be dissolved among the 40ml 2N HCl, under stirring ethanolic soln slowly is added drop-wise in the hydrochloric acid soln, keep reacting liquid temperature at 20 ℃-30 ℃, sustained reaction 3 hours methoxyl group phenylhydrazine 6.9g.Filter, obtain pale brown look solid.Use the benzene recrystallization, obtain white powder 5.75g, productive rate 50%.Mp：117.2-117.9℃；MS：233(M+1)，174；
1HNMR：1.93(s，3H，CH
3)，2.94(t，2H，CH
2CH
2NH)，3.59(dd，2H，CH
2CH
2NH)，3.86(s，3H，OCH
3)，5.58(s，1H，NH)，6.86-7.26(m，4H，Ph-H&Indol-H)，8.02(s，1H，Indol-NH)。
Embodiment 4
(1) compound (II) is the synthetic of 4-aminobutyric acid methyl ester hydrochloride
Get 4-aminobutyric acid 10.3g, be dissolved in the 150ml anhydrous methanol, be cooled to 0-5 ℃, slowly drip thionyl chloride (8ml), dripped off in one hour with ice-water bath.React 84h under the room temperature.Decompression is steamed and is slipped when being left the 20ml solvent, adds anhydrous diethyl ether 60ml.Stir 0.5h, filter white solid, behind the drying under reduced pressure white crystal 14.6g, productive rate 95%.MS：m/z＝118(M+1)；
1H?NMR(D
2O)：1.7-1.8(2H，CH
2CH
2CH
2)，2.34-2.39(2H，CH
2CH
2CO)，3.12-3.16(2H，NH
2CH
2)，3.64(3H，OCH
3)。
(2) compound (III) is the synthetic of N-ethanoyl methyl-butyrate
Get 4-aminobutyric acid methyl ester hydrochloride (15.3g), be dissolved in the 500ml methylene dichloride, add Anhydrous potassium carbonate 85g, stir half an hour, be cooled to 0-5 ℃, slowly drip the 9ml Acetyl Chloride 98Min., stirred 3 hours down at 5 ℃-10 ℃ with ice-water bath.Cross the sodium salt of filtrable volume, concentrating under reduced pressure obtains water white transparency thick liquid 15.1g, productive rate 95%.MS：m/z＝160(M+1)；
1HNMR(DMSO)：1.6-1.7(2H，CH
2CH
2CH
2)，1.84(3H，CH
3CO)，2.30-2.34(2H，CH
2CO)，3.03-3.07(2H，NHCH
2)，3.59(3H，OCH
3)，8.2(1H，NH)。
(3) compound (V) is the synthetic of 4-acetylamino butanols
Get N-ethanoyl methyl-butyrate (15.9g), be dissolved in the 200ml dehydrated alcohol, repeatedly add the 4.94g lithium aluminum hydride in batches, added in 45 minutes, 25 ℃ were stirred 2 hours down.The slowly Dropwise 5 ml shrend reaction of going out, the tetrahydrofuran (THF) extraction, saturated common salt water washing three times, the anhydrous magnesium sulfate drying organic layer filters, and obtains water white liquid 8.5g, productive rate 65% after filtrate is concentrated.MS：m/z＝132(M+1)；
1HNMR(D
2O)：1.445(4H，CH
2CH
2)，1.87(3H，CH
3CO)，3.07(2H，NHCH
2)，3.5(2H，CH
2OH)，3.64(1H，OH)，7.94(1H，NHCO)。
(4) compound (VI) is the synthetic of N-ethanoyl butyraldehyde
The 26.72g chromium trioxide is dissolved in the 23ml vitriol oil, is diluted to 100ml with water then and promptly gets Jones reagent.Under ice bath, slowly join the 100ml acetone soln of 13.1gN-ethanoyl butanols, react 4h under the room temperature, TLC monitoring reaction process.Reaction solution leaves standstill 0.5h, and upper strata liquid is crossed silicagel column, and anhydrous magnesium sulfate drying acetone concentrates organic layer, obtains yellow liquid 10.96g, productive rate 85%.
(5) compound (VII) is the synthetic of N-ethanoyl-5-methoxytryptamine
Get N-ethanoyl butyraldehyde 6.45g, be dissolved in the 80ml dehydrated alcohol, get, be dissolved among the 40ml3N HCl, under stirring ethanolic soln slowly is added drop-wise in the hydrochloric acid soln, keep reacting liquid temperature at 20 ℃-30 ℃, sustained reaction 3 hours methoxyl group phenylhydrazine 6.9g.Filter, obtain pale brown look solid.Use the acetone-water recrystallization, obtain white powder 3.68g, productive rate 32%.Mp：117.2-117.9℃；MS：233(M+1)，174；
1HNMR：1.93(s，3H，CH
3)，2.94(t，2H，CH
2CH
2NH)，3.59(dd，2H，CH
2CH
2NH)，3.86(s，3H，OCH
3)，5.58(s，1H，NH)，6.86-7.26(m，4H，Ph-H&Indol-H)，8.02(s，1H，Indol-NH)
Embodiment 5
(1) compound (II) is the synthetic of 4-aminobutyric acid methyl ester hydrochloride
Get 4-aminobutyric acid 10.3g, be dissolved in the 150ml anhydrous methanol, be cooled to 0-5 ℃, slowly drip thionyl chloride (8ml), dripped off in one hour with ice-water bath.Reaction is 84 hours under the room temperature.Decompression is steamed and is slipped when being left the 25ml solvent, adds anhydrous diethyl ether 60ml.Stir half an hour, filter white solid, behind the drying under reduced pressure white crystal 13.5g, productive rate 88%.MS：m/z＝118(M+1)；
1H?NMR(D
2O)：1.7-1.8(2H，CH
2CH
2CH
2)，2.34-2.39(2H，CH
2CH
2CO)，3.12-3.16(2H，NH
2CH
2)，3.64(3H，OCH
3)。
(2) compound (III) is the synthetic of N-ethanoyl methyl-butyrate
Get 4-aminobutyric acid methyl ester hydrochloride (15.3g), be dissolved in the 500ml methylene dichloride, add anhydrous sodium bicarbonate 80g, stir half an hour, be cooled to 0-5 ℃, slowly drip the 9ml Acetyl Chloride 98Min., stirred 3 hours down at 5 ℃-10 ℃ with ice-water bath.Cross the sodium salt of filtrable volume, concentrating under reduced pressure obtains water white transparency thick liquid 12.6g, productive rate 82%.MS：m/z＝160(M+1)；
1HNMR(DMSO)：1.6-1.7(2H，CH
2CH
2CH
2)，1.84(3H，CH
3CO)，2.30-2.34(2H，CH
2CO)，3.03-3.07(2H，NHCH
2)，3.59(3H，OCH
3)，8.2(1H，NH)。
(3) compound (V) is the synthetic of 4-acetylamino butanols
Get N-ethanoyl methyl-butyrate (15.9g), be dissolved in the 200ml dehydrated alcohol, repeatedly add the 4.94g lithium aluminum hydride in batches, added in 45 minutes, 25 ℃ were stirred 4.5 hours down.The slowly Dropwise 5 ml shrend reaction of going out, the toluene extraction, saturated common salt water washing three times, the anhydrous magnesium sulfate drying organic layer filters, and obtains water white liquid 5.3g, productive rate 41% after filtrate is concentrated.MS：m/z＝132(M+1)；
1HNMR(D
2O)：1.445(4H，CH
2CH
2)，1.87(3H，CH
3CO)，3.07(2H，NHCH
2)，3.5(2H，CH
2OH)，3.64(1H，OH)，7.94(1H，NHCO)。
(4) compound (VI) is the synthetic of N-ethanoyl butyraldehyde
Get 32gPCC, be dissolved in the 150ml acetone, slowly drip the acetone soln 100ml that contains 13.1gN-ethanoyl butanols, react 2h under the room temperature, TLC monitoring reaction process.Reaction solution leaves standstill 0.5h, and upper strata liquid is crossed silicagel column, concentrates acetone soln, obtains yellow liquid 8.71g, productive rate 68%.
(5) compound (VII) is the synthetic of N-ethanoyl-5-methoxytryptamine
Get N-ethanoyl butyraldehyde 6.45g, be dissolved in the 90ml dehydrated alcohol, get, be dissolved among the 40ml 2N HCl, under stirring ethanolic soln slowly is added drop-wise in the hydrochloric acid soln, keep reacting liquid temperature at 30 ℃-40 ℃, sustained reaction 3 hours methoxyl group phenylhydrazine 6.9g.Filter, obtain pale brown look solid.Use the acetone-water recrystallization, obtain white powder 6.3g, productive rate 55%.Mp：117.2-117.9℃；MS：233(M+1)，174；
1HNMR：1.93(s，3H，CH
3)，2.94(t，2H，CH
2CH
2NH)，3.59(dd，2H，CH
2CH
2NH)，3.86(s，3H，OCH
3)，5.58(s，1H，NH)，6.86-7.26(m，4H，Ph-H&Indol-H)，8.02(s，1H，Indol-NH)。
Claims (4)
1. method for preparing melatonin is characterized in that may further comprise the steps:
(1) with 4-aminobutyric acid (I) be raw material in the presence of methyl alcohol and thionyl chloride, reaction obtains compound (II); Wherein the amount ranges of thionyl chloride is: the 2-6 equivalent;
(2) get the compound (II) that step (1) obtains and in the presence of alkaline reagents, obtain compound (III) with the acetylation reagent reaction;
(3) compound (III) also can be by being obtained in the presence of methyl alcohol and thionyl chloride by compound (IV); Wherein the amount ranges of thionyl chloride is: the 2-6 equivalent;
(4) in the presence of alkaline reagents, obtain compound (IV) for raw material by 4-aminobutyric acid (I) with the acetylation reagent reaction;
(5) get the compound (III) and borane reducing agent hydride reaction that step (2) obtains, obtain compound (V);
(6) get compound (V) that step (5) obtains in the presence of Jones reagent or Sha Ruite reagent or Dess-martin oxygenant, obtain compound (VI);
(7) get compound (VI) that step (6) obtains with to the anisole hydrazine reaction, make solvent generation compound (VII) with methyl alcohol and water mixed solution, promptly obtain melatonin.
2, the method for preparing melatonin according to claim 1 is characterized in that, the described formylation reagent thionyl chloride of step (1) is: the 2-6 equivalent.
3, the method for preparing melatonin according to claim 1 is characterized in that, the consumption of described Jones reagent of step (6) or Sha Ruite reagent or Dess-martin oxygenant is the 1-2.5 equivalent, and temperature of reaction 0-40 ℃, reaction solvent is preferably toluene, benzene.
4, the method for preparing melatonin according to claim 1 is characterized in that, described methyl alcohol of step (7) and water mixed solution, and wherein the ratio of methyl alcohol and water is 60%-95%, temperature of reaction is 55 ℃-85 ℃.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103875673A (en) * | 2014-03-24 | 2014-06-25 | 中国农业科学院农业质量标准与检测技术研究所 | Novel application of melatonin to promotion of plant growth |
| CN104496882A (en) * | 2014-11-29 | 2015-04-08 | 湖北金赛药业有限公司 | Synthesis method of melatonin |
| CN106622070A (en) * | 2016-12-26 | 2017-05-10 | 武汉工程大学 | Method for continuously preparing melatonin by using microreactor |
| CN113387868A (en) * | 2021-07-13 | 2021-09-14 | 河北维达康生物科技有限公司 | Synthesis process of melatonin intermediate N-acetyl serotonin |
| CN113402437A (en) * | 2021-06-29 | 2021-09-17 | 河北维达康生物科技有限公司 | Novel method for synthesizing dietary supplement melatonin |
| CN117049993A (en) * | 2023-10-11 | 2023-11-14 | 潍坊海通新材料科技有限公司 | Preparation method of melatonin |
| US11957653B2 (en) | 2020-04-30 | 2024-04-16 | MBI Distributing | Compositions comprising N-acetyl methyl GABA and related methods |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH606076A5 (en) * | 1973-08-06 | 1978-10-13 | Scherico Ltd |
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2009
- 2009-06-19 CN CN2009100333969A patent/CN101575311B/en not_active Expired - Fee Related
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103875673A (en) * | 2014-03-24 | 2014-06-25 | 中国农业科学院农业质量标准与检测技术研究所 | Novel application of melatonin to promotion of plant growth |
| CN104496882A (en) * | 2014-11-29 | 2015-04-08 | 湖北金赛药业有限公司 | Synthesis method of melatonin |
| CN106622070A (en) * | 2016-12-26 | 2017-05-10 | 武汉工程大学 | Method for continuously preparing melatonin by using microreactor |
| US11957653B2 (en) | 2020-04-30 | 2024-04-16 | MBI Distributing | Compositions comprising N-acetyl methyl GABA and related methods |
| CN113402437A (en) * | 2021-06-29 | 2021-09-17 | 河北维达康生物科技有限公司 | Novel method for synthesizing dietary supplement melatonin |
| CN113402437B (en) * | 2021-06-29 | 2023-07-14 | 河北维达康生物科技有限公司 | Novel method for synthesizing dietary supplement melatonin |
| CN113387868A (en) * | 2021-07-13 | 2021-09-14 | 河北维达康生物科技有限公司 | Synthesis process of melatonin intermediate N-acetyl serotonin |
| CN117049993A (en) * | 2023-10-11 | 2023-11-14 | 潍坊海通新材料科技有限公司 | Preparation method of melatonin |
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|---|---|
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